Jean Pierre Lindenmayer

Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia

BACKGROUNDnNeurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity.nnnMETHODSnWe examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability.nnnRESULTSnThe Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores.nnnCONCLUSIONSnThe findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the prefrontal dopamine hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression.

Antipsychotic-induced weight gain and therapeutic response: A differential association

This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.

Overt Aggression and Psychotic Symptoms in Patients with Schizophrenia Treated with Clozapine, Olanzapine, Risperidone, or Haloperidol

Abstract: The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.

Adjunctive high-dose glycine in the treatment of schizophrenia.

Glycine is an agonist at brain N-methyl-D-aspartate receptors and crosses the blood-brain barrier following high-dose oral administration. In a previous study, significant improvements in negative and cognitive symptoms were observed in a group of 21 schizophrenic patients receiving high-dose glycine in addition to antipsychotic treatment. This study evaluated the degree to which symptom improvements might be related to alterations in antipsychotic drug levels in an additional group of 12 subjects. Glycine treatment was associated with an 8-fold increase in serum glycine levels, similar to that observed previously. A significant 34% reduction in negative symptoms was observed during glycine treatment. Serum antipsychotic levels were not significantly altered. Significant clinical effects were observed despite the fact that the majority of subjects were receiving atypical antipsychotics (clozapine or olanzapine). As in earlier studies, improvement persisted following glycine discontinuation.

Medication nonadherence and treatment outcome in patients with schizophrenia or schizoaffective disorder with suboptimal prior response.

OBJECTIVEnTo examine the impact of medication nonadherence on treatment outcome in schizophrenia and potential risk factors for nonadherence.nnnMETHODnA post hoc analysis of a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10, 20, and 40 mg/day for patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) with suboptimal response to current treatment (N = 599) was conducted between September 12, 2003, and November 3, 2005, at 55 study centers in the United States. Nonadherence was defined as not taking medication as prescribed based on daily pill counts. Because there was no significant difference in nonadherence between dose groups, effects of nonadherence on efficacy and safety outcomes were examined using all 3 groups combined. Baseline demographics and symptom severity were investigated as potential risk factors for nonadherence.nnnRESULTSnDuring the 8-week study, 34.5% of patients were nonadherent at least once. Nonadherent patients had significantly less improvement compared to adherent patients as measured by change in Positive and Negative Syndrome Scale total score (-22.57 vs. -26.84, p = .002). Longer duration of nonadherence was associated with reduced likelihood of treatment response (odds ratio = 0.94, 95% CI = 0.90 to 0.99, p = .008). The early treatment discontinuation rate was higher in nonadherent compared to adherent patients (40.8% vs. 24.5%, p < .001). Adherent and nonadherent patients had comparable outcomes in most safety measures, except for weight change, for which adherent patients had greater weight gain than nonadherent patients (2.63 kg vs. 1.96 kg, p = .02). Greater depression severity at baseline (p = .01) and greater hostility level during the study were significant risk factors for nonadherence (p = .02).nnnCONCLUSIONSnMedication nonadherence had a significantly negative impact on treatment response, highlighting the importance of adherence to achieve satisfactory treatment outcome. Findings may also help clinicians identify patients at risk for nonadherence and utilize interventions to improve adherence.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00100776.

Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder

OBJECTIVEnVarenicline has been shown to be an effective anti-smoking treatment in smokers without identified psychiatric illness, and the drugs pharmacology suggests possibilities of pro-cognitive effects. However, recent reports suggest varenicline may have the potential for important psychiatric side-effects in some people. We present the first prospective quantitative data on the effects of varenicline on cognitive function, cigarette smoking, and psychopathology in a small sample of schizophrenic patients.nnnMETHODnFourteen schizophrenic smokers were enrolled in an open-label study of varenicline with a pre-post design. Measures of cognitive function (RBANS, Virtual Water-Maze Task), cigarette smoking (cotinine levels, CO levels, self-reported smoking and smoking urges), and psychopathology (PANSS) were evaluated prior to and during treatment with varenicline. Data on psychopathology changes among schizophrenic smokers in another drug study, in which patients were not receiving varenicline, were used for comparison.nnnRESULTSn12 patients completed the study, and 2 patients terminated in the first two weeks of active varenicline because of complaints of nausea or shaking. Varenicline produced significant improvements in some cognitive test scores, primarily associated with verbal learning and memory, but not in scores on visual-spatial learning or memory, or attention. Varenicline significantly decreased all indices of smoking, but did not produce complete smoking abstinence in most patients. During treatment with varenicline there were no significant increases in psychopathology scores and no patient developed signs of clinical depression or suicidal ideation.nnnCONCLUSIONSnOur small prospective study suggests that treatment with varenicline appears to have some beneficial cognitive effects which need to be confirmed in larger studies with additional neuropsychological tests. Varenicline appears to have some anti-smoking efficacy in schizophrenia but longer studies are needed to determine whether it will produce rates of smoking abstinence similar to those found in control smokers. Treatment with varenicline may not increase psychopathology or depression in most patients with schizophrenia, but we cannot accurately estimate the absolute risk of a potentially rare side-effect from this small sample.

The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: A randomized, double-blind, fixed-dose study

Abstract The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (−10.5 [10 mg/d], −1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P ≤ 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.

The InterSePT scale for suicidal thinking reliability and validity

BACKGROUNDnThe InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies.nnnMETHODnIn Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined.nnnRESULTSnThe intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented.nnnCONCLUSIONnThe ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers.

Suggestive association between the C825T polymorphism of the G-protein β3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia

G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response. We hypothesized that this polymorphism may be associated with response to antipsychotics in a population of 145 chronic schizophrenic patients deriving from two study-samples and being mainly treated with clozapine for up to 6 months. Overall, the C/C genotype was significantly associated with relative clinical improvement as measured by Brief Psychiatric Rating Scale (BPRS) change scores after 6 and 12 weeks (p<0.01 and p=0.03, respectively), with estimated effect sizes ranging from 4.8 to 7%. Our results further suggest that this effect is only attributable to Caucasians when compared to African-Americans. Moreover, our findings point to the role of intracellular mechanisms in antipsychotic response.