Early Intervention in Psychosis: Rationale, Results ...

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Keywords: Clinical high-risk, duration of untreated psychosis, early identification, early intervention, neurocognition, prevention, prodromal psychosis, psychosis, ...
Adolescent Psychiatry, 2012, 2, ??-??

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Early Intervention in Psychosis: Rationale, Results and Implications for Treatment of Adolescents at Risk William R. McFarlane*,1, Barbara Cornblatt2 and Cameron S. Carter3 1

Maine Medical Center Research Institute, Tufts University Medical School, 22 Bramhall Street, Portland, Maine 04012, USA 2

Recognition and Assessment of Psychosis, Zucker-Hillside Hospital, Albert Einstein College of Medicine, Glen Oaks, New York, USA 3

Center for Neuroscience and the Imaging Research Center, University of California Davis, 4701 X Street, Sacramento, CA 95817, USA Abstract: This article reviews the theoretical, conceptual and empirical background for the current and growing research on early identification and early intervention to obtain improved outcomes in psychotic disorders. The goal is to prevent episodes of psychosis and the functional disability that accompanies them. Described are the studies linking duration of untreated psychosis and later outcomes, the precedents for psychosis, current methods for assessing the likelihood of onset, and the treatment trials conducted to date. We conclude that the evidence is increasing that justifies early identification and prevention being routine clinical practice. We also conclude that further research needs to refine assessment methods to achieve higher predictive power and that treatments need to be better adapted to the specific conditions usually present during the prodromal period. Finally, larger-scale clinical trials and effectiveness studies need to be carried out to achieve better assessment accuracy and treatment efficacy. Such studies are currently underway in North America and Europe, with results expected in 2012.

Keywords: Clinical high-risk, duration of untreated psychosis, early identification, early intervention, neurocognition, prevention, prodromal psychosis, psychosis, schizophrenia. HISTORICAL BACKGROUND Among all medical disorders, schizophrenia is one of the most costly and severe, creating nearly continuous disability for a lifetime in the great majority of cases. 1% of the population suffers from this disorder, even though the incidence is low, about 1/10,000 per year. It is a devastating disorder for families, who often assume major caretaking and psychological burdens secondary to the functional deficits that this and other psychotic disorders impose. It has been estimated that the total lifetime cost for a single case of schizophrenia is greater than $10,000,000 (Rupp & Keith, 1993). While often not as severe, the major mood disorders exact a significant toll on persons who have the disorders and those who attempt to care for, support and, sometimes, control them. The Surgeon General as early as 1998 found that mental illnesses accounted for as many years of lost productivity as cancer, second only to heart disease. Active psychosis ranks in the top three most disabling conditions worldwide (Thase & Comptom, 2008). It is estimated that 23% of the adult population eventually carries a psychotic diagnosis and suffers the disabilities that accompany it. Those functional disabilities, particularly devastating in schizophrenia and other psychotic disorders, often appear to *Address correspondence to this author at the Maine Medical Center Research Institute, Tufts University Medical School, 22 Bramhall Street, Portland, Maine 04012, USA; Tel: 207-662-2091 Fax: 207-662-3300; E-mail: [email protected] 2210-6766/12 $58.00+.00

be the result of deficit processes that usually begin prior to the psychotic symptoms but then persist in spite of treatment and may get worse with time and subsequent episodes. Psychosis has its onset in adolescence or young adulthood in at least 70% of the affected population (Kirkbride et al., 2006). It is increasingly clear that for many cases there is a substantial period of time within which it is possible to identify individuals in the prodromal period of psychosis, allowing secondary preventative intervention that may avert the most common and persistent residual deficits. Early treatment is increasingly seen as the necessary step to preventing deterioration and resistance to treatment. Patrick McGorry (P. D. McGorry, 2002), founder of the International Early Psychosis Association wrote, To argue against early detection and optimal treatment seems to defend the indefensible; namely requiring patients and families to reach a high threshold of risk, disruption and deterioration to access acute care and demonstrate a relapsing or chronically disabling pattern to justify continuing care. For those at risk, early intervention has the potential to prevent conversion to a full psychotic disorder diagnosis but may also treat the disorders, symptoms and impaired cognitive, social, and occupational functioning that are already present, as well as alleviate family distress. Early intervention programs may reduce duration of untreated psychosis (DUP) for individuals who already meet criteria © 2012 Bentham Science Publishers

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for a psychotic disorder. Reducing DUP may ameliorate the known impact psychosis can have on symptomatology, functioning, trauma, social networks, and the community at large (Bertelsen et al., 2007, 2008; T. K. Larsen et al., 2001; T. K. Larsen et al., 2011; ; Melle et al., 2005; Nordentoft & Hjorthoj, 2007). Perhaps the most intriguing question is, given the severe disabilities, suicides and large proportion of the population affected, why the psychotic disorders have not been defined more broadly as a major public health issue. CONUNDRUM OF PREVENTION EFFICACY VS. PREVENTION ACCURACY A number of issues have prevented schizophrenia and other psychotic disorders from being defined in a public health framework and from benefiting from populationbased preventive programs. For one, until recently the first episode psychosis (FEP hereafter) was defined by psychiatrists, particularly in the United States, as a psychological problem, not a disease. Attempts under the Kennedy Act to include prevention in the mission of community mental health centers may have inadvertently had the reverse effect, since those efforts often were defined as community-wide improvements in income, housing, racial integration and other general enhancements to communities with a high level of poverty. The failure of that largely unrealistic effort to garner wide support took prevention off the agenda for a decade or more. Stigma has also served as a barrier to more openly addressing schizophrenia and its societal burdens. Often suffering as much as the patients because of emotional, social and economic burdens, community rejection and blame, family members have organized to counter stigma. Those organizations have had notable successes in legislation seeking parity of mental with physical disorders regarding insurance claims and benefits. The most significant empirical influence on the emergence of efforts to prevent psychoses has been the mounting evidence that intervening during the period preceding and including the first episode of psychosis may have some of the most enduring impacts on the course of illness of any known factor, perhaps including treatment. Recent studies of first episode psychosis document that the average time between onset of psychotic symptoms and the initiation of treatment is from one to two years, depending on the study (Norman & Malla, 2001). These findings are troubling when one considers other studies that have shown a deteriorating course of illness and reduced response to treatment as the DUP lengthens and with each episode of psychosis (Haas, Garratt, & Sweeney, 1998; Lieberman et al., 2001; Loebel et al., 1992; Opjordsmoen, 1991). Similarly, frequency and severity of recurrence of severe affective disorders may be increased by exposure to periods of untreated depression or mania, and decreased by effective treatment (Jung & Newton, 2009; Olvet, Stearns, McLaughlin, Auther, Correll & Cornblatt, 2010; Post, Weiss, Leverich, George, Frye & Ketter, 1996; Rea, Tompson, Miklowitz, Goldstein, Hwang & Mintz, 2003; Yildiz & Sachs, 2003). Substance abuse and psychosocial stressors are also associated with persisting increased vulnerability.

