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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.

Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose preference test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal cannabinoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors.

Ziprasidone, a widely used atypical antipsychotic drug, has been demonstrated to have therapeutic effects in patients with post-traumatic stress disorder (PTSD), but its underlying mechanisms remain poorly understood. One possible explanation is that the neuroprotective and neurogenetic actions of ziprasidone can attenuate the neuronal apoptosis which occurs in the hippocampus. To test this hypothesis, the present study was designed to assess the effects of ziprasidone treatment on anxiety-like behaviors, hippocampal neurogenesis, and in vivo/in vitro expression of pERK1/2 and Bcl-2 in male Sprague-Dawley rats. The methodology involved 3 different experiments, and the investigations also included the assessment of U0126 interference in ziprasidone treatment. It was found that the in vivo, administration of ziprasidone not only reversed the anxiety-like behaviors in rats that exposed to an enhanced single prolonged stress paradigm, but also restored the proliferation and the protein expression of pERK1/2 and Bcl-2 in the hippocampus of these rats. Also, mild concentrations of ziprasidone promoted the in vitro proliferation of hippocampal-derived neural stem cells (NSCs) and increased the levels of pERK1/2 and Bcl-2 in NSCs. Interestingly, the observed effects of ziprasidone were inhibited by U0126. These data support the use of ziprasidone for the treatment of PTSD and indicate that the changes in the ERK1/2 signaling cascade may play a critical role in the pathophysiology of PTSD and its treatment modalities. Further investigations are needed to elucidate the detailed signal cascades involved in the pathophysiology of stress-related disorders, and confirm the efficacy of ziprasidone in anti-PTSD treatment.

Quetiapine, an atypical antipsychotic, may have efficacy as augmentation therapy in treatment resistant depression (TRD), but evidence is limited and the underlying mechanism remains poorly understood. Therefore, this study was aimed to investigate whether and how quetiapine can be served as an augmentation agent in fluoxetine treatment resistant depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, the effects of CUMS regimen and antidepressant treatment were assessed by behavioral tests and hippocampal neurogenesis. Approximately 20-30% of depressive rats respond poorly to fluoxetine treatment. In their hippocampus, a significant decrease of neurogenesis was also observed. However, quetiapine add-on therapy significantly improved the depressive behaviors and increased the number of the newborn neurons in the hippocampus of fluoxetine treatment resistant depressive rats. Thus, our results suggest that quetiapine may be used as an augmentation agent in the treatment resistant depression partly mediated by increasing the number of newborn neurons in the hippocampus.

We investigated the antidepressant effects of bilateral intra-the ventrolateral orbital cortex (VLO) administration of sanguinarine (SA), a selective mitogen-activated protein kinase phosphatase-1 (Mkp-1) inhibitor, in rats that had been subjected to a forced swimming test (FST) which is a classic animal model of depression. The expression of Mkp-1 and activation of ERK (ratio of phosphor-ERK to ERK) were also examined by immunoblotting. A single bilateral intra-VLO infusion of SA (2.5, 5 or 10 μg/0.5 μl per side) significantly reduced immobility time in the FST in dose-dependent fashion, as compared to vehicle-treated controls. A similar antidepressant effect was also observed in rats systemically administered fluoxetine, a classic antidepressant. The effects observed in the FST could not be attributed to non-specific increases in activity as neither microinjection of SA into the VLO nor fluoxetine treatment altered the behavior of the rats during the locomotion test. In addition, a decrease in the expression of Mkp-1 and a correlative increase in ERK activation were involved in the antidepressant effects of the bilateral SA administration into the VLO. The results indicated that Mkp-1 within the VLO is involved in the process of depression and may be a potential target for therapeutic action of antidepressant treatment.

Background: White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown. Methods: The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period. Results: Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167. Conclusions: The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone-induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs.

Although classical and atypical antipsychotics may have different effects against neurotoxicity, the underlying mechanisms remain to be elucidated. In the present study, we compared the atypical agents, risperidone (RIP), olanzapine (OLZ), and quetiapine (QTP), with the classical agent haloperidol (HAL) in reducing cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor, in PC12 cells. We also determined whether there were differential effects of RIP and HAL on the expression of brain-derived neurotrophic factor (BDNF), signal transducers and activators of transcription-3 (STAT-3), and the immediate early gene c-fos, as well as intracellular levels of calcium. Exposure to 6 muM rotenone for 24 h resulted in a significant decrease in cell viability and apoptotic alteration. The rotenone-induced cytotoxicity was dose-dependently worsened by pretreatment with HAL, but significantly improved by the aforementioned atypical agents at low doses. Real-time PCR analysis revealed that HAL pretreatment significantly increased BDNF mRNA expression but did not alter c-fos and STAT-3 expression compared to rotenone-exposed cells. Unlike HAL, RIP pretreatment produced a significant elevation of all the three substance mRNA expression and the expression intensity was 2.6- to 4.6-fold greater than HAL. Pretreatment with RIP, but not HAL, also effectively prevented an elevation of intracellular levels of calcium provoked by rotenone. These results suggest that the protective effects of atypical antipsychotics are associated with a greater capacity to enhance pro-cell survival factors, therapeutic biomarker expression, and blockade of calcium influx. This may provide an alternative for explaining therapeutic advantages of atypical agents observed in clinical use.

The majority of the previous studies of thyroid abnormalities in bipolar patients was conducted in populations containing various proportions of lithium-treated subjects. In the present study, we sought to determine whether there exist differences in hypothyroid profile between lithium-free and -treated bipolar patients. Bipolar patients never treated with lithium and carbamazepine (n=78) and those currently in lithium therapy (n=53) were included in this study. Serum concentrations of total thyroxine (T(4)), total triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH) were compared between lithium-free and -treated patients. The rate of hypothyroidism in lithium-free patients was significantly lower than those treated with lithium (6.3%-10.8% vs. 28.0%-32.1%). Significant changes in the three thyroid indices indicative of hypothyroidism were consistently associated with longer illness duration in lithium-free manic patients, but with greater severity of mania and more mood episodes in their lithium-treated counterparts. In lithium-free depressed patients, more episodes were associated with lower T(4) levels; whereas in their lithium-treated counterparts, longer illness duration was associated with higher TSH levels and females with lower T(3) levels. These results suggest that bipolar patients with and without lithium exposure differ in prevalence and association of hypothyroidism and may have different response to thyroid hormone therapy.

Background Repetitive transcranial magnetic stimulation (rTMS) has been employed for decades as a non-pharmacologic treatment for post-traumatic stress disorder (PTSD). Although a link has been suggested between PTSD and impaired sensorimotor gating (SG), studies assessing the effects of rTMS against PTSD or PTSD with impaired SG are scarce. Aim To assess the benefit of rTMS in a rat model of PTSD. Methods Using a modified single prolonged stress (SPS&S) rat model of PTSD, behavioral parameters were acquired using open field test (OFT), elevated plus maze test (EPMT), and prepulse inhibition trial (PPI), with or without 7 days of high frequency (10Hz) rTMS treatment of SPS&S rats. Results Anxiety-like behavior, impaired SG and increased plasma level of cortisol were observed in SPS&S animals after stress for a prolonged time. Interestingly, rTMS administered immediately after stress prevented those impairment. Conclusion Stress-induced anxiety-like behavior, increased plasma level of cortisol and impaired PPI occur after stress and high-frequency rTMS has the potential to ameliorate this behavior, suggesting that high frequency rTMS should be further evaluated for its use as a method for preventing PTSD.