The WPA is an association of national psychiatric societies

aimed to increase knowledge and skills necessary for work in

the field of mental health and the care for the mentally ill. Its

member societies are presently 135, spanning 118 different

countries and representing more than 180,000 psychiatrists.

The WPA organizes the World Congress of Psychiatry

every three years. It also organizes international and regional

congresses and meetings, and thematic conferences. It has 65

scientific sections, aimed to disseminate information and promote

collaborative work in specific domains of psychiatry. It

has produced several educational programmes and series of

books. It has developed ethical guidelines for psychiatric

practice, including the Madrid Declaration (1996).

Further information on theWPA can be found on the website

www.wpanet.org.

President – J.E. Mezzich (USA)

President-Elect – M. Maj (Italy)

Secretary General – J. Cox (UK)

Secretary for Finances – S. Tyano (Israel)

Secretary for Meetings – P. Ruiz (USA)

Secretary for Education – A. Tasman (USA)

Secretary for Publications – H. Herrman (Australia)

Secretary for Sections – M. Jorge (Brazil)

Psychiatric Hospital, 2 Ch. du Petit-Bel-Air, 1225 Chêne-

Bourg, Geneva, Switzerland. Phone: +41223055736; Fax:

+41223055735; E-mail: wpasecretariat@wpanet.org.

World Psychiatry is the official journal of the World

Psychiatric Association. It is published in three issues per year

and is sent free of charge to psychiatrists whose names and

addresses are provided by WPA member societies and sections.

Research Reports containing unpublished data are welcome

for submission to the journal. They should be subdivided

into four sections (Introduction, Methods, Results,

Discussion). References should be numbered consecutively in

the text and listed at the end according to the following style:

1. Bathe KJ, Wilson EL. Solution methods for eigenvalue

problems in structural mechanics. Int J Num Math Engng

1973;6:213-26.

2. McRae TW. The impact of computers on accounting.

London: Wiley, 1964.

3. Fraeijs de Veubeke B. Displacement and equilibrium models

in the finite element method. In: Zienkiewicz OC, Hollister

GS (eds). Stress analysis. London: Wiley, 1965:145-97.

All submissions should be sent to the office of the Editor.

(Israel), P. Ruiz (USA), A. Tasman (USA), M. Jorge (Brazil).

S. Bloch (Australia), G. Christodoulou (Greece), H. Freeman

(UK), M. Kastrup (Denmark), H. Katschnig (Austria), D.

Lipsitt (USA), F. Lolas (Chile), J.J. López-Ibor (Spain), R.

Montenegro (Argentina), D. Moussaoui (Morocco), P. Munk-

Jorgensen (Denmark), F. Njenga (Kenya), A. Okasha (Egypt), J.

Parnas (Denmark), V. Patel (India), N. Sartorius (Switzerland),

B. Singh (Australia), P. Smolik (Czech Republic),

R. Srinivasa Murthy (India), J. Talbott (USA), M. Tansella

(Italy), J. Zohar (Israel).

Office of the Editor – Department of Psychiatry, University of

Naples SUN, Largo Madonna delle Grazie, 80138 Naples,

Italy. Phone: +390815666502; Fax: +390815666523; E-mail:

majmario@tin.it.

Managing Director & Legal Responsibility - Wubbo Tempel

(Italy).

Published by Elsevier S.r.l., Via P. Paleocapa 7, 20121 Milan,

Italy.

129

The activity of the WPA during the triennium of my presidency

will be guided by an Action Plan, which has been

approved by the WPA General Assembly during the World

Congress of Psychiatry held in Prague last September. This

Action Plan consists of ten institutional goals and a series of

initiatives by which these goals will be pursued. I am sharing

here these goals and some of the relevant initiatives with the

psychiatrists in 121 countries.

The first institutional goal of the WPA during the triennium

2008-2011 will be to enhance the image of psychiatry

worldwide among the general public, health professionals

and policy makers. Unfortunately, the image of our profession

is currently not very brilliant, and this has an obvious

negative impact on the motivation of persons with mental

disorders and their families to seek for our advice and help

and to adhere to our therapeutic interventions, as well as on

the motivation of medical students to choose psychiatry as

a career.

The image of psychiatry as a modern medical specialty,

that deals with a vast range of mental disorders, some of

which are very common in the general population, and that

delivers a variety of therapeutic interventions, some of which

are among the most effective that medicine has at its disposal,

is currently unfamiliar to the general public in most

countries of the world.

On the contrary, the limitations of our diagnostic tools

and our treatments often receive a great emphasis in the lay

press, with messages which are frequently biased by ideological

prejudice. The source of this biased information is

sometimes represented by psychiatrists themselves. Antipsychiatry

within psychiatry is still a reality in several countries,

and our profession is unique among medical specialties in

its ability to generate auto-antibodies.

We aim to pursue the goal to enhance the image of psychiatry

worldwide by: a) giving visibility to successful experiences

in the mental health field, through regular press releases

and reports in a section of the WPA website intended

for the general public; b) funding three projects on improving

the public image of psychiatry, selected on the basis of

an international call for proposals; c) producing a set of

guidelines on how to combat stigmatization of psychiatry

and psychiatrists, to be posted on the WPA website and

translated in several languages; d) establishing a regular

track at World and International Congresses and a special

of mental health care in the various regions of the

world; e) launching an international programme aiming to

raise the awareness of the prevalence and prognostic impli-

The WPA Action Plan 2008-2011

President, World Psychiatric Association

cations of depression in persons with physical diseases, in

collaboration with other international and national medical

associations and with organizations of users and families.

Our second institutional goal will be to partner with our

Member Societies in their efforts to improve the quality of

mental health care, education and research in their countries

and regions, and in their attempts to upgrade their own

structure, governance and organizational capacity. More

specifically, we will join and assist Member Societies, upon

their request: a) in their interactions with national and regional

institutions concerning policy matters; b) in the production

and implementation of guidelines, ethical codes

and research protocols; c) in promoting the refinement of

curricula for graduate and post-graduate psychiatric and

public mental health education; d) in the development and

implementation of programmes for continuing education of

psychiatrists, other mental health professionals and primary

care practitioners; e) in refining their structure and organization.

We will produce a template for graduate and post-graduate

psychiatric education to be posted on the WPA website

and translated in several languages. We will organize a series

of seminars at World and International Congresses in which

leaders of selected Member Societies will illustrate the structure

and activities of their associations to representatives of

other Member Societies, answer their questions and provide

advice on specific issues.

Our third institutional goal will be to promote the dissemination

of information on recent clinical, service and

research developments in such a way that it can be assimilated

by psychiatrists of all regions of the world, including

those who are not able to read English. This goal will be

pursued by: a) the implementation of high-quality itinerant

educational workshops, to be replicated in the four WPA

Regions (the Americas, Europe, Africa and the Middle East,

Asia/Australasia); b) the development of a CME online programme;

c) the production of a series of guidelines on issues

of great practical relevance, translated into several languages;

the promotion of the translation of entire issues or selected

articles in several languages, making them available on the

WPA website and on the websites of relevant Member Societies;

e) activities aimed to support the development of selected

national psychiatric journals.

Our fourth institutional goal will be to promote the professional

development of young psychiatrists worldwide. This

goal will be pursued by: a) launching, in collaboration with

a network of centers of excellence, a programme of one-year

fellowships for young psychiatrists from low-income countries,

who will commit themselves to apply in their country

of origin what they have learnt; b) organizing a series of

workshops on leadership and professional skills for young

psychiatrists; c) facilitating the participation of young psychiatrists

in WPA Congresses and other worthwhile scientific

meetings; d) stimulating the participation of young psychiatrists

in the activities of WPA Scientific Sections; e) joining

and assisting Member Societies in the development and

implementation of programmes for young psychiatrists.

Our fifth institutional goal will be to contribute to the

integration of mental health care into primary care in lowincome

countries. We will develop a “training the trainers”

programme, targeting nurses and clinical officers working in

dispensaries and health centers, to be implemented in selected

low-income countries, among which the first will be

Nigeria.

Our sixth institutional goal will be to foster the participation

of psychiatrists from all regions of the world in the international

dialogue on clinical, service and research issues, by

ensuring an adequate representation of colleagues from all

regions in WPA programmes, scientific meetings and publications,

and in the activities of WPA Scientific Sections.

Our seventh institutional goal will be to promote the

highest ethical standards in psychiatric practice and to advocate

for the rights of persons with mental disorders in all

regions of the world. This goal will be pursued by: a) launching

an international programme on the protection and promotion

of physical health in persons with severe mental

disorders, in collaboration with other international and national

medical associations and with organizations of users

and families; b) supporting international and national programmes

aiming to protect the human rights of persons with

mental disorders; to promote the meaningful involvement of

these persons in the planning and implementation of mental

health services; to encourage the assessment and development

of these persons’ talents, strengths and aspirations;

and to promote equity in the access to mental health services

for persons of different age, gender, race/ethnicity, religion

and socioeconomic status.

Our eighth institutional goal will be to promote the establishment

of networks of scientists conducting collaborative

research in the mental health field. We will fund at least two

high-quality international research projects conducted by

WPA Scientific Sections, and will facilitate the involvement

of the most prominent scientists in the activities of these Sections.

Our ninth institutional goal will be to increase the visibility

and credibility of the WPA, by ensuring that the initiatives

and products of the Association are of the highest possible

quality level, with a fully effective utilization of available human

resources.

Our tenth institutional goal will be to build up a longterm,

solid and transparent partnership with potential donors.

A consortium of donors has been created, which will

partially fund the above-mentioned activities.

informed or wish to contribute to the above initiatives are

welcome to contact the WPA Secretariat (wpasecretariat@

wpanet.org).

131

Over the past thirty years, there has been increasing recognition

of the persistence of attention-deficit/hyperactivity

disorder (ADHD) into adulthood. Once perceived to be exclusively

a childhood disorder, it is now well accepted that

about 4% of the adult population has ADHD (1-3). ADHD

does not initially appear in adulthood. All valid diagnoses of

adult ADHD have a clear developmental history of impairing

symptoms dating back to childhood. However, it is possible

ADHD in adulthood (4). It is not uncommon to find adults

self-referring themselves for an ADHD evaluation without

having been diagnosed in childhood, and some data suggest

that only 25% of adult ADHD cases had been diagnosed in

childhood or adolescence (5).

This article provides an overview of the diagnosis, epidemiology

and management of ADHD in adults.

Diagnosing ADHD in adults

Several sources of evidence show that ADHD can be diagnosed

in a reliable and valid manner. Psychometric studies

find clinician-administered ADHD rating scales to have

high internal consistency and inter-rater reliability (6-8), and

ADHD symptoms in adults are associated with clear signs

of functional impairment (9-12). For screening purposes, a

psychometrically validated self-report measure of adult ADHD

is also available (8).

Despite substantial evidence for the validity of DSM diagnoses

of ADHD, some questions remain regarding how

the criteria are implemented when diagnosing adults, which

requires a two stage process: a) determining that the adult

met criteria for ADHD in childhood and b) determining that

the adult currently meets criteria for the disorder. We will

base our discussion on the DSM-IV-TR (13), which is the

gold standard and most commonly applied method for diagnosing

ADHD across the lifespan in the United States and

is widely used in ADHD research around the world.

Diagnosing and treating attention-deficit/hyperactivity

disorder in adults

Department of Psychiatry and Behavioral Sciences, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA

Diagnosing childhood onset ADHD in adults

When making the diagnosis of ADHD in adults, clinicians

must establish that diagnostic criteria for the disorder

were met in childhood. Because the passage of time may

make symptoms difficult to recall, it is possible that the

threshold for caseness should be lowered when making

these retrospective diagnoses. But, as shown by Faraone and

Biederman (6) in a population survey of 966 adults, lowering

symptom thresholds can increase the risk for false positive

diagnoses. They estimated a prevalence of 2.9% for narrow

ADHD (meeting DSM-IV criteria in both childhood

and adulthood) and 16.4% for broad ADHD (adding to that

definition those meeting subtreshold criteria).

In a series of papers, Faraone et al (4,14,15) examined the

validity of diagnosing ADHD in patients having impairing

symptoms of ADHD which never exceeded DSM-IV’s

threshold for diagnosis (subthreshold ADHD). They evaluated

the validity of these atypical diagnoses based on Robins

and Guze’s (16) criteria for the validity of psychiatric diagnoses,

including clinical correlates, family history, treatment

response, laboratory studies, course and outcome. They

found that subthreshold ADHD had less psychiatric comorbidity,

less neuropsychological dysfunction, and fewer substance

use problems compared with full threshold ADHD.

Moreover, the pattern of familial transmission for subthreshold

ADHD differed from full threshold ADHD. These data

suggested that cases of subthreshold ADHD should be

viewed cautiously. Some might be a milder form of true ADHD,

but others may be false positive diagnoses.

Several studies of youth have challenged the validity of

the age at onset criterion (AOC) established by the DSM-IV

for the diagnosis of ADHD (onset prior to age 7). One study

comparing teenagers with onset before or after age 13 found

no link between age at onset and severity of symptoms, types

of adjustment difficulties, or the persistence of the disorder

(17). Rohde et al (18) compared clinical features between

ing all criteria except the AOC. Because these two groups

had similar profiles of clinical features, the authors concluded

that DSM-IV’s age at onset criterion should be revised.

In an epidemiologically ascertained sample of adolescents,

Willoughby et al (19) found that adolescents meeting full

criteria for combined type ADHD had worse clinical outcomes

than those failing to meet the AOC, but found no

differences attributable to the AOC for the inattentive subtype

of ADHD. In the DSM-IV field trials, requiring an AOC

of 7 reduced the accuracy of identifying currently impaired

cases of ADHD and reduced agreement with clinician judgments

(20). Hesslinger et al (21) found that adults with late

onset ADHD had the same pattern of psychiatric comorbidity

as adults whose ADHD onset met DSM-IV’s criterion. In

contrast, in an epidemiologic sample of 9 to 16 year old

children, Willoughby et al (19) did not find late onset ADHD

to be associated with oppositional defiant, conduct or anxiety

disorders, while it was associated with depression among

inattentive ADHD cases. In the series of papers by Faraone

et al (4,14,15), late onset and full ADHD subjects had similar

patterns of psychiatric comorbidity, neuropsychological

impairment, substance use disorders and familial transmission.

All of their late onset cases had onset in adolescence.

Taken together, studies of late onset ADHD suggest that

the DSM’s AOC is too low. Although these studies do not

provide definitive evidence for a specific threshold, they

clearly suggest that moving the AOC into adolescence (e.g.,

to 12 or 13) would be valid.

Diagnosing persistent ADHD in adults

After determining that the patient meets diagnostic criteria

for ADHD in childhood, clinicians must determine if

some of these symptoms have persisted into adulthood.

When doing so, it is important to remember that the DSMIV-

TR criteria for ADHD allow the diagnoses to be made in

adolescents and adults when only residual, impairing, symptoms

of the disorder are evident. As Faraone et al’s (22) review

of longitudinal studies showed, about two-thirds of

ADHD children will continue to have some impairing symptoms

of ADHD in adulthood.

Barkley (23) has suggested that the DSM symptoms and

symptom thresholds for ADHD are overly restrictive for diagnosing

the disorder in adults. For example, he studied

DSM symptom thresholds in two longitudinal samples followed

into adulthood. As adults, 98% of their control participants

endorsed three or fewer symptoms of inattention

and 100% endorsed three or fewer of hyperactive impulsive

behavior. In contrast, 100% of the ADHD group endorsed

three or more inattention symptoms and 72% endorsed

three or more hyperactive symptoms (23). These data suggest

that six symptoms of inattention or hyperactivity (as

required by the current DSM) is too high a threshold when

diagnosing the current presence of ADHD in adults. However,

when making a retrospective diagnosis about the occurrence

of ADHD in childhood, the DSM threshold of six

symptoms should be used (4,14,15).

In regards to symptom specificity and differentiating ADHD

from other forms of psychopathology (e.g., mood disorders),

Barkley (23) reported that symptoms of difficulty organizing

tasks, having difficulty staying seated and talking

excessively were equally prevalent in ADHD adults and

adults with mood disorders or anxiety disorders. Three

DSM-IV-TR inattentive symptoms correctly classified 87%

of the ADHD group and 44% of the clinical control group:

failing to give close attention to details; difficulty sustaining

attention to tasks; failing to follow through on instructions.

Three hyperactive/impulsive symptoms accurately classified

76% of ADHD cases and 49% of clinical control cases: fidgeting

with hands/feet or squirms in seat; difficulty engaging

in leisure quietly; interrupting or intruding on others.

Differentiating ADHD from other clinical disorders is often

the most difficult part of making an ADHD diagnosis in

adults, given the high comorbidity between ADHD and other

psychiatric disorders (15). To further guide this differential

diagnosis, Barkley (23) developed symptoms based upon his

executive functioning theory of ADHD (24). The symptoms

which best discriminated ADHD cases from those adults

with other forms of psychopathology were: making decisions

impulsively; having difficulty stopping activities or behavior

when should do so; starting projects or tasks without reading

or listening to directions carefully; poor follow through on

promises; trouble doing things in their proper order; driving

with excessive speed. These six items correctly classified

ADHD with 85% accuracy (23). Making decisions impulsively

and having difficulty stopping activities or behavior

when one should were the best at discriminating adults with

ADHD from adults with other forms of psychopathology. It

is interesting that hyperactivity in adults may not distinguish

adults with ADHD from normal adults or adults with other

clinical disorders (23). As it is conceptualized now, however,

hyperactivity is a core aspect of DSM-IV ADHD.

Assessing impairment in ADHD adults

While the relationship between symptoms and impairment

C, which requires impairment in two or more settings,

is central to the diagnosis of ADHD. It is essential that the

diagnostic interview ask questions such as how is he/she

doing at work, school, parenting, child-rearing, managing

finances, driving, leisure time, and maintaining fulfilling relationships.

The focus on functional impairments is central

to the diagnosis of ADHD, most especially in an adult who

does not have an ADHD diagnosis from childhood. Barkley’s

longitudinal data suggest that, in rank order from most

to least impairing, educational impairments, home responsibilities,

and occupational domains are the three most functionally

impaired domains in adults with ADHD (23).

133

Unlike childhood disorders, in which the parents’ and

teachers’ reports are frequently used, adult ADHD is often

diagnosed with considerable or sole emphasis on self-report,

because other informants are often not available. However,

information from spouses, parents or other informants can be

useful for several reasons, including the possibility of malingering

symptoms for secondary gain (26). Similarly, given the

positive illusory bias which has been documented in both children

(27,28) and adults (29) with ADHD, it may be that adults

with ADHD are not the best reporters of their own functioning.

However, gaining collateral report from spouses, employers,

coworkers, friends, etc. may be either difficult to obtain or

clinically contraindicated. Nonetheless, we believe it should

be obtained in a sensitive fashion whenever possible.

Diagnosing ADHD: primary care vs. psychiatry

Primary care physicians are increasingly being asked to

make ADHD diagnoses. In a medical record review of 854

adults with persistent childhood-onset ADHD, Faraone et al

(5) examined the diagnostic practices of primary care physicians

and psychiatrists. They found that primary care physicians

were less likely than psychiatrists to make an initial

diagnosis of ADHD in adults if no pediatric ADHD diagnosis

had been made. Primary care physicians were also more

likely than psychiatrists to seek outside consultation before

making an ADHD diagnosis in adults, with 15% of primary

care physicians making a referral to another provider, most

often a psychologist. Psychiatrists were also more likely to

diagnose a comorbid psychiatric condition than primary

care physicians (44% vs. 20% respectively).

Epidemiology of ADHD in adults

National Comorbidity Survey Replication (NCS-R)

As discussed above, Faraone et al (6) computed a population

prevalence of 2.9% for adult ADHD. Another estimate

of population prevalence comes from the National Comorbidity

Survey Replication (NCS-R) (3), an epidemiologic

study of 9,200 adults ages 18-44. In this sample, the prevalence

of adult ADHD was estimated to be 4.4%. Additional

results indicated that adults with ADHD had lower educational

levels, were less likely to be employed and were more

likely to be separated/divorced than those without ADHD.

ADHD was also less commonly reported in African-Americans

and Latinos compared to Caucasians (3).

Fayyad et al (30) conducted an epidemiological study of

adult ADHD in ten countries in the Americas, Europe and the

Middle East. Their prevalence estimates ranged from 1.2 to

7.3%, with an average of 3.4%. The prevalence was lower in

lower income (1.9%) compared with higher income countries

(4.2%). Consistent with other studies, ADHD was associated

with psychiatric comorbidity and functional impairment.

In children, ADHD is more commonly diagnosed in

males (31).The NCS-R data suggest that sex differences are

less pronounced in adult ADHD (3), which is consistent

with data from clinical samples (4,32). The relative equal sex

ratio in adult ADHD may indicate that ADHD in females is

more persistent. It is also possible that this finding is due to

referral biases in childhood: boys with ADHD are more

likely to have conduct disorder and be referred for treatment

(31). By being able to refer themselves, adults with ADHD

may be less likely to have this referral bias.

Psychiatric comorbidity

Comorbid anxiety, mood and substance use disorders are

commonly reported in adult ADHD (3,23,33-38). These comorbidity

rates do not differ as a function of gender (3,39).

The NCS-R data suggest that 43% of people with ADHD

between 18 and 29 years of age experienced a psychiatric

comorbidity, compared to 56% of those between 30 and 44

years of age.

In clinic-referred populations, histories of conduct disorder

and oppositional defiant disorder occur in approximately

24-35% of adults with ADHD (1,35). This is lower than

the rates often reported in pediatric ADHD (50-60%) (40).

Alcohol use disorders are also common in clinic-referred

adults with ADHD; alcohol dependence or abuse disorders

lifetime prevalence rates range from 21 to 53% (1,15,35,41).

Cannabis and cocaine use disorders are both also relatively

common in adults with ADHD (42,43). Cigarette smoking

has also been demonstrated to be more prevalent in adult

ADHD (44). Comorbid conduct or bipolar disorder increases

the risk for substance use disorders (45,46); however, ADHD

is an independent risk factor for later substance use

disorders (43,47). Those with comorbid ADHD and substance

use disorders have been reported to have earlier onset

of substance abuse relative to adults with substance abuse

yet without ADHD (48) and a greater severity of substance

abuse/dependence (49,50).

Mood disorders such as major depressive disorder occur

in children with ADHD, especially those with conduct disorder

(51). Between 16 and 31% of adults with ADHD have

current comorbid major depressive disorder (1,3,23,35,41),

with lifetime rates as high as 45% (3).

About 25% of children with ADHD have a comorbid anxiety

disorder (40); rates of anxiety disorders in adult ADHD

appear similar. For example, 25-43% of adults with ADHD

meet criteria for generalized anxiety disorder (1,3,35,38,41),

with lifetime rates as high as 59% (3). Panic disorder, obsessive

compulsive disorder and social phobia are less common,

yet can be comorbid conditions (3,38,52).

Treating ADHD in adults

ing majority of adults with ADHD are untreated; the NCS-R

(3) demonstrated that only 11% of adults with ADHD are

treated.

Pharmacotherapy

Stimulant medications, especially extended release formulations,

are a front-line management strategy in both pediatric

and adult ADHD (53,54). Approximately 3 of every

4 adults with ADHD will have a positive response to a stimulant

medication. Two stimulants are FDA approved for use

in ADHD adults: extended release mixed amphetamine salts

and lisdexamfetamine dimesylate. Atomoxetine is a nonstimulant

that is FDA approved for managing adult ADHD

and may be particularly effective for adults with ADHD and

comorbid depression (55) or for those with a comorbid substance

use disorder addictive potential (56). Both the stimulants

and atomoxetine improve core symptoms of hyperactivity,

inattention and impulsivity (54,57,58). Secondary to

psychiatric comorbidity, polypharmacy may be more likely

in adult ADHD than pediatric ADHD (59).

Adherence to stimulant medications in ADHD wanes as

a function of age (60), and efforts should be instituted to

attempt to avert poor adherence. Stimulant misuse and/or

diversion is another clinical reality in ADHD pharmacotherapy

(61). Those with comorbid conduct disorder or substance

abuse diagnoses are most at risk for stimulant misuse

and/or diversion (61,62).

Psychosocial treatments

Substance use disorders may also require interventions,

many of which may be independent of the ADHD interventions.

