Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

MicroRNAs as potential biomarkers for diagnosis of schizophrenia and influence of antipsychotic treatment

Chara cterized by positive symptoms(such as changes in behavior or thoughts,including delusions and hallu cinations),negative symptoms(such as apathy,anhedonia,and social withdrawal),and cognitive impairments,schizophrenia is a chro nic,severe,and disabling mental disorder with late adolescence or early adulthood onset,Antipsychotics are the most commonly used drugs to treat schizophrenia,but those currently in use do not fully reverse all three types of symptoms characte rizing this condition.Schizophrenia is frequently misdiagnosed,resulting in a delay of or inappropriate treatment.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of schizophrenia.The recent studies reviewed included microRNA profiling in blood-and urine-based materials and nervous tissue mate rials.From the studies that had validated the preliminary findings,potential candidate biomarkers for schizophrenia in adults could be miR-22-3p,-30e-5p,-92a-3p,-148b-5p,-181a-3p,-181a-5p,-181b-5p,-199 b-5p,-137 in whole blood,and miR-130b,-193a-3p in blood plasma.Antipsychotic treatment of schizophrenia patients was found to modulate the expression of certain microRNAs including miR-130b,-193a-3p,-132,-195,-30e,-432 in blood plasma.Further studies are warranted with adolescents and young adults having schizophrenia and consideration should be given to using animal models of the disorder to investigate the effect of suppressing or overexpressing specific microRNAs.

Outcomes of long-acting injectable antipsychotics use in pregnancy:A literature review

BACKGROUND Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy.Long-acting injectable(LAI)antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders,but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy.AIM To summarize relevant data on maternal,pregnancy,neonatal,and developmental outcomes from published cases of LAI antipsychotic use in pregnancy.METHODS A literature search was performed through November 11,2023,using three online databases:PubMed/MEDLINE,Scopus,and Web of Science.Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy,with available full texts,were included.Descriptive statistics,narrative summation,and tabulation of the extracted data were performed.RESULTS A total of 19 publications satisfied the inclusion criteria:3 case series,15 case reports,and 1 conference abstract.They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies.The use of secondgeneration LAI antipsychotics was reported in the majority(n=47;61.0%)of pregnancies.First-generation LAI antipsychotics were administered during 30 pregnancies(39.0%).Most of the women(approximately 64%)had either satisfactory control of symptoms or no information about relapse,while approximately 12%of them had developed gestational diabetes mellitus.A minority of cases reported adverse outcomes such as stillbirth,spontaneous abortion,preterm birth,low birth weight,congenital anomalies,and neurological manifestations in newborns.However,there were no reports of negative long-term developmental outcomes.CONCLUSION Currently available data seem reassuring,but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.

A Comparison of Quality of Life, Medication Side-Effect and Adherence among Schizophrenia Patients on Conventional versus Atypical Antipsychotics

Quality of life (QoL) is becoming a widely accepted schizophrenia management outcome. But it is still not very clear if there are any significant differences between the conventional and atypical antipsychotics in terms of QoL improvement among people with schizophrenia (PWS). It is also imperative that antipsychotic drug-related factors, such as medication adherence and side-effect, which could directly or indirectly affect the QoL of PWS, are determined and compared among PWS on different classes of the drugs. Data were collected on Socio-demographic Characteristics, Quality of Life and Medication adherence using Socio-demographic and Schizophrenia Clinical Characteristics questionnaire, World Health Organization Quality of Life (WHOQoL)-Brief, and Morisky Medication Adherence Scale (MMAS) respectively from 250 respondents attending a tertiary health center’s Psychiatric clinic in Kano, Nigeria. Although PWS on the two classes of antipsychotic drugs showed inequalities in different aspects and domains of QoL, as well as in the levels of adherence and side-effects, the differences were all insignificant. However, presence of drug side effects was significantly associated with lower health-related QoL in the conventional antipsychotics group (p = 0.001), and lower score in the physical domain of QoL in the atypical antipsychotics group (p = 0.044). Medication adherence was found to be associated with better scores in different domains of QoL in both groups of PWS. There are no significant differences in terms of QoL, medication side-effect and adherence among PWS on the two classes of antipsychotics. However, drug side-effects and adherence were significantly and respectively associated with lower and higher scores in different domains of QoL in both groups.

