Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia: A Critical Review and Meta-Analysis

Transcription

1 Reviews and Overviews Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia: A Critical Review and Meta-Analysis Diana O. Perkins, M.D., M.P.H. Hongbin Gu, Ph.D. Kalina Boteva, M.D. Jeffrey A. Lieberman, M.D. Objective: The duration of untreated psychosis may influence response to treatment, reflecting a potentially malleable progressive pathological process. The authors reviewed the literature on the association of duration of untreated psychosis with symptom severity at first treatment contact and with treatment outcomes and conducted a meta-analysis examining these relationships. Method: English-language articles on duration of untreated psychosis published in peer-reviewed journals through July 2004 were reviewed. Studies that quantitatively assessed the duration of untreated psychosis; identified study subjects who met the criteria for nonaffective psychotic disorders at or close to first treatment; employed cross-sectional analyses of duration of untreated psychosis and of baseline symptoms, neurocognition, brain morphology, or functional measures or prospectively analyzed symptom change, response, or relapse; assessed psychopathology with clinician-rated instruments; and reported subjects diagnoses (a total of 43 publications from 28 sites) were included in the meta-analysis. Results: Shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes. At the time of treatment initiation, duration of initially untreated psychosis was associated with the severity of negative symptoms but not with the severity of positive symptoms, general psychopathology, or neurocognitive function. Conclusions: Duration of untreated psychosis may be a potentially modifiable prognostic factor. Understanding the mechanism by which duration of untreated psychosis influences prognosis may lead to better understanding of the pathophysiology of schizophrenia and to improved treatment strategies. (Am J Psychiatry 2005; 162: ) Schizophrenia is a chronic, disabling disorder for most affected individuals. Although vulnerability to schizophrenia is likely to be related to genetic and environmental factors that influence early brain development, the disorder is only minimally expressed until adolescence or young adulthood. Despite historical pessimism about prognosis, more recent studies suggest that early intervention can improve outcome (1). These findings have stimulated great interest and enthusiasm for the idea that intervention at or even prior to the onset of the first episode might improve response to antipsychotic treatment and longterm outcome. Numerous early psychosis or prodromal clinics have been developed to facilitate early interventions (2 5). Efforts at early identification and treatment are based in part on the assumption that through an as-yet unknown process, illness duration causally influences treatment responsivity and outcome (6). Understanding the causes and consequences of untreated psychosis is important for at least two reasons. First, the duration of psychosis before initiation of treatment is a potentially modifiable prognostic factor, and understanding its relation to outcome could lead to improved therapeutic strategies and public health initiatives. Second, a relationship of duration of untreated psychosis to outcome may indicate a neurodegenerative process and so have important implications for understanding the pathophysiology of schizophrenia. Alternatively, the length of initially untreated psychosis may be related to the severity of illness and thus may be a marker rather than a determinant of outcome (7). Given the growing interest and debate in this area, a meta-analysis and review of the evidence bearing on the issue of illness duration and prognosis are relevant. We used meta-analytic techniques to evaluate the association of duration of untreated psychosis with symptom severity and function at first treatment contact and in response to antipsychotic treatment. We present the results of the metaanalysis and review the relationship of duration of untreated psychosis to relapse risk, neurocognitive function, and brain morphology. The methodological limitations of current research on duration of untreated psychosis are discussed, and strategies for further research are suggested. Am J Psychiatry 162:10, October

2 DURATION OF UNTREATED PSYCHOSIS TABLE 1. Studies Included in a Review and Meta-Analysis of the Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia Site and Study N Diagnostic Criteria Bonn, Germany: Huber, 1997 (42) 491 Schneiderian critieria for schizophrenia Woodbridge Hospital, Singapore: Kua et al., 2003 (49) 402 ICD-9 schizophrenia World Health Organization (WHO) International Study on Schizophrenia Wiersma et al., 2000 (11) 195 a ICD-9 schizophrenia Wiersma et al., 1998 (18) 63 ICD-9 broad definition of schizophrenia Psychiatric Hospital at Ludwig Maximilians University, Munich Bottlender et al., 2003 (9) 58 DSM-III-R schizophrenia Bottlender et al., 2000 (8) 329 ICD-9 schizophrenia University of Amsterdam, Amsterdam: De Haan et al., 2003 (50) 88 DSM-III-R schizophrenia, schizoaffective disorder, or schizophreniform disorder Bispebjerg Hospital, Copenhagen: Madsen et al., 1999 (26) 21 DSM-III-R schizophrenia Hillside Hospital, Glen Oaks, N.Y. Robinson et al., 1999 (17) 104 Research Diagnostic Criteria (RDC) schizophrenia or schizoaffective disorder Robinson et al., 1999 (25) 118 RDC Rabiner et al., 1986 (44) 36 b RDC University of North Carolina, Chapel Hill: Perkins et al., 2004 (14) 191 DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder Suffolk County, N.Y. Craig et al., 2000 (20) 155 b DSM-III-R schizophrenia or schizoaffective disorder Hoff et al., 2000 (27) 50 DSM-III-R schizophrenia Am J Psychiatry 162:10, October 2005

