Improvement In Positive Symptoms Research Articles

Predicting Symptomatic and Functional Improvements over 1 Year in Patients with First-Episode Psychosis Using Resting-State Electroencephalography

ObjectiveAlthough early intervention from the beginning of a psychotic episode is essential for a better prognosis, biomarkers predictive of symptomatic and functional improvement in early psychotic disorders are lacking. This study aimed to investigate whether the spectral power of resting-state electroencephalography (EEG) can be used as a predictive marker of the 1-year prognosis in patients with first-episode psychosis (FEP). MethodsTwenty-four patients with FEP and matched healthy control (HC) subjects were examined with resting-state EEG at baseline. The symptomatic severity and functional status of FEP patients were assessed at baseline and reassessed after 1 year of usual treatment. Repeated measures analysis of variance was conducted to compare EEG spectral powers across the groups. Multiple regression analysis revealed EEG spectral powers predictive of symptomatic and functional improvement in FEP patients at the 1-year follow-up. ResultsDelta band power in the frontal and posterior regions was significantly higher in patients with FEP than in HCs. Higher delta band power in the posterior region predicted later improvement of positive symptoms and general functional status. Lower delta band power in the frontal region predicted improvement of negative symptoms and general functioning after 1 year. ConclusionThese results suggest that increased delta absolute power is observed from the beginning of psychotic disorders. Furthermore, decreased delta power in the frontal region and increased delta power in the posterior region might be used as a predictive marker of a better prognosis of FEP, which would aid early intervention in clinical practice.

Treatment outcomes and associations in an adolescent-specific early intervention for psychosis service.

Compared with adult onset psychosis, adolescent psychosis has been associated with poorer outcomes in terms of social and cognitive functioning and negative symptoms. Young people experiencing first episode psychosis have developmental needs that frequently pre-date and are compounded by psychosis onset (a previous study). There is a lack of published studies of adolescent onset psychosis and further information is needed so that developmentally appropriate interventions can be developed. We report an observational naturalistic cohort study of an adolescent specific service, the Early Psychosis Support service (EPSS). We examined baseline demographic and clinical variables, treatments outcomes and predictors of outcome for this population. The mean age of our sample was 16.3 years. Median duration of untreated illness (DUI) was 88 weeks, and median duration of untreated psychosis (DUP) was 16 weeks. We found significant improvements in positive symptoms, negative symptoms, disorganization, excitement, emotional distress and depression from 0 to 12 months. We found that baseline positive symptoms and DUI significantly predicted positive symptoms at 12 months and only negative symptoms at baseline predicted 12-month negative symptoms. Our finding that specialist early intervention for adolescents experiencing psychosis is effective suggests that such treatment should be routinely offered in line with existing clinical guidelines. Our finding that DUI is predictive of poorer outcome at 12 months suggests that even earlier intervention from a specialist team may further improve treatment outcomes.

Targeting relapse prevention and positive symptom in first-episode schizophrenia using brief cognitive behavioral therapy: A pilot randomized controlled study

The present study aimed to provide preliminary evaluation of the effectiveness of a brief CBT intervention focusing on relapse prevention and positive symptom in a Chinese first episode schizophrenia (FES) population. This randomized controlled trial recruited eighty outpatients with FES (as determined using the DSM-IV), aged 16–45 years, and on a current atypical antipsychotic. Patients were randomized to either 10 sessions of individual CBT (intervention group) adjunctive to treatment as usual (TAU) or TAU alone (control group). Outcome assessment of symptoms, relapse, hospitalization, insight and social functioning were administered at baseline and then post treatment (10 weeks), and at 6-month and 12-month follow ups. At 12 months, patients in the intervention group had significantly greater improvements in positive symptoms, general psychopathology and social functioning, as well as significantly lower rates of relapse, compared to the control group. Although patients in both groups demonstrated significantly improved negative symptom and insight scores from baseline, no group differences were found.This RCT demonstrates that FES patient can greatly benefit from CBT designed to target relapse prevention and positive symptom, with improvements sustained for 1 year following treatment.

A Dissociation in Effects of Risperidone Monotherapy on Functional and Anatomical Connectivity Within the Default Mode Network.

