Effects Of Second-generation Antipsychotics Research Articles

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase (Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

You lack the season of all natures, sleep.

You lack the season of all natures, sleep.

Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk

ObjectiveAdipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes. MethodsAbdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22–64 yr; BMI: 21.7–27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naïve), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 µM and 2.0 µM), aripiprazole (1.0 µM and 10 µM) and its active metabolite dehydroaripiprazole (0.4 µM and 4.0 µM). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pre-treated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co-culture for mRNA expression analysis of genes involved in inflammation. ResultsCo-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B, IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages. ConclusionTogether, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.

Integrative Management of Metabolic Syndrome in Youth Prescribed Second-Generation Antipsychotics

Weight gain and metabolic syndrome are common side effects of second-generation antipsychotics and carry significant health consequences both in childhood and into adulthood. This review highlights evidence-based, non-pharmacologic interventions to assist in the management of these side effects. Such intervention categories include dietary, physical activity, sleep, stress management, and nutritional supplementation. Interventions with the highest quality evidence include increasing the consumption of fruits, vegetables, and whole grains, increasing physical activity, improving sleep, and fish oil supplementation. We suggest that clinicians work with patients on managing metabolic side effects in a patient-centered way, incorporating principles of motivational interviewing, to reduce the risk of metabolic syndrome.

The effect of second-generation antipsychotics on basal ganglia and thalamus in first-episode psychosis patients

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients.

The influence of substance use on the effectiveness of antipsychotic medication: a prospective, pragmatic study

Background: Psychosis is associated with a high prevalence of substance use, leading to worsened prognosis. Less is known about how comorbid substance abuse may influence the effectiveness of antipsychotic medications. The aim of this study was to compare the effectiveness of second generation antipsychotics in patients with psychosis with and without substance use.Methods: All patients (n = 226) were aged >18 years old had symptom level scores of ≥4 on selected psychosis items on the Positive and Negative Syndrome Scale and met ICD-10 diagnostic criteria for psychosis. Information on substance use was collected based on the Clinician Drug Use Scale. Patients were grouped at baseline according to the presence of substance use, medication history and diagnosis group. Clinical symptoms at baseline and changes at follow-up were assessed with the PANSS.Results: At baseline about 30% of the patients used substances, most frequently cannabis followed by methamphetamine. About half (47%) of the patients had no prior exposure to antipsychotic medication at inclusion. Patients who had consumed substances showed no substantial differences in the PANSS score reduction as a result of antipsychotic medication compared to patients without substance. There were, however, some group differences in relation to pattern of change that were influenced by medication history. Substance use was found to be related to stronger reduction of positive symptoms from week 4 to week 27.Conclusion: Substance use alone did not influence antipsychotic effectiveness in this sample of patients with psychosis.

Effect of second-generation antipsychotics on brain network topology in first-episode schizophrenia: A longitudinal rs-fMRI study

ObjectiveWe aimed to evaluate the functional network properties in first-episode schizophrenia (SZ) patients at baseline and after 4-months treatment with second-generation antipsychotic drugs. MethodsResting-state functional magnetic resonance imaging and graph theory approaches were utilized to evaluate the functional integration and segregation of brain networks in 36 first-episode patients (20 male/16 female) with SZ and 36 age and sex matched healthy controls (20 male/16 female). ResultsCompared with healthy controls, SZ at baseline showed lower clustering coefficient (Cp) and local network efficiency (Eloc), and this abnormal pattern was modulated with treatment of antipsychotic drugs at follow-up. Longitudinally, the increase of Cp was associated with the improvement of negative symptom. We found that the strength of functional connectivity between brain regions were significantly increased in three connections after treatment, mainly involving the frontal, parietal and occipital lobes. ConclusionThe current study suggested that antipsychotic drugs could modulate the faulty local clustering of the functional connectome in SZ. Furthermore, Cp, the parameter that reflects local clustering of topological organization, demonstrated the potential to be a connectome-based biomarker of treatment response to second-generation antipsychotics in patients with SZ.

