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.

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.

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).

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.

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.

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.

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.

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.

Role of antipsychotics for treating behavioral and psychological symptoms of dementia

Over the past three decades, concerns about the high prevalence of antipsychotic use in the nursing homes （NHs） for the management of behavioral and psychological symptoms of dementia continue to be emphasized and intervened by many. However, despite the numerous side effects and the recent blackbox warning by the United States Food and Drug Administration about the increased risks for stroke and sudden death associated with the use of antipsychotics in dementia, the preva-lence of antipsychotic use in NHs remains high. While the use of antipsychotics appeared to have modest effcacy in reducing symptoms of aggression and psychosis in dementia, there is insuffcient evidence to routinely rec-ommend the use of alternative psychopharmacological treatments for these symptoms. Hence, clinicians have to balance the safety warnings against the need to treat these symptoms in order to prevent harm to the resident that may result from his/her dangerous behaviors. Although the use of antipsychotics may be warranted in some cases, organizational, resource and training support should be provided to encourage and equip NH staff to participate in interventions so as to minimize inappropriate use of these medicines in NHs. This review will discuss the place in therapy, the trend and appropriateness of antipsychotic use in NHs, as well as the effectiveness of current and future strategies for reducing antipsychotic use in the NHs.

Efficacy and Safety of Antipsychotics for the Treatment of Major Depressive Disorder in Adolescents and Adults: Current Issues and Clinical Perspective

Objectives: Atypical antipsychotics are increasingly being prescribed for the treatment of mood disorders, often off-label. This review describes existing published literature on the efficacy and safety of antipsychotics for the treatment of major depressive disorder (MDD) in adults and adolescents. We discuss current clinical considerations: role as monotherapy, adjunctive, or augmentation therapy, side effect profiles, and optimal dose and duration of therapy. Potential areas for future research and methodological considerations are also highlighted. Method: We conducted a literature search of MEDLINE, EMBASE, PsycINFO, and Cochrane databases. Relevant articles and references were identified. MDD practice guidelines for adolescents and adults were reviewed. Results: Evidence for using atypical antipsychotics to treat MDD is heterogeneous. It is thus difficult to draw firm conclusions regarding their role in therapy. Most current guidelines do not include recommendations for atypical antipsychotics, but off-label use is common in clinical practice. Primary use is adjunct or augmentation therapy for treatment resistant depression. Potential benefits versus side effects must be cautiously considered, especially for children and adolescents. Clinicians must rely on their clinical experience and professional judgment to determine an optimal dose and duration of therapy. Conclusions: There is progressive research to support the use of atypical antipsychotics to treat MDD in adults. However, additional research and well-designed studies are needed to determine the appropriate and safe use of atypical antipsychotics for treating child and adolescent depression. Other subpopulations that may benefit from combination therapy, such as individuals with dual diagnoses, may be identified through future research.

Differences in Baseline Characteristics of Patients Treated with Olanzapine or Other Antipsychotics in Japanese Patients with Acute Schizophrenia: A 1-Year Observational Study under Routine Clinical Practice in Japan

Objective: Baseline characteristics of acute schizophrenia patients were analyzed to identify differences in the baseline characteristics of patients treated with olanzapine monotherapy compared with those treated with other antipsychotic monotherapies. Methods: This prospective, naturalistic observational study was designed to evaluate discontinuation rates of olanzapine and non-olanzapine antipsychotic monotherapy in Japanese adult patients with acute schizophrenia. Results: A total of 1089 patients were assessed: 578 patients were treated with olanzapine, 487 with non-olanzapine atypical antipsychotics, and 24 with typical antipsychotics. The mean Clinical Global Impression-Severity (CGI-S) Schizophrenia, Brief Psychiatric Rating Scale (BPRS) total, and BPRS positive scores were higher in patients treated with olanzapine compared with most of the non-olanzapine treated patients. The majority of patients with a CGI-S Schizophrenia score of 7 (29/41 patients) as well as patients with a BPRS total score of 90 or higher (14/18 patients) were treated with olanzapine. On the other hand, physicians tended to prescribe antipsychotics other than olanzapine for patients with heavier body weight or diabetes mellitus. Conclusion: The present study demonstrated that olanzapine was more likely to be prescribed to patients with more severe schizophrenia symptoms. However, further studies are warranted to reach a definite conclusion.

Broader Role for Antipsychotics in the Treatment of Obsessive Compulsive Disorder and Schizophrenia—A Malaysian Case Series

Obsessive compulsive disorder (OCD) and schizophrenia have been considered to be variants of the same disorder. At the advent of psychiatry, there was a distinction between neurotic, mood disorders and psychotic disorders. As perceptions and thoughts evolve in this dynamic field, there has been a paradigm shift in the way these disorders are being perceived. Of particular interest is that concerning OCD and schizophrenia. In a much anticipated and very welcomed move, DSM V has now included delusional beliefs as a specifier of OCD. However the much spoken about schizo- obsessive syndrome is yet to be explored and addressed. Recurrent and intrusive thoughts, impulses and images are key experiences seen in OCD. How we differentiate these vivid images from visual hallucination is a question yet to be answered. The following case series is an example of how difficult the boundaries between severe OCD and schizophrenia can be, and the promising usage of atypical antipsychotic in controlling obsessive compulsive symptoms. Whether untreated OCD is a significant prodromal symptom of schizophrenia, a subtype of schizophrenia or an initial indicator of various syndromes, remains to be seen, depending on environmental effects on the neuroplasticity of the mind and brain. The cases discussed will highlight the role of antipsychotics in patients diagnosed as having OCD, and gives strength to the idea that perhaps antipsychotics should be used more liberally in the treatment of OCD in schizophrenia. Here, we present a case series to show the use of atypical antipsychotics as monotherapy or augmenter in quelling obsessive-compulsive symptoms in patients who fulfilled the DSM V criteria for both schizophrenia and OCD. The efficacy of antipsychotics in reducing OCD symptoms in psychotic patients, as shown in this case series, contributes to the body of evidence that OCD and schizophrenia are really spectrum disorders with a common denominator. It is hoped that this exciting finding will lead to a paradigm shift in the usage of antipsychotics in OCD and eventually change how this disease is viewed and treated.