Some have suggested that ADHD interventions should

be initiated first to determine the extent to which ADHD is

contributing to substance use disorders (23). The rationale

for this is that the presence of ADHD appears to potentiate

the substance use disorder, resulting in a more severe disorder

(63) and poorer outcomes (64). However, because it can

be very difficult to treat ADHD patients who are actively

abusing alcohol or drugs, one must often treat the substance

use disorder first. Given the potential for abuse or misuse of

stimulant medications (65), in patients with a history of substance

use disorders, one should use either long-acting stimulants

(because their formulations make them less abusable)

or a nonstimulant. The long-acting, prodrug stimulant, lisdexamfetamine

dimesylate, is of particular interest given its

lower abuse-related liking scores compared with equipotent

doses of immediate-release d-amphetamine (58).

Similar to pediatric ADHD, a psychosocial treatment

component is typically recommended in adult ADHD (66).

What constitutes the psychosocial component, however, is

different in adult ADHD relative to pediatric ADHD. For

example, neither cognitive behavioral therapy (CBT) nor

cognitive therapy is effective for pediatric ADHD (67-71). In

contrast, there are some data to suggest that CBT is efficacious

for adults with ADHD. For example, in the adult ADHD

literature, there is some evidence that CBT reduces

functional impairments in adults concurrently treated with

stimulants (72,73).

Treating ADHD: primary care vs. psychiatry

Psychiatrists are more likely than primary care physicians

to prescribe a medication for adult ADHD (91% vs. 78%

respectively) (5). While both psychiatrists and primary care

physicians most often prescribed a stimulant (84%) or an

antidepressant (12%), psychiatrists were more likely to prescribe

dextroamphetamine, generic methylphenidate hydrochloride,

mixed amphetamine salts, and oral osmotic controlled-

release methylphenidate. Psychiatrists were less likely

than primary care physicians to prescribe immediate release

methylphenidate (5). Drug holidays were prescribed in approximately

20% of adults with ADHD, yet were more often

prescribed by psychiatrists (24% vs. 17% respectively).

Conclusions

Within the last 30 years, the persistence of ADHD into

adulthood has become increasingly well accepted, to the

point that it is now considered a valid and impairing disorder.

This suggests that the number of adults seeking clinical

services for ADHD will likely continue to increase. Those

working with adult populations need to be aware of the

symptom presentation differences between pediatric and

adult ADHD and the importance of assessing the functional

impairments caused by ADHD symptoms.

Significant functional impairment and psychiatric comorbidity

are the hallmark of adult ADHD. Especially in

those adults with psychiatric comorbidities, treatments need

to be multimodal and include both pharmacotherapy and

psychosocial interventions.

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137

Depression in mid-life women is a significant cause of

morbidity and disability (1). The unique manifestations and

multifactorial etiology of mid-life depression makes it difficult

to recognize and treat (2). In addition, symptoms of

depression may overlap with those associated with menopause,

presenting a clinical dilemma for psychiatrists and

other health professionals in women’s health (3). As the

baby-boomer generation of women approaches and passes

menopause, mid-life depression has become a serious public

health issue and the subject of interest of a growing number

of epidemiological and clinical studies.

This paper examines the evidence for and the nature of

relationships between mood symptoms and aging in women,

including chronological and reproductive aging, and

between mood symptoms and other psychosocial, lifestyle,

and health factors. In addition, the biological basis for development

of depressive symptoms in mid-life women, and

the potential for hormonal and non-hormonal therapies to

provide relief, are discussed.

Mood, mid-life and menopause

Mid-life women may seek medical advice due to such

symptoms as hot flashes, aches and stiff joints, trouble sleeping,

and lack of energy. In the Melbourne Women’s Mid-Life

Health Project (4), some of these symptoms were experienced

at baseline by more than 40% of the 438 women surveyed

in the late stages of the menopausal transition. Of

particular interest, nervous tension and feelings of downheartedness

and sadness were among the six most common

complaints.

The unique challenges of managing depression

in mid-life women

1Office for Gender and Health, Department of Psychiatry, University of Melbourne, Victoria 3050, Australia

2Women’s Health Concerns Clinic, McMaster University, 301 James Street South, FB 638, Hamilton, Ontario L8P 3B6, Canada

The causal relationships between depressive symptoms

and menopause, however, are unclear; a particular controversy

has been established around the question whether depressed

mood is caused by psychological factors related to

aging or whether ovarian hormonal changes may play a significant

role in its occurrence.

Research on the relationship between menopause and

depressive symptoms has provided contradictory results.

Several studies revealed no relationship (5-7), while others

found that mood symptoms decreased with increasing age

(8), or that there was an increase in depression among women

in the menopausal transition (9). Controlling for the presence

of vasomotor symptoms reduced the correlations between

depression and menopause in some reports (10). A

strong relationship was found between hysterectomy and

depressed mood (11).

Longitudinal studies that followed subjects through the

transition from regular menstruation to the post-menopausal

period have provided contradictory results as well. Different

methodologies and the confounding effect of chronological

aging make the results of these studies difficult to compare.

In addition, correlations between changes in ovarian hormones

and mood are not clear, because few studies measured

these parameters. Some longitudinal studies have shown no

relationship between depression and menopause (10,12).

Other studies demonstrated an increased risk of depression

during the transitional phase from peri-menopause to postmenopause

(13,14); in particular, women entering this transitional

phase earlier had a significant risk of developing

new-onset depression (15). Dennerstein et al (12) found both

an improvement in mood during mid-life and a decrease in

negative mood as menopausal symptoms improved.

Reproductive aging in women has been divided into stages

by the Stages of Reproductive Aging Workshop (STRAW)

consensus (16). A recent restaging study (17) has used data

to provide clinicians with practical definitions of the stages

of the menopausal transition. Irregular menses, defined as

more than 7 days difference persistently occurring between

the length of cycles, is characteristic of the early menopausal

transition, which begins at about age 35. The late menopausal

transition begins when there have been at least two

missed menstrual periods, and the post-menopause is the

period which begins after the last menstrual period. The

Melbourne Women’s Mid-Life Health Project study showed

that estradiol levels varied widely early in the menopausal

transition, with a dramatic decrease in the late menopausal

transition period, while follicle-stimulating hormone (FSH)

increased (18). After the final menstrual period, estradiol

levels continued to fall and FSH continued to rise.

The occurrence of physical and mental symptoms in women

during menopausal transition stages was documented in

the Women’s International Study of Health and Sexuality

(WISHeS), a large cross-sectional survey of women aged 20

to 70 years in France, Germany, Italy, the United Kingdom,

and the United States. Subgroups of women at several stages

were prospectively defined, and symptoms in physical, vasomotor,

psychosocial and sexual domains were evaluated (19).

Regularly menstruating women aged 20 to 49 were compared

with post-menopausal women aged 50 to 70 and also with

women who had surgical menopause before and after age 50.

Subjects with surgical menopause were of interest because

oophorectomy removes approximately half of circulating androgens,

as well as estradiol, and the effects are more severe

and sudden than naturally occurring menopause (20).

This important study showed that some symptoms experienced

by mid-life women were clearly related to declining

estradiol, including vasomotor symptoms, poor memory,

trouble sleeping, aches in the neck/head/shoulder area,

vaginal dryness, and difficulty with sexual arousal. These

symptoms reached a maximum prevalence at age 50 and

occurred earlier in women who had early (before age 50)

surgical menopause. There was a curvilinear effect of age,

and there were no differences between women from different

countries and no effect of body mass index on the prevalence

of this group of symptoms (19).

In contrast, psychological symptoms, such as mood

swings, and breast pain showed a curvilinear pattern that

peaked much earlier at age 35 to 40 years, or during the

early menopausal transition period. After age 35 to 40 years,

mood symptoms decreased with age through menopause

and into the post-menopausal period and were increased in

the presence of other physical or mental health problems.

Interestingly, significant differences were found between

women from different countries in the prevalence of this

group of symptoms (19).

A third cluster of symptoms was also observed that did

exhibit a linear effect of age with no maximum prevalence at

age 50. These symptoms, such as decreasing physical strength

and lack of energy, are the expected effects of increasing age

and were also affected by the country of origin, body mass

index, and other physical and mental problems (19).

Similar results were found in the Melbourne Women’s

Mid-Life Health Project, in which positive and negative

moods, as well as hormone levels, were followed in a longitudinal

fashion. Depressed mood declined significantly with

aging. The results also showed that being in the menopausal

transition phase amplified the negative mood effects of other

major life events, such as poor health or job loss (12).

These observations suggest that the menopausal transition

may be considered a “window of vulnerability” during

which women are at high risk for depressive symptoms. This

vulnerability period is similar in nature to other well-known

vulnerability phases, such as the premenstrual period and

the immediate post-partum period. The Melbourne Women’s

Mid-Life Health Project investigators found several risk

factors associated with depression during the menopausal

transition. A previous history of depression or premenstrual

tension, negative attitudes about menopause, as well as lifestyle

and psychosocial variables, were important risk factors

for depressive symptoms (12). In addition, a follow-up study

11 years later of women aged 57 to 67 found that depression

was highest for those who had surgical menopause and for

those who were still menstruating (11).

In another substudy, happiness scores during and after

the menopausal transition were followed and found to be

significantly related to happiness scores recorded before the

transition began. Before and after the menopausal transition,

happiness scores were the effect of intrinsic personality

factors and extrinsic factors, such as marital status, work

satisfaction, and life events (21). In general, well-being increased

over time as women passed through the menopausal

transition, and no direct effect of hormone levels could be

ascertained (22).

Another area of interest was the effect of the “empty nest

syndrome” on mood symptoms for women in the menopausal

transition. This substudy of the Melbourne Women’s

Mid-Life Health Project showed decreases in depressed

mood and daily hassles with increases in positive mood and

well-being associated with the “last exit event”, when the

last child left home. Interestingly, the return of children to

home during the menopausal transition resulted in reductions

of positive mood and decline in the frequency of sexual

activity for women (23).

The consequences of physical, emotional, or sexual violence

on mood in mid-life women were also evaluated. This

substudy of the Melbourne Women’s Mid-Life Health Project

showed that intimate partner violence predicted depressed

mood, divorce or separation, low sexual functioning,

and use of psychotropic drugs (24). Among the overall

population, 22% had used psychotropic drugs, most often

antidepressants. Four percent had had psychiatric hospital

admissions and 7% had had counseling. Psychotropic drug

use was associated with interpersonal stress, poor self-ratings

of health, and premenstrual depression (25).

139

Structural equation modeling has been used to show the

relationships between changing estradiol levels and the

symptoms specifically associated with declining estradiol

levels. Women’s sleep and perception of health are affected

by vasomotor symptoms. Poor lifestyle choices, daily hassles,

and stressors also affect mood. Also, decreases in estradiol

compromise mood by affecting sexual functioning and

women’s feelings for partners (26).

Is treatment for depression different

in mid-life women?

Chaotic changes in hormone levels during the menopausal

transition may be one of the major factors in increased

risk of depression (27-29). Clinicians have an opportunity to

provide a targeted therapy in the form of a stable hormonal

milieu, which may exert a prophylactic and/or neuroprotective

effect to prevent depression, as well as a therapeutic

effect (29,30).

An ongoing longitudinal study, the Harvard Study of

Moods and Cycles, reported on the long-term, prospective

evaluation of 1000 women who were pre-menopausal (36 to

44 years of age) at the time of enrollment. They received

periodic hormonal, psychiatric, and quality of life assessments,

and the results were controlled for factors that are

commonly investigated in depression, such as body mass

index, smoking, marital status, and occupational status. The

data from this study indicate that peri-menopausal women

were two times more likely than premenstrual women to

develop new-onset severe depression. In addition, the risk

was exacerbated in those who developed vasomotor symptoms

during peri-menopause (15).

This study indicates that peri-menopause and vasomotor

symptoms, caused by estrogen fluctuations, may have a

common biochemical pathway with depressive symptoms.

The history of estrogen research provides ample evidence to

support a strong role for estrogen in regulating brain function.

Neuroprotective effects and a role in preserving memory

and cognition are well documented, as are thermoregulatory

and antidepressant effects in animal and clinical studies.

The brain regions most likely to be affected by estrogen

are those more likely to be related to monoaminergic systems,

including the serotonergic and norepinephrine systems

(31), and other evidence supports the role of estrogens

in synthesis, release, and receptor activity of serotonin and

norepinephrine (32,33). Consequently, it is intuitive to believe

that the absence or intense fluctuation of estrogen

could result in mood and behavioral changes, as well as vasomotor

and other menopausal symptoms.

Several controlled clinical studies examined whether estrogen

therapy may have an antidepressant effect in perimenopausal

and post-menopausal women with major depressive

disorder (30,34-37). An important finding of these

studies was that estrogen was not efficacious for depression

in post-menopausal women, suggesting that fluctuating estrogen

levels, rather than absolute estrogen levels, may be

more important for the antidepressant effects of estrogen. Another

interesting aspect of these studies was that positive results

were associated with use of transdermal rather than oral

estrogen. This finding may be due to the heightened bioavailability

of estradiol with transdermal administration, which

could be advantageous for the interaction with estrogen receptors

in brain areas that regulate mood and behavior.

Another point for consideration in treatment of depression

in mid-life women is the efficacy of antidepressant therapies

for relief of physical symptoms of menopause, such as

hot flashes. A set of prescription data collected by McIntyre

et al (38), before and after publication of negative results

concerning the use of hormone replacement therapy from

the Women’s Health Initiative in July 2002 (39), may be relevant

to this question. The initial reports of the Women’s

Health Initiative study suggested no protective effect against

(actually, a slightly increased risk for) cardiovascular events

(e.g., stroke, myocardial infarction) among post-menopausal

women using hormone therapies. As a result, physicians became

more reluctant in prescribing estrogen, even for younger,

symptomatic women. The study by McIntyre et al (38)

demonstrated that hormone replacement therapy prescriptions

decreased in the year following the Women’s Health

Initiative results; interestingly, the number of prescriptions

for antidepressants significantly increased, suggesting either

that women developed psychological symptoms (e.g., depressive

symptoms, anxiety) as they stopped using estrogen

or that antidepressants were being used to treat menopauserelated

symptoms. Limited comparisons of estrogen and antidepressant

therapies for treatment of depression in women

with menopausal symptoms have indicated similar efficacy

of escitalopram (40) and hormone therapies for relief of

menopausal symptoms and improvement in menopause-related

quality of life measures. Duloxetine (41) and citalopram

(42) open trials also suggest that antidepressants may

have a positive impact on menopausal symptoms, an important

treatment consideration for women who cannot or will

not take estrogen.

Other point of interest is whether age and menopausal

status of mid-life women could affect the efficacy of some

antidepressant therapies. Several clinical trials have shown

differences between the responses to antidepressants of prevs.

post-menopausal women (43) and younger vs. older

women (44-47). In a pooled analysis, responses to selective

serotonin reuptake inhibitors (SSRIs) appear to be affected

by age (i.e., higher in women younger than 50 years of age

than in women older than 50 years), whereas responses to

venlafaxine, a serotonin-norepinephrine uptake inhibitor

(SNRI) were similar across age groups (48).

The question of whether estrogen plays a role in this difference

in efficacy was investigated in a pooled analysis of

data from women over 50 years of age who were or were not

receiving concomitant estrogen therapy during treatment

with SSRIs or venlafaxine in eight studies. This study showed

higher response rates to venlafaxine than SSRIs in both

groups. However, the gap in efficacy between SSRIs and

venlafaxine was significantly larger in women who did not

receive estrogen therapy, and SSRIs were significantly more

effective than placebo only in the women who received estrogen

(48). These data support previous evidence that estrogen

might modulate or prime binding affinity/response to

SSRIs (49).

The emergence of vasomotor symptoms in mid-life women

is hypothesized to be the result of disturbed thermoregulatory

function, a complex, hypothalamus-based process. As

estrogen levels fluctuate, the so-called thermoneutral zone

becomes significantly narrowed, leading to frequent sweating

or shivering in response to normal changes in body temperature

and producing the characteristic heat dissipation of

menopause (50). Thus, the treatment for hot flashes aims to

restore/expand the thermoneutral zone and consequently

keep the changes in body temperature within that zone.

Although estrogen remains the gold standard for treatment

of vasomotor symptoms, several alternative therapies, including

many natural remedies, have been investigated. These

include psychoactive medications, such as antidepressants,

mood stabilizers, anticonvulsant medications, and anti-anxiety

therapies (51-58). It should be pointed out that two of the

most popular natural remedies for vasomotor symptoms, soy

and black cohosh, have been found to have very little impact

on these symptoms when compared with placebo in controlled

trials (59) and that women may still be exposed to

adverse events and side effects through their use.

Another strategy for women with significant nocturnal

vasomotor symptoms (night sweats) would be to improve

sleep patterns. A trial of the sleep agent eszopiclone for

menopausal women with insomnia and awakenings due to

hot flashes was recently shown to have a positive effect on

these symptoms. The treatment also promoted improvement

of mood and quality of life, possibly due to improved sleep

patterns (60).

Conclusions

Epidemiological and clinical studies demonstrate that

mood changes and depressive symptoms may occur in some

women during the menopausal transition. This period of

fluctuating hormone levels constitutes a “window of vulnerability”

for depression, especially for women with a previous

history of depression or for those with concomitant, severe

menopausal symptoms. Estrogen fluctuations may affect

mood changes indirectly, through mediation of menopauserelated

physical symptoms, particularly sleep and sexual disturbances.

In addition, estrogen may affect both vasomotor

and depressive disturbances through common biochemical

pathways and receptor-mediated actions on brain function.

Estrogen therapy has been shown to improve both mood

and vasomotor symptoms and remains a viable option for

symptomatic mid-life women. Recent concerns involving the

long-term safety of estrogen therapy have led clinicians to

pursue non-hormonal treatment strategies. Low-dose antidepressant

therapy has been shown to improve vasomotor

symptoms as well as depression and may be the preferred

alternative for women with depression who cannot receive

estrogen. Clinical evidence also supports use of some anticonvulsant

and anti-anxiety therapies, as well as sleep agents,

for treatment of hot flashes. Natural remedies in general have

not shown a positive impact on vasomotor symptoms.

We conclude that, although depression in mid-life women

presents unique challenges due to the added complexity

associated with the menopausal transition, the “window of

vulnerability” for depression also constitutes an opportunity

to provide targeted and effective therapies that address both

physical and mood symptoms in mid-life women.

Acknowledgements

This paper is based on a lecture given by the authors at

the WPA International Congress, Melbourne, November

2007. The authors received funding from CME Outfitters,

Rockville, MD, USA. The authors wish to thank Lisa Brauer

for her assistance with this paper.

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143

Deficit schizophrenia is a syndrome defined by the following

criteria: a) presence of at least two out of six negative

symptoms: restricted affect (referring to observed behaviours

rather than to the patient’s subjective experience); diminished

emotional range (i.e., reduced range of the patient’s

subjective emotional experience); poverty of speech; curbing

of interests; diminished sense of purpose; diminished

social drive; b) some combination of two or more of the

above symptoms have been present for the preceding 12

months and were always present during periods of clinical

stability; c) the above symptoms are primary or idiopathic,

i.e., not secondary to factors such as anxiety, drug effect,

psychotic symptoms, mental retardation, depression; d) the

patient meets DSM criteria for schizophrenia (1-3).

In 2001, a review of the literature suggested that deficit

schizophrenia is a disease separate from other, nondeficit

forms of schizophrenia (3). The proposal of a separate disease

was based on the evidence that deficit and nondeficit

schizophrenia differ on five dimensions typically used to distinguish

diseases: signs and symptoms, course of illness,

pathophysiological correlates, risk and etiological factors,

and treatment response. The deficit group has a poorer quality

of life and level of function, so one potential interpretation

of the above evidence is that the deficit group simply

has a more severe form of the same illness as nondeficit

schizophrenia. However, in some studies, the deficit group

was closer to healthy controls than the nondeficit group

with respect to some variables (e.g., the volume of some

brain regions), while in other studies the two groups were

simply different from each other, as well as from control

subjects (e.g., with respect to season of birth) (3).

In the years following the publication of that review, there

have been a number of other studies focused on deficit

schizophrenia, as defined by the above criteria. These have

advanced our understanding of this group of patients, but

have also clarified the remaining weaknesses in this research

area (4). Here we will focus on those studies comparing patients

with deficit vs. nondeficit schizophrenia.

Deficit schizophrenia: an update

1Department of Psychiatry and Health Behavior, Medical College of Georgia, 997 St. Sebastian Way, Augusta, GA 30912, USA

2Department of Psychiatry, University of Naples SUN, 80138 Naples, Italy

Risk and etiological factors

Family history

Kirkpatrick et al (3) reviewed studies showing that the

deficit/nondeficit categorization has a significant concordance

within families and that family members of deficit

probands, compared with relatives of nondeficit probands,

have more severe social withdrawal and an increased risk of

schizophrenia.

Since that time, another study found an increased prevalence

of subclinical negative symptoms in the relatives of

deficit compared to nondeficit probands (5). In an unpublished

study, we have also replicated the finding of a significant

concordance within families: in families with more than

one affected member, the deficit/nondeficit categorization of

one member predicted the categorization of the other family

member at a rate greater than chance.

Genetics

A few studies have examined the genetics of deficit and

nondeficit schizophrenia, but the results have been disappointing.

Hong et al (6) reported that the dihydropyrimidinase-

related protein 2 (DRP-2) gene was associated with

risk for both deficit and nondeficit schizophrenia; however,

after correcting for multiple comparisons, the association

with nondeficit schizophrenia was not significant, and for

deficit schizophrenia the association was present only for

Caucasian but not African-American subjects.

Galderisi et al (7), in a sample of 56 deficit and 50 nondeficit

patients, found that the Val(158)Met polymorphism

of catechol-O-methyl transferase (COMT) influenced neuromotor

performance in the deficit but not the nondeficit

group. Wonodi et al (8) did not find an association between

COMT polymorphism and the deficit/nondeficit categorization,

but the total number of deficit and nondeficit subjects

was 86. Limitations in sample size undermine the value of

all of these studies, and replications to date are lacking.

Other risk factors

has been replicated by several studies, especially in the

Northern hemisphere. The effect size is small, with a 5% to

8% excess of births (9). This association applies to schizophrenia

as a whole, that is, without regard to deficit vs. nondeficit

categorization. The 2001 review (3) cited studies that

had found an association between deficit (but not nondeficit)

with the deficit group differing from both nondeficit

schizophrenia and control subjects. Since that time, summer

birth has been confirmed as a risk factor for deficit schizophrenia

in a combined analysis of 10 datasets from 6 countries

(10).

In a study with 88 deficit and 235 nondeficit patients, an

association was found between cytomegalovirus seropositivity

and deficit schizophrenia (11). The association remained

significant after covarying for psychotic symptoms

and for demographic features known to be associated with

cytomegalovirus seropositivity, and after correcting for multiple

comparisons. No association was found with five other

human herpesviruses. Goff et al (12) found that serum folate

concentration was significantly lower in patients with deficit

than nondeficit schizophrenia, a result whose interest increases

in view of their finding that the C677T polymorphism

of methylenetetrahydrofolate reductase was associated

with negative symptoms (13). Replication is needed.

A meta-analysis has confirmed that male gender is a risk

factor for deficit (but not for nondeficit) schizophrenia (14).

Course of illness

Premorbid functioning

Evidence of worse psychosocial functioning in patients

with deficit than in those with nondeficit schizophrenia,

both before the appearance of positive symptoms and later

in the course of the illness, was reviewed in Kirkpatrick et al

(3). The higher degree of impairment could not be attributed

to more severe positive symptoms, depressive mood or other

dysphoric affect, or substance abuse.

Since that review, Galderisi et al (15) have replicated the

finding of poorer premorbid adjustment during childhood

and adolescence, but not in adulthood, in patients with

deficit schizophrenia than in those with nondeficit schizophrenia.

They also showed that the association between the

deficit state and poor premorbid adjustment was not due to

the presence of more severe negative symptoms in the deficit

group.