Respective changes in functional and anatomical connectivities of default mode network (DMN) after antipsychotic treatment have been reported. However, alterations in structure-function coupling after treatment remain unknown. We performed diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging in 42 drug-naive first-episode schizophrenia patients (FESP) both at baseline and after 8-weeks risperidone monotherapy, and in 38 healthy volunteers. Independent component analysis was used to assess voxel-wise DMN synchrony. A 3-step procedure was used to trace fiber paths between DMN components. Structure-function couplings were assessed by Pearson's correlations between mean fractional anisotropy and temporal correlation coefficients in major tracts of DMN. Pretreatment, FESP showed impaired functional connectivity in posterior cingulate cortex/precuneus (PCC/PCUN) and medial prefrontal cortex (mPFC), but no abnormalities in fibers connecting DMN components. After treatment, there were significant increases in functional connectivities of PCC/PCUN. Increases in functional connectivity between PCC/PCUN and mPFC correlated with improvement in positive symptoms. The structure-function coupling in tracts connecting PCC/PCUN and bilateral medial temporal lobes decreased after treatment. No alterations in DMN fiber integrity were detected. This combination of functional and anatomical findings in FESP contributes novel evidence related to neurobehavioral treatment effects. Increased functional connectivities between PCC/PCUN and mPFC may be treatment response biomarkers for positive symptoms. Increases in functional connectivities, no alterations in fiber integrity, combined with decreases in structural-functional coupling, suggest that DMN connectivities may be dissociated by modality after 8-week treatment. Major limitations of this study, however, include lack of repeat scans in healthy volunteers and control group of patients taking placebo or comparator antipsychotics.

ECT-induced brain plasticity correlates with positive symptom improvement in schizophrenia by voxel-based morphometry analysis of grey matter

BackgroundElectroconvulsive therapy (ECT) is often considered as an augmentation of antipsychotic treatment for schizophrenia in drug-refractory cases. However, the mechanisms underlying the observed therapeutic effects are still not understood. ObjectiveWe aimed to investigate changes in whole brain grey matter volume (GMV) before and after modified ECT. GMV was determined using voxel-based morphometry (VBM) whole brain analysis. Correlations of brain structural changes with clinical improvement were also investigated. MethodsTwenty-one schizophrenia patients treated with a full course of ECT combined with antipsychotics (ECT group) and 21 schizophrenia patients treated only with antipsychotics (Drug group) were observed in parallel. Magnetic resonance imaging scans were performed at baseline (T1) and follow-up (T2) for each patient. Data were compared to a healthy control group (HC group) of 23 persons who were only scanned at baseline. Demographic data were matched between the three groups. ResultsSignificant interactions of group by time were found within four brain regions: the left parahippocampal gyrus/hippocampus, right parahippocampal gyrus/hippocampus, right temporal_pole_mid/superior temporal gyrus, and right insula. Post-hoc analysis revealed an increase of GMV across all four regions amongst ECT group, but a decrease of GMV within the Drug group. Furthermore, the ECT group showed a significant positive correlation of GMV change in the right parahippocampal gyrus/hippocampus with a reduction of positive subscore in the positive and negative syndrome scale. Both treatment groups did not differ significantly in terms of GMV from the HC group in these regions either at T1 or at T2. ConclusionOur findings indicate that ECT may induce brain plasticity as indexed by grey matter volume change during the treatment of schizophrenia via distinct mechanics from those by antipsychotic medications. ECT may ameliorate the positive psychotic symptoms of patients suffering from schizophrenia by preferentially targeting limbic brain areas such as the parahippocampal gyrus/hippocampus.

Adjunctive nutrients in first-episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms.

