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Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.
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Expert Rev Neurother. 2010 August ; 10(8): 13471359. doi:10.1586/ern.10.93.
Early signs, diagnosis and therapeutics of the prodromal phase of

schizophrenia and related psychotic disorders
Molly K Larson1, Elaine F Walker1, and Michael T Compton,2

1Graduate School of Arts and Sciences of Emory University, Department of Psychology, Atlanta,
GA, USA
2EmoryUniversity School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta,
GA, USA
Abstract
During recent decades, interest in the prevention of mental illnesses has increased. Improved
diagnostic tools, the advent of atypical antipsychotic medications and the development of phase-
specific psychosocial treatments have made intervention research in people at ultra-high risk for
developing schizophrenia or a related psychotic disorder possible. Preliminary data suggest that low
doses of atypical antipsychotic medications augmented by psychosocial treatments may delay the
onset of psychosis in some individuals. Findings support further research for the establishment of
best-practice standards.
Keywords
cognitivebehavioral therapy; early intervention; olanzapine; omega-3 fatty acids; prodrome;
psychosis; risperidone; ultra-high risk; ziprasidone
A brief overview of schizophrenia

The early 1900s saw the beginning of research on the clinical syndrome of schizophrenia and
other psychotic disorders [1,2]. Psychosis, a syndrome that markedly interferes with an
individuals functioning, entails a significant departure from reality, often including false
perceptions or beliefs and disordered thoughts and speech. These psychotic symptoms are often
accompanied by blunted or inappropriate emotional expressions and motivational deficits.

Abnormalities in mood (e.g., anxiety, depression) and sleep disturbances are also common.
Current diagnostic systems differentiate between the nonaffective and affective psychoses
based on whether the mood, or affective symptoms, consistently co-occur with the psychotic
symptoms. Nonaffective psychotic disorders involve psychotic episodes that typically occur
outside of a mood episode, and are typically considered to include schizophrenia,
schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic
disorder, shared psychotic disorder, psychotic disorder due to medical condition, substance-
induced psychotic disorder and psychotic disorder not otherwise specified. Affective psychotic
2010 Expert Reviews Ltd

Author for correspondence: mcompto@emory.edu.
Financial & competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Larson et al. Page 2
disorders differ in that the psychotic episodes co-occur with severe mood disturbances, and
include disorders such as bipolar disorder with psychotic features and depression with
psychotic features. This article addresses the characteristics of and treatment research on the
primarily nonaffective psychotic disorders, with a focus on the prodromal period of such
disorders. This is one of the few articles to comprehensively review pharmacological and
psychological interventions in the prodromal phase of psychotic disorders.
Symptoms
The widely recognized symptoms of schizophrenia are organized into distinct, but not
necessarily independent, categories of symptoms. The distinction between the positive and
negative symptoms dates back at least as far as Hughlings-Jacksons writings [3], but it was
not until Strauss and Carpenter [4] reintroduced these terms that modern psychology and
psychiatry began extensive research on these symptom dimensions. In a series of studies,
researchers examined the relevance of positive and negative symptom distinctions in
consecutively admitted inpatients diagnosed with schizophrenia [5,6]. They found three
symptom dimensions: the negative dimension remained but the positive dimension was divided
into two, one including delusions and hallucinations (reality distortion) and a second factor
including bizarre behavior and formal thought disorder. The latter represents disorganization
in the form or linearity, rather than content, of thoughts and speech.
Within the psychotic spectrum of positive symptoms, Kurt Schneider postulated that first-
rank symptoms were seemingly pathognomonic to schizophrenia [7]. First-rank symptoms

include: audible thoughts (hearing ones own thoughts spoken aloud); hearing voices
commenting on ones own activities; hearing voices discussing/arguing about oneself; normal
perception followed by delusionally personalized interpretation; thought insertion, withdrawal
and broadcasting; and somatic passivity (experiencing ones emotions, impulses or motor
activity as being controlled by an external force). Subsequent research has shown that these
first-rank symptoms may also be present in other psychotic illnesses [8]. Liddle published a
seminal paper in which he provided support for a disorganized symptom dimension, including
disorganized speech and/or behavior [9]. Disorganized symptoms are currently included as one
aspect of psychosis. Symptoms such as anxiety, depression and sleep disturbances also often
accompany the clinical presentation of psychotic disorders and are termed general
psychopathology symptoms.
Cognitive, social & functional deficits

Schizophrenia and other psychotic disorders are among the most debilitating mental illnesses
because multiple facets of functioning are impaired. Furthermore, patients commonly
experience social and functional deficits, such as less social contact, difficulty obtaining and
maintaining employment and challenges to independent living that significantly impact their
quality of life. Since psychosis was first formally described, researchers have found evidence
of subtle cognitive impairments at the first episode of psychosis. Specifically, deficits in the
speed of processing, executive functioning, sustained attention/vigilance, working memory,
verbal learning and memory, reasoning and problem solving, verbal comprehension and social
cognition have been replicated across several studies [10,11]. Some research has indicated that
verbal memory and executive functioning most strongly affect patients work and social
functioning [1214], while others argue that overall intelligence quotient (IQ) is a better
predictor of social functioning (e.g., [15]). There is evidence that isolated cognitive skills within
the domains of immediate attention, procedural memory and emotional processing are
unaffected; however, when coordination of cognitive skills is required, deficits are often more
readily apparent [16]. Neurocognitive impairments and functional decline often precede the
onset of psychosis and are thought to influence the severity of social and occupational
dysfunction later in the illness [17,18].