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It has been widely hypothesized that the very earliest signs of development of psychosis arise during adolescence as a consequence of abnormal neurodevelopmental processes, which may have their effects early in development (prenatally), during early adolescence, or during both phases of development. Once present, symptoms and impairments may then be amplified and even triggered by psychosocial stress acting on cognitive, sensory, motor and other impairments in brain function, particularly after cognitive impairments begin to be manifest in deteriorating functioning. The intent and hope for early intervention is that this accelerating course may be altered or even reversed by earlier treatment (Barnes, Hutton, Chapman, Mutsatsa, Puri and Joyce, 2000; Black, Peters, Rui, Milliken, Whitehorn and Kopala, 2001; Craig, Bromet, Fennig, Tanenberg, Lavelle and Galambos, 2000; T. Larsen, More, Vibe-Hansen and Johannessen, 2000; Norman, Townsend and Malla, 2001; Verdoux, Liraud, Bergey, Assens, Abalan and van Os, 2001). In essence, present data suggest that symptomatic and, at least in part, functional outcomes may be determined by the duration of the untreated prodromal state. Supporting the new prevention effort is our growing knowledge of the pathophysiology of psychotic disorders. A large body of data suggest that primary genetic and neurodevelopmental components create a vulnerability to family, social and other environmental stressors (Reiss, Neiderhiser, Heatherington and Plomin, 2000; Tienari et al., 2004). The combined influence of these two strands of scientific and clinical progress has prompted several groups, especially in Europe and Australia, to develop assessment methods and/or treatment programs explicitly designed to intervene very early in the first episode and, more recently, in the period between onset of attenuated (subtle, or subclinical) psychotic symptoms and the onset of frank psychosis. This period has been termed the prodrome, borrowing a term from study of epilepsy, or “clinical highrisk” (CHR). Thus, at present, prevention of FEP is secondary prevention, or in current terminology, indicated. The cohort to be identified and treated preventively is, in the most technical terms, already experiencing the onset of illness, i.e., subtle symptoms of psychosis, and is often partially disabled cognitively and socially. During the prodromal period, these impairments usually do not rise to the level needed to meet current criteria for a schizophrenic or psychotic disorder. The principal barrier to this effort is accurate identification. In all indicated prevention approaches, there is an inherent contradiction between intervening early enough to prevent onset versus intervening with assurance in disorders that are actually present. Fig. (1) displays this contradiction graphically as it relates to psychoses. The earlier the point of intervention, the more ambiguous is the diagnosis, until diagnostic precision becomes clinically inadequate. The current scientific and clinical interest is in the prodromal or clinical high-risk (CHR) period in which disorder is manifest, though usually not in a form traditionally associated with an acute episode of psychosis. Fig. (1) could as well describe this limitation for breast cancer in relation to predictive accuracy of mammograms or for myocardial infarction in relation to pre-existing angina or

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Fig. (1). Validity of diagnosis across phases of psychosis.

elevated low-density lipoprotein levels. The nearly irreducible conundrum is that clinical indicators always carry the risk of over-identifying those at risk, including those who are not likely, at least in a reasonable period, to develop a fully expressed illness. Those indicators can also predict inaccurately by rejecting false-negatives. The psychosis prevention effort has focused on the positive predictive value as the proper measure, because it combines specificity and sensitivity, incorporating the four possibilities of the probability quadrant—false and true positives and false and true negatives. The specific psychiatric version of this conundrum is that many prodromal positive and negative symptoms and cognitive impairments are substantially confounded by developmental phenomena observed during normal adolescence. In addition, adolescents may be experiencing the onset of non-psychotic mood disorders, cluster-B personality disorders and severe anxiety disorders (especially PTSD and OCD), as well as acute grief reactions and, rarely, onset of major auto-immune disorders. Adolescents with long-standing attention-deficit disorder or Asperger’s Disorder further confuse the diagnostic process. All of these disorders may at times be accompanied by psychotic symptoms, symptoms similar to negative symptoms or transient impairments of cognition. To further complicate diagnostic validity, initially non-psychotic mood disorders, especially bipolar I, PTSD and OCD, can later develop into severe psychotic forms that may even evolve into schizophrenia or schizoaffective disorder. As Hafner

demonstrated, the most common prodromal indicator for schizophrenia is non-psychotic major depression or severe dysthymia, preceding the onset of attenuated psychotic symptoms (Hafner, Maurer, Trendler, an der Heiden & Schmidt, 2005). And, of course, those disorders usually do not progress to psychosis. To confound diagnosis and prognosis further, McGorry found that nearly every adolescent surveyed had briefly experienced at least one psychotic symptom (McGorry, McFarlane, Patton, Hibbert, Jackson & Bowes, 1995). Thus, even though evidence-based treatments for psychosis have been available for decades, the fundamental barrier has been developing assessment methods accurate enough to justify using those treatments, both from the perspective of effectiveness and ethical practice. The confounding with adolescent developmental aspects is especially challenging and has only recently been partially disentangled. However, as has been demonstrated in a number of basic and clinical studies, the course of psychosis onset differs substantially and to an increasing degree from several of the major markers of adolescent development. Alterations of normal developmental pathways in the pre-psychosis period include a disturbing reversal of intellectual development, with some adolescents losing 10 or even 20 points on IQ tests. The usual trend toward increased social engagement with peers and interests outside the family is replaced by encroaching social withdrawal and loss of social skills, in the end state often involving withdrawal even from family contact. At the same time, the prodromal adolescent is

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becoming increasingly dependent on family support, in sharp contrast to peers. While adolescents typically develop a broader and more finely differentiated range of emotional experience and expression, the adolescent at risk is often experiencing a flattening of affect, depression, affective lability or uncontrollable mood swings. In the later phase of onset, there is a disabling loss of executive, organizational and life skills that contrasts markedly with the growing skills and capabilities of peers and siblings. In the phase accompanying attenuated psychotic symptoms, the at-risk adolescent is often eccentric in behavior and appearance, projecting an oddness that contrasts with even the most socially deviant of peers. Finally, in contrast to expanding verbal skills and vocabulary, these young people often complain of increasing expressive and receptive aphasia, an experience that for some is severely incapacitating and anxiety-provoking. A common subjective symptom is that the adolescent feels that he or she is becoming dumb, retarded or demented. That is often reflected in deteriorating academic performance, in spite of their best, continuing academic effort. One of the most subjectively frightening aspects, again contrasting with normal development, is diffusion and fragmentation of identity, a subtle but often one of the more debilitating symptoms of encroaching psychosis, one that may carry a substantial suicide risk. Thus, as the adolescent progresses toward an acute psychotic episode, he or she increasingly differs from peers, siblings and, most importantly, from his or her previous developmental trajectory. THE PRECEDENTS AND PREDICTORS OF THE FIRST PSYCHOTIC EPISODE Attenuated Positive Symptoms There are now widely used valid and reliable instruments to identify individuals at risk of psychosis or experiencing early symptoms of a first episode of psychosis. In response to the evidence for longer DUP predicting poor outcome, research has increasingly focused on the opposite tendency—to reduce DUP to the minimum possible, and to go farther, and reduce it to less than zero. Most of this issue is devoted to the latter alternative, but it begins with this rather simple observation, described in detail above,—that being psychotic for long periods leaves one vulnerable to increasing severity, more disability and reduced response to treatment. The practical effect has been to spur development of indicators that could predict likelihood of short-term onset of psychosis. All have focused on symptoms that are more characteristic of schizophrenia, even though psychosis itself is not limited to a single diagnostic entity. Beginning with well-known risk factors—schizoid tendencies, having a first degree relative with a psychotic disorder—the effort to develop instruments to select high risk-for-psychosis subjects has centered primarily on attenuated or more subtle or “subthreshold” versions of psychotic symptoms. Thus, four well-described criteria sets, one with an interview schedule, have arisen. Two are variations on the DSM-IIIR definition of prodromal schizophrenia. The Comprehensive Assessment for At Risk Mental States (CAARMS) (Yung et al., 2003) and the Structured Interview

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for the Prodromal Syndrome (SIPS) (Miller et al., 2003) define risk for psychosis under three categories: (1) attenuated psychotic symptoms, (2) brief and intermittent psychotic episodes (1 week to one month) and (3) having a first degree relative with a psychotic disorder and/or having schizotypal personality disorder and recent marked functional deterioration. The Bonn Scale for the Assessment of Basic Symptoms (BSABS), developed by Huber and refined and tested by a group at the University of Cologne, assesses for elements of thought disorder (interference, perseveration, pressure, blockage, derealization, etc.) and achieves 70-80% predictive accuracy for onset of later psychosis (Klosterkotter, Hellmich, Steinmeyer and Schultze-Lutter, 2001). Cornblatt has added a measure of negative symptoms, finding that a large proportion of cases of psychosis will manifest subtle versions of this deficitrelated syndrome, even prior to onset of attenuated psychotic symptoms (Cornblatt, Obuchowski, Roberts, Pollack, & Erlenmeyer-Kimling, 1999). A review compiled results of 16 follow-up studies (Haroun, Dunn, Haroun and Cadenhead, 2005). In the early studies, the overall average for conversion to psychosis using the various existing criteria sets was 43%, or about 2.5 % per month or 30-35% per year. In some samples treatment was provided, and given the results of recent clinical trials, that would be expected to reduce the rate of conversion to psychosis. Three prospective, multisite naturalistic follow-up studies have been, or are being, conducted that provide a more methodologically rigorous assessment of current predictive power, as well as the clinical and functional fate of their samples and important subgroups. The Cologne study is described above (Klosterkotter, et al., 2001). The North American Prodromal Longitudinal Study (NAPLS) involves 8 sites in the U.S. and Canada and is following subjects based on the SIPS criteria (Cannon, Cadenhead, Cornblatt, Woods, Addington, Walker, Seidman, Perkins, Tsuang, McGlashan and Heinssen, 2008). The European Prediction of Psychosis Study (EPOS) involves six sites in Germany, Netherlands, Finland and the U.K., following subjects found to be at risk by algorithms based on both the SIPS and the BSABS (Ruhrmann, Schultze-Lutter, Salokangas, Heinimaa, Linszen, Dingemans, Birchwood, Patterson, Juckel, Heinz, Morrison, Lewis, von Reventlow and Klosterkotter, 2010). The conversion rates reported in the EPOS were 49% at 9.6 years, 35% at 2.5 years and 19% at 1.5 years, respectively, reflecting the variation in risk observed over time and place. In NAPLS, prediction algorithms combining 2 or 3 of 5 factors resulted in increases in positive predictive power (i.e., 68%-80%) compared with the prodromal criteria alone, though cases meeting these more predictive criteria were low in frequency, which limits the practical utility of these findings for broad-based early identification. The factors that were most predictive were: genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. In EPOS, a subgroup with the highest prognostic score was found to have a hazard rate of over 80%, based on 6 factors—SIPS Positive symptoms, bizarre thinking, sleep disturbance, schizotypal personality disorder, Global Assessment of Functioning (GAF) score

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and years of education. These results suggest that predictive accuracy is likely to increase as research on other factors proceeds. A frequent criticism has been made of the fact that numerous non-converting subjects are false positive for psychosis, reflecting concern that ethical practice would dictate watchful waiting to determine diagnosis (Haroun, et al., 2005). However, there is a consensus that such persons are often quite functionally disabled, regardless of their nearterm fate with respect to developing a frank psychosis (Ruhrmann, Paruch, Bechdolf, Pukrop, Wagner, Berning, Schultze-Lutter, Janssen, Gaebel, Moller, Maier and Klosterkotter, 2008; Ruhrmann, Schultze-Lutter and Klosterkotter, 2010). In EPOS, poor social functioning alone predicted conversion to psychosis (Velthorst, Nieman, Linszen, Becker, de Haan, Dingemans, Birchwood, Patterson, Salokangas, Heinimaa, Heinz, Juckel, von Reventlow, French, Stevens, Schultze-Lutter, Klosterkotter and Ruhrmann, 2010). Further, one study with a much longer observation period (mean 9.6 years) found an increasing rate of true positives (Klosterkotter, et al., 2001). The current system of early identification for indicated prevention is an advance, and most sites have found that it selects a reasonably accurate sample of those at risk. However, there has been a trend toward lower rates of conversion at sites that have been doing research on the clinical high risk sub-population. This change suggests that over time, earlier identification tends to reduce the incidence of those close to onset of frank psychosis, very high risk cases and youth with longer prodromal periods. Serial measures of conversion rates in the same location, particularly Melbourne, have found a decreasing rate of conversion in untreated samples and control subsamples in clinical trials. This observation suggests either a limitation in the identification process and a tendency for an increased false positive rate with broader based ascertainment, or the longer-term effect of early intervention across more than a decade within a specific population in which early intervention has become widespread (A.R. Yung, Yuen, Berger, Francey, Hung, Nelson, Phillips and McGorry, 2007).(A.R. Yung, et al., 2007). The latter is the more parsimonious explanation and is concordance with the experience of indicated interventions in medical disorders. Given that there is a considerable proportion of false positive cases identified, efforts are underway to make more precise the identification process. Among many, reported examples include: (1) a brief test exposing subjects to a recording of six conversations at once discriminates those with the prodrome and high risk for conversion from normals (Hoffman, Woods, Hawkins, Pittman, Tohen, Preda, Breier, Glist, Addington, Perkins and McGlashan, 2007); (2) a constellation of impairments in working memory, verbal memory, executive function and impaired sensory sensitivity seems to be specific to the schizophrenia prodromal state (B. Cornblatt, Malhotra and al., 2001; B. A. Cornblatt, et al., 1999); (3) a test of smell sensitivity that is highly correlated with schizophrenia and is markedly abnormal in the prodromal period (Woodberry, Seidman, Giuliano, Verdi, Cook and McFarlane, 2010); and (4) a change in cortical volume on MRI examination (Sun, Phillips, Velakoulis,