3 PERKINS, GU, BOTEVA, ET AL. Definition of Variables Onset of psychosis not specified; onset of treatment not specified; duration of untreated psychosis dichotomized as short (<1 year) and long (>1 year) Onset of psychosis defined as time of emergence of psychotic symptoms based on patient or caregiver report; onset of treatment defined as first hospitalization; duration of untreated psychosis classified as <1 month, 1 6 months, and >6 months Study Analysis Time Points Outcome Variables 22 years Treatment response 5, 10, 15, and 20 years Function (Global Assessment Scale [GAS] modified to score on scale of 0 to 6, with results further collapsed to a 3-point scale of good, fair, or poor functional outcome) Onset of psychosis not specified; onset treatment of not specified; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis determined by subject interview and medical records; onset of treatment not specified; duration of untreated psychosis dichotomized as <3 months or 3 months 15 years Function (WHO Disability Assessment Schedule) 15 years Treatment response; relapse Onset of psychosis defined as onset of first psychotic symptom; onset of treatment defined as first hospital admission; duration of untreated psychosis categorized as 6 months, 6 12 months, >12 months Onset of psychosis defined as onset of first psychotic symptom; onset of treatment defined as first hospital admission; duration of untreated psychosis categorized into eight unequal groups: 1 week, >1 week and 1 month, >1 month and 3 months, >3 months and 6 months, >6 months and 1 year, >1 year and 2 years, >2 years and 3 years, >3 years Onset of psychosis defined by parent report and subject self-report of onset of hallucinations, delusions, or disorganization; onset of treatment defined by parent report and subject self-report of first episode of antipsychotic treatment of >6 weeks duration; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis defined a first psychotic symptom ; onset of treatment defined as hospitalization; duration of untreated psychosis analyzed as log-transformed continuous variable Onset of psychosis defined by subject and family member interview about onset of first psychotic symptom; onset of treatment not specified; duration of untreated psychosis dichotomized as short (<1 year) and long ( 1 year) Onset of psychosis defined as onset of first noticeable change in behavior; onset of treatment defined as baseline evaluation; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis defined as first psychotic symptom determined by clinical interview (Symptom Onset in Schizophrenia [SOS]) of subject and family; onset of treatment defined as clinically meaningful antipsychotic trial; duration of untreated psychosis analyzed as log-transformed continuous variable Onset of psychosis defined as occurrence of the first clear psychotic symptom based on information from the Structured Clinical Interview for DSM-III-R, medical records, and significant others, and revised if new information was available at follow-up; onset of treatment defined as first hospitalization; duration of untreated psychosis categorized into three groups: <4 weeks, 4 weeks 1 year, >1 year (for the meta-analysis, results were dichotomized as 1 year or >1 year) Onset of psychosis defined as first occurrence of hallucinations, delusions, and disorganization on the basis of clinical interviews with patient and family and using best-estimate procedures; onset of treatment not specified; duration of untreated psychosis analyzed as a continuous variable and dichotomized as short (<1 year) and long ( 1 year) 15 years Positive symptoms (Positive and Negative Syndrome Scale [PANSS]); negative symptoms (PANSS and Scale for the Assessment of Negative Symptoms [SANS]); function (GAS) Positive symptoms (Association for Methodology and Documentation in Psychiatry [AMDP] system); negative symptoms (AMDP system) Mean of 57 days (hospital discharge) 6 years Relapse Positive symptoms (AMDP system); negative symptoms (AMDP system); function (Global Assessment of Functioning Scale [GAF]) 4 7 years Treatment response; brain morphology 5 years Relapse 1 year Treatment response 1 year Treatment response 2 years Treatment response; global symptoms (PANSS); positive symptoms (PANSS); negative symptoms (PANSS); function (Heinrich-Carpenter Quality of Life [HCQOL]) 2 years Treatment response; positive symptoms (Scale for the Assessment of Positive Symptoms [SAPS]); negative symptoms: SANS; function (GAF) Brain morphology; neurocognition (tests not specified, but included language, executive function, verbal memory, spatial memory, concentration, sensory perception, global cognitive function tests) (continued) Am J Psychiatry 162:10, October

4 DURATION OF UNTREATED PSYCHOSIS TABLE 1. Studies Included in a Review and Meta-Analysis of the Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia (continued) Site and Study N Diagnostic Criteria Bordeaux Psychiatric Hospital, Bordeaux, France Verdoux et al., 2001 (21) 65 DSM-IV schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder (N=28), psychotic affective disorders (N=26), other psychotic disorders (N=11); eight patients had been treated with an antipsychotic for >1 month before hospitalization Verdoux et al., 1998 (39) 59 DSM-IV schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder (N=25), psychotic affective disorders (N=24), other psychotic disorders (N=6); seven patients had been treated with an antipsychotic for >1 month before hospitalization Calgary Early Psychosis Program, Calgary, Canada: Addington et al., 2004 (13) 200 DSM-IV nonaffective psychosis Northwick Park study, Harrow, U.K.: Crow et al., 1986 (22) 120 Schizophrenia (according to the Present State Examination) Rogaland Hospital, Stavanger, Norway Larsen et al., 2000 (28) 43 DSM-III-R nonaffective psychotic disorder Larsen et al., 1996 (43) 43 As for Larsen et al., 2000 (28) Early Psychosis Prevention and Intervention Centre (EPPIC), Sydney, Australia Harrigan et al., 2003 (12) 203 b DSM-III-R schizophrenia or schizophreniform disorder Amminger et al., 2002 (35) 42 DSM-III-R schizophrenia or schizophreniform disorder McGorry et al., 1996 (2) DSM-III-R schizophrenia or schizophreniform disorder, 91 other psychotic disorder diagnoses Method An electronic MEDLINE search strategy was used to identify relevant English-language studies published through July The following key words were used in the search: ( duration of untreated psychosis OR DUP OR outcome OR recovery ) AND ( psychosis OR schizophrenia OR schizoaffective disorder OR schizophreniform disorder ) AND ( first episode OR first admission ). This search yielded 497 references. The titles and abstracts of these references were searched to eliminate obviously irrelevant studies, yielding 125 publications for detailed review. The reference sections of these 125 publications also were reviewed, and three other potentially relevant publications were identified Am J Psychiatry 162:10, October 2005

