Contrasting Fos expression induced by acute reboxetine and fluoxetine in the rat forebrain: neuroanatomical substrates for the antidepressant effect.

RATIONALE: Antidepressants preferentially facilitating serotonin seem to be particularly effective for treating the anxiety and aggressive component of the depressive syndrome, whereas those with a noradrenergic profile seem to be more effective in reducing psychomotor retardation, although their overall antidepressant effects are about the same. However, the mechanism of this difference remains unknown. OBJECTIVES: To investigate the neural substrate for the different therapeutic efficacies of fluoxetine and reboxetine, we examined the regional Fos immunoreactivity (Fos-ir) induced by the two agents. METHODS: Male Wistar rats (290-330 g) were given a subcutaneous injection of fluoxetine (5 or 10 mg/kg), reboxetine (5 or 10 mg/kg) or saline. Two hours later, rats were perfused through the ascending aorta and their brains were processed for Fos immunohistochemistry. Fos-ir was quantified by counting the number of Fos-ir-positive nuclei in six areas of the forebrain. RESULTS: The shell of the nucleus accumbens was the only region in which both fluoxetine and reboxetine equally increased Fos-ir expression. Fluoxetine particularly induced Fos-ir in the central nucleus of the amygdala. In contrast, reboxetine induced Fos-ir in the cingulate cortex area 3 and the lateral orbital cortex. CONCLUSIONS: These results suggest that the shell region may be one possible target for the antidepressant effects of fluoxetine and reboxetine. Furthermore, the difference in their clinical effects may depend on their different target sites of action.

Atypical properties of several classes of antipsychotic drugs on the basis of differential induction of Fos-like immunoreactivity in the rat brain.

Acute administration of typical and atypical antipsychotics has been reported to induce regionally distinct patterns of c-Fos expression in the rat forebrain. Furthermore, atypical index, the difference in the extent of increased Fos-like immunoreactivity (Fos-LI) in the nucleus accumbens (NAc) shell versus the dorsolateral striatum (DLSt), has been proposed to classify antipsychotics into typical or atypical antipsychotics. The present study was conducted to investigate the atypical properties of 24 antipsychotics that are used in Japan and blonanserin, a novel 5-HT2A and D2 receptor antagonist. We systematically examined the effects of the drugs on Fos-LI in the NAc and DLSt in the rat brain using immunohistochemistry and calculated the atypical index, comparing with those of haloperidol and clozapine. Floropipamide, oxypertine, nemonapride, pimozide and mosapramine, as well as clozapine, olanzapine, quetiapine and risperidone, showed high positive atypical index. Zotepine, perospirone, sulpiride, moperone, sultopride, thioridazine, carpipramine, clocapramine and blonanserin showed moderate ones. In contrast, fluphenazine, bromperidol, timiperone, spiperone, propericiazine, perphenazine, chlorpromazine and levomepromazine had negative atypical index like haloperidol. These results suggest that not only so-called atypical antipsychotics, but also several conventional drugs, possess atypical properties.

Efficacy of second-generation antipsychotics in patients at ultra-high risk and those with first-episode or multi-episode schizophrenia.

AIM: The aim of this study was to examine the speed of response, doses, and safety of treatment with second-generation antipsychotics (SGAs) in patients at ultra-high risk (UHR) compared to those with schizophrenia. METHODS: A 12-week open-label, prospective study of SGAs was performed in UHR patients and those with first-episode schizophrenia (FES) and multi-episode schizophrenia (MES). The subjects were 14-30 years old and were recruited at Zikei Hospital, Okayama, Japan from December 1, 2006 to December 1, 2011. Treatment was carried out in a natural setting in an open-label format, but clinical evaluation was performed blind. The clinical rating scales include the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression-Severity scale (CGI-S). RESULTS: UHR (n = 17), FES (n = 23), and MES (n = 21) patients all showed significant improvements on the GAF, PANSS, and CGI-S. However, the UHR patients showed significantly greater improvement on the GAF at weeks 4, 8, and 12 compared to the other groups, and a significantly lower modal dose of SGAs (chlorpromazine equivalent: 183 [201.1] mg/day, mean [SD]) was needed for improvement in the UHR group. Each group was also prescribed anticholinergic agents during the study period and the UHR group had significantly fewer extrapyramidal symptoms (only 6%) compared with the FES group. CONCLUSION: Our findings suggest that UHR patients have a better response to SGAs compared to patients with schizophrenia, and that these drugs can be given safely by minimizing the dosage of SGAs and using anticholinergic agents.