Neurodevelopmental & neurodegenerative models of schizophrenia

There is evidence that schizophrenia is both a neurodevelopmental and neurodegenerative
disorder. The term neurodevelopmental was initially used to refer to the notion that
vulnerability to psychosis originates in abnormal fetal brain development [19]. More recent
theoretical formulations assume that abnormalities in adolescent brain development may also
be involved. Thus, psychotic disorders probably have origins in early development, but are
generally manifested in late adolescence as a result of the developmental trajectory of the brain.
That is, the human brain continues to mature into at least the second decade of life; it is
hypothesized that it is not until this time that underlying neural structures evidence functional
deficits to the extent that they lead to behavioral manifestations of frank psychotic symptoms.
Evidence from childhood development of persons later diagnosed with schizophrenia indicates
early intellectual and neuromotor abnormalities [2024]. By the first episode of psychosis,
those affected evidence, on average, slightly larger lateral ventricle and slightly less cerebral
gray matter volume than healthy controls [25]. These findings support the notion that at least
part of the disease process is developmental.
There is also evidence that neurodegeneration may influence the course of psychosis after onset
of the disorder. As early as Kraepelins observations [2], researchers have noted that a longer
duration of illness, now characterized as the duration of untreated psychosis (DUP), is
associated with persistent symptoms and functional disabilities. Recent research indicates that
a longer DUP is directly associated with worse functional outcomes in addition to greater
symptoms, poorer quality of life and a poorer response to antipsychotic medications [2628].
Controlling for potential confounding variables, such as premorbid functioning, does not
negate the association [29,30]. Post-mortem research and structural MRI studies indicate
abnormal hippocampal, temporal lobe and prefrontal cortex structure [3133] and gray matter
changes (e.g., [34,35]) that are associated with clinical deterioration, including functioning and
cognitive declines and increased symptom severity [36]. This degeneration may occur during
the period of time between the onset of frank psychotic symptoms and the time at which
appropriate treatment is obtained, such that a longer DUP is associated with poorer outcome
(often operationalized as fewer gains in social and occupational functioning) relative to patients
with a shorter DUP. Reducing DUP by initiating treatment as early as possible (a secondary
prevention approach) may afford patients and mental healthcare providers a unique opportunity
to forestall or ameliorate the poor social and cognitive functioning often associated with
psychosis. In addition to the period between psychosis onset and treatment, the prodromal
period is commonly characterized by accumulation of cognitive and functional impairments.
Although DUP is a prognostic factor for individuals who have already developed a psychotic
disorder, the early identification of individuals at high risk for developing a psychotic disorder
may afford unique opportunities to intervene even earlier in the disease process, thereby
contributing to further improvements in the prognosis of patients with psychosis.
The prodrome
Although treatments are gradually improving, the illness course for patients with psychotic
disorders is often marked by multiple hospitalizations and a lifetime of antipsychotic
medication prescriptions. As the field is far from a cure for psychotic disorders, advancing
prevention and early intervention is vital to ameliorating functional deficits. Identification of
those most at risk for developing a psychotic disorder is a crucial step. The onset of psychosis
may be preceded by weeks, months or years of psychological and behavioral abnormalities,
including disturbances in cognition, emotion, perception, communication, motivation and
sleep. The incipient development of these symptoms allows researchers an opportunity to
identify those at heightened risk for conversion to a psychotic disorder, thus providing a unique
opportunity for research on early treatment.

Researchers have also attempted to describe the course of the prodrome. Evidence suggests
that the following course is typically observed [3740]. First, individuals commonly experience
negative or nonspecific clinical symptoms, such as depression, anxiety symptoms, social
isolation and school/occupational failure. This is often followed by the emergence of basic
symptoms, attenuated positive symptoms (APS) or brief, intermittent APS of moderate
intensity. Most proximal to psychosis, individuals commonly exhibit more serious APS that
remain subpsychotic in terms of frequency (once or twice a month), duration (often lasting for
only a few minutes and usually less than a day) and intensity (skepticism as to the veracity of
hallucinations or delusions can still be induced [41]). During this final high-risk period,
individuals often exhibit predelusional unusual thoughts, prehallucinatory perceptual
abnormalities or prethought disordered speech disturbances.
The fact that these symptoms and experiences negatively impact social, emotional and
cognitive development makes early detection and intervention especially important.
Early signs
The period of subclinical signs and symptoms that precedes the onset of psychosis is referred
to as the prodrome. The prodromal period can last from weeks to several years, and comorbid
disorders are very common during this period [42]. The prodrome of schizophrenia and other
psychotic disorders is characterized as a process of changes or deterioration in heterogeneous
subjective and behavioral symptoms that precede the onset of clinical psychotic symptoms.
In the 1960s a group of researchers examined longitudinal data and found that subtle deficits
were often present in patients with psychotic disorders prior to or early in the illness, which
were then used to develop the Bonn Scale for the Assessment of Basic Symptoms (BSABS
[4345]). Basic symptoms are considered a core feature of the illness and include subjective
experiences of thought, language, perception and motor disturbances; impaired bodily
sensations; impaired tolerance to stress; disorders of emotion, thought, energy, concentration
and memory; and, disturbances in social functioning [46]. These basic symptoms have since
been included in a number of assessment scales designed to identify persons at risk for
developing a psychotic disorder (e.g., Comprehensive Assessment of At-Risk Mental States
[CAARMS] and Scale of Prodromal Symptoms [SOPS]).
One promising area of research addresses the development of psychotic disorders in

adolescents with schizotypal personality disorder (SPD). Similar to other individuals
experiencing putatively prodromal symptoms, adolescents with SPD do not warrant a
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis
of a psychotic disorder as they have not experienced a full psychotic break, but display
abnormal behavior similar to, but milder than, that seen in psychotic patients [47].
Prodromal individuals are often adolescents and young adults experiencing mild or moderate
disturbances in perception, cognition, language, motor function, will, initiative, level of energy
and stress tolerance [48]. This period of prepsychotic disturbance, in which attenuated or
subthreshold psychotic features begin to manifest, differs from frank psychotic features in
intensity, frequency and/or duration. The threshold, albeit relatively subjective and arbitrary,
is based on symptom severity and the presence of frank psychotic symptoms, which would
warrant immediate antipsychotic medication treatment, signifying the end point of the
prodromal period [49]. Although the prodrome has been viewed traditionally as a retrospective
construct, efforts are now underway to identify and characterize the prodromal period
prospectively.

