A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis.

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. CONCLUSION: DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.

Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode nonaffective psychosis: a 12-week randomized, flexible-dose, open-label trial.

BACKGROUND: Differences among antipsychotics in terms of effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second generation antipsychotics (SGAs) are scarce. We aimed to compare the clinical effectiveness in the short-term of Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode schizophrenia-spectrum disorders. METHOD: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. 202 first-episode drug-naïve patients were randomly assigned to Aripiprazole (N = 78), Ziprasidone (N = 62), or Quetiapine (N = 62) and followed-up for 3 months. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat populations was conducted in the analysis for clinical efficacy. RESULTS: The overall dropout rate at 3 months was small (13.86%). The treatment discontinuation rate differed significantly between treatment groups (Aripiprazole = 23.1%, Ziprasidone = 37.1% and Quetiapine = 61.3%) (χ(2) = 21.334; p < 0.001). Insufficient efficacy in the group of Quetiapine is the main reason for discontinuation rate differences (χ(2) = 20.223; p < 0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank = 23.467 p < 0.001). Aripiprazole and Quetiapine were associated with a greater depressive symptoms improvement (p = 0.043). The profile of side-effects varies between treatments. Patients on Quetiapine were less likely to be prescribed hypnotics. CONCLUSIONS: Patients treated with Quetiapine had a higher risk of treatment discontinuation in the short-term after a first episode due to insufficient efficacy. Establishing differences between SGAs may help clinicians in prescribing decisions for the treatment of individuals presenting with first-episode schizophrenia.

Prediction of acute clinical response following a first episode of non affective psychosis: results of a cohort of 375 patients from the Spanish PAFIP study.

OBJECTIVE: Predicting response to antipsychotic treatment might optimize treatment strategies in early phases of schizophrenia. We aimed to investigate sociodemographic, premorbid and clinical predictors of response to antipsychotic treatment after a first episode of non-affective psychosis. METHOD: 375 (216 males) patients with a diagnosis of non affective psychosis entered the study. The main outcome measure was clinical response at 6 weeks and variables at baseline were evaluated as predictors of response. ANOVA for continuous and chi-square for categorical data were used to compare responders and non-responders. Multivariate logistic regression was used to establish a prediction model. RESULTS: 53.3% of study subjects responded to antipsychotic treatment. The following variables were associated with an unfavorable response: 1.--lower severity of symptoms at baseline; 2.--diagnosis of schizophrenia; 3.--longer DUI and DUP; 4.--poorer premorbid adjustment during adolescence and adulthood; 5.--family history of psychosis, and 6.--hospitalization. Patients with a family history of psychosis, longer DUP, poor premorbid functioning and lower severity of psychotic symptoms at intake have a reduced likelihood of responding to antipsychotic treatment. CONCLUSION: Helping clinicians to identify those first episode patients with a lower probability of having a favorable clinical response is meant as a first step to achieve a successful initial treatment.

The early phases of anxiety disorders: from prevention to treatment.

The 'early intervention' model has been applied with good results to the care of a range of serious medical conditions. The key rationale for this model is to guarantee early identification and treatment for the illness, thus preventing its progression to a more advanced and severe stage. It would also provide a framework for optimal treatment according to the stage of the disorders. Although in the field of psychiatry this model has mainly been implemented in nonaffective psychosis, research evidence supports its application in other mental disorders. To promote this initiative, the chapter explores the available evidence demonstrating the feasibility of adopting the key elements of the model in the care of the whole spectrum of anxiety disorders. In addition, the chapter describes the different stages that are possible to identify in the process of developing an illness, and also the phase-specific interventions that could be applied. Finally, the service repercussions of implementing an early intervention model in anxiety disorders are discussed.

Predictors of clinical remission following a first episode of non-affective psychosis: sociodemographics, premorbid and clinical variables.

The aim of the study was to identify predictors associated with a lower likelihood of achieving a clinical remission 1 year after the first break of the illness. Participants were 174 consecutive subjects included in a first episode programme with no prior treatment with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone in a randomized, open-label, prospective clinical trial. The main outcome variable was the remission criteria developed by the Remission in Schizophrenia Working Group. Clinical variables were included in a logistic regression analysis in order to predict the remission state at 1 year. At 1 year, 31% of patients met criteria for remission. The logistic regression analysis revealed that the strongest predictors of achieving clinical remission 1 year away from a first episode of non-affective psychosis were the length of duration of untreated psychosis (DUP), the severity of negative symptomatology and the educational level attained at baseline. The results suggest that: (1) patients with a lengthy DUP, a greater severity of negative symptomatology at baseline and with a lower education level are in a higher risk of not achieving a clinical remission during the first year of treatment; and (2) early intervention clinical programs should aim to reduce the length of DUP in order to provide a better outcome for patients.