Long-term prognosis

Recent studies confirmed that the diagnosis of deficit

schizophrenia is associated with a worse long-term prognosis,

as compared with nondeficit schizophrenia. Tek et al

(16), in a prospective study including 46 patients with deficit

and 174 with nondeficit schizophrenia, found that after an

average of five years, the deficit patients had a poorer quality

of life, poorer social and occupational functioning, and

more severe negative symptoms, but were less distressed and

did not show more severe positive symptoms. In a study by

Chemerinski et al (17), 111 chronic patients with deficit

schizophrenia and 96 with nondeficit schizophrenia were

followed up for 6 years. The nondeficit group was further

subdivided into delusional and disorganized types. Functional

impairment was greatest in delusional, lowest in disorganized

and intermediate in the deficit group.

Response to treatment

Convincing evidence is available that both old and newgeneration

antipsychotics may act on secondary negative

symptoms by removing, in part or completely, some of their

causes, such as positive symptoms, depression or extrapyramidal

symptoms. However, the efficacy of these drugs on

primary and persistent negative symptoms has not been

proven (18).

A meta-analysis by Leucht et al (19) showed that amisulpride

was significantly superior to placebo, but not to conventional

antipsychotics, in patients suffering predominantly

from persistent negative symptoms. A study of Buchanan

et al (20) found no efficacy for clozapine on negative symptoms

among deficit patients. No other evidence supports the

efficacy of clozapine on primary and enduring negative

symptoms (see 17 for a systematic review). Kopelowicz et al

(21) investigated the efficacy of olanzapine in 39 patients

with deficit or nondeficit schizophrenia: an improvement of

positive, negative and extrapyramidal symptoms was observed

among nondeficit patients, while in the deficit group

only extrapyramidal symptoms improved, strongly suggesting

that olanzapine is efficacious for secondary but not for

primary negative symptoms of schizophrenia. Lindenmayer

et al (22) tested the efficacy of olanzapine on primary negative

symptoms in 35 patients with deficit schizophrenia.

They reported a significantly higher decrease of the negative

symptoms score of the Positive and Negative Syndrome

Scale (PANSS) in the olanzapine than in the haloperidol

group, in the absence of significant changes of positive

symptoms, general psychopathology and depression, and

considered these findings as an evidence of olanzapine efficacy

in the treatment of primary negative symptoms. However,

in the absence of data on a nondeficit group, these

findings are difficult to interpret and do not rule out the possibility

that olanzapine reduces secondary but not primary

negative symptoms.

145

Based on the hypoglutamatergic hypothesis, several studies

investigated the possibility that primary negative symptoms

would improve following treatment with compounds

that increase NMDA receptor transmission. Full agonists of

the glycine site, such as glycine and D-serine, as well as a

partial agonist of the glycine site, D-cycloserine, when used

as adjuncts to antipsychotic drugs, have shown a favorable

effect in the treatment of negative symptoms, including deficit

or primary negative symptoms (23-26). However, in a

large multicenter, double-blind study, 157 patients with

schizophrenia or schizoaffective disorder who had substantial

negative symptoms but at most mild positive, depressive,

or extrapyramidal symptoms, were randomly assigned to adjunctive

treatment with glycine, D-cycloserine or placebo for

16 weeks (27). Neither glycine nor D-cycloserine was superior

to placebo for negative symptoms; no evidence was

found that treatment effects differed in deficit versus nondeficit

subjects. According to the authors, the discrepancy

between their findings and those from previous studies might

be due to the high percentage of patients treated with newgeneration

antipsychotics in their trial; in fact, evidence has

been provided that the efficacy of compounds increasing the

NMDA transmission on negative symptoms is more robust

in subjects treated with conventional antipsychotics than in

those treated with new-generation antipsychotics (28).

A need for effective pharmacological treatment is one of

the most important research issues in the area of deficit

schizophrenia.

Neurocognitive and neurological findings

Early neurocognitive studies reported a greater impairment

on tests sensitive to fronto-parietal dysfunction in

deficit compared with nondeficit schizophrenia patients

(29-31). With one exception (32), more recent investigations

failed to confirm these results (15,33-38).

A recent meta-analysis (37) including 13 neuropsychological

studies concluded that patients with the deficit syndrome

were globally more neuropsychologically impaired

than nondeficit patients. Most effect sizes were small, but

those for tests of olfaction (1.11), social cognition (0.56),

global cognition (0.52), and language (0.51) were moderate

or large. According to Cohen et al (37), the neuropsychological

profile of deficit patients does not support the hypothesis

that deficit schizophrenia is the more severe end of

a continuum: if it were so, the greatest effect sizes should be

found for memory, attention and working memory, i.e. the

domains most significantly involved in schizophrenia (39).

Studies including a structured neurological examination

confirmed the previously reported greater neurological impairment

in patients with deficit than in those with nondeficit

schizophrenia (15,34,40), supporting the hypothesis

that the former is related to non-progressive, non-localized

brain damage. However, two out of these three studies did

not confirm the previously reported association between the

deficit syndrome and an impairment of sensory integration

(40), and found instead an association with an impaired sequencing

of complex motor acts (15,34). The most recent

study reporting an association between deficit schizophrenia

and sensory integration deficits included a small sample

of patients with the syndrome (n=12) and did not assess the

simultaneous effect of negative symptoms and deficit/nondeficit

categorization on neurological impairment (41).

Brain imaging findings

Four studies found no enlargement of the lateral ventricles

in patients with the deficit syndrome (42-45). The negative

finding is surprising: the enlargement of the lateral ventricles

is one of the most replicated brain imaging findings in

schizophrenia, and has been – although not consistently –

reported to be associated with negative symptoms and poor

outcome. Except for the study by Sigmundsson et al (43), all

the others included a group of patients with nondeficit

schizophrenia, in which lateral ventricles were larger than

in healthy controls.

An involvement of fronto-parietal brain circuits in deficit

schizophrenia was suggested by early functional brain imaging

studies (46-49), in agreement with early cognitive findings.

More recent investigations confirmed metabolism/cerebral

blood flow abnormalities in the frontal and/or parietal

regions in patients with deficit compared to nondeficit

schizophrenia (50-52). Neuronal loss in prefrontal cortex is

suggested by a proton magnetic resonance spectroscopy

this region in a small sample of deficit patients compared to

nondeficit patients and healthy controls (53).

Electrophysiological findings

Recent event-related potential (ERP) studies do not support

the severity continuum hypothesis. Turetsky et al (54)

investigated a putative endophenotype of schizophrenia, the

left lateralized amplitude reduction of the P3 component of

the event-related potentials (ERPs). This abnormality was

found in nondeficit schizophrenia, while a right parietal reduction

of the component was observed in the deficit group.

Bucci et al (55) investigated evoked and induced 40-Hz

gamma power, fronto-parietal and fronto-temporal event-related

coherence in patients with deficit or nondeficit schizophrenia

and in matched healthy controls. A reduction of both

induced gamma power and event-related coherence was observed

only in nondeficit patients with respect to controls. As

these measures reflect cortical functional connectivity, it

might be speculated that the fronto-temporal and fronto-parietal

dysconnection hypothesis only applies to nondeficit

schizophrenia. In a partially overlapping sample, Mucci et al

(56) found evidence of a double dissociation of ERP abnormalities:

compared to healthy subjects, only patients with

deficit schizophrenia showed an amplitude reduction of the

N1 component over the scalp central leads, and a reduced

activity of its cortical generators in the cingulate and parahippocampal

gyrus, whereas only patients with nondeficit

schizophrenia showed a left-sided reduction of the P3 component

and of its generators’ activity, that was also reduced in

bilateral frontal, cingulate and parietal areas.

Other findings

A factor analysis of the Schedule for the Deficit Syndrome

(SDS), used to assign patients to deficit or nondeficit subgroups,

suggested that the six negative symptoms of the SDS

loaded onto two factors (57). The first, which the authors of

the study called the avolition factor, consisted of curbing of

interest, diminished sense of purpose, and diminished social

drive; the second one, named emotional expression, included

restricted affect, diminished emotional range, and poverty

of speech. A review of the literature suggested a fairly

similar pattern in studies of schizophrenia as a whole (58).

These findings raise the interesting possibility that there are

somewhat separate circuits or mechanisms for these two

broad groups of negative symptoms, a possibility that could

be explored with imaging and other studies.

Discussion

Since the time of the 2001 review, additional studies have

provided evidence for the separate disease hypothesis of

deficit schizophrenia. Most notably, the findings that deficit

subjects have increased summer births and more normal regional

brain volume, compared to nondeficit subjects, have

received further support.

Other intriguing findings have also emerged. The most

important is the double dissociation of the deficit and nondeficit

groups with event-related potentials (56), as a double

dissociation supports the separate disease hypothesis. The

association with cytomegalovirus seropositivity is also potentially

important, as this marker could be used in studies

of gene/environment interaction. Both findings, however,

await replication.

There are also disappointments in the research to date. As

noted above, earlier evidence had suggested that glycine

agonists might be effective treatments for the negative symptoms

of deficit patients, but a large multicenter trial did not

confirm these preliminary studies. Thus there remains no

proven treatment for primary negative symptoms (59). Drugs

with innovative mechanisms of action will probably be required.

There has also been a lack of progress in the area of genetics.

The most appropriate strategy at this juncture may be a

genome-wide association study, in which deficit subjects are

considered as if they were a separate disease. The existing

family studies, as well as the replicated difference with regard

to an environmental risk factor – summer birth – suggest

that there may be genetic differences between deficit

and nondeficit schizophrenia.

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efficacy of treatments for the deficit syndrome of schizophrenia.

Psychotic disorders and particularly

schizophrenia are serious and sometimes

fatal illnesses which typically

emerge during the sensitive developmental

period of adolescence and emerging

adulthood (1). For over a century, a corrosive

blend of pessimism, stigma and

neglect have confined therapeutic efforts

to delayed and inconsistent palliative

care. Much of this can be attributed

to the conceptual error underpinning

the concept of schizophrenia, namely

that a true disorder could be validly defined

by its (poor) outcome. This error

was, in turn, a legacy of the 19th century

degeneration theory, which has been allowed

to influence the field well beyond

its use-by date (2). Although Kraepelin

himself and some of his contemporaries

ultimately recognized the fallacy, his dichotomy

(between dementia praecox

and manic depressive insanity) has withstood

several challenges and has been

strongly reinforced with the advent of

operational diagnostic systems. This has

not only hampered neurobiological research,

but has caused widespread iatrogenic

harm and inhibited early diagnosis

because of an exaggerated fear of

Early intervention in psychosis: concepts, evidence

and future directions

1ORYGEN Research Centre and Department of Psychiatry, and 2 Department of Psychology, University of Melbourne, 35 Poplar Rd., Parkville, Victoria, Australia

the expected outcome.

Until recently, apart from transient

and illusory optimism generated by the

mental hygiene movement in the 1920s,

early intervention for psychotic disorders

has been the furthest thing from

the minds of clinicians and researchers.

Ironically, however, since the early

1990s, this hitherto barren landscape

has seen the growth of an increasingly

rich harvest of evidence, and widespread

national and international efforts

for reform in services and treatment approaches,

setting the scene for more

serious efforts in early intervention in

other mental disorders (3-5).

Development of early

intervention services

Building on seminal research on first

episode psychosis from the 1980s (6-8),

frontline early psychosis clinical services

were established, first in Melbourne

(9) and soon after in many key locations

in the UK, Europe, North America and

Asia (10). There are now hundreds of

early intervention programs worldwide,

of varying intensity and duration, which

focus on the special needs of young people

and their families. International clinical

practice guidelines and a consensus

statement have been published (11) and

clinical practice guidelines for the treatment

of schizophrenia now typically

have a major section on early psychosis

(12,13). The International Early Psychosis

Association (www.iepa.org.au), an

international organization which seeks

to improve knowledge, clinical care and

service reform in early psychosis, has

been in existence for over ten years, led

by a highly collegial leadership group of

clinicians and researchers. This association

has over 3000 members from over

60 different countries, and by 2008 will

have held six international conferences,

stimulating and capturing a large volume

of research and experience.

In recent months, responding to the

widespread international momentum,

the US National Institute of Mental

Health has announced a large new

funding initiative to study and promote

the development of better services for

patients with first episode psychosis

(www.nimh.nih.gov).

149

Shift in thinking: pessimism

to optimism

The advent of preventive thinking has

required a shift in the way schizophrenia

and other psychotic disorders are

viewed. Rather than seeing them as having

inevitably poor prognoses with deterioration

in social and functional outcome

as the norm, more recent thinking

backed up by evidence from large international

studies (14-25) views the course

of these disorders as much more fluid

and malleable.

Examination of risk factors which

can influence outcome has revealed that

many of these may be reversible. For

example, disruption of peer and family

networks and vocational drop-out commonly

occur around and even before

the onset of a first psychotic episode.

Attention to these areas as part of treatment

has the potential to limit or repair

the damage.

Comorbid depression, substance use,

personality dysfunction and post-traumatic

stress disorder (PTSD) are all factors

which may influence outcome in

a person with first episode psychosis.

Again, early and vigorous management

of these problems can result in better

outcomes (26).

What is early intervention?

Early intervention is a potentially

confusing term. Because there is no

aetiopathological basis for diagnosing

psychotic disorders, they can only be

diagnosed by symptoms or combinations

of symptoms. In addition, we have

no known malleable causal risk factors

which predict onset of psychotic disorder

with any specificity. Thus, it seems

that primary prevention is currently out

of our reach. Early intervention, therefore,

In keeping with the clinical staging

model (27) articulated below, early intervention

in psychosis can be defined

as comprising three foci or stages: ultrahigh

risk, first episode, and the recovery

or critical period. The principal reason

for making such distinctions relates to

the underlying risk of chronicity, and

specifically the timing and duration of

prescription of antipsychotic medication,

since psychosocial interventions

are needed at all stages, though these

interventions too vary by stage.

What is the target for early intervention:

schizophrenia or psychosis?

Clinicians and researchers have debated

whether to focus on the preventive

target of schizophrenia or of psychotic

disorders more broadly. There are

several reasons for stepping out of the

current diagnostic silos and preferring a

relatively broad target.

As described above, schizophrenia

is conceived and defined in part as an

outcome as much as a diagnosis. While

it is very stable once applied (28-31), it

is intrinsically difficult to apply until the

patient has been ill for a prolonged period

of time. Within a sample of ultra-high

risk cases (already defined in order to

preferentially predict transition to nonaffective

psychosis), only 75% of those

who go on to develop a first episode

psychosis will progress to a schizophrenia

diagnosis (32). So, the false positive

rate is higher for schizophrenia than for

first episode psychosis. Even within a

first episode psychosis sample, only 30-

40% will meet criteria for schizophrenia,

and this percentage will increase over

time with additional diagnostic flux.

Thus, some cases of first episode psychosis

which do not meet criteria for

schizophrenia can be seen as being at

risk for this in the future (33). Schizophrenia,

therefore, is to some extent a

more distal target than psychosis, which

is a better and broader initial waystation

for critical treatment decisions. An even

earlier and broader point for intervention

is the ultra-high risk clinical stage,

where there is a need for care prior to

the positive psychotic symptoms having

become severe and sustained.

In addition, due to fear and stigma

derived from the notion of intrinsic poor

prognosis, clinicians are reluctant to

use the label “schizophrenia” early on

anyway, justifiably concerned about iatrogenic

effects on hope and the potential

for recovery (34). This has led some

countries, such as Japan, to change their

diagnostic terminology and eschew the

word “schizophrenia” (35). Our preferred

alternative is to retain it for the time being,

as one subtype of psychotic disorder

outcome, admittedly a major one, among

a small range of distal targets.

Psychosis itself is a variable syndrome,

defined by the presence of positive psychotic

symptoms, especially delusions

and hallucinations, and typically features

one or many comorbidities, including

negative symptoms, mood syndromes,

personality disorders, substance use

disorders, medical diseases and PTSD.

The relative prominence of the positive

symptoms and comorbidities varies, and

this leads to a more heterogeneous group

of patients. As a consequence of this, a

broader range of clinical skills will be required

in early psychosis programs than

in narrower schizophrenia programs.

Some have argued that the schizophrenia

focus allows the other psychotic

disorders, especially psychotic mood

disorders and psychoses associated with

certain personality disorders and PTSD,

to be treated in more appropriate settings.

However, provided there is a flexible

attitude and a broad range of clinical

expertise available, both groups of patients

benefit more from this broad, early,

and inclusive focus on the spectrum

of psychosis. It provides a good balance

between specialization and addressing

common needs, and also facilitates both

clinical and aetiological research, which

increasingly needs to transcend traditional

diagnostic barriers.

Enhancing the value

of diagnosis: The clinical

staging model

Many of the problems of categorical

diagnosis flow from a telescoping of

syndromes and stages of illness which

conceals and distorts the natural ebb

and flow of illness, remission and progression.

In addition to augmenting

categorical approaches with symptom

dimensions, consideration needs to be

given to the dimensions of time, severity,

persistence and recurrence.

The notion of staging can be borrowed

and adapted from mainstream medicine

to assist us here. A clinical staging model

provides a heuristic framework allowing

the development and evaluation of broad

and specific interventions as well as

the study of the variables and processes

underlying the evolution of psychiatric

disorder (27,36).

What is clinical staging?

Clinical staging is simply a more refined

form of diagnosis (37,38). Its value

is recognized in the treatment of malignancies,

where quality of life and survival

rely on the earliest possible delivery

of effective interventions. However, it

also has applicability in a diverse range

of diseases. Clinical staging differs from

conventional diagnostic practice in that

it defines the extent of progression of

disease at a particular point in time, and

where a person lies currently along the

continuum of the course of illness (36).

The differentiation of early and milder

clinical phenomena from those that accompany

illness extension, progression

and chronicity lies at the heart of the

concept. It enables the clinician to select

treatments relevant to earlier stages, and

assumes that such interventions will be

both more effective and less harmful than

treatments delivered later in the course.

While staging links treatment selection

and prediction, its role in the former

is more crucial than in the latter, particularly

since early successful treatment

may change the prognosis and thus prevent

progression to subsequent stages.

In addition to guiding treatment selection,

a staging framework, which moves

beyond the current diagnostic silos to

encompass a broader range of clinical

phenotypes, and which at the same time

introduces subtypes along a longitudinal

dimension, has the potential to organize

endophenotypic data in a more coherent

and mutually validating fashion (36).

How do we define the stages

of a disorder?

In other medical conditions, clinical

stages are defined by the degree of extent,

progression and biological impact

of illness in the patient, which in turn

must correlate with prognosis. This approach

usually depends upon a capacity

to define pathologically as well as clinically

the limits or extent of the disease

process.

In clinical psychiatry, this could involve

not only a cross-sectional clinical

definition, but a wider biopsychosocial

definition of extent or progression.

Therefore, in addition to the severity,

persistence and recurrence of symptoms,

biological changes (e.g., hippocampal

volume loss), and the social impact of

the disorder (e.g., the collateral damage

affecting social relationships and

employment), could also be drawn into

the definition. Ultimately, something approaching

a clinicopathological model

could emerge.

What are the potential benefits

of staging?

On the clinical side, defining discrete

stages according to progression of

disease creates a prevention-oriented

framework for the evaluation of interventions.

The key positive health outcomes

are prevention of progression

to more advanced stages, or regression

to an earlier stage. This requires an accurate

understanding of those broad

social, biological and personal risk and

protective factors which influence progression

from one stage to the next.

Furthermore, we need to know the

relative potency of these risk factors and

which of them may be responsive to current

interventions. While some factors

may operate across several or all stage

transitions, others may be stage-specific,

for example substance abuse or stress

may be especially harmful in triggering

onset of the first episode of illness,

yet be less toxic subsequently (or vice

versa). Gene-environment interactions

almost certainly underpin and mediate

these transitions, where environmental

variables − such as substance abuse,

psychosocial stressors, cognitive style,

medication adherence and social isolation

− may interact with genetic and

other biological risk factors (39-41).

From an aetiological perspective, over

a century of research with traditional diagnostic

categories of psychosis and severe

mood disorders has failed to relate

these flawed concepts to any discrete

pathophysiology (42,43). A clinical staging

model, which allows the relationship

of biological markers to stage of illness

to be mapped, may help to validate the

boundaries of current or newly defined

clinical entities, distinguish core biological

processes from epiphenomena and

sequelae, and enable existing knowledge

to be better represented and understood.

The stages of early psychosis

Stage 1: Ultra-high risk

In psychotic disorders, an early

prepsychotic stage is known to exist, one

in which much of the collateral psychosocial

damage is known to occur (44).

This earliest stage could, in retrospect, be

termed the “prodrome”, i.e., the precursor

of the psychotic stage. However, since

we can only apply the term “prodrome”

with certainty if the definitive psychotic

stage does indeed develop, terms such as

the “ultra-high risk” (34) or “clinical high

risk” (45) stage have been developed to

indicate that psychosis is not inevitable

and that false positive cases also occur.

This symptomatic yet prepsychotic stage

is the earliest point at which preventive

interventions for psychosis can concurrently

be conceived (46).

The challenge in detecting such a

stage prospectively is firstly to define the

clinical frontier for earliest intervention

and “need for care” which represents

the boundary between normal human

experience and pathology. Secondly, a

set of clinical and other predictors need

to be defined which identify a subgroup

at imminent risk for psychotic disorder.

This is a complex task and the key issues

involved have been covered in many

recent publications (47-55). Earlier

writers (56) aspired to the diagnosis of

schizophrenia in the prodromal phase.

German psychopathologists in the mid

20th century emphasized subtle changes

in experience and behaviour, though

151

their complexity meant that they had

little impact on Anglophone psychiatry

initially. A practical operational definition

of a prepsychotic “at risk” or “ultrahigh

risk” mental state, which could be

shown to confer a substantially high risk

of fully fledged psychosis within a 12

month period, was then developed and

tested in the early 1990s (57). This has

captured the attention of the field and

has been the focus of much subsequent

research, focusing on prediction, treatment

and neurobiological aspects.

These criteria do indeed predict an

“ultra-high risk” group for early transition

to psychosis (32), leading to a relative

risk of 40% compared to the incident

rate of psychotic disorders in the general

population (58). However, there is still a

significant false positive rate of 60-80%,

though they typically are or turn out to

be true positives for other disorders, notably

depression and anxiety disorders.

While the predictive power for psychosis

by the use of key variables such as genetic

risk, depression, functional impairment

and substance use (58,59), this is

of limited utility due to the “prevention

paradox”. This means that increasing

the positive predictive value reduces the

number and percentage of cases that can

benefit. So, if the sample is narrowed,

one is on firmer ground, but most cases

who do go on to develop the disorder

are missed due to the narrower focus

(51). We know already that most cases

of first episode psychosis are already

missed by prodrome clinics.

There have been a series of clinical trials

of relatively small sample size examining

both antipsychotics and/or cognitive

therapy as preventive treatment

strategies for ultra-high risk patients (60-

62). These trials suggest that cognitive

therapy and antipsychotics may prevent

or at least delay the onset of psychotic

disorder and reduce symptomatology. A

second generation of single site clinical

trials has recently been completed, with

interesting results for a range of psychosocial

and biological therapies, including

cognitive therapy (62), lithium (63),

omega-3 fatty acids (64), and atypical

antipsychotics (60).

However, treating young people in

the putative prodromal phase does cause

some understandable concern that patients

might be exposed to unnecessary

and potentially harmful treatments. This

has created controversy in the US in particular

around this type of research. This

in turn has led to so-called “naturalistic

designs” (58,65) being preferred above

the traditional randomized designs. Paradoxically,

the ethical considerations

that drove this thinking have allowed

the same treatments that could not be

researched under rigorous conditions

of informed consent within a randomized

controlled trial to be used off label

in a widespread and uncontrolled fashion

in these naturalistic studies. Hence

the term “naturalistic” becomes a misnomer,

since the natural course may be

profoundly influenced by uncontrolled

treatment. These “naturalistic” studies

reveal that extensive non-evidencebased

use of antipsychotic medications

seems to be common in clinical settings

in the US, ironically side by side with

long delayed and inadequate treatment

of first episode and established psychotic

disorders (66).

Clinical trial data is crucial to determining

the risks and benefits of various

forms of treatment in a new clinical focus

and creating solid foundations for

an evidence-based approach. This is the

best antidote to fears on widespread and

potentially harmful and unnecessary

use of antipsychotic medications in particular.

The “prodromal” or ultra-high

risk field remains in clinical equipoise,

since we do not yet know which treatments

will be most helpful and acceptable

to patients, and crucially in which

sequence or combination.

Prospective or naturalistic data can

best be collected in the most sound and

interpretable fashion in the context of

a large well-funded multicentre clinical

trial, with an “effectiveness” rather than

efficacy design and a minimal intervention

arm, to which non-consenters to

randomisation can be assigned.