Adiposity-independent hypoadiponectinemia as a potential marker of insulin resistance and inflammation in schizophrenia patients treated with second generation antipsychotics

ObjectiveThe purpose of this study was to explore body fat independent effect of second generation antipsychotics (SGAs) on measures of glucose and adipokine homeostasis, and markers of inflammation. MethodEight non-diabetic men with schizophrenia (age: 55±3years, BMI: 29.7±1.2kg/m2) on SGAs were studied after an overnight fast. DXA and single-cut CT of abdomen were respectively used for the assessment of total body and abdominal fat. Blood samples were collected for measurements of glucose, insulin, leptin, adiponectin, C-reactive protein (CRP), and TNF-α. Data in schizophrenic subjects were compared to eight age (55±2.8years) and BMI (29.6±1.1kg/m2) matched healthy men. ResultsThe results were significant for markedly decreased serum adiponectin in schizophrenia patients (4.6±0.9 vs 11.1±1.5ng/mL, p=0.001). Lower levels of adiponectin in schizophrenia men were associated with significant increases in insulin resistance (4.2±0.7 vs 1.7±0.4, p=0.004), CRP (3.5±1.2 vs 1.2±0.3, p=0.037), and leptin (12±1.4 vs 8.5±1.4ng/mL, p=0.05). Various measures of adiposity, including fat mass index (FMI) and abdominal fat were not different in the two study groups. ConclusionsThese findings in the context of comparable age and total body/abdominal fat mass are assumed to be either disease specific, and/or treatment inflicted. The definitive invoking etiology and a presumptive role of hypoadiponectinemia in the development of insulin resistance and increased risk of inflammation warrant future investigation.

The effect of second-generation antipsychotics on hippocampal volume in first episode of psychosis: longitudinal study.

BackgroundCurrent neuroscience literature has related treatment with aripiprazole to improved memory performance and subcellular changes in the hippocampus.AimsTo explore the volumetric changes in hippocampal grey matter in people with a first episode of psychosis (FEP) treated with second-generation antipsychotics.MethodBaseline and 1-year follow-up magnetic resonance images were obtained. Hippocampal volumes were estimated by using FreeSurfer and MAGeT-Brain. Subgroups included: aripiprazole (n=13), olanzapine (n=12), risperidone/paliperidone (n=24), refused-antipsychotics (n=13) and controls (n=44).ResultsAripiprazole subgroup displayed significant increases in bilateral hippocampal volume compared with all other subgroups (FreeSurfer: all P’s<0.012; MAGeT-Brain: all P’s<0.040).ConclusionsAripiprazole is a first-line, second-generation treatment option that may provide an added benefit of pro-hippocampal growth. The biological underpinnings of these changes should be the focus of future investigations and may be key towards achieving a better clinical outcome for more individuals.Declaration of interestM.L. received financial assistance/compensation for research and educational events from Janssen-Ortho, Eli Lilly, Roche and Otsuka/Lundbeck Alliance. A.K.M. received financial assistance/compensation for research and educational activities from Pfizer, Janssen-Ortho, AstraZeneca and Bristol-Myers Squibb. R.J. received consultancy honorariums from Pfizer and Janssen-Ortho.Copyright and usage© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Are Second-Generation Antipsychotics Useful in Tardive Dystonia?

To review the current evidence on the effectiveness of second-generation antipsychotics (SGAs) in the treatment of tardive dystonia (TDt) and give recommendations for treatment. Medline/PubMed/Psyclit/Embase database searches were conducted in January 2015, and a manual review of references within the retrieved articles was done. All articles in English and those that had English abstracts and dealt with treatment of TDt were included. Our search and review yielded a total of 88 reports (none of them a controlled trial) involving 145 patients treated with one of the 5 SGAs. Clozapine has the maximum number of published reports (52 reports involving 90 subjects, whereas there were 36 reports involving 55 subjects treated with other SGAs, including olanzapine, risperidone, quetiapine, aripiprazole, and perospirone). The available evidence points to the effectiveness of clozapine as monotherapy and in combination with clonazepam for the treatment of TDt. When clozapine is not an option, olanzapine and quetiapine are reasonable alternatives. Given the lack of controlled trials, future focus should be on conducting randomized, placebo-controlled, multicenter, collaborative controlled clinical trials of several years' duration.

