Effects Of Atypical Antipsychotic Drugs Research Articles

Antipsychotic Drug-Mediated Adverse Effects on Rat Testicles May Be Caused by Altered Redox and Hormonal Homeostasis.

Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs) for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a recommended daily dose for atypical antipsychotic therapy), induced histopathological changes both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis.

Atypical antipsychotic drugs deregulate the cholesterol metabolism of macrophage-foam cells by activating NOX-ROS-PPARγ-CD36 signaling pathway

BackgroundClinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored. MethodsIn this study, we used apolipoprotein E-deficient (apoe−/−) hyperlipidemic mice and apoe−/−cd36−/− mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells. ResultsIn vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe−/− mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages. ConclusionCollectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases.

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

Comparative Study of the Effects of Atypical Antipsychotic Drugs on Plasma and Urine Biomarkers of Oxidative Stress in Schizophrenic Patients.

PurposeEvidence that antipsychotic drugs (ADs) can affect oxidative stress estimated with various biomarkers in schizophrenic patients is controversial and limited. Therefore, in the present study, we assessed the ability of six atypical ADs (clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone) used in schizophrenia treatment to modulate oxidative damage to different biomolecules such as lipids and proteins.Patients and MethodsWe measured the levels of oxidative stress markers in plasma and urine: total antioxidant capacity by FRAP (according to a modified method of Benzie & Strain), thiobarbituric acid reactive species – TBARS (spectrophotometric method), 4-hydroxy-2-nonenal (4-HNE) (OxiSelect™ HNE Adduct Competitive ELISA Kit), 3-nitrotyrosine (3-NT) (OxiSelect™ Nitrotyrosine ELISA Kit) in plasma, and F2-isoprostanes (BIOXYTECH® Urinary 8-epi-Prostaglandin F2α) in the urine of 60 schizophrenic patients (before and after treatment) and in 30 healthy subjects.ResultsOur results showed that in schizophrenic patients levels of lipid peroxidation markers (TBARS, F2-isoprostanes) were higher than in healthy subjects but FRAP in schizophrenic patients was lower than in healthy controls and increased after 4-week treatment with tested ADs. A 4-week treatment with ADs caused the improvement of psychopathology symptoms estimated by Positive and Negative Syndrome Scale (PANSS) that was accompanied by decreased lipid peroxidation (F2-isoprostanes, TBARS; p=2.9x10−6, p=7.6x10−5, respectively) and an increase in total antioxidative capacity (FRAP) (p=5.16x10−16).ConclusionAtypical antipsychotics especially clozapine, olanzapine and quetiapine demonstrate the effective outcome of antipsychotic treatment, beneficial antioxidative action by reducing lipid peroxidation and increased total plasma antioxidant activity.

Treatment of chronic insomnia with atypical antipsychotics: results from a follow-up study.

ObjectiveSecond generation (atypical) antipsychotics are increasingly being used for treatment of insomnia, but there is little evidence to show long-term efficacy of these medication. This follow-up study was designed to assess patients with chronic insomnia who were treated with atypical antipsychotics.Material and MethodsIn this follow-up study, forty patients with chronic insomnia were evaluated between 2016 and 2018 following after one year of treatment with two atypical antipsychotic drugs of olanzapine and quetiapine in two groups in the sleep disorders research center of Kermanshah University of Medical Science in Iran. The Pittsburgh Sleep Quality Questionnaire (PSQI) and 5 consecutive nights of Actigraphy were utilized to evaluate both subjective and objective measures of sleep quality. Lastly, sleep quality before and after treatment and comparisons of sleep quality between the two groups were performed.ResultsNine male participants comprised olanzapine group (n=22) and six male participants comprised the quetiapine group (n=18). The average age in the olanzapine group was 45.23±10.18 and the average age in the quetiapine group was 46.33±7.99. Results showed total PSQI score improved significantly in both groups (p<0.05), while the actigraphy results showed only significant improvement in sleep quality parameters in the quetiapine group (p<0.05).ConclusionTwo atypical antipsychotics drugs of olanzapine and quetiapine have long-term efficacy in managing chronic insomnia. More improvements in objective sleep quality with quetiapine is promising for patients with chronic insomnia. Further research to evaluate long-term adverse effects of atypical antipsychotic drugs is recommended.

Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin

BackgroundMetabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. MethodsTo gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. ResultsUpstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. ConclusionThese findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

Research progress of neuroimmune mechanisms of cognitive function in schizophrenia and effect of atypical antipsychotic drugs on it

Research progress of neuroimmune mechanisms of cognitive function in schizophrenia and effect of atypical antipsychotic drugs on it

The Effect of Atypical Antipsychotic Drugs on the Neurotrophic Factors Gene Expression in the MPTP Model of Parkinson’s Disease

Atypical antipsychotics (AAP) are used in the therapy of Parkinson’s disease (PD) for elimination of psychotic symptoms. As the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF) play a crucial role in the PD treatment, the aim of our study was the investigation of the effects of chronic treatment with commonly used AAP, clozapine and quetiapine, on the motor behavior and the BDNF, GDNF and CDNF genes expression in the mouse brain in the PD model produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Clozapine and quetiapine (1 mg/kg, i.p.) were administered 48 hours after the last MPTP injection, and treatment continued for the following 16 days. Then animals were euthanized, substantia nigra (SN), striatum (St) and hippocampus (Hc) were extracted for RT-PCR and tyrosine hydroxylase (TH) western blot assessment. MPTP treatment led to 50% depletion in the TH protein level in the St. MPTP caused significant decrease in both BDNF and GDNF mRNA level in the Hc and St, respectively. At the same time, increase in the GDNF expression in the MPTP + clozapine group in the SN was found. MPTP caused dramatic decrease in the CDNF mRNA level in the SN with simultaneous increase in the St. Both clozapine and quetiapine decreased it to a normal level in the St. The effect of AAP clozapine and quetiapine on the GDNF and CDNF genes expression in the pharmacological model of PD has been shown for the first time.

Antipsychotic drugs scavenge radiation-induced hydroxyl radicals and intracellular ROS formation, and protect apoptosis in human lymphoma U937 cells

Antioxidant activity has been reported for some atypical antipsychotic drugs; however, the detailed mechanism is not well known. Here, we investigated the effects of atypical antipsychotic drugs on •OH radical formation, intracellular reactive oxygen species (ROS), and apoptosis induced by ionising radiation. The reaction rate constants with •OH radicals were determined for five antipsychotic drugs as follows, in descending order: olanzapine, aripiprazole, clozapine, haloperidol, and risperidone. Experiments with aminophenyl fluorescein, a fluorescent dye, showed that olanzapine and clozapine could scavenge intracellular ROS. However, experiments with hydroxyphenyl fluorescein showed that only olanzapine inhibited ROS generation. X-irradiation-induced apoptosis in human lymphoma U937 cells was inhibited by clozapine at relatively low concentrations and by olanzapine at higher concentrations. Clozapine inhibited caspase-8 and caspase-3 activation and prevented loss of mitochondrial membrane potential. In contrast, olanzapine inhibited X-irradiation-induced p-JNK activation. Although the atypical antipsychotic drugs used here have relatively high reaction rate constants with •OH radicals in aqueous solutions, inhibition of intracellular ROS was not due to •OH radical scavenging. In addition, suppression of X-irradiation-induced apoptosis was not directly linked with intracellular ROS scavenging. When apoptosis signalling pathways were studied, clozapine-mediated inhibition of apoptosis was dependent on caspase-3 and caspase-8. In contrast, olanzapine inhibited apoptosis via down regulation of X-irradiation-induced p-JNK. These results suggested that both olanzapine and clozapine have antioxidative and antiapoptotic activities via distinct pathways, and provide useful information for better understanding of drug characteristics.

The effect of atypical antipsychotic drugs on the neurotrophic factors gene expression in the MPTP model of Parkinson's disease

Atypical antipsychotics (AAP) are used in the therapy of Parkinson’s disease (PD) for elimination of psychotic symptoms. As the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF) play a crucial role in the PD treatment, the aim of our study was the investigation of the effects of chronic treatment with commonly used AAP, clozapine and quetiapine, on the motor behavior and the BDNF, GDNF and CDNF genes expression in the mouse brain in the PD model produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Clozapine and quetiapine (1 mg/kg, i.p.) were administered 48 hours after the last MPTP injection, and treatment continued for the following 16 days. Then animals were euthanized, substantia nigra (SN), striatum (St) and hippocampus (Hc) were extracted for RT-PCR and tyrosine hydroxylase (TH) western blot assessment. MPTP treatment led to 50% depletion in the TH protein level in the St. MPTP caused significant decrease in both BDNF and GDNF mRNA level in the Hc and St, respectively. At the same time, increase in the GDNF expression in the MPTP + clozapine group in the SN was found. MPTP caused dramatic decrease in the CDNF mRNA level in the SN with simultaneous increase in the St. Both clozapine and quetiapine decreased it to a normal level in the St. The effect of AAP clozapine and quetiapine on the GDNF and CDNF genes expression in the pharmacological model of PD has been shown for the first time.

