Antipsychotic Treatment Effectiveness in First Episode of Psychosis: PAFIP 3-Year Follow-Up Randomized Clinical Trials Comparing Haloperidol, Olanzapine, Risperidone, Aripiprazole, Quetiapine, and Ziprasidone

Background: Different effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. Method: From February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. A total of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n=55), risperidone (n=63), haloperidol (n=56), aripiprazole (n=78), ziprasidone (n=62), or quetiapine (n=62) and followed up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3 years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine=69.09, risperidone=71.43, aripiprazole=73.08%, ziprasidone=79.03%, haloperidol=89.28%, and quetiapine=95.53%) (x2=79.86; P=.000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank=92.240; P=.000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea. Conclusions: Olanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis

Data regarding active psychosis and functional outcome, among other clinical variables, during early phases of the illness in first-episode psychosis in the PAFIP 10-year follow-up program

This article describes data related to the research study entitled ?Duration of active psychosis during early phases of the illness and functional outcome: The PAFIP 10-year follow-up study.? [1]. We present data concerning the clinical and sociodemographic characteristics of a sample of drug-naïve patients with a first episode of non-affective psychosis. The dataset was obtained from a 3-year longitudinal intervention program as part of an ongoing 10-year epidemiological study. The tables and figure shown present the data from the analysis between the active psychosis (presence of positive psychotic symptoms), among other sociodemographic and clinical predictor variables, recorded during the 3-year longitudinal intervention program and the evaluation of the functional outcome (social functioning and functional recovery) present at the 10-year mark. The data explores how those early parameters could influence long-term outcome

Aripiprazole vs Risperidone Head-to-Head Effectiveness in First-Episode Non-Affective-Psychosis: A 3-Month Randomized, Flexible-Dose, Open-Label Clinical Trial

Background: Antipsychotic choice for the acute phase of a first episode of psychosis (FEP) is of the utmost importance since it may influence long-term outcome. However, head-to-head comparisons between second-generation antipsychotics remain scarce. The aim of this study was to compare the effectiveness in the short term of aripiprazole and risperidone after FEP outbreak. Methods: From February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode drug-naïve patients were randomly assigned to aripiprazole (n = 136) or risperidone (n = 130) and followed-up for 12 weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy. Results: The overall dropout rate at 12 weeks was small (6.39%). Effectiveness measures were similar between treatment arms as treatment discontinuation rates (? 2 = 0,409; P = .522), and mean time to all-cause discontinuation (log rank ? 2 = -1.009; P = .316) showed no statistically significant differences. Despite no statistically significant differences between groups regarding clinical efficacy, aripiprazole required higher chlorpromazine equivalent dosage (? 2 = 2.160; P = .032) and extended mean time (W = 8183.5; P = .008) to reach clinical response. Sex-related adverse events and rigidity were more frequent in the risperidone group, whereas sialorrhea was on the aripiprazole group. Conclusions: No differences regarding effectiveness were found between aripiprazole and risperidone for the short-phase treatment of FEP. Despite the importance of efficacy during this phase, differences in side effect profiles and patient's preferences are essential factors that may lead clinical decisions for these patients

Long-Term Antipsychotic Effectiveness in First Episode of Psychosis: A 3-Year Follow-Up Randomized Clinical Trial Comparing Aripiprazole, Quetiapine, and Ziprasidone

BACKGROUND: Different effectiveness profiles among second-generation antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to affect long-term outcome. The aim of this study was to compare the clinical effectiveness of aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. METHOD: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. Two hundred-two first-episode, drug-naïve patients were randomly assigned to aripiprazole (n=78), ziprasidone (n =62), or quetiapine (n=62) and followed-up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on the intention-to-treat principle was conducted in the analysis for clinical efficacy. RESULTS: The overall dropout rate at 3 years reached 19.3%. Treatment discontinuation rates were significantly different among treatment groups (aripiprazole=73.08%, ziprasidone=79.03%, and quetiapine=95.16%) (?2=11.680; P=.001). Statistically significant differences in terms of nonefficacy, nonadherence, and side effects were observed among treatment groups along the 3-year follow-up determining significant differences in time to all-cause discontinuation (log-rank=32.260; P=.001). Significant differences between treatments were found in the categories of sleepiness/sedation (?2=9.617; P=.008) and increased sleep duration (?2=6.192; P=.004). No significant differences were found in the profile of extrapyramidal symptoms. Patients on aripiprazole were more likely to be prescribed benzodiazepines. CONCLUSIONS: First-episode psychosis patients on quetiapine were more likely to discontinue treatment due to nonefficacy. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis.This work was supported by Plan Nacional de Drogas Research (2005-Orden sco/3246/2004); SENY Fundacio (CI 2005–0308007); Fundacion Marques de Valdecilla (API07/011); and Gerencia Regional de Salud de Castilla y Leon (INT/M/04/17). The study was carried out at the Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain. Unrestricted educational and research grants from AstraZeneca, Pfizer, Bristol-Myers Squibb, and Johnson & Johnson provided support for PAFIP activities. No pharmaceutical industry or institutional sponsors participated in the study design, data collection, analysis, or interpretation of the results