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Yung, McGorry, Wood, van Erp, Thompson, Toga, Cannon and Pantelis, 2009), and (5) increased pre-synaptic dopamine in the striatum measured using PET imaging(Fusar-Poli, Howes, Allen, Broome, Valli, Asselin, Montgomery, Grasby and McGuire, 2011). It is likely that the current clinicalinterview and symptom criteria approach will be supplemented with validated biological and neurocognitive markers that will improve accuracy of prediction. Paradoxically, given the severe functional difficulties being experienced by false-positive cases, the prodromal population may still be appropriate for targeted evidencebased preventive intervention at the public health level, regardless of the ultimate risk for a psychotic episode. The North American Prodromal Longitudinal Study found that about 20% of clinical high risk youth were still symptomatic at 1 year, while 24% had fully remitted their prodromal symptoms (Addington, Cornblatt, Cadenhead, Cannon, McGlashan, Perkins, Seidman, Tsuang, Walker, Woods and Heinssen, 2011). Early intervention will most likely arrest the onset of other, non-psychotic but still very serious disorders, particularly severe mood and anxiety disorders, some of which are as disabling as better-prognosis schizophrenia. Also, the Cologne study suggests that some false-positive cases observed during a one-year period may actually be “false-false-positives”, because some ultimately psychotic patients may have a long prodromal period (Klosterkotter, et al., 2001). Other individuals with attenuated psychotic symptoms, negative symptoms and functional disabilities for a long period experience increasingly serious and treatment-resistant disability. Improved identification could well build on the current strategy of identifying those at risk of psychosis by improving accuracy of risk for general psychiatric disability, including serious mood and anxiety disorders, as opposed to more accurately identifying a specific psychotic disorder. Schizotypy It has long been proposed that schizophrenia develops upon a substrate of abnormal brain, cognitive and psychological functions, collectively known as schizotaxia (Lenzenweger and Moldin, 1990). One clinical manifestation of this predisposing substrate may be schizotypy. Schizotypal personality disorder is included as one risk factor in both CAARMS and SIPS. Two studies have validated it as a risk factor, the first in Denmark, a clinical trial known as OPUS (Merete Nordentoft, Thorup, Petersen, Ohlenschlaeger, Melau, Christensen, Krarup, Jorgensen and Jeppesen, 2006), in which the transition rate by two years was 48%, and the other based on data from the NAPLS study (Woods, Addington, Cadenhead, Cannon, Cornblatt, Heinssen, Perkins, Seidman, Tsuang, Walker and McGlashan, 2009). However, the well-known tendency of persons with that diagnosis to avoid treatment and social engagement will likely limit the clinical utility of that diagnosis as a means of identifying substantial portions of the at risk population. Negative Symptoms and Cognitive Impairment Cognitive deficits have long been shown to be core components of the underlying vulnerability to psychosis (W.

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J. Brewer, S. J. Wood, L. J. Phillips, S. M. Francey, C. Pantelis, A. R. Yung, B. Cornblatt and P. D. McGorry, 2006) and are considered to more directly reflect underlying brain abnormalities than clinical symptoms (i.e. to be endophenotypes of psychosis; Gottesman et al., 2003). As a result, the nature of early cognitive dysfunctions, which may precede positive symptoms by many years, should serve to both inform treatment and point to individuals at true risk. It thus follows that adding specific cognitive deficits to the criteria defining clinical risk should improve predictive accuracy. While some progress has been made in achieving this goal, there are a number of problems yet to be resolved before expectations about the predictive role of cognition will be met in clinical high risk research. In general, a number of studies have reported that prodromal subjects, as a group, are impaired cognitively relative to healthy controls. (Carrion, Goldberg, McLaughlin, Auther, Correll and Cornblatt, 2011; Hawkins, McGlashan, Quinlan, Miller, Perkins, Zipursky, Addington and Woods, 2004; Lencz, Smith, McLaughlin, Auther, Nakayama, Hovey & Cornblatt, 2006; Seidman et al., 2010; Woodberry, et al., 2010). However, there are several issues to resolve before these findings can be considered clinically applicable. First, there is considerable inconsistency across studies when identifying which specific deficits are involved, suggesting that this is a generalized deficit and results may be dependent on the measures used. An alternative perspective, based upon constructs from cognitive neuroscience, has suggested that cognitive control deficits, depending upon neural systems regulated by the prefrontal cortex, may underlie a wide range of cognitive deficits seen in schizophrenia and at risk individuals(Lesh, Niendam, Minzenberg and Carter, 2011 ). The magnitude of cognitive deficits in prodromal individuals (between .5 and 1.0 standard deviations below normal) on most neurocognitive measures (e.g. Trials A, Letter-Number Span, Continuous Performance Test-Identical Pairs version, and Digit Symbol Coding of the MATRICS battery; Green et al.; 2004a) lies midway between normal controls and patients (who are typically around 2 or more standard deviations below normal on such measures). It thus appears that cognition is not as impaired in the prodromal stage as it will become later in the illness, suggesting an opportunity for early intervention. However, it is as yet unclear if this pattern of intermediate deficits is due to the high false positive rate in the prodromal group, where false positive individuals would be expected to perform normally on measures, such as those in the MATRICS, and thus pull up the group mean, or is due to the fact that neurocognition gets worse as psychosis becomes chronic. Given the lack of consensus as to a possible gold standard measure, it will be difficult to generate comparable assessments across clinical settings. Intervention plans are based on normalizing cognitive deficits that are not yet severe. However, this remains an assumption because the notion that cognition becomes increasingly impaired is largely based on crosssectional studies in which a group of prodromal individuals is compared to a group of converted subjects. Few prospective longitudinal studies have yet published data addressing the course of cognitive changes across illness stages. As a result, the point at which cognitive problems start to develop is unclear, and therefore it is unknown when