AimThe effects of nutrient‐based treatments, including adjunctive vitamin or antioxidant supplementation, have been explored extensively in long‐term schizophrenia. However, no systematic evaluation of trials in “first‐episode psychosis” (FEP) has been conducted, despite the potential benefits of using these treatments during the early stages of illness. Therefore, we aimed to review all studies examining efficacy, tolerability and the biological mechanisms of action, of nutrient supplementation in FEP.MethodsA systematic review of electronic databases was conducted from inception to July 2017. All information on feasibility, clinical outcomes and mechanistic findings from nutrient supplementation clinical trials was extracted and systematically synthesized.ResultsEleven studies with a total of 451 patients with FEP (from 8 independent randomized controlled trials) were eligible for inclusion. Six studies examined omega‐3 fatty acids, with inconsistent effects on psychiatric symptoms. However, mechanistic studies found significant improvements in hippocampal neuronal health and brain glutathione. Antioxidants “n‐acetyl cysteine” (n = 1) and vitamin C (n = 2) also improved oxidative status in FEP, which was associated with reduced psychiatric symptoms. No benefits were found for vitamin E (n = 1). Finally, one study trialling the amino acid taurine, showed significant improvements in positive symptoms and psychosocial functioning.ConclusionThere is preliminary evidence that taurine improves outcomes in FEP, whereas effects of omega‐3 and antioxidant vitamins/amino‐acids are inconsistent; perhaps mainly benefitting patients with high levels of oxidative stress. Future studies should evaluate multifaceted dietary and supplementation interventions in FEP; targeting‐specific nutritional deficits and the range of aberrant biological processes implicated in the disorder.

Adjunctive cannabidiol shows promise in trial for schizophrenia

A Phase 2 double‐blind, placebo‐controlled trial involving 88 patients with schizophrenia has found that cannabidiol used as adjunctive therapy with an antipsychotic resulted in significant improvement in positive symptoms over placebo. Treating clinicians also were more likely to report patient improvement for participants receiving adjunctive cannabidiol than for patients receiving adjunctive placebo.

Selective noradrenaline reuptake inhibitors for schizophrenia.

Selective noradrenaline reuptake inhibitors for schizophrenia.

Efficacy and safety of MIN-101: A new drug for the treatment of negative symptoms in schizophrenia a 12-week randomized, double blind, placebo-controlled trial

ObjectiveTo compare the efficacy, safety, and tolerability of MIN-101, a compound with high affinities for sigma 2 and 5-HT 2A receptors, to placebo in treating negative symptoms, in stabilized patients with schizophrenia.MethodsThis multi-national phase 2b trial enrolled 244 patients with schizophrenia who were symptomatically stable for ≥ 3 months prior to entering the trial and had scores ≥ 20 negative subscale of the PANSS. Patients were randomized to monotherapy with MIN-101 32 mg/day, MIN-101 64 mg/day or placebo in a 1:1:1 ratio. The primary endpoint was the PANSS negative symptom score based on the five factors (pentagonal) model.ResultsStatistically significant reduction in the primary endpoint score was demonstrated for MIN-101 32 mg and 64 mg compared to placebo (P ≤ 0.022, ES 0.45 and ≤ 0.003, ES 0.58, respectively). This was supported by similar effects on most of the secondary measurements including: the PANSS three factors negative symptoms subscale, PANSS total score, CGI, BACS, CDSS, and PSP. There were no statistically significant differences in PANSS positive subscale scores between MIN-101 and placebo. No weight gain or clinically significant changes in vital sings, prolactin levels, routine laboratory values, metabolic indices and extrapyramidal symptom scores (EPS) were observed.ConclusionsSince positive symptoms and EPS did not change, the improvement in negative symptoms was not secondary to improvement in positive symptoms or EPS, suggesting that MIN-101 might be the first specific treatment to have a direct effect on negative symptoms.Disclosure of interestI have received consultant fees from Minerva Neuroscience the sponsor of this trial and own stock of Minerva Neuroscience

N-acetyl-cysteine in a double-blind randomized placebo-controlled trial: Towards biomarker guided treatment in early psychosis

PurposeRecent evidence points to a critical role of redox dysregulation induced oxidative stress in the pathophysiology of early phases of schizophrenia. An add-on trial with n-acetyl-cysteine (NAC) led to a reduction in negative symptoms in chronic schizophrenia patients. Aim of this study was to explore impact of addition of NAC to standard treatment in early psychosis (EP) patients.MethodsDouble-blind, randomized, placebo-controlled trial of addition of NAC, 2700 mg daily, to antipsychotic treatment over 6 months. Monthly assessment of PANSS, GAF, SOFAS and antipsychotics treatment; quantification of brain glutathione levels (GSHmPFC) by 1H-magnetic-resonance-spectroscopy and of blood cells glutathione (GSHBC) and glutathione peroxidase activity (GPxBC) as marker of oxidation status at the beginning and end of treatment.ResultsOverall, 63 patients were included. Spectroscopy data showed that GSHmPFC increased by +23% in the NAC group, while it tended to decrease by −5% in the placebo group (P = 0.005). No significant difference between NAC and placebo was observed on global changes in negative symptoms, positive symptoms or functional outcome. However, in patients with high-baseline oxidation status (GPxBC>22.3U/gHb), subgroup explorations revealed an improvement of positive symptoms over time compared to patients with low-baseline GPx (P = 0.02).ConclusionsWhile addition of NAC induced an increase of brain GSH, it had no impact on symptomatic and functional outcome in EP patients. However, in patients with high oxidation status, addition of NAC leads to significantly greater improvement in positive symptoms. Future studies on antioxidant interventions in EP should consider biomarker-guided treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