5 PERKINS, GU, BOTEVA, ET AL. Definition of Variables Study Analysis Time Points Outcome Variables Onset of psychosis defined as onset of first psychotic symptom; onset of treatment defined as hospital admission; duration of untreated psychosis dichotomized at median split into short (<3 months) and long ( 3 months) Onset of psychosis defined as onset of first psychotic symptom; onset of treatment defined as hospital admission; duration of untreated psychosis dichotomized at median split into short (<3 months) and long 3 months) Onset of psychosis defined by using the Instrument for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS) (51), as the first appearance of a positive symptom (any one positive symptom [hallucinations, delusions, thought disorder] rated 4 on the PANSS that lasted throughout the day for several days or several times a week); onset of treatment defined as onset of first effective treatment; duration of untreated psychosis analyzed as a logtransformed continuous variable Onset of psychosis defined as onset index episode; onset of treatment defined in terms of hospital admission; duration of untreated psychosis dichotomized as short (<1 year) and long (>1 year) 2 years Treatment response; relapse 2 years; baseline 2 years Relapse Global symptoms (PANSS); positive symptoms (PANSS); negative symptoms (PANSS) Positive symptoms (PANSS); negative symptoms (PANSS); function (quality of life); neurocognition (Controlled Oral Word Association Test and Category Instances, logical memory subtests of the Wechsler Memory Scale Revised [WMS-R], Rey Auditory Verbal Learning Test, Rey Complex Figure, Letter-Number Span, Wisconsin Card Sorting Test (WCST), Continuous Performance Test, Span of Apprehension, Trail Making Test A and B, Grooved Pegboard) Onset of psychosis defined as first appearance of positive psychotic symptoms a score 4 or higher on one of the positive items in PANSS lasting throughout the day for several days or several times a week, not being limited to a few brief moments ; onset of treatment defined as giving an antipsychotic drug in sufficient time and amount so that it would lead to clinical response in the average nonchronic schizophrenic patient with hospitalization regarded as initiation of adequate treatment ; duration of untreated psychosis analyzed as a continuous variable 1 year Treatment response; positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) As for Larsen et al., 2000 (28) Positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) Onset of psychosis defined as the emergence of the first sustained psychotic symptom of any type at threshold level dated as precisely as possible to the nearest day, week or month ; onset of treatment defined as initiation of treatment ; duration of untreated psychosis analyzed as a log-transformed continuous variable and as a categorical variable (0 7 days, 8 days to 4 weeks, >4 weeks to 3 months, >3 months to 1 year, >1 year) Onset of psychosis defined as first experience of hallucinations or delusions on the basis of clinical interview; onset of treatment defined as admission into treatment program (EPPIC); duration of untreated psychosis analyzed as a log-transformed continuous variable and as a categorical variable (<29 days, days, and >181 days) Onset of psychosis operationally defined and assessed by the Royal Park Multidiagnostic Instrument for Psychosis (52); onset of treatment operationally defined and assessed by the Royal Park Multidiagnostic Instrument for Psychosis; duration of untreated psychosis analyzed as a log-transformed continuous variable and also dichotomized at median split into short (<28 days) and long ( 28 days) 1 year Positive symptoms (Brief Psychiatric Rating Scale [BPRS] positive subscale); negative symptoms (SANS); function (HCQOL) After stabilization with antipsychotics Neurocognition (National Adult Reading Test [NART] IQ, WAIS-R, cognitive deterioration index measured by ratio of performance on WAIS hold [information and vocabulary] to no-hold [digit symbol] tests) 1 year Global symptoms (BPRS); function (GAF) Global symptoms (BPRS); negative symptoms (SANS); function (GAF) (continued) Studies were included if the following criteria were met: 1) the study quantitatively assessed the duration of initially untreated psychosis; 2) most study subjects were identified at or close to first treatment; 3) the study used cross-sectional analyses of the duration of untreated psychosis and baseline symptom, brain morphology, neurocognition, or functional measures or prospectively analyzed symptom change or the proportion of subjects who met the study definition of treatment response or relapse ; 4) psychopathology was assessed by using clinician-rated instruments and the summary statistics were reported; and 5) the study reported subjects diagnoses and most of the subjects met the standard diagnostic system criteria for a nonaffective psychotic disorder. In addition, the following rules were applied: 1) if a study included subjects with affective psychotic disorders but Am J Psychiatry 162:10, October

