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Background: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine., Aims: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before., Method: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year., Results: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001)., Conclusions: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

Competing Interests: Competing interests: Lena Palaniyappan has received personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited UK and the Canadian Psychiatric Association, and book royalties from Oxford University Press. No other competing interests were declared. Funding: Lena Palaniyappan acknowledges research support from Monique H. Bourgeois Chair in Developmental Disorders and Graham Boeckh Foundation through the Douglas Research Centre, McGill University and a salary award from the Fonds de recherche du Québec - Santé.

Background: Persistent negative symptoms (PNS, e.g., avolition, anhedonia, alogia) are present in up to 30% of individuals diagnosed with a first episode of psychosis and greatly impact functional outcomes. PNS and secondary PNS (sPNS: concomitant with positive, depressive, or extrapyramidal symptoms) may index distinct pathophysiologies reflected by structural brain changes, particularly in the medial temporal lobe (MTL) and basal ganglia., Aims: We sought to characterize dynamic brain changes related to PNS over the course of 2 years following a first episode of psychosis., Method: Longitudinal volumetric trajectories within the MTL (hippocampus, parahippocampal gyrus, entorhinal cortex, perirhinal cortex) and basal ganglia (caudate, putamen, pallidum) were investigated in 98 patients with first-episode psychosis and 86 healthy controls using generalized estimating equations., Results: In left hippocampus, PNS (n = 25 at baseline) showed decreased volumes over time, sPNS (n = 26) volumes remained stable, and non-PNS (n = 47) volumes increased over time to control levels. PNS-specific changes were observed in left hippocampus and left perirhinal cortex, with the greatest decline from 12 to 24 months to levels significantly below those of non-PNS and controls. Affective/non-affective diagnosis, antipsychotic medication dosage and adherence at baseline did not significantly impact these findings. Basal ganglia volume trajectories did not distinguish between PNS and sPNS., Conclusions: The current study highlights distinct structural brain trajectories in PNS that are prominent in the left MTL. Basal ganglia alterations may contribute to PNS irrespective of their etiology. Left MTL volume reductions were most evident after 1 year of treatment, highlighting the importance of targeted early interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To study the impact of supervised antipsychotic medication discontinuation on clinical and functional outcomes in first-episode psychosis (FEP) in two different cultural environments., Method: FEP patients(N = 253), treated in two early intervention services (Montreal, Canada and Chennai, India) for 2 years, were assessed for medication use, positive and negative symptom remission and social-occupational functioning at regular intervals., Results: Between months 4 and 24 of treatment, 107 patients discontinued medication ('Off'group) as compared to 146 who stayed on medication ('On'group). Medication discontinuation was higher in Chennai as compared to Montreal (n = 80, 49.07% vs n = 27, 16.87%; χ 2 37.80, p < 0.001), with no difference in time to discontinuation [Means(SDs) = 10.64(6.82) and 10.04(5.43), respectively, p = 0.71). At month 24 (N = 235), there were no differences in the rate of positive symptom remission between the on and Off groups (81.5 vs 88.0%, respectively) at both sites. The rate of negative symptom remission was lower among patients in the On compared to the Off group (63.2 vs 87.9%, respectively, χ 2  = 17.91, p < 0.001), but only in Montreal (55.4% vs 80.0%, respectively, χ 2  = 4.12, p < 0.05). Social and Occupational Functioning Assessment Scale scores were equally high in both Off and On medication groups in Chennai [Means (SDs) = 79.43(12.95) and 73.59(17.63), respectively] but higher in the Off compared to the On group in Montreal Means (SDs) = 77.47(14.97) and 64.94(19.02), respectively; Time × site interaction F = 3.96(1,217), p < 0.05]. Medication status (On-Off) had no impact on the outcomes, independent of other variables known to influence outcomes., Conclusion: Certain cultural environments and patient characteristics may facilitate supervised discontinuation of antipsychotic medication following treatment of an FEP without negative consequences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Adherence to therapeutic guidelines in psychiatry is anchored and facilitated by rating scales. However, they are rarely used in routine care, particularly for psychotic disorders. Consequently, adherence to treatment guidelines are not ideal and patient outcomes are often sub-optimal. In this study, we used the clinician-rated Clinical Global Impressions Scale (CGI) to implement a measurement-based care (MBC) approach and derive indices of quality of care at a first episode psychosis (FEP) program., Methods: At the individual level, an algorithm was created using CGI scores and their changes over time to define the concept of Patient Requiring Clinical Attention (PRCA) that encompasses several categories (e.g. episode of severity, treatment inertia, or treatment resistance). At the service level, CGI scores were used to derive several indices of quality of care: severity of illness and its change over time, conformity to the use of low doses of antipsychotic medications, and clozapine offer index., Results: 135 Patients were included in this study of whom 19 patients were identified as PRCA. Of these, 12 (63%) received timely medication, and 7 (37%) were suspected cases of therapeutic inertia. Additionally, 15 patients met criteria for treatment resistance of whom 7 were offered clozapine (47%). At the service level, the average CGI improved by 2 points from baseline to month 1 and average doses of antipsychotic medications prescribed were in line with prescription guidelines for FEP patients., Conclusion: The proposed CGI-based treatment algorithm and service evaluation strategy can help to optimize quality care and services for patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Negative symptoms are present at the onset of psychosis and their persistence is significantly associated with poor psychosocial functioning and lower quality of life. Persistent negative symptoms (PNS) may be idiopathic or secondary to other factors such as depression, positive symptoms, and medication side-effects. Several studies have examined neurocognitive functions in early psychosis patients with PNS relative to non-PNS, but have not systematically controlled for secondary PNS (sPNS). The latter may have a distinct neurocognitive profile that could obscure differences between PNS and non-PNS. Using a large (n = 425) sample, we examined neurocognitive functions in PNS, sPNS, and non-PNS and hypothesized that PNS would be associated with greater impairments relative to non-PNS. Following admission to an early intervention program, a neurocognitive battery was administered after at least 3 months of treatment, and symptom data collected during a subsequent 6-month period were used to classify patients as PNS, sPNS and non-PNS. At month 12, both PNS and sPNS groups had significantly lower level of functioning relative to the non-PNS group but the sPNS group experienced higher levels of depressive and positive symptoms and were on a higher dose of antipsychotics. Relative to non-PNS, PNS patients exhibited significant impairments in verbal memory and working memory, whereas sPNS patients exhibited a trend towards greater impairments in verbal memory. This study confirms that the presence of PNS or sPNS negatively influences functioning with more selective cognitive impairments found in PNS, providing evidence that these groups of patients could benefit from different personalised interventions., Competing Interests: Declaration of Competing Interest Salary awards include: FRSQ to J.L.S., R.J., M.B., and M.L.; a Canada Research Chair to A.M.; and a James McGill Professorship to M.L. M.L. reports grants from Otsuka Lundbeck Alliance, diaMentis personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, and personal fees from MedAvante-Prophase, outside the submitted work. R.J. reports receipt of grants, speaker's and consultant's honoraria from Janssen, Lundbeck, Otsuka, Pfizer, Shire, Perdue, HLS and Myelin and royalties from Henry Stewart Talks. A.M. reports research funding for an investigator-initiated project from BMS Canada and honoraria for lectures and consulting activities (e.g. advisory board participation) with Otsuka and Lundbeck, all unrelated to the present article. All other authors report no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: R. Joober sits on the advisory boards and speakers’ bureaus of Pfizer, Janssen Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin; he has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer and Perdue for CME presentations and royalties from Henry Stewart talks. He is co-editor in chief of JPN, and was not involved in the review of this manuscript or in the decision to accept it for publication. No other competing interests were declared.