17. Effects of Cariprazine on Negative Symptoms, Cognitive Impairment, and Prosocial Functioning in Patients With Predominant Negative Symptoms: Post Hoc Analysis of a Phase III, Placebo-, and Active-Controlled Study

Abstract Background: Negative symptoms and cognitive deficits are core symptoms of schizophrenia that have proven to be difficult to treat and are associated with poor social/vocational functioning. Cariprazine (CAR), a D3/D2 receptor partial agonist, is approved in the United States for the treatment of schizophrenia in adults. This post hoc analysis of a Phase 3, randomized, double-blind, placebo- and active-controlled CAR study in adults with acute exacerbation of schizophrenia evaluated the effects of CAR on positive, negative, cognitive, and prosocial functioning domains in a subset of patients with predominant negative symptoms (PNS). Methods: Randomized patients received 6 weeks of double-blind treatment with CAR 3 mg/d, CAR 6 mg/d, aripiprazole 10 mg/d (ARI), or placebo (PBO). For post hoc analyses, patients with PNS were identified using baseline Positive and Negative Syndrome Scale factor scores (PANSS-FS) for positive symptoms (score ≤19; mild to moderate), negative symptoms (score ≥24; moderate to severe), and cognitive impairment (score ≥27; severe). Efficacy parameters included change from baseline to Week 6 in PANSS total score and PANSS-FS for negative, cognitive, and prosocial domains. Results: In all, 131 of 604 randomized patients met criteria for PNS (placebo = 35; CAR 3 mg/d = 27; CAR 6 mg/d = 34; ARI = 35). For CAR 6 mg/d, least squares mean differences (LSMDs) of change from baseline to Week 6 versus placebo were statistically significant on the PANSS total score (-13.9, P = .0132), and negative (-3.3, P = .0112), cognitive (-1.6, P = .0092), and prosocial (-2.9, P = .0035) factor scores. For CAR 3 mg/d, LSMDs versus placebo at Week 6 were statistically significant on the PANSS total score (-14.0; P = .0156), and cognitive (-1.5, P = .0164) and prosocial (-2.5, P = .0187) factor scores. For the negative symptoms factor score, numerical improvement was seen for CAR 3 mg/d over placebo, but the LSMD was not statistically significant at Week 6 (-2.6, P = .0515). In contrast, LSMDs for aripiprazole versus placebo were not statistically significant on PANSS total score (-9.6, P = .0800), negative (-0.6, P = .6449), cognitive (-0.6, P = .3108), or prosocial factor scores (-1.1, P = .2482). In addition, on PANSS-FS for negative symptoms, the LSMD between CAR 6 mg/d and ARI met statistical significance (-2.8, P = .0315). Conclusion: Cariprazine significantly improved overall schizophrenia symptoms, as well as negative, cognitive, and prosocial function versus placebo, in a subset of patients with PNS. These results suggest that cariprazine may be an effective treatment option for the negative symptoms of schizophrenia and its associated domains. Limitations of this analysis include the short duration (6 weeks) for evaluation of negative symptom improvement and the potential that improvements in at least some of the negative symptoms may have been secondary to improvements in positive symptoms.