We can readily accept that antipsychotics

and indeed antidepressants

(67) and neuroprotective agents such as

omega-3 fatty acids and lithium are legitimate

therapies to be further researched,

but their use in research should be protocolized

within rigorous study designs.

In the meantime, the international clinical

practice guidelines on early psychosis

(11), which advocate a conservative

approach to the use of antipsychotic

medications and more liberal use of

psychosocial interventions, should be

followed. This rather conservative approach

to treatment of ultra-high risk

individuals is even more imperative, as

recently it has been discovered that the

rates of early transition to first episode

psychosis have been falling in the more

established prodromal centres (52), with

a much higher rate of so-called “false

positives” being accepted into these

services. This may be due to sampling

variation, earlier detection of ultra-high

risk cases, or improved efficacy of interventions

provided (52).

This reduction in transition rate and

uncertainty over treatment in the ultrahigh

risk group has led to valid concerns

about identification of and intervention

with these individuals. Yet help-seeking

patients defined by the ultra-high

risk criteria for first episode psychosis

are at risk not only for schizophrenia or

psychosis but for other adverse mental

health outcomes (68). We may need to

define an even broader pluripotential

initial clinical stage with a range of possible

exit or target syndromes. Consequently,

we have broadened our own

clinical and research strategy (69), crosssectionally

with the development of a

broader and more accessible system of

clinical care for those in the peak age of

risk for all types of mental disorders (70-

72), and longitudinally with the creation

of a clinical staging model for psychotic,

mood and anxiety disorders (27).

This enables a serial enriching strategy

to unfold to ensure that the declining

transition rates in ultra-high risk

samples (52) and the consequently

high false positive rate can be handled

in future clinical trials, and that other

exit syndromes and indeed remission

and resolution can be included. These

strategies help us to move beyond some

of the obstacles to early diagnosis and

intervention: namely the “false positive”

issue, potential problems with stigma,

the challenge of comorbidity, and lack

of predictive specificity. As we move further

down this road, the problems with

our historically determined classification

systems loom larger and the need

to loosen the shackles becomes more

apparent.

Stage 2: Early detection and treatment

of first episode psychosis

The second stage involves a therapeutic

focus on the period after the onset of

fully-fledged psychosis (often known

as “first episode psychosis”). This is divided

into the period before psychosis

is detected and the period after detection.

Unfortunately, the undetected or

untreated phase can be prolonged, even

in developed countries (73). Of course,

even when psychosis is detected, the

initiation of effective treatment may still

be delayed. The goal is to minimize this

duration of untreated psychosis (DUP).

Post-detection, the intervention goals

are engagement and initiation of pharmacological

and psychosocial treatments.

Intensive interventions aimed at

maximal symptomatic and functional

recovery and the prevention of relapse

are ideally delivered during the early

weeks and months of treatment.

The controversy surrounding the importance

of DUP and treatment delay

in first episode psychosis seems to have

been largely resolved following the publication

of some key systematic reviews

(74,75) and recent influential longitudinal

research. These studies have now

established that longer DUP is both a

poor outcome. The Early Treatment and

Identification of Psychosis (TIPS) study

in Scandinavia has shown, through the

best possible design, that reducing DUP

leads to early benefits in reducing suicidal

risk and severity of illness at initial

treatment and sustained benefits in

terms of negative symptoms and social

functioning (18-21). The relationship

between DUP and outcome is robust,

being sustained over many years of follow-

up (76,77). However, these studies

do show that, though being a malleable

risk factor, DUP accounts for a relatively

modest amount of outcome variance,

underlining the importance of treatment

access and quality during the early years

of illness.

There is an extensive literature attesting

to the benefits of comprehensive

care of the first psychotic episode.

This is summarised in the International

Clinical Practice Guidelines for Early

Psychosis (11), published in 2005. Since

2005, the growth in research in this area

has continued. This has led to the emergence

of the following findings.

The large multicentre European First

Episode Schizophrenia Trial (EUFEST)

has shown that in the treatment of first

episode schizophreniform and schizophrenic

disorders, atypical or secondgeneration

antipsychotics have some

clear-cut advantages (78). While most

patients responded surprisingly well to

both typical and atypical medications,

with no significant efficacy differences,

discontinuation rates and tolerability

were clearly superior for atypical agents.

This was true even when contrasted with

very low-dose haloperidol. While the

authors’ conclusions and recommendations

were conservative, highlighting

the equivalent efficacy of the two classes

of drug, the EUFEST findings contrast

markedly with those of the Clinical Antipsychotic

Trials of Intervention Effectiveness

(CATIE) study (79) in chronic

schizophrenia, where no dramatic advantages

were found for atypicals using

similar outcome measures. The EUFEST

data support the recommendations of the

International Clinical Practice Guidelines

in Early Psychosis (11), which favor

the use of atypicals as first line therapy,

because of better tolerability (a crucial issue

in drug-naïve first episode patients)

and reduced risk for tardive dyskinesia.

However, some atypicals have a particularly

high risk of weight gain and metabolic

problems, and these risks need to

be carefully managed and prevented

wherever possible. A recent paper (80),

however, suggests that weight gain is a

problem in the first year of therapy for

first episode patients on both typicals

and atypicals, with the key difference being

the rate at which it develops.

Psychosocial treatments in early psychosis

have been extensively studied,

and there are positive findings pointing

to the value of cognitive therapies in accelerating

and maximizing symptomatic

and functional recovery (81,82). Increasingly

there has been attention to the

fact that medications, while assisting in

symptomatic recovery, do not, by themselves,

contribute to a return to functioning.

This has led to an increased focus on

the need to enhance social recovery (68)

especially educational and vocational aspects

(83-85), through the combination

of effective psychosocial interventions

with well-managed medication. There

is also an increasing focus on targeted

cognitive remediation (86) to limit the

degree of cognitive decline that is often

found as illness progresses.

Initial scepticism regarding DUP has

slowly melted in the face of evidence but

also the logic of early diagnosis. If we

believe we have effective interventions

in psychosis, it is perverse to argue that

delayed treatment is acceptable. Sceptics

find themselves being asked how

long a delay is acceptable: 2 months? 6

months? 2 years? In reducing the DUP

the two key components of intervention

are community awareness and mobile

detection services. Both are important,

as the data from TIPS (87) and other

studies (88) have shown. When both are

in place, it is possible to achieve very low

levels of DUP (a median of a few weeks

only). These strategies also result in a less

risky and traumatic mode of entry into

care and enable patients to be engaged

without a surge of positive symptoms

or disturbed behaviour being required

to force entry into poorly accessible or

highly defended service systems. They

should be available in all developed

communities and a standard feature of

all mental health systems.

In terms of the specific elements of

first episode psychosis intervention, a

number of trials have shown that atypical

antipsychotics in low dose are superior

for first episode patients where tolerability

and safety are at a premium, though

153

some may be ruled out on exactly these

grounds in many patients. The recent

EUFEST study is especially compelling

(78). The place of new injectables and

clozapine needs to be clarified, as well as

that of adjunctive neuroprotective agents

such as omega-3 fatty acids, lithium and

N-acetyl cysteine. Cognitive behavioural

therapy and vocational rehabilitation

(89) are the key psychosocial interventions

in early psychosis and need to be

much more intensively and widely deployed.

Assertive community treatment

for the subset of poorly engaged patients

is vital (11). Family interventions are also

an essential element of care, even though

the formal evidence is not yet fully available

(90).

Stage 3: The critical period of the first

5 years after diagnosis

This third stage involves the critical

early years beyond the first episode,

which can be viewed as the critical period

(91). Treatment goals in this phase

are the management of effective medication

and the use of effective psychosocial

interventions to minimize the

development of disability and maximize

functioning. Proof of concept is now

established for these strategies (14,15).

However, there remains a large gap in

most communities between what works

and what is available, even in high income

countries and certainly in the low

and middle income countries (92).

Beyond the first episode, we know

that the first 2-5 years post-diagnosis are

crucial in setting the parameters for longer

term recovery and outcome. This is

the period of maximum risk for disengagement,

relapse and suicide, as well as

coinciding with the major developmental

challenges of forming a stable identity,

peer network, vocational training and

intimate relationships. It makes sense

that a stream of care specially focused

on young people and on this stage of illness

is required to maximize the chances

of engagement, continuity of care, appropriate

lifestyle changes, adherence

to treatment, family support and vocational

recovery and progress. Indeed, the

available evidence from naturalistic and

randomized studies strongly supports

the value of specialized early psychosis

programs in improving outcome in the

short term (89,93). If these programs

are only provided for 1-2 years, there is

also evidence that some of the gains are

eroded, suggesting that, for a substantial

subset at least, specialized early psychosis

care needs to be provided for a longer

period, probably up to 5 years in many

cases (77,94,95).

The best available evidence indicates

that streamed care provides superior

outcomes in the short to medium term

compared to generic care (16,17). While

this may be insufficient to meet the

most stringent Cochrane criteria, such

evidence, combined with face validity

and obvious poorly met need, has been

sufficient to convince mental health

policy makers and service providers

in hundreds of locations worldwide to

adopt, adapt and implement this model.

The randomized controlled trials so far

have only tested partial versions of this

streaming, with a specialized assertive

community treatment model being the

main feature evaluated. Even so the results

are positive for the first 2 years of

care. It seems likely that, for a significant

subset at least, if these gains are to be

maintained, the streamed early psychosis

model must be continued for longer,

perhaps up to 5 years (89). At this point,

persisting illness and disability may be

present in a much smaller percentage of

people, whose needs may subsequently

be well met by more traditional mental

health services for older adults. This may

be a much better point to transfer care.

The process of reform

The pace of reform is typically slow

in health care. While early intervention

in psychosis has made great progress in

recent years, dissemination remains in

many ways frustratingly slow. Many developed

and most developing countries

have made no progress at all, and even

those countries which have made significant

investments have only achieved

partial coverage. We have previously

commented on this inertia and some of

the reasons for it (92,96).

Evidence-based health policy (97)

can be seen as a blend of evidence-based

health care and public policy analysis,

in which evidence is only one of a range

of influential variables. Pure evidencebased

health policy derives from a technical

perspective and regards the task as

identifying and overcoming barriers to

smooth flow of best available evidence

into practice. This has been characterised

as “naïve rationalism” (98), since cultural

and political values and the dynamics

of change and reform are other key influences

on policy making. Evidence is a

product as well as a driver of reform and

the evidence-based paradigm, by setting

impossible prerequisite standards, and

by shifting the goalposts once evidence

is forthcoming, can be used as a weapon

to frustrate and delay overdue reform in

a manner that would be unacceptable in

other branches of medicine (99).

In better understanding this phenomenon,

it is worthwhile to reflect on

how innovation and reform in health

care works. Diffusion of innovations is

a major challenge in all industries, from

agriculture to manufacturing. The study

of diffusion of innovation has a long

history in the social sciences. Many nations

have established centres and strategies

to understand and promote this in

health care (100,101).

There are many contextual factors

involved, but there are also predictable

characteristics of individuals and health

care systems which influence the process

(102). Firstly, we must consider perceptions

of the innovation. There must be

perceived benefit; the innovation should

be compatible with the values and needs

of those considering it. It should be simple

or capable of simplification and, in

the process of spread, it is vital that innovations

be adapted and reinvented in

relation to local needs. Secondly, there

are several groups of adopters involved

in the process of innovation. The innovators

are the smallest group and create

the novel ideas and skills. They are novelty

seekers who form wider national

and international networks or cliques

and they invest energy in these connections.

They may be thought of as mavericks

heavily invested in a specialized

issue. The early adopters are a larger

group of opinion leaders who draw on

the innovators and cross-pollinate with

one another. They are open to a range

of new ideas and have the resources and

risk tolerance to try new things. Most

importantly, they are closely watched by

the next group, the early majority, who

are more local in their focus and more

risk averse. The early majority look to

the early adopters for guidance about

what is safe to try. The fourth group, the

late majority, are even more conservative

and look to the early majority, adopting

an innovation only when it appears to be

the new status quo. Finally, we have the

laggards, apparent members of a modern

day flat earth society, whose point

of reference is the past. To be fair, this

description underestimates their value,

since they usefully point to the need to

retain some valuable elements of current

and prior practice. However, they are

also exposed defending the indefensible

and demanding impossible and unrealistic

levels of evidence before accepting

change. Furthermore, the evidence

standards demanded for innovations are

rarely if ever applied to the status quo,

which in mental health at least is typically

less evidence-based than the new

approach. This active rearguard action

is aided and abetted by the tendency of

systems to rapidly build inertia and reinstitutionalize

after periods of progress.

Despite the welcome progress in early

intervention, the laggards have been

prominent in the early intervention

field. While evidence-based medicine is

by far the best antidote for taking wrong

and potentially dangerous and wasteful

turns in health care, opponents of

change have been observed to misuse

the paradigm to frustrate change which

is overdue and in the best interests of

the community. There is regrettably insufficient

debate about where the onus

of proof lies in such matters, and what

considerations other than evidence

should influence decisions, especially

where changes have high face validity,

such as emergency care and indeed

early intervention. Finally, it is unlikely

that oncologists would debate the relative

value of early diagnosis and palliative

care, which is where psychiatry has

got stuck repeatedly.

Berwick points out that the dissemination

of innovation has a tipping point

(103), usually around 15-20% adoption.

Certainly, once the early majority have

swung in behind an innovation, the late

majority are likely to feel comfortable to

move as well. This is a process that can

be facilitated by several strategies. These

include identifying sound innovations,

leading by example, supporting innovators

and early adopters with resources

and time, making the activities of early

adopters highly visible, and valuing reinvention

as a form of learning rather

than requiring exact replication of innovations.

Conclusions

Many of the obstacles to early intervention

are the same ones which impede

progress in mental health more

widely, as illustrated in the Lancet Series

on Global Mental Health (104). They

include stigma, pessimism, the silence

that surrounds the mentally ill, and a

consequent failure to invest. Developed

and rapidly developing countries need

to recognize the public health importance

of untreated and poorly treated

mental disorders. A key aspect which is

beginning to be recognized is that mental

disorders are the chronic diseases of

the young (105). Most adult type mental

disorders − notably psychotic, mood,

anxiety, substance use and personality

disorders − have their onset and maximum

impact in late adolescence and

early adult life. A broader focus for early

intervention would solve many of the

second order issues raised by the early

psychosis reform process, such as diagnostic

uncertainty despite a clear-cut

need for care, stigma and engagement,

and should be more effective in mobilizing

community support for investment

and reform in mental health. This

is occurring in Australia (106,107) and

Ireland (108), and is attracting increasing

attention in a number of other countries,

along the lines of the innovation

process described above. It currently

represents a vital and challenging project

for early adopters in global psychiatry

to consider.

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Early psychosis: where we’ve been, where

we have to go. Epidemiologia e Psichiatria

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OPUS study: suicidal behaviour, suicidal

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157

Department of Psychiatry, McGill University, Montreal,

Quebec, Canada

A burgeoning interest in understanding

and treating the early phase of psychotic

disorders, especially schizophrenia,

has brought forth a sense of optimism

of altering the course of these disorders.

McGorry et al highlight many aspects of

the progress made, as well as some of the

challenges to furthering the application of

a broader preventive model of care based

on a hierarchical model of understanding

mental disorders.

It may not be entirely ironic that development

of early intervention theory and

practice in psychiatric disorders should

have started with the disorder viewed

most pessimistically with poor outcome

(schizophrenia). Indeed, a great deal of

progress has been made since the initial

seminal studies of first episode psychosis

(1) and the influential review by Wyatt

(2). Such progress has extended beyond

understanding the effects of delay in treatment

to a more substantial understanding

of neurobiology and outcome during

early phase of psychotic disorders. It has

been particularly remarkable that, while

research in phenomenology, neurobiology

and cognitive psychology of first episode

psychosis and the putative periods

preceding the onset of psychosis has

flourished, there has been a parallel and

equally prolific development of services

specializing in treatment of early phases

of the illness. Such developments have

taken research out of artificial settings

to real life new specialized services, thus

making available large epidemiologically

based cohorts of subjects for investigation.

Such research is likely to be more

meaningful in the long run, as the findings

will be applicable to larger groups

of patients. As McGorry et al suggest, it

is time now to think more broadly and

extend the scope of such developments

in service and research to a larger group

of disorders without the constraint of a

strictly categorical diagnostic system.

Despite the well justified enthusiasm,

there are, however, a number of issues

that remain either unclear or unaddressed.

The term “early intervention” has often

been taken to imply “earlier” intervention

predicated on an association between

duration of untreated psychosis (DUP)

and clinical outcome. However, this is an

oversimplification: there is in fact much

more to “early intervention” than simply

intervening early (3). The evidence to support

enriched and comprehensive interventions

is indeed strong and replicated

in controlled studies (4-6) and confirmed

in a recent meta-analysis (7). While it

requires no more than face validity to

support quick, unencumbered and userfriendly

access to specialized treatment

of new cases of psychotic disorders, the

evidence for more elaborate and relatively

expensive interventions to improve early

case detection remains either confined

to specific jurisdictions (8) or applicable

only to a subgroup of patients (9). In order

to benefit larger number of patients, it

may be easier to convince mental health

policy makers to apply a more effective

treatment model with improved access

than to expect them to support elaborate

and expensive interventions to reduce

DUP through active case detection. There

is still a need to identify what methods of

early case identification and improved

access would work in which settings,

given large variations in composition of

populations (e.g. ethnicity, urban vs. rural

setting) and nature and quality of the

prevailing primary and specialist health

care. On the other hand, large scale campaigns

at the community level to improve

general mental health literacy and engage

communities in a dialogue about mental

illness have heuristic value even if their

direct impact on reducing delay in treatment

of specific disorders may be difficult

to demonstrate.

McGorry et al correctly identify the

greater conceptual accuracy of “ultra-high

risk” as opposed to “prodromal” patients

to whom interventions could be provided

to prevent or delay onset of psychosis.

While there has been progress in demonstrating

efficacy of individual interventions

in small controlled trials, we are not

yet at a stage to recommend any particular

approach. Apart from the need for more

substantial evidence, there are several

reasons for such caution. The transition

from a non-psychotic high risk state to

psychosis occurs in only a fraction of such

patients, even without the use of antipsychotic

medications, especially if they are

provided with adequate care and support

for the problems they present with. This

raises the risk of treating many more false

positives for a putative impending psychosis.

Further, not enough attention has

been paid to the relatively fluid and ambiguous

boundary between sub-threshold

and threshold level of symptoms of psychosis,

creating a risk of reporting results

based on a categorical fallacy. Until such

time as further methodologically sound

research using large samples produces

clear evidence based interventions, we

run the risk of encouraging clinicians to

become cavalier in using antipsychotic

medications for treating symptoms they

observe over a single assessment, as is already

happening in many jurisdictions.

Other major challenges that must be

faced, if “early intervention” is to benefit

a larger population of patients, include

the patients’ refusal to accept or engage in

treatment (estimate 15-50%), those who

drop out early in the course of or do not

adhere to treatment, and those who present

with substance abuse as an additional

problem. Lack of adherence to treatment

and presence of substance abuse have

been identified as major obstacles to

achieving and maintaining symptomatic

remission following treatment of first episode

psychosis (10-12). Indeed, such malleable

predictors of outcome overshadow

the significance of delay in treatment in

achieving better outcomes. Further, it appears

that the gains made with specialized

treatment of early phase of psychosis over

the first two years are difficult to sustain (5),

and further systematic study of the length

of specialized treatment is required if we

The promises and challenges of early intervention

in psychotic disorders

are to make a difference in the long-term

course of psychotic disorders. Last, but

not least, there is a dire need to understand

the process of recovery and what promotes

or hinders it during the early “critical

period”. Both qualitative and quantitative

research, which takes into account

patients’ and families’ perspectives and

examines the effect of various treatments

on recovery (13), should be a priority for

the early intervention field.

References

1. Johnstone EC, Crow TJ, Johnson AL et al.

The Northwick Park Study of first episodes

of schizophrenia. I. Presentation of the illness

and problems relating to admission. Br

J Psychiatry 1986;148:115-20.

2. Wyatt RJ. Neuroleptics and the natural

course of schizophrenia. Schizophr Bull

1991;17:325-51.

3. Malla AM, Norman RM. Treating psychosis:

is there more to early intervention than

intervening early? Can J Psychiatry 2001;46:

645-8.

4. Petersen L, Nordentoft M, Jeppesen P et al.

Improving 1-year outcome in first-episode

psychosis: OPUS trial. Br J Psychiatry 2005;

187(Suppl. 48):s98-s103.

5. Bertelsen M, Jeppesen P, Petersen L et al.

Five-year follow-up of a randomized multicenter

trial of intensive early intervention vs

standard treatment for patients with a first

episode of psychotic illness: the OPUS trial.

Arch Gen Psychiatry 2008;65:762-71.

6. Garety PA, Craig TK, Dunn G et al. Specialised

care for early psychosis: symptoms,

social functioning and patient satisfaction:

randomised controlled trial. Br J Psychiatry

2006;188:37-45.

7. Harvey PO, Lepage M, Malla A. Benefits

of enriched intervention compared with

standard care for patients with recent-onset

psychosis: a metaanalytic approach. Can J

Psychiatry 2007;52:464-72.

8. Melle I, Larsen TK, Haahr U et al. Reducing

the duration of untreated first-episode

psychosis: effects on clinical presentation.

Arch Gen Psychiatry 2004;61:143-50.

9. Cassidy CM, Schmitz N, Norman R et al.

Long-term effects of a community intervention

for early identification of first-episode

psychosis. Acta Psychiatr Scand 2008;117:

440-8.

10. Wade D, Harrigan S, Edwards J et al. Substance

misuse in first-episode psychosis:

15-month prospective follow-up study. Br J

Psychiatry 2006;189:229-34.

11. Malla A, Norman R, Bechard-Evans L et al.

Factors influencing relapse during a 2-year

follow-up of first-episode psychosis in a

specialized early intervention service. Psychol

Med (in press).

12. Malla A, Norman R, Schmitz N et al. Predictors

of rate and time to remission in

first-episode psychosis: a two-year outcome

study. Psychol Med 2006;36:649-58.

13. Farkas M. The vision of recovery today:

what it is and what it means for services.

World Psychiatry 2007;6:68-74.

Department of Psychology, King’s College London;

Institute of Psychiatry, Department of Psychology,

Box PO77, Henry Wellcome Building, De Crespigny

Park, Denmark Hill, London SE5 8AF, UK

As McGorry et al point out, the model

for early intervention in psychosis draws

on physical illness (typically cancer),

where the idea is that early detection

leads to treatment that is less radical,

more successful and averts a poor or fatal

outcome. Unfortunately in psychosis

there is neither an early nor a specific

biological marker, so that early intervention

is really not early at all, but closer to

secondary prevention where symptoms

are already present, even if they are not

yet severe. This means that all prodromal

services can do is offer treatments to help

seekers, up to 80% of whom will never

make the transition. Prodromal services,

by definition, do not offer help to those

who deny they have problems and who

may be at the more severe end of the spectrum

with longer duration of untreated

psychosis (DUP), more negative symptoms

and poorer outcomes after an episode.

Similarly, early intervention services

can only offer help to those who will stay

engaged.

Thus, the early intervention medical

model is not correct for psychosis; those

treated, or those who will accept treatment,

by definition are unlikely to be

those who will need it most. This is the

first difficulty that services face, and until

more specific markers are discovered,

it will remain a stumbling block to the

hope of preventing episodes or of offering

comprehensive services to everyone

at risk of an episode: a true early intervention

model.

Of course, there are humanitarian reasons

for offering services early; these are

The case for early, medium and late

intervention in psychosis

mainly to reduce the DUP, associated

with a poorer response to antipsychotic

medication (1), and the sometimes brutal

and shocking realities of sectioning

and admission that individuals can face

if problems are left until a crisis. Offering

a service that people collaborate with and

take up before crises develop is entirely

laudable. However, we have no evidence

yet, apart from the DUP evidence, that

such early treatment changes longer term

course. We are still not able to look at 10

to 20 year follow-ups of early intervention,

including deaths from all causes.

Further into his article, McGorry et al

promote their idea of a “staged” model.