Mental impact of Covid-19 among Spanish healthcare workers. A large longitudinal survey

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia e Innovación; Gerencia Regional de Salud de Castilla y León (SACYL, GRS COVID 32/A/20).Aims Longitudinal data on the mental health impact of the coronavirus disease 2019 (Covid-19) pandemic in healthcare workers is limited. We estimated prevalence, incidence and persistence of probable mental disorders in a cohort of Spanish healthcare workers (Covid-19 waves 1 and 2) -and identified associated risk factors. Methods 8996 healthcare workers evaluated on 5 May-7 September 2020 (baseline) were invited to a second web-based survey (October-December 2020). Major depressive disorder (PHQ-8 ≥ 10), generalised anxiety disorder (GAD-7 ≥ 10), panic attacks, post-traumatic stress disorder (PCL-5 ≥ 7), and alcohol use disorder (CAGE-AID ≥ 2) were assessed. Distal (pre-pandemic) and proximal (pandemic) risk factors were included. We estimated the incidence of probable mental disorders (among those without disorders at baseline) and persistence (among those with disorders at baseline). Logistic regression of individual-level [odds ratios (OR)] and population-level (population attributable risk proportions) associations were estimated, adjusting by all distal risk factors, health care centre and time of baseline interview. Results 4809 healthcare workers participated at four months follow-up (cooperation rate = 65.7%; mean = 120 days s.d. = 22 days from baseline assessment). Follow-up prevalence of any disorder was 41.5%, (v. 45.4% at baseline, p < 0.001); incidence, 19.7% (s.e. = 1.6) and persistence, 67.7% (s.e. = 2.3). Proximal factors showing significant bivariate-adjusted associations with incidence included: work-related factors [prioritising Covid-19 patients (OR = 1.62)], stress factors [personal health-related stress (OR = 1.61)], interpersonal stress (OR = 1.53) and financial factors [significant income loss (OR = 1.37)]. Risk factors associated with persistence were largely similar. Conclusions Our study indicates that the prevalence of probable mental disorders among Spanish healthcare workers during the second wave of the Covid-19 pandemic was similarly high to that after the first wave. This was in good part due to the persistence of mental disorders detected at the baseline, but with a relevant incidence of about 1 in 5 of HCWs without mental disorders during the first wave of the Covid-19 pandemic. Health-related factors, work-related factors and interpersonal stress are important risks of persistence of mental disorders and of incidence of mental disorders. Adequately addressing these factors might have prevented a considerable amount of mental health impact of the pandemic among this vulnerable population. Addressing health-related stress, work-related factors and interpersonal stress might reduce the prevalence of these disorders substantially. Study registration number: NCT0455656

Polimorfismo VAL158MET del gen Catecol-O-Metiltransferasa y características clínicas en primeros episodios de psicosis

RESUMEN: La esquizofrenia está considerada un síndrome clínico heterogéneo con una etiopatogenia de origen multifactorial, en el que se incluyen factores ambientales, caracteriales y genéticos. A pesar de que más del 50% de la variabilidad de la enfermedad se puede deber a uno o varios factores genéticos, sólo un número limitado de variantes de riesgo genético y con un efecto muy débil han podido ser identificados. Muchos de ellos no han podido reproducirse tanto por la diversidad de las muestras y poblaciones estudiadas como por su asociación a diversas enfermedades mentales. Parte de esta heterogeneidad ha intentado ser solventada mediante el uso de endofenotipos o fenotipos intermedios y marcadores biológicos, usados como marcadores de vulnerabilidad genética. El gen de la Catecol-O-Metil Transferasa (COMT), que codifica un enzima catabolizador de dopamina en el córtex prefrontal ha sido estudiado como uno de los genes candidatos más prometedores en el estudio de la etiopatogenia de la esquizofrenia, especialmente el polimorfismo rs4680 (COMT Val158Met). La posibilidad de asociar alteraciones en la regulación dopaminérgica prefrontal se encontraría refrendada por la hipótesis dopaminérgica revisada, según la cual, en la esquizofrenia existiría un desequilibrio dopaminérgico, con un incremento en la función dopaminérgica subcortical D2 y un déficit de estimulación D1 cortical. El polimorfismo COMT Val158Met no ha podido confirmar su asociación con esquizofrenia, existiendo en todo caso un riesgo muy débil asociado al alelo hiperfuncionante Val158. El estudio de endofenotipos y marcadores biológicos ha sugerido la asociación del polimorfismo con alteraciones cognitivas, neurofisiológicas, neuroanatómicas y a fenotipos clínicos como agresividad, suicidio, síntomas psicóticos, edad de inicio y respuesta clínica, encontrándose resultados heterogéneos, así como la existencia de una modulación del riesgo de asociación por el consumo de cannabis. Gran parte de la heterogeneidad puede explicarse por problemas metodológicos, relacionados con la validez y representatividad de las muestras, que podrían solventarse con la recogida sistemática de variables en muestras epidemiológicas en fases iniciales de la enfermedad. Partiendo de la hipótesis de la existencia de una alteración dopaminérgica prefrontal en la esquizofenia, el alelo Val158 del gen COMT estaría asociado a una expresión de síntomas psicóticos más graves, especialmente los negativos y a factores de mal pronóstico. Igualmente el consumo de cannabis podría modular este riesgo, incrementando el riesgo o contrarrestando los factores protectores. El objetivo principal fue estudiar la asociación de la presentación clínica y evolución a las seis semanas de tratamiento antipsicótico de pacientes con un primer episodio de psicosis y las variantes del polimorfismo COMT Val158Met así como su interacción con el consumo de cánnabis premórbido. Los objetivos secundarios fueron estudiar la incidencia de esquizofrenia y validar la representatividad de la muestra, analizar la relación entre el polimorfismo Val158Met y sintomatología clínica, edad de inicio, respuesta al tratamiento y estimar la presencia de interacciones gen-ambiente con el consumo de cánnabis premórbido. Para ello, se reclutaron 174 pacientes consecutivos con un primer episodio de psicosis de esquizofrenia, trastorno esquizofreniforme, trastorno esquizoafectivo, trastorno psicótico breve o trastorno psicótico no especificado, incluidos dentro del programa PAFIP, diseñado para la detección y tratamiento de los casos incidentes en la comunidad de Cantabria de Febrero 2001 a Febrero 2005. Los pacientes fueron evaluados con una entrevista semiestructurada, las escalas SANS, SAPS, HDRS, CDS, YMRS y la entrevista SCID-I. Fueron seguidos durante las primeras seis semanas de tratamiento antipsicótico de asignación aleatoria (olanzapina, risperidona o haloperidol). El genotipo del polimorfismo rs4680 se determinó en muestras de sangre venosa. Un primer estudio mostró una incidencia tratada de 1.38/10000 y la asociación de esta incidencia a factores de riesgo como edad menor de 25 años, sexo masculino, estado marital soltero, desempleo nivel educativo primario, ambiente urbano y consumo de cannabis. Un segundo estudio encontró una asociación del alelo Val158 con sintomatología negativa al inicio y edad de inicio temprana, diagnóstico de esquizofrenia y duración de psicosis sin tratar prolongada en mujeres. En un tercer estudio se mostró la asociación del consumo de cánnabis premórbido con edad de inicio más temprana y una interacción entre consumo de cannabis y el genotipo, de modo que el consumo de cannabis contrarresta el efecto protector del alelo 158 Met. Finalmente, en un cuarto estudio se confirmó la persistencia de la asociación del genotipo Val158Met con mayor sintomatología negativa tras seis semanas de tratamiento, no encontrando diferencias en cuanto a la respuesta clínica. Los resultados muestran que el polimorfismo COMT Val158Met pueden estar asociados a una edad de inicio más temprana y una mayor gravedad de síntomas negativos. Del mismo modo, el consumo de cánnabis premórbido se asocia a una menor edad de inicio y