Long-term effect of haloperidol, olanzapine, and risperidone on plasma prolactin levels in patients with first-episode psychosis.

OBJECTIVE: The main goal of this study was to assess the long-term effect of haloperidol, olanzapine, and risperidone on serum prolactin levels in a naturalistically treated first-episode psychosis population. METHODS: Patients included in this study were drawn from a prospective, randomized, open-label clinical trial. Prolactin levels were measured in 110 patients with medication-naive first-episode psychosis at baseline, 3 months, and 1 year. RESULTS: A repeated-measures analysis of variance revealed a significant difference between treatments (F = 17.28, P < 0.001). At 1-year follow-up, most patients in the haloperidol and olanzapine arms had prolactin values that fell within the reference range. Patients treated with risperidone experienced a significant increase at 3 months resulting in prolactin levels above the reference range in 90% of men and 87% of women. The levels showed a tendency to decrease at 1 year, although still more than 70% of the values remained above the normative range. Sexual adverse drug reactions at 1 year assessed by the Udvalg for Kliniske Undersogelser scale showed that a higher percentage (39.3%) of patients had symptoms in the risperidone group compared to the olanzapine group (24%) or haloperidol group (20%), but the difference did not reach statistical significance (P = 0.281). CONCLUSION: Olanzapine and haloperidol treatments do not significantly affect serum prolactin levels at long term. After 1 year, elevated prolactin levels persist in most patients treated with risperidone.

Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.

BACKGROUND: Imaging evidence indicates that brain alterations are primary to the full-blown onset of schizophrenia and seem to progress across time. The potential effects of antipsychotic medication on brain structure represent a key factor in understanding brain changes in psychosis. We aimed to investigate the effects of low doses of haloperidol, risperidone and olanzapine on cortical thickness. METHOD: We investigated the effects of risperidone (N=16), olanzapine (N=18) and low doses of haloperidol (N=18) in cortical thickness changes during 1-year follow-up period in a large and heterogeneous sample of schizophrenia spectrum patients. The relationship between cortical thickness changes and clinical and cognitive outcome was also assessed. A group of 45 healthy volunteers was also longitudinally evaluated. Magnetic resonance imaging brain scans (1.5T) were obtained and images were analyzed by using BRAINS2. RESULTS: There were no significant effects of time (F(1,47)<1.66; P>0.204), treatment group (F(2,47)<1.47; P>0.242) or group-by-time interaction (F(2,47)<1.82; P>0.174) for any of the cortical thickness variables. When the group of healthy controls was included in the analyses, it is of note that group-by-time interaction showed a significant result for the frontal lobe at trend level (F(3,81)=2.686; P=0.052). After the Bonferroni adjustment for multiple comparisons, there were no significant associations between changes in cortical thickness and clinical and cognitive outcome. CONCLUSIONS: Low doses of haloperidol, risperidone, and olanzapine seem to equally affect gray matter cortical thickness, overall and lobes, at the medium-term (1 year). The clinical effectiveness of treatments was not significantly related to changes in cortical thickness.

One year longitudinal study of the straight gyrus morphometry in first-episode schizophrenia-spectrum patients.

The aim of this study was to use a region-of-interest approach with magnetic resonance imaging to examine the volume of the straight gyrus volume change in first-episode schizophrenia-spectrum patients compared with healthy subjects over a 1-year follow-up period. We did not find a differential pattern of volumetric change between the two groups.

Early intervention in bipolar disorder: the Jano program at Hospital Universitario Marqués de Valdecilla.

UNLABELLED: In order to improve relapse and recurrence prevention in bipolar disorder, the purposes of this paper are: (i) to summarize the evidence published on treatments for this disorder, particularly on psychological interventions in its early phases; (ii) to provide a description of the Jano Intervention and Research Program on the Early Phases of Bipolar Disorder, which is being developed at Valdecilla Hospital (Santander, Spain). Firstly, we review the data from randomized controlled trials and systematic reviews regarding four psychotherapies proven to be effective in the treatment of bipolar disorder: psychoeducation, cognitive-behavioral therapy, family therapy and interpersonal and social rhythm therapy. Secondly, we display a systematic review on the effectiveness of psychological therapies during the early stage of bipolar disorder. Out of 456 studies, all were excluded due to not meeting the inclusion criteria. Finally, we outline the Jano Program, which provides psychiatric management, psychoeducation, psychotherapy and family therapy for patients in the early stage of bipolar disorder. Several standardized clinical, social and neuropsychological tests are administered to the patients at the beginning of the program, and also at 2, 4, 6 and 8 weeks, 3 and 6 months, 1, 2, 3 and 5 years later. CONCLUSIONS: It's necessary to enlarge the sample and finish our data collection in order to determine the effectiveness and efficiency of this kind of program, and specially of its psychological components. Early intervention for bipolar disorder may need to be adapted in some way from usual treatments to better reach our goals.

