Nigel Bark

Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior.

We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).

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.

Psychopathology of Schizophrenia: Initial Validation of a 5-Factor Model

Schizophrenic psychopathology is heterogeneous and multidimensional. One of the more fruitful strategies to investigate more homogenous domains of psychopathology has been the positive-negative syndrome approach. However, this approach is unable to address a number of important issues. Most schizophrenics present a mixed syndrome; the criteria for what constitutes a positive and negative syndrome are variable; distinguishing primary from secondary negative symptoms can be difficult. In order to address some of these problems, we propose the introduction of a 5-syndrome model based on a reanalysis of factor-analytic procedures used on 240 schizophrenics assessed with the Positive and Negative Syndrome Scale: A negative, positive, excitement, cognitive and depression/anxiety factor. This 5-factor solution is supported by 4 independent and comparable factor analyses. Data on internal consistency of the 5 factors and on initial validation using demographic and clinical variables are presented.

Pharmacokinetics of Aripiprazole and Concomitant Lithium and Valproate

The objective of this study was to assess the pharmacokinetics of the antipsychotic aripiprazole when coadministered with lithium or valproate. Two open‐label, sequential treatment design studies were conducted in chronically institutionalized patients with schizophrenia or schizoaffective disorder requiring treatment with lithium (n = 12) or valproate (divalproex sodium) (n=10). Patients received aripiprazole 30 mg/day on days 1 to 14 and aripiprazole with concomitant therapy on days 15 to 36. Lithium was titrated from 900 mg until serum concentrations reached 1.0 to 1.4 mEq/L for at least 5 days. Valproate was titrated to 50 to 125 mg/L. Coadministration with lithium increased mean Cmax and AUC values of aripiprazole by about 19% and 15%, respectively, whereas the apparent oral clearance decreased by 15%. There was no effect on the steady‐state pharmacokinetics of the active metabolite of aripiprazole. Coadministration with valproate decreased the AUC and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite. Therapeutic doses of lithium and divalproex had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.

High-dose treatment with haloperidol: the effect of dose reduction.

High doses of antipsychotic medications are sometimes prescribed in clinical practice, although the efficacy and safety of such treatment have not been established. The purpose of this study was to determine whether high-dose, long-term antipsychotic treatment prescribed on the basis of clinical judgment can be justified. Patients who were receiving high doses of haloperidol were screened, and those patients whose plasma levels were at least 15 ng/mL were randomly assigned to an experimental group (N = 11) or to a control group (N = 12). The experimental group underwent a dose reduction to achieve the target plasma level of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control group treatment was maintained at the original level. Both groups were then followed up for another 16 weeks, during which the plasma levels of haloperidol were kept constant. The study used double-blind procedures. Both groups showed an average slight symptom reduction. There was no significant difference in the severity of symptoms between the two groups at any time point. The dose reduction had no apparent adverse effects. Thus, the results of this study did not provide justification for high-dose, long-term antipsychotic treatment. However, these results must be interpreted with caution because the sample studied here was small and biased.

Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: A randomized double-blind study

BACKGROUND Schizophrenic patients treated with antipsychotic drugs (AP) have an increased frequency of glucose-lipid metabolic abnormalities and diabetes. Pioglitazone has been shown to be effective in the treatment of glucose and lipid abnormalities in diabetes and decreasing longer-term conversion of impaired glucose tolerance to frank diabetes. Some studies also suggest possible pro-cognitive and antidepressant effects of pioglitazone. We studied the effects of pioglitazone on potential metabolic, symptomatic and cognitive benefits in schizophrenic patients treated with AP. METHODS 54 schizophrenic patients with at least both a)impaired glucose and b) triglycerides≥120mg/dL and/or low HDL levels, participated in a double-blind placebo controlled study of 3month treatment with Pioglitazone (30-45mg/day) or matched placebo, at 5 sites (4 U.S., 1 China). Fasting glucose and lipid parameters, and psychopathology (PANSS scale) were assessed monthly, and patients had a glucose tolerance test and cognitive testing (RBANS and CPT) at baseline and at the end of study. Statistical analysis used mixed model repeated measures analysis, supplemented by completer and LOCF analysis. RESULTS In the total sample there was an overall effect (Ps<.05 to <.01) of pioglitazone on preventing deterioration in fasting glucose and improving HDL and PANSS depression scores; in the pioglitazone group comparison of baseline vs 3month values also showed significant (P<.05) decreases in fasting insulin, 2h glucose in GTT and insulin resistance (HOMA-IR). However there were marked differences between the responses of patients in the U.S. sites vs the China site. In the U.S. sample, patients treated with pioglitazone, when compared to placebo treated patents, had significantly lower fasting glucose (F=3.99, P=0.02), improved insulin sensitivity (lower H0MA-IR, F=6.24, P=.002), lower triglycerides (F=2.68, P=.06) and increased HDL (F=6.50, P=.001). By the end of the study 52% of the pioglitazone treated patients compared to 15% of the placebo patients had fasting glucose in the normal range (Fishers exact test P=.02). Pioglitazone also significantly improved PANSS depression factor scores (F=2.82, P=0.05). It did not improve cognitive performance on the RBANS or CPT tasks. Pioglitazone did not increase weight or produce any other significant side-effects. In the small mainland China site sample, pioglitazone treatment, as compared to placebo, did not show greater improvement in metabolic parameters or psychopathology ratings. CONCLUSIONS In the sample of patients from the U.S., pioglitazone was an efficacious and safe treatment for glucose and lipid metabolic abnormalities in schizophrenic patients treated with AP, and it may also have beneficial effects on depressive symptoms. It may be particularly useful in patients whose weight gain effects from antipsychotics have plateaued and where weight loss is not the primary goal. The risk vs. benefits of longer term treatment with pioglitazone has to be carefully evaluated for individual patients.

Heterogeneity of serotonergic response in treatment-refractory schizophrenia patients

Oral metachlorophenylpiperazine (m-CPP) as a direct-acting postsynaptic serotonergic agonist was used to study serotonergic dysfunction in treatment-refractory chronic schizophrenia based on the hypothesis that some patients may show central serotonergic hypersensitivity. Seventeen DSM-III-R chronic schizophrenic patients with a history of neuroleptic nonresponse underwent double-blind challenge with oral m-CPP (0.25 mg/kg body weight) and placebo after medication washout: m-CPP significantly elevated both prolactin and cortisol levels as compared to placebo. There was a significant relationship between change in cortisol level and change in psychopathology under m-CPP; a blunted cortisol response was associated with a decrease in total psychopathology, while an increase in cortisol response related to an increase in psychopathology. Similarly, decrease in severity of the activation factor and the hostility factor was associated with a smaller cortisol response in the m-CPP condition. These results point to heterogeneity in central serotonergic sensitivity within the context of different subpopulations of serotonergic receptors.

VITAMIN D IN SEVERELY MENTALLY ILL HOSPITALIZED PATIENTS

differencewas also observed between samples on the K10 (t(181.71)= -7.51, p=.00), indicating the schizophrenia sample experienced greater psychological distress compared to controls. The schizophrenia sample also experienced significantly greater dysfunctional problem-solving compared to controls (t(230.65) =7.01, p=.00). Correlations between the two samples on all measures were significantly related (p<0.00). Discussion: People with schizophrenia experience greater difficulties in emotional regulation, have higher levels of psychological distress and poorer social problem-solving ability compared to controls. These findings have implications for theory, research and clinical decision making in relation to the treatment of schizophrenia.