Background: The influence of socioeconomic deprivation on the cardiovascular health of patients with psychosis-spectrum disorders (PSD) has not been investigated despite the growing recognition of social factors as determinants of health, and the disproportionate rates of cardiovascular mortality observed in PSD. Discordant results have been documented when studying dyslipidemia -a core cardiovascular risk factor- in first-episode psychosis (FEP), before chronic exposure to antipsychotic medications. The objective of the present study is to determine the extent to which socioeconomic deprivation affects blood lipids in patients with FEP, and examine its implications for cardiovascular risk in PSD., Methods: Linear regression models, controlling for age, sex, exposure to pharmacotherapy, and physical anergia, were used to test the association between area-based measures of material and social deprivation and blood lipid levels in a sample of FEP patients (n = 208)., Results: Social, but not material deprivation, was associated with lower levels of total and HDL cholesterol. This effect was statistically significant in patients with affective psychoses, but not in schizophrenia-spectrum disorders., Conclusions: Contrary to other reports from the literature, the relationship between socioeconomic disadvantage and blood lipid levels was contingent on the social rather than the material aspects of deprivation. Furthermore, this association also depended on the main diagnostic category of psychosis, suggesting a complex interaction between the environment, psychopathology, and physical health. Future studies exploring health issues in psychosis might benefit from taking these associations into consideration. A better understanding of the biology of blood lipids in this context is necessary., Competing Interests: Declaration of competing interest Dr. Malla has received grants from Roche and Bristol-Myers Squibb, and other funding support for consulting and conference lectures from Otsuka, Lundbeck, and Janssen-Ortho, all of it outside the submitted work. Dr. Joober has received grants from BMS, Otsuka, Lundbeck, Astra Zeneca and HLS, has made part of consulting committees for Pfizer, Janssen, BMS, Sunovian and Myelin, has been a speaker for Pfizer, Janssen Myelin, Otsuka, Lundbeck, Shire and Perdue, and has received royalties from Henry Stewart talks, all of it outside the submitted work. Drs. Iyer, Rho and Veru-Lesmes have no conflicts of interest to disclose., (Copyright © 2019. Published by Elsevier B.V.)

