Effects of clozapine on behavioral sensitization induced by cocaine.

Using cocaine-sensitized mice as a model for psychosis, this study investigated whether subchronic treatment with clozapine could affect the sensitized state of the animals and examined the accompanying molecular changes in the brain. To induce sensitization, ICR mice (n=44) were treated with cocaine for 5 days. After 7 days of withdrawal, sensitization was confirmed by a cocaine challenge. Then, the sensitized animals were treated with clozapine for 5 days and rechallenged with cocaine. The frontal cortices were removed from the mice (n=16) 24 h after the last challenge, and the phosphorylation status of some key signaling molecules was investigated. Compared with the sensitized mice receiving the vehicle treatment, the sensitized mice receiving subchronic clozapine showed less locomotor activity, with an activity level similar to that of non-sensitized mice. However, clozapine did not directly affect the stimulatory effect of cocaine. Clozapine also reversed some of the sensitization-induced biochemical changes, including increased phosphorylation of GSK-3beta and CREB, in the frontal cortex. Subchronic treatment with clozapine apparently de-sensitized the sensitized mice. The long-term effect of clozapine on stimulant-induced sensitization may be related to the therapeutic effect of the drug as an antipsychotic agent.

Effects of electroconvulsive shock on the phosphorylation of DARPP-32 in rat striatum.

Dopamine- and cAMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP-32) is a key integrative molecule in the dopaminergic and glutamatergic signaling pathways in the striatum. Electroconvulsive shock (ECS), which induces massive neuronal depolarization, can activate various signaling pathways. In this study we investigated whether ECS could affect the phosphorylation status of DARPP-32. Male Sprague-Dawley rats underwent ECS and were sacrificed by decapitation at 0, 2, 10, 60, and 180 min after treatment. The phosphorylations of Thr34 and Thr75 residues of DARPP-32 and Ser159 residue of cyclin-dependent kinase 5 (CDK5) were investigated in the striatum. The activity of protein phosphatase 1 (PP1) and the binding between DARPP-32 and PP1 were also analyzed. Thr34 phosphorylation of DARPP-32 increased immediately after ECS and this state was maintained for more than 60 min. The activity of PP1 decreased and the binding between PP1 and DARPP-32 increased in accordance with this phosphorylation pattern. However, the phosphorylation at Thr75 showed no significant change except for an initial transient decrease. The phosphorylation of CDK5, which is responsible for Thr75 phosphorylation of DARPP-32, did not exhibit significant fluctuations. Our findings indicate that ECS increases Thr34 phosphorylation of DARPP-32, and thus inhibits the activity of PP1.

Exploring clinical characteristics of bipolar depression: internal structure of the bipolar depression rating scale.

OBJECTIVE: Due to its pleomorphic phenomenology, the clinical features of bipolar depression are difficult to assess. The objective of the present study was therefore to explore the internal structure of the Bipolar Depression Rating Scale (BDRS) in terms of the phenomenological characteristics of bipolar depression. METHODS: Sixty patients with DSM-IV bipolar depression completed the BDRS, depression and excitement subscales of the Positive and Negative Syndrome Scale (PANSS-D and PANSS-E), 17-item Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Young Mania Rating Scale (YMRS), and the Drug-Induced Extrapyramidal Symptoms Scale. The internal structure of the BDRS was explored through hierarchical cluster analysis (HCA) using Ward's method and multidimensional scaling (MDS). RESULTS: From 20-item BDRS data, the HCA yielded two symptom clusters. The first cluster included 12 items of conventional depressive symptoms. The second cluster included eight items of mixed symptoms. The MDS identified a depressive-mixed dimension. The depressive symptom cluster showed a more cohesive and conglomerate cluster structure on the MDS map compared to the mixed symptom cluster. After controlling for the effects of treatment-emergent extrapyramidal symptoms, strong positive correlations were observed between the BDRS and other depression rating scales, and the BDRS also weakly correlated with the YMRS and the PANSS-E. CONCLUSIONS: The internal structure of BDRS appears to be sensitive to complex features of bipolar depression. Hence, the BDRS may have an advantage in evaluating clinical changes in patients with bipolar depression within the therapeutic process.

Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Inadequate response to clozapine poses a substantial problem in the pharmaco-therapy of refractory schizophrenia. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia. METHOD: Patients with DSM-IV schizophrenia who had a history of treatment failure or partial response to long-term clozapine treatment were recruited. A total of 62 patients with either a baseline Brief Psychiatric Rating Scale (BPRS) score of at least 35 or more than 2 Schedule for Assessment of Negative Symptoms (SANS) global rating item scores of at least 3 were randomly assigned to double-blind augmentation treatment with either aripiprazole (5-30 mg/day) or placebo over 8 weeks. The primary outcome measure was change in BPRS total score from baseline. The study was conducted between December 1, 2005, and December 10, 2006. RESULTS: There was no significant difference in the primary outcome measure between the 2 groups. In secondary analyses, improvement was significantly greater with aripiprazole treatment than with placebo for negative symptoms assessed by both the BPRS negative symptom sub-scale and the SANS total score but not for positive symptoms. Prolactin and triglyceride levels were significantly lower in the aripiprazole group than in the placebo group. No significant differences between the 2 groups were observed in adverse effects, including extrapyramidal symptoms and serum glucose levels. CONCLUSION: Although aripiprazole augmentation of clozapine did not lead to a significant improvement of total symptom severity in schizophrenia, a favorable change in the negative symptom domain was observed.