Psychosis in mania: specificity of its role in severity and treatment response.

BACKGROUND: Psychosis is a prominent characteristic of manic episodes. We investigated relationships between the presence of psychotic features, the severity of the manic syndrome, and syndrome severity's response to treatment. METHOD: 179 subjects meeting Research Diagnostic Criteria for a manic episode of bipolar I disorder were hospitalized for acute manic episodes and treated in a randomized trial of lithium, divalproex sodium, or placebo. Factor and cluster analyses were carried out using the clinician-rated Schedule for Affective Disorders and Schizophrenia, Change version (SADS-C) and the nurse-rated Affective Disorder Rating Scale (ADRS). RESULTS: Subjects with psychotic features had significantly (p < .005) greater overall impairment (lower Global Assessment Scale [GAS] scores) but did not differ in severity of mania scores compared with those without psychotic features. Psychosis factor scores correlated significantly (p < .000001) with GAS scores but not with mania scores. Baseline psychosis factor scores did not correlate with subsequent treatment-associated change in mania scores, but change in mania scores during treatment correlated significantly (p < .000001) with change in the psychosis factor. Changes in psychosis factor scores correlated significantly with changes in mania rating scale scores regardless of treatment. CONCLUSIONS: Psychotic features as a component of manic episodes contribute substantially to overall impairment. Treatments that successfully treat mania also reduce psychosis scores.

Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone.

OBJECTIVE: This study compared the specific antihostility effects of atypical antipsychotic monotherapy (olanzapine or risperidone) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode. METHODS: A total of 249 inpatients with schizophrenia were randomly assigned to receive olanzapine plus placebo, olanzapine plus divalproex, risperidone plus placebo, or risperidone plus divalproex in a double-blind, 28-day multicenter trial. The target daily dose was 15 milligrams for olanzapine, 6 milligrams for risperidone, and up to 30 milligrams per kilogram (minimum, 15 milligrams per kilogram) for divalproex. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the PANSS items reflecting positive symptoms of schizophrenia (delusions, suspiciousness/persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinatory behavior). RESULTS: Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy. Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy. This result was not seen beyond the first week of treatment, but there was a trend toward a difference in effect for the entire treatment period. The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking, a formal thought disorder, or hallucinations. CONCLUSIONS: Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode.

GABA and schizophrenia: a review of basic science and clinical studies.

BACKGROUND: A converging body of evidence implicates the gamma-aminobutyric acid (GABA) neurotransmitter system in the pathogenesis of schizophrenia. METHODS: The authors review neuroscience literature and clinical studies investigating the role of the GABA system in the pathophysiology of schizophrenia. First, a background on the GABA system is provided, including GABA pharmacology and neuroanatomy of GABAergic neurons. Results from basic science schizophrenia animal models and human studies are reviewed. The role of GABA in cognitive dysfunction in schizophrenia is then presented, followed by a discussion of GABAergic compounds used in monotherapy or adjunctively in clinical schizophrenia studies. RESULTS: In basic studies, reductions in GABAergic neuronal density and abnormalities in receptors and reuptake sites have been identified in several cortical and subcortical GABA systems. A model has been developed suggesting GABA's role (including GABA-dopamine interactions) in schizophrenia. In several clinical studies, the use of adjunctive GABA agonists was associated with greater improvement in core schizophrenia symptoms. CONCLUSIONS: Alterations in the GABA neurotransmitter system are found in clinical and basic neuroscience schizophrenia studies as well as animal models and may be involved in the pathophysiology of schizophrenia. The interaction of GABA with other well-characterized neurotransmitter abnormalities remains to be understood. Future studies should elucidate the potential therapeutic role for GABA ligands in schizophrenia treatment.

NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.