Antipsychotic-treated Patients Research Articles

"Antipsychotic treatment in patients with dementia receiving palliative care: efficiency, fall risk and cognitive impact"

"Antipsychotic treatment in patients with dementia receiving palliative care: efficiency, fall risk and cognitive impact"

Pattern of expression of Toll like receptor (TLR)-3 and -4 genes in drug-naïve and antipsychotic treated patients diagnosed with schizophrenia

Toll like receptors (TLRs), a class of conserved immune molecules are crucially involved in initiating innate immune response to infection. TLR activation and subsequent inflammation are linked to pathogenesis of many brain disorders. Preliminary studies indicate a possible role of TLR-driven immuno-inflammatory responses in schizophrenia. However, gene expression data of TLRs in drug-naïve as well as antipsychotic treated patients diagnosed with schizophrenia are albeit limited. In this study, expression profile of TLR3 and TLR4 genes in peripheral blood mononuclear cells (PBMCs) was compared between drug-naïve patients diagnosed with schizophrenia (N = 31) and healthy controls (N = 30). In addition, the pattern of expression of TLR3 and TLR4 genes were also examined after three months of antipsychotic medication in patients. Compared to healthy controls, gene expression levels of only TLR4 (F = 3.87, p = 0.05, ηp2 = 0.06), not TLR3 (F = 0.17, p = 0.71, ηp2 = 0.003) was significantly up-regulated in drug-naïve patients. The changes in the levels of gene expression of TLR3 (t = 0.09, p = 0.93, d = 0.02) and TLR4 (t = 0.29, p = 0.77, d = 0.06) before and after antipsychotic medication were not found to be statistically significant. This finding suggests possible contribution of TLR4 in immunopathogenetic pathway of schizophrenia.

Achieving the Lowest Effective Antipsychotic Dose for Patients with Remitted Psychosis: A Proposed Guided Dose-Reduction Algorithm.

Continuing antipsychotic treatment in patients with schizophrenia under clinical remission remains controversial. Even though the mainstream opinion declares an outweighed balance against medication discontinuation, recent reviews and critiques suggest that some patients may remain symptom free and well functioning after stopping antipsychotics, but few predictors can identify who can try medication discontinuation, whilst no guidelines exist for reducing medication to reach the lowest effective dose safely. Analyzing the findings from studies employing different methodologies, adopting evidence from pharmacodynamic research, and observing dose reduction in stable patients, as well as taking inspiration from the metaphor of the Cantor set in natural philosophy, we introduce an alternative solution and propose a guided dose-reduction algorithm that follows a set of clear precautions and instructions. The algorithm recommends only a fraction (no more than 25%) of the dosage to be reduced at a time, with at least a 6-month stabilization period required before reducing another 25% of the dose. Patients are empowered to actively participate in decision making when they are ready for further dose tapering, or should they retreat to a previous dosage if warning signs of a relapse re-emerge. An intermittent or irregular dosing schedule can be used to adapt this algorithm to real-world practice. Our preliminary findings suggest that patients with remitted psychosis can do well along this path. We anticipate that this approach can help optimize the risk-benefit ratio and instill a hope in patients with schizophrenia that they can maintain in stable remission under a lower antipsychotic dose without an increased risk of relapse.

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Brexpiprazole has a low risk of dopamine D2 receptor sensitization and inhibits rebound phenomena related to D2 and serotonin 5-HT2A receptors in rats.

BackgroundLong‐term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic.MethodsThe maximum D2 receptor density (B max) and apomorphine (a D2 receptor agonist)‐induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max, 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine‐induced hyperlocomotion and (±)‐2,5‐dimethoxy‐4‐iodoamphetamine hydrochloride (DOI: a 5‐HT2A receptor agonist)‐induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days.ResultsHaloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti‐apomorphine‐induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max and apomorphine‐induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine‐induced hyperlocomotion and also DOI‐induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine‐induced hyperlocomotion.ConclusionBrexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5‐HT2A receptors after a repeated administration of risperidone.

The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis.

