Antipsychotic-treated Patients Research Articles

Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder.

Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform-specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy. Cross-sectional observational study. Clinical research services center at an academic center. Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months. A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75-g oral glucose tolerance test. Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation-sensitive high-resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed. Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment.

Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia.

To evaluate the efficacy and safety of antidepressant augmentation of antipsychotics in schizophrenia. Systematic literature search (PubMed/MEDLINE/PsycINFO/Cochrane Library) from database inception until 10/10/2017 for randomized, double-blind, efficacy-focused trials comparing adjunctive antidepressants vs. placebo in schizophrenia. In a random-effects meta-analysis (studies=42, n=1934, duration=10.1±8.1weeks), antidepressant augmentation outperformed placebo regarding total symptom reduction [standardized mean difference (SMD)=-0.37, 95% confidence interval (CI)=-0.57 to -0.17, P<0.001], driven by negative (SMD=-0.25, 95% CI=-0.44-0.06, P=0.010), but not positive (P=0.190) or general (P=0.089) symptom reduction. Superiority regarding negative symptoms was confirmed in studies augmenting first-generation antipsychotics (FGAs) (SMD=-0.42, 95% CI=-0.77, -0.07, P=0.019), but not second-generation antipsychotics (P=0.144). Uniquely, superiority in total symptom reduction by NaSSAs (SMD=-0.71, 95% CI=-1.21, -0.20, P=0.006) was not driven by negative (P=0.438), but by positive symptom reduction (SMD=-0.43, 95% CI=-0.77, -0.09, P=0.012). Antidepressants did not improve depressive symptoms more than placebo (P=0.185). Except for more dry mouth [risk ratio (RR)=1.57, 95% CI=1.04-2.36, P=0.03], antidepressant augmentation was not associated with more adverse events or all-cause/specific-cause discontinuation. For schizophrenia patients on stable antipsychotic treatment, adjunctive antidepressants are effective for total and particularly negative symptom reduction. However, effects are small-to-medium, differ across antidepressants, and negative symptom improvement seems restricted to the augmentation of FGAs.

Allostatic load is associated with psychotic symptoms and decreases with antipsychotic treatment in patients with schizophrenia and first-episode psychosis

Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated if allostatic load (AL), an integrative index of neuroendocrine, immune and metabolic dysregulation in response to chronic stress, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning. Additionally, we assessed the temporal dynamics of AL in response to treatment with second-generation antipsychotics. AL, psychotic symptoms and psychosocial functioning were assessed in a longitudinal design in patients with SCZ (n = 28), FEP (n = 28), and healthy controls (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. AL at baseline was higher in patients with SCZ and FEP relative to controls, but not different between patients with SCZ and FEP. Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL and psychosocial functioning was negatively correlated with AL at trend level. Linear mixed model analysis demonstrated that AL decreased after treatment was commenced in patients with SCZ and FEP between the baseline assessment and the 6 and 12-week follow-up. AL was not predictive of treatment response or symptomatic remission. Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful tool to monitor biological signatures related to chronic stress and unhealthy behaviors in schizophrenia.

Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence.

This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE.

Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Elderly Antipsychotic-Treated Women With Type 2 Diabetes and Subclinical Hypothyroidism: A Preliminary Study.

Metformin was found to reduce elevated serum thyrotropin levels, and this effect was partially determined by endogenous dopaminergic tone. The aim of this study was to compare the effect of metformin treatment on hypothalamic-pituitary-thyroid axis activity in elderly women with subclinical hypothyroidism treated with antipsychotic agents and not receiving this drug. The study population consisted of 34 elderly women with subclinical hypothyroidism, 16 of whom received antipsychotic drugs. Because of coexistent type 2 diabetes, these women were treated with metformin (2.55-3 g daily). Glucose homeostasis markers as well as serum levels of thyrotropin, free thyroid hormones and prolactin were measured at the beginning of the study and 6 months later. Thirty women completed the study. With the exception of prolactin, baseline serum levels of the assessed hormones were comparable in both study groups. Although metformin reduced serum thyrotropin levels in both groups, this effect was more pronounced in the antipsychotic-treated than in the antipsychotic-naive patients. The effect on serum prolactin was observed only in antipsychotic-treated patients. The impact on serum thyrotropin levels correlated with improvement in insulin sensitivity and with a reduction in prolactin levels. Free thyroxine and free triiodothyronine remained at a similar level throughout the study. The obtained results indicate that metformin reduces serum thyrotropin levels in elderly women, and this effect is particularly pronounced in women with diminished dopaminergic transmission.