6 DURATION OF UNTREATED PSYCHOSIS TABLE 1. Studies Included in a Review and Meta-Analysis of the Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia (continued) Site and Study N Diagnostic Criteria University of Western Ontario and London Health Sciences Centre, Ontario, Canada Malla et al., 2002 (37) 114 DSM-IV criteria for schizophrenia or schizophreniform disorder Malla et al., 2002 (30) 88 DSM-IV schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder (N=72), affective psychosis (N=7), drug-induced psychotic disorder (N=3), psychosis not otherwise specified (N=4) Malla et al., 2002 (16) 66 DSM-IV for schizophrenia, schizophreniform disorder, schizoaffective disorder, or psychosis not otherwise specified Townsend et al., 2002 (36) 83 DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder Norman et al., 2001 (32) 113 DSM-IV schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder (N=71); affective psychosis (N=8), other (N=13), psychosis not otherwise specified (N=21) Beijing: Lieberman et al., 2003 (40) 160 DSM-IV schizophrenia Manchester, U.K.: Ring et al., 1991 (41) 101 RDC schizophrenia, schizoaffective disorder, schizophreniform disorder (N=76), manic psychosis (N=17), other psychosis (N=8) Iowa Prospective Longitudinal Study of Recent- Onset Psychoses, Iowa City, Iowa Ho et al., 2000 (15) 74 DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder Ho et al., 2003 (33) 102 As for Ho et al., 2000 (15) reported results separately for the nonaffective psychotic disorder subgroup, then the subgroup results were used; 2) when more than one study from the same research group reported results on overlapping subject groups, the study with the largest number of subjects for the particular outcome was included; and 3) when study results were reported for multiple follow-up periods, the longest follow-up period was used, with one exception a study with both short-term and long-term follow-up in which the results for the long-term follow-up were reported for a relatively small subgroup of subjects (8, 9). A total of 43 publications from 28 sites met the inclusion criteria (2, 8 49). Because the literature was sparse, we included one additional study (50) in the review of the relationship between duration of untreated psychosis and relapse. That study used chart review to determine relapse and selfreport and parental report to determine duration of untreated psychosis and symptom severity. Table 1 summarizes key features of these studies. Statistical Methods The statistical meta-analyses was based on studies that included quantitative assessment of function with the Global Assessment of Functioning (GAF) Scale or the Global Assessment Scale (GAS) (53) and quantitative assessment of psychopathology with the Positive and Negative Syndrome Scale (54), the Brief Psychiatric Rating Scale, the Association for Methodology and Documentation in Psychiatry system (55), the Present State Examination (56), the Scale for the Assessment of Positive Symptoms (57), or the Scale for the Assessment of Negative Symptoms (58), as specified in Table 1. Separate measures for effect sizes in Hedges s gu and correlation coefficients were calculated for studies analyz Am J Psychiatry 162:10, October 2005

7 PERKINS, GU, BOTEVA, ET AL. Definition of Variables Study Analysis Time Points Outcome Variables Onset of psychosis defined as onset any psychotic symptoms from IRAOS (51); onset of treatment not specified; statistical analysis of duration of untreated psychosis not specified Onset of psychosis defined as onset of first psychotic symptoms contiguous with presenting episode ; onset of treatment defined as time of having received antipsychotic therapy for a period of 2 months unless significant response to medication was achieved earlier ; duration of untreated psychosis analyzed as a logtransformed continuous variable and also dichotomized as short (<22 weeks) and long (>22 weeks) Onset of psychosis defined as onset of first psychotic symptom contiguous with present episode based on Circumstances of Onset and Relapse in Schizophrenia Interview (unpublished), a modification of IRAOS (51); onset of treatment defined as initiation of adequate antipsychotic treatment defined by duration of at least 1 month or until a response to treatment is observed, whichever is earlier ; duration of untreated psychosis analyzed as a log-transformed continuous variable Onset of psychosis determined by subject interview with IRAOS (51) and defined as onset of first psychotic symptom; onset of treatment defined as onset of treatment of at least 1 month or until a response to treatment is observed, whichever is earlier ; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis not specified; onset of treatment defined as commencement of antipsychotic therapy within PEPP [Prevention and Early Intervention Program for Psychosis] ; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis not specified; onset of treatment not specified; duration of untreated psychosis analyzed as a log-transformed continuous variable Onset of psychosis not specified, determined by interviews; onset of treatment not specified; duration of untreated psychosis analyzed as a log-transformed continuous variable Brain morphology (computed tomography scan) 1 year Treatment response; positive symptoms (SAPS); negative symptoms (SANS) 1 year Function (Wisconsin Quality of Life Index social relations subscale [rated by provider]) 1 year Neurocognition (NART, WAIS, WMS, Paced Auditory Serial Addition Test [PASAT], WCST, Stroop Color- Word Test, Continuous Performance Test, Trail Making A and B, Thurstone Word Fluency Test) Neurocognition (NART, WAIS, WMS, PASAT, WCST, Stroop Color-Word Test, Continuous Performance Test, Trail Making Test A and B, Thurstone Word Fluency Test, prospective memory screening) 1 year Treatment response 1 year Negative symptoms (SANS) Positive symptoms (Present State Examination); negative symptoms (SANS) Onset of psychosis defined as the first occurrence of positive symptoms (delusions, hallucinations, bizarre behavior, formal thought disorder, catatonic motor behavior) at a severity level of moderate or worse ; onset of treatment defined as initiation of neuroleptic treatment ; duration of untreated psychosis analyzed as a continuous variable and also dichotomized by median split as short (<9 months) and long (>9 months) 6 months Treatment response; positive symptoms (SAPS); negative symptoms (SANS); function (GAS), social and vocational function assessed with the Psychiatric Status You Currently Have interview As for Ho et al., 2000 (15) Brain morphology (magnetic resonance imaging [MRI]); neurocognition (verbal memory, nonverbal memory, working memory, language, visuospatial skills, problem solving, motor speed, attention) (continued) ing duration of untreated psychosis as a categorical variable (long versus short duration) and for the studies analyzing duration of untreated psychosis as a continuous