Intervención temprana en Trastorno Bipolar: el programa Jano del Hospital Universitario Marqués de Valdecilla / Early intervention in Bipolar Disorder: the Jano program at Hospital Universitario Marqués de Valdecilla

Con el fin de mejorar la prevención de recaídas y recurrencias en el trastorno bipolar, los objetivos de este trabajo son: (i) resumir la evidencia disponible en la literatura sobre los tratamientos para este trastorno, en particular las intervenciones psicológicas para fases tempranas; (ii) describir el Programa Jano de Intervención e Investigación en Fases Tempranas del Trastorno Bipolar, que se desarrolla actualmente en el Hospital Valdecilla (Santander, España).Primero revisamos los datos extraídos de estudios aleatorizados y revisiones sistemáticas relativos a cuatro psicoterapias de eficacia probada en el tratamiento del trastorno bipolar: psicoeducación, terapia cognitivo-conductual, terapia familiar y psicoterapia interpersonal del ritmo social. En segundo lugar, exponemos una revisión sistemática sobre la eficacia de los tratamientos psicológicos en fases tempranas de este trastorno. De 456 estudios, todos hubieron de ser excluidos por no cumplir los criterios de inclusión. Finalmente, describimos el Programa Jano, que ofrece consultas psiquiátricas, psicoeducación, psicoterapia y terapia familiar para pacientes en fases iniciales del trastorno bipolar. Se les administran además varios tests estandarizados clínicos, sociales y neuropsicológicos, al inicio del programa, a las 2, 4, 6 y 8semanas, 3 y 6 meses, y 1, 2, 3 y 5 años después del inicio. Conclusiones. Es necesario ampliar nuestra muestra actual y finalizar la recogida de datos para determinar la eficacia y eficiencia de este tipo de programas, y en especial de sus componentes psicológicos. La intervención precoz para el trastorno bipolar podría requerir algún tipo de adaptación desde los tratamientos existentes al uso para lograr nuestros objetivos (AU)

In order to improve relapse and recurrence prevention in bipolar disorder, the purposes of this paper are: (i) to summarize the evidence published on treatments for this disorder, particularly on psychological interventions in its early phases; (ii) to provide a description of the Jano Intervention and Research Program on the Early Phases of Bipolar Disorder, which is being developed at Valdecilla Hospital (Santander, Spain).Firstly, we review the data from randomized controlled trials and systematic reviews regarding four psychotherapies proven to be effective in the treatment of bipolar disorder: psychoeducation, cognitive-behavioral therapy, family therapy and interpersonal and social rhythm therapy. Secondly, we display a systematic review on the effectiveness of psychological therapies during the early stage of bipolar disorder. Out of 456 studies, all were excluded due to not meeting the inclusion criteria. Finally, we outline the Jano Program, which provides psychiatric management, psychoeducation, psychotherapy and family therapy for patients in the early stage of bipolar disorder. Several standardized clinical, social and neuropsychological tests are administered to the patients at the beginning of the program, and also at 2, 4, 6 and 8 weeks, 3 and 6 months, 1, 2, 3 and5 years later. Conclusions. It’s necessary to enlarge the sample andfinish our data collection in order to determine the effectiveness and efficiency of this kind of program, and specially of its psychological components. Early intervention for bipolar disorder may need to be adapted in some way from usual treatments to better reach our goals (AU)

Identifying attentional deficits in people with first-episode psychosis with the Scale for the Assessment of Negative Symptoms attention subscale: is it possible?