Prevalence of Antipsychotic-Treated Patients in a Cohort of Adult Addicted Patients.

The objective of this cross-sectional study was to describe and estimate the prevalence of antipsychotics (AP) in a cohort of addicted patients, and to compare the profiles of addictive patients receiving AP or not. We included all adult patients seen at the addiction care center of Montpellier University Hospital, between January 1, 2015, and March 31, 2015. Demographic, clinical, and therapeutic data were collected from the patients' medical records. During the study period, 415 patients were included, with a mean age of 38 ± 10 years. They were mostly men (73.3%), French (54.9%), and unemployed (61.8%). Among the study population, 93 patients (patients treated with AP [trAP], 22.4%) were treated by 111 different AP, mainly cyamemazine (29.0% of treated patients), aripiprazole (20.4%), olanzapine (17.2%), and quetiapine (16.1%), mostly in monotherapy (80.6%) and by oral route (93.2% of AP). Psychiatric history was more frequent in trAP than in those without AP (untrAP) (55.9% vs 35.4% respectively; P < 0.001). Professional activity tended to be less frequent in patients with AP (25.3% vs 38.9%, P = 0.08).When compared with untrAP, trAP consumed more amphetamine (10.8% vs 4.4%; P = 0.02) and tended to consume less opiates (7.5% vs 14.9%; P = 0.06); the consumptions of cannabis (43.0% vs 35.7%; P = 0.20) and cocaine (22.6% vs 16.8%; P = 0.20) were not statistically different.Opiate maintenance therapy was reported in 63.7% of trAP and 68.4% of untrAP (P = 0.41): it consisted of methadone (trAP, 60.3% vs untrAP, 56.5%) and buprenorphine (trAP, 39.7% vs untrAP, 43.5%). The concomitant management of psychiatric and substance use disorders in the same center may explain the high prevalence of trAP in this study. Cannabis and psychostimulants may have been used in these patients as self-medication for mental disease-related symptoms or adverse effects of APs.

Atropinic (anticholinergic) burden in antipsychotic-treated patients.

Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of this study was to investigate anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi-Pyrénées PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross-sectional study was to calculate anticholinergic burden in antipsychotic-treated patients; the secondary one was to investigate associated factors. Among the 1948 reports, the average number of atropinic drugs per report was 2.4 ± 1.4. At least one atropinic drug was found in 59.4% of reports (1158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 ± 2.9. A value ≥3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age, and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be used to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, such as antiparkinsonians, H1 antihistamines, or imipraminic antidepressants in these patients.

Transformed PANSS Factors Intended to Reduce Pseudospecificity Among Symptom Domains and Enhance Understanding of Symptom Change in Antipsychotic-Treated Patients With Schizophrenia.

Positive and Negative Syndrome Scale (PANSS) total score is the standard primary efficacy measure in acute treatment studies of schizophrenia. However, PANSS factors that have been derived from factor analytic approaches over the past several decades have uncertain clinical and regulatory status as they are, to varying degrees, intercorrelated. As a consequence of cross-factor correlations, the apparent improvement in key clinical domains (eg, negative symptoms, disorganized thinking/behavior) may largely be attributable to improvement in a related clinical domain, such as positive symptoms, a problem often referred to as pseudospecificity. Here, we analyzed correlations among PANSS items, at baseline and change post-baseline, in a pooled sample of 5 placebo-controlled clinical trials (N = 1710 patients), using clustering and factor analysis to identify an uncorrelated PANSS score matrix (UPSM) that minimized the degree of correlation between each resulting transformed PANSS factor. The transformed PANSS factors corresponded well with discrete symptom domains described by prior factor analyses, but between-factor change-scores correlations were markedly lower. We then used the UPSM to transform PANSS in data from 4657 unique schizophrenia patients included in 12 additional lurasidone clinical trials. The results confirmed that transformed PANSS factors retained a high degree of specificity, thus validating that low between-factor correlations are a reliable property of the USPM when transforming PANSS data from a variety of clinical trial data sets. These results provide a more robust understanding of the structure of symptom change in schizophrenia and suggest a means to evaluate the specificity of antipsychotic treatment effects.