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients., (Copyright © 2019. Published by Elsevier B.V.)

Competing Interests: None declared by N. Garel. R. Joober sits on the advisory boards and speakers’ bureaus of Pfizer, Janssen Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin; he has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer and Perdue for CME presentations and royalties from Henry Stewart talks. He is coeditor-inchief of JPN, but was not involved in the review of this manuscript or the decision to accept it for publication.

Objective: It has been shown that men with a longstanding psychotic disorder have worse clinical and functional outcomes than women. Our objectives were to examine whether these sex differences are also present among patients treated in an early intervention service (EIS) for psychosis and to determine if these differences are related to risk factors other than sex., Method: Patients ( N = 569) were assessed for demographic/clinical characteristics at entry and for symptoms/functioning over 2 years of treatment. Clinical outcomes included remission of positive, negative, and total symptoms. Functional outcomes included good functioning and functional remission. Logistic regression models examined the relationship between sex and outcomes after 1 and 2 years of treatment while controlling for the influence of other risk factors., Results: Men reported to be less educated and have a longer duration of untreated psychosis, poorer childhood and early adolescent premorbid functioning, higher rates of substance abuse/dependence disorders, greater severity of baseline negative symptoms, and poorer baseline social/occupational functioning than women. Women were more likely to achieve symptom remission than men after 2 years of treatment (negative odds ratio [OR], 1.69; 95% confidence interval [CI], 1.02 to 2.78; total OR, 1.79; 95% CI, 1.08 to 2.98). Women were also more likely than men to exhibit good functioning (OR, 1.61; 95% CI, 1.04 to 2.49) after 1 but not after 2 years of treatment. These results did not persist after controlling for other risk factors that could confound these associations (i.e., childhood premorbid functioning and age at onset of psychosis)., Conclusions: Sex differences seen in outcomes among patients treated in an EIS for psychosis may be largely influenced by the disparity of other risk factors that exist between the 2 sexes.