SummaryThe response to antipsychotic treatment in schizophrenia appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis. Randomised controlled trials comparing placebo and antipsychotics in acute treatment of schizophrenia listed in PubMed, EMBASE and PsycINFO from inception until November 30, 2018 were examined. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges’ g. In addition, individual patient data from two clinical trials was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors. 11,006 articles were identified. 66 met inclusion criteria, reporting on 17,202 patients. Compared with placebo, antipsychotic-treated patients demonstrated greater total symptom improvement (g=0.47, p<0.001) and reduced variability in symptomatic improvement for total (CVR=0.86, p<0.001), positive (CVR=0.89, p<0.001), and negative symptoms (CVR=0.86, p=0.001). Lower variability in antipsychotic-response was associated with studies published earlier (z=3.98, p<0.001), younger patients (z=3.07, p=0.002), higher dose treatments (z=-2.62, p=0.009), and greater mean-difference in symptom-change (z=-5.70, p<0.001). In the individual patient dataset (N=522 patients), antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response. Compared to placebo, antipsychotic treatment shows greater improvement and lower variability of change in total, positive and negative symptoms. This is contrary to the hypothesis that there is a subtype of antipsychotic non-responsive schizophrenia. Instead our findings, provide evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

Psychiatrist and Psychiatric Pharmacists Beliefs and Preferences for Atypical Antipsychotic Treatments in Patients With Schizophrenia and Bipolar Disorders

Background: Selection of schizophrenia or bipolar disorder treatments is complicated by treatment-effect heterogeneity. Objectives: This study assessed how clinicians’ beliefs and health system/ insurace policies impact choice of atypical antipsychotic agent in schizophrenia and bipolar disorder. Methods: A cross-sectional survey was conducted of members of the American College of Clinical Pharmacy and College of Psychiatric & Neurologic Pharmacists. Beliefs regarding atypical antipsychotic effectiveness and safety, impact of comorbidity on drug selection, and factors influencing atypical antipsychotic therapy selection were assessed. Results: Twenty-four psychiatric pharmacists and 18 psychiatrists participated. Mean age was 39.6 years, 57.1% were female. Most clinicians (64.3%) believed medication effectiveness and safety equally important, while 26.2% believed safety and 9.4% believed effectiveness more important. The most important medication properties for schizophrenia were reducing positive symptoms (92.7%) and hospitalizations (87.8%) and for bipolar disorder were reducing manic episodes (87.8%), episode relapse (53.7%), and hospitalizations (53.7%). Agranulocytosis (78.1%), arrhythmias (70.7%), and extrapyramidal side effects (68.3%) were most concerning. Restrictions affected antipsychotic choice at 80.5% of sites and were believed to affect medication adherence (55.0%) and outcomes (53.4%). Conclusion: Efficacy and safety were considered equally important when choosing atypical antipsychotics. Formulary restrictions were perceived as impacting treatment choice and outcomes.

Functional brain networks in never-treated and treated long-term Ill schizophrenia patients.

This study compared the topological organization of brain function in never-treated and treated long-term schizophrenia patients. In a cross-sectional study, 21 never-treated schizophrenia patients with illness duration over 5 years, 26 illness duration-matched antipsychotic-treated patients and 24 demographically-matched healthy controls underwent a resting-state functional magnetic resonance imaging (MRI) scan. The topological properties of brain functional networks were compared across groups, and then we tested for differential age-related effects in regions with significant group differences. Both never-treated and antipsychotic-treated schizophrenia patient groups showed altered nodal centralities in left pre-/postcentral gyri relative to controls. Never-treated patients demonstrated reduced global efficacy, decreased nodal centralities in right amygdala/hippocampus and bilateral putamen/caudate relative to antipsychotic-treated patients and controls. No significant relationships of age and altered functional metrics were seen in either patient group, and no alterations were greater in the treated group. These findings provide insight into brain function deficits over the longer-term course of schizophrenia independent from potential effects of antipsychotic medication. The presence of greater alterations in never-treated than treated patients suggests that long-term antipsychotic treatment may partially protect or enhance brain global and nodal topological function over the course of schizophrenia, notably involving the amygdala, hippocampus, and striatum that have long been associated with the disorder.