Thirty years of scientific research on second-generation antipsychotic drugs in Japan: A bibliometric analysis

Aims:Research on second-generation antipsychotic drugs (SGAs) has experienced great development in last decades.We did a bibliometric study on the scientific publications on SGAs in Japan.Methods: With theEMBASEandMEDLINEdatabases, we chose papers published from Japan with SGA descriptors. Price’s law and Bradford’s law has been used as bibliometric indicators for quantitating production and dispersion, respectively, of published papers on SGAs. We also calculated the participation index of different countries, and correlated those bibliometric data with some social and health data from Japan (such as totalper capitaexpenditure on health and gross domestic expenditure on research and development). Results: A sum of 669 original documents were published from Japan from 1982 to 2011. Those results fulfilled Price’s law, with scientific production on SGAs showing exponential growth (correlation coefficientr= 0.9261, as against anr= 0.8709 after linear adjustment). The most studied SGAs in Japan wererisperidone (n= 192), aripiprazole (n= 109), and olanzapine (n= 106). Division of documents into Bradford zones yielded a nucleus occupied exclusively by theProgress in Neuro-Psychopharmacology and Biological Psychiatry(49 articles). Those publications were in 157 different journals. Seven of the first 10 frequently used journals had an impact factor of being greater than 3. Conclusions: The SGA publications in Japan have been through exponential growth over the studied period, without evidence of reaching a saturation point.

Antipsychotics cardiotoxicity:What's known and what's next

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling,sometimes lifeshortening adverse effects.Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns.These cardiotoxic effects range from arrhythmia to heart failure in the clinic,with myocarditis/cardiomyopathy,ischemic injuries,and unexplained cardiac lesions as the pathological bases.Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity.This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level.We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity.We propose that third-generation antipsychotics or drug adjuvant therapy,such as cannabinoid receptor modulators that confer dual benefits—i.e.,alleviating cardiotoxicity and improving metabolic disorders—deserve further clinical evaluation and marketing.

Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics

Accumulating evidence suggests that a disruption of early brain development,in which insulin-like growth factor-2(IGF-2)has a crucial role,may underlie the pathophysiology of schizophrenia.Our previous study has shown that decreased serum IGF-2 was correlated with the severity of psychopathology in patients with schizophrenia.Here we conducted a prospective observation trial to investigate the effects of atypical antipsychotics on serum IGF-2 level and its relationship with clinical improvements in schizophrenia patients.Thirty-one schizophrenia patients with acute exacerbation and 30 healthy individuals were recruited in this study.Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale(PANSS)and serum IGF-2 levels were determined using ELISA.We found that schizophrenia patients with acute exacerbation had lower serum IGF-2 levels than control individuals at baseline(P<0.05).After 2 months of atypical antipsychotic treatment,a significant improvement in each PANSS subscore and total score was observed in patients(all P<0.01),and the serum IGF-2 levels of patients were significantly increased compared with those at baseline(203.13±64.62 vs.426.99±124.26 ng/mL;t=−5.044,P<0.001).Correlation analysis revealed that the changes of serum IGF-2 levels in patients were significantly correlated with the improvements of negative symptoms(r=−0.522,P=0.006).Collectively,our findings demonstrated changes of serum IGF-2 response to improvements of negative symptoms in schizophrenia patients treated with atypical antipsychotics,suggesting that serum IGF-2 might be a treatment biomarker for schizophrenia.