Objective: The experience of pre-onset subthreshold psychotic symptoms (STPS, signifying a clinical high-risk state) in first episode psychosis (FEP) predicts poorer outcomes during treatment, possibly through differential adherence to medication. We explored whether adherence differs between FEP patients with and without pre-onset STPS., Methods: Antipsychotic medication adherence was compared in 263 STPS+ and 158 STPS- subjects in a specialized early intervention program for FEP. Data were gathered from a larger observational study conducted between 2003 and 2016. STPS status, sociodemographic, and baseline clinical variables were tested as predictors of non-adherence using univariate and multivariate logistic regressions. Time to onset of non-adherence was analyzed using Kaplan-Meier curves. The same predictors were tested as predictors of time to onset of non-adherence using Cox regression models., Results: Medication non-adherence was higher in STPS+ participants (78.9% vs. 68.9%). STPS status (OR 1.709), substance use disorder (OR 1.767), and milder positive symptoms (OR 0.972) were significant baseline predictors of non-adherence. Substance use disorder (HR 1.410), milder positive symptoms (HR 0.990), and lack of contact between the clinical team and relatives (HR 1.356) were significant baseline predictors of time to non-adherence., Conclusion: FEP patients who experience pre-onset STPS are more likely to be non-adherent to antipsychotic medication over 2 years of intervention. FEP programs should routinely evaluate pre-onset symptomatology to deliver more personalized treatments, with emphasis on engaging both patients and family members from the beginning of care., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Discontinuation of the initial oral antipsychotic prescribed for a first episode of psychosis (FEP) can derail outcome. Our objective was to examine the rate of and time to all-cause discontinuation of the first antipsychotic prescribed and the factors influencing such discontinuation., Methods: In a sample of 390 FEP patients, we estimated the rate of and time to discontinuation of the initial antipsychotic over a one-year period. The effects of a number of putative predictors of discontinuation were estimated using regression analyses., Results: Rate of discontinuation of the first antipsychotic was 72%, with no difference between the 3 investigated antipsychotics (olanzapine (73%), risperidone (68%) and aripiprazole (75%)), (χ 2 (2) = 1.89, p = 0.388). Mean time to discontinuation was 7.2 (4.6) months and was not different among the three antipsychotics (Log-rank χ 2 (2) = 0.257, p = 0.879). Binary logistic regression showed that higher positive and negative symptoms remission and baseline functioning were associated with lower rates of discontinuation (Nagelkerke R 2  = 0.36, χ 2 (10) = 66.9, p < 0.001). Multiple linear regression showed the same predictors, in addition to male gender and less weight gain per month of exposure to the initial antipsychotic, to be associated with longer time to discontinuation (adjusted R 2  = 0.336, F (9, 219) = 13.8, p < 0.001)., Conclusion: Discontinuation of the initial antipsychotic is a major concern in the course of treating FEP. Symptom relief, better functioning and lower side effects appear to be the major factors associated with continuing an antipsychotic medication., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Research and development of early intervention (EI) services for first-episode psychosis have brought much-needed transformation of service delivery for this serious mental disorder to many jurisdictions. The effectiveness of the EI model of service delivery is contingent on timely access to all evidence-informed treatment interventions, including a rational approach to pharmacotherapy. In this perspective paper, we present a brief review of the well-established effectiveness of clozapine in patients who clearly show lack of response to regular antipsychotic therapy. We concentrate, in particular, on the need to identify eligibility for clozapine therapy very early on following failure of treatment on 2 antipsychotic medications. We suggest that attention to the low use of clozapine in the very early phase of treatment of psychosis may be of particular value, as the response to clozapine at this stage is likely to produce larger benefits in other domains of outcomes because of the greater retention of patients' personal and social agency., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Aripiprazole has been associated with a low prevalence of metabolic side effects as compared to other second generation antipsychotic (SGA) medications mostly in patients with long standing illness. The purpose of the present study was to assess specifically the effectiveness and safety of aripiprazole as a first choice for antipsychotic therapy for young patients presenting with a previously untreated first episode of a psychotic disorder (FEP)., Methods: Seventy-three patients presenting with a FEP and with minimal prior exposure to antipsychotic medications were recruited to be part of an open label naturalistic outcome study using aripiprazole as the first choice of antipsychotic medication. Data on positive, negative and total symptom severity including general psychopathological symptoms, level of functioning and metabolic indices were collected prospectively over a one-year period., Results: As compared to baseline, patients treated with aripiprazole (mean dose 9.6mg) improved significantly on measures of positive (p<0.001), negative (p<0.001) and total severity-general psychopathology symptoms (p<0.001) and level of functioning (p<0.001). Seventy two percent of the participants achieved positive symptom remission and 50% achieved total remission (positive and negative) at one year of follow up. Unlike reports on patients with longer standing illness, significant weight gain (p<0.001) was observed, with 44% of participants experiencing >7% increase in body weight., Conclusion: FEP patients starting treatment with aripiprazole improved on symptoms and social and occupational functioning. Aripiprazole was well tolerated except for a significant weight gain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Psychotic disorders (PDs) and attention-deficit hyperactivity disorder (ADHD) are frequently comorbid. Clinicians are often reticent to treat ADHD in patients with psychosis, fearing that psychostimulants will worsen psychotic symptoms. Advances in neurobiology have challenged the simplistic dichotomy where PD is considered a disorder of high dopamine (DA), treated by DA antagonists, and ADHD a disorder of low DA, treated by DA agonists. In our paper, we review the literature on comorbid ADHD and psychosis. Treating ADHD with psychostimulants may be considered in patients with PD who have been stabilized with antipsychotics (APs). Not treating ADHD may have consequences because ADHD may predispose patients to drug abuse, which further increases the risk of PD. Nevertheless, more systematic studies are needed as there remains some uncertainty on the combined use of APs and psychostimulants in comorbid PD and ADHD.