111. Efficacy and Safety of MIN-101: A New Drug for the Treatment of Negative Symptoms in Schizophrenia. A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial

Background: To compare the efficacy, safety, and tolerability of MIN-101, a compound with high affinities for sigma 2 and 5-HT2A receptors, to placebo in treating negative symptoms, in stabilized patients with schizophrenia. Methods: This multi-national Phase 2b trial enrolled 244 patients diagnosed with schizophrenia who were symptomatically stable for ≥3 months prior to entering the trial and had scores ≥20 on the three factors negative subscale of the Positive and Negative Syndrome Scale (PANSS). Patients were randomized to monotherapy with MIN 101 32 mg/day, MIN-101 64 mg/day or placebo in a 1:1:1 ratio. The primary endpoint was the PANSS negative symptom score based on the five factors (pentagonal) model. Secondary outcomes were the three factors PANSS negative symptom subscale score, the PANSS total score, the PANSS positive symptom score, the Clinical Global Impression (CGI), the Brief Negative Symptoms Scale (BNSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Calgary Depression Scale for Schizophrenia (CDSS), and the Personal and Social Performance (PSP) scale. Safety parameters included treatment-emergent adverse events (TEAE), clinical laboratory, vital signs, electrocardiograms, Sheehan-suicidality tracking scale (S-STS), and the Abnormal Involuntary Movement Scale (AIMS). The Mixed-Effect Model Repeated Measure (MMRM) was used for analyzing the efficacy data. Results: The three treatment groups were balanced on all demographic and illness-related baseline characteristics. Statistically significant reduction in the primary endpoint score was demonstrated for MIN-101 32 mg and 64 mg compared to placebo (P ≤ .022, ES 0.45 and ≤ .003, ES 0.58, respectively). This was supported by similar effects on most of the secondary measurements including: the PANSS three factors negative symptoms subscale, PANSS total score, CGI, BACS, CDSS, and PSP. There were no statistically significant differences in PANSS positive subscale scores between MIN 101 and placebo. No weight gain or clinically significant changes in vital sings, prolactin levels, routine laboratory values, metabolic indices and extrapyramidal symptom scores (EPS) were observed. One patient on 64 mg MIN-101 was discontinued from the trial based on a-priori established QT interval prolongation criteria and a second one following an episode of syncope. Conclusion: MIN-101 at dosages of 32 and 64 mg/day demonstrated statistically significant efficacy of medium ES in reducing negative symptoms and good tolerability in stable schizophrenia patients. Since positive symptoms and EPS did not change, the improvement in negative symptoms was not secondary to improvement in positive symptoms or EPS, suggesting that MIN-101 might be the first specific treatment to have a direct effect on negative symptoms.

SA19. N-Acetyl-Cysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis

Background: Biomarker-guided treatments are needed in psychiatry and previous data suggest redox dysregulation / oxidative stress may be a target in schizophrenia (1,2). A previous add-on trial with the antioxidant N-Acetyl-Cysteine (NAC) led to negative symptoms reductions in chronic patients (3). We aim to study NAC impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. Methods: In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition (MATRICS Consensus Cognitive Battery [MCCB]), and redox markers (brain GSH [GSH-mPFC], blood cells GSH [GSH-BC] levels, and GSH peroxidase activity [GPx-BC]). Results: No changes in negative, positive symptoms, or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on the MCCB Processing Speed factor and two of its components: Trail Making and Verbal Fluency. NAC leads to increases in GSH-mPFC by 23% (P = .005) and GSH-BC by 19% (P = .05). In patients with high-baseline GPx-BC (>22.3U/gHb), subgroup explorations revealed an improvement with NAC of positive symptoms when compared to patients with low-baseline GPx (P = .02), with an improvement of positive symptoms in parallel with that of the redox status. Conclusion: In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest levels at baseline. However, NAC leads to neurocognition improvement as well as to brain GSH levels increases, pointing to good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help to identify a subgroup of patients who improve their positive symptoms with NAC. Future trials with antioxidant in EP should consider biomarker-guided treatment.

Acceptance and commitment therapy for psychosis: randomised controlled trial.

The efficacy of acceptance and commitment therapy (ACT) in psychosis has been reported but not for medication-resistant psychosis. To test the efficacy of ACT in a sample of community-residing patients with persisting psychotic symptoms. (Australian New Zealand Clinical Trials Registry: ACTRN12608000210370.) METHOD: The primary outcome was overall mental state at post-therapy (Positive and Negative Syndrome Scale - total); secondary outcomes were psychotic symptom dimensions and functioning. In total, 96 patients were randomised to ACT (n = 49) or befriending (n = 47). Symptom, functioning and process measures were administered at baseline, post-therapy and 6 months later. There was no group difference on overall mental state. In secondary analyses the ACT group showed greater improvement in positive symptoms and hallucination distress at follow-up: Cohen's d = 0.52 (95% CI 0.07-0.98) and 0.65 (95% CI 0.24-1.06), respectively. Improvements reflected the treatment focus on positive symptoms; however, absence of process-measure changes suggests that the ACT intervention used did not manipulate targeted processes beyond befriending. Symptom-specific therapy refinements, improved investigation of process and attention to cognitive functioning and dose are warranted in future research.

