A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode.

On the basis of 3-week studies, lithium and valproate are both recommended for first-line treatment of acute mania. It is, however, also important to demonstrate that antimanic efficacy can be maintained. This study has been designed to compare the efficacy and tolerability of valproate and lithium over 12 weeks in the treatment of acute mania in patients with type I bipolar disorder. Three hundred patients with bipolar I disorder presenting with acute mania were randomized to open treatment with lithium (starting dose: 400 mg/day) or valproate (starting dose: 20 mg/kg/day) for 12 weeks. The primary efficacy criterion was remission (YMRS score or=2 on the CGI-BP severity scale). Remission rates were 65.5% (lithium group) and 72.3% (valproate group). Noninferiority of valproate with respect to lithium was demonstrated [between-group difference: 6.78% (95% confidence intervals: -3.80 to 17.36%)]. Remission rates assessed by the secondary mixed model repeated measures analysis were significantly greater with valproate than with lithium. Adverse events were reported in 44% of patients in both groups. Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks.

A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety.

BACKGROUND: Several open trials and case studies have reported beneficial effects following the addition of risperidone for partial responders to clozapine. The purpose of this study was to carry out a placebo-controlled, randomized, double-blind trial of the efficacy, safety, and tolerability of adjunctive treatment with risperidone in patients with schizophrenia partially responsive to clozapine. METHOD: In this 6-week double-blind study, 30 patients with DSM-IV schizophrenia who had partial response to clozapine despite being treated for a mean of 32 months were randomly assigned to risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale, the Clinical Global Impressions-Severity of Illness scale, the Global Assessment of Functioning scale, and the Quality of Life Scale. A variety of safety and tolerability measures were also obtained. Data were collected between November 2001 and July 2003. RESULTS: Significant improvement was noted in both groups on a variety of measures of psychopathology, but there was significantly greater improvement in the placebo-treated patients on the primary outcome measure, the PANSS positive symptom subscale. There were no significant differences between the treatment groups regarding extrapyramidal symptoms, weight gain, vital signs, serum clozapine levels, and QTc interval. The only side effect significantly more severe in risperidone-treated compared to placebo-treated patients was sedation. The patients treated with risperidone developed significant increases in plasma prolactin levels. CONCLUSION: Adjunctive risperidone treatment in schizophrenia patients partially responsive to clozapine does not significantly improve psychopathology or quality of life compared to placebo in a 6-week period.

Neurological soft signs in schizophrenic patients and their nonpsychotic siblings.

OBJECTIVE: (a) To investigate the prevalence of neurological soft signs (NSS) in schizophrenic patients and their nonpsychotic siblings and (b) to examine the clinical correlates of NSS in the schizophrenic group. METHODS: Ninety-nine schizophrenic patients, 80 of their nonpsychotic siblings and 59 healthy controls were included in the study. NSS were assessed with the Neurological Evaluation Scale (NES). Psychiatric assessment of the patients was conducted with the Positive and Negative Syndrome Scale (PANSS). Siblings and the control group were evaluated with Schedules for Clinical Assessment in Neuropsychiatry (SCAN) to determine the presence of any past or current psychotic disorder. RESULTS: Schizophrenic patients had significantly higher scores overall and on each subscale of NES than the sibling and control groups. The sibling group's scores were intermediate between those of the schizophrenic patients and those of the healthy controls. All subscale scores and the total NES scores correlated positively with the negative symptoms subscale scores of PANSS. The general psychopathology subscale scores of PANSS also showed a positive correlation with all subscale scores of NES, except the 'sequencing of complex motor acts' subscale. The total NES scores of the patients as well as their scores for the 'sequencing of complex motor acts' and 'others' subscales were significantly correlated with the respective scores of their own siblings. CONCLUSIONS: These results support the findings of previous studies suggesting that there might be common genetic and/or environmental factors in the pathogenesis of neurological impairment in schizophrenic patients and their siblings. They also indicate that neurological soft signs in schizophrenic patients are associated with prominent negative symptoms.

Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitamin-D-dependent rickets type IIA.

The vitamin D hypothesis of schizophrenia is a recent concept bringing together old observations on environmental risk factors and new findings on the neurodevelopmental effects of vitamin D. Candidate genes related to the vitamin D endocrine system have not yet been fully explored for this purpose. The coexistence of vitamin-D-dependent-rickets type II with alopecia (VDDR IIA) and different forms of psychosis in the same inbred family has provided us with an opportunity to investigate the presumed relationship between vitamin D deficiency and psychosis. Psychiatric examination and molecular genetic studies were performed in this family overloaded with psychotic disorders and VDDR IIA. Forty members were evaluated in order to describe their phenotypic features. The family was tested for a linkage to the chromosome 12q12-q14 region where the vitamin D receptor (VDR) gene is located. Psychosis was the common phenotype in the 18 psychiatrically affected members. Pedigree analysis did not show a cosegregation of psychosis and rickets. Lod scores were not significant to prove a linkage between psychosis and VDR locus. The authors concluded that (1) the neurodevelopmental consequences of vitamin D deficiency do not play a causative role in psychotic disorders, (2) these two syndromes are inherited independently, and (3) vitamin D deficiency does not act as a risk factor in subjects susceptible to psychosis.

[A review on augmentation of clozapine treatment]. / Klozapin tedavisini güçlendirme: bir gözden geçirme.