Diagnosis & classification of high-risk individuals

In an attempt to better categorize the prodromal period of schizophrenia and other psychotic
disorders, and to elucidate the process of change or deterioration that represents a deviation
from an individuals previous experience or behavior, researchers have proposed several

diagnostic and classification systems for individuals at high risk of developing a psychotic
disorder [50].
The Personal Assessment and Crisis Evaluation (PACE) clinic in Melbourne, Australia, was
the first to develop a standardized classification of prodromal syndromes, which they referred
to as the ultra-high-risk (UHR) states. Risk factors such as age, family history of psychosis
and symptom scores were combined in a multifactorial index of risk [50,51]. From this work
came the creation of the CAARMS, which takes into account the intensity, frequency and
duration of emerging positive symptoms, as well as declines in functioning. Help-seeking
individuals between the ages of 14 and 29 years are categorized as UHR if they experienced
APS during the past year, experience brief limited intermittent psychotic symptoms (BLIPS),
and/or have schizotypal personality disorder or a family history of psychosis in concert with a
significant decrease in functioning during the past year.
Shortly after the CAARMS was developed, the Prevention through Risk Identification,
Management, and Education (PRIME) prodromal research team at Yale University (CT, USA)
developed the Structured Interview for Prodromal Syndromes (SIPS) and an accompanying
scoring system termed the SOPS with criteria for the UHR/prodromal state (the Criteria of
Prodromal Syndromes [COPS]). The COPS and the CAARMS prospectively operationalize
the prodrome using almost identical criteria, with only small differences in ratings of frequency
and duration criteria and, thus, are often used interchangeably [52]. Some of the symptoms
included in these measures were derived partly from the previously mentioned basic
symptoms included in the BSABS.
Predictive validity
The prospectively identified prodromal period being studied by several research groups is
associated with a high rate of conversion to schizophrenia or another psychotic disorder. The
conversion rates range from approximately 20% to as high as 40% [5358]. For example, a
recent multisite longitudinal study (North American Prodrome Longitudinal Study [NAPLS])
examined the predictive power of an algorithm consisting of five features among 291 putatively
prodromal participants, 82 (28.2%) of whom developed psychosis over the 2.5-year follow-up
period. The features that best predicted transition to psychosis were: genetic risk of psychosis
with recent deterioration in functioning; history of substance abuse; and higher levels of
unusual thought content, suspiciousness/paranoia or social impairment. The researchers found
that when two or three of these variables were combined, in addition to the prodromal criteria
afforded by the COPS, positive predictive power ranged from 68 to 80% [59]. Another research
group examined 104 UHR individuals over a year and found a positive predictive value of
80.8% when one or more predictor variables were taken into account. The variables most
predictive of developing psychosis included poor functioning, long duration of symptoms, high
levels of depression, reduced attention and family history and deterioration of functioning
paired with experiencing subthreshold psychotic symptoms [60]. Together, these data suggest
that the field is moving closer to developing a model of risk factors that is highly predictive of
which UHR participants will go on to develop a psychotic disorder.
Despite the indications of improvement in predictive validity, there is concern that a high false-
positive rate (identifying an individual as prodromal who does not go on to develop psychosis)
may cause individuals to be stigmatized or exposed to unnecessary treatments. A number of
factors affecting accurate identification of those who will go on to develop a psychotic disorder

have been proposed. First, research suggests that the method of assessment influences
predictive validity. For example, participants with both self-reported and clinician-rated
subclinical psychotic symptoms at baseline were more likely to exhibit psychotic symptoms
and a need for care at 3-year follow-up than those participants who reported symptoms but
whom clinicians did not rate as exhibiting attenuated psychotic symptoms [61]. Second, it is
possible that being identified as at-risk early in the progression of the illness may decrease the
transition rate, thereby creating a subgroup of false false-positive individuals (UHR
participants who may have transitioned to psychosis but did not as a result of early identification
and intervention). Recent evidence from the PACE group suggests that earlier identification
and intervention of UHR individuals may decrease the transition rate from the putatively
prodromal state to psychosis [62]. Specifically, the researchers found that during a 6-year
period (19952000), there was evidence of a decline in the rate of transition in their UHR
participants. This may be explained by a significant reduction in the duration of untreated
symptoms (1995 mean duration of symptoms = 560 days; 2000 mean duration of symptoms =
46 days), such that earlier detection and care may decrease the rate of developing psychosis
(suggesting the decline in transition rates is due to an increase in false false-positives). An
alternative explanation of these data is that the attempt to identify individuals earlier has
resulted in a dramatic increase in false-positives. Thus, while the early identification and
intervention of prodromal patients could adversely affect erroneously identified individuals,
there is also evidence that correctly identified individuals may be positively affected. The
ethical implications of these data are further addressed in the Ethical implications section of
this article.
Prognosis
There is evidence for several factors that contribute to the prognosis of individuals identified
as UHR for developing a psychotic disorder. These risk/protective factors include premorbid
cognitive and social skills, comorbidity and history of substance abuse. Logically, social and
occupational functioning are influenced by premorbid cognitive and social skills. Studies show
that lower cognitive functioning (e.g., lower overall IQ or greater cognitive impairment) is
associated with a poorer prognosis [13,6366]. Prospective and retrospective studies indicate
that comorbid disorders are very common during the prodrome [38,6769] and may negatively
impact outcome [70].
One of the most common comorbid disorders in schizophrenia, substance abuse, is associated
with longer duration of illness episodes, more frequent hospitalizations and poorer social and
functional recovery throughout the lifetime of an affected individual [71,72]. Recent research
suggests that persons at risk for developing a psychotic disorder or who are already psychotic
evidence unique vulnerability to the effects of substances on brain systems. Specifically,
studies of substance effects on persons with schizophrenia suggest that the vulnerability may
confer increased sensitivity, such that smaller doses bring about detrimental effects [73,74].
Furthermore, substance abuse interferes with education, social and emotional development and
brain maturation [75]. This evidence from participants with schizophrenia suggests that
adolescents and young adults who are at risk for both developing psychosis and using
substances may be uniquely vulnerable to developing schizophrenia and other psychotic
disorders, and represents an area of potential intervention [76,77].
Two studies have addressed the relationship between substance use and psychosis outcomes
in UHR individuals. The first examined cannabis use in 100 participants at baseline and again
1 year later [78]. Of the 35 who used cannabis in the year prior to baseline, 13 (37.1%)
developed psychosis; 19 of the remaining 65 (29.2%) participants developed psychosis at 1-
year follow-up. In total, 18 participants met DSM-IV criteria for cannabis dependence in the
year prior to baseline; 7 (38.9%) developed psychosis. Of the remaining 82 participants, 25

(30.5%) developed a psychotic disorder. These differences were not statistically significant.
A critical limitation of the study was that cannabis use was assessed for only the year preceding
baseline. A second study addressed this limitation. Lifetime use was assessed in 48 UHR
participants at baseline and again at 1-year follow-up [79]. Those who reported current abuse/
dependence were excluded, such that only minimal use was allowed. Urine toxicology screens
were preformed during the course of the study to assess use throughout the year. Thus, these
researchers collected a more comprehensive account of cannabis use, both in terms of lifetime
use (compared with use limited to 1 year prior to baseline) and continued use assessment
throughout the follow-up period. Of the six participants who used cannabis during the course
of the study, three (50.0%) developed psychosis. Of the 16 participants (33.3%) who reported
lifetime abuse/dependence, five (31.3%) developed psychosis. Of the 32 participants who
reported no lifetime abuse/dependence, one (3.1%) developed psychosis. These results suggest
that heavy, long-term use may adversely influence the development of psychosis and that
samples should be assessed for lifetime use rather than only use 1 year prior to baseline.
Therapeutics being investigated for the prodrome

Although meeting established prodromal criteria is the single best predictor of future psychosis
(three- to four-fold higher than family history of psychosis alone), additional research is
warranted to develop algorithms with improved predictive utility that will allow us to better
understand the mechanisms of disease progression and highlight potential interventions to
prevent or forestall development of a psychotic disorder [80]. Over the past decade, there has
been a push for empirical evidence for the best way to intervene during the prodrome. The
clinical staging model of treatment suggests that treatments should be tailored to the patients
needs with safer and simpler treatments preceding psychotic onset and increasingly intensive
and aggressive treatments following psychosis onset [81]. However, there is evidence that an
overly conservative approach to treatment may not be sufficient to ameliorate the deterioration
in the early course of a psychotic disorder [82]. That is, the model of care, not just contact with
a health professional, is important [30]. The studies addressing models of care indicate that the
type of antipsychotic, the mode of psychotherapy, treatment of comorbid disorders and
consideration of factors influencing adherence all impact treatment outcome. Competing with
the importance of obtaining effective treatment as early in the course of the illness as possible
is the threat of stigmatization, adverse events and side effects of medications, costs and,
although this is improving, a dearth of compelling evidence that treatments significantly alter
the early course.
Pharmacological interventions
Antipsychotic medication has been established as a standard of care for persons diagnosed with
a psychotic disorder. Antipsychotic medications work as antagonists at dopamine receptors
and provide support for the hypothesis that psychotic symptoms are in part due to dysregulated
dopaminergic transmission. Patients often evidence decreases in positive symptoms with
antipsychotic medication treatment. Prolonged exposure to conventional (also known as typical
or first-generation) antipsychotic medication has been associated with side effects including
extrapyramidal symptoms (EPS) and adverse events, such as tardive dyskinesia, an irreversible
motor disorder. Newer atypical, or second-generation, antipsychotics are associated with much
fewer EPS, although they have liabilities, such as weight gain and metabolic disturbances.
Some research suggests that atypical agents may be preferable over conventional
antipsychotics. For example, research indicates that when the effects of an atypical
antipsychotic (olanzapine) were compared with the effects of a first-generation antipsychotic
(haloperidol) in patients experiencing a first episode of psychosis, olanzapine-treated patients
fared better. Specifically, over the first 12 weeks of treatment, olanzapine-treated patients
showed no gray matter changes while haloperidol-treated patients showed significant decreases

in gray matter volume. Less lateral ventricular volume increases in the olanzapine group was
associated with greater improvements in Positive and Negative Syndrome Scale (PANSS) total
and negative symptom scores; on the other hand, greater decreases in gray matter volumes in
the haloperidol-treated patients were associated with less improvement in neurocognitive