se encuentra un patrón de interacción con el polimorfismo, eliminando los efectos protectores del alelo Met158. Los hallazgos sugieren la importancia del polimorfismo COMT Val158Met y del consumo de cannabis en la etiopatogenia de la esquizofrenia, que podría explicarse por la disminución de trasmisión dopaminérgica prefrontal.ABSTRACT: The schizophrenia is considered a heterogeneous syndrome which has multifactorial causes, including environmental, characterial and genetic factors. Despite the fact that 50% of the variability of the illness is explained by genetic factors, only a limited number of genetic variants have been identified as weak risk factors. Most of them have not been replicated because of the heterogeneity of the studied samples and the association with other mental illnesses. This variability has been tried to be solved by the use of endophenotypes and biological markers, as indicators of genetic vulnerability. Catechol-O-Methyltransferase gene, that codifies a dopamine degradation enzyme active in prefrontal cortex, has been studied as one of the most promising candidates in the etiopathogenesis of schizophrenia, particularly the rs4860 polymorphism (Val158Met). The possible association with an altered prefrontal dopaminergic transmission would be supported by the revised dopaminergic theory. Following this theory, there is a dopaminergic disequilibrium in schizophrenia, with an increase in subcortical D2 dopaminergic transmission and a deficit in D1 cortical stimulation. COMT Val158Met polymorphism has not consistently associated with schizophrenia. The study of endophenotypes and biological markers has suggested associations with cognitive deficits, neurophysiologic and neuroanatomic markers and with clinical phenotypes, such as aggressiveness, suicide, psychotic symptoms, age of onset and clinical response. It also has been reported an interaction with cannabis in the modulation of the risk of psychosis. This heterogeneity could be explained by methodological biases, related to the validity and representativeness of the studied samples and may be solved with the systematic study of epidemiological samples of patients in the initial phases of psychosis. Following the hypothesis of the existence of an altered prefrontal dopaminergic transmission, the Val158 allele in the COMT gene would be associated with more severe psychotic symptoms, particularly negative symptoms and with poor prognostic factors. Likewise, the premorbid use of cannabis could modulate this risk, increasing the risk or counteract the protective factors. The main objective was to study the association between the clinical onset and evolution in the first 6 weeks of treatment and the COMT Val158Met polymorphism as well as the interaction with premorbid cannabis use. The secondary objectives were to study the incidence of schizophrenia and validate the representativeness of the sample, to analyse the relation between the Val158Met polymorphism and clinical symptoms, age of onset, clinical response to treatment and to estimate the presence of gen-environment interactions with the premorbid cannabis use. 174 consecutive first episode psychosis patients with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder or psychosis non-otherwise specified were included in the PAFIP program. The program was designed for the detection and treatment of all cases in the region of Cantabria, form February 2001 to February 2005. The patients were assessed with a semi-structured interview, SANS, SAPS, HDRS, CDS, YMRS scales and the SCID-I interview. They were followed up to 6 weeks and treated with a randomly assigned antipsychotic (olanzapine, risperidone or haloperidol). Rs4680 polymorphism was assessed in peripheric blood samples. A first study showed a treated incidence of 1.38/10000 and the association with several risk factors such as age under 25 years, male gender, single marital status, unemployment, primary educational level, urban environment and cannabis use. A second study found an association between the Val158 allele and negative symptoms severity at onset, early age of onset, schizophrenia diagnosis and longer duration of untreated psychosis in females. A third study showed an association between premorbid cannabis use and early age of onset and an interaction between cannabis use and genotype, indicating that the cannabis use counter act the protective effect of the Met158Met allele in age of onset. Finally, in a fourth study the association between the Val158 allele and negative symptoms was confirmed after 6 weeks of treatment, although no relation was found with clinical response. The results showed that the COMT Val158Met polymorphism could be associated with an earlier age of onset and a higher severity of negative symptoms. Likewise, the premorbid use of cannabis was associated with an earlier age of onset and there was found a gene-environmental interaction, deleting the protective effect of the Met158 Allele. These findings suggest the importance of COMT Val158Met polymorphism and premorbid cannabis use in the etiopathogenesis of the schizophrenia that could be explained by a decrease in the prefrontal dopaminergic transmission

Active psychosis and pro-inflammatory cytokines in first-episode of psychosis

Higher levels of pro-inflammatory cytokines are consistently found in the serum of first episode psychosis (FEP) patients and this immune dysfunction could contribute to neural harm. On the other hand, lengthy periods of active psychosis during the early phases of the illness appear to be associated to worst functional outcome. We aim to explore the possible relationship between lengthy periods of active psychosis during early phases of the illness and the levels of pro-inflammatory cytokines. This is a prospective clinical study consisting of a 3-year clinical follow-up. We assessed the relation between the duration of active psychosis in patients with FEP and the serum levels of 21 cytokines at baseline and 3 months after initiating antipsychotic medication. We used the Human High Sensitivity T Cell Magnetic Bead Panel protocol from the Milliplex® Map Kit. The sample consisted of 59 patients with a FEP. The percentage of variation of the serum levels of the chemokine MIP-3α during the first 3 months of antipsychotic treatment and the score in negative psychotic symptoms 3 months after the initiation of antipsychotic medication, acted as predictors of the initial time to remission of positive psychotic symptoms. Our findings open the possibility to investigating the potential use of the variation in chemokine MIP-3α serum levels during the first months of antipsychotic treatment to identify a subtype of FEP patients that could benefit from an add-on treatment with immune modulators

Aripiprazole vs Risperidone for the acute-phase treatment of first-episode psychosis: A 6-week randomized, flexible-dose, open-label clinical trial

Selecting the first antipsychotic agent for the acute phase of a first episode of psychosis (FEP) is a critical task that may impact on the long-term outcome. Despite that, there is a lack of research comparing head-to-head different second-generation antipsychotics at this stage. The aim of this study was to compare the effectiveness of aripiprazole and risperidone in the treatment of the acute phase after a FEP. For that purpose, from February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode, drug-naïve patients were randomly assigned to aripiprazole (n = 136), or risperidone (n = 130) and followed-up for 6-weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy. The overall dropout rate at 6-week reached 19.5%. Effectiveness measures were similar between both treatment groups as treatment discontinuation rates (χ2 = 1.863; p = 0.172) and mean time until all-cause discontinuation (log rank = 1.421; p = 0.233) showed no statistically significant differences. In terms of clinical efficacy, risperidone proved a statistically significant better performance according to BPRS mean change between baseline and 6-week total score (t = 3.187; p = 0.002). Patients under risperidone treatment were significantly more likely to suffer sex-related adverse events. In conclusion, no differences regarding effectiveness were found between aripiprazole and risperidone for the acute-phase treatment of FEP. Despite the importance of efficacy during this phase of treatment, selecting the most effective treatment for the long-term outcome, requires addressing safety and patient´s preferences.This study was conducted as part of a the PAFIP-3 clinical trial “Effectiveness of Second Generation Antipsychotics in First Episode Psychosis Patients: 1-year Follow-up (PAFIP3_1Y)”. ClinicalTrials.gov Identifier: (NCT02532491). The authors wish to thank all “Programa Asistencial de las Fases Iniciales de Psicosis”(PAFIP) research team and all patients and family members who participated in the study

Duration of active psychosis during early phases of the illness and functional outcome: The PAFIP 10-year follow-up study

PAFIP research group.[Introduction] Longer duration of active psychosis (presence of positive psychotic symptoms) has been associated to worsening of functional and symptomatic outcome in patients with a first-episode of psychosis. There could be a “critical period” of increased brain vulnerability in the early phases of the illness when the effect of active psychosis would be exceptionally pernicious.[Objectives] We aim to explore the impact of lengthy periods of active psychosis during early phases of illness on long-term functional outcome.[Methods] This is a prospective clinical study. We assessed the effect of the duration active psychosis in patients with a first-episode of nonaffective psychosis on long-term social functioning and functional recovery. The study consisted of a 3-year clinical follow-up and a functional evaluation performed after a 10-year period.[Results] The sample consisted of 169 patients with a first-episode of non-affective psychosis. The duration of active psychosis after treatment (DAT) during the 3-year clinical follow-up acted as predictor of social functioning at the 10-year functional evaluation (Wald: 10.705; p = .001), but not of functional recovery. The duration of untreated psychosis (DUP) did not act as a predictor of any of the two long-term measures of functional outcome.[Conclusions] Active psychosis in early phases of the illness seems to be correlated to worst long-term functionality. In this study the duration of active psychosis after treatment (DAT) was a better predictor of long-term outcome than the duration of untreated psychosis (DUP). Reducing DAT should be considered an important objective for early intervention programs

Early Improvement As a Predictor of Later Response to Antipsychotics in Schizophrenia: A Diagnostic Test Review

OBJECTIVE How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse. METHOD The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4-12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2. Secondary outcomes were absent cross-sectional symptomatic remission and <20% PANSS or BPRS reduction at endpoint. Potential moderator variables were examined by meta-regression. RESULTS In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity=86%, PPV=85%) or lack of remission (specificity=77%, PPV=88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity=70%, PPV=55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration. CONCLUSIONS Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change