Galectin-3 possible involvement in antipsychotic-induced metabolic changes of schizophrenia:A minireview

Recently,specific immunometabolic profiles have been postulated in patients with schizophrenia,even before full-blown disease and independent of antipsychotic treatment.Proteomic profiling studies offer a promising potential for elucidating the cellular and molecular pathways that may be involved in the onset and progression of schizophrenia symptoms,and co-occurrent metabolic changes.In view of all this,we were intrigued to explore galectin-3(Gal-3)as a glycan,and in our previous study,we measured its elevated levels in remission of schizophrenia.The finding may be a consequence of antipsychotic treatment and may have an impact on the onset of inflammation,the development of obesity,and the presumed cognitive changes in schizophrenia.In the animal study,it was shown that downregulation of Gal-3 was beneficial in insulin regulation of obesity and cognitive preservation.Strategies involving plasma exchange are discussed in this review,particularly in the context of Gal-3 elimination.

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia:State-of-the-art and future perspectives

Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia,resulting in a higher mortality rate and shorter life expectancy compared with those in the general population.Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks,antipsychotics,particularly those of second generation,may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia.This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms,monitoring guidelines,and interventions.Nearly all antipsychotics are associated with weight gain,but the degree of the weight gain varies considerably.Although certain neurotransmitter receptorbinding affinities and hormones are correlated with weight gain and specific metabolic abnormalities,the precise mechanisms underlying antipsychoticinduced weight gain and metabolic disturbances remain unclear.Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances.Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed,they are not routinely implemented in clinical care.Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances.Thus,patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs.If lifestyle intervention fails,switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered.Antipsychotic medications are essential for schizophrenia treatment,hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.

Influence of different second generation antipsychotics on the QTc interval: A pragmatic study

AIM To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics(SGAs) in psychosis.METHODS Data were drawn from a pragmatic, randomized headto-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequenceof the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat(ITT) analyses were also performed. RESULTS A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations(SD) were 3.4(1.2) for risperidone, 13.9(4.6) for olanzapine, 325.9(185.8) for quetiapine, and 97.2(42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups(Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was-0.0030(0.0280) for risperidone;-0.0099(0.0108) for olanzapine;-0.0027(0.0170) for quetiapine, and-0.0081(0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups(the randomization groups), revealed almost identical slopes with-0.0063(0.0160) for risperidone,-0.0130(0.0126) for olanzapine,-0.0034(0.0168) for quetiapine, and-0.0045(0.0225) for ziprasidone. CONCLUSION None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found.

Audit of physical health monitoring in children and adolescents receiving antipsychotics in neurodevelopmental clinics in Northumberland

AIM To ascertain performance against the standards set by National Institute for Clinical Excellence (NICE) guidelines on physical health monitoring of thirty children and adolescents prescribed antipsychotics in neurodevelopmental clinics in Northumberland and identifying areas for improvement in practice. METHODS The audit involved a review of recorded documentation pertaining to physical health monitoring in patient electronic records pertaining to children and adolescents attending neurodevelopmental clinics in Northumberland prescribed antipsychotics. Clients were also contacted by telephone if relevant documentation could not be identified or retrieved to confirm the details. 32 case notes were perused of which 2 were excluded as they had refused to have venepuncture which was documented in the electronic records. RESULTS The overall audit results demonstrated partial compliance with NICE guidelines on physical health monitoring in children and adolescents prescribed antipsychotics. Bi-annual recording of height, weight, blood pressure, pulse rate and review of side effects was completed in 100% of subjects. However, annual monitoring for blood tests including liver function, renal function full blood count as well as biannual monitoring of serum prolactin, serum lipid profile was completed only in 56% of subjects. Comparative baseline characteristics between the two groups (compliant and non-compliant with guidelines) found no differences based on any socio-demographic or clinical variables. However, the proportion of patients in the group compliant to guidelines was higher in the age group of 12-17 years as compared to < 12 years (70.58% vs 38.46%), though not statistically significant (χ~2 = 1.236; P = 0.24). CONCLUSION Development of tailored and specific guidelines for physical health monitoring in children and adolescents prescribed antipsychotics taking into consideration clinical effectiveness and safety profile is likely to improve adherence rates.

Moderators and mediators of antipsychotic response in delusional disorder:Further steps are needed

Delusional disorder(DD)has been traditionally considered a relatively rare and treatment-resistant psychotic disorder.In the last decade,increasing attention has focused on therapeutic outcomes of individuals affected by this disorder.The aim of this paper is to provide a synthesis of the literature addressing two very important questions arising from DD research:(1)For which patients with DD do antipsychotic medications work best(the moderators of response);and(2)What variables best explain the relationship between such treatments and their effectiveness(the mediators of response).We searched PubMed and Google Scholar databases for English,German,French and Spanish language papers published since 2000.We also included a few classic earlier papers addressing this topic.Variables potentially moderating antipsychotic response in DD are gender,reproductive status,age,duration of illness,the presence of comorbidity(especially psychiatric comorbidity)and its treatment,brain structure,and genetics of neurochemical receptors and drug metabolizing enzymes.Antipsychotic and hormonal blood levels during treatment,as well as functional brain changes,are potential mediating variables.Some,but not all,patients with DD benefit from antipsychotic treatment.Understanding the circumstances under which treatment works best can serve to guide optimal management.

Newer antipsychotics: Brexpiprazole, cariprazine, and lumateperone: A pledge or another unkept promise?

Antipsychotic agents are used for various indications in the treatment of psychiatric disorders.Despite their proven roles in multiple conditions,the treatment-emergent side effects of antipsychotic medications,such as metabolic side effects,are often the limiting factor for their long-term and short-term uses.Moreover,antipsychotic medications are often criticized for being less effective in treating different disabling symptoms such as negative symptoms of schizophrenia.As a result,the search for safer and more efficacious antipsychotic agents is ongoing.Newer antipsychotic agents are gaining attention related to emerging efficacy and tolerability data in treating neuropsychiatric conditions.In this review,we attempt to appraise the scientific data on psychopharmacology,safety profile,and efficacy of the newer additions to the list of second-generation antipsychotics,namely brexpiprazole,cariprazine,and lumateperone.We conducted a selective review utilizing PubMed,clinicaltrials.gov,and Cochrane databases to gather appropriate publications,keeping broad inclusion criteria.There were no restrictions on the age of the study population or the year of publication.We also cross-referenced articles and references to capture all existing studies.Our review of the current literature indicates that all three antipsychotic agents appear to be promising based on their short-term studies,while long-term studies remain limited.There is also a need for a head to head comparison between the newer antipsychotics with the other antipsychotic agents to ascertain if the newer agents are any better than the others.

Trajectories of response in schizophrenia-spectrum disorders: A one-year prospective cohort study of antipsychotic effectiveness

BACKGROUND Antipsychotic drugs remain the mainstay of schizophrenia treatment;however,their effectiveness has been questioned,and it is not possible to predict the response to a specific antipsychotic drug in an individual patient.Thus,it is important to compare the effectiveness of the various antipsychotics and search for possible response predictors.AIM To investigate the effectiveness of antipsychotic drugs,we examined response trajectories and predictors for belonging to different trajectory groups.METHODS The Bergen-Stavanger-Innsbruck-Trondheim(BeSt InTro)trial compared the effectiveness of three atypical antipsychotics-amisulpride,aripiprazole,and olanzapine-in a prospective,semirandomized,rater-blind,head-to-head design.Adult participants with a schizophrenia spectrum disorder diagnosis,according to international classification of diseases,Tenth Revision(ICD-10)F20–29,were included.Participants were followed for a period of 12 mo,with assessments at baseline;after one,three and six weeks;and after three,six,nine and 12 mo.A latent class mixed model was fitted to our data.The three-trajectory model based on the Positive and Negative Syndrome Scale(PANSS)total score reduction was found to have adequate fit,and the study drugs,as well as various demographic and clinical parameters,were tested as predictors for belonging to the different trajectory groups.RESULTS Overall,144 participants were included,and 41%completed the 12-mo study period.The largest trajectory group,consisting of 74%of participants,showed a PANSS total score reduction of 59%from baseline to 12 mo(Good response group).A trajectory group comprising 13%of participants had their PANSS total score reduced by 82.5%at 12 mo(Strong response group),while the last response trajectory group comprising 13%of the participants had a PANSS total score reduction of 13.6%(Slight response group).The largest part of the total reduction for the Good and Strong response groups occurred at six weeks of treatment,amounting to 45%and 48%reductions from baseline,respectively.The use of amisulpride predicted belonging to the Strong response group,while unemployment,depression,and negative psychotic symptoms at baseline increased the chance of belonging to the Slight response group,indicating a poor response to antipsychotic drug treatment.CONCLUSION Most of the participants(87%)had a good outcome after one year.Amisulpride users,more often than aripiprazole and olanzapine users,belonged to the response trajectory group with a strong response.