Curcumin as Add-On to Antipsychotic Treatment in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.

Introduction of old and new generations of antipsychotics leads to significant improvements in the positive symptoms of schizophrenia. However, negative symptoms remain refractory to conventional trials of antipsychotic therapy. Recently, there were several open clinical human trials with curcumin. Curcumin is a natural polyphenol, which has a variety of pharmacological activities, including antioxidative and neuroprotective effects. The studies showed that curcumin improved the negative symptoms of schizophrenia. The purpose of our study was to examine the efficacy of curcumin as an add-on agent to regular antipsychotic medications in patients with chronic schizophrenia. Thirty-eight patients with chronic schizophrenia were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 3000 mg/d curcumin or placebo combined with antipsychotics from January 2015 to February 2017. The outcome measures were the Positive and Negative Symptoms Scale (PANSS) and the Calgary Depression Scale for Schizophrenia. Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. There was a significant response to curcumin within 6 months in total PANSS (P = 0.02) and in the negative symptoms subscale (P = 0.04). There were no differences in the positive and general PANSS subscales, and the Calgary Depression Scale for Schizophrenia scores between the treatment and placebo groups. No patient complained of any adverse effect. The promising results of curcumin as an add-on to antipsychotics in the treatment of negative symptoms may open a new and safe therapeutic option for the management of schizophrenia. However, these results should be replicated in further studies.ClinicalTrials.gov Identifier: NCT02298985.

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density.

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score < −2, and 23% of patients (17% of women and 29% of men) displayed −2.5 < T-scores < –1 indicating osteopenia, but none had osteoporosis. After treatment, PINP decreased at trend level significance (P = 0.05), and body mass index BMD increased for L2–L4 (P = 0.016). No changes in bone markers were significant after correction for mean prolactin levels.Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin.

No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia.

AKT1 and GSK3B take part in one of the intracellular cascades activated by the D2 dopamine receptor (DRD2). This receptor is antagonized by antipsychotics and plays a role in the pathogenesis of antipsychotic-induced tardive dyskinesia (TD). The present study investigated association of several polymorphisms in the two candidate genes, AKT1 and GSK3B, with TD in antipsychotic-treated patients with schizophrenia. DNA samples from 449 patients from several Siberian regions (Russia) were genotyped, and the results were analyzed using chi-squared tests and analyses of variance. Antipsychotic-induced TD was not associated with either of the tested functional polymorphisms (rs334558, rs1130214, and rs3730358). Despite regulation of AKT1 and GSK3B by DRD2, we found no evidence that these two kinases play a major role in the pathogenesis of antipsychotic-induced TD. These results agree with previously published data and necessitate further exploration of other pathogenic mechanisms, such as neurotoxicity due to excessive dopamine metabolism.

Hospitalization risk factors in antipsychotic-treated schizophrenia, bipolar I disorder or major depressive disorder.

To examine hospitalization risk factors in antipsychotic-treated patients with schizophrenia, bipolar I disorder (BD-I) or major depressive disorder (MDD). Using Truven Health MarketScan® Commercial, Medicaid and Medicare Supplemental data (01/01/2012-06/30/2016), logistic regression models were performed to identify risk factors for both psychiatric and all-cause hospitalization in three separate analyses. Significant risk factors included prior hospitalization (schizophrenia: odds ratio [95% CI]: 2.83 [2.50-3.21; psychiatric]; 2.58 [2.31-2.87; all-cause]; BD-I: 2.42 [2.23-2.63]; 2.09 [1.96-2.23]; MDD: 2.81 [2.49-3.16]; 2.21 [2.03-2.40]), previous antipsychotic treatment (schizophrenia: 1.71 [1.52-1.93]; 1.31 [1.18-1.46]; BD-I: 1.33 [1.23-1.44]; 1.22 [1.14-1.30]; MDD: 1.31 (1.11-1.54); 1.17 (1.04-1.32) and substance abuse (schizophrenia: 1.42 [1.27-1.60]; 1.37 [1.23-1.53]; BD-I: 1.72 [1.58-1.86]; 1.61 [1.50-1.72]; MDD: 1.90 [1.68-2.15] and 1.55 [1.41-1.71]). Prior hospitalization, previous antipsychotic treatment and substance abuse were associated with increased hospitalization risk in schizophrenia, BD-I or MDD.