Again this is a transfer of ideas from physical

medicine. While a useful research programme,

we have no way of yet knowing

what markers, biological or social, predict

better or worse outcomes, or would

respond to less treatment (perhaps not

needing medication for instance). While of

interest, we are not in a position to implement

anything like this kind of detailed and

specified service delivery for psychosis.

McGorry et al touch on, but do not

elaborate, the point that most successful

early intervention psychosis treatment includes

considerable social and vocational

input. Young people with psychosis typically

wish to reduce their social exclusion

– they wish to “get back to normal”, and

have easy access to meaningful activity

(jobs), study and relationships. Early

intervention services typically include

a large “dose” of vocational help. This

suggests that it is not only psychosis that

needs treating, but society’s and the individual’s

attitude to the difficulties it can

cause. Easing people back into “normal”

environments, despite problems such as

their sensitivity to stress and possible

poor concentration, is made more difficult

Therefore, in terms of improving service

user and carer outcomes, offering early

intervention, including family intervention,

from the beginning of episodes has

to be sensible.

Finally, it is hard to argue against the

idea that early detection, prodromal and

early intervention services are a “good”

thing. It must be good practice to offer

the best service we can. As Max Birchwood

has noted, early intervention aims

particularly to reduce the chaos and high

suicide rates of the first “critical” years of

psychosis (9). However, we only have

emerging evidence that it can reduce relapse

and improve engagement (10) and

none showing that longer term course

will improve. As I have suggested before

(11), offering high quality, comprehensive,

presentation, early, medium or later, including

offering optimism and hope of

recovery (12), would seem to be a more

reasonable strategy.

References

1. Perkins DO, Gu H, Boteva K et al. Relationship

between duration of untreated psychosis

and outcome in first-episode schizophrenia:

a critical review and meta-analysis. Am

J Psychiatry 2005;162:1785-804.

2. Weinman J. Personal communication.

3. Lobban F, Barrowclough C, Jones S. The

impact of beliefs about mental health problems

and coping on outcome in schizophrenia.

Psychol Med 2004;34:1165-76.

4. Watson PWB, Garety PA, Weinman J et al.

Emotional dysfunction in schizophrenia

spectrum psychosis: the role of illness perceptions.

Psychol Med 2006;36:761-70.

5. Grawe RW, Falloon IRH, Widen JH et al.

Two years of continued early treatment for

recent-onset schizophrenia: a randomized

controlled study. Acta Psychiatr Scand 2006;

114:328-36.

6. Addington J, McCleery A, Addington D.

Three-year outcome of family work in an early

psychosis program. Schizoph Res 2005;

79:107-16.

7. Raune D, Kuipers E, Bebbington P. EE at

first episode psychosis: investigating a carer

appraisal model. Br J Psychiatry 2004;184:

321-6.

8. Barrowclough C. Families of people with

schizophrenia. In: Sartorius N, Leff J, Lopez-

Ibor JJ et al (eds). Families and mental

disorders: from burden to empowerment.

Chichester: Wiley 2005:1-24.

9. Pelosi AJ, Birchwood M. Is early intervention

for psychosis a waste of valuable resources?

Br J Psychiatry 2003;182:196-8.

10. Craig TKJ, Garety P, Power P et al. The

Lambeth Early Onset (LEO) Team: randomized

controlled trial of the effectiveness

of specialized care for early psychosis. Br

Med J 2004;329:1067.

11. Kuipers E, Holloway F, Rabe-Hesketh S

et al. An RCT of early intervention in psychosis:

Croydon Outreach and Assertive

Support Team (COAST). Soc Psychiatry

Psychiatr Epidemiol 2004;39:358-63.

12. Resnick SG, Fontana A, Lehman AF et al. An

empirical conceptualization of the recovery

orientation. Schizophr Res 2005;75:119-28.

standing, fear and stigma, that surrounds

these diagnoses and prevents re-integration.

The current anti-stigma campaigns

in some countries are trying to improve

this aspect.

However, it is not just society’s reaction.

Illness perception research shows

that, as with physical illness, people with

psychosis, and their carers, can have

understandably negative views about

the consequences of, and their ability to

control problems, which can affect decisions

about treatment. Because of this,

as John Weinman has pointed out (2),

“illness perceptions account for a significant

and important amount of variance in

outcome in physical illness”. People with

psychosis share these attitudes (3,4). Certainly

we know that rejecting medication,

because of its side effects, as well as failing

to engage with our services, remain concerns

for this population.

Thirdly, McGorry et al only touch on

the issue of family intervention for early

psychosis. There is some evidence that it

is helpful (5,6). However, we also know

that there are more carers at early episodes,

perhaps 60%, and that these carers

experience similar difficulties and

reactions as do later carers (7). We also

know that the impact of care for relatives

is related to long-term depression,

and higher levels of stress and exhaustion

while the caring role continues (8).

Department of Psychiatry and Psychotherapy, University

of Cologne, Kerpener Strasse 62, 50924 Cologne,

Germany

In their paper, McGorry et al advocate

the international introduction of a

clinical staging model into clinical diagnosis

in the different mental health care

systems.

For the early course of psychotic disorders,

three stages with different implications

for diagnosis and therapy are

distinguished: a) the ultra-high risk stage

The clinical staging and the endophenotype approach

as an integrative future perspective for psychiatry

according to the criteria developed by

the Melbourne working group, b) the

first-episode psychosis and c) the most

crucial first 2-5-year period following

the first diagnosis of psychosis.

Elsewhere (1), the staging model has

already been extended to depressive and

bipolar disorders and subdivided into

eight different stage definitions. According

to this more differentiated model, one

more stage (Ia) with mild or non-specific

symptoms, including neurocognitive deficits

and mild functional changes or decline,

precedes the ultra-high risk states

in psychotic and severe mood disorders

(Ib). Even prior to these, an increased risk

stage (0) without symptoms might exist.

Furthermore, the critical period (stage

III) after first-episode psychosis (stage II)

is subdivided into stages of incomplete remission

(IIIa), recurrence or relapse (IIIb)

or multiple relapses (IIIc), and a stage IV

is identified for persistent or unremitting

psychotic and severe mood disorders.

Any early intervention strategy, however,

presupposes available retrospective

and/or prospective findings on the early

lated to these. In the German Research

Network of Schizophrenia (GRNS, 2),

for example, the early detection and intervention

projects (3) proceeded from

studies which had already aimed for a

thorough characterization of the initial

prodromal stages prior to first-episode

psychosis with optimized retrospective

(4,5) and prospective (6) methodologies.

These studies had revealed a duration of

the initial prodrome of 5-6 years on average

and, within this phase, had identified

some syndrome sequences, from nonspecific

symptoms, via cognitive-perceptual

basic symptoms, attenuated and transient

psychotic symptoms, to first-episode psychosis

(7). These early cognitive-perceptual

basic symptoms had shown a good

predictive accuracy, with a transition

rate of 63% within the average 9.6-years

follow-up (6). Thus, in combination with

available data on transition rates for

ultra-high risk criteria, a subdivision of

the prodromal phase into an early initial

and a late initial prodromal state has

been proposed, that is quite similar to

the above differentiation between stages

Ia and Ib. This model has been the basis

for the early detection and intervention

projects in the GRNS (8) and, slightly

modified, the multinational prospective

European Prediction of Psychosis Study

(EPOS, 9).

The EPOS results confirmed an emerging

problem that the Melbourne group

has described for its own ultra-high risk

approach, i.e., that the short-term transition

rates are lower in recently collected

samples compared to the initially studied

ones. As a solution to the resulting

problem of increased false-positive predictions

of first-episode psychosis, the

EPOS group has proposed a two-step

procedure: first, the combination of the

more late prodrome-aligned ultra-high

risk criteria with the more early prodromal-

related basic symptom criteria will allow

a more sensitive and more specific

allocation to the initial prodromal risk

stage. Second, new prognostic indices

could be calculated, which, for each individual,

determine the probability and

the time expected to pass until transition

into first-episode psychosis. Thereby, the

clinical staging could be combined with

an individual risk estimation.

The clinical staging model differs from

the endophenotype approach (10,11).

The clinical staging model assumes that

at-risk subjects develop their first mild

symptoms already in adolescent years.

Depending on a variety of neurobiological,

social and personal risk as well as

protective factors, these can increase

and transgress thresholds of more severe

stages. Therefore, it is essential to

prevent this progress as early as possible.

This, in turn, requires detailed knowledge

of the patient’s stage of the disease

and the risk and protective factors relevant

to this stage. The endophenotype

approach focuses on heritability, familial

association, co-segregation and even

state-independence. Candidate markers

are regarded as constant traits, which are

present at all clinical stages and, most

importantly, even at the non-clinical atrisk

state.

Within the GRNS, the two approaches

have been combined. Substantial interest

has been paid to possible changes of

the neurobiological correlates during a

person’s transition across different stages

from 0 to IV. The differentiation between

early initial and late initial prodromal

states, with its diagnostic and therapeutic

implications, has been included in the

new German Clinical Practice Guidelines.

However, despite all progress, both

the clinical staging and the endophenotype

approach still require consolidation

by further research, before they can be

sensibly implemented in international

diagnostic systems.

References

1. McGorry PD, Purcell R, Hickie IB et al.

Clinical staging: a heuristic model for psychiatry

and youth mental health. Med J

Australia 2007;187(Suppl. 7):40-2.

2. Häfner H, Maurer K, Ruhrmann S et al.

Early detection and secondary prevention

of psychosis: facts and visions. Eur Arch

Psychiatry Clin Neurosci 2004;254:117-28.

3. Bechdolf A, Ruhrmann S, Wagner M et al.

Interventions in the initial prodromal states

of psychosis in Germany: concept and recruitment.

Br J Psychiatry 2005;187(Suppl.

48):s45-8.

4. Häfner H, Maurer K, Löffler W et al. Modeling

the early course of schizophrenia.

Schizophr Bull 2003;29:325-40.

5. Häfner H, Maurer K. Early detection of schizophrenia:

current evidence and future perspectives.

World Psychiatry 2006;5:130-8.

6. Klosterkötter J, Hellmich M, Steinmeyer

EM et al. Diagnosing schizophrenia in the

initial prodromal phase. Arch Gen Psychiatry

2001;58:158-64.

7. Schultze-Lutter F, Ruhrmann S, Berning J

et al. Basic symptoms and ultra-high risk

criteria: symptom development in the initial

prodromal state. Schizophr Bull (in press).

8. Ruhrmann S, Schultze-Lutter F, Klosterkötter

J. Early detection and intervention in

the initial prodromal phase of schizophrenia.

Pharmacopsychiatry 2003;36(Suppl. 3):

162-7.

9. Klosterkötter J, Ruhrmann S, Schultze-

Lutter F et al. The European Prediction of

Psychosis Study (EPOS): integrating early

recognition and intervention in Europe.

World Psychiatry 2005;4:161-7.

10. Chan RCK, Gottesman II. Neurological soft

signs as candidate endophenotypes for schizophrenia:

a shooting star or a Northern star?

Neurosci Biobehav Rev 2008;32:957-71.

11. Braff DL, Greenwood TA, Swerdlow NR et

al. Advances in endophenotyping schizophrenia.

World Psychiatry 2008;7:11-8.

Staging intervention and meeting

needs in early psychosis

Department of Psychiatry, University of Turku; Psychiatric

Clinic, Turku University Central Hospital,

Kiinamyllynkatu 4-8, 20520 Turku, Finland

Kraepelin’s idea to use outcome as a

diagnostic criterion for dementia praecox,

so that the outcome of this condition was

by definition gloomy, was criticized from

the very beginning. Bleuler (1) defended

the view that a schizophrenia diagnosis

should be set at the beginning of the illness,

so that a patient with schizophrenia

had the possibility to recover without retrospective

re-diagnosing. The Bleulerian

approach, fertilized by Freudian psychodynamic

ingredients, led to the broadening

of the schizophrenia concept, resulting,

however, in unreliable schizophrenia

diagnoses. In reaction to this untenable

161

situation, the neo-Kraepelinian diagnostic

classification (DSM-III) was produced,

and outcome once again became a diagnostic

criterion. This diagnostic reform

meant a setback for early intervention,

because a clinician had to wait for a long

time before the correct diagnosis could be

confirmed and evidence-based intervention

could be introduced.

To overcome the disadvantage caused

by the current clinical diagnostic practice,

McGorry et al suggest to concentrate

not on schizophrenia, but on all

(functional) psychotic disorders, considering

their development as stages from

risk state, via first episode, to recovery

or critical period. From the point of view

of early intervention, this psychosis staging

is justified. Only a small proportion

of ultra-high risk patients who develop

psychosis will progress to a schizophrenia

diagnosis. Early and comprehensive

intervention could reach patients at their

pre-psychotic stage and possibly prevent

or delay their sliding into psychosis.

These patients may suffer from rather severe

(subclinical or subsyndromal) symptoms

and functional decline: they do not

fulfil the criteria for clinical diagnoses,

but can progress to various types of psychoses,

thus requiring a broader range of

clinical skills than treatment for patients

with confirmed schizophrenia. Actually,

the care of ultra-high risk patients follows

the principles of the dimensional

approach, and focuses on treating various

symptoms and functional deficits,

without waiting for a structural diagnosis;

preventive thinking characterizes the

whole disorder detection and intervention

process.

The ultra-high risk or late initial prodromal

state is now well defined, and

there are reliable instruments for detecting

ultra-high risk subjects, although the

distinction between an ultra-high risk

condition (brief intermittent psychotic

symptoms) and brief psychoses is not

clear-cut. The early initial prodromal

state, defined by basic symptoms, may

precede the late initial prodromal one,

and offer an earlier stage for psychosocial

intervention (2,3). Although there

is no consensus as yet on how to treat

patients with early prodromal states,

a few intervention studies suggest that

both psychosocial and pharmacological

intervention are promising.

It is rather surprising how vigorously

the authors defend atypical over

conventional antipsychotic drugs. It is

true that, in the EUFEST study (4), the

discontinuation rate among patients receiving

low dose haloperidol was higher

than among patients with atypical drugs.

However, this study was open and, as the

authors state, “expectations of psychiatrists

could have led to haloperidol being

discontinued more often”. Both conventional

and atypical antipsychotic drugs

are heterogeneous groups, and we have

no good comparative studies between

different antipsychotics in the treatment

of patients at risk of psychosis or with

first-episode schizophrenia. A couple

of studies using perphenazine (CATIE)

(5) or several conventionals (CUtLASS)

(6) as comparative drugs suggest that

the differences in effectiveness between

conventional and atypical drugs may

be small. The poor reputation of conventional

neuroleptics is mainly due to

the high daily doses patients were prescribed.

The clinical staging approach,

when speaking about psychoses instead

of schizophrenia, aims to reduce the

stigma related to the concept of schizophrenia.

This same strategy may also suit

the names of antipsychotic drugs. As the

authors state, it is paradoxical that antipsychotic

drugs are widely used in the

treatment of patients in the prodromal

phase, while they are not allowed in

clinical trials. By changing the names of

drugs from antipsychotic back to neuroleptic

drugs, a large amount of the fears

related to the psychosis concept and use

of drugs could be overcome.

Intervention studies have shown that,

even in optimal conditions, only a part

of psychoses, including schizophrenia,

can be prevented. However, at the community

level, the duration of untreated

psychosis can be shortened (7). This is

one of the most important achievements

of the early detection and intervention

approach. Still, the need for comprehensive

care is considerable. On the basis

of his studies and long experience, Alanen

(8) launched the concept of needadapted

treatment, which includes five

main elements: a) flexible and individually

planned and carried out therapeutic

activities; b) examination and treatment

dominated by a psychotherapeutic attitude;

c) different therapeutic approaches

should supplement, not replace each other;

d) treatment should attain and maintain

a continuous interactional process,

and e) follow-up of the individual patient

and the efficacy of the treatment. Moreover,

need-adapted treatment emphasizes

that the needs of an individual patient

may change. The treatment system

should be sensitive to these changes and

try to meet the actual needs comprehensively.

This also means that the need for

care can extend over the so-called critical

period.

The question of special early detection

and intervention clinics is important.

Most patients with prodromal

states attend primary care and/or community

mental health centres, depending

on the local treatment system. This

means that all teams meeting patients

with mental problems should be aware

of the possibility of psychosis and should

try to screen and examine patients also

from this point of view. Specialized clinics

may meet only a (small) proportion

of patients at risk of psychosis, but they

have on important role to play in educating

community and other teams.

References

1. Bleuler E. Dementia Praecox oder die

Gruppe der Schizophrenien. New York:

International University Press, 1911/1950.

2. Schultze-Lutter F, Ruhrmann S, Berning J

et al. Basic symptoms and ultra-high risk

criteria: symptom development in the initial

prodromal state. Schizophr Bull (in press).

3. Bechdolf A, Wagner M, Veith V et al. A

randomized controlled trail of cognitive-behavioral

therapy in the early initial prodromal

state of psychosis. Schizophr Res 2006;

81(Suppl.):22-3.

4. Kahn RS, Fleischhacker WW, Boter H et al.

Effectiveness of antipsychotic drugs in firstepisode

schizophrenia and schizophreniform

disorder: an open randomised clinical

trial. Lancet 2008;371:1085-97.

5. Lieberman JA, Stroup TS, McEvoy JP et al.

Effectiveness of antipsychotic drugs in patients

with chronic schizophrenia. N Engl J

Med 2005;353:1209-23.

6. Jones PB, Barnes TR, Davies L et al. Randomized

controlled trial of the effect on

quality of life of second- vs first-generation

antipsychotic drugs in schizophrenia: Cost

Utility of the Latest Antipsychotic Drugs in

Schizophrenia Study (CUtLASS 1). Arch

Gen Psychiatry 2006;63:1079-87.

7. Friis S, Vaglum P, Haahr U et al. Effect of

an early detection programme on duration

of untreated psychosis: part of the Scandinavian

TIPS study. Br J Psychiatry 2005;187

(Suppl. 48):s29-s32.

8. Alanen YO. Schizophrenia. Its origins and

need-adapted treatment. Exeter: Karnac

Books, 1997.

1Institute of Psychiatry, King’s College London, Camberwell,

London, SE5 8AF, UK

2PET Psychiatry Unit, MRC Clinical Sciences Centre,

Hammersmith Hospital, London, UK

McGorry et al in Melbourne, and a

select number of other groups around

the world, have been instrumental in

a paradigm change in the approach to

schizophrenia over the last fifteen years

or so. They have infused an illness that

was seen as inexorably deteriorating

with new hope, new data and new therapeutic

optimism. The academia and the

clinicians have responded to their idea.

A quick search of PubMed shows that

from 1993, when the first articles entitled

“early intervention in schizophrenia” appeared,

there have been at least 480 publications

in the field. There were 22 in

the field in the years before 1992. Mental

health services around the world have

reconfigured and invested in establishing

early intervention teams for psychosis,

and there has been an explosion in research

in this area. Of course, there have

been other developments over the same

period that have contributed to clinical

and research optimism – developments

in neurobiological research, and the introduction

of new therapeutic agents for

example – but few others have linked the

clinical and research domains so directly.

McGorry et al, in their article in this issue,

show they are still leading the evolution

of thinking in research and clinical

practice in this field.

It is worth reflecting on how what was

recently inconceivable – the prevention

of schizophrenia – has become conceivable,

though not achievable. Currently

the best we can aim for is secondary

prevention – intervention in individuals

who are already symptomatic and

functionally impaired to reduce the likelihood

of their condition worsening. In

this article McGorry et al draw on general

medicine to introduce the concept

of clinical staging to psychosis, with the

proposal for three stages: ultra-high risk

(putatively prodromal), first episode and

recovery. However, a critical constraint

on the applicability of a clinicopathological

staging model to psychosis is our

limited understanding of the underlying

pathophysiology. Currently we rely on

purely clinical factors to predict outcomes,

for example which ultra-high risk

patient will develop psychosis, or which

first episode patient will respond to treatment.

However, this approach still lacks

satisfactory sensitivity and specificity

and, in most cases, independent validation.

More crucially, it does not suggest

targeted, stage specific interventions.

Since our criteria for separating ultrahigh

risk from first episode are symptomatic,

our treatments for the two must be

distinct if we are to call one “secondary

prevention” and the other “early treatment”.

Since McGorry et al borrow from

the rest of medicine, let’s take an example

from the rest of medicine to illustrate this

point. Understanding the pathophysiology

that leads to a heart attack has enabled

clinicians to identify biomarkers for

risk that can be combined to target intervention

most appropriately. To prevent

coronary artery disease, doctors identify

patients with elevated cholesterol levels

and treat them with dietary intervention

or statins; or, if the patient has hypertension

in addition, they are offered

a beta-blocker. However, they are not

Understanding pathophysiology

is crucial in linking clinical staging

to targeted therapeutics

immediately offered a mini-angioplasty.

The point being that the treatments used

in secondary prevention are targeted at

processes different from that used to treat

the illness. We are not there as yet in psychosis.

The treatments that are provided

to patients in the first episode and have

been evaluated in those with prodromal

signs (antipsychotic drugs, cognitive-behavioural

therapy and case management)

are essentially the same interventions that

are given to patients with established psychosis.

Moreover, we do not know which

form of intervention will work for whom,

or what to give those who will respond

poorly to treatment. Understanding the

pathophysiology of risk factors, the prodromal

signs of the illness, the first episode

and determinants of recovery and

response to treatment is a crucial first step

towards the sort of clinical staging used in

general medicine.

Nevertheless, there is some scope

for optimism that the pathophysiology

of these stages can be determined. The

application of standardized criteria for

characterizing people who are likely to

be in the prodromal phase of psychotic

illness (1,2) has provided a means of

prospectively studying the development

of psychosis, while the development of

early intervention services has increased

contact with patients in the early phases

of psychosis. This has permitted the investigation

of an area of clinical equipoise

– whether to initiate treatment in people

with prodromal signs – and informed the

development of methods for secondary

prevention. At the same time, it has enabled

significant advances in the understanding

the neurobiology of psychosis.

Structural and functional neuroimaging

studies have shown that many of the

abnormalities seen in chronic psychotic

disorders are not only evident at the first

episode of psychosis, but also in individuals

with prodromal signs (reviewed in

3, 4). These include reduced frontal, cingulate

and temporal grey matter volume

(5-9), altered activation in these regions

163

during tasks that engage executive functions

and working memory (10-11), and

changes in the white matter tracts that

interconnect them (12). Molecular imaging

and magnetic resonance spectroscopy

studies in people with prodromal

signs have also revealed elevated presynaptic

dopamine function, and alterations

in glutamate levels and serotonin

receptors (13-16). Moreover, longitudinal

neuroimaging studies indicate that

some of the structural anomalies evident

in the prodromal phase progress as individuals

make the transition to psychosis

(5). Progressive reductions in grey matter

volume appear to continue after the

first episode and may be related to long

term clinical outcome (17-19).

Whilst these studies are promising

steps in identifying the neurobiology that

might underpin a clinical staging model,

a number of requirements need to be met

before research findings can find clinical

utility. Firstly, predictive findings need to

be replicated in independent samples.

This is beginning to happen for structural

anomalies, but has yet to have been

done for functional changes. Secondly,

specificity not just to psychosis, but also

to functional outcome and stage needs

to be established. Biomarkers that meet

these requirements can provide clear targets

for the development of novel, stage

specific therapies (20).

Progress in our field has come from

many directions. Till now the major developments

have been the result of astute

clinical advances or new medications

from the pharmaceutical industry. And

while we should be truly grateful that this

has happened, neither of them are explicitly

linked to the underlying pathophysiology

of the illness. As a result, the illness

of schizophrenia has been a subject of

constant reconceptualization and redefinition.

Therefore, if the clinical staging

model could be anchored to an evolving

pathophysiology, it would offer the opportunity

of a new conceptualization that

might outlast its earlier counterparts.

References

1. Miller TJ, McGlashan TH, Rosen JL et al.

Prospective diagnosis of the initial prodrome

for schizophrenia based on the

Structured Interview for Prodromal Syndromes:

preliminary evidence of interrater

reliability and predictive validity. Am J Psychiatry

2002;159:863-5.

2. Yung AR, Yuen HP, McGorry PD et al. Mapping

the onset of psychosis: the Comprehensive

Assessment of At-Risk Mental States.

Aust N Zeal J Psychiatry 2005;39:964-71.

3. Fusar-Poli P, Perez J, Broome B et al. Neurofunctional

correlates of vulnerability to psychosis:

a systematic review and meta-analysis.