Predictors of Discontinuation of Antipsychotic Therapy in Patients with Acute Schizophrenia: A 1-Year Observational Study with More Than 1000 Patients

Discontinuation of antipsychotic therapy has been a significant clinical issue among patients with schizophrenia, since the patients who discontinued antipsychotic treatment showed worse clinical and functional outcomes, and higher risks of relapse of schizophrenia symptoms and hospitalization. We conducted a post-hoc analysis of a post-marketing research with a 12-month follow-up period to identify the predictors for discontinuation of antipsychotic monotherapy in Japan. This is a prospective, naturalistic multicenter observational study, designed to evaluate the discontinuation rates of olanzapine monotherapy and non-olanzapine antipsychotic monotherapy in Japanese adult patients with acute schizophrenia. Patients were treatment-naive, or had switched from other antipsychotics or from poly-pharmacotherapy to oral antipsychotic monotherapy. We analyzed the correlation of discontinuation of antipsychotic monotherapy with baseline characteristics of patients. A total of 1089 patients (578 patients treated with olanzapine and 511 with non-olanzapine antipsychotics) were eligible for analysis. By the end of the 12-month study period, 614 patients (56.4%) discontinued antipsychotic therapy. Multivariate logistic regression analyses indicated significantly lower discontinuation rates in all patients treated with antipsychotics: older age (Odds ratio [OR], 0.871;95% confidence interval [CI], 0.797 to 0.953;p = 0.003), outpatient status (OR, 0.508;95% CI, 0.383 to 0.675;p < 0.001), prior use of antipsychotics (OR, 0.693;95% CI, 0.516 to 0.930;p = 0.015), and olanzapine group showed lower discontinuation rate than that of non-olanzapine group (OR, 1.416;95% CI, 1.086 to 1.846;p = 0.010). The present study indicated that the outpatient status, older age, and prior use of antipsychotics have better adherence to antipsychotic treatment. In addition to these factors, use of anti-parkinson agents showed lower discontinuation rates in the olanzapine monotherapy group.

Antipsychotic and Anticholinergic Drug Prescribing Pattern in Psychiatry: Extent of Evidence-Based Practice in Bahrain