variable, respectively. All analyses were performed using SAS version 8.0 software (SAS Institute, Cary, N.C.). Fixed-effects models were used after checking the homogeneity among studies. Fixed-effects estimations for effect sizes were withheld if the homogeneity assumption was violated, but a random-effects model was not fitted because of the small number of studies available in this analysis. We checked for publication bias by means of Begg s funnel plot. The variety of distinctive clinical definitions and statistical approaches used to evaluate treatment response limits the effective sample size required by the analytical meta-analysis approach. We instead categorized the studies according to their statistical approaches and tabulated their findings accordingly. Results Duration of Untreated Psychosis and First-Episode Treatment Outcome Figure 1 illustrates the individual study results and combined study summary statistics examining the relationship between duration of untreated psychosis and symptom response in patients with first-episode psychosis. The results of studies that used comparisons of means are summarized on the left side of Figure 1, and the results of studies that used correlational methods are summarized on the right side of Figure 1. Am J Psychiatry 162:10, October

8 DURATION OF UNTREATED PSYCHOSIS TABLE 1. Studies Included in a Review and Meta-Analysis of the Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia (continued) Site and Study N Diagnostic Criteria Nova Scotia Early Psychosis Program, Halifax, 19 DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform Canada: Black et al., 2001 (45) disorder University of Pennsylvania, Philadelphia: Szymanski et al., 1996 (19) 36 b DSM-III-R schizophrenia Payne Whitney Clinic, New York City: Haas and Sweeney, 1992 (46) 71 DSM-III-R schizophrenia, schizophreniform disorder, or schizoaffective disorder Manchester, Liverpool, North Nottinghamshire, U.K. (Study of Cognitive Reality Alignment Therapy in Early Schizophrenia [SOCRATES]): Drake et al., 2000 (23) 248 DSM-IV schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or psychosis not otherwise specified Early Treatment and Identification of Psychosis (TIPS), Norway Melle et al., 2004 (10) 281 DSM-IV schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic episode, delusional disorder, affective psychosis with mood-incongruent delusions, psychotic disorder not otherwise specified Rund et al., 2004 (34) 207 As for Melle et al., 2004 (10) West London, U.K. Barnes et al., 2000 (24) 53 DSM-IV schizophrenia or schizophreniform disorder Joyce et al., 2002 (31) 136 As for Barnes et al., 2000 (24) The duration of treatment varied considerably in these studies, ranging from the end of the first hospitalization to 15 years. Shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment, as measured by improvement or endpoint severity of global psychopathology (five studies), positive symptom severity (13 studies), and negative symptom severity (14 studies). The effect size for duration of untreated psychosis and symptomatic response for the combined (all studies) statistic was consistently significant and of small to moderate magnitude (global psychopathology: combined Hedges s gu=0.51 [95% confidence interval (CI)= ]; positive symptom severity: combined Hedges s gu= 0.41 [95% CI= ]; negative symptom severity: combined Hedges s gu=0.3 [95% CI= ]; global psychopathology: combined r=0.29 [95% CI= ]; positive Am J Psychiatry 162:10, October 2005

9 PERKINS, GU, BOTEVA, ET AL. Definition of Variables Onset of psychosis defined by using the IRAOS (51) as onset of positive psychotic symptoms according to the criteria of Larsen [43] ; onset of treatment defined as initiation of antipsychotic treatment; duration of untreated psychosis dichotomized by median split as short (<57 weeks) and long ( 57 weeks) Onset of psychosis defined as the first time psychotic symptoms were noticed by the patient, family, or other in the context of a decline in functioning ; onset of treatment not specified; duration of untreated psychosis analyzed as a continuous variable Onset of psychosis defined as onset of first positive symptom; onset of treatment defined as first hospitalization; duration of untreated psychosis dichotomized by median split as short (<1 year) or long ( 1 year) Onset of psychosis defined as first onset of delusions and hallucinations on the basis of interviews and medical record review; onset of treatment defined as hospital admission; duration of untreated psychosis analyzed as a log-transformed continuous variable Study Analysis Time Points Outcome Variables 6 months Treatment response; global psychopathology (PANSS); positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) Global psychopathology (PANSS); positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) 6 months Positive symptoms (SAPS) Global symptoms (BPRS); positive symptoms (SAPS); negative symptoms (SANS); function (GAS) 3 months Global symptoms (PANSS) Global symptoms (PANSS); positive symptoms (PANSS); negative symptoms (PANSS); function (Social Functioning Scale) Onset of psychosis defined as first appearance of positive psychotic symptoms, defined as the first week with symptoms corresponding to a PANSS score of 4 or more on positive subscale items 1, 3, 5, or 6 or on general subscale item 9 ; onset of treatment defined as onset of adequate treatment...defined as the start of structured treatment with antipsychotic medications or the start of hospitalization in highly staffed psychotic wards ; duration of untreated psychosis analyzed as a log-transformed continuous variable As for Melle et al., 2004 (10) Onset of psychosis defined as onset of positive psychotic symptoms ; onset of treatment defined as first treatment with antipsychotic medication; duration of untreated psychosis dichotomized at median split as short (<26 weeks) and long ( 26 weeks) Onset of psychosis defined as onset of positive psychotic symptoms ; onset of treatment defined as first treatment with antipsychotic medication; duration of untreated psychosis analyzed as a log-transformed continuous variable symptom severity: combined r=0.27 [95% CI= ]; negative symptom severity: combined