OBJECTIVE: The aim of this study was to examine the correspondence between clinical ratings of inattention problems in the early course of a psychotic disorder and concurrent neuropsychological data for sustained attention and speed of processing/executive functioning (SP/EF) derived from a comprehensive neuropsychological test battery. METHOD: A sample of 131 patients with first-episode psychosis (FEP) was clinically rated after clinical stabilization with the attention subscale of the Scale for the Assessment of Negative Symptoms (SANS) and a completed neuropsychological test battery, which included measurements of sustained attention and SP/EF. To test the associations of the clinical ratings and objective data, correlations and regression analyses were conducted. RESULTS: Clinical ratings of inattention showed only weak correlations with the global score of SP/EF and with the clinical ratings of negative symptoms (ρ < 0.25). None of the independent variables entered in the logistic regression model were significant (all P values > .05). Percentages of agreement between clinical judgment and neuropsychological measures were unacceptably low (ranged from 53% to 68%). κ values indicate only slight agreement (κ < 0.2). CONCLUSIONS: Clinical ratings based on the SANS attention subscale do not reliably match neuropsychological test measures of attention or other related cognitive processes in FEP. Even for those cognitive domains more pronouncedly impaired, mental health professionals will likely need to rely on psychometric testing or, alternatively, specific guidelines and also, probably, to collect data from different sources to adequately identify cognitive impairments.

Long-term (3-year) effectiveness of haloperidol, risperidone and olanzapine: results of a randomized, flexible-dose, open-label comparison in first-episode nonaffective psychosis.

RATIONALE: To enhance the effectiveness of antipsychotics in first-episode psychosis is crucial in order to achieve the most favourable prognosis. Difference in effectiveness between antipsychotics is still under debate. OBJECTIVE: The purpose of this study is to determine the long-term (3-year) effectiveness and efficacy of haloperidol, risperidone and olanzapine in first-episode schizophrenia-spectrum disorders. METHOD: This is a prospective, randomized, open-label study. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention programme of first-episode psychosis. One hundred seventy-four patients were randomly assigned to haloperidol (N = 56), olanzapine (N = 55), or risperidone (N = 63) and followed up for 3 years. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on per-protocol populations was conducted in the analysis for clinical efficacy. RESULTS: The treatment discontinuation rate for any cause differed significantly between treatment groups (χ (2) = 10.752; p = 0.005), with a higher rate in haloperidol than in risperidone and olanzapine. The difference in the discontinuation rate between risperidone and olanzapine showed a tendency towards significance (χ (2) = 3.022; p = 0.082). There was a significant difference in the mean time to all-cause discontinuation between groups (log-rank χ ( 2 ) = 12.657;df = 2; p = 0.002). There were no significant advantages to any of the three treatments in reducing the psychopathology severity. CONCLUSIONS: After 3 years of treatment, a lower effectiveness was observed in haloperidol compared to second-generation antipsychotics (SGAs). The use of SGAs for the treatment of early phases of nonaffective psychosis may enhance the effectiveness of antipsychotics.

Sex-specific variation of MRI-based cortical morphometry in adult healthy volunteers: the effect on cognitive functioning.

Previous investigations have revealed sex-specific differences in brain morphometry. The effect of sex on cortical thickness may be influencing cognitive differences between sexes. With this exploratory study, we aimed to investigate the effect of sex in MRI-based cerebral cortex morphometry in healthy young volunteers and how the variability in cortical measures might affect cognitive functioning in men and women. 76 young healthy volunteers (45 men and 31 women) underwent a 1.5 T MR scan and 53 of them completed a comprehensive cognitive battery. Overall no gross significant differences between sexes were found in cortical thickness, surface area and curvature indexes. However, there was a significant group by hemisphere interaction in the total cortical thickness (F(1,72)=5.02; p=0.03). A greater leftward asymmetry was observed in cortical thickness in males. Only females show significant associations between cortical thickness and cognitive functioning (IQ and executive functioning). In conclusion, our findings do not support the notion of sexual dimorphism in cortical mantle morphology. The results also suggest that variability in cortical thickness may affect cognitive functioning in females but not in males.

Straight gyrus morphology in first-episode schizophrenia-spectrum patients.

Previous studies on the straight gyrus have shown inconsistent results in first-episode schizophrenia. In the present study, straight gyrus morphometry in first-episode schizophrenia-spectrum patients was investigated by using a region-of-interest methodology. 141 schizophrenia-spectrum patients and 81 healthy subjects were studied. Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using BRAINS2. The main resulting measurements were straight gyrus gray matter volume and cortical surface area. Patients with schizophrenia-spectrum disorders did not significantly differ from controls in the straight gyrus morphometric variables evaluated (p>0.115). There was neither significant group-by-side (p>0.199) or group-by-gender interaction (p>0.096). Clinical variables were not significantly related with straight gyrus morphology. Our results, based on a large and representative sample, do not confirm the presence of significant straight gyrus morphometric anomalies in schizophrenia-spectrum disorders, after controlling for potential confounding variables.

Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis.