5-HT1A parital agonism and 5-HT7 antagonism restore episodic memory in subchronic phencyclidine-treated mice: role of brain glutamate, dopamine, acetylcholine and GABA.

The effect of atypical antipsychotic drugs (AAPDs), e.g., lurasidone, to improve cognitive impairment associated with schizophrenia (CIAS), has been suggested to be due, in part, to enhancing release of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in cortex and hippocampus. The present study found acute lurasidone reversed the cognitive deficit in novel object recognition (NOR) in subchronic (sc) phencyclidine (PCP)-treated mice, an animal model for CIAS. This effect of lurasidone was blocked by pretreatment with the 5-HT1AR antagonist, WAY-100635, or the 5-HT7R agonist, AS 19. Lurasidone significantly increased medial prefrontal cortex (mPFC) ACh, DA, and Glu efflux, all of which were blocked by WAY-100635, with similar effects in the dorsal striatum (dSTR), except for the absence of an effect on Glu increase. AS 19 inhibited Glu, but not DA efflux, in the dSTR. The selective 5-HT7R antagonist, SB-26970, increased mPFC DA, 5-HT, Glu, and, importantly, also GABA efflux and striatal DA, NE, 5-HT, and Glu efflux, indicating tonic inhibition of the release of these neurotransmitters by 5-HT7R stimulation. These results provide new evidence that GABA release in the mPFC is tonically inhibited by 5-HT7R stimulation and suggest that a selective 5-HT7R antagonist might be clinically useful to enhance cortical GABAergic release. All SB-269970 effects were blocked by AS 19 or WAY-100635, suggesting 5-HT1AR agonism is necessary for the release of these neurotransmitters by SB-269970. Lurasidone increased ACh, DA, and NE but not Glu efflux in mPFC and dSTR DA and Glu efflux in 5-HT7 KO mice. We conclude that lurasidone-induced Glu efflux in mPFC requires 5-HT7R antagonism while its effects on cortical ACh and DA efflux are mainly due to 5-HT1AR stimulation.

Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders.

Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders. We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole. Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose. The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established.

New Trends in the Treatment of Schizophrenia.

This article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments. Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine- type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects are becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia are emerging but have not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed. The heterogeneity of the pathophysiology of the various domains of schizophrenia requires a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.

Effects of different antipsychotics on sugar, lipid metabolism and body mass in female patients with first-episode schizophrenia

Objective To study the effects of atypical antipsychotic drugs on glucose and lipid metabolism and body weight in female patients with schizophrenia. Methods 120 patients with schizophrenia were randomly divided into three groups according to the number randomized method.Group 1(olanzapine group) was treated with olanzapine, group 2(ziprasidone group) was treated with ziprasidone, group 3(risperidone group) was treated with risperidone.The total cholesterol (TC), triglyceride (TG) and body mass index (BMI) in the three groups were analyzed retrospectively. Results After treatment for 8 weeks, the fasting blood glucose of the olanzapine group and risperidone group increased significantly compared with before treatment, the differences were statistically significant(t=-2.81, P 0.05). After treatment for 8 weeks, the BMI of the olanzapine group and risperidone group had statistically significant difference compared with before treatment(t=-3.62, P 0.05). After treatment for 8 weeks, the TG, TC levels of the olanzapine group had statistically significant differences compared with before treatment (t=-3.89, P 0.05; t=-1.06, P>0.05; t=-0.55, P>0.05; t=-0.62, P>0.05). Conclusion Ziprasidone in the treatment of female first episode schizophrenia, has less influence on sugar, lipid metabolism and weight, with high compliance and more advantages compared with other atypical antipsychotics. Key words: Schizophrenia; Antipsychotics agents; Metabolism; Body weight; Female

Comparison of cortisol levels in patients with schizophrenia and in healthy controls

IntroductionThe hypothalamus-pituitary-adrenal axis (HPAA) plays a pivotal role in response to a range of external and internal factors often described as “stress”. Growing evidence in a literature, suggest various dysregulations of HPAA, in course of numerous mental disorders. Patients with schizophrenia and bipolar disorder seem to have elevated basal cortisol secretion, what might be caused by the diminution of glucocorticoid receptors’ amount. It was of the interest if the cortisol concentration in patients, with diagnosed schizophrenia, differs from healthy individuals.Materials and methodsTwo groups of participants were included into the study. First group (study) consisted of 10 patients with diagnosed schizophrenia and control group which included 38 healthy individuals. Study was divided into two stages, first one (pilot) included only control group, and utilized cortisol concentrations measurement from saliva, blood and 24 h urine sample. Second part (main study) involved both groups although focused on a salivary cortisol concentrations.ResultsA mean salivary cortisol concentration in patients with schizophrenia who underwent treatment was significantly lower in comparison with healthy individuals.ConclusionsObtained results indicate that patients who underwent a treatment, and does not present notable clinical signs of schizophrenia, may have moderately lowered levels of salivary cortisol. This may be a reflection of relenting psychotic symptoms as well as a direct effect of atypical antipsychotic drugs on a HPA axis activity.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Treating bipolar disorder in pregnancy