Objective: Our study examines the unique influence of social and family support on adherence to medication in a sample of patients treated for first-episode psychosis (FEP)., Method: Social and family support using the Multidimensional Scale of Perceived Social Support and medication adherence (consensus of subjective and objective data) were evaluated on a monthly basis during a 6-month period in a sample of 82 FEP patients. The relation between social support and adherence was evaluated using correlational and linear regression analyses, controlling for other relevant variables. A longitudinal analysis using hierarchical linear models was conducted to model change in adherence over time., Results: Monthly correlations between social support and adherence were significant at 4 of 7 time points during a 6-month period. There was a modest correlation between the percentage of months of good adherence and the average level of family support across the study period. The linear regression failed to demonstrate a significant relation between baseline social support and overall adherence during the entire study period. Change in social support over time was inversely associated with change in adherence., Conclusions: Our study emphasizes the concurrent influence of social (mostly family) support on adherence but this effect does not persist over time. Changes in the degree of social support may have a complex effect on changes in adherence.

Objective: Poor adherence to medication is a major determinant of relapse following treatment of first-episode psychosis (FEP). However, medication-adherent patients also relapse. We examined what factors influence the risk of relapse after controlling for adherence., Method: We selected a sample of fully adherent patients (n = 65) who had achieved remission at one point. We then compared patients who relapsed, using 2 different definitions of relapse, to those who did not relapse by 12 months on age, sex, premorbid adjustment, duration of untreated psychosis, length of prodrome, and substance abuse., Results: Among the 65 medication-adherent patients in remission, 9 (14%) relapsed according to criteria for relapse requiring a change in medication. These patients differed from those who remained in remission only in the pattern of premorbid adjustment (greater proportion with deteriorating pattern), although this was not independent of other variables. No differences were found on any other variable. Using a more commonly used metric for relapse, based on symptom ratings alone, an additional 14 (21.5%) patients relapsed. Substance abuse significantly predicted relapse, with substance abusers having more than 25 times the odds of relapsing by 12 months (OR 25.6; 95% CI 2.4 to 278.1, P = 0.008)., Conclusion: Using a more conservative definition of relapse in this adherent-to-medication population, we find a very low rate of relapse associated, at least partially, with poor premorbid adjustment. As substance abuse was a significant predictor of symptomatic relapse, this would suggest that there should be a greater emphasis on interventions focused on reducing substance abuse in FEP.

This study evaluates how much agreement there is between subjective reports of adherence to antipsychotic medication and objective or derived measures of adherence in first-episode psychosis (FEP) and asks if any adherence measure could approximate a gold standard based on correlation to symptom improvement in the early phase of treatment. Adherence was assessed in 81 FEP subjects on a monthly basis by reports from patients, clinicians, family, and pill counting. A consensus measure of adherence was derived from all available sources of adherence data. Symptoms were measured using the Positive and Negative Syndrome Scale at study entry and 3 months subsequently. Adherence as measured by patient report, pill count, and clinician report were in good agreement with each other (intraclass correlation coefficient = 0.84), and all of these measures were highly correlated to consensus adherence (r values between 0.86 and 0.98). Mean adherence was slightly higher as rated by patients (83% full doses taken per month) and family members (91%) than by clinicians (76%), pill counting (73%), or consensus value (74%). Early in treatment, each measure of adherence (except family report) was significantly associated with positive symptom reduction, although the order of magnitude of this correlation was greater for pill count and consensus adherence (P < 0.01) compared with patient- or clinician-reported adherence (P < 0.05). Patient or clinician reports provide a reasonable estimate of medication adherence in FEP, but introducing pill counting or a derived measure of adherence may allow more accurate measurement.

Objective: To examine the hypothesis that poorer social and family support, identifiable at the onset of treatment, is associated with nonadherence in the first 6 months of treatment of patients with first-episode psychosis (FEP), independent of other patient-related factors., Method: Consecutive patients (n = 100) admitted to a specialized early intervention service for FEP who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for either a schizophrenia spectrum disorder or an affective psychosis were evaluated monthly for 6 months regarding their adherence to medications. Using sociodemographic and illness-related factors, including social and family support, as independent variables and adherence as the dependent variable, univariate analyses were followed by logistic regression., Results: Fifty-six patients (54.9%) were adherent (76% to 100% of doses taken) and 46 (45.1%) nonadherent (less than 76% of doses taken). Nonadherent patients were less likely to have received a good level of social support (chi (2) = 5.89, df = 1, P = 0.02), as rated by their respective case manager, and more likely to be single (Fisher exact test, P = 0.019) and to have refused medication at the first offer of treatment (chi (2) = 19.70, df = 1, P = 0.001). Using logistic regression, both the level of social support (OR = 3.552, P = 0.03) and early medication acceptance (OR = 11.092, P < 0.001) were significant as predictors of adherence., Conclusion: These results suggest the significance of social and family support in achieving adherence to medications very early in the course of treatment of FEP, in addition to the influence of early acceptance or rejection of medication.

Background: Outcome from psychotic disorders is heterogeneous with poorer outcomes frequently identified too late to be influenced. Symptomatic ratings at 1 or more years following initiation of treatment have been related to cognition in first-episode psychosis. However, the relationship between cognition and early outcome remains unclear., Aims: To determine whether specific cognitive domains could identify poor short-term outcome among individuals with first-episode psychosis., Method: One hundred and fifty-one individuals with first-episode psychosis were divided into two groups based on 6-month clinical data after the initiation of treatment. Six cognitive domains were compared among 78 participants with poor outcomes, 73 with good outcomes and 31 healthy controls., Results: Lower performance on verbal memory (z-scores: poor outcome=-1.3 (s.d.=1.1); good outcome=-0.8 (s.d.=0.9); P=0.001) and working memory (poor outcome=-1.0 (s.d.=1.2); good outcome=-0.4 (s.d.=0.9); P=0.003) identified individuals with first-episode psychosis with a poor outcome after 6 months of treatment., Conclusions: The early identification of those individuals with first-episode psychosis with a poor clinical outcome may encourage clinicians to pay special attention to them in the form of alternative pharmacological and psychological treatments for a more favourable outcome in the long term.

Objective: It is suggested that schizophrenic patients who respond to neuroleptic medication and those who do not might differ with respect to their pathogenesis. In particular, it has been proposed that genetic factors may contribute to treatment response and/or outcome. In order to test this hypothesis, we compared the pattern of familial aggregation of schizophrenia related disorders in schizophrenic patients who are either responders (R) or nonresponders (NR) to typical neuroleptics., Method: R (n=36) or NR (n=35) patients to typical neuroleptics and healthy controls (n=63) were recruited. At least one key informant relative of each proband was interviewed blind as to the status of the proband using the Family Interview for Genetic Studies. Morbid risk for schizophrenia and cluster A personality disorders and family loading score for schizophrenia were examined in first- and second-degree relatives of these probands., Results: First-degree relatives of NR patients were at a significantly higher risk for schizophrenia (MR=8.84), compared, respectively, to relatives of controls (MR=1.52) or relatives of R patients (MR=2.45). The same pattern was observed in second-degree relatives. Family loading score for schizophrenia in first- and second-degree relatives was significantly higher in NR compared to R patients., Conclusions: Schizophrenic patients who do not respond to typical neuroleptics may suffer from a more familial form of schizophrenia compared to patients who are responders.

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

The antipsychotic drugs (APDs) are fundamental tools in current psychiatric practice. A new generation of agents, the atypical APDs, represents an important progress in the treatment of psychotic disorders. Unfortunately, some of them induce excessive body weight gain (BWG), obesity, hyperglycemia and dyslipidemia in the following order: clozapine approximately equal to olanzapine > quetiapine > risperidone > ziprasidone = aripiprazole. Appetite stimulation is probably the main mechanism of BWG and this is strongly correlated with the APD affinity for H1 (histaminergic) and alpha1 (adrenergic) receptors. A composed ratio of the APD affinity for diverse neurotransmitters involved in food intake (FI) regulation correlates with BWG as well. Endocrine/metabolic mechanisms, such as the activation of the hypothalamus-pituitary-adrenal axis, changes in insulin sensitivity (by conventional and atypical agents), hyperprolactinemia and gonadal dysfunction (by conventional APDs and risperidone) may also be involved. Importantly, patients with schizophrenia may have a genetically-based predisposition to appetite dysregulation, insulin resistance and endocrine imbalance involving gonadal steroids. Excessive BWG must be prevented or attenuated by proper drug selection, combining or switching agents, nutritional assistance and physical exercise. Amantadine. metformin and reboxetine proved to significantly lessen APD-induced BWG. Notwithstanding this, novel strategies are necessary to treat this side effect in a clinical population particularly prone to poor compliance and under a high risk of negative drug interaction.