Clozapine is one of the most effective pharmacological agents in the treatment of treatment-resistant patients with schizophrenia, schizoaffective and bipolar disorder. Nevertheless, there is still an important proportion of patients who do not respond to clozapine treatment given at a sufficient dose and duration. Some patients cannot tolerate the dosage necessary for an adequate treatment. Case reports, series, various open and controlled trials suggest that there are effective strategies of augmenting clozapine treatment in such cases. In this article, strategies of clozapine augmentation are reviewed in the light of findings related with the efficacy, safety and pharmacokinetic/dynamic interaction profiles of such combinations used for augmentation. To our knowledge, there is only one study in the current literature reviewing this subject. Augmenting strategies are reviewed through the combination of clozapine with the serotonin reuptake inhibitors (SSRI), typical and atypical antipsychotics, mood stabilizers, NMDA agonists and electroconvulsive treatment (ECT).

[Hunting the susceptibility gene for psychosis: a study of a family overloaded with schizophrenia and bipolar disorder]. / Sizofreni ve bipolar bozuklugun yüklülük gösterdigi genis bir ailede psikoza yatkinlik geninin arastirilmasi.

OBJECTIVE: It is a long-standing debate whether schizophrenia and bipolar disorder are separate clinical entities or different poles on a spectrum. In this paper we present a family overloaded with schizophrenia, and schizoaffective, bipolar and unipolar disorders. Common loci for bipolar affective disorder and schizophrenia were tested by linkage analysis. METHOD: The pedigree of an index family which had been followed by our department for nearly 20 years was extended. The index family members were diagnosed by two psychiatrists with two distinct structured interview schedules (SCID-I and SADS-L). A field visit was undertaken for the evaluation of the extended family (n= 40) and SADS-L was used for psychiatric assessment. Blood samples were collected for molecular studies. A linkage study has been performed for overlapping susceptibility regions for schizophrenia and affective disorders (10p13-p12, 13q32, 18p and 22q11-q13) and a locus (20p11.2-q13) to which a linkage had been shown in a bipolar family who lived in the same region. Both autosomal recessive and dominant mode of inheritance were assumed in the analysis. RESULTS: The pedigree consisted of 108 individuals of whom 23 are affected. All affected subjects presented psychotic features except for 5 unipolar patients. The pedigree was reconstructed with respect to psychosis phenotype. Further linkage and haplotype analysis excluded all five loci on chromosomes 10, 13, 18, 20 and 22 under both autosomal dominant and recessive modes of inheritance assumption. CONCLUSION: A potential linkage between the psychosis gene and reported susceptibility loci overlapping in bipolar affective disorder and schizophrenia was not demonstrated Genome-wide analysis should be performed.

A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition.

BACKGROUND: Atypical antipsychotic drugs produce improvement in some domains of cognition as well as psychopathology in patients with schizophrenia. However, the effect of combinations of atypical antipsychotic drugs on cognitive function is unknown. The aim of this study was to compare the effect of risperidone or placebo on cognitive function in patients with schizophrenia who were previously treated with clozapine monotherapy. METHOD: This prospective, randomized, double-blind, placebo-controlled, 6-week study included 30 patients with DSM-IV schizophrenia. Patients whose psychopathology was no more than partially responsive to clozapine treatment were randomly assigned to receive adjunctive treatment with risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Cognitive test scores for verbal learning and memory, verbal fluency, attention, executive function, verbal working memory, and motor function were the primary outcome measures. Secondary outcome measures included assessment of psychopathology, extrapyramidal side effects, and global functioning. Data were collected between November 2001 and July 2003. RESULTS: Significant improvement was found in both treatment groups in a variety of cognitive measures, but there was significantly greater improvement in the placebo-augmented group on measures of initial learning acquisition and attention. The improvement in cognition was not correlated with improvement in psychopathology. There were significant correlations between improvement in verbal working memory, verbal learning and memory, and attention and quality of life and global functioning in the placebo-augmented but not the risperidone-augmented group. CONCLUSION: Adjunctive treatment with risperidone for 6 weeks in patients with schizophrenia who had received chronic treatment with clozapine does not significantly improve cognitive function.

Reexamination of the characteristics of the deficit schizophrenia patients.

The aim of this study was to reexamine and compare the characteristics of the deficit and nondeficit schizophrenic patients. This cross-sectional study consisted of 62 in- and out-patients, 18-65 years of age, diagnosed with schizophrenia according to DSM-IV. The sociodemographic variables, premorbid adjustment, clinical course and general functioning level in the past five years were evaluated by utilizing the appropriate sections of Comprehensive Assessment of Symptoms and History (CASH). In addition, GAF, the Schedule for the Deficit Syndrome (SDS), Positive and Negative Syndrome Scale (PANSS), Montgomery Asberg Depression Scale (MADRS), the Neurological Evaluation Scale (NES) and the Simpson Angus Extrapyramidal Side Effects (EPS) Rating Scale, Trail A and B, Verbal Fluency, Stroop, Block Design and Finger Tapper tests were administered. Using the SDS, 19 patients (30.6 %) were categorized as deficit; 43 (69.4 %) were categorized as nondeficit. The deficit patients were worse on the Functioning During Past Five Years score of CASH. The PANSS and MADRS mean scores were not significantly different between the two groups, except a higher level of negative symptoms observed in the deficit group. NES scores were also significantly higher in the deficit group. However, sociodemographic and other clinical variables, neurocognitive measures and EPS symptoms did not show any significant difference between the two groups. Our findings suggest that the deficit schizophrenia is a distinct subgroup comprised of patients who have more negative symptoms, neurological impairment and poor functioning which may have a common underlying pathology.

A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia.

Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.