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.

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).

Use of Antipsychotics: A Study from the French National Insurance Healthcare System Database

A marked increase in antipsychotic prescriptions has been observed in most countries since the introduction of second-generation antipsychotics. Misuse could partly explain this rise. We described the use of antipsychotic medication in France. This retrospective analysis was conducted on the sample “Echantillon généraliste de beneficiaries” from the French National Insurance Healthcare System. All reimbursements for antipsychotic medications in 2010 were identified. Antipsychotics use was described in terms of patient’s profiles and condition of use. In 2010, we identified 11,729 single patients with at least one reimbursement for antipsychotic medication (2.23% of French health insurance beneficiaries). The mean age in the population was 54 (sd 20) years. Forty-one percent had declared psychiatric disorder and 15% had a psychiatric follow-up for unknown diseases. Schizophrenia, others psychosis and personality disorders were the three main diagnoses of psychiatric disease. Patients without declared psychiatric disorders and without psychiatric follow-up accounted for 23% (aged between 15 and 65) and 20% (aged 65 years and over) of the population using antipsychotics. Forty-five percent of patients aged between 15 and 65 had more than 3 months of treatment refunded. Patients aged 65 years and over were 69% without dementia and 47% had more than three months of treatment of antipsychotics refunded during the year. These results suggested that antipsychotic treatments were used in France at long term in particular for patients without declared psychiatric disorder or psychiatric follow-up.

In vivo immunomodulatory effects of antipsychotics on inflammatory mediators:A review

Background: Substantial evidence demonstrates the presence of an inflammatory syndrome in schizophrenia, which is manifested by increased peripheral levels of interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), and interleukin-1 receptor antagonist (IL-1RA). Unfortunately, the immunomodulatory effects of antipsychotics on peripheral cytokine levels remain poorly understood. Objectives: The objectives of the current systematic review are to determine if antipsychotics have anti-inflammatory effects in patients with schizophrenia-spectrum disorders and to examine the relationships between antipsychotic-induced cytokine changes and drug response or common side effects. Method: A systematic search was performed in the electronic databases PubMed and EMBASE. Results: We identified 39 studies measureing the effects of 8 antipsychotics on 13 inflammatory mediators and 4 cytokine receptors. This literature suggests that antipsychotics (especially clozapine) consistently decrease peripheral interleukin-2 (IL-2) levels and increase sIL-2R and soluble tumor-necrosis factor (sTNF-R) receptor levels. Changes in IL-2/sIL- 2R levels seem to correlate with changes in positive symptoms. Preliminary results suggest that antipsychotics decrease interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels, and increase interleukin-4 (IL-4) levels. Antipsychotic-induced changes in IL-6, C-reactive protein (CRP) and tumor-necrosis factor-α (TNF-α) have been linked with common antipsychotic side effects (metabolic, fever). Discussion: Despite significant clinical heterogeneity across studies, this review has evidenced that antipsychotics can produce both anti- and pro-inflammatory effects that may partially contribute to drug response and drug-induced side effects. In the future, a better understanding of the molecular mechanisms of action of antipsychotics on inflammatory mediators will help to identify novel therapeutic strategies as well as novel biomarkers of treatment response and of drug-induced side effects in schizophrenia.

Quantitative Structure-Activity Relationship Study of Some Antipsychotics by Multiple Linear Regressions

The retention behavior and lipophilicity parameters of some antiphychotics were determined using reversed-phase thin layer chromatography. Quantitative structure-activity relationships studies have been performed to correlate the molecular characteristics of observed compounds with their retention as well as with their chromatographically determinated lipophilicity parameters. The effect of different organic modifiers (acetone, tetrahydrofuran, and methanol) has been studied. The retention of investigated compounds decreases linearly with increasing concentration of organic modifier. The chemical structures of the antipsychotics have been characterized by molecular descriptors which are calculated from the structure and related to chromatographically determinated lipophilicity parameters by multiple linear regression analysis. This approach gives us the possibility to gain insight into factors responsible for the retention as well as lipophilicity of the investigated set of the compounds. The most prominent factors affecting lipophilicity of the investigated substances are Solubility, Energy of the highest occupied molecular orbital, and Energy of the lowest unoccupied molecular orbital. The obtained models were used for interpretation of the lipophilicity of the investigated compounds. The prediction results are in good agreement with the experimental value. This study provides good information about pharmacologically important physico-chemical parameters of observed antipsychotics relevant to variations in molecular lipophilicity and chromatographic behavior. Established QSAR models could be helpful in design of novel multitarget antipsychotic compounds.