IntroductionBipolar disorder is a chronic psychiatric illnesses characterized by alternating episodes of mania/hypomania and major depression, or with mixed features. Acute exacerbations and maintenance treatment with appropriate pharmacotherapy are mandatory. Long-term treatment with mood-stabilizing medications is typically required. The incidence of bipolar disorders in women during the primary reproductive years is very high, and the episodes of mania or depression are thought to occur in an estimated 25%–30% of women with bipolar disorder during pregnancy.ObjectivesProvide a clinically focused review of the available information on the effectiveness and safety of the different pharmacotherapies in the treatment of bipolar disorder during pregnancy.MethodsA bibliographic review is made of the pregnancy in bipolar disorder, based on the data published in PubMed.ResultsClinical decision making about the use of mood stabilizers and atypical anti-psychotics by pregnant women can be conceptualized as balancing the competing risks imposed by withholding or stopping pharmacotherapeutic treatment against that of continuing or initiating pharmacotherapy during pregnancy. Some of the most effective pharmacotherapies have been associated with the occurrence of congenital malformations or other adverse neonatal effects in offspring. There is few information about the safety profile and clinical effectiveness of atypical anti-psychotic drugs when used to treat bipolar disorder during pregnancy.ConclusionsTreating women with bipolar disorders during pregnancy is a challenge. There are no uniformly effective or risk-free treatment options. Fully informed decision-making requires the review of the risks of both untreated maternal bipolar disorder and risks associated with potentials interventions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study

Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

An analysis of QTc prolongation with atypical antipsychotic medications and selective serotonin reuptake inhibitors using a large ECG record database

ABSTRACTBackground: This study evaluated the effects of atypical antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs) on the corrected QT (QTc) interval using a large database obtained from clinical settings. Additionally, the effects of factors including age on QTc intervals were estimated.Methods: Using an open-access QT database (ECG-ViEW), QTc-lengthening effects of 14 selected atypical antipsychotics and SSRIs were compared to those of a positive control drug, cilostazol, and a negative control drug, diazepam. We also evaluated effects of age, sexgender, and select electrolyte levels on observed QTc intervals.Results: The frequency of QTc prolongation with the pooled data of the 14 study drugs was lower than that with cilostazol (age-adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.27-0.69), but no significant difference was found relative to when compared with that with diazepam (age-adjusted OR = 0.89, 95% CI = 0.55-1.47). Furthermore, administration of the 14 study drugs significantly increased the QTc interval by 2.89 ms after each 10-year age increment (p-value < 0.0001).Conclusions: This study suggests that atypical antipsychotic drugs and SSRIs are less likely to be associated with QTc prolongation in clinical settings. In addition, age showed a significant association with the QTc interval. Further studies with well-characterized cohorts are warranted.

2-Bromoterguride-a potential atypical antipsychotic drug without metabolic effects in rats.

RationaleRecently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy.ObjectiveTo extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs).ResultsAcute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity.ConclusionsOur data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.

Effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats subjected to immobilization stress

The present study examined the effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats with and without immobilization stress. Rats were subjected to immobilization stress 6h/day for 3 weeks. The effects of atypical antipsychotic drugs, olanzapine and aripiprazole, on expression of serine9-phosphorylated GSK-3β, β-catenin, BDNF, PSD-95, and synaptophysin were determined by Western blotting. A typical antipsychotic drug, haloperidol, was used for comparison. Immobilization stress significantly decreased the expression of these proteins in the frontal cortex. Chronic administration of olanzapine and aripiprazole significantly attenuated the immobilization stress-induced decrease in the levels of these proteins, whereas haloperidol had no such effect. Additionally, olanzapine and aripiprazole significantly increased levels of phosphorylated GSK-3β under normal conditions without stress, and aripiprazole also increased BDNF levels under this condition. These results indicate that olanzapine and aripiprazole, and, haloperidol, differentially regulate the levels of synapse-associated proteins in the rat frontal cortex. These findings may contribute to explain the neurobiological basis of how olanzapine and aripiprazole up-regulated synapse-associated proteins.