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intervention should start and at what level of remediation (severe deficits might require different methods than moderate to mild impairments). Severity concerns are based on the possibility that the moderate impairment level characteristic of prodromal individuals as a group might well represent a mix between true positives with severe deficits and false positive individuals (around 70% of any given prodromal population) who perform relatively close to normal. When combined, these two different groups generate an averaged, moderate deficit level for prodromal subjects overall which masks the true nature of the deficit. The inconsistency in specific deficits, uncertainty as to when these deficits occur and how severe they are, makes it currently difficult to operationalize neurocognitive criteria in a way that would help to improve prediction. At present, the notion that prodromal subjects have a general cognitive impairment, or, comparably, a generally lower IQ, is too non-specific to be useful in a clinical setting. Only a handful of studies have included cognition when directly evaluating prediction, and the findings reported in these cases have been inconsistent. A range of specific deficits, including verbal memory, working memory, processing speed, and olfactory identification have been reported to have potential as predictors of psychosis (W.J. Brewer, Francey, Wood, Jackson, Pantelis, Phillips, Yung, Anderson and McGorry, 2005; W. J. Brewer, Wood, Pantelis, Berger, Copolov and McGorry, 2007; W.J. Brewer, S.J. Wood, L.J. Phillips, S.M. Francey, C. Pantelis, A.R. Yung, B. Cornblatt and P.D. McGorry, 2006; Eastvold, Heaton and Cadenhead, 2007; Lencz, et al., 2006; Woodberry, et al., 2010). Social deficits have been shown to predict psychosis (Velthorst, et al., 2010). However, the cognitive dysfunctions that appear to be the strongest predictors differ from study to study and Seidman (Seidman, et al., 2010) did not find that any neurocognitive abnormalities added to prediction accuracy above the variance accounted for by clinical risk factors. Furthermore, impaired neurocognition has typically been considered by many researchers to be more closely associated with longterm functioning than with positive symptoms (M. F. Green, 1996; Michael F. Green, Kern and Heaton, 2004b), raising theoretical questions about the usefulness of cognitive deficits for predicting psychosis in any case. While the relationship between cognitive and functional difficulties in patients is quite substantial (M. F. Green, 1996), a recent report by Carrion, et al (2011) indicates that during the prodromal phase, the overlap is only about 20%, suggesting that social and role problems, and possibly other negative symptoms, should be studied as possible predictors in their own right. Although very little attention has been directed to the role of negative symptoms in general, impaired social functioning, in particular, has been reported to predict psychosis in several studies, while, at the same time, appearing to be a basic component of the long term disability typically associated with psychosis (Cannon, et al., 2008; Carrion, et al., 2011; Barbara A. Cornblatt, Auther, Niendam, Smith, Zinberg, Bearden and Cannon, 2007). Genetic Risk Beyond using early symptoms of illness, the search for indicators of risk has been based on the known predictors of

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schizophrenia. The risk factors for which there is the best evidence fall into three broad categories: (1) genetic abnormality, usually heritable but possibly also secondary to de novo mutations; (2) disruptions of fetal brain development during the first and early second trimesters by viral infections and other intrauterine stressors, and perinatal brain injury; and (3) marked negativity, rejection, psychological trauma, life events, and sustained stress in family, social and occupational environments and interactions. Primary among known and previously studied risk factors is genetic risk. Schizophrenia and bipolar disorder have been shown to have heritability rates of over 80%, based on twin and other studies of family history and analyses of transmission rates (Kendler, 2000). Linkage studies have had limited success in associating specific genes, many with functions related to brain function and even to specific neurotransmitters associated with schizophrenia. The leading candidates currently are: (1) neuregulin, which has a key role in fetal neural development (Lewis, Levinson and Wise, 2003); (2) brain-derived neurotrophic factor, which regulates synaptic formation and is also associated with major depression (Rosa, Cuesta, Fatjo-Vilas, Peralta, Zarzuela and Fananas, 2006); (3) dystrobrevin binding protein, which is involved in synapse formation and possibly with GABA receptor expression (Schwab, Knapp, Mondabon and al., 2003); (4) G72 and G30, which also are associated with bipolar disorder (Chumakov, Blumenthal, Guerassimenko and al., 2002); (5) G72 and G30, which also are associated with bipolar disorder (Chumakov, et al., 2002); and (6) dopamine3 receptor gene (Lohmueller, Pearce and Pike, 2003). The most recent evidence suggests that the most common genetic mechanism may actually be spontaneous mutation (Need, Ge, Weale, Maia, Feng, Heinzen, Shianna, Yoon, Kasperaviciute, Gennarelli, Strittmatter, Bonvicini, Rossi, Jayathilake, Cola, McEvoy, Keefe, Fisher, St Jean, Giegling, Hartmann, Moller, Ruppert, Fraser, Crombie, Middleton, St Clair, Roses, Muglia, Francks, Rujescu, Meltzer and Goldstein, 2009; Walsh, McClellan, McCarthy, Addington, Pierce, Cooper, Nord, Kusenda, Malhotra, Bhandari, Stray, Rippey, Roccanova, Makarov, Lakshmi, Findling, Sikich, Stromberg, Merriman, Gogtay, Butler, Eckstrand, Noory, Gochman, Long, Chen, Davis, Baker, Eichler, Meltzer, Nelson, Singleton, Lee, Rapoport, King and Sebat, 2008). Given the number of single-locus genes and non-specific mutations associated with psychotic disorders, it is unlikely that any single genetic marker will lead to reliable prediction or that a new single nucleotide-polymorphism will become a target for treatment. However, identifying constellations of genetic predictors could improve prediction, perhaps prior to the prodromal period. Further, providing protection against known causes of mutation during gestation could yield a new approach to primary prevention in families with elevated genetic risk. Evidence is inconsistent for some and effect sizes are modest. In any case, their relevance to prevention efforts at a public health level is currently remote. The conundrum of genetic approaches to prevention has been that most cases of schizophrenia do not manifest a family history. That reality suggests: (1) incomplete penetrance for a syndrome-specific,

Adolescent Psychiatry, 2012, Vol. 2, No. 2

7

universally present genetic substrate, or (2) random mutations occurring in parents and transmitted to offspring or occurring spontaneously during fetal development, or (3) a mixed etiology, with some having a genetic basis, perhaps following Mendelian patterns, and others predisposed by a number of non-heritable, mostly fetal or neurodevelopmental, abnormalities. The latter have been increasingly well demonstrated, opening more opportunities for selective or universal prevention. Currently, evidence for several such factors, some biological and others social, has developed. These include winter birth, (Torrey, Miller, Rawlings and al., 1997) prenatal maternal viral infection (Brown, 2006; Buka, Tsuang, Torrey and al., 2001); obstetrical complications (Boog, 2004; Heinrichs, 2001); Rh incompatibility (Hollister, Laing and Mednick, 1996); older parental age (El-Saadi, Pedersen, McNeil, Saha, Welham, O'Callaghan, Cantor-Graae, Chant, Mortensen and McGrath, 2004; Malaspina, 2001); immune system abnormalities, (DeLisi, Boccio, Riordan and al., 1991) (Wright, Sham, Gilvarry et al., 1996) (Eaton, Mortensen, Mors and al., 2004) fetal exposure to heavy metals, (Opler, Brown, Graziano, Desai, Zheng, Schaefer, Factor-Litvak and Susser, 2004) and early and heavy cannabis abuse (Weiser, Reichenberg and Rabinowitz, 2003). In spite of the high heritability of the psychotic disorders, clinical use of a family history of psychosis alone has proved to be of limited predictive value. On the other hand, family history of psychosis increases risk and is a necessary copredictor in interaction with family interaction stressors (MJ Goldstein, Rosenfarb, Woo & Nuechterlein, 1994; Tienari, et al., 2004). In prodromal populations, family history increases risk if there is a history of recent functional decline, and other risk factors, such as social problems or substance abuse, are also present (Cannon, et al., 2008). Environmental Risk Factors The article on family intervention and environmental factors in this issue describes the evidence for several psychosocial factors that predict onset or relapse in psychotic disorders, particularly schizophrenia. To summarize, those factors include high expressed emotion, communication disturbance, experiences of stigma by patient and family, social isolation, misattribution and misunderstanding, and stressful life events (M. Goldstein, 1985; W. R. McFarlane and Cook, 2007; Tienari, et al., 2004). In addition, there is increasing evidence that some families react to the onset of the prodromal phase in ways that are understandable, even expectable, but that are stressors in themselves. Some families actually visit trauma on the vulnerable child or adolescent, provoking PTSD and, especially in cases with genetic risk, early psychosis (Scott, Chant, Andrews, Martin & McGrath, 2007). Epidemiological studies have documented clear evidence that urban residence itself is a risk factor, especially if that includes racial or ethnic discrimination and/or isolation from ethnic or cultural communities (Eaton and Harrison, 2000; Marcelis, NavarroMateu, Murray and al., 1998). Finally, as clinical experience and research on cognition in this phase of onset has accumulated, it has become clear that interactions and relationships with peers and educational effort are often stressors, if only because increasing cognitive and social

8 Adolescent Psychiatry, 2012, Vol. 2, No. 2

impairments leave the individual unusually vulnerable to them. Biosocial Hypothesis Reflecting this large body of research, the first author has proposed a unifying biosocial theory upon which to base the design of preventive intervention (McFarlane, 2002). It states that the origin and course of schizophrenia and other severe psychiatric disorders are determined by the continual interaction of specific biological defects with specific social and other environmental influences (See Fig. 2). This theory has been validated by empirical demonstrations for the efficacy of combined pharmacological and psychosocial interventions in schizophrenia and other psychotic disorders. Those interventions are also beginning to prove effective in indicated prevention research. TREATMENT TRIALS TO DATE General Approach to Preventive Intervention The models of indicated prevention in heart disease and cancer, as well as the evidence for the long-term negative impact of untreated psychosis, have led to early treatment being increasingly considered as the necessary step to preventing onset of psychosis, deterioration and treatment resistance. Given the long prodromal period (often a year or longer) within which it is possible to identify individuals at risk, early identification and intervention may make possible a substantial improvement in functioning, symptomatology and prognosis. Recent clinical research has shown that application of existing, slightly modified evidence-based

Fig. (2). Biosocial causal interaction in schizophrenic prodrome. CD: Communication Deviance. EOI: Emotional Over-involvement. EE: Expressed Emotion.

McFarlane et al.

treatments for schizophrenia and mood disorders may alter short-term risk for psychosis, improve functional outcome and may enhance the ultimate prognosis. Six clinical trials have found that conversion to psychosis can be limited to about half or less of the expected (control) rate with medication and/or psychosocial treatment (Amminger, Schafer, Papageorgiou, Klier, Cotton, Harrigan, Mackinnon, McGorry and Berger, 2010; Bechdolf, Wagner, Veith, Ruhrmann, Pukrop, Brockhaus-Dumke, Berning, Stamm, Janssen, Decker, Bottlender, Moller, Gaebel, Maier and Klosterkotter, 2007; McGlashan, Zipursky, Perkins, Addington, Miller, Woods, Hawkins, Hoffman, Preda, Epstein, Addington, Lindborg, Trzaskoma, Tohen and Breier, 2006; P. McGorry, Yung, Phillips, Yuen, Francey, Cosgrave, Germano, Bravin, McDonald, Blair, Adlard and Jackson, 2002; Morrison, French, Walford, Lewis, Kilcommons, Green, Parker and Bentall, 2004; Merete Nordentoft, et al., 2006). Reviewed here is the current evidence that psychosocial and/or psychopharmacological treatment may be preventive and improve outcomes, but only if applied prior to onset of frank psychosis (see Table 1). Buckingham Falloon described a public health program in Buckingham and an adjoining county in England that was designed to detect and treat psychotic and prodromal states as early as possible (Falloon, 1992). Treatment was continued until prodromal symptoms had remitted. Sixteen cases were identified over the four years of the project, after

Early Intervention in Psychosis

Table 1.

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9

Clinical Trials of Indicated Prevention of Psychosis Control

Experimental

n

Converted

N

Converted

PACE

28

10 (35.7%)

31

6 (19.4%)

PRIME

29

11 (37.9%)

31

5 (16.1%)

OPUS

30

10 (33.3%)

37

3 (5.7%)

EDIE

23

6 (26.1%)

35

2 (5.7%)

O-3FAs

40

11 (27.5%)

41

2 (4.9%)

148

13 (8.8%)

323

31

PIER Total

150 Mean conversion rate

48 32.0%

9.6%

Rates for conversion to psychosis after one year of treatment or follow-up.

assessing more than one thousand referrals. Thirteen of those prodromal cases experienced recovery after family intervention and in some cases antipsychotic drug treatment. The other three had onset of psychosis or mania, but were treated to remission. There was a ten-fold reduction of the incidence rate in the catchment area. Manchester Cognitive Therapy Trial (EDIE) Morrison and his colleagues mounted a comparative clinical trial of cognitive therapy (CT) for young adults at risk to test efficacy for the prevention of transition to psychosis (Morrison, French, Parker, Roberts, Stevens, Bentall and Lewis, 2007). They randomly assigned 58 patients at high risk of developing a first episode to either CT or treatment as usual. Therapy was provided over 6 months, with monitoring for 12 months. Logistic regression demonstrated that cognitive therapy significantly reduced the likelihood of progressing to psychosis over 12 months, of being prescribed antipsychotic medication and of meeting criteria for a DSM-IV diagnosis of a psychotic disorder. It also improved positive symptoms. At three years, CT significantly reduced likelihood of being prescribed antipsychotic medication, but it did not affect transition to psychosis (Morrison, et al., 2007). With that and other methodological caveats, cognitive therapy appears to be acceptable and modestly effective for the older range of young adults whose cognitive development has been largely completed. German Research Network on Schizophrenia Another trial of cognitive therapy was reported from the German Research Network on Schizophrenia (Bechdolf, et al., 2007). A multisite study involving centers in Cologne, Bonn, Düsseldorf and Munich, the protocol involved subjects who were in the very earliest phase, manifesting basic symptoms (e.g., thought disorder and alterations of perception) which were used, along with full psychosis, as outcome indicators. The cognitive therapy addressed thought and perception deficits, negative symptoms, general anxiety and depression and family and occupational problems. This