T38 - Preliminary Model For The Genetic Prediction Of Clozapine Response

Background Despite its clinical utility, the antipsychotic clozapine (CLZ) has not yet had a promising pharmacogenetic test developed for prediction of response. In the past 20 years, multiple genetic variants (e.g. dopamine, serotonin) have been suggested to be associated with CLZ response. Arranz et al (2000) proposed a model to predict response, but it was not replicated in independent samples. Since then, no other studies have sought to create a genetic panel predicting response to CLZ. Thus, we reinitiated the effort to develop a genetic model for CLZ response incorporating the most promising findings from our group’s repository of CLZ response studies. Methods Our sample consisted of 151 Caucasian subjects with schizophrenia (SCZ) (DSM-III) treated with CLZ for six months. Response was assessed using the Brief Psychiatric Rating Scale (BPRS), and evaluated using absolute score change and binary response (Kane et al. 1988 criteria), with baseline score as a covariate. A total of 99 polymorphisms were tested from a range of candidate genes. Variants showing at least a nominal statistical trend (p Results Four markers from genes encoding for dopamine D2 receptor (DRD2), serotonin-6 receptor (5-HT6), brain-derived neurotrophic factor (BDNF), and neurexin-1 (NRXN1) were included in the model. We observed a statistically significant association between genetic risk score with BPRS score change (p=0.000039, Adjusted R^2=0.565) and binary response (p=0.004, Nagelkerke R^2=0.097) assuming a linear increase in response for each additional risk allele. The model had an accuracy of 62%, a sensitivity of 70%, and a specificity of 47%. The model was not significantly associated with response in the independent CATIE European Caucasian subsample treated with other antipsychotics (p=0.10). Discussion We have developed a preliminary genetic model for CLZ response that includes genes with strong rationale for involvement. NRXN1 is a synaptic membrane cell-adhesion protein that has been suggested to modulate NMDA receptor activity, which is indirectly regulated by CLZ. The 5-HT6 receptor is involved in neurite growth and has lower expression in the hippocampus of SCZ patients compared to healthy controls. It mediates cognitive function, anxiety, and positive symptom improvement in animal models of SCZ. The model does not appear to generalize to other antipsychotics. For CLZ response prediction per se, replication in independent studies of CLZ response in SCZ is required to confirm the validity of these findings.

Obsessive\u2013compulsive symptoms and overall psychopathology in psychotic disorders: longitudinal assessment of patients and siblings

The course of obsessive–compulsive symptoms (OCS) and its association with alterations in other clinical variables in patients with psychotic disorders is insufficiently known. Patients (n = 602) and unaffected siblings (n = 652) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study were investigated at baseline and after 3 years. Participants were assigned to four groups based on the course of OCS over time: no-OCS, persistent OCS, initial OCS and de novo OCS. In addition to cross-sectional comparisons, longitudinal associations between changes in OCS and symptoms of schizophrenia and general functioning were investigated. Patients with co-occurring OCS reported significantly higher severity of psychotic and affective symptoms as well as lower overall functioning compared to patients without OCS. These differences were stable over time for patients reporting persistent OCS. Subsequent repeated measure analysis revealed significant interaction effects for groups reporting changes in their OCS. Whereas the group with remission of initial OCS showed significant improvement in positive symptoms, emotional distress and functioning, the de novo group showed no significant change in these variables, but rather reported stable higher psychopathology. Similar results were found on a subclinical level in siblings. Patients with co-occurring OCS present a more severe clinical picture, especially if symptoms persist over time. The remission of OCS was associated with overall improvement, whereas individuals with de novo OCS already reported higher clinical impairment before OCS onset. More research is needed to elucidate causal pathways and to develop effective interventions for persistent comorbid OCS.

PRM40 - Challenges in Economic Evaluations Conducted Alongside Clinical Trials of Schizophrenia: The Case of the Actions Study

Improvement in outcