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.

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.

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.

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.

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.

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.

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.

Insular cortex thinning in first episode schizophrenia patients.

Overall and regional cortical thinning has been observed at the first break of schizophrenia. Due to the fact that structural abnormalities in the insular cortex have been described in schizophrenia, we investigated insular thickness anomalies in first episode schizophrenia. Participants comprised 118 schizophrenia patients and 83 healthy subjects. Magnetic resonance imaging brain scans (1.5T) were obtained, and images were analyzed by using BRAINS2. The contribution of sociodemographic, cognitive and clinical characterictics was controlled. Schizophrenia patients demonstrated a significant right insular thinning, and a significant group by gender interaction was found for left insular thickness. Post-hoc comparisons revealed that male schizophrenia patients had a significant left insular thinning compared with healthy male subjects. There were no significant associations between insular thickness, the severity of symptoms at baseline and cognitive measurements and premorbid variables. The fact that insular thinning is already present at early phases of the illness and is independent of intervening variables offers evidence for the potential of these changes to be a biological marker of the illness.

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.

Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis.

There is substantial evidence suggesting that individual variability in antipsychotic treatment response could be genetically determined. Variations in several serotonin transporter (5-HTT) gene polymorphisms have been associated with antipsychotic response among chronic patients with schizophrenia, although their implication in early response among first-episode patients remains unclear. Two polymorphisms in the 5-HTT gene (a 44 bp insertion/deletion in the promoter region and the functional polymorphism rs25531) were genotyped in a sample of 147 drug-naïve patients experiencing a first episode of a non-affective psychosis. Early (6 weeks) response to antipsychotic treatment with haloperidol, olanzapine or risperidone was assessed with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. No clear association was found between the rs25531 variant and treatment response. However, significant associations were observed between 5-HTT-LPR variants and early negative symptom response among first-episode patients with psychosis. Our results suggest a minor contribution to antipsychotic drug response of genetic alterations in the 5-HTT gene.

Effects of family psychoeducation on expressed emotion and burden of care in first-episode psychosis: a prospective observational study.

The present study aimed to examine the levels and interactions of family burden (FB) and expressed emotion (EE) in first episode psychosis (FEP) patients and, secondly, to observe the potential change after a brief psychoeducational group intervention implemented in a real world clinical setting. Twenty-three key relatives of FEP patients received a brief psychoeducational group intervention. FB and EE were assessed before and after the intervention. EE-change and correlations between variables were examined. Half of the sample of key-relatives showed high levels of EE. No severe family burden was observed. FB and EE did not change after the intervention. Family subjective and objective burden were correlated with emotional overinvolvement, but not with criticism. Brief psychoeducational groups may not be sufficient to reduce FB and EE associated to the experience of caregiving for a family member with a first-episode psychotic disorder.

Caring for people with depression or with schizophrenia: are the consequences different?

Attention to caregiver consequences has been mainly restricted to caregivers of patients with schizophrenia. The few studies done in depression were conducted on small samples and/or with non-validated instruments. Caregiver consequences in depression and schizophrenia were measured with the validated Involvement Evaluation Questionnaire (IEQ). IEQ scores of caregivers of 252 mainly outpatients with depression and caregivers of 151 mainly outpatients with schizophrenia were compared. IEQ scores were quite similar for depression and schizophrenia. Caregivers of patients with schizophrenia worry more and have more nursing tasks; in case of depression caregivers experience more tension between spouses. In case of many consequences caregivers live close to a patient who has more acute symptoms. They have more additional expenses on behalf of the patient, and report higher distress scores. In case of depression caregivers report less social support, and less coping abilities. Caregiver consequences of depression and schizophrenia are very similar. Differences reflect the context in which caregiving takes place: In schizophrenia mostly elderly mother caring for their ill (adult) child, in depression mostly spouses caring for their partner. Caregivers of patients with depression should be given more attention and support by professionals.

Lack of influence of COMT Val158Met genotype on cognition in first-episode non-affective psychosis.

COMT gene is a logical candidate gene for schizophrenia. Moreover, variations in the COMT Val158Met functional polymorphism have been associated with prefrontal cognitive abnormalities among patients with schizophrenia, healthy relatives and controls. In this study, using an epidemiologically-based sample of 130 patients experiencing a first-episode of a non-affective psychosis, we examined whether COMT Val158Met genotype influenced cognitive performance on the phenotypic expression of psychosis. We found no significant differences in any cognitive measure according to COMT genotype. These findings, together with previously published research, put the relationship between COMT genotype and cognitive performance in doubt.

Antipsychotic-induced weight gain in chronic and first-episode psychotic disorders: a systematic critical reappraisal.

Antipsychotic-induced weight gain is an important issue in the treatment of psychotic illnesses, and affects 80% of individuals being treated with antipsychotic drugs. However, the true dimension of weight gain and many accepted 'facts' in this area remain unclear as most research has been conducted in short-term trials and has included individuals receiving prolonged antipsychotic treatment. This review aims to systematically and critically review the evidence on weight gain induced by the two leading second-generation antipsychotics (olanzapine and risperidone) and the most widely researched first-generation antipsychotic (haloperidol) in patients with chronic and first-episode psychotic disorders. Weight gain was 3- to 4-fold greater in studies that included young patients with limited previous exposure to antipsychotic agents in both short-term studies (7.1-9.2 kg for olanzapine, 4.0-5.6 kg for risperidone and 2.6-3.8 kg for haloperidol vs 1.8-5.4 kg, 1.0-2.3 kg and 0.01-1.4 kg, respectively, in studies that included patients with chronic psychotic disorders) and long-term trials (10.2-15.4 kg for olanzapine, 6.6-8.9 kg for risperidone and 4.0-9.7 kg for haloperidol vs 2.0-6.2 kg, 0.4-3.9 kg and -0.7 to 0.4 kg, respectively). The same disparity was observed regarding the proportion of patients increasing their baseline weight by > or =7% (the cut-off for clinically significant weight gain). Recent studies carried out in young patients with first-episode psychosis (FEP), along with methodological artefacts in studies of chronic populations, suggest that the magnitude of weight gain reported by much of the literature could in fact be an underestimation of the true magnitude of this adverse effect. Although antipsychotics present idiosyncratic patterns of weight gain, they may also generate similar absolute gains.

Cognitive functioning and negative symptoms in first episode schizophrenia: different patterns of correlates.

Negative symptoms of schizophrenia have been related to disturbances of executive functions, memory, attention and motor functioning. The executive functions dimension comprises a variety of cognitive subprocesses, including speed of processing, flexibility and working memory. We independently analysed the relationship between different cognitive tasks and clinical symptoms (negative, positive and disorganized) in a sample of 126 first-episode patients with schizophrenia spectrum disorders. Negative symptoms were significantly associated with performance on executive-functions and motor coordination tasks. Within the executive functions domain only those tests that required speeded performance showed a significant association with the negative dimension. The widely described relationship between negative symptoms and executive impairments in schizophrenia appears to be mediated by likely dysfunctions in the speed of processing instead of by working memory impairment.

Interleukin-12 plasma levels in drug-naïve patients with a first episode of psychosis: effects of antipsychotic drugs.

An overactivation of the Th1 activity in schizophrenia had been described. Interleukin-12 (IL-12), a proinflammatory cytokine, plays a key role in the regulation of the Th1 response. The aims of this study were to investigate the effect of first and second generation antipsychotic drugs on IL-12 production during the acute phase of the illness and its association with clinical features. Participants comprised 56 drug-naïve first episode psychotic patients and 28 healthy volunteers. Patients were initially randomly assigned to risperidone (n=16), olanzapine (n=20) or haloperidol (n=20); subject were maintained on the same medication throughout the study. Clinical assessments were conducted at baseline and at 6 weeks. IL-12 plasma levels were assessed at baseline and after 6 weeks of antipsychotic treatment. IL-12 haplotypes were also analysed. Patients showed higher IL-12 plasma levels at baseline compared with controls, and had a significant increase in IL-12 plasma level after 6 weeks of antipsychotic treatment. No significant differences in IL-12 level increase were found among the three antipsychotic treatments. IL-12 plasma levels at week 6 were not significantly associated with the severity of psychopathology at week 6. Thus, patients with a first episode of psychosis have inflammatory-like immunological function during early phases of the illness that it is independent of the antipsychotic treatment used.