Neurosci Biobehav Rev 2007;31:465-84.

4. Howes OD, Montgomery AJ, Asselin MC

et al. Molecular imaging studies of the striatal

dopaminergic system in psychosis and

predictions for the prodromal phase of psychosis.

Br J Psychiatry 2007;191(Suppl. 51):

s13-8.

5. Pantelis C, Velakoulis D, McGorry PD et al.

Neuroanatomical abnormalities before and

after onset of psychosis: a cross-sectional and

longitudinal MRI comparison. Lancet 2003;

361:281-8.

6. Borgwardt SJ, Riecher-Rossler A, Dazzan P

et al. Regional gray matter volume abnormalities

in the at risk mental state. Biol Psychiatry

2007;61:1148-56.

7. Borgwardt SJ, McGuire PK, Aston J et al.

Structural brain abnormalities in individuals

with an at-risk mental state who later

develop psychosis. Br J Psychiatry 2007;

191(Suppl. 51):s69-s75.

8. Lappin J, Dazzan P, Morgan K et al. Duration

of prodromal phase and severity of

volumetric abnormalities in first episode

psychosis. Br J Psychiatry 2007;191:123-7.

9. Meisenzahl E, Koutsouleris N, Gaser C et

al. Structural brain alterations in subjects at

high-risk of psychosis: a voxel-based morphometric

study. Schizophr Res (in press).

10. Broome M, Matthiasson P, Fusar-Poli P et

al. Neural correlates of executive function

and working memory in the ‘at-risk mental

state’. Br J Psychiatry (in press).

11. Morey RA, Inan S, Mitchell TV et al. Imaging

frontostriatal function in ultra-high-risk, early,

and chronic schizophrenia during executive

processing. Arch Gen Psychiatry 2005;

62:254-62.

12. Walterfang M, McGuire P, Yung A et al. White

matter volume changes in people who develop

psychosis. Br J Psychiatry 2008;192:1-6.

13. Howes OD, Montgomery A, Asselin MC

et al. Elevated striatal dopamine function

linked to prodromal signs of schizophrenia.

Arch Gen Psychiatry (in press).

14. Hurlemann R, Matusch A, Kuhn KU et al.

5-HT2A receptor density is decreased in the

at-risk mental state. Psychopharmacology

2008;195:579-90.

15. Wood SJ, Berger G, Velakoulis D et al. Proton

magnetic resonance spectroscopy in first

episode psychosis and ultra high-risk individuals.

Schizophr Bull 2003;29:831-43.

16. Stone JM, McLean MA, Lythgoe DJ et al.

Brain glutamate and grey matter volume in

the early phase of psychosis. Schizophr Res

2008;98:115-6.

17. Nakamura M, Salisbury DF, Hirayasu Y et

al. Neocortical gray matter volume in firstepisode

schizophrenia and first-episode affective

psychosis: a cross-sectional and longitudinal

MRI study. Biol Psychiatry 2007;

62:773-83.

18. van Haren NE, Hulshoff Pol HE, Schnack

HG et al. Focal gray matter changes in

schizophrenia across the course of the illness:

a 5-year follow-up study. Neuropsychopharmacology

2007;32:2057-66.

19. Wood SJ, Velakoulis D, Smith DJ et al. A

longitudinal study of hippocampal volume

in first episode psychosis and chronic schizophrenia.

Schizophr Res 2001;52:37-46.

20. McGuire P, Howes O, Stone J et al. Functional

neuroimaging as a tool for drug development

in schizophrenia. Trends Pharmacol

Sci 2008;29:91-8.

Real-world implementation of early

intervention in psychosis: resources,

funding models and evidence-based

practice

Department of Psychiatry, University of Hong Kong,

Pokfulam Road, Hong Kong

It has been repeatedly pointed out that

clinical practices are often based not on

evidence but on accidents in the past. For

the first time in the history of psychiatry,

evidence is now building up to make a

rational case for early intervention for

psychosis. The successful implementation

of this early intervention, however,

is still inevitably determined by many

contextual factors unrelated to our level

of knowledge. Apart from perceptions

and group dynamics, as highlighted in

University of Nairobi and Africa Mental Health

Foundation (AMHF), Nairobi, Kenya

McGorry et al have persuasively and

passionately advanced the case for early

intervention in psychosis. The urgency

to intervene early in life is underpinned

by the fact that psychosis, like most other

mental disorders, tends to have an onset

in adolescence and early adulthood,

which happen to be highly sensitive developmental

periods in the life cycle.

Though heuristic, early intervention

in psychosis is handicapped by problems

of clinical staging and acceptability.

Clinical staging has a continuum,

ranging from the earliest possible beginning

of psychosis to first episode diagnosis

of psychosis and the critical first 5

years after the diagnosis. The beginning

pre-dates the “prodrome”, which term

assumes certainty that the psychotic

state will develop. We are talking of the

to transit to abnormal.

The concept of ultra-high risk has

been coined in the attempt to pre-date

the “prodrome”. Efforts to increase the

predictive value of ultra-high risk criteria

have the potential to produce false

negatives and in the process deny people

Early intervention in psychosis:

concepts, evidence and perspectives

McGorry et al’s article, the availability of

resources and local funding models are

among the issues shaping early psychosis

service provision in the real world.

In places with low mental health resources,

systematic screening and preventive

intervention for ultra-high risk

individuals remain difficult. Certain areas

have adopted a strategy to focus service

on “stage 2”, or early detection and treatment

of first-episode psychosis. In the

Hong Kong experience, limited public

funding is carefully allocated to optimizing

treatment in the first 2 years of a diagnosable

psychotic illness (1). Although

this approach means that some stages of

psychosis might not be receiving enough

attention, emerging evidence on costeffectiveness

of early intervention programmes

will provide a more solid rationale

for further developments.

The attitudes of service providers

as “early adopters”, “late majority” or

“laggards” may largely be determined

by local health service funding models

or payment methods. Studies have revealed

that these models exert different

effects on service utilization (2) as well

as service provision (3). It is likely that,

in systems closer to the fee-for-service

model, there will be lower motivation

for providing health education and preventive

intervention, as it may be perceived

to result in reduced service usage

and income. On the other hand, inertia

against reform or development might

be expected to be strongest in systems

similar to fixed salaries: such system reduces

incentives for care providers to

outperform (4), and might create barriers

for early help-seeking (as this leads

to a perceived increase in workload).

In this aspect, a budget or populationbased

funding model may be the most

fertile ground for the development of

early intervention programmes, where

investment in preventive approaches

can be favoured compared with less efficient

tertiary care.

A clinical staging model of psychosis

may provide a powerful tool that transcends

monetary incentives by orienting

patients and providers’ awareness towards

interventional outcome in a welldefined

population. From the research

perspective, staging psychosis could be

an optimal way to identify specific factors

affecting outcome, while minimizing

noise due to sample heterogeneity. The

0-4 stage model proposed by McGorry

et al (5) can serve as a useful framework,

upon which future research can be

based, to progressively construct an augmented

model with more specific markers

and best management strategies. A

positive research-practice cycle towards

“best practice” in psychosis can thus be

started, whereby well organized services

provide the setting for optimal research,

and the new emergent data are then used

to inform evidence-based clinical practice

guidelines for specific stages in psychotic

disorders.

References

1. Chen E. Developing an early intervention

service in Hong Kong. In: Ehmann T, Mac-

Ewan GW, Honer WG (eds). Best care in

early psychosis intervention. London: Taylor

& Francis, 2004:125-30.

2. Crampton P, Sutton F, Foley J. Capitation

funding of primary care services: principles

and prospects. New Zeal Med J 2002;

115:271-4.

3. Gosden T, Forland F, Kristiansen IS et al.

Capitation, salary, fee-for-service and mixed

systems of payment: effects on the behaviour

of primary care physicians. Cochrane

Database Sys Rev 2000;3:CD002215.

4. Carrin G, Hanvoravongchai P. Provider

payments and patient charges as policy

tools for cost-containment: how successful

are they in high-income countries? Hum

Resour Health 2003;1:6.

5. McGorry PD, Hickie IB, Yung AR et al.

Clinical staging of psychiatric disorders: a

heuristic framework for choosing earlier,

safer and more effective interventions. Aust

N Zeal J Psychiatry 2006;40:616-22.

who would otherwise benefit from early

intervention the opportunity for treatment.

On the other hand, less predictive

ultra-high risk criteria would lead to false

positives and in the process end up putting

people on treatment when they do

not need it, more so given the side effects

and the negative impact at an early age.

Despite the evidence, there are still

skeptics who argue that there is not

enough evidence for the concept of early

psychosis and/or that early intervention

works. Nevertheless, such skeptics have

a role to play in keeping the inventors of

the evidence on their toes while both appealing

to a wider audience and eventually

influencing policy and practice. This

is indeed a healthy debate.

Nearly all research on early intervention

in psychosis comes from resourcerich

countries, and little from developing

165

countries and in particular from Africa. It

is true there is a gross shortage of human

and financial resources in this continent

(1-3). This cannot, however, be an excuse

for Africa to be left out of this endeavour.

This continent has a young population,

with more than 50% being less than 25

years of age, and a total population which

is about 12% of the global one. Thus, Africa

has a claim to this endeavour. The

major players in this kind of research and

their respective funders should collaborate

with researchers operating in Africa

in designing simple community-based

identification of ultra-high risk individuals

and initiating interventions. This does

not require highly skilled psychiatrists.

The social support is still intact in most

societies in Africa and affordable drugs

such as haloperidol, despite their limitations,

are widely available.

As happens with any new ideas, regardless

of the overwhelming supportive

evidence, the progression from evidence

to policy and practice will be on a continuum.

On this continuum will be on

the one hand the few researchers producing

the evidence and, on the other,

the skeptics or laggards demanding for

more evidence. In between will be a

continually increasing number of acceptors,

initially on the basis of the evidence,

then on the basis of an increasing

number of opinion leaders who practice

the intervention, and finally on the basis

of standard practice without even questioning

the evidence for or against.

The challenge to the inventors is

whether or not they have the tenacity to

generate both new and more evidence

and navigate their inventions through

this continuum while at the same time

constructively engaging the skeptics. The

way to achieve this is through research

designs that will provide focused evidence

of the earliest possible time intervention

can be initiated, minimizing both

false positives and false negatives. This

should be a collective effort that takes on

board globally representative participants

with diverse sociocultural and economic

backgrounds. This way, it will be much

easier for the results to be co-owned

and therefore easily accepted and implemented.

Scientific evidence alone is not

always enough.

References

1. Saxena S, Sharan P, Garrido Cumbrera M

et al. World Health Organization’s Mental

Health Atlas 2005: implications for policy development.

World Psychiatry 2006;5:179-84.

2. Patel V, Boardman J, Prince M et al. Returning

the debt: how rich countries can invest

in mental health capacity in developing

countries. World Psychiatry 2006;5:67-70.

3. Ndetei DM, Ongecha FA, Mutiso V et al. The

challenges of human resources in mental

health in Kenya. South Africa Psychiatry Rev

2007;10:33-6.

HIV risk behaviors among outpatients with severe

mental illness in Rio de Janeiro, Brazil

1New York State Psychiatric Institute and Columbia University, 1051 Riverside Drive, New York, NY 10032, USA

2Federal University of Rio de Janeiro, Brazil

3Department of Social Work, Helen Bader School of Social Welfare, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA

* The Investigators of PRISSMA are listed in the Appendix

Relatively little is known about HIV risk taking among

individuals with severe mental illness (SMI) outside the

United States. Two recent reviews of more than 50 published

studies of HIV risk behaviors among people with SMI (1,2)

found only ten from non-US countries, and nearly all were

conducted in developed countries. US studies reported

higher rates of sexual risk behavior compared to international

studies, particularly with respect to sex trade and injection

drug use (IDU) (2). Across all of these studies, substantial

rates of recent sexual activity and sexual risk behavior

were reported: sexual activity in the past 3 to 12 months

by 32% to 74% of patients; multiple sexual partners in the

past 3 to 12 months by 13% to 69%; regular condom use in

the past 3 to 12 months by 8% to 49%; sex trade in the past

year by 2% to 42%; IDU ever by 12% to 45%; and needle

sharing ever by 15% to 73% of injection drug users.

These risks were present despite relatively high levels of

HIV/AIDS knowledge. Although measures used in prior

studies of psychiatric populations varied, the average HIV

knowledge score (i.e., percent correct responses) ranged

from 63% to 80% (3-6). While not sufficient alone to change

behavior, knowledge is a necessary component to effect risk

behavior reduction (7).

In Brazil, sexual risk behavior studies about psychiatric

patients are limited. In one study conducted in Minas Gerais,

68.2% of the sexually active sample reported not using condoms,

20.1% reported a risky partner, and 2.6% reported

sex in exchange for alcohol, drugs or shelter (8). Another

study in Rio de Janeiro found considerable sexual risk-taking

in the previous year: 63% were sexually active; of those,

72% did not use condoms regularly and 49% never used

condoms (9). However, the reliability of the measures used

to obtain these data was not tested, and samples did not

include only people with SMI. To date, no IDU or HIV

knowledge rates have been reported among Brazilian adults

with SMI.

This paper is the first report of HIV-related behaviors by

people with SMI in Brazil obtained using a sexual risk behavior

assessment that has demonstrated reliability with

psychiatric patients (10-12). We report the degree of knowledge

about HIV/AIDS, prevalence of IDU and needle sharing,

rates of sexual activity, sexual risk-taking and protective

behaviors, as well as reasons for sexual abstinence and for

not using condoms in a sample of outpatients with SMI in

Rio de Janeiro.

METHODS

Setting and participants

Participants were adults with SMI attending the outpatient

psychiatric clinic and the day-hospital of the Psychiatric

Institute of the Federal University of Rio de Janeiro. In

this setting, patients whose primary treatment need is represented

by substance use disorder are referred to dual diagnosis

clinics elsewhere. As part of standard clinical care,

informal sexual health drop-in group education sessions are

offered every other week to all patients interested in participating.

All study procedures were approved by institutional review

boards of both the New York State Psychiatric Institute

and the Psychiatric Institute of the Federal University of Rio

de Janeiro, as well as the National Ethics Commission on

167

Research of the National Council of Health, Brazilian Ministry

of Health. Patients were either self-referred or referred

by clinic providers. Eligible, consenting patients participated

in a baseline interview before participating in a pilot riskreduction

intervention (13). This paper reports findings from

baseline interviews.

Patients were eligible if they were 18 years of age or older;

diagnosed with schizophrenia, schizoaffective disorder, bipolar

disorder, major depression with psychotic features, or

psychosis not otherwise specified; and capable of giving

written informed consent. Patients were not eligible if they

had acute psychosis or suicidality at the time of the screening

interview; developmental disability as a primary diagnosis;

or a substance-induced psychotic disorder. Inclusion

criteria did not require participants to be sexually active in

the last three months.

Both a licensed mental health professional who was a

member of the patient’s clinical treatment team and a research

team psychiatrist evaluated patients’ capacity to consent to

participation in the study. Patients who declined to participate

in the intervention pilot study or who met any of the

exclusion criteria were informed about the ongoing sexual

health drop-in groups that are part of standard clinical care.

Of the 221 patients (110 females/111 males) screened,

139 (63%) with interest and capacity to participate gave

written informed consent. Of these, 36 (26% of those who

consented) did not meet inclusion criteria. Reports of four

participants were excluded due to responses that were rated

by interviewers as unreliable. The remaining 98 patients

comprised the study sample. Participation in the study was

not compensated, but transportation vouchers and refreshments

were offered to participants.

Assessment procedures

All assessments were conducted in face-to-face interviews

between October 2004 and August 2005. Instruments that

had not been previously used in Brazil were translated and

tailored to enhance cultural specificity for Brazilian SMI

men and women after a year of formative ethnographic work

(13). Patients completed all measures in approximately two

and a half hours, on average.

Psychiatric diagnosis was obtained by research team psychiatrists

using the Mini International Neuropsychiatric Interview

– PLUS (MINI PLUS), a structured psychiatric assessment

developed and validated for DSM-IV and ICD-10

diagnosis with both US and Brazilian patients (14,15).

Information on sexual risk behaviors in the past three

months was obtained by research interviewers (clinical psychologists)

using the Sexual Risk Behavior Assessment

and contexts specific to the patient population in Brazil. The

Brazilian SERBAS (SERBAS-B) is a semi-structured interview

that elicits detailed information regarding sexual practices

and related alcohol and other drug use in the past three

months. Data collected include the number, gender, and

type (casual, steady, new) of sexual partners; the types of

sexual acts performed at each encounter; whether sexual

acts were protected by condoms; whether alcohol or other

drugs were used during sexual occasions; whether sex was

bought, sold or exchanged for something (e.g., drugs, shelter);

and a participant’s knowledge of his/her partner’s HIV

testing history and status. The interview underwent rigorous

reliability testing and showed reasonable to excellent test

re-test reliability (11), comparable to findings in US samples

(10,12). For exploratory purposes, data also were collected

on HIV protective behaviors in the past three months, to

determine whether participants had engaged in behaviors

deliberately as a means of reducing the risk of contracting or

transmitting HIV. Protective behaviors included reducing

the number of sex occasions, reducing the number of sex

partners, changing specific sexual practices, and using condoms

more frequently.

Participants were asked how often in the past three

months they injected drugs into their veins or under their

skin, with answers scored on a 5-point scale ranging from

never to daily. If any patient reported injecting behavior, information

was to be collected on the use of injection implements

(e.g., needles, syringes, wash water, cottons) after

someone else had used them, and on any cleaning of implements

prior to using them to inject themselves.

Knowledge about HIV transmission and prevention was

assessed using the Brief HIV Knowledge Questionnaire

(Brief HIV-KQ), an 18-item true/false scale (16), with higher

scores indicating greater HIV-related knowledge. This

instrument was translated from English into Portuguese,

and back-translation from Portuguese to English was performed

to check for errors and fidelity to the original English

version. This process resulted in the elimination of one item

due to confusing double-negative phrasing in Portuguese.

Scores in the current study therefore range from 0 to 17.

After clarification of what an HIV test is, participants

were asked if they had taken the HIV test in the past 3

months. A negative answer prompted inquiring about the

last time the participant had been tested for HIV. “Not sure/

don’t know” responses prompted clarification. Known positive

or negative test results were elicited, as were decisions

not to return for testing results.

Participants were asked whether, within the last year, they

had participated in any type of program specifically intended

to help them decrease sexual risks or increase safer sex. Although

the standard-care drop-in groups were focused on

sexuality and not, specifically, on HIV prevention or sexual

risk behavior, this question did not expressly include or exclude

the ongoing sexual health drop-in groups offered in the

treatment programs from which the sample was selected.

Data analysis

Differences in being sexually active (versus not sexually

active) by key demographic and clinical characteristics were

tested using Fisher’s exact test for categorical data and t-tests

for continuous data. Because engaging in sexual activity

within the prior three months was not an eligibility criterion

for study participation, some sexual risk and protective behaviors

were reported by proportions of the sample that

could not be reliably subjected to statistical tests of significance

due to small cell sizes. We therefore present descriptive

data on HIV risk and protective behaviors in the previous

three months, as well as reasons given for not being

sexually active and for not using condoms.

RESULTS

The total sample (n=98) comprised 49.0% men and

51.0% women. Self-described racial/ethnic categories were

45.9% white, 37.8% multiracial, and 16.3% black. The

mean age of participants was 41.8±11.1 years (range 21-70).

Most of the sample (72.5%) was single; 13.3% reported being

married/in a long-term relationship, and 14.3% were

separated, divorced or widowed. Half of the participants

(50.0%) had a diagnosis of schizophrenia, 27.6% of bipolar

disorder, 10.2% of major depressive disorder with psychotic

features, 4.1% of schizoaffective disorder, and 8.2% of psychosis

not otherwise specified. A current comorbid substance

use disorder was present in 11.2% of the sample. Of

those with a substance use disorder, six reported abuse/dependence

of marijuana (54.4%), two of alcohol (18.2%),

two of benzodiazepines (18.2%), and one of cocaine (9%).

About two-fifths of the sample (38.8%) had completed primary

school, 40.8% had completed secondary school, 9.2%

had completed college, while 11.2% had not completed or

attended primary school.

The mean score for HIV knowledge for the entire sample

was 10.4±3.3 out of 17 (range 1-16), corresponding to 61.2%

correct responses.

Of the 98 study participants, 53 (54.1%) reported having

been tested ever. Of those tested, one (1.9%) reported a

positive HIV status and one (1.9%) reported not receiving

the test result; the remaining 51 (96.2%) reported negative

HIV test results. Twenty-two (41.5%) of the tested patients

reported that their HIV test had been done in the past year.

Nineteen of 98 participants (19.4%) reported having participated

in a program specifically provided to increase sexual

safety or reduce unsafe sexual activity in the previous

year. No participant reported IDU in the past 3 months.

A total of 41.8% of the sample reported engaging in vaginal

or anal sex within the past three months. Table 1 presents

differences in sexual activity versus inactivity by demographic

variables. Significant differences included the following:

those who were sexually active were younger (t=2.43, df=96,

p<0.01), were more likely to be married or in a long-term

p<0.01), had a higher mean HIV knowledge score (t=-2.92,

Gender (% male) 45.6 53.7 0.62 0.54

Age (years, mean ± SD) 44.0±11.1 38.7±10.4 2.43 0.02

Race/ethnicity (%)

Black

White

Multi-racial

14.0

50.9

35.1

19.5

39.0

41.5

1.43 0.50

Marital status (%)

Single

Married/long-term relationship

Separated/divorced/widowed

77.2

5.3

17.5

65.9

24.4

9.8

8.01 0.02

Diagnosis (%)

Schizophrenia

Bipolar disorder

Major depressive disorder with psychotic features

Other (schizoaffective disorder and psychosis not otherwise specified)

54.4

21.1

12.3

12.3

43.9

36.6

7.3

12.2

3.19 0.38

Comorbid substance use disorder (%) 1.8 24.4 12.03 0.001

Education completed (%)

Grade school

High school and beyond

Did not attend/complete grade school

36.8

50.9

12.3

41.5

48.8

9.8

0.29 0.88

HIV-relevant history

HIV knowledge score (mean ± SD)

HIV/AIDS prevention programs experience (past year, %)

HIV test (lifetime, %)

9.6± 3.5

19.3

40.4

11.5±2.7

19.5

73.2

-2.92

0.01

10.34

0.001

1.00

0.001

SMI – severe mental illness

169

df=96, p<0.01), and were more likely to have received HIV

were reported by 10.4% of men and 2.0% of women.

One sexually active participant reported being HIV positive.

There were no differences in sexual activity by gender or

diagnosis.

Fifty-two of 57 participants who were sexually inactive in

the past three months provided one or more reasons why

they did not engage in sexual activity. Almost half of the men

(45.8%) and women (46.4%) reported not having a current

partner as the most common reason for sexual inactivity.

Lack of interest in sexual activity was cited by 16.7% of men

and 28.6% of women. Among men, other common reasons

given were mental illness/medication side effects (20.8%),

and concern about being (re)infected with HIV by partner

(16.7%). Among women, other common reasons given were

concern about being (re)infected by partners (10.7%), and

fear or anxiety related to sexual activity (10.7%).

Table 2 shows prevalence of HIV risk and HIV protective

behaviors among those who were sexually active (n=41)

within the past three months. Almost half (43.9%) of those

who engaged in vaginal or anal sex reported no condom use

in the prior three months and 34.2% reported inconsistent

condom use; only nine participants (22.0%) reported using

condoms on every sex occasion. Over half (53.7%) reported

having partners whose HIV status was unknown, and 26.8%

reported having more than one partner (partner range 2-12).

Almost two-fifths (39.0%) reported using alcohol or drugs

prior to sexual activity, and 19.5% (all men) reported sex

exchange, with the majority of this activity involving purchasing

sex. Of those who were sexually active, the range of

risk behaviors was 0-6, with 56.1% engaging in three or

more. Only 4.9% reported no risk behaviors.

Sexually active participants who did not use condoms

(n=32) were asked to provide reasons for not doing so. Half

(50.0%) of the 16 male participants cited trust in their

partner(s). Other common reasons among men were perception

of self as not at risk (18.8%), participant’s own preference

not to use condoms (18.8%), difficulty sustaining an

erection when wearing a condom (12.5%), and other sexual

dysfunction (12.5%). Among the 16 female participants,

60.5% reported not using a condom due to their partners’

preference. Other common reasons among women were:

condoms unavailable at the time of intercourse (31.3%),

trust in their partner(s) (25.0%), not being in the habit of

using condoms (18.8%), and participant’s own preference

not to use condoms (18.8%).