Genetic factors play an important role in the understanding of clinical response to antipsychotic treatments. We aimed to assess the effect of the catechol-O-methyltransferase (COMT) genotype in the short-term (6 weeks) clinical response of 161 first-episode psychosis patients. COMT genotype was not related to clinical response at 6 weeks. Val homozygote patients showed higher negative symptoms than Met homozygote patients. The COMT Val158 genotype seems to be related to the severity of negative symptoms rather than to clinical response.

A digit symbol coding task as a screening instrument for cognitive impairment in first-episode psychosis.

Cognitive impairment may be detected largely by examining the performance on a single neuropsychological measure. The purpose of the present study was to evaluate the validity and diagnostic accuracy of a coding task in comparison with other related tasks. One hundred thirty-one first-episode psychosis patients were administered five cognitive tasks related to a "speed of processing and executive functioning" dimension (Digit Symbol, Trail Making Test [TMT] parts A and B, Cancellation Test, and Digit Span-backward) and an additional measure of functional outcome. Digit Symbol provided good indices of accuracy and correlations with the global composite score of a comprehensive neuropsychological assessment represented large effect sizes. Correlations with a functional outcome were modest. Similar results were observed with the TMT. The processing speed, as measured by Digit Symbol, may be particularly good in capturing the generalized dysfunction which may be causing the widespread cognitive failures in schizophrenia spectrum disorders.

Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment.

Weight gain is one of the major adverse effects of antipsychotics. Although mechanisms remain unclear, genetic susceptibility has become increasingly attractive as a potential mechanism that could explain a significant part of interindividual variability. Most investigations have explored genes related with the mechanism of action of antipsychotic drugs. An alternative approach to investigate the role that genetic factors play in weight gain secondary to antipsychotic treatment is to study those genetic variants that have been found associated with obesity. The aim of this study was to determine whether the fat mass and obesity-associated gene (FTO) rs9939609 variant, the single nucleotide polymorphism that has shown the strongest association with common obesity in different populations, influences weight gain during the first year of antipsychotic treatment. We investigated also the genetic variants in other 3 strong candidates genes involved in the leptin-signaling pathway including leptin, leptin receptor, and Src homology 2. We carried out a prospective study on 239 patients with first-episode psychosis. Two hundred five patients completed the follow-up at 1 year (85.8%). Before antipsychotic treatment, the homozygous subjects for the risk allele A of the FTOrs9939609 variant had a higher body mass index at baseline (24.2 T 3.8 kg/m²) than the AT/TT group (22.82 T 3.3 kg/m2; F = 5.744; P = 0.018). After 1 year, the magnitude of weight increase was similar in the 3 genotypes defined by the rs9939609 variant. These results suggest that the pharmacological intervention accompanied by changes in energy intake and expenditure could suppress the genetic susceptibility conferred by the FTO genotype. None of the other single nucleotide polymorphisms evaluated were associated with weight gain during the first 12 months of antipsychotic therapy.

Temporal pole morphology in first-episode schizophrenia patients: clinical correlations.

Studies of the temporal pole (TP) in schizophrenia patients are not consistent. The aim of this study was to investigate morphometric anomalies of the TP in first-episode schizophrenia patients. Patients did not significantly differ from controls in the TP morphometric variables evaluated. Clinical variables were not significantly related to the TP.

Cannabis use and cognitive functioning in first-episode schizophrenia patients.

Cannabis is one of the most widely used illicit drugs in the world. In healthy individuals cannabis is associated with cognitive impairments. Research into the effect of cannabis use in schizophrenia has yielded contradictory findings. Our aim has been to explore the correlates of cannabis use in cognitive and psychopathological features, both cross-sectional and longitudinally, in early phases of schizophrenia. 104 patients with a first episode of non-affective psychosis and 37 healthy controls were studied. Patients were classified according to their use of cannabis prior to the onset of the illness (47 users vs. 57 non-users). They were cross-sectionally and longitudinally studied and compared on clinical and cognitive variables and also on their level of premorbid adjustment. Cannabis user patients had better attention and executive functions than non-cannabis user patients at baseline and after 1 year of treatment. Both groups showed similar improvement in their cognitive functioning during the 1-year follow-up period. We also found that users had a better social premorbid adjustment, particularly during the early periods of life. The amount of cannabis consumed and the length of time of consumption did not significantly relate to cognitive performance. The use of cannabis does not seem to be associated with a negative effect on cognition in a representative sample of first-episode schizophrenia patients. Cannabis user patients appear to comprise a subgroup of patients with a better premorbid adjustment and premorbid frontal cognitive functions.

Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications.

New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis-COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.