condition was compared to supportive counseling, which comprised assessment, patient education and empathic, but unstructured, support. No medication was used. The treatment goal was to improve psychosocial and occupational functioning, which had not been shown to change in previous clinical trials in the prodromal phase. 113 cases were assessed, randomized and treated. While there were significant improvements over time for the sample in both conditions, there were no significant differences for CT over the comparison treatment. On the other hand, deterioration did not occur and the mean level of functioning improved significantly in both study treatment conditions. Danish National Schizophrenia Study of Integrated Treatment (OPUS) One multisite trial that proved to be preventive in nature was originally focused on early intervention in the initial psychosis. The Danish National Schizophrenia Project (OPUS, in Danish) compared outcomes in three treatments at six sites across a prospective intervention and follow-up period of 2 years, with plans for a 5-year assessment (Rosenbaum, Valbak, Harder, Knudsen, Koster, Lajer, Lindhardt, Winter, Petersen, Jorgensen, Nordentoft and Andreasen, 2006). After being identified as having an initial psychosis, participants, aged 16-35, were assigned to: (1) supportive psychodynamic psychotherapy (n=119), (2) integrated treatment (n=139) or (3) treatment as usual (n=304). Integrated treatment consisted of multifamily psychoeducational groups (William R. McFarlane, 2002), assertive community treatment and anti-psychotic medication, an evidence-based approach for established schizophrenia, termed FACT (Family-aided Assertive Community Treatment) in the US (W. McFarlane, Stastny and Deakins, 1992). In these first episode patients, integrated treatment achieved the best results for measures of functioning and negative symptoms (OR = 3-7). A fortuitous result of the OPUS Study was that 79 cases were recruited with schizotypal personality disorder (SPD) but not psychosis and assigned to the same treatments (Merete Nordentoft, et al., 2006). At the end of two years of treatment, 48.3% of the participants in the treatment-as-usual

10 Adolescent Psychiatry, 2012, Vol. 2, No. 2

McFarlane et al.

group had a psychotic episode, compared with 25% of those in the integrated treatment arm, which was a significant difference. This study supported the efficacy of family-based treatment as a preventive intervention, but also suggested another avenue for early identification—finding youth and young adults with SPD and offering treatment with evidence-based treatments for schizophrenia.

of the weight gained was lost. A measure of functioning showed a slight, though significant, improvement over time (mean Global Assessment of Functioning (GAF) improved from 42 to 48). This study, relying almost solely on medication for prevention effect, found that at two years, with no treatment in the second year, 79% and 80%, respectively had converted or dropped out.

Personal Assessment and Crisis Evaluation (PACE)

Prevention of Psychosis by Omega-3 Fatty Acids

Yung, McGorry and colleagues have spent the past 12 years developing a large-scale program in Melbourne, Australia (P. McGorry, et al., 2002). The PACE Program intervened with young people who were seen to be at risk for imminent onset of psychosis. The PACE service relied on referral from the general practitioner, similarly to Falloon's project in the UK, and school counselors, teachers and youth workers. The intervention tested included stress management, social skills training, problem-solving, family education and crisis support, symptom monitoring and targeted medication at low doses (primarily risperidone). Those who met CAARMS criteria for high risk for psychosis were randomly assigned to (1) a comparison group consisting of assessment and supportive treatment, an approach termed Needs-Based Intervention (NBI), or (2) cognitive therapy and symptom-specific medication (lowdose (1-2 mg.) risperidone), given by symptom indication for six months, after which they received NBI (P. McGorry, et al., 2002). After 6 months, among 59 who were randomly assigned, the NBI cohort had a conversion rate of 36%; the experimental group receiving and adhering to intensive psychosocial treatment showed a rate of 7% (p=0.03); those offered but not adhering to medication treatment manifested a rate of 12% (n.s.). Measures of functioning were unchanged from baseline. The specific-treated group had better outcomes for conversion, but over half did not accept medication, and among that group, there was a higher conversion rate during the second six month follow-up period. Those results held true at three years. The number needed to treat to “prevent” 1 case was 4.

A super-nutritional strategy was tested by Amminger and colleagues, who conducted a randomized clinical trial in which omega-3 fatty acids (O-3 FAs) (without concomitant antipsychotic drugs) were tested against placebo for 12 weeks, with psychosocial intervention held constant (Amminger, et al., 2010). At one year, the O-3 FAs condition had a conversion rate of 4.9% versus 27.5% in the placebo condition. Effects were correlated with blood level of O-3 FAs at baseline. After the O-3 FAs were discontinued at 12 weeks, the preventive effect persisted at one year. Positive and negative symptoms and functioning all improved significantly. The number needed to treat was, again, 4. This trial needs replication given the unusual intervention.

Prevention through Risk Identification, Management and Education (PRIME) McGlashan and colleagues at four sites in North America used olanzapine in an industry-sponsored controlled trial to treat adolescents and young adults experiencing prodromal psychotic symptoms (McGlashan, et al., 2006). The study served as a rigorous test of a unimodal pharmacological strategy to prodromal intervention. This study used the SIPS. Sixty cases were randomly assigned to olanzapine or placebo and treated for one year, followed by observation without treatment for one year. The sample averaged 17.7 years of age. The rate of conversion was 38% for the control group and 16% for the treated group (p = .09), and the drop out rate was 35% for the placebo and 55% for the treated group. During the second year, 25% and 33%, respectively, of the initially non-converting cases converted. The differences for conversion were at a trend level. The treated group had a significantly superior effect for positive symptoms, but also experienced marked weight gain (mean 8.8 kg.). The number needed to treat was 4.5. During the second year, without medication, symptoms worsened for both groups, but some

Portland Identification and Early Referral (PIER) The PIER program was developed in 2000, to undertake systematic early detection, intervention and prevention of psychosis throughout an entire urban area, by providing treatment during the prodromal period. The intent was to reduce incidence of psychotic disorders and schizophrenia specifically for a defined population, while also testing the efficacy of FACT as a preventive treatment. In order to achieve effectiveness, the PIER program: (1) developed a community-wide referral network (described in this issue (Ruff, et al.), (2) mounted a major public education campaign and (3) operated a special multidisciplinary team to treat those young people at the highest risk of onset of psychosis. The initial focus of the PIER team's effort was on educating and training for all school and college health and counseling professionals, primary health care and pediatric physicians and mental health clinicians serving youth and young adults. The focus was on a defined catchment area of about 340,000 (W. R. McFarlane, Cook, Downing, Verdi, Woodberry and Ruff, 2010). The clinical approach used was FACT, as in OPUS. Families were engaged systematically in all cases. The model was based on the fact that family intervention was highly effective in established psychotic and mood disorders and that adolescents in particular would be difficult to engage and maintain in treatment without family involvement (McFarlane, 2001). Preliminary outcome data are available for one year of treatment over the first six years of intake. Between 5/7/01 and 9/30/2007, of 148 prodromal participants averaging 16.5 years of age, 8.8% developed a full psychosis. The identification and referrals yielded a referral rate of 46% of the expected rate for all psychotic disorders. The mean GAF scores went from 38 at entry to 55 at the 12 month assessment (functioning in role as expected, but with moderate or intermittent symptoms). The PIER treatment model is currently being tested in a NIH-sponsored

