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Background Ziprasidone (ZIP) is often used with olanzapine (OLZ) in ‘switch’ and combination therapy but empirical evidence to support these strategies is limited. Objective This study was therefore designed to compare the efficacy and tolerability of switching from OLZ to ZIP, the combination of both medications, and OLZ and ZIP monotherapy, in patients with schizophrenia spectrum disorders (SSD). Methods In this 12 week open-label, assessor-blinded randomized trial, 148 patients with SSD who had not used antipsychotics for at least 3 months were assigned to ZIP (n = 49) or OLZ monotherapy (n = 31); OLZ for 4 weeks then a switch to ZIP (OLZ/ZIP, n = 35); or combination therapy (OLZ + ZIP, n = 33). The severity of psychosis and abnormal involuntary movements was evaluated at baseline, 1, 2, 4, 8, and 12 weeks using standard instruments. Baseline-to-endpoint changes in weight gain and metabolic measures were compared. Results The efficacy of both OLZ/ZIP and OLZ + ZIP was comparable OLZ monotherapy and better than ZIP monotherapy in reducing overall psychotic and negative symptoms at most 8 and 12 week measurement points. Changes in weight gain, glucose, and lipid measures did not differ between OLZ/ZIP and OLZ + ZIP, but were markedly higher following OLZ monotherapy. The OLZ + ZIP group had the lowest overall incidence of adverse events and extrapyramidal symptoms of all the treatment regimens. Conclusions We conclude that combining ZIP and OLZ at the outset of treatment is superior to switching from OLZ to ZIP in terms of improving psychotic symptoms and limiting movement side effects without increasing the risk of metabolic syndrome.

Our previous studies have shown the therapeutic efficacy and underlying mechanisms of Peony-Glycyrrhiza Decoction (PGD), an herbal preparation, in treating antipsychotic-induced hyperprolactinemia in cultured cells, animal models, and human subjects. In the present study, we further evaluated pharmacokinetic interactions of PGD with clozapine (CLZ) in human liver microsomes (HLM), recombinantly expressed cytochrome P450s (P450s), and flavin-containing monooxygenases (FMOs). CLZ metabolites, N-demethyl-clozapine and clozapine-N-oxide, were measured. PGD, individual peony and glycyrrhiza preparations, and the two individual preparations in combination reduced production of CLZ metabolites to different extents in HLM. While the known bioactive constituents of PGD play a relatively minor role in the kinetic effects of PGD on P450 activity, PGD as a whole had a weak-to-moderate inhibitory potency toward P450s, in particular CYP1A2 and CYP3A4. FMOs are less actively involved in mediating CLZ metabolism and the PGD inhibition of CLZ. These results suggest that PGD has the capacity to suppress CLZ metabolism in the human liver microsomal system. This suppression is principally associated with the inhibition of related P450 activity but not FMOs. The present study provides in vitro evidence of herb-antipsychotic interactions.

According to Traditional Chinese Medicine (TCM), the liver is the origin or most associated with stress related disorders such as depression. Sinisan, a TCM prescription, has been used as a hepatic protectant. We examined whether Sinisan exerts therapeutic effects in an experimental animal model: the chronic restraint stress (CRS) model. Sinisan was administered in the animal's drinking water at a concentration of 100mg/kg for 21 days (7 days pre-CRS and 14 days during the CRS). Spatial learning and memory were measured 24h after the CRS procedures using the Morris Water Maze (MWM). Aggressive behavior and body weight were determined as well. The Sinisan treatment decreased aggressive behaviors and reversed CRS-induced impairment of spatial learning and memory as well as decreased rate of growth. In conclusion, our results suggest that Sinisan does exert measurable therapeutic effects in an experimental chronic stress model.

There is little information available on the mechanisms underlying the neuroprotective actions of the organoselenium compound ebselen. In this study, we sought to determine the relationship between alterations in the expression of Bcl-2 and Bax proteins and intracellular levels of calcium and the protective effects of ebselen with a concentration range of 0.01-20 microM against glutamate toxicity in cultured mouse cortical neurons. Pretreatment with ebselen at moderate doses (4-12 microM), but not at lower or higher doses, significantly improved glutamate-induced suppression of cell viability. Pretreatment with ebselen (8 microM) also prevented apoptotic alterations, completely reversed the suppression of Bcl-2 expression, and significantly inhibited Bax overexpression, but did not alter elevated intracellular concentrations of calcium induced by glutamate. Pre-, co-, and post-treatment with ebselen (8 microM) had similar potency in improving the decreased viability of glutamate-exposed cells. These results indicate that the neuroprotective effects of ebselen at low doses are associated with the regulation of Bcl-2 and Bax proteins but appear to be independent of glutamate-mediated elevation of intracellular calcium, suggesting that different mechanisms are involved in the actions of low and high dose regimens. Ebselen may be an effective agent used for early treatment of acute brain injuries.