The aim of this study is to determine the antipsychotic prescribing pattern and the prevalence of concurrent anticholinergic prescribing in a psychiatric referral hospital. A retrospective audit of prescriptions issued for outpatients was carried out at the Psychiatric Hospital, the only facility that provides psychiatric services for both inpatients and outpatients in the Kingdom of Bahrain. Antipsychotic monotherapy was prescribed for 89.2% patients, whereas polytherapy with two- and three-drugs in 10.4 and 0.4%, respectively. Atypical antipsychotics were prescribed more often (67.7%) than typical antipsychotics. Risperidone and haloperidol were the most frequently prescribed antipsychotics. Long-acting risperidone injection was the only depot preparation prescribed. The mean antipsychotic dose expressed as chlorpromazine equivalent (CPZeq;mg/day) was 242 (220 for monotherapy and 414 for polytherapy). The prevalence of high dose antipsychotic (mean CPZeq > 1000 mg/day) was 1.8%, prescribed at a mean CPZeq dose of 1531 (1925 for monotherapy and 1137 for polytherapy), mainly attributed to haloperidol. Anticholinergics were co-prescribed for almost two third of patients receiving antipsychotics, particularly for those on polytherapy (monotherapy 57.3%;poly-therapy 87.5%). Antipsychotic polytherapy, high dose and co-prescription of an oral with a depot antipsychotic preparation were strongly associated with concurrent prescription of anticholinergics. Procyclidine and orphenadrine were the most often prescribed anticholinergics. In Bahrain, antipsychotic monotherapy is a common practice for outpatients with psychotic disorders. Some of the antipsychotic polytherapies, dosage strategies, and high prevalence of anticholinergic use are therapeutic issues that need to be addressed to foster evidence-based prescribing practice.

Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury

Antipsychotics may prolong or retain telomere length,affect mitochondrial function,and then affect the metabolism of nerve cells.To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury,leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient.The mononuclear cells layer was resuspended in cell culture medium.Oxidative stress was induced with hydrogen peroxide in cultured leukocytes.Four days later,leukocytes were treated with aripiprazole,haloperidol or clozapine for 7 days.Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23%and 20%in peripheral blood mononuclear cells after acute oxidative stress injury.These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress.The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of Sao Paulo(FMUSP/CAAE approval No.52622616.8.0000.0065).

Tinospora cordifolia attenuates antipsychotic drug induced hyperprolactinemia in Wistar rats

Objective: To evaluate the anti-hyperprolactinemic effect of methanolic extract of Tinospora cordifolia against antipsychotic/neuroleptic drug induced hyperprolactinemia. Methods: A total of 48 Wistar albino rats were chosen in the study. To induce hyperprolactinemia, haloperidol at 5 mg/kg/day was intraperitoneally administered for 16 continuous days and sulpiride at 20 mg/kg/day was administered intraperitoneally for 28 continuous days. Methanolic extract of Tinospora cordifolia at 200 mg/kg/day and 400 mg/kg/day were administered orally 30 min before administration of haloperidol and sulpiride for 16 and 28 days, respectively. Then, we had evaluated prolactin, dopamine and antioxidant status in the treatment group as compared to haloperidol and sulpiride. Results: There was a significant (P<0.05) increase in serum prolactin level and decrease in dopamine level in the haloperidol and sulpiride treated animals. However, methanolic extract of Tinospora cordifolia significantly (P<0.05) decreased serum prolactin level and increased brain dopamine level. Further, superoxide dismutase and catalase level were also decreased significantly in the haloperidol and sulpiride treated groups as compared to those of the control group and the antioxidant status was restored significantly on treatment with methanolic extract of Tinospora cordifolia. Furthermore, methanolic extract of Tinospora cordifolia also reduced total leukocyte count, and increased red blood cell count and hemoglobin concentration. In addition, the spleen did not show signs of infection or inflammation in the experiments. Conclusions: Methanolic extract of Tinospora cordifolia has a significant anti-hyperprolactinemic effect which may be attributed to neuroprotective and antioxidant effects of its signature constituents like stepharanine.

Underlying disease may increase mortality risk in users of atypical antipsychotics

Schizophrenia is a group of the most common types of mental illness.Commonly used antischizophrenia drugs all increase mortality to some extent.The increased risk of death in older individuals and patients with dementia using atypical antips-ychotics may be due to myocardial damage,increased mobility and increased risk of stroke.

Cardiotoxicity of current antipsychotics:Newer antipsychotics or adjunct therapy?

Use of newer antipsychotics for substitution of current antipsychotics might be one way awaiting to be clinically verified to address antipsychotic cardiotoxic effects.Alternatively,the combination of existing antipsychotics with cardioprotective agents is also beneficial for patients with mental disorders for avoiding cardiotoxicity to the maximum.