When asked to describe all methods they had used expressly

to avoid HIV/AIDS in the past three months, 22.0% of

sexually active patients said they used condoms for every

sexual occasion, 25.0% reported using more condoms, 20.0%

reported having fewer partners, and 12.5% reported having

fewer sex occasions as practices to avoid contracting HIV.

Overall, the range of protective behaviors reported was 0-3,

with 25.0% engaging in two or more protective behaviors;

42.5% reported not engaging in HIV-protective behaviors.

DISCUSSION

We have presented findings from the first study to examine

HIV risk behaviors among Brazilian SMI patients using

a risk-assessment instrument with proven reliability among

SMI populations. We found that almost 42% of SMI patients

were sexually active in the past three months, a rate

comparable to the weighted mean for sexual activity in the

past three months across all prior studies of SMI patients

(2). Almost all of those who were sexually active engaged in

HIV-related sexual risk behaviors, and over half of them engaged

in three or more such behaviors.

Though, from an HIV prevention perspective, sexual inactivity

for the prior three months among nearly 60% of

patients may seem reassuring, those patients who are abstinent

now may be active in the future. In this study, the most

common reason given by participants for sexual inactivity

was lack of a current partner, cited by two-fifths of men and

women; only one-fifth reported no interest in sex. The absence

of a regular partner may lead to future sexual activity

with poorly known or risky partners when opportunities

present themselves (17). As a form of public health inoculation,

efficacious prevention interventions should be offered

to all interested patients, regardless of their current sexual

activity. It is also possible that, from a quality of life perspective,

sexual inactivity among psychiatric patients living in

the community is a problem that needs to be addressed. Understanding

more about the context and reasons why individuals

with SMI are sexually inactive is an important goal

of future research.

Compared to sexually inactive subjects, those who reported

sexual activity were younger, were more likely to be in a

long-term relationship, to have a comorbid substance use

disorder and to have had an HIV antibody test, and had a

among SMI patients within the past three months (n=41)

Any risk behavior (%)

<100% condom use (%)

No condom use (%)

High risk partners - unknown HIV diagnosis (%)

High risk partners - HIV+ partner (%)

Multiple partners (%)

Any sex exchange/trade (%)

Any drug during sex (%)

Any IDU history (%)

95.1

34.2

43.9

57.5

26.8

19.5

39.0

0

Any protective behavior (%)

Always use condoms (%)

Reduced sex occasions (%)

Reduced number of sexual partners (%)

Changed specific sexual practices (%)

Used more condoms (%)

Other (%)

53.7

22.0

12.5

20.0

25.0

No protective behaviors (%) 42.5

SMI – severe mental illness; IDU – injection drug use

higher mean HIV knowledge score. As with SMI samples

elsewhere (2) and other populations (7), these findings suggest

that patients most at risk for HIV are aware of the problem/

disease. HIV testing in the prior year was reported by

42% of participants, comparable to the rate of voluntary testing

reported in the US (18), but the average HIV knowledge

score in our Brazil sample was lower than the range found in

prior studies of psychiatric populations (3-6), despite the fact

that one in five of our subjects had participated in some type

of HIV prevention program and all of them had access to

ongoing sexual health drop-in groups. Patients who had attended

prior HIV prevention programs did not have better

HIV knowledge than those who had not received these services.

Besides addressing sexual risk reduction skills, interventions

developed for Brazilian SMI people must increase

basic knowledge of HIV risk and transmission and attend to

misperceptions about risk held by participants.

Almost 28% of our sample reported being in a current or

prior marriage or long-term relationship. Although we did

not ascertain to what extent the expectation of monogamy

was part of these relationships, half of the sexually active

men and a quarter of the sexually active women cited trust

in their partners as the reason for not using condoms. As

Gordon et al (19) found among SMI in the US, it may be that

stable partnerships are perceived as “safe” and, as such, negotiation

about HIV or condoms may not be considered

necessary. Future research should examine closely these

stable relationships, and, if they are unsafe, HIV interventions

will need to address the difficult task of introducing

condoms in a long-term or significant relationship. This task

may be complicated by economic dependence (19,20) and

the belief that people with SMI are not in the position to

choose or negotiate with their partners (21).

Despite the low rate of substance use disorder among this

sample, almost 40% of those sexually active reported using

substances during sexual intercourse. Substance use during

sexual activity has been associated with lower condom use

rates among SMI patients elsewhere (22). Moreover, substance

use in other populations (e.g., men who have sex with

men, injection drug users) has been shown to increase sexual

risk-taking, in part, by attenuating or counteracting anxiety

around sexual activity (23,24). Individuals with SMI

may use substances to some extent as a way to minimize

stigma-related social or sexual anxiety. In addition to reducing

risk behaviors and increasing skills associated with condom

use such as assertiveness and negotiation (6,25-29),

interventions for SMI in Brazil must also target the use of

alcohol or drugs during sex.

It is important to highlight some key differences compared

with prior SMI studies that may help to guide prevention

intervention development, adaptation, and implementation

in Brazil and in other countries where psychiatric

patients are particularly vulnerable. While comparison with

other studies of psychiatric patients is difficult, due to different

instrumentation and assessment time periods, sexually

active patients in this Brazilian sample had a lower rate of

condom use compared to samples enrolled in previous studies

(2). We did not collect data on condom acceptability or

availability for this population, but patients did cite relationship

(e.g., trust in partner) and sexual performance (e.g., difficulty

sustaining an erection) aspects of condom use that

deserve attention in future studies. Still, the most common

(60%) reason among sexually active women for not using a

condom was their partners’ preference, a reason that was

cited by none of the men. This finding is consistent with

patterns seen among women in a variety of populations in

the AIDS epidemic, and is an impetus for more widespread

development and uptake of female controlled methods,

such as the female condom and microbicides. In fact, Brazil’s

epidemic has been characterized as “feminizing, heterosexualizing,

and pauperizing” (30). Distribution at a reasonable

cost of female condoms and development of safe and

effective microbicides should be viewed as priorities in the

control of HIV in Brazil, including among those with SMI.

In this Brazilian SMI sample, about one-third of the sexually

active men reported purchasing sex, a proportion much

higher than previously reported in non-homeless or nonindigent

persons with SMI (2), and none of the sexually active

women reported engaging in sex exchange, in contrast

with prior studies that found that women with SMI may

engage in “survival sex” (2,20), exchanging sex for money,

food, shelter, or drugs. Adults in treatment for SMI in Brazil

tend to live with their families, which may protect them from

having to give sex for food or shelter. Further, substance use

during sex was common, but substance abuse/dependence,

which may fuel sex trading, was not. Research that examines

the context in which those with SMI purchase sex or exchange

sex is important to undertake, as is examining those

behaviors’ relationship to condom use, in order to identify

the salient social and economic factors (e.g., poverty, relational

power imbalances) driving risk behaviors in this population

and to design appropriate interventions to address

those factors.

Unlike in previous studies, we examined whether sexually

active SMI patients were deliberately taking measures to

reduce HIV transmission regardless of participation in any

type of prevention program: 58% of sexually active patients

had taken at least one protective measure, most commonly

using more condoms and having fewer partners. Nevertheless,

only 5% of these patients reported no HIV-related risk

behaviors, and 56% reported three or more risk behaviors.

Understanding what motivates HIV-protective behaviors

and changes and how those motivations can be incorporated

into efficacious prevention interventions will be an

important next step for researchers to take.

The absence of IDU is a major difference when compared

to the weighted lifetime rate across all prior SMI studies of

nearly 22% and the weighted past-year rates of 4% (2). This

may simply reflect the geographic distribution of IDU, which

is clearly more prevalent in some countries than in others

and in some regions of Brazil, though less so in Rio de Janeiro,

than elsewhere (31). Further, our sample was drawn

171

from clinical settings where the primary disorder being treated

was not substance use disorder. IDU is more prevalent

and frequent among those with primary substance use disorder

than among SMI patients whose substance use is not a

determinant of the presenting psychiatric problem (32).

Moreover, substances preferred by those with comorbid substance

use disorder in this sample (marijuana, alcohol, benzodiazepine,

and cocaine) do not require being injected to

achieve potency. Prevention interventions with demonstrated

efficacy among psychiatric patients have focused on sexual

behavior, including that which occurs while drinking or

using drugs, rather than on IDU (6,25-29). Such focus seems

appropriate for intervention with samples like ours, although

harm reduction strategies for IDU may be an important component

of interventions for SMI patients with even intermittent

injection behaviors and should not be presumed to be

irrelevant even if IDU is not a current behavior.

In our study, except for psychiatric diagnoses, all data

were based on self-report and are therefore subject to response

bias (33). With the exception of protective behaviors,

we used dependent measures with documented test-retest

reliability (11), thereby minimizing such bias. We examined

vaginal and anal sex occasions, possibly missing opportunities

to understand whether participants may have engaged

in oral sex as a “safer” alternative. Also, the use of a convenience

sample raises the possibility of selection bias: for example,

our sample was older (mean age 42 years) relative to

those in prior SMI risk behavior studies (2), possibly leading

us to underestimate sexual activity and risk behavior. The

results of the current study may not generalize to adults with

SMI who are in treatment but are not inclined to participate

in research, those who do not receive psychiatric treatment,

or those whose personal, clinical, socioeconomic, or cultural

situations differ from those of our sample. Moreover,

the low rate of substance use disorders in this sample limits

the generalizability to SMI with comorbid substance disorders.

Finally, cross-sectional data were obtained; longitudinal

studies with larger samples are needed to elucidate the

direction and temporal nature of the relationships between

HIV risk behaviors and patients’ characteristics.

In Brazil, where sexuality is considered a human right,

helping patients develop relationship skills and overcome

mental illness-related obstacles to developing intimate connections

is seen as a desirable goal by many mental health

care providers and their patients. However, the unstructured,

informal drop-in sexual health group is not the standard

of care throughout Brazil, and policy there, as elsewhere,

has been slow to address sexuality in the SMI population

with anything but proscription (21).

HIV prevention interventions for the SMI population

must be carefully tailored to their specific needs. An HIV

prevention intervention is now being tested in a randomized

controlled trial taking place in municipal mental health centers

throughout Rio de Janeiro. Thus, Brazil is poised to continue

its legacy as a world leader in fighting AIDS (30,34) by

reaching the vulnerable population of people with SMI. Brazil’s

programmatic and policy decisions can aid in the development

of integrated programs in other low- and middleincome

countries, and inform similar programs and policies

in developed countries as well.

We found similarities (i.e., similar rates of sexual activity

and risk) and differences (i.e., no IDU and sex exchange

primarily consisting of purchasing sex) in our Rio de Janeiro

sample compared to other regions of the world. By looking

at the differences between countries, we may learn more

about the impact of environmental factors on risky and protective

behaviors among adults with SMI, and target interventions

to address them effectively.

APPENDIX

The team members of PRISSMA 2002-2006 (Projeto Interdisciplinar

em Sexualidade, Saúde Mental e AIDS – Interdisciplinary

Project in Sexuality, Mental Health and

AIDS) are Denise Feijó, Tatiana Dutra, Carlos Linhares, Alfredo

Gonzalez, André Nunes, Fernanda Gomes, Abmael

de Sousa Alves, Alexander Ramalho, Débora Salles, Denise

Corrêa, Erínia Belchior, Márcia Silviano, Maria Tavares,

and Vandré Matias Vidal.

Acknowledgements

This research was supported by grants R01-MH65163

and P30-MH43520 from the National Institute of Mental

Health and National Research Service Award grant T32-

MH19139. The authors gratefully acknowledge the enormous

contributions made to PRISSMA by people receiving

care at the Institute of Psychiatry of the Federal University

of Rio de Janeiro and by mental health care providers and

other staff at that institution.

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173

A sex difference in the age of onset of schizophrenia has

been reported since the time dementia praecox was described

by Kraepelin (1). A later age of onset in females has

been reported in several recent studies (2,3). Studies have

also observed that females with schizophrenia have an older

age at first admission (4,5). Overall, these studies suggested

a difference of 3-5 years between the sexes for age of onset

of the disorder. The ICD-10 (6) and the DSM-IV-TR (7) also

note that females have a later age of onset of schizophrenia.

This difference is proposed to be due to both males having

an earlier and pronounced peak incidence in their early 20s

and females having a second, later peak incidence in their

late 40s (2).

However, some studies from Asia and Africa do not seem

to support this finding. The International Pilot Study of

Schizophrenia (IPSS, 8), the Madras Longitudinal study (9),

and three studies from the National Institute of Mental

Health and Neuro Sciences (NIMHANS), Bangalore (10-

12) found no difference in age of onset of the disorder between

the sexes. More recently, a study from Pakistan (13)

also did not find a sex difference in the age of onset of schizophrenia.

Actually, in one of the above studies (11), there was

a female preponderance among patients with the earliest

onset. A relatively greater loss of male infants due to poor

perinatal care, which eliminated a proportion of earliest onset

male schizophrenics, was hypothesized as a possible explanation.

Indeed, a comparison of patients from regions

with high and low infant mortality rate showed that there

was a reversed gender effect on age of onset of schizophrenia

in the former but not in the latter region (12).

One limitation common to the above reports was that all

of them included patients who sought help. In a country like

Sex difference in age of onset of schizophrenia:

findings from a community-based study in India

1Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore 560029, India

2Department of Biostatistics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, India

3Manasa Nursing Home, Thirthahalli, India

India, with a huge population/psychiatrist ratio (14), a large

proportion of patients with schizophrenia live without treatment

in the community. Treatment-seeking patients may not

be representative of all schizophrenia patients. This study

was conducted to explore whether the finding of a lack of

sex difference in age of onset of the disorder could be replicated

in a community sample consisting of both treated and

untreated schizophrenia patients.

Methods

Subjects

The sample for this study included patients with schizophrenia

recruited for the Community Intervention in Psychotic

Disorders (CoInPsyD) project in Thirthahalli (an

administrative block in South India with a population of

143,000). The project aims to identify all patients with

schizophrenia living in this rural community and treat them.

Fifty-four rural health workers were trained in identifying

patients with severe mental disorders in the community by

a team of senior consultants from the NIMHANS. This included

didactic lectures on symptoms and course of schizophrenia,

video clippings of patients with schizophrenia, and

question-answer sessions. These were done on three different

occasions separated by about a month each. At the end

of the training, the health workers were shown video interviews

of different psychiatric patients and were asked to

identify those with schizophrenia: they were able to identify

them accurately.

Two trained social workers interviewed the Thirthahalli

health workers about the presence of persons with symptoms

suggesting psychosis in each family (a total of 29,432

families for the entire community). All patients thus identified

were clinically interviewed by a research psychiatrist,

and diagnoses were assigned using the ICD-10-Diagnostic

Criteria for Research (ICD-10-DCR, 6). The diagnosis of

schizophrenia was confirmed by another psychiatrist after

an independent clinical interview.

A total of 209 persons were diagnosed as having schizophrenia.

Of these, five could not give reliable information

about age of onset of the disorder. The diagnosis of two patients

changed (one to bipolar disorder and the other to organic

psychosis) during follow-up. The final sample thus

consisted of 202 subjects. Of these, 103 were males and 99

were females. One hundred and fourteen (56.4%) were receiving

treatment at the time of evaluation; the rest were

living without any treatment.

The health workers reported about the presence, in the

community, of 20 other persons with features suggesting

schizophrenia. These could not be interviewed because of

several reasons, including refusal to give consent or being

severely ill with no caretakers to give any information.

Assessments

Information concerning the age of onset of the disorder

was collected by the Interview for Retrospective Assessment

of Onset of Schizophrenia (IRAOS, 15), used by a research

psychiatrist. Subjects, family members who were in continuous

contact with them and the health workers were interviewed

and the age of onset of the first psychotic episode was

determined. Two social workers collected the sociodemographic

details of the subjects, including lifetime use of alcohol

and illicit substances. This included a question on the age

of onset of schizophrenia. The age of onset assessed using the

IRAOS by the psychiatrist had a high degree of interrater reliability

with the age of onset as recorded by the social worker

(intraclass correlation coefficient: 0.86).

The study obtained ethical clearance from the Institute’s

Ethics Committee and all subjects were recruited after obtaining

written informant consent.

Statistical analysis

Independent-sample t-test and Kaplan-Meier survival

analysis were used to analyze the difference between males

and females in age of onset of schizophrenia. The Statistical

Package for Social Sciences version 10.0.1 was used for the

analysis.

Results

Table 1 shows the sociodemographic and clinical features

of males and females. The mean age of onset of schizophrenia

was 29.2±8.8 years for males and 30.8±11.4 years for

females (t=1.12; p=0.27). A cut-off age of onset at 33 years

was taken to classify patients as having earlier or later age of

onset of the disorder. Figure 1 shows the survival analysis

using Kaplan-Meier survival curve for both groups: in the

earlier age-of-onset group, females had a significantly lower

age of onset of the disorder; in the later age-of-onset group,

they had a significantly higher age of onset.

Figure 2 shows the number of males and females who had

their onset at different ages. Females had two peaks: the first,

higher peak in the 20-25 years range and another in the 35-

40 years range. Males had a steady rise through the early

ages to a peak at 30-35 years; this was followed by a steep

decline through the older age-range.

The results were not different among those with illness

duration less than 10 years: 32.1±8.8 years for males (n=41)

and 33.1±12.5 years for females (n=51) (t=0.45; p=0.66).

Discussion

This study shows that in India there is no significant difference

between the sexes in the age of onset of schizophre-

Current age (years, mean±SD) 41.4±9.7 41.6±11.9 0.1 0.92

Age of onset of schizophrenia (years, mean±SD)

Total sample

Age of onset < 33 years

Age of onset >33 years

29.2±8.8

24.8±5.8

39.5±5.2

30.8±11.4

22.9±4.9

43.0±6.9

1.12

2.01

2.35

0.27

0.046

0.022

Duration of illness (years, mean ±SD) 12.7±6.9 10.8±9.3 1.07 0.29

Socio-economic status (%)

Lower

Middle

Upper

42.4

33.3

24.2

50.6

34.1

15.3

1.42 0.496

Education (years, mean±SD) 6.8±4.7 6.4±4.8 0.43 0.664

Alcohol abuse/dependence (%) 31.2 2.1 30.154 <0.001

175

nia. Among early-onset patients, females have a significantly

earlier age of onset than males, and among late-onset

patients, they have a later age of onset.

The important merit of this study is that it included all

patients from a defined geographical area in a rural setting.

The sample included both treated and untreated patients with

schizophrenia living in the community. We found that about

39% of the patients were living untreated. Hospital-based

studies would have missed these patients. Though this study

was not aimed to assess the prevalence of schizophrenia in

the community, the point prevalence, as can be made out, is

1.6 per thousand (95% CI: 1.3-1.8 per thousand). This is comparable

to the prevalence reported from other areas in India

(16) and other South Asian countries like Sri Lanka (17).

We identified patients who were either currently symptomatic

(on or off treatment) or in remission while being on

antipsychotic medications; we might have missed patients

who had sustained remission of their schizophrenic episode

despite being off treatment currently. We may have also

missed a few patients as we conducted a “key informant”

rather than a door-to-door survey. However, the number of

such missing cases is likely to be low. The health workers

visit the families once every month; they are thus quite

knowledgeable about the families under their care and they

would not have missed patients with symptoms of schizophrenia

or receiving treatment for the same.

The diagnosis of schizophrenia was made by two psychiatrists

after independent interviews and remained stable

at six-month follow-up in the 202 subjects included in the

analysis. There were only two subjects who had a duration

of psychosis of less than 6 months – the sample was not

“contaminated” by inclusion of acute psychosis patients.

A psychiatrist trained in administering the IRAOS assessed

the age of onset of the disorder. There was a high degree

of interrater reliability between his findings and the assessment

by an independent interviewer. The age of onset

recorded in this community sample is comparable with other

hospital studies from India (10-12).

The duration of psychosis in this sample ranged from 4

months to 46 years. Eighty-one (50.3%) of the subjects had

a duration of illness of ten years or more. To rule out a possible

difficulty in recall in those with a long duration of psychosis,

we compared the age of onset of males and females

where the duration of psychosis was less than 10 years: this

did not alter the findings.

Our results show that, similar to the literature from West-

1.0

.8

.6

.4

.2

0.0

10 15 20 25 30 35

Age of onset in years

Age of onset in years

1.0

.8

.6

.4

.2

0.0

30 35 40 45 50 55 60 65

females

Percent

25

20

15

10

5

0

1 2 3 4 5 6 7 8 9 10

Age of onset

Males

Females

1=<15 years

2=16-20 years

3=21-25 years

4=26-30 years

5=31-35 years

6=36-40 years

7=41-45 years

8=46-50 years

9=51-55 years

10=> 55 years

ern countries (2), women have an earlier, higher peak in age

of onset in the early twenties and a later, lower peak in their

late thirties. However, unlike Western countries, men had a

fairly later peak in age of onset in the early thirties, followed

by a steep decline through the older age ranges. It may be

reasoned that this is because of lesser number of men with

very early age of onset in our sample.

Our sample had 80% power to detect a mean difference

of 3.9 years, which is the reported figure in the similar studies

from the West (2). The difference in mean age of onset for

the whole sample was 1.6 years, and this difference was not

statistically significant. One might argue that our study did

not have adequate power to detect this difference. Though

larger samples could detect this difference, the magnitude of

the difference is likely to be substantially lower than what

literature suggests.

In our previous studies on this issue, we have argued that

poor perinatal care in India might result in preferential attrition

of birth-injured male children, who, in the Western

samples, would have contributed to age of onset being lower

among males (12). This explanation may be true of the

current sample too. An alternative explanation can be sought

in the present study. None of the patients had used illegal

substances anytime in their lives. It is known that abuse of

illicit substances is associated with earlier age at onset (18-

20). Greater proportion of male patients abuse illicit substances

than female patients (21,22). This might contribute

to earlier age at onset of schizophrenia in males in Western

countries. Absence of such abuse also may contribute to the

lack of sex differences in our sample. A lower rate of substance

abuse has been suggested to explain the near-equal

sex ratio in the incidence of schizophrenia in the developing

countries (23). A sex ratio of 1:1 in our sample perhaps reflects

a similar trend.

This work was done in a rural South Indian setting and

the results may thus be generalized to similar populations.

However, our earlier reports, which showed similar results,

were from a mixed rural-urban population from a tertiary

center, which draws patients from all over India. Taken together,

these consistent findings suggest that the epidemiology

of schizophrenia is different in India from Western

countries, at least with respect to age of onset of the disorder:

there seems to be a relative lack of earliest onset male

schizophrenia patients in our population. The note in the

diagnostic systems about sex differences in age of onset of

schizophrenia cannot thus be generalized.

Acknowledgement

This project was funded by National Mental Health Programme,

Government of India’s research grants to B.N.

Gangadhar.

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DK, Kaliaperumal VG (eds). Statistical methods and application

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and schizophrenia: reversed gender effect. Acta Psychiatr Scand

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177

In contrast to the decades-long tradition of a biopsychosocial

model, many mental health clinics have adopted a

model that promotes a split between biological and psychosocial

treatments. Following a single initial assessment, psychiatrists

see patients briefly for “medication checks”, while

non-medical clinicians provide psychotherapy. Team meetings

occur to ratify treatment plans, but there is little time

available for integration of pharmacotherapy with other

treatment modalities.

In the US, the split model of care has principally been

driven by a shortage of psychiatrists and by reimbursement

protocols that are based on the unsubstantiated premise that

it is cheaper to pay psychiatrists to write prescriptions and

other clinicians to provide psychotherapy than it is to pay

psychiatrists to provide comprehensive patient care. One

outcome of this approach is that the domain of the psychiatrist

is increasingly restricted only to prescribing medications,

a service that itself is seen as so straightforward that a

minimal amount of time is needed after a diagnosis has been

made. To the extent that prescribing psychotropic medications

is an uncomplicated process, nurse practitioners and

other clinicians with prescribing authority have been recruited

to replace rather than supplement psychiatrists on

the grounds that they cost less and that they are just as effective

– a belief equally unsubstantiated by any credible data.