functioning [83]. Research has consistently indicated that cognitive deficits improve or are
stable across testretest atypical antipsychotic medication trials in patients with a psychotic
disorder [8486]. The studies suggest that medication is associated with improvements in areas
such as attention and executive functioning cognitive processes often associated with
functional outcome [13,87,88]. Overall, many view the literature as suggesting an advantage
for atypical antipsychotics over typical antipsychotics in terms of safety and outcome, although
debate continues.
The advent of atypical antipsychotics and the concomitant improvement in safety in terms of
EPS and tardive dyskinesia has allowed for clinical trials of antipsychotic medications in the
prodrome. The first such study examined low doses of risperidone augmented by enriched
psychosocial treatment (cognitive behavioral therapy) compared with a standard supportive
psychosocial intervention (including basic problem solving, case management, symptom
monitoring, as well as active listening, reflection and support [89]). A total of 59 individuals
who evidenced subthreshold psychotic symptoms were randomized in this open-label
treatment study. Antidepressant medications were allowed in both groups. The results indicated
that of the 31 participants receiving medication and enriched psychosocial intervention, three
(9.7%) transitioned to a psychotic disorder over the 6-month period of the active treatment
phase of the study. By contrast, of the 28 participants receiving standard supportive
psychosocial treatment, ten (35.7%) converted to a psychotic disorder (results significant, p <
0.05). At the 12-month follow-up (during which no treatment was administered over the second
6-month period), three more of the participants in the experimental group had converted while
no additional control participants converted. This study does not allow for determination of
the relative contribution of antipsychotic medication versus the enriched psychosocial
intervention, and the design did not include a no treatment group. However, the results suggest
that combined pharmacologic and psychosocial treatment may delay or avert the onset of
psychosis. Some treatment studies compute the number of participants needed to treat in order
to prevent one case (number needed to treat [NNT]). The authors of this study found a NNT
of four. This is lower than that needed for prevention of stroke in patients with moderate
hypertension (NNT = 13). The results from the first 6-month period of the study in which active
treatment appeared to delay conversion and the relatively low NNT suggested that additional
clinical trials were warranted.
The researchers recently published medium-term (34-year) follow-up data of this study
[90]. Of the original 59 participants, 41 (69.5%) agreed to participate in the follow-up; there
were no significant differences between the two groups in follow-up rates, the probability of
developing psychosis, symptomatology or functioning. The authors noted that many of the
participants who had still not converted, and thus can be considered false-positives, continued
to experience symptoms and needed/sought treatment over the 34-year follow-up period.
Since no factors were controlled over this follow-up period, the conclusions that can be drawn
are limited. It appears, however, that any direct protective or preventive effects evidenced
during the 6 months of active treatment did not extend into the subsequent 34 years.
A small, nonrandomized, open-label clinical trial/pilot study of risperidone provided evidence

for the potential efficacy of this antipsychotic medication for prodromal patients [91]. Six first-
episode schizophrenia patients were compared with four participants deemed to be at UHR for
psychosis. Participants were not on any other medications. At follow-up (8 weeks for
schizophrenia patients, 12 weeks for prodromal patients) both groups of participants evidenced
significant reductions in positive symptoms and improvements in neurocognition. The small

sample size, lack of blinding and absence of a control group significantly limited any
conclusions that could be drawn, but the results provided further support for the potential of
this line of research.
Next, the first double-blind, randomized, parallel-groups, placebo-controlled study was

conducted across four sites to examine the effect of olanzapine on symptom severity in the
prodrome (SOPS and PANSS scores). The 30 patients in the olanzapine-treated group
evidenced a significant improvement in symptoms relative to the placebo-administered group
over the 8-week treatment period. The participants were not currently on antidepressant
medication, although 40% of the sample had previously been prescribed antidepressants. The
olanzapine group also gained significantly more weight; however, EPS ratings were similar
across groups. Thus, olanzapine is a tenable option for acute symptomatic treatment [92], but
safety concerns regarding weight gain should be seriously considered.
In the same study, the researchers also examined the effect of olanzapine versus placebo on
conversion rates over a longer time period (2 years) in a randomized, double-blind trial of 60
treatment-seeking participants. After the first year of treatment, five out of 31 (16.1%) of the
olanzapine-treated group converted to psychosis. Furthermore, there was a trend toward
improvement in mean positive symptoms. By contrast, 11 out of 29 (37.9%) of the placebo-
administered group converted. These results did not reach statistical significance, but were
suggestive of a potentially meaningful effect. Only 17 of the original 60 participants continued
the study into the second year, during which no active treatment was administered. After this
year, the conversion rate did not differ between the two groups (33% for the experimental
group, 25% for the control group). The olanzapine groups conversion rate increased and the
prodromal symptoms were significantly higher in severity after the drug was stopped. The
overall conversion rate for the whole sample was 35% (21 out of 60). These results suggest
that the treatment did not afford protection after it ceased. Thus, active treatment may delay
conversion to psychosis, but there is no evidence that short-term treatment will avert
conversion. The NNT found in the McGorry et al. [89] study (NNT = 4) was similar to the
NNT found in this study (NNT = 4.5) [93].
In two additional open-label studies, researchers have examined the effect of atypical
antipsychotics on symptom severity in putatively prodromal individuals. A small,
nonrandomized study examined 15 participants after 8 weeks of receiving aripiprazole. Results
indicated reductions in positive, negative, disorganization and general symptoms and a
significant functional improvement [94]. A randomized parallel-group study compared
amisulpride plus needs-based treatment (n = 61) to needs-based treatment alone (n = 40). The
needs-based treatment included psychoeducation, crisis intervention, family counseling and
assistance with education or work-related difficulties. None of the participants were taking
antidepressant medications. At the 12-week outcome, amisulpride plus needs-based treatment

was associated with a reduction in positive, basic, negative and depressive symptoms, as well
as an improvement in functional deficits [95]. Both aripiprazole and amisulpride were
associated with less weight gain than has been observed with olanzapine or risperidone.
In summary, five studies have examined the effects of antipsychotic medications during the
prodrome. The results from these studies suggest that intervention may delay conversion to
psychosis and ameliorate symptoms during the active phase of treatment but there is no
evidence of lasting effects after treatment cessation. Of concern is recent evidence that long-
term use of even low doses of antipsychotic medication can cause sensitization of dopamine
receptors in the brain. This has been suggested to possibly lead to supersensitivity psychosis
or rapid-onset psychosis following cessation of antipsychotic medication [96]. This suggests
an additional risk not considered in previous clinical trials that incorporate cessation as part of
the research design. Two separate research groups found that four or five individuals need to

be treated to prevent one individual from converting to a psychotic disorder. The question of
whether or not this is an acceptable NNT, in light of the problem of false-positives, is open to
debate (for further discussion, see the Ethical implications section of this article).
The past few years have seen an increase in naturalistic studies exploring the effects that
antidepressants can have on reducing conversion to psychosis. In a naturalistic treatment study,
48 prodromal patients were prospectively examined [97]. Of the 20 patients prescribed
antidepressants, none converted to a psychotic disorder over the next 2 years. By contrast, of
the 28 patients prescribed antipsychotics, 12 (42.9%) went on to develop psychosis. The only
baseline difference noted between these two groups was significantly more disorganized
thinking in the antipsychotic-treated group. However, of the 12 patients who were prescribed
antipsychotics, 11 were nonadherent (defined as a failure to take medication for 4 or more
weeks). By comparison, four out of 20 were nonadherent to antidepressants. Thus, 91.7% who
converted were not receiving any treatment. The researchers concluded that antidepressants
may be a beneficial start to treatment in prodromal adolescents as this study suggests adherence
is higher for antidepressants in this group.
Subsequently, another research group retrospectively examined naturalistic data and found that
of the 35 participants prescribed antipsychotics, ten (28.6%) went on to develop psychosis in
the next 2 years, while one of the 13 (7.7%) prescribed antidepressants developed psychosis
in the next 2 years [98]. Two potential explanations for these results have been offered. First,
something about the participants presentation may have prompted prescription of

antidepressants instead of antipsychotics and vice versa. For example, in the Cornblatt et al.
study, the higher level of disorganized thinking may have been both an indicator for higher
risk and a prompt for healthcare professionals to prescribe antipsychotics [97]. Second,
antidepressants may have an effect on the development of psychosis. Antidepressants could
improve mood, thereby reducing faulty attributions and appraisals of prodromal symptoms.
Similarly, antidepressants may also influence the risk of psychosis by modulating how
participants respond to environmental stressors [98].
A third study naturalistically examined the effects of antipsychotics and antidepressants on

symptom severity. In a large, multisite study including 191 patients, those prescribed
antipsychotics (9%) evidenced higher baseline-attenuated positive symptom scores but a
greater decline in positive and disorganized symptom severity at 6-month follow-up when
compared with those who did not receive antipsychotic medication. Those prescribed
antidepressants (42%) did not evidence a significant decline in symptom severity [99]. These
data suggest that patients with more severe symptoms are prescribed antipsychotics in routine,
naturalistic settings and that antipsychotics are associated with a decline in symptom severity;
patients prescribed antidepressants were not as symptomatic at baseline and did not evidence
a significant improvement in symptoms over the 6-month period. The duration the participants
were taking antidepressants was not available, so it is possible that the effect had already taken
place and, thus, was not captured in this study.
Overall, the results of these three studies suggest that antidepressant medications are associated
with symptomatic improvement among potentially prodromal adolescents and young adults.
However, the causal relationship has not been determined. At this time, it is equally possible
that those with less severe symptoms are more likely to be prescribed an antidepressant as it
is antidepressants that contribute to a decrease in prepsychotic symptom severity. As there is
evidence that antidepressants are better tolerated in prodromal participants compared with
antipsychotics, double-blind, randomized, parallel-group, placebo-controlled trials are
warranted.

Psychological interventions
Although data suggest that pharmacotherapy could be a fruitful avenue to explore for effective
intervention during the prodrome, even individuals with psychosis who are adherent to
medication and whose symptoms respond well to antipsychotics commonly evidence residual
symptoms and functional impairments. Psychological interventions have been explored as
cost-effective, well-tolerated adjuncts to pharmacological agents. In patients with
schizophrenia, research indicates that social skills, cognition and interaction training programs
lead to improvements in measures of social functioning [100,101]. Psychoeducational family
interventions also improve social adjustment as well as quality of life, family burden and
treatment adherence [102]. When provided as an adjunct to other treatments, cognitive
remediation has been shown to improve psychosocial functioning, functional outcomes and
cognition [103]. Regarding symptom amelioration, cognitivebehavioral therapy (CBT) has
been used to guide patients to challenge and modify thoughts, emotions and behaviors, as well
as improve coping strategies as a means of decreasing the level of conviction of delusions and
hallucinations (and therefore severity). One meta-analysis found an effect size for reduction
of psychotic symptoms with CBT of 0.65 [104]. Lasting results were found with 6- to 12-month
post-treatment follow-up analyses (e.g., effect size = 0.93) [104109]. Thus, meta-analyses
and reviews strongly support the use of adjunct psychological interventions in patients with
schizophrenia. Considerably less research has been conducted in prodromal individuals.
One early intervention study examining a small sample using a nonstandardized treatment
design found that psychosocial stress management in concert with neuroleptic treatment on an
as-needed basis might have reduced the incidence of schizophrenia in one catchment area in
the UK [110]. In Australia, 10 years later, risperidone augmented with CBT was compared
with standard supportive psychosocial intervention in prodromal individuals [89]. As
previously noted, the results do not allow for examination of the relative contributions of
risperidone and CBT, but the encouraging findings that psychosis may have been delayed or
prevented spurred further studies. In the UK, 58 help-seeking UHR patients were randomly
assigned to 6 months of cognitive therapy (CT; median number of sessions = 11) or treatment
as usual (mean of 12 sessions) and then followed-up 12 months later. CT significantly reduced
the likelihood of transition to psychosis over 12 months and the likelihood of being prescribed
an antipsychotic medication. The intervention group also had significantly improved APS. The
low withdrawal rate (14%) led researchers to conclude that the treatment was well-tolerated
and that further research was warranted [57]. A total of 49% (n = 17) of participants in the CT
condition and 43% (n = 10) in the monitoring-only condition were followed-up 3 years later
[111]. Participants in the CT condition continued to evidence a decreased likelihood of being
prescribed antipsychotics, but the previous main effect of CT-assigned participants decreased
transition to psychosis was not maintained on standard measures of conversion. The authors
cite the low follow-up rate as a possible explanation for the findings. Another randomized
controlled trial compared CBT to supportive counseling in 67 prodromal individuals. The

researchers did not find a statistically significant difference between the two types of treatment;
both were associated with improvements in work and global functioning ratings as well as
social functioning [112].
As noted previously, persons with SPD also evidence an increased risk for developing a
psychotic disorder. Participants meeting criteria for SPD (mean age = 24.9 years) were
randomized to 2 years in an integrated treatment or standard treatment group [113]. The
integrated treatment included weekly assessment of symptoms, social skills training (groups
or individually), psychoeducation in multiple-family groups and antipsychotic medication. The
standard treatment at a community mental health center only rarely included social skills or
daily living activity training, but did provide antipsychotic medication. Thus, only the
psychosocial treatment of the group was manipulated; antipsychotic medication was not

controlled and was relatively common (68% overall, no difference between groups). After the
first year, of the 67 participants, three out of 37 (8.1%) in the integrated treatment group and
ten out of 30 (33.3%) in the standard treatment group had converted to a psychotic disorder.
Nine of the 13 (69.2%) who converted had been treated with an antipsychotic medication. The
participants in the integrated treatment group evidenced significantly lower negative symptoms
after the first year of treatment. After the second year, of the 65 patients, nine out of 36 (25%)
in the integrated treatment group and 14 out of 29 (48.3%) in the standard treatment group had
converted to a psychotic disorder. Of the 23 who converted, 15 (65.2%) were being treated
with antipsychotic medication. At that point, there were no statistically significant differences
between the treatment groups. Since antipsychotic medication was not controlled and
adherence was not measured, it is impossible to conclude what effect medication had in this
study. However, the results from the first year suggest, that integrated treatment postpones
transition to psychosis in some individuals.
Thus, the extant research indicates that psychological interventions in the prodrome improve
functioning and symptomatology, but the active components of these therapies have not yet
been identified.
Emerging/recent treatments
Evidence on neurodevelopmental disorders suggests that fatty acid deficiencies or imbalances
may be a contributing factor [114]. Researchers have begun to examine the effects of fatty
acids, such as omega-3 fish oils (eicosapentaenoic acid [EPA] and docosahexaenoic acid
[DHA]), on neuropsychiatric disorders. There is evidence that 13 g/day of EPA or 10 g/day
of fish oil (mix of EPA and DHA) may be beneficial in the treatment of symptoms of
schizophrenia, depression, bipolar disorder, autism, attention-deficit/hyperactivity disorder,
dyslexia and dyspraxia [115118]. A double-blind, randomized, placebo-controlled treatment
study of omega-3 fatty acids found a reduction in the rate of transition to psychosis in 76 UHR
individuals; 38 participants were administered 1.5 g/day omega-3 fatty acids (0.84 g/day EPA;
0.7 g/day DHA) and 38 received placebo. After 12 weeks, one of the 38 (2.6%) participants in
the treatment group and eight of the 38 (21.1%) in the placebo group had converted to a
psychotic disorder. A significantly higher global assessment of functioning score in the
treatment group accompanied the significant difference in transition rate. No serious side
effects or adverse events were reported [119].
Recently, Amminger et al. reported findings from a follow-up to this study [120]. At the 12-
month follow-up, two participants in the omega-3 group (5%) and 11 in the placebo group
(29%) had converted to a psychotic disorder. In total, 67 of the 76 participants were included
in a 12-month follow-up for other outcomes. Those administered omega-3 evidenced reduced
attenuated positive, negative and general symptoms, as well as improved functioning compared
with the placebo-administered group. It is remarkable that the differences were robust through
the 12-month follow-up, as none of the previous randomized controlled trials of antipsychotics
in prodromal individuals have evidenced this sustained effect. In addition, the researchers
reported a high consent and low withdrawal rate, suggesting that this treatment is well tolerated.
Again, further research is clearly warranted to follow-up on these promising initial findings.
An ongoing, 24-week, randomized, double-blind trial is being conducted in approximately

eight sites in North America to determine whether the rate of progression to psychosis is lower
during 6 months of treatment with ziprasidone compared with 6 months of treatment with
placebo. The study, which aims to enroll 80 late adolescents and young adults meeting
established prodromal criteria (~40 in each arm), will secondarily examine whether ziprasidone
is more efficacious than placebo for prodromal symptoms and establish safety and tolerability
of ziprasidone in this population. Dosing of this atypical antipsychotic in the study follows a
fixed-flexible schedule, with participants weighing at least 45 kg being started at 20 mg twice

daily, with a titration schedule up to 80 mg twice daily unless a slower titration is needed owing
to side effects. The upcoming results of this study will substantially expand the literature on
the use of second-generation antipsychotics among individuals meeting prodromal, or UHR,
criteria.
Ethical implications
Ethical considerations have been reviewed elsewhere in great detail [121124]. The predictive
accuracy of UHR criteria is improving and researchers are developing predictive algorithms
that aim to significantly reduce the rate of false-positives. Despite these improvements, the
risks and benefits of treatment during the putative prodrome must be carefully weighed. Risks
include antipsychotic medication side effects (i.e., weight gain and somnolence) and adverse
events, as well as concern that stigmatization associated with the words psychosis and
schizophrenia may adversely affect UHR individuals. It is important to note that those who
meet UHR criteria are often help-seeking adolescents and young adults with serious mental
health challenges and declining functioning; those who do not transition to psychosis often
seek and obtain mental health services for a myriad of other disorders [52]. Furthermore, there
is emerging evidence that psychoeducation is often accepted and does not appear to be
stigmatizing [125]. Research on early intervention is still in its infancy; the benefits, indicated
duration and identification of when to discontinue treatment have not been established. At this
point, the benefits of intervention appear to include: reducing symptoms, delaying psychosis
onset while the patient participates in active treatment, and intervening during a time when the
individuals may retain a level of insight that may allow for establishment of trust with mental
health professionals and improved adherence to treatment [89,126]. These risks and benefits
must be considered in the context of psychological development. Adolescence and young
adulthood are critical periods of neurodevelopment and maturation of social, academic and
occupational skills. As such, delays in treatment may significantly impact functioning.
Alternatively, concern and stigma associated with psychosis may result in an unnecessary
curtailing of activities. For example, individuals may withdraw from presumably stressful
situations (e.g., living on their own, attending college) in an attempt to preserve their mental
health. In the case of false-positives, this could be detrimental to normal development. Best-
practice standards suggest the clinical staging model of care should be followed intervention
should begin with the most benign treatment administered as early in the illness as possible
and become increasingly aggressive as the development of the disorder progresses. Although
the risks of psychoeducation and treatments such as omega-3 fatty acids remain in question,
the benefits may outweigh the risks. This suggests that these treatments may represent safe and
efficacious interventions for the prodromal period, although further research is necessary.
Expert commentary
Adolescents and young adults who appear to be prodromal or at UHR should be monitored
and provided with symptom-targeted treatments (e.g., antidepressants, psychosocial
treatments). Antipsychotics should be used as soon as frank psychosis emerges. For the
investigational treatments reviewed herein, prodromal-appearing adolescents and young adults
should be referred to specialized research programs when possible. The potential benefits, and
minimal risks, associated with omega-3 fatty acids suggest that this treatment is promising as
an early intervention.
Five-year view
Over the next 5 years, the following advancements in the study of the prodromal phase of
schizophrenia and related psychotic disorders would greatly advance our understanding of the
development of psychosis and effective therapeutics:

Improvements in diagnostic tools to facilitate identification of those most likely to

benefit from early intervention (lower false-positive rate);
Randomized controlled trials to narrow in on a therapeutically effective dose of
antipsychotic medications elucidate the relationship between antidepressants and

conversion to a psychotic disorder, and better understand the effective/essential
components of psychosocial interventions;
Replications of the findings of Amminger et al. [120] on effectiveness of omega-3
fatty acids as a treatment with very low side effects.
Key issues
Schizophrenia and other psychotic disorders are often characterized by a
heterogeneous constellation of positive, negative and disorganized symptoms, as
well as accompanying cognitive, social and functional deficits.
Neurodevelopmental and neurodegenerative processes probably contribute to the
development of psychosis.
Early intervention programs target the period immediately preceding the onset of
frank psychotic symptoms (the prodromal period) and others work to reduce
treatment delays (duration of untreated psychosis) among those who already
exhibit frank psychotic symptoms.

Classification/diagnostic systems have identified early signs often seen in
individuals at high risk for developing a psychotic disorder. These include: basic
symptoms, attenuated positive symptoms, brief limited intermittent psychotic
symptoms, features of schizotypal personality disorder, genetic risk paired with
functional deterioration, as well as general symptoms that are not specific to
psychosis.
Currently, the predictive validity of these systems ranges from 25 to 40%. When
additional factors are taken into account, positive predictive value may increase
to 6880%. Thus, 2075% of individuals may be erroneously classified as
prodromal (false-positives).
Research has focused on early interventions, such as administration of
antipsychotic and/or antidepressant medications, psychotherapy for individuals
and families (cognitivebehavioral therpay has received the most support from the
few existing randomized, controlled trials), omega-3 fatty acids and combinations
of these treatments.
Weighing of risks/benefits leads some to consider the false-positive rate too high
to warrant early intervention with antipsychotics as a standard practice until further
research accumulates. The low risk associated with omega-3 fatty acids and
psychosocial interventions suggests that these are particularly good candidates for
more research on indicated preventive interventions for putatively prodromal
individuals.
Acknowledgments
Michael T Compton receives research support from the National Institute of Mental Health, focusing on first-episode
psychosis. He is the Emory University site principal investigator for a trial involving ziprasidone in the prodrome, led
by Scott Woods at Yale University and funded by Pfizer.

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Expert Rev Neurother. 2010 August ; 10(8): 13471359. doi:10.1586/ern.10.93.

Early signs, diagnosis and therapeutics of the prodromal phase of

Molly K Larson1, Elaine F Walker1, and Michael T Compton,2

A brief overview of schizophrenia

accompanied by blunted or inappropriate emotional expressions and motivational deficits.

2010 Expert Reviews Ltd

rank symptoms were seemingly pathognomonic to schizophrenia [7]. First-rank symptoms

Cognitive, social & functional deficits

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Neurodevelopmental & neurodegenerative models of schizophrenia

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

One promising area of research addresses the development of psychotic disorders in

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Diagnosis & classification of high-risk individuals

from an individuals previous experience or behavior, researchers have proposed several

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Therapeutics being investigated for the prodrome

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

the haloperidol-treated patients were associated with less improvement in neurocognitive

A small, nonrandomized, open-label clinical trial/pilot study of risperidone provided evidence

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Next, the first double-blind, randomized, parallel-groups, placebo-controlled study was

antidepressant medications. At the 12-week outcome, amisulpride plus needs-based treatment

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

something about the participants presentation may have prompted prescription of

A third study naturalistically examined the effects of antipsychotics and antidepressants on

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

controlled trial compared CBT to supportive counseling in 67 prodromal individuals. The

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

An ongoing, 24-week, randomized, double-blind trial is being conducted in approximately

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Improvements in diagnostic tools to facilitate identification of those most likely to

antipsychotic medications elucidate the relationship between antidepressants and

exhibit frank psychotic symptoms.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

20. Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M. Behavioural and

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

risk of developing psychosis.

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr. Bull

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am. J. Psychiatry

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

2001;51:4754. [PubMed: 11479065]

Expert Rev Neurother. Author manuscript; available in PMC 2011 June 1.

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