r=0.23 [95% CI= ]). Similarly, the effect size examining the relationship of duration of untreated psychosis and global functional outcome (measured with the GAF or GAS) (seven studies), which takes into account symptom severity and social and vocational function, was also consistently statistically significant and of small to moderate magnitude 3 months Positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) At remission or 3 months, whichever came first (82 subjects were tested between 3 9 months) Positive symptoms (PANSS); negative symptoms (PANSS); function (GAF) Neurocognition (California Verbal Learning Test, Backward Masking Test, Finger Tapping, WCST, Controlled Oral Word Association Task, Trail Making Test A and B, digit span distractibility test, Continuous Performance Test, WAIS-R; IQ estimated by similarities, block design, digit span tests) 6 weeks Treatment response Neurocognition (NART, WAIS-R IQ, Cambridge Neuropsychological Test Automated Battery [CANTAB]); positive symptoms (SAPS); negative symptoms (SANS); function (likelihood of being homeless or unemployed) Neurocognition (NART IQ, CANTAB) (continued) (combined Hedges s gu=0.6 [95% CI= ]; combined r=0.21 [95% CI= ]). Duration of Untreated Psychosis and Response Fourteen studies examined the relationship of duration of untreated psychosis and likelihood of meeting response criteria for the initial treatment of a first psychotic episode. The data analytic strategies used in these studies Am J Psychiatry 162:10, October

10 DURATION OF UNTREATED PSYCHOSIS TABLE 1. Studies Included in a Review and Meta-Analysis of the Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia (continued) Site and Study N Diagnostic Criteria Istanbul, Turkey: Ucok et al., 2004 (47) 79 DSM-IV schizophrenia Cluain Mhuire Family Centre, Dublin: Browne et al., 2000 (29) 61 DSM-IV schizophrenia or schizoaffective disorder London: Fannon et al., 2000 (38) 37 DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder Finland and Spain (collaborative first episode study): Kalla et al., 2002 (48) Finland: N=49; Spain: N=37 DSM-III-R nonaffective psychosis a Data on duration of untreated psychosis were available for 195 of the total of 349 subjects. b Subjects who met the criteria for a schizophrenia spectrum disorder were a subsample of a larger group of subjects with first-episode psychosis; only the results for the subsample were used in the meta-analysis. varied and included 1) survival analysis (six studies), 2) comparison of the proportion of subjects who met response criteria in groups with short versus long duration of untreated psychosis (five studies), and 3) comparison of the mean duration of untreated psychosis in subjects who did and did not meet study response criteria (three studies). Because of differences in the methods of analysis used in these studies, meta-analytic techniques were not used to combine the results. The results of these studies are summarized in Table 2. Statistical comparisons using survival analysis are the most appropriate for these purposes, because this technique adjusts for different lengths of follow-up and for the fact that a subject may not have met the response criteria before discontinuing from the study. Unlike the other analytic strategies, survival analysis accounts for time in study and so is less likely to produce biased results if the likelihood of dropout is influenced by treatment response. Four of the six studies using survival analysis found a significant relationship between duration of untreated psychosis and treatment response. Possible reasons for the differences in the study results include variation in the definitions of treatment response and in the lengths of the follow-up period. Duration of Untreated Psychosis and Other Functional Outcome Measures The results of studies evaluating the association between duration of untreated psychosis and a variety of other functional outcome measures are mixed. One study using a modified GAF in which symptoms and function were rated separately found duration of untreated psychosis to be significantly associated with 3-month global symptom severity and global function outcomes (r 2 = 0.41 and r 2 = 0.30, respectively, p<0.01) (10). In another study that used a modified version of the GAS and logistic regression modeling, duration of untreated psychosis was significantly related to function at 5-, 10-, 15-, and 20-year follow-ups (odds ratio= , p<0.05) (49). Duration of untreated psychosis was related to overall function as measured by the WHO Disability Assessment Schedule at 2- and 15-year follow-up (11), to Heinrich-Carpenter Quality of Life at 1-year follow-up (Pearson s r= 0.29, p= 0.001) (12), and to 2-year follow-up (Pearson s r= 0.20, p<0.05) (13). In contrast, another study did not find a relationship between duration of untreated psychosis and social or vocational function at 2-year follow-up as measured by the Heinrich-Carpenter Quality of Life (14). In a study that included the Psychiatric Status You Currently Have interview, no relationship was found between duration of untreated psychosis and 6-month social and vocational outcomes (15). In a study in which the Wisconsin Quality of Life Index was administered at 1-year follow-up, a significant relationship was found between duration of untreated psychosis and social function (r= 0.23, p<0.05), but this relationship did not remain significant in a regression model that included the variables of premorbid adjustment, residual symptom severity, and adherence to medication (16) Am J Psychiatry 162:10, October 2005