Changes in the cytokine profile in first-episode, drug-naïve patients with psychosis after short-term antipsychotic treatment

An increasing body of evidence suggests that antipsychotic medication can cause immunological changes that could be attributed to the amelioration of psychotic symptoms or the metabolic side effects of the drugs. So far, the results of the studies remain controversial. Our aim was to compare the levels of interleukin (IL) IL-2, IL-6 and transforming growth factor-β2 (TGF-β2) in drug-naïve, first-episode patients with psychosis before and after six weeks of antipsychotic medication. Thirty-nine first-episode patients with psychosis were enrolled in the study. Serum levels of IL-2, IL-6 and TGF-β2 were measured by enzyme linked immunosorbent assay (ELISA) before and six weeks after the initiation of antipsychotics. In addition, clinical psychopathology was assessed using Positive and Negative Syndrome Scale (PANSS) before and after treatment. Serum levels of IL-2 were significantly increased six weeks after the initiation of antipsychotic treatment (p <0.001) while TGF-β2 levels were decreased (p <0.001). IL-6 levels were overall increased (p <0.004), but this occurred in a non-linear way. These findings, although preliminary, provide further evidence that antipsychotic treatment in patients with psychosis may be correlated with immunological changes but further research is needed.

Effect of the MTHFR C677T Polymorphism on Antipsychotic Drug Dosage and Treatment Response of Psychotic Patients in a Naturalistic Setting

The T allele of the methylene tetrahydrofolate reductase (MTHFR) C667T polymorphism (rs1801133) encodes an enzyme with decreased activity, increased folic acid requirements and elevated plasma homocysteine concentration. The same allele has been associated in the past with lower age of onset of schizophrenia and better response to antipsychotic treatment in patients of northern European descent. In this study, we have examined the association of MTHFR C667T with the age of onset, dose requirements and response to treatment in a group of Greek patients suffering from schizophrenia and other psychotic disorders. One hundred and four patients were recruited from the 2nd Department of Psychiatry of the Psychiatric Hospital of Thessaloniki, from July 2014 until October 2015, of which 96 were successfully genotyped for the polymorphism with a PCR-RFLP method. Response to antipsychotic treatment involving typical and atypical antipsychotics, with doses converted to chorpromazine equivalents (CPZeqs), was estimated by a follow-up assessment with PANSS after 4 weeks of treatment. In patients suffering from psychotic disorders other than schizophrenia the T allele of rs1801133 was significantly associated (P = 0.034) with better response to antipsychotic medication. Also, carriers of the T allele tended to receive lower drug doses than non-carriers (P = 0.069). These associations were independent of the effect of CYP2D6 genotype. No associations were detected in the subgroup of patients with diagnosis of schizophrenia. The polymorphism was not associated with age of onset in either subgroup. The MTHFR C667T polymorphism appears to affect response to treatment and antipsychotic dosage requirements but its effect is modulated by diagnosis and, presumably, the strength of the intervention.

Clozapine versus other antipsychotics during the first 18 weeks of treatment: A retrospective study on risk factor increase of blood dyscrasias

Blood dyscrasias excluding agranulocytosis received limited attention in antipsychotic-treated patients during the first 18 weeks of therapy, although severe clinical conditions have been reported in a few cases. We extracted data records of 285 Caucasian patients after 18 weeks of antipsychotic treatments to investigate risk factors of blood dyscrasias. We observed a higher risk to develop both transient and persistent anemia, neutrophilia and eosinophilia in clozapine-treated patients, whereas in those treated with other atypical antipsychotics when compared to a reference group under typical antipsychotics, emerged an increased risk for transient neutrophilia and eosinophilia. Male patients revealed a higher risk of persistent eosinophilia, neutrophilia, and leukocytosis. Concomitant treatments with mood stabilizers or benzodiazepines proved to be risk factors for transient anemia, antidepressants for transient eosinophilia. Severe complications emerged in 3 cases of agranulocytosis. Cross-tabulation analysis showed a higher probability of a poor response in clozapine-treated patients with persistent anemia and a positive with persistent neutrophilia and eosinophilia. Our data evidenced that emerging blood dyscrasias were not associated with critical adverse effects, and only agranulocytosis required a treatment interruption. Other atypical antipsychotics might represent a viable alternative to potentially harmful clozapine and typical antipsychotics at the onset of life-threatening haematological alterations.

Low-Dose of Bergamot-Derived Polyphenolic Fraction (BPF) Did Not Improve Metabolic Parameters in Second Generation Antipsychotics-Treated Patients: Results from a 60-days Open-Label Study.

Objectives: The nutraceutical approach to the management of metabolic syndrome (MetS) might be a promising strategy in the prevention of cardio-metabolic risk. Low-dose bergamot-derived polyphenolic fraction (BPF) has been proven effective in patients with MetS, as demonstrated by a concomitant improvement in lipemic and glycemic profiles. The present study was aimed to further explore, in a sample of subjects receiving second generation antipsychotics (SGAs), the effects on body weight and metabolic parameters of a low dose of BPF (500 mg/day) administered for 60 days.Methods: Twenty-eight outpatients treated with SGAs assumed BPF at single daily dose of 500 mg/day for 60 days. Body weight, BMI, fasting levels of glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were determined; moreover, Brief Psychiatric Rating Scale (BPRS) was administered.Results: Low-dose BPF administration did not change clinical and metabolic parameters, as well as clinical symptoms in the study sample. At the end of the trial, among completers (n = 24) only nine patients (37.5%) reached an LDL reduction >0 but <50%.Conclusions: Our results demonstrate that patients treated with SGAs may need higher BPF doses for obtaining the positive effects on body weight and metabolic parameters previously found in the general population at lower doses.

Association between prolactin gene polymorphism (–1149 G/T) and hyperprolactinemia in anti-psychotic treated patients with schizophrenia

Hyperprolactinemia (HPRL) is a classical side effect of anti-psychotic drugs. Extrapituitary prolactin (PRL) production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism – 1149 G/T (rs134,1239) in prolactin gene. We examined whether this polymorphism is associated with hyperprolactinemia in patients with schizophrenia. The experimental group comprised 443 patients with schizophrenia. The control group comprised 126 healthy persons. The PRL concentration was measured in serum using the AccuBind ELISA Microwells kit. The functional polymorphism – 1149 G/T (rs134,1239) of the PRL gene was genotyped using the The MassARRAY® system. Genotype and allele frequencies were compared using χ2 test. A total of 227 patients suffered from HPRL (98 males/129 females) according to the criteria of hyperprolactinemia. The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed that the frequency of G allele in patients with hyperprolactinemia is significantly higher than in patients without hyperprolactinemia (χ2 = 7.25; P = 0.007; OR = 1.44 [1.10–1.89]). Accordingly, the genotype GG was found to be more often in patients with hyperprolactinemia than without it (χ2 = 9.49; P = 0.009). A significant association of the polymorphic variant rs134,1239 with the development of hyperprolactinemia in patients with schizophrenia treated with anti-psychotic drugs was revealed. Therefore, the serum concentration of prolactin in anti-psychotic treatment patients with schizophrenia may also give an indication of the activity of gene regulating extrapituitary prolactin expression.The study was supported by the Russian Science Foundation, Grant 14-35-00023.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Polycystic ovarian syndrome in patients with schizophrenia treated with atypical anti-psychotics: A case control study

ObjectiveObjective was to compare the prevalence of probable polycystic ovarian syndrome (PCOS) in females treated with atypical anti-psychotics with normal controls.AimsTo compare the prevalence of PCOS in patients treated with atypical anti-psychotics and normal controls. To study the hormone profiles in these two groups.MethodsCases consisted of 102 reproductive age females with schizophrenia treated with atypical anti-psychotics for ≥6 months and had gained ≥10% body weight. Control group was 123 age and BMI matched females. Menstrual history, physical examination for hirsuitism, acne, androgenic alopecia, anthropometrics measures, Ultrasound abdomen and hormone analysis were done.ResultsMean age of cases = 33.17 years (SD 8.9) and controls = 33.08 years (SD 5.6). Mean BMI of cases = 25.92 (SD 5.2) and controls = 25.03 (SD 4.3). Polycystic ovarian morphology of ovaries on ultra sound scan was significantly more in cases 49 (48%) than controls 16 (13.%) (P &lt; 0.001). Probable PCOS was significantly more in atypical anti-psychotic treated females (n = 22, 21.56%) than in normal controls (n = 10, 8.13%) (P = 0.04). Atypical anti-psychotic treated patients with PCOS had significantly lower mean LH levels 6.69 mIU/L than those without PCOS 10.30 (P = 0.35). There was no significant difference in testosterone, FSH, prolactin, TSH and free T4 levels.ConclusionTreatment with atypical anti-psychotics is associated with higher prevalence of PCOS. This has not been reported previously. The hormonal profile in these patients may be different with low testosterone and LH levels.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Body and liver fat content and adipokines in schizophrenia: a magnetic resonance imaging and spectroscopy study.

Although antipsychotic treatment often causes weight gain and lipid abnormalities, quantitative analyses of tissue-specific body fat content and its distribution along with adipokines have not been reported for antipsychotic-treated patients. The purposes of the present study were to quantitatively assess abdominal and liver fat in patients with schizophrenia on antipsychotic treatment and age- and body mass index (BMI)-matched healthy controls and to evaluate their associations with plasma leptin and adiponectin levels. In 13 schizophrenia patients on antipsychotic treatment and 11 age- and BMI-matched controls, we simultaneously quantified visceral and subcutaneous fat content using T1-weighted magnetic resonance imaging and liver fat content by 1H magnetic resonance spectroscopy. Associations of tissue-specific fat content with plasma levels of leptin and adiponectin were evaluated. Plasma adiponectin level (μg/mL) was not statistically different between groups (7.02±2.67 vs. 7.59±2.92), whereas plasma leptin level (ng/mL) trended to be higher in patients than in controls (11.82±7.89 vs. 7.93±5.25). The values of liver fat (%), visceral fat (L), and subcutaneous fat (L) were 9.64±8.03 vs. 7.07±7.35, 4.41±1.64 vs. 3.31±1.97, and 8.37±3.34 vs. 7.16±2.99 in patients vs. controls, respectively. Liver fat content was inversely correlated with adiponectin in controls (r = - 0.87, p < 0.001) but not in patients (r = - 0.26, p = 0.39). In both groups, visceral fat was inversely associated with adiponectin (controls : r = - 0.66, p = 0.03; patients : r = - 0.65, p = 0.02), while subcutaneous fat was positively correlated with leptin (controls : r = 0.90, p < 0.001; patients : r = 0.67, p = 0.01). These findings suggest that antipsychotic treatment may disrupt the physiological relationship between liver fat content and adiponectin but does not essentially affect the associations of adiponectin and leptin with visceral and subcutaneous compartments.

No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.

Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found. The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.

63. Predicting Outcomes in Psychosis

Abstract Overall Abstract: A fundamental problem in the clinical management of psychosis is that it is difficult to predict outcomes on the basis of the patient’s clinical features. However, data from recent research suggest that a number of different neuroimaging measures and peripheral biomarkers may be used to distinguish patients who present with similar symptoms but have quite distinct clinical outcomes. This approach appears to be particularly promising in relation to two key clinical issues: predicting the onset of illness onset in people at high risk for psychosis and predicting the response to antipsychotic treatment in patients who have developed psychosis. Key findings from studies in these 2 areas of research will be reviewed, and the challenges associated with translating them into clinical practice will be discussed.

Atypical antipsychotics: recent research findings and applications to clinical practice: Proceedings of a symposium presented at the 29th Annual European College of Neuropsychopharmacology Congress, 19 September 2016, Vienna, Austria.

Available evidence suggests that second-generation atypical antipsychotics are broadly similar to first-generation agents in terms of their efficacy, but may have a more favourable tolerability profile, primarily by being less likely to cause extrapyramidal symptoms. However, atypical antipsychotics are variably associated with disturbances in the cardiometabolic arena, including increased body weight and the development of metabolic syndrome, which may reflect differences in their receptor binding profiles. Effective management of schizophrenia must ensure that the physical health of patients is addressed together with their mental health. This should therefore involve consideration of the specific tolerability profiles of available agents and individualization of treatment to minimize the likelihood of adverse metabolic sequelae, thereby improving long-term adherence and optimizing overall treatment outcomes. Alongside this, modifiable risk factors (such as exercise, diet, obesity/body weight and smoking status) must be addressed, in order to optimize patients' overall health and quality of life (QoL). In addition to antipsychotic-induced side effects, the clinical management of early nonresponders and psychopharmacological approaches for patients with treatment-resistant schizophrenia remain important unmet needs. Evidence suggests that antipsychotic response starts early in the course of treatment and that early nonresponse accurately predicts nonresponse over the longer term. Early nonresponse therefore represents an important modifiable risk factor for poor efficacy and effectiveness outcomes, since switching or augmenting antipsychotic treatment in patients showing early nonresponse has been shown to improve the likelihood of subsequent treatment outcomes. Recent evidence has also demonstrated that patients showing early nonresponse to treatment with lurasidone at 2 weeks may benefit from an increase in dose at this timepoint without compromising tolerability/safety. However, further research is required to determine whether these findings are generalizable to other antipsychotic agents.

Dysphagia with second-generation antipsychotics: A case report and review of the literature.

Background:All antipsychotics are associated with extrapyramidal symptoms (EPS). These can present as dysphagia, esophageal dysmotility, or aspiration, all of which may not be recognized as EPS.Case Report:A 62-year-old with schizophrenia, prescribed olanzapine 5 mg daily, presented agitated and endorsed difficulty swallowing. Speech therapy suggested her complaints were related to either reflux or dysmotility. Esophageal manometry showed her lower esophageal sphincter was not fully relaxing, and identified an esophagogastric junction outflow obstruction. Despite therapeutic dilation, oral intake remained poor. Following an increase in olanzapine, she developed EPS, her dysphagia worsened, and she was choking on food. Following a switch to aripiprazole her EPS and appetite improved, and she ceased complaining of dysphagia.Discussion:Dysphagia has been reported with first- and second-generation antipsychotics. A review of the second-generation antipsychotic literature identified case reports of dysphagia with clozapine (n = 5), risperidone (n = 5), olanzapine (n = 2), quetiapine (n = 2), aripiprazole (n = 1), and paliperidone (n = 1). Postulated mechanisms of antipsychotic-induced dysphagia include that it may be an extrapyramidal adverse reaction or related to anticholinergic effects of antipsychotics. Management of dysphagia includes discontinuing the antipsychotic, reducing the dose, dividing the dose, or switching to another antipsychotic. Complications of dysphagia include airway obstruction (eg, choking, asphyxia), aspiration pneumonia, and weight loss. Additional complications include dehydration, malnutrition, and nonadherence to oral medications.Conclusion:It is important to recognize symptoms of dysphagia and esophageal dysmotility in antipsychotic-treated patients. Intervention is necessary to prevent complications.

Analysis of differential gene expression mediated by clozapine in human postmortem brains

Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: GCLM, ZNF652, and GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.