In the UK, a dramatic example of the relegation of the

psychiatrist to a marginal role was the proposal by Lord

Layard (1) that led to expanding psychological therapy for

anxiety and depression in the British national health system.

In this initiative, a senior non-physician psychotherapist

would make initial diagnoses and assign the patient to a

junior therapist, who would be supervised, motivated and

trained by senior therapists. Psychiatrists would be elsewhere

in the national health system, with the task of administering

drug treatment to the most severely ill patients, and

would not be involved at all in the treatment of most mood

and anxiety disorders.

There are a number of features of the treatment process

The mental health clinic: a new model

Department of Psychiatry, State University of New York at Buffalo, 462 Grider Street, Buffalo, NY 14215, USA

that may also limit the role of the psychiatrist and inhibit

comprehensive treatment. For example, in the current clinic

model which is endorsed in many contexts worldwide, a

diagnosis and treatment plan that are usually developed after

a single initial visit are supposed to be followed in the

subsequent months or years without any additional time for

re-evaluation. This approach is based on a unidimensional,

cross-sectional view of the disorder, assuming that the illness

does not evolve and the diagnosis does not change

over time. Yet, it is not uncommon for apparently clear-cut

major depression to be re-diagnosed as bipolar disorder

(2-4), because the prodromes of the manic episode were

overlooked or masked at the initial assessment (5). Accurate

diagnosis and effective treatment often depend on repeated

assessments, but in some clinic settings there is insufficient

time available to the prescriber for this process

(5). Even if the therapist had sufficient expertise to refine

the diagnosis, time and structure are not available for a

collaborative discussion with the prescriber for comprehensive

reconsideration.

Another common issue involves medical evaluation. Between

20% and 50% of psychiatric patients have active

medical illnesses (6,7) and psychiatric medications such as

some atypical antipsychotics pose additional medical risks

(8). A full understanding of the patient’s medical condition

is important not only to clarify psychiatric symptoms, but

also to determine the need for general medical care and to

choose psychiatric treatments that do not interact adversely

with the medical illness and its treatment (9). It is axiomatic

that a medical diagnosis depends on a careful history and

physical examination, with laboratory investigations as indicated

(9). Yet, such evaluations are rarely performed in the

clinic setting by psychiatrists or anyone else (10), despite

their responsibility for the overall health of their patients

(11). Indeed, psychiatric outpatient clinics generally operate

in isolation from the rest of the medical system.

Recovery has increasingly become a stated goal of mental

health treatment (12), but there is increasing awareness that

complete remission of symptoms and restoration of normal

function is not frequent in such psychiatric disorders as major

depression (13), panic disorder (14), obsessive-compulsive

disorder (15), eating disorders (16) and schizophrenia

(17). For example, only 28% of patients with fairly uncomplicated

unipolar depression receiving flexible doses of citalopram

were found to be symptomatically (let alone functionally)

remitted (18). Lack of remission is associated with

subsequent relapse, while treatment of residual symptoms

may improve functioning and reduce the risk of relapse and

recurrence (5).

Combinations of medications and of psychotherapy and

pharmacotherapy can improve remission rates (19). In some

cases, treatments that are administered in sequential order

(psychotherapy after pharmacotherapy, psychotherapy followed

by pharmacotherapy, one drug treatment following

another or one psychotherapeutic treatment following another)

may be more successful in eliminating residual symptomatology

than introducing all treatments at the same time

(20). Maximizing remission requires repeated assessments,

modification of initial treatment plans and efficient integration

of treatment team members, which requires more time

than is usually allocated.

Psychotherapy is an obvious component of treatment in

the mental health clinic, and over the past two decades there

has been impressive progress in the effectiveness of shortterm

psychotherapeutic strategies such as cognitive behavioral

therapies and interpersonal therapy in a number of

psychiatric disorders (21). These psychotherapies have been

found to be effective alternatives or supplements to pharmacotherapy,

with enduring benefits after treatment is discontinued

(20,21). However, while many clinics provide psychotherapies

in various forms, true manualized evidencebased

psychotherapies are often not available, and coordination

with pharmacotherapy is rarely possible for most

patients, because of brief “medication check” visits to psychiatrists

that leave no time for consultation with therapists.

A new model

One way to develop a model of more comprehensive and

integrated outpatient mental health care is to consider a

mental health clinic affiliated with an academic department

of psychiatry or other psychiatric organization in the community.

Referral sources may be psychiatric inpatient units,

psychiatrists in other settings, primary care physicians and

other medical specialists or other agencies, or patients may

refer themselves. We will discuss the staffing, functioning

and modalities of integration of the basic operational unit of

the clinic, which could be multiplied according to the number

and needs of the patients served.

The basic unit includes a psychiatrist, an internist, and

four psychotherapists, who could be clinical psychologists,

nurse clinicians or social workers. The psychiatrist should

have an adequate background both in psychopharmacology

and psychotherapy. Experience in performing psychotherapy

is essential, whether or not the psychiatrist will

provide it in the clinic, since referral to psychotherapy requires

a deep understanding of the indications, contraindications

and expectations of the psychotherapeutic technique

that is proposed.

The internist should be able to provide specialized medical

evaluation, especially of endocrine and cardiovascular

problems. Psychotherapists may have different levels of experience

and training in evidence-based psychotherapeutic

strategies (21). Individual, family or group formats may be

performed, according to the needs of the patients and the

skills of the therapists (22). Properly trained clinical psychologists

and social workers may be most experienced at

individual and group psychotherapy. Nurse clinicians, in the

long-standing experience of the Maudsley Institute (23),

may be the most appropriate individuals to supervise selftherapy

approaches such as exposure, to monitor stable

medication regimens, and to emphasize the role of the patient

in the process of recovery (13), including diet and exercise

(24). To illustrate the functioning of the clinic, consider

the entry of a new patient into the system.

The initial assessment is performed by the psychiatrist. In

addition to the customary psychiatric examination to determine

categorical and dimensional diagnoses (9), the task of

this assessment is to establish treatment priorities, since

many patients qualify for more than one diagnosis (25-27).

The process of assessing the relationship between co-occurring

syndromes to decide where treatment should commence

is called macro-analysis (28,29). For instance, a patient

may present with major depressive disorder, obsessivecompulsive

disorder and hypochondriasis. In a macro-analysis,

the clinician may give priority to the pharmacological

treatment of depression, leaving to second stage assessment

the determination of whether obsessive-compulsive disorder

and hypochondriasis are epiphenomena that will resolve

with resolution of depression, or whether they will persist,

despite improvement of depression. In the latter case, it will

be necessary to determine whether further treatment is necessary.

If one syndrome is addressed initially, macro-analysis

requires re-assessment after the first line of treatment has

been completed. Treatment is therefore staged according to

the seriousness, extension and course of the disorder (30-

33). For instance, certain psychotherapeutic strategies can

be deferred until antidepressant medications have improved

mood to a point where cognitive reorganization with psychotherapy

is more likely to be retained (34). Staging has the

potential to improve the logic and timing of interventions in

psychiatry, just as it does in many complex and serious medical

disorders (31).

The planning of sequential treatment requires determination

of the symptomatic target of the first line approach (e.g.,

vegetative symptoms and mental energy for pharmacotherapy),

and tentative identification of other areas of concern

to be addressed by concomitant or subsequent treatment

179

(e.g., dysfunctional thinking and relationships targeted by

psychotherapy). Addressing one dimension of illness after

an earlier feature has improved can increase the likelihood

of more complete remission.

Medical assessment in the psychiatric setting is not as

straightforward as in the medical setting (6). Medical evaluation

requires familiarity with the interactions of psychiatric

illnesses and medications with medical disorders and their

treatment, as well as with the complex health attitudes of

psychiatric patients (35,36). Collaboration of the psychiatrist

with an internist who is familiar with psychiatric illness

may be necessary for effective treatment planning when a

comorbid medical illness is present.

While macro-analysis involves an assessment of the relationship

between co-occurring syndromes, micro-analysis is

a detailed analysis of symptoms for functional assessment

(28). It involves consideration of the onset of complaints,

their course, circumstances that aggravate or ameliorate

symptoms, short-term and long-term impact of symptoms

on quality of life, and work and social adjustment (28). Micro-

analysis may also include specific tests and rating scales

(9,37), which must be integrated into the rest of the assessment

and not viewed in isolation (38). This dimension of

micro-analysis is performed by a clinical psychologist and

may either complete the diagnostic assessment or pave the

way for further evaluation.

This information should facilitate the formulation of an

initial treatment plan, which may involve no need for treatment;

referral to other institutions; pharmacotherapy only;

psychotherapy only; or use of both pharmacotherapy and psychotherapy,

which may be simultaneous or sequential (20).

There is often a tendency to regard simultaneous administration

of pharmacotherapy and psychotherapy as the optimal

treatment. However, not all data support the initiation

of both treatments at the same time, especially in anxiety and

mood disorders (20,39). Sequencing pharmacotherapy and

psychotherapy may be more effective in chronic and severe

cases (39,40). Assignment to the first line of treatment may

involve pharmacotherapy provided or monitored by the psychiatrist,

psychotherapy provided by a psychotherapist with

expertise in the proposed therapeutic modality, or both.

However, even when pharmacotherapy alone is the preferred

initial treatment, it is less likely to be effective if the

patient does not have the opportunity to develop a therapeutic

alliance with a prescriber who is sufficiently available

to provide appropriate optimism, an opportunity to ventilate

thoughts and feelings, and the development of an interest

in self-examination (41,42).

If non-pharmacologic approaches are instituted before

pharmacotherapy, they may involve sessions by nurse clinicians,

emphasizing lifestyle modification, dietary measures,

physical exercise, encouragement of exposure and use of

computer aided strategies (43,44). Initial psychotherapy

may involve cognitive behavioral therapy for panic disorder

with agoraphobia, social phobia, obsessive-compulsive disorder

or post-traumatic stress disorder; cognitive behavioral

or interpersonal psychotherapy for major depression; or

dialectic behavior or expressive therapy for a personality disorder

(45). Conversely, certain psychotherapies, for example

cognitive therapy for schizophrenia or family focused therapy

or interpersonal and social rhythms therapy for bipolar

disorder (46), are usually instituted at the same time as pharmacotherapy.

It is very important to reassess the patient after the first

line of treatment has been completed, to reconfirm the diagnosis

and refine the treatment plan. Certain approaches may

limit a satisfactory assessment of the patient in this stage.

The first is re-examination of only a few target symptoms,

instead of the full spectrum of psychopathology as would be

done with a new patient.

The second pitfall is to determine severity by the number

of symptoms, not by their intensity, quality or impact on

functioning (29). The result is treatment aimed at a diagnosis

based on a certain number of symptoms (which may be of

mild intensity and of doubtful impact on quality of life), instead

of individual symptoms or dysfunctions that may be

incapacitating. Conversely, subclinical symptomatology, as

frequently occurs in partially remitted disorders (5,13,14),

may require aggressive treatment, because it continues to

impair functioning and because it increases the risk of relapse

or recurrence of the full syndrome (13-15,17).

Another issue is that symptoms are usually elicited

through a clinical interview. However, state-dependent recall

may limit information available by this method and a

diary or daily rating scale can be an important source of information

that is not readily apparent in an interview.

Consistent with the principle that health is traditionally

equated with the absence of illness rather than the presence

of wellness (47), assessment in psychiatry is mostly based on

appraisal of psychopathological dysfunction instead of a

balance between positive and negative factors (41). To determine

whether the patient is well, it is necessary to assess

positive health and functioning in addition to symptoms.

The most comprehensive reassessment after the completion

of psychotherapy and somatic therapy should be performed

by the psychiatrist. The assessment performed in this phase

is crucial in determining the level of remission after the first

course of treatment, whether residual symptoms are present

and whether further treatment is necessary. Since the available

data suggest that only a minority of patients are likely

to display a satisfactory degree of recovery with monotherapy

or a single phase of treatment (13,15,17,18), it is often

necessary to decide whether psychotherapeutic or pharmacological

approaches or both should substitute for or supplement

the first line of treatment.

Since any residual symptoms increase the risk of relapse

and recurrence (5,13,48), another reassessment is necessary

after treatment is completed, for example when a depressed

patient has completed psychotherapy following pharmacotherapy

(20). If any residual symptoms persist, new treatment

strategies, such as indefinite drug therapy and maintenance

psychotherapy, should be considered.

At all stages of therapy, integrating treatments requires

regular meetings of all team members (including the internist).

The goals of these meetings include diagnosis and formulation

of treatment plans; monitoring of treatment progress;

modification of initial diagnostic formulations and

treatment plans; discussion of the role of medical and psychosocial

factors; introduction of brief, targeted interventions;

supervision of psychotherapy by the psychiatrist or

other designated senior psychotherapist; and consideration

of maintenance treatment after completion of therapy. The

cost of such meetings is compensated for by improved outcomes

and less need for multiple episodes of acute treatment

after relapse.

Conclusions

The predominant model of the mental health clinic has

the potential to marginalize the psychiatrist to a point that

could impede recruitment of this specialist into clinic settings.

By making use of the ability of the psychiatrist to synthesize

psychiatric, medical and psychological data from

diverse sources, interact with different specialists and disciplines,

and develop a comprehensive treatment plan, the

model proposed here defines a role that many psychiatrists

would find desirable while not detracting from the skills of

other clinicians working with the patient. Ideological influences

that tend to minimize the psychiatrist’s role are reduced

while maintaining an effective team approach.

We believe that research into the effectiveness of the model

would demonstrate that any increase in cost related to

using some of the psychiatrist’s time for treatment planning,

which is normally not directly reimbursed, is offset by more

efficient utilization of all services and improved outcomes as

well as more successful recruitment of psychiatrists into the

public sector.

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Consideration has often been given to placing greater emphasis

on the utility of classificatory systems, particularly

because of the lack of progress in developing an etiologically

based system and the recognition that a “naturalistic”

approach to classification might be unrealistic (1-3).

The classificatory system and clinical formulations are

central to the clinical logic of connecting the assessment

information to the patient recovery plan (4). Multiaxial classificatory

systems can be thought of as attempts to standardize

regularly informative components of formulation into a

classificatory framework.

In recent years there has been increasing emphasis on the

concept of risk assessment. For example, there have been

several publications in the area of risk of suicide (5,6), risk

of harm/violence to others (7) and more extended risks to

the patient themselves, such as self-neglect (8). The understanding

of these risk factors has been gradually increased

by more precise epidemiologically guided research. Public

and health service concerns about the consequences of inadequate

risk management have led to the gradual emergence

of a number of guidelines (9-11). Almost inevitably

these guidelines, which connect risk assessment and risk

management, concentrate on only one of the three major

risk areas referred to above, despite the recognition that a

single, comprehensive clinical management or recovery plan

best serves patient/consumer needs.

We would argue that incorporating the clinical management

consequences of risk assessment as one dimension of

a multiaxial classificatory system would increase both clinical

effectiveness and efficiency. This paper sets out a possible

structure for such an axis, with its rationale.

Risk assessment vs. risk management

It has been noted that, when predicting risk of violence,

psychiatrists are likely to be very often wrong (12-15). We

also know that by developing the skills of risk formulation

An axis for risk management in classificatory systems

as a contribution to efficient clinical practice

Department of Psychiatry, Waikato Clinical School, University of Auckland, Private Bag 3200, Hamilton, New Zealand

(12) and risk management (16) they are likely to achieve

better results. The distinction between the tasks of risk assessment

for clinical management and event prediction is

subtle but significant. A classic study in this regard was conducted

by Lidz et al (17), who reported that clinicians were

reasonably accurate in assessing dangerousness, since the

patients who did prove to be violent on follow-up over six

months were detected with reasonable sensitivity. On the

other hand, many patients who were rated as dangerous by

clinicians did not prove to be more violent than the other

patients (low specificity).

A clinical determination that a patient presents sufficient

risk to justify intervention is one goal of assessment of risk.

Risk assessment must identify clinical or situational factors

which can be modified to reduce risk. It is noteworthy that

inquiries into homicides by persons with mental illness have

consistently found that only a minority of incidents are predictable,

whilst the majority are preventable with good quality

clinical assessment, communication and intervention

(18,19). We can use our psychiatric training to introduce

interventions according to the needs of an individual and

master the art of risk management by constantly considering

the dynamic nature of risk and paying attention to the needs

and deficits of an individual.

The issue of shifting focus from risk prediction to risk

management becomes more relevant when one considers

the ethical implications of the two (14). Often the outcome

of risk assessment is that a patient with a history of violence

is identified as “potentially violent”, which easily gets distorted

as “violent”. These adjectives accumulate in the file

and are of little utility unless ways are identified to manage

risk. Our responsibility as psychiatrists does not end with

stating that a given patient is potentially dangerous. The

ethical justification for risk assessment by a treating psychiatrist

is risk reduction through risk management. Risk

changes with time and circumstance and therefore the risk

of violence needs to be assessed and reviewed regularly.

ment of risk of violence to others, the same principles apply

to the other two main types of risk that clinicians routinely

assess in general adult psychiatric settings.

Axis design issues

The major organizing principle for our proposed axis is

that it should inform and assist the development of patient

recovery plans. It will do that best by incorporating both

positive and negative risk factors which need to be addressed

or harnessed to facilitate patient recovery.

Clinicians most commonly undertake three types of risk

assessment – violence, suicide and self-neglect – which are

embedded in the legislations on compulsory treatment in

many places (14,20). In order to be accepted and widely

used, a risk axis will need to be simple yet comprehensive.

It should be sufficiently comprehensive not only to capture

all the types of risk assessed, but also to be able to address

the unique aspects of each risk. It needs to be able to capture

all three types of risk in one format, rather than the tripartite

guidelines which are beginning to appear in a number of

nations – for example, in the UK (9) and in New Zealand

(10). Having a separate system for each type of risk is confusing

and burdensome for clinicians, and therefore more likely

to be observed in the breach than in the action. It also

means there are often several different management plans in

different parts of the clinical file.

A history of violence is known to evoke strong emotions

and aversion in the people conducting such risk assessment

(14). It is likely that in patients who have committed previous

violent acts, clinicians may either miss or underestimate other

types of risks such as of suicide or self-neglect. Incorporating

the three types of risk in one axis will encourage their

assessment in a manner similar to how detection of personality

disorder and physical illnesses have improved with the

introduction of multiaxial diagnostic systems (21-23).

A retrospective study (24), based on a case note review

that looked at the practicality of extracting risk-related information,

found that on average it took 5 hours to conduct a

thorough review, rendering retrospective case note reviews

an impractical, incomplete and misleading way of conducting

the three types of risk assessment. The authors recommended

prospective recording as a more practical method if

used selectively, but cautioned that it required a standardized

approach to clinical recording and case note maintenance. It

may be worth noting that taking a (multidisciplinary) team

approach to risk assessment may not only reduce biases in

clinical decision making (25), but also speed the process due

to cumulative knowledge about the risk issues.

We note that each type of risk has both dynamic or clinical

factors and static or historical factors, which are assessed

by clinical or actuarial methods respectively. It has been argued

that for better outcomes the two methods should be

combined (7,26). A risk axis could enable clinicians to attend

to both tasks and serve as an “aide memoire”, yet have

sufficient in-built flexibility to allow individual or unique

aspects of the patient’s presentation to be taken into account

in the clinical recovery plan.

We believe, as stated above, that risk assessment should be

carried out primarily with a view to managing the risk, otherwise

the task becomes unethical and disadvantageous to the

patient. Therefore the risk axis should be able to inform the

development of the individual care plan. For each of the three

types of risk (self-neglect, suicide and violence to others),

static, dynamic and management factors (targeting on the latter

may well reduce the risk) will need to be described in a

manner that informs the patient recovery plan. Some risk factors

and their managements are common to all three.

Static factors for risk of self-neglect include male gender,

older age, poverty, living alone and physical problems (e.g.,

history of hip fracture/stroke) (8); dynamic factors include

clinically significant depressive symptoms, cognitive impairment,

a deteriorating physical condition, non-compliance

with treatment and/or support consistent with self-neglect,

hoarding of rubbish and persistent neglect of rotting food,

denial of danger from malfunctioning appliances, disconnection

of essential services and leaving home with doors

unlocked and open (27). To the best of our knowledge, no

studies have looked at factors that may have a specific protective

effect against the risk of self-neglect.

Static risk factors for suicide have been identified in a

recent systematic review (10): they include sex (while more

male die by suicide, many more females attempt suicide),

age (aged 15-24 years and those over 60 years), history of

previous attempts, ethanol and drug abuse, sexual abuse,

comorbid anxiety disorders (particularly panic disorder),

personality disorders (antisocial and borderline), conduct

disorder and oppositional defiance disorder, and identifiable

stressful events. Identified dynamic factors include depression,

impaired rational thinking, presence of organized

plan, loneliness or debilitating medical illness, and experiences

of adversity. Management or protective factors are

presence of support networks, relief about not completing

suicide, people relying on them for ongoing care, a sense of

unfinished business, framework for meaning (e.g., religious

belief), beliefs about the need to care for children, good selfesteem,

self-confidence and awareness of significant others

about their suicidal thoughts.

Finally, static factors for risk of violence to others include

previous violence, young age at first violence, psychopathy,

early maladjustment, personality disorder, prior supervision

failure; dynamic factors include relationship instability, employment

problems, substance use problems, lack of insight,

negative attitudes, active symptoms of major mental illness,

impulsivity and unresponsiveness to treatment. Management

or protective factors include level and type of personal

support, dealing with stressors, working on medication adherence.

All the above could be combined in a qualitative or quantitative

format which could be completed as a part of a multiaxial

summary of the clinical assessment process.

Conclusions

The assessment of risk of self-neglect, suicide and violence

to others is a task that clinicians routinely undertake.

However, current classificatory systems do not make any

provision for it. A dedicated risk management axis would

help clinicians by integrating the findings of the assessment

into the clinical recovery plan and may improve the utility

of the classificatory systems by aligning them better to routine

clinical work. Such an axis will need to combine actuarial

and clinical factors. Our understanding of actuarial

factors associated with the three types of risks has improved

greatly in the recent years, making the development of such

an axis now possible.

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185

Having now passed the 12th anniversary of the WPA

Global Program to Fight Stigma and Discrimination Because

of Schizophrenia, and the third year of operation of

the WPA Scientific Section on Stigma and Mental Health, it

is timely to reflect on the past perspectives that have led us

to our current position, review present activities and accomplishments,

and identify challenges that the Section members

will face in their future efforts to reduce the stigma

caused by mental disorders.

Past perspectives

of shame or degradation, is thought to have appeared in the

more broadly used to indicate a tattoo or mark that might

have been used for decorative or religious purposes, or for

utilitarian reasons, such as a brand placed on criminals or

slaves so that they could be identified if they ran away and

to indicate their inferior social position. The evolution of the

term notwithstanding, negative societal responses to the

mentally ill have been ubiquitous throughout history – a

situation that has persisted through changing concepts of

mental illness – even through the rise of medical theories

and biologically-based explanations for most mental disorders

(1,2).

Contemporary notions of stigma are grounded in sociological

and psychological theoretical traditions. For example,

our modern understanding of stigma and its effects

stems largely from the seminal work of Erving Goffman,

effects of stigma, which reduces the bearer from a whole

person to one that is irredeemably tainted (3). In Goffman’s

Fighting the stigma caused by mental disorders:

past perspectives, present activities, and future

directions

1WPA Section on Stigma and Mental Health

2Department of Community Health and Epidemiology, Queen’s University, Abramsky Hall, Kingston, Ontario K7L 3NS, Canada

view, mental illness was one of the most deeply discrediting

and socially damaging of all stigmas, such that people with

mental illnesses start out with rights and relationships, but

end up with little of either (4). Goffman was deeply critical

of mental hospitals for their stigmatizing and anti-therapeutic

effects (5) and, along with contemporaries such as Szasz

(6) and Scheff (7), reinforced the perception that stigma was

rooted in the nature of psychiatric diagnosis and treatment.

From this original focus on stigma as a by-product of the

social organization of psychiatry, contemporary social theorists

have taken a much broader, ecological view; one that

recognizes the complex interplay of social-structural, interpersonal

and psychological factors in the creation and maintenance

of stigma (8,9). From this perspective, stigma is pervasive,

pernicious, and resistant to change and, to be successful,

anti-stigma programs must be comprehensive, multipronged

and directed to individual, interpersonal, and system-