Rationale: Schizophrenia is a heterogeneous syndrome both at the etiological and clinical levels. In particular, patients with schizophrenia exhibit important variability in their therapeutic and metabolic responses to clozapine, an antipsychotic medication., Objective: Here, we determine whether two mouse strains show differing clozapine responses with respect to weight gain, enhancement of prepulse inhibition of acoustic startle, and reversal of amphetamine-induced locomotion. Observed between-strain differences may be partly due to genetic factors that can be subsequently mapped using quantitative genetic approaches., Methods: We treated the A/J and C57BL/6J inbred mouse strains with clozapine for 22 days. Prepulse inhibition and amphetamine-induced locomotion were measured after 3-4 days of clozapine treatment and again after 21-22 days of treatment. Weight gain was also monitored during treatment. RESULTS. Three-day treatment with clozapine increased prepulse inhibition in both strains. Four-day clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain. Long-term (21-22 days) clozapine treatment did not affect these behaviors in either strain. After an initial weight loss during the first 5 days, clozapine (4 mg/kg) induced a significant weight gain in both strains., Conclusions: The reversal of schizophrenia-related behaviors after short-term, but not long-term, clozapine treatment is consistent with other rodent studies. Although short-term clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain, strain differences in amphetamine responses confound the interpretation of these results; therefore, quantitative genetic approaches may be difficult to carry out with this trait. In contrast, enhancement of prepulse inhibition after three days of clozapine treatment and weight gain induced by clozapine are relatively straightforward to quantify, making these trait more amenable to quantitative genetic approaches.

Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.

To determine whether two groups of schizophrenic patients representing the two extremes of the neuroleptic response-spectrum (consistent responders vs. consistent nonresponders) differ with respect to their neuropsychological profile. Neuroleptic-responder (R; n=36) and -nonresponder (NR; n=39) schizophrenic patients were recruited according to a priori defined criteria of responsiveness to typical neuroleptics. Seven neuropsychological domains were assessed and compared between groups: attention-vigilance, abstraction-flexibility, spatial organization, visual-motor processing, visual memory, verbal abilities, and verbal memory and learning. All measures were standardized using the scores of 36 healthy volunteers. NR schizophrenic patients performed worse in all neuropsychological domains compared to normal controls and R schizophrenic patients. However, only performances on visual memory, verbal abilities, and verbal memory and learning were significantly poorer in NR compared to R patients. Only the latter domain significantly differentiated NR patients from the other two groups. R patients performed at an intermediate level in all domains. This report of differences in neuropsychological profile between neuroleptic-responder and -nonresponder schizophrenic patients adds to the growing evidence supporting the value of distinguishing schizophrenic patients on the basis of their therapeutic response to neuroleptics.

Although clozapine (CLZ) is effective in resistant schizophrenia, it fails in some cases leading to a therapeutic problem. Authors report a case of schizophrenia which resists several neuroleptic trials (including haloperidol, chlorpromazine and thioproperazine) and responds to a sequence of CLZ and amisulpride. These two atypical neuroleptics have the same main target (mesolimbic system) but have different and complementary affinities to neuromediator receptors: CLZ has strong serotoninergic and anticholinergic action, noradrenergic alpha 1 affinity and moderately active dopaminergic antagonism; amisulpride has a high and specific dopaminergic D2 antagonism when used at high posology. This clinical improvement can be related to "second treatment effect", described by Goldman in 1966: his study included two groups of refractory schizophrenic patients who received successively during two 6 months periods, 2 neuroleptics (fluphenazine and trifluperazine). Without initial therapeutic response, he noted a significant improvement only after change of neuroleptic medication. Tricyclic antidepressants may turn to be effective, after an initial failure, when they are given after an uneffective ECT trial. The same model may be applied and the clozapine-amisulpride sequence is proposed as an alternative treatment in resistant schizophrenia: even if CLZ is uneffective, it may produce carryover effects which ease the action of amisulpride. The hypothesis of an action on 5HT2-D2 antagonism is advanced. It leads to the general question of the opportunity of neuroleptic sequential prescription in resistant schizophrenia as a therapeutic option.

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamineexpanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab lC2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]