11 PERKINS, GU, BOTEVA, ET AL. Definition of Variables Onset of psychosis defined as onset of first identifiable positive symptom as determined by a senior psychiatrist on the basis of a best-estimate approach using data gathered from multiple sources, including medical records, a direct patient interview, and family interview; onset of treatment defined as first hospitalization; duration of untreated psychosis dichotomized by median split as short (<6 months) or long ( 6 months) and also analyzed as a continuous variable Onset of psychosis defined as emergence of psychotic symptoms ; onset of treatment defined as initiation of treatment ; duration of untreated psychosis dichotomized as short (<1 year) or long ( 1 year) Onset of psychosis defined as onset of first psychotic symptom; onset of treatment defined as time of MRI scanning (no subject had more than 12 weeks of antipsychotic treatment); duration of untreated psychosis analyzed as a continuous variable Onset of psychosis defined as first manifestation of psychotic symptoms such as delusions, hallucinations, thought disorder or inappropriate bizarre behavior lasting throughout the day for several days or several times a week, not being limited to a few brief moments, and requiring an unambiguous intervention ; onset of treatment defined as admission for treatment; duration of untreated psychosis analyzed as a continuous variable Study Analysis Time Points At end of hospitalization (mean=35.5 days) Outcome Variables Global symptoms (BPRS); positive symptoms (SAPS); negative symptoms (SANS) (SANS findings were not included in meta-analysis, because statistical values were not given, but the relationship with duration of untreated psychosis was reported as nonsignificant.) Global symptoms (BPRS); positive symptoms (SAPS); negative symptoms (SANS) Global symptoms (PANSS); positive symptoms (PANSS); negative symptoms (PANSS); function (HCQOL) Brain morphology (MRI) Global symptoms (BPRS); positive symptoms (BPRS); negative symptoms (BPRS); function (GAS) Duration of Untreated Psychosis and Relapse Risk Even with complete recovery from a first psychotic episode, relapse risk remains very high. More than 90% of patients experience a relapse within 5 years of initial treatment response (17, 18, 59), and maintenance antipsychotic treatment is a strong predictor of relapse risk in most (17, 19, 60, 61) but not all (12, 20) studies. Studies that examined the association between duration of untreated psychosis and relapse risk showed mixed results. One study that used parent and self-report ratings to evaluate psychopathology and duration of untreated psychosis found a significant relationship between longer duration of untreated psychosis and relapse risk (assessed by chart review) at 6-year follow-up (50). In a second study this relationship approached significance (p=0.08) at 2-year follow-up (21). In a prospective 2-year study comparing maintenance antipsychotic medication to placebo, the relapse rate was high in both the antipsychotic-treated group (45%) and the placebo (62%) group, and duration of untreated psychosis before initiation of antipsychotic treatment predicted relapse in both groups (22). Two other studies, however, found no relationship between duration of untreated psychosis and risk of relapse after recovery from a first episode of psychosis (17, 18). Potential Confounding Factors The interpretation of the consistent findings that duration of untreated psychosis is associated with the level of recovery from a first psychotic episode depends on whether the relationship is confounded through an association with vulnerability factors for a poor prognostic subtype of schizophrenia, social factors not directly related to the schizophrenia pathophysiology, or both. A variety of potentially confounding factors have been considered, including chronological age (8, 9, 13, 20, 23), age at illness onset (12, 15, 19, 24), age at first hospitalization (9, 62), sex (8, 9, 12, 23, 25 27, 63 66), premorbid functioning (9, 12 15, 21, 28, 29, 63, 64), mode of onset (67, 68), diagnosis (59, 69), education (12, 23, 62), marital and socioeconomic status (9, 64), family history of psychiatric illness (12, 26), ethnicity (23), and duration or continuity of antipsychotic treatment (12, 13, 16, 19). Duration of untreated psychosis has been shown to be longer for subjects with a diagnosis of schizophrenia or schizoaffective disorder, compared to mood disorders with psychotic features (2, 20). Given that psychotic affective disorders may have both a better prognosis and a shorter duration of untreated psychosis than nonaffective psychosis, most research groups either exclude individuals with affective psychosis or report data separately for subjects with schizophrenia spectrum psychotic disorders (Table 1). Most studies find that the relationship of duration of untreated psychosis and outcome persists after adjustment for potential confounders. In particular, poor premorbid function and mode of onset are theoretically important variables that could confound the relationship between duration of untreated psychosis and outcome, because both could lead to delays in recognizing illness, and both are associated with poor prognosis (7). Studies that mod- Am J Psychiatry 162:10, October

12 DURATION OF UNTREATED PSYCHOSIS TABLE 2. Studies Examining the Relationship Between Duration of Untreated Psychosis and Treatment Response Follow- Up Period (months) Initial N N at End of Follow- Up Period Definition of Response Results Type of Analysis and Study Survival analyses Wiersma et al., 1998 (18) No positive rating for psychotic items (hallucinations, delusions, cognitive disorganization, marked psychomotor disturbance, grossly inappropriate behavior) on the Present State Examination and Dysfunctional Attitude Scale for >4 weeks Perkins et al., 2004 (14) No rating of >3 (mild) on items P1, P2, P3, P5, and P6 of the Positive and Negative Syndrome Scale (PANSS) and a Clinical Global Impression (CGI) severity score 3 (mildly ill) for 4 weeks Craig et al., 2000 (20) Response defined by World Health Organization 8-point system, with subjects classified as either continuously ill, achieving partial remission, or achieving full remission Lieberman et al., 2003 (40) Robinson et al., 1999 (25) No item >3 (mild) on Brief Psychiatric Rating Scale (BPRS) and 50% reduction in total BPRS score No rating >3 on the Schedule for Affective Disorders and Schizophrenia, Change Version, psychosis and disorganization scale psychosis items; CGI severity of mild or less; rating of at least much improved on CGI improvement scale for 8 weeks Ho et al., 2000 (15) 6 n.s. a 74 A rating of 2 ( mild) on Scale for the Assessment of Positive Symptoms (SAPS) global psychotic and disorganization items persisting for at least 8 consecutive weeks Comparisons of the proportion