Using marginal structural models to identify the cardiovascular adverse effects of second generation antipsychotics in children and adolescents

In pediatric patients, we examined the association between exposure to five second generation antipsychotics (SGAs) and incidentcardiovascular events (arrhythmic or ischemic/myocardial) over time using marginal structural models (MSM), while controllingfor salient comorbid conditions and co-prescribed psychotropic medications. A retrospective cohort, longitudinal/ observationalstudy design was used to evaluate Medicaid medical and pharmacy claims in 4140 children and adolescents prescribed SGAsfrom South Carolina USA’s Medicaid program covering outpatient and inpatient medical services and medication prescriptionsbetween January, 1996 and December, 2005. Exposure to multiple SGAs (Risk Ratio [RR]=2.37; 95% CI=1.17-4.83), coprescribedpsychostimulants (RR=1.37; CI=1.03-1.81), and comorbid hypertension (RR=2.23; CI=1.28-3.89) were associatedwith a significantly increased risk of arrhythmias compared to those not exposed, whereas exposure to co-prescribed serotoninnorepinephrine reuptake inhibitor/heterocyclic compounds was associated with a significantly decreased risk of arrhythmias(RR=0.59; CI=0.35-0.99). The risk of incident ischemic/myocardial events was significantly associated with the co-prescription ofmood stabilizers (RR=1.68; CI=1.06-2.68) or selective serotonin reuptake inhibitors (RR=1.91; CI=1.18-3.09), and the presenceof comorbid hypertension (RR=3.97; CI=1.96-8.07) and obesity (RR=2.21; CI=1.34-3.67). MSM analyses comparing multipletreatments while controlling for confounding variables in an observational, longitudinal data set provide important, differentialestimates of outcome, when randomized, controlled trials estimating low-incidence outcomes such as cardiovascular adverseevents in large pediatric patient populations are not feasible.

Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients.

PurposeAlterations in one-carbon metabolism (OCM) have been repeatedly reported in schizophrenia. However, there is a scarcity of studies addressing the effects of antipsychotics on selected OCM markers in schizophrenia and provided results are inconsistent.MethodsWe recruited 39 first-episode schizophrenia (FES) patients and determined serum profile of total homocysteine (tHcy), folate, vitamin B12, lipoproteins and glucose at baseline and after 12 weeks of treatment with second-generation antipsychotics (SGA) including olanzapine and risperidone in monotherapy.ResultsAfter 12 weeks of treatment, all patients had significantly higher body mass index (BMI), serum levels of total cholesterol (TC), low-density lipoproteins (LDL), triglycerides (TG) and tHcy together with significantly lower levels of folate and vitamin B12. The analysis of differences between SGA revealed the same biochemical alterations in patients treated with olanzapine as in the whole group, while those receiving risperidone had no statistically significant changes in serum folate, vitamin B12 and TG. There was a significantly higher increase in BMI and TC in patients treated with olanzapine in comparison with those treated with risperidone. Patients receiving olanzapine had a higher decrease in vitamin B12 than those assigned to the treatment with risperidone. Changes in folate, vitamin B12, tHcy and TC levels were significant only in males, even after Bonferroni correction. Multiple regression analysis revealed that changes in tHcy levels are associated with gender and baseline metabolic parameters (BMI, glucose, TC, LDL and HDL) but not with selected SGA.ConclusionsThese results indicate that SGA may influence OCM, especially in first-episode schizophrenia (FES) males.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-014-1762-2) contains supplementary material, which is available to authorized users.

Pharmacogenetic study of second-generation antipsychotic long-term treatment metabolic side effects (the SLiM Study): rationale, objectives, design and sample description.

Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs. The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited. This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline. Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment.

Daytime sleepiness and EEG abnormalities in patients treated with second generation antipsychotic agents

BackgroundThe aim of this study was to verify whether or not an increased prevalence of excessive daytime sleepiness (EDS) or EEG abnormalities is observed in patients with schizophrenia spectrum disorders (SSD), and to compare the effects of second generation antipsychotics (SGA) on patients’ daytime sleepiness level and EEG recordings. MethodsEEG recordings and self-reports of EDS, assessed with Epworth (ESS) and Stanford (SSS) Sleepiness Scales, were compared between 244 patients with SSD and 82 patients with anxiety, personality or behavioral disorders (non-psychotic disorders, NPD). To examine the effects of various SGA, patients treated in monotherapy with aripiprazole, olanzapine, clozapine, risperidone and sertindole were compared. ResultsA higher prevalence of abnormal EEG recordings was observed in SSD patients. No significant differences in average daytime sleepiness were found between patients with SSD and NPD; however, patients with SSD had longer sleep duration. Aripiprazole treatment was associated with significantly smaller and less frequent EEG abnormalities than treatment with any other SGA, while treatment with clozapine and olanzapine was related to an increased prevalence of severe EEG abnormalities. Patients with SSD treated with SGA in monotherapy were less sleepy than unmedicated patients with NPD. ConclusionsAlthough antipsychotics may have profound effects on EEG patients with schizophrenia do not have higher daytime sleepiness than patients with anxiety/personality disorders. Patients with schizophrenia may compensate sedative effects of antipsychotic treatment with sleep duration prolongation and report even less sleepiness than non-psychotic patients.