Interleukin-1 receptor antagonist genotype and brain morphometry in first-episode non-affective psychosis.

Studies of schizophrenia that combine imaging and genetic approaches attempt to map structural brain anomalies associated with genetic risk variants. The aim of the present study was to investigate whether variations in the interleukin-1 receptor antagonist (IL-1RN) were associated with structural brain characteristics of 73 minimally medicated first-episode non-affective psychotic patients. We did not find evidence for association between genetic variation in the IL-1RN gene and brain morphometry at early phases of the illness.

Preserved orbitofrontal function in first-episode schizophrenia: further evidence from the object alternation paradigm.

Neuropsychological literature indicates that performance on Object Alternation Task (OAT) can be linked to the orbitofrontal cortex (OFC). Patients with chronic schizophrenia perform poorly on behavioral and neuropsychological tasks related to OFC functions. In a previous study using the Iowa Gambling Task, we found unimpaired performance in a sample of individuals with first-episode schizophrenia (FES) spectrum disorders. In this study, we aimed to extend our study of OFC functions by using the OAT paradigm, to determine whether there are abnormalities in the early phases of schizophrenia. We examined the performance of 70 patients with FES and 21 healthy controls on a computerized version of OAT. There were no significant differences between patients and control subjects with respect to the OAT. This finding suggests that the OFC function, as measured by decision-making tasks, is preserved in the early phases of schizophrenia.

Catechol-O-methyltransferase Val158Met polymorphism and clinical characteristics in first episode non-affective psychosis.

Catechol-O-methyltransferase (COMT) Val158Met polymorphism has been identified as a potential etiologic factor in schizophrenia. It has been proposed that this polymorphism could be associated with specific clinical markers. The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset. Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis. The COMT Val158Met polymorphism was typed using PCR amplification of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with COMT and gender as independent variables. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers. Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness. These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders.

Caudate nucleus volume and its clinical and cognitive correlations in first episode schizophrenia.

OBJECTIVE: Striatal dysfunction has been traditionally implicated in the pathophysiology of schizophrenia. The purpose of this study is to examine the relationship between caudate nucleus volumes and clinical and cognitive features of schizophrenic patients in an early phase of their illness. METHODS: Caudate nucleus volumes in previously untreated first episode patients with non-affective psychosis (N=76) and healthy comparison subjects (N=45) were measured. Caudate nucleus volume in the right and left hemispheres were automatically segmented and analyzed using BRAINS2. Analysis of covariance was used to control for intracranial volume. Severity of clinical symptoms was assessed using SAPS and SANS total scores. The relationship between cognitive dimensions, and caudate nucleus volume was evaluated. Finally, we examined the correlation between caudate volumes and the duration of untreated illness (DUI), duration of untreated psychosis (DUP) and duration of prodrome period (DPP). RESULTS: Right, left, and total caudate nucleus volumes did not differ significantly between patients and controls. Those patients with a longer DUP have smaller caudate nucleus. In addition, caudate nucleus volume was positively correlated with the severity of psychotic symptomatology. No significant associations were found between caudate nucleus volume and cognitive functioning. CONCLUSION: This group of first episode schizophrenia patients did not exhibit significant volumetric anomalies of the caudate nucleus. Despite this lack of volumetric abnormalities, a delay in receiving antipsychotic treatment and the severity of initial positive symptomatology were significantly associated with reduced caudate volume.