of subjects who met response criteria in groups with short versus long duration of untreated psychosis Malla et al., 2002 (30) Ratings of 2 on all global SAPS items over the previous 1-month period Black et al., 2001 (45) No PANSS positive symptom items with rating >3 at follow-up Duration of untreated psychosis predicted time to response (hazard ratio=2.33, p<0.01). Longer duration of untreated psychosis was associated with decreased likelihood of meeting response criteria; remission hazard ratio would increase by 18% if duration of untreated psychosis was reduced by half (χ 2 =14.6, df=1, p= ). No relationship of duration of untreated psychosis and response categories: full versus partial remission (χ 2 =0.19, p=0.67), full remission versus continually ill (χ 2 = 1.7, p=0.19), partial remission versus continuously ill (χ 2 =0.85, p=0.36) Longer duration of untreated psychosis was associated with decreased likelihood of meeting response criteria; for every increase of 1 year in duration of untreated psychosis, odds of response were reduced by 15% (odds ratio=0.85, CI= , p=0.006). Duration of untreated psychosis predicted time to response (χ 2 = 5.04, df=1, p=0.03). No relationship between duration of untreated psychosis and likelihood of meeting response criteria (χ 2 <0.07, p>0.80) Thirty-six (83.7%) of 43 subjects with short duration of untreated psychosis and 28 (65.1%) of 43 with long duration of untreated psychosis met the response criteria (χ 2 =3.90, df=1, p<0.05). Nine of nine subjects with short duration of untreated psychosis and five of 10 with long duration of untreated psychosis met the remission criteria (χ 2 =8.0, df=1, p<0.04). Thirteen (87%) of 15 individuals with long duration of untreated psychosis were continuously psychotic, compared to two (13%) of 15 with short duration of untreated psychosis (odds ratio=9.0, 95% CI= , p=0.02). No difference in response for short and long duration of untreated psychosis groups (p=0.50) Am J Psychiatry 162:10, October 2005

13 PERKINS, GU, BOTEVA, ET AL. TABLE 2. Studies Examining the Relationship Between Duration of Untreated Psychosis and Treatment Response (continued) Eight studies reported in nine publications examined the relationship between duration of untreated psychosis and baseline neurocognitive function (13, 24, 27, 31 33) or neurocognitive function after a period of antipsychotic treatment (13, 34 36). Table 1 summarizes the neurocognitive test batteries used in each of these studies. These studies generally found no relationship, except as noted here. One study of 42 first-episode subjects found longer duration of untreated psychosis associated with worse performance on WAIS digit symbol and comprehension subtests (35). In this study, longer duration of untreated psychosis was also associated with estimated cognitive decline before treatment (assessed as the ratio of the WAIS information and vocabulary subtest scores, which are relatively intact in schizophrenia, to the WAIS digit symbol subtest score, which is believed to decline in schizophrenia). In a second study of 136 subjects that measured neurocognitive function with the Cambridge Neuropsychological Test Automated Battery, there was a significant relationship between duration of untreated psychosis and performance on an attentional set-shifting task that mea- Follow- Up Period (months) N at End of Follow- Up Period Definition of Response Results Initial Type of Analysis and Study N Verdoux et al., 2001 (21) Course type of continuously psychotic versus other outcomes Thirteen (87%) of 15 individuals with long duration of untreated psychosis were continuously psychotic, compared to two (13%) of 15 with short duration of untreated psychosis (odds ratio=9.0, 95% CI= , p=0.02). Barnes et al., 2000 (24) Brenner scale used to determine response No difference in response for short and long duration of untreated psychosis groups (p=0.50). Huber, 1997 (42) Complete response versus residual symptoms Comparisons of the mean or median duration of untreated psychosis in subjects who did and did not meet response criteria Madsen et al., 1999 (26) Without productive psychotic symptoms according to psychiatric records or nonpsychotic at follow-up study evaluation Larsen et al., 2000 (28) No PANSS positive symptoms with rating of >3 for 2 months Rabiner et al., 1986 (44) Research Diagnostic Criteria delusions, hallucinations, and formal thought disorder absent for at least 3 months a Not stated. Seventy-six (28%) of 273 subjects with short duration of psychosis versus 30 (14%) of 218 patients with long duration of psychosis had complete response. Median duration of untreated psychosis was 60 months for responders and 5 months for nonresponders (p<0.05). Mean duration of untreated psychosis was 61.7 weeks in responders versus weeks in nonresponders (t= 2.35, df=41, p=0.002). Mean duration of untreated psychosis was 9.11 months for responders and weeks for nonresponders (p<0.05). eled the relationship of duration of untreated psychosis to treatment response and included adjustment for premorbid function (9, 10, 12 14, 18, 21, 28, 30, 63) or mode of onset (9) consistently found that duration of untreated psychosis is an independent predictor, although the strength of the relationship varied. Duration of Untreated Psychosis and Symptom Severity at First Treatment Contact Figure 2 summarizes the results of studies that analyzed the relationship between duration of untreated psychosis and symptom severity at first treatment contact. The results of studies that used comparisons of means are summarized on the left side of Figure 2, and the results of studies that used correlational methods are summarized on the right side of Figure 2. Greater severity of negative symptoms at first treatment contact was significantly associated with longer duration of untreated psychosis (combined Hedges s gu=0.28, 95% CI= ; combined correlation: r=0.15, 95% CI= ). Duration of untreated psychosis was not related to severity of global psychopathology or positive symptoms or to global assessments of function (assessed with the GAF or GAS) at first treatment contact. Duration of Untreated Psychosis and Neurocognition Am J Psychiatry 162:10, October