The effects of second-generation antipsychotics on food intake, resting energy expenditure and physical activity

Second-generation antipsychotics (SGA) are associated with weight gain and metabolic alterations including hyperglycemia, dyslipidemia, hypertension and metabolic syndrome. These metabolic side effects increase cardiovascular risk and are related to medication non-compliance. Patients without previous exposure to these or other antipsychotic drugs (naive patients) seem to be more prone to develop these metabolic abnormalities. The mechanisms behind weight gain can be an increase in food intake and/or a decrease in energy expenditure. This review comprehensively examines the current knowledge on the impact of these drugs on food intake and energy expenditure. The influence of these drugs on appetite and food intake (total caloric intake and food sources) is reviewed as well as the evidence of abnormal eating behaviors. The studies evaluating the effect on resting energy expenditure are critically examined, taking into account the influence of body composition and previous exposure to antipsychotics (naive vs non-naive patients). Finally, the influence of these drugs on physical activity is also discussed. The knowledge of the mechanisms of weight gain in patients starting these drugs may be useful to further prompt research in this field and ameliorate the metabolic side effects associated with these treatments.

The effect of leptin on prepulse inhibition in a developmental model of schizophrenia

Post-weaning social isolation is a developmental animal model of schizophrenia. Impairment of prepulse inhibition (PPI), possibly due to increased activity of the mesolimbic dopaminergic system, has frequently been reported in this model. There are some reports of increased level of leptin in schizophrenic patients. It has been shown that intracerebroventricular (ICV) injection of leptin decreases dopamine in the nucleus accumbens of rats. Here we investigated the effect of leptin on PPI impairment following social isolation. Five groups of Sprague-Dawley rats were reared post weaning in social or isolated conditions for 14 weeks. PPI was measured before treatment in week 12, and after ICV injection of vehicle or different doses of leptin (1, 5, and 10μg/5μl) in week 14. Results showed reduced PPI in untreated isolated compared to socially-reared rats in week 12 (p=0.009), but not in week 14 (p=0.45). Results also showed that leptin dose-dependently increased the basal PPI in isolated rats compared to vehicle, that was significant at a dose of 10μg (p=0.002). A considerable but non-significant effect of treatment with leptin on startle response (p=0.13) was seen. In conclusion, our results reveal that leptin significantly increases PPI in socially-isolated rats. The findings of this study suggest possible antipsychotic properties for leptin. We suggest further studies on the possible disruption of leptin signaling in schizophrenia, and also the possible interaction of leptin with therapeutic effects of second generation antipsychotics.

Negative symptoms in schizophrenia – the remarkable impact of inclusion definitions in clinical trials and their consequences

BackgroundNegative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. ObjectivesWe examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. MethodUsing anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. ResultsOperational criteria for negative symptoms in trials vary greatly in their inclusion of patients from “typical” trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. ConclusionsApplying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.

P.4.012 Effects of second generation antipsychotics on cognitive domains measured with the Matrics Consensus Cognitive Battery in early psychoses

P.4.012 Effects of second generation antipsychotics on cognitive domains measured with the Matrics Consensus Cognitive Battery in early psychoses

Adverse Effects of Second-Generation Antipsychotics in Children and Adolescents: A Bayesian Meta-Analysis

Adverse Effects of Second-Generation Antipsychotics in Children and Adolescents: A Bayesian Meta-Analysis

P.3.c.017 The effect of second generation antipsychotics on cognition in patients with early psychosis

P.3.c.017 The effect of second generation antipsychotics on cognition in patients with early psychosis