Early Intervention in Psychosis

randomized clinical trial in Portland and in six sites nationally. Preliminary results suggest that the program has decreased incidence rates of psychotic disorders and mood disorder NOS, compared to the other urban areas in Maine. Summary of Studies of Indicated Preventive Intervention Systems of early detection, intervention and secondary or indicated prevention have been developed and tested in the UK, Australia, Scandinavia, Germany, Austria and North America. Most involve specialized treatment with existing, empirically-validated methods. These published studies of preventive intervention have achieved reductions in rates of onset of frank psychosis and in reducing prodromal and psychotic symptoms. A simple compilation pooling data across studies suggests that the average conversion rate is 9.6% of treated cases versus 32% of untreated or treatmentas-usual control cases. In three studies, the number needed to treat was 4-5, comparable or superior to other medical preventive interventions. A Cochrane Review in 2011, which did not include one of the more recent trials described above, concluded that there were insufficient studies and data to draw conclusions (Marshall & Rathbone, 2011). However, two of those trials—OPUS and Omega-3—both had significant treatment effect differences and relatively high control conversion rates, both of which increase confidence that treatment was effective. Contrarily, the most recent trial from Melbourne found conversion rates at 6 months to be 7% and 5%, clearly not a significant difference and illustrating the declining conversion rates in established prodromal research centers (Yung et al., 2011). To date, some studies have been compromised by a high drop-out rate, marginally significant results and major side effects with antipsychotic medications. Those studies that have used evidence-based, longer-term family and rehabilitative (OPUS and PIER) or super-nutritional interventions have had significant main effects, better retention rates, persistence of effects and improved psychosocial functioning. Psychosocial functioning is emerging as the area requiring the greatest clinical and rehabilitative effort and in which the value of psychosocial intervention is likely to be paramount. The evidence for long-term treatment effects and changes in prognosis is presently modest, being extrapolations of long-term outcomes of treatment for typical cases of schizophrenia. Further, some studies found that progression of disorder occurred after discontinuing a six- or twelve-month course of treatment. However, experience demonstrates that arrest of deterioration, reduction of untreated psychosis and shortterm delay or prevention of onset of psychosis are relatively consistent across studies and sites. The results do confirm that early detection is feasible. As is described in this issue, a clinical trial is underway to test a cognitive remediation strategy in the clinical high-risk population, on the basis of the data showing a substantial cognitive impairment prior to the first psychotic episode. The major caveats are that no intervention strategy has yet emerged as superior to others, some earlier studies did not achieve statistical significance for conversion rates, longer-term effects are still unknown and psychosocial functioning has not improved in all the trials. Several

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previously efficacious treatments for psychotic disorders have shown at least marginal efficacy in the clinical highrisk population. As suggested by a Cochrane review (Marshall & Rathbone, 2011), the current results are promising but not definitive. The least ambiguous results have followed psychosocial and super-nutritional treatment, less so antipsychotic drug therapy. CONCLUSION Emerging evidence of effective treatment for youth at risk for psychotic disorders and with a first episode of psychosis offers an opportunity for clinicians working with adolescents to change the assumptions that exist for those who are developing or have early psychotic disorders. That evidence suggests that clinicians working with adolescents begin, as early as possible and as indicated by emerging symptoms, to offer treatment that positively influences the trajectory of an individual’s development. This is currently most supportable with reference to lower-risk approaches, such as family intervention, supported education, and nutritional and wellness enhancement. As more evidence accumulates, the “wait and see” approach should increasingly be replaced by an “ounce of prevention is worth a pound of cure” strategy. AUTHOR INFORMATION William R. McFarlane, M.D. is Director of the Center for Psychiatric Research at the Maine Medical Center Research Institute and Professor of Psychiatry at Tufts University Medical School, Portland, Maine, USA. Barbara Cornblatt, Ph.D., M.B.A. is Director of the the Recognition and Assessment of Psychosis, Zucker-Hillside Hospital, and Professor of Psychiatry at Albert Einstein College of Medicine, Glen Oaks, New York, N.Y., USA. Cameron S. Carter, M.D. is Director of the Center for Neuroscience and the Imaging Research Center, and Professor of Psychiatry, University of California Davis, Sacramento, California, USA. DISCLOSURES Dr. McFarlane is the Director of the PIER Training Institute, LLC, which provides on-request training and consulting services for evidence-based practices and early psychosis programs. Dr. Carter discloses that he has served as a consultant for Merck, Lilly, Pfizer and Servier and has received research funding from Glaxo Smith Kline. ACKNOWLEDGEMENTS The authors are the principal and co-investigators for Early Detection and Intervention for the Prevention of Psychosis Program, a National Program sponsored by the Robert Wood Johnson Foundation, grant number 58920. ABBREVIATIONS BSABS

= Bonn Scale for the Assessment of Basic Symptoms

CAARMS = Comprehensive Assessment for At Risk Mental States CD

= communication deviance

12 Adolescent Psychiatry, 2012, Vol. 2, No. 2

McFarlane et al.

CHR

= clinical high-risk

CT

= cognitive therapy

DUP

= duration of untreated psychosis

EDIE

= Manchester Cognitive Therapy Trial

EE

= expressed emotion

EPOS

= European Prediction of Psychosis Study

EOI

= emotional over-involvement

FACT

= Family-aided Treatment

FEP

= first episode psychosis

GABA

= gamma-amino butyric acid

GAF

= Global Assessment of Functioning

NAPLS

= North American Prodromal Longitudinal Study

NBI

= Needs-Based Intervention

NIH

= National Institute of Health

NRG-1

= Neuregulin-1

PACE

= Personal Assessment and Crisis Evaluation

PIER

= Portland Identification and Early Referral

PTSD

= post-traumatic stress disorder

O-3 FAs

= omega-3 fatty acids

OCD

= obsessive-compulsive disorder

OPUS

= Danish National Schizophrenia Project

SIPS

= Structured Interview for the Prodromal Syndrome

SPD

= schizotypal personality disorder

Assertive

Community

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Yung, A. R., Yuen, H. P., Berger, G. E., Francey, S., Hung, T. C., Nelson, B., . . . McGorry, P. D. (2007). Declining transition rates in ultra

Received: October 11, 2011

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high risk (prodromal) services: Dilution or reduction of risk? Schizophrenia Bulletin, 33, 673-681.

Revised: December 14, 2011

Accepted: January 21, 2012