Adesão à terapêutica nos doentes com esquizofrenia: uma revisão da literatura

Resumo: Introdução: Avaliar a adesão ao tratamento com agentes antipsicóticos em doentes com esquizofrenia é um desafio para qualquer médico psiquiatra, dada a subjetividade inerente ao tema. Apesar disso, a falta de adesão à terapêutica é prejudicial para o curso clínico da doença, resultando num risco aumentado de agudizações da doença e de internamentos hospitalares. O objetivo do presente estudo é rever a literatura corrente relativa aos fatores que influenciam a adesão ao tratamento antipsicótico em doentes com esquizofrenia. Métodos: Foi revista a literatura escrita em inglês entre 2006 e 2016 integralmente disponível no PubMed/MEDLINE que avaliasse potenciais fatores de risco para a adesão ao tratamento em doentes adultos (com mais de 18 anos) com esquizofrenia, através das palavras-chave: adherence, nonadherence, compliance, noncompliance, schizophrenia, psychosis, antipsychotic, neuroleptic. Resultados: Foram incluídos 39 estudos na revisão final. A média dos níveis de adesão ao tratamento foi de 32%. Foram identificados os seguintes fatores de risco para a falta de adesão ao tratamento: idade jovem, abuso de substâncias, psicopatologia psicótica presente, ausência de insight sobre a doença e a necessidade de tratamento, atitudes negativas perante o tratamento, relação médico-doente de má qualidade ou falta de apoio social e familiar. Conclusões: As intervenções direcionadas para melhorar a adesão à terapêutica devem ser individualizadas para cada doente, baseadas numa história clínica completa, para que todos os aspetos individuais que contribuam para esta variável possam ser convenientemente avaliados.

Baseline brain structural and functional predictors of clinical outcome in the early course of schizophrenia.

Although schizophrenia is considered a brain disorder, the role of brain organization for symptomatic improvement remains inadequately defined. We investigated the relationship between baseline brain morphology, resting-state network connectivity and clinical response after 24-weeks of antipsychotic treatment in patients with schizophrenia (n=95) using integrated multivariate analyses. There was no significant association between clinical response and measures of cortical thickness (r=0.37, p=0.98) and subcortical volume (r=0.56, p=0.15). By contrast, we identified a strong mode of covariation linking functional network connectivity to clinical response (r=0.70; p=0.04), and particularly to improvement in positive (weight=0.62) and anxious/depressive symptoms (weight=0.49). Higher internal cohesiveness of the default mode network was the single most important positive predictor. Key negative predictors involved the functional cohesiveness of central executive subnetworks anchored in the frontoparietal cortices and subcortical regions (including the thalamus and striatum) and the inter-network integration between the default mode and sensorimotor networks. The present findings establish links between clinical response and the functional organization of brain networks involved both in perception and in spontaneous and goal-directed cognition, thereby advancing our understanding of the pathophysiology of schizophrenia.

White Matter Abnormalities in Never-Treated Patients With Long-Term Schizophrenia.

This study tested for differences of white matter integrity between treated and never-treated long-term schizophrenia patients, matched on illness duration, and for differential changes in relation to age in these two groups relative to healthy comparison subjects. This cross-sectional diffusion tensor imaging study included 31 never-treated and 46 matched antipsychotic-treated patients with long-term schizophrenia and 58 healthy comparison subjects. Fractional anisotropy measures of white matter tracts were extracted and compared. Linear regression analysis was used to explore the association between age and fractional anisotropy among the three groups. Fractional anisotropy significantly differed among the three groups in 14 of 20 white matter tracts defined in the Johns Hopkins University white matter template. Never-treated patients displayed greater reduction of fractional anisotropy than antipsychotic-treated patients in the left anterior thalamic radiation, the left cingulum-hippocampus pathway, the splenium and genu of the corpus callosum, and the left superior longitudinal fasciculus, and greater fractional anisotropy in the right uncinate fasciculus. Both patient groups showed multiple reductions relative to healthy comparison subjects. Never-treated patients showed an accelerated and clinically relevant age-related reduction of fractional anisotropy in the genu of the corpus callosum. These psychoradiological findings provide insight into the regional distribution of white matter deficits in the years after illness onset in long-term schizophrenia. Findings of greater impairments in never-treated patients, and a greater age-related reduction in the genu of the corpus callosum in these patients, suggest that long-term antipsychotic treatment does not adversely affect white matter tracts over the longer-term course of illness and may confer benefits.

Dysconnectivity of Large-Scale Functional Networks in Early Psychosis: A Meta-analysis.

Increasingly, studies have identified abnormalities in the functional connectivity (FC) of large-scale neural networks in early psychosis, but the findings thus far have been inconclusive. Therefore, the aim of this study was to identify robust alterations in FC of the default mode (DMN), salience (SN), and central executive networks (CEN), in patients with first-episode psychosis (FEP) using a meta-analytic approach. Included studies were required to be resting-state, seed-to-whole brain, FC neuroimaging studies, comparing FEP patients to healthy controls (HC), with seeds within the boundaries of the region-of-interest networks. Peak effect coordinates and peak t, z, or p values were meta-analyzed using Seed-based d Mapping software. The DMN seeds primarily displayed within-network hypoconnectivity (largest clusters including the middle orbital gyrus; and ventral anterior cingulate gyrus). The SN seeds displayed hypoconnectivity with regions in the DMN and CEN (largest clusters located in the bilateral middle temporal gyri). Review of the limited CEN data revealed hypo- and hyperconnectivity across the networks. Negative symptoms were positively correlated with all DMN FC abnormalities in the FEP group. Antipsychotic-treated patients displayed greater hypoconnectivity than antipsychotic-naïve patients between both the DMN/SN seeds and prefrontal regions. These findings provide substantial evidence of widespread resting-state FC abnormalities of the DMN, SN, and CEN in early psychosis; particularly implicating DMN and SN dysconnectivity as a core deficit underlying the psychopathology of psychosis. Additionally, we highlight the importance of disentangling connectivity abnormalities resulting from disease processes, from those that result from antipsychotic treatment.

Impact of NTRK2, DRD2 and ACE polymorphisms on prolactin levels in antipsychotic-treated patients with first-episode psychosis.

Hyperprolactinemia is a common side-effect of antipsychotics (APs), which may trigger serious secondary problems and compromise the adherence to treatment which is crucial for prognosis, especially in patients presenting with a first-episode of psychosis (FEP). We evaluated, in some cases for the first time, the effect of polymorphisms in multiple candidate genes on serum prolactin (PRL) levels in an AP-treated FEP cohort recruited in the multicenter PEPs study (Phenotype - genotype and environmental interaction; Application of a predictive model in first psychotic episodes). PRL concentration was measured in serum from 222 patients. A total of 167 polymorphisms were selected in 23 genes. Genetic association analysis was performed in the whole sample and also in homogenous subgroups of patients treated with APs with a high (N = 101) or low risk (N = 95) of increasing PRL release, which showed significant differences in their PRL levels. After Bonferroni correction, polymorphisms in NTRK2, DRD2 and ACE genes were associated with PRL concentration. Our results give more support to the impact of DRD2, but also of other genes related to dopamine availability such as ACE. Moreover, this study provides the first evidence for the involvement of NTRK2, which suggests that pathways other than the ones related to dopamine or serotonin may participate in the AP-related PRL levels.

The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial.

Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial. This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly. There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group. At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects. https://clinicaltrials.gov/ct2/show/NCT00588731.

31.3 CLINICAL UTILITY OF MRI SCANNING IN FIRST EPISODE PSYCHOSIS

BackgroundThe response to antipsychotic treatment in patients with psychosis is difficult to predict on the basis of the patient’s clinical features. As a result, patients are generally treated in a similar way, even though their response can vary dramatically.Recent neuroimaging studies suggest that the pattern of brain abnormalities in patients with psychosis may vary in relation to treatment response. However, in many of these studies, patients had already been treated, and it was unclear if this had contributed to the findings.MethodsIn Optimise we obtained a structural Magnetic Resonance Imaging data from n=203 minimally treated patients at their first presentation for a psychotic episode. All patients then started treatment with standard doses of amisulpride. After 4 weeks, 56% were in symptomatic remission.ResultsWe identified brain neoplasms in 3 patients, but the most common radiological findings were non-specific white matter T2-weighted hyperintensities (n=48); cavum septi pelludici (n=34); and arachnoid cysts (n=9).Cortical thickness, surface area, and gyrification were measured using Freesurfer (). Preliminary analyses applying machine learning to these measures at baseline indicated that symptomatic remission at 4 weeks could be predicted with an accuracy of 64%.DiscussionThese findings suggest that radiological assessment can identify abnormalties that require an alternative to conventional treatment in a minority of patients. In most patients with psychosis, neuroimaging abnormalities may be better detected using statistical approaches, and these have greater potential for the stratification of patients according to future antipsychotic response.

T45. A COMPARISON OF SCHIZOPHRENIA RELAPSE RATES OF 3 PALIPERIDONE FORMULATIONS, ONCE-DAILY, ONCE-MONTHLY AND ONCE EVERY-3-MONTH: POST-HOC ANALYSIS FROM 3 RANDOMIZED CONTROLLED TRIALS

BackgroundPoor adherence to antipsychotic treatment in patients with schizophrenia can result in recurrent relapses, worsening disease, functional impairment and reduction in treatment responsiveness. Long-acting antipsychotic formulations can maintain therapeutic plasma levels for longer durations, reducing dosing frequency and delaying time to relapse compared to oral formulations. Consequently, relatively lower rates of relapse can be expected in patients on long-acting injectables (LAIs) who have discontinued treatment versus those discontinuing oral medications of the same antipsychotic. However, there is no available evidence to support this association. In this post hoc analysis, the percentage of patients who relapsed and the time to relapse for three different formulations of the same molecule (oral paliperidone extended release [ER]; paliperidone palmitate once monthly [PP1M] LAI, and paliperidone palmitate three monthly [PP3M] LAI) were evaluated in adults with schizophrenia, comparing the active and placebo arms.MethodsData from three similarly designed, randomized, double-blind, placebo-controlled relapse prevention studies in adult patients with schizophrenia (DSM-IV-TR criteria) with similar inclusion/exclusion and relapse criteria were analyzed. Patients stabilized during an open-label stabilization phase with either paliperidone ER, PP1M or PP3M were then randomized to receive either placebo (analogous to non-adherent patients in the real-world) or the same active treatment used during stabilization phase (analogous to adherent patients). The primary outcome in each study was the time to relapse after entering the randomization phase, estimated using Kaplan-Meier method. In this report, the percentage of patients who relapsed as well as time to relapse in the three studies were indirectly compared.ResultsIn total 922 patients were included in this analysis, 473 continued to receive the same active treatment and 449 patients were randomized to receive placebo. The percentage of patients who relapsed was lowest with PP3M as compared with PP1M and paliperidone ER in both the active treatment group (PP3M, 9% < PP1M, 18% < paliperidone ER, 22%) and placebo group (PP3M, 29% < PP1M, 48% < paliperidone ER, 52%) patients. The post discontinuation median time to relapse (95% confidence interval) in placebo group was highest with PP3M, 395 days (274 days to not reached) > PP1M, 172 days (134 to 222 days) > paliperidone ER, 58 days (42 to 114 days) but was not estimable in the paliperidone group.DiscussionTreatment with longer acting formulations of paliperidone are associated with lower percentage of relapse and longer time to relapse in patients with schizophrenia. Lower percentage of patients with relapse observed with LAI therapy (PP1M and PP3M) could presumably be due to ensured therapeutic plasma levels. The lower percentage of relapse observed with PP3M treatment as compared with PP1M and oral paliperidone ER treatment in the placebo group could be advantageous to non-adherent patients, as this mimics the real-world scenario where patients discontinue their antipsychotics suddenly. These findings are of relevance in schizophrenia patients as fewer and delayed relapses over the course of a lifetime of schizophrenia may provide higher protection against grey matter damage and help preserve functioning.