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Advances in the Early Detection and Prevention of Schizophrenia

Authors: Michael T. Compton, MD, MPH   Faculty and Disclosures

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A number of sessions at the annual meeting featured presentations pertaining to the early detection and intervention paradigm for psychotic disorders and research findings were discussed from around the world that may inform future prevention approaches. While the primary prevention of schizophrenia on a population level may remain a somewhat distant goal, early detection and intervention strategies are promising in terms of the secondary prevention of schizophrenia and related psychotic disorders.

In an industry-sponsored symposium entitled "Treating Patients Early: Updates on the Controversy," [1] Patrick D. McGorry, MD, PhD, Professor of Youth Mental Health at the University of Melbourne and Director of ORYGEN Youth Health and the ORYGEN Research Centre in Victoria, Australia, spoke on "The 'Prodromal' or Ultra-high Risk Stage of Schizophrenia and Related Psychoses: A Window for Understanding and Intervention." Dr. McGorry noted that interest in this area was stimulated in part by the 1994 Institute of Medicine (IOM) report entitled "Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research."[2] Dr. McGorry stated that the "entrenched level of disability" often associated with schizophrenia (eg, social withdrawal, dropping out of school, substance use, and other social collateral damage) often occurs prior to the initial psychotic episode, during the prodromal period. However, a significant portion of patients who have the same clinical phenotype as the prodrome do not go on to develop a psychotic illness. Symptoms may resolve or patients may develop another illness, such as major depression. Thus, for researchers attempting to identify potentially prodromal adolescents and young adults for prospective research, these individuals would be considered false positives.[1] Dr. McGorry also described a "false false positive" concept in which patients receive treatment or other protective factors during the prodrome that avert a psychotic episode, thus creating the appearance that the patient had been false positive for the prodrome, but actually the illness had been delayed or prevented.[1] Also of relevance, Dr. McGorry noted, is the recent work suggesting that the phenotype of psychotic symptoms extends to subclinical features in the general population. For example, the work of Dr. Jim van Os in the Netherlands has shown that up to nearly 20% of individuals in the general population endorse some level of minor psychotic experiences.[3-5]

The ultra-high risk or "prodromal" state is an undifferentiated mix of clinical features, which may include subthreshold or even intermittent suprathreshold psychotic symptoms. Dr. McGorry and his collaborators, particularly Alison R. Yung, MD, Medical Director of the Personal Assessment and Crisis Evaluation (PACE) Program in Melbourne[6], defined 3 types of syndromes to more fully classify the ultra-high-risk state.[7,8] A number of prodromal research programs around the world have demonstrated that the criteria for these 3 syndromal states predict conversion to psychosis in approximately 20% to 50% of individuals meeting the research criteria.

Dr. McGorry reviewed a sentinel series of randomized controlled trials that have given preliminary evidence for the possibility of reducing the risk of conversion from the ultra-high risk or prodromal state to frank psychosis. These include studies from Australia,[9] the United Kingdom,[10] North America,[11] and Austria.[12]

"All this adds up to an approach that we call the 'clinical staging model,'" Dr. McGorry stated.[1] That is, less-differentiated, early phases of psychiatric disorders benefit from broad-spectrum, simpler treatments. As clear target syndromes emerge, more specific interventions can be used. Because the evidence is still accumulating, clinical practice guidelines for youth who appear to be in a prodromal state are fairly conservative, and include tenets like engaging in youth-friendly services, carefully monitoring symptoms, and treating comorbidity.[13] Antipsychotics are generally not recommended unless frank psychotic symptoms emerge.

Barbara Cornblatt, PhD, MBA, Professor of Psychiatry at the Albert Einstein College of Medicine and Director of the Recognition and Prevention Program (RAP) at the Zucker Hillside Hospital at Long Island Jewish Health System in New York, spoke about "Differentiating between Prodromal Schizophrenia and Prodromal Bipolar Disorder."[1] The RAP program is designed for adolescents and young adults (aged 12-22 years) at clinical high risk (CHR) for schizophrenia, and more recently, bipolar disorder. In general, CHR is equivalent to the previously described ultra-high risk and "prodromal" states. Dr. Cornblatt noted that the marked increase in interest in these areas over the past decade relates to the fact that such research could lead us to more direct pathways to prevention. She presented her neurodevelopmental model of schizophrenia, which provides the theoretical underpinning for her program and research. In addition to a genetic diathesis, this model proposes a "second hit" during adolescence, such as abnormal cortical pruning, which is also genetically determined.

According to Dr. Cornblatt's model, 4 domains that are most representative of the underlying vulnerability for psychosis include cognitive deficits; affective symptoms, especially depression; social isolation; and school failure, which also relates to inability to function in work after the school years. Two particular areas that appear to predict conversion to psychosis in the RAP program and other North American prodromal research sites are lower verbal learning[14] and social isolation.[15,16]

Evidence suggests that the prodromal phase of bipolar disorder may be similar to the schizophrenia prodrome. At the end of phase 1 of Dr. Cornblatt's RAP program (which ended in 2005), 121 subjects had been assessed who were considered to be prodromal for schizophrenia. Of 31 patients who converted to psychosis, schizophrenia developed in 25 and bipolar disorder developed in 6. When Dr. Cornblatt examined her data to differentiate the bipolar prodrome from the schizophrenia prodrome, she found that the 2 types of prodromal periods looked remarkably similar. Preliminary data suggest that 1 possible risk factor -- impairments in verbal learning -- may be more specific for the schizophrenia prodrome. Other phenotypes (eg, social functioning, school performance) are probably overlapping in the prodromes for the 2 disorders. Dr. Cornblatt's group at Zucker Hillside Hospital is currently looking at abnormalities in circadian rhythm and temperament (eg, cyclothymic-hypersensitive traits) as possible ways to differentiate the prodrome of bipolar disorder from the prodrome of schizophrenia.[1]

A scientific and clinical report session , chaired by Derya Iren Akbihik, MD, PhD, focused on the question "Can Early Symptoms Predict the Course of Schizophrenia?"[17] This line of research is relevant to early detection and intervention for schizophrenia by virtue of improved prediction. Cherise Rosen, PhD, from the Harrow Chicago Follow-up Study spoke about "The Predictive Value of First-Rank Symptoms in Patients with Schizophrenia versus Psychotic Bipolar Mania."[17] Dr. Rosen began with a brief history of conceptualizations of schizophrenia, including descriptions of Emil Kraepelin, Eugen Bleuler, and Kurt Schneider. The latter writer identified 11 first-rank symptoms that were thought to be pathognomonic for schizophrenia, including audible thoughts, delusional perception, "made" feelings, "made" impulses or drives, "made" volitional acts, somatic passivity or an influence playing on the body, thought diffusion or broadcasting, thought insertion or thoughts ascribed to others, thought withdrawal, voices arguing, and voices commenting on one's actions.[18] Dr. Rosen presented a study that evaluated patients at index hospitalization and then at multiple timepoints over the next 25 years. The study addressed the degree to which first-rank symptoms, identified early in the illness, predict course. The sample included 86 hospitalized patients with schizophrenia and 30 with psychotic mania. Dr. Rosen reported that their findings indicate that patients with bipolar disorder do experience first-rank symptoms, although to a lesser extent than is seen in schizophrenia. Thus, first-rank symptoms are not specific to schizophrenia, but appear to be more prevalent and more persistent in schizophrenia. In terms of the impact of first-rank symptoms on recovery, those with first-rank symptoms were less likely to achieve remission.

Also in this scientific and clinical report session, Pirjo Mäki, MD, PhD, senior lecturer in the Department of Psychiatry, University of Oulu, Finland, discussed "Negative Features of Psychosis Precede Onset of Psychosis in a Prospective General Population Sample of Adolescents."[17] In clinical samples, it has become clear that negative symptoms and general symptoms precede psychosis, and may precede the onset of other disorders. This study aimed to identify whether a questionnaire-based psychopathology assessment could predict the onset of psychosis among general population adolescents. The study was based on the 1985-1986 Finnish birth cohort (all births in northern Finland in a 1-year period, which included 9432 births). The Finnish Hospital Discharge Register was used to find later cases of psychotic episodes. Members of the cohort were invited to participate in a field study in 2001-2002 when subjects were 15-16 years old. A 21-item scale measuring prodromal symptoms over the previous 6 months was administered. Two thirds of the cohort participated. Factorial structure of the questionnaire revealed factors of positive symptoms (11 items), negative symptoms (4 items), and general symptoms (5 items). Receiver operator characteristics curve analyses were used to determine cutoff points with the best sensitivity and specificity.

Six-month prevalences of positive features ranged from 6% to 35%. Girls reported more positive features; three-fourths of girls reported at least 1 positive feature, compared to about half of boys. Six-month prevalences of negative features ranged from 2% to 13%. Again, girls reported more negative features; one third of girls and about one fifth of boys reported 1 or more negative features. Six-month prevalences of affective or general features ranged from 9% to 24%. Girls once again reported more general features; more than one half of girls and about one third of boys reported one or more general features. Of the cohort members, 17 received treatment for a first episode of psychosis, and 95 received treatment for a nonpsychotic disorder in 2002-2005. Approximately 77% of those developing psychosis had endorsed 3 or more positive symptoms, compared to only 36% among those with a nonpsychotic disorder and 28% among those with no disorder (the latter 2 proportions were not statistically significantly different from one another). Roughly half (53%) of those developing a psychotic disorder had endorsed at least 2 negative symptoms, compared to 11% among those with a nonpsychotic disorder and 8% among those with no disorder (again, the latter 2 proportions were not statistically significantly different from one another). Nearly two thirds (65%) of those developing psychosis had endorsed at least 3 general symptoms, compared to 25% among those with nonpsychotic disorders and 15% among those with no disorder (in this instance, all 3 comparisons were statistically significant). Thus, prodromal-appearing features of psychosis are prevalent in adolescence, and all 3 symptom domains are associated with the later onset of psychosis. However, these very prevalent "prodromal" symptoms are not very good predictors of such a rare disorder. Risk prediction strategies will require greater refinement through the use of other risk factors and vulnerability indicators to improve the predictive utility of early subclinical, or subthreshold, symptom domains.[17]

In an international symposium on "The Emergence of Subthreshold Psychiatry," chaired by Ahmed Okasha, PhD(Director of the World Health Organization's Center for Training and Research in Mental Health) and Hagop S. Akiskal, MD , Dr. Okasha discussed "The Emergence of Subthreshold Psychiatry."[19] Dr. Okasha began by noting that "subthreshold disorders are recognized by all of you." He stated that subthreshold disorders -- syndromes that do not meet the threshold for formal diagnostic entities -- are associated with suffering, impairment, and disability; yet they are not classified by psychiatry's formal diagnostic systems. As such, subthreshold disorders are marginalized as atypical or "not otherwise specified." Over the past decade, there has been increased interest in subthreshold psychiatric syndromes.[20] However, little is known about the natural history and course of subthreshold conditions. For example, do they tend to be self-limiting, progressive, or persistent? Furthermore, virtually nothing is known about the effects of treatments on subthreshold syndromes. Multiple sources of data suggest that subthreshold conditions exist along a continuum with full syndromic disorders, and across many diagnostic categories. Critics tend to focus on the field of psychiatry extending of the boundaries of what is considered a mental disorder, arguing that this is a medicalization of normal human distress. Dr. Okasha noted that we don't have enough evidence yet to justify pre-onset pharmacologic treatments due to potential risks of side effects, but we do know that subthreshold conditions are in fact associated with impairment and require further research.

Another symposium, entitled "Recent Advances in Prevention Science: Implications for Practice and DSM-V," was chaired by William R. Beardslee, MD of the Judge Baker Children's Center and Harvard University.[21] This symposium was sponsored by the APA Corresponding Committee on Prevention of Mental Disorders and Promotion of Mental Health. In this symposium, Thomas H. McGlashan, MD, Professor of Psychiatry at the Yale University School of Medicine, discussed "Recent Progress in Preventing Schizophrenia." Dr. McGlashan pointed out that the field of schizophrenia research is alive with interest in the clues that early detection and treatment may hold for prevention of this disorder. Studies in this area include those that aim for early detection both after the onset of psychosis (during the first episode) and before the onset of psychosis (during the prodromal period). The former are exemplified by studies aiming to reduce the duration of untreated psychosis (DUP), such as the TIPS project in Norway and Denmark.[22,23] The latter is exemplified by several controlled studies of interventions during the prodrome mentioned above[9-12] and the recent work from the North American Prodrome Longitudinal Study (NAPLS) consortium.[15] In his concluding remarks on clinical implications, Dr. McGlashan stated that "close clinical monitoring, to see if potentially prodromal patients are indeed getting worse, is clinically indicated," even though much more research is needed on potential pharmacologic treatments during the prodromal period.

A symposium sponsored by the National Institute of Mental Health focused on "Advances in Early Detection, Treatment, and Prevention of Psychosis: Findings from the North American Prodrome Longitudinal Study."[24] This symposium that summarized multiple findings from the NAPLS consortium was chaired by Dr. McGlashan, along with Robert K. Heinssen, PhD of the National Institute of Mental Health. Dr. McGlashan opened the session by commenting that the importance of early detection prior to psychosis (during the prodrome) was recognized as early as 1927 by Harry Stack Sullivan, and the research field was launched largely by Drs. Alison Yung and Patrick McGorry in Melbourne, Australia, who defined 3 prodromal syndromes.[7,8] This symposium was comprised of a series of talks. These included: (1) "Predicting Psychosis Onset in Youth at High Clinical Risk: The Effects of Prodromal Symptoms, Neurocognition, and Family History" by Larry J. Seidman, PhD, from the Harvard Medical School and Massachusetts Mental Health Center; (2) "Risk of Mania in Persons at Heightened Clinical Risk of Psychosis" by Diana O. Perkins, MD, MPH, from the University of North Carolina at Chapel Hill; (3) "Cannabis Misuse and Risk for Psychosis in a Prodromal Sample" by Kristin Cadenhead, MD, from the University of California, San Diego; (4) "The Relation of Antipsychotics and SSRIs with Baseline Symptoms and Symptom Progression in Prodromal Subjects" by Elaine F. Walker, PhD, from Emory University; (5) "Psychosocial Treatments for the Psychosis Prodrome" by Jean M. Addington, PhD, from the University of Toronto; and (6) "Should the Psychosis Prodrome Be Included in DSM-V?" by Scott W. Woods, MD, from Yale University. Some findings from the NAPLS group have recently been published.[15]

In summary, the 161st Annual Meeting of the American Psychiatric Association had a number of interesting sessions on advances in the early detection and prevention of schizophrenia. These ranged from discussions of recent research findings on the prodrome of schizophrenia, to presentations on early predictive signs in first-episode psychosis, to provocative sessions on subthreshold psychiatry and incorporating the prodrome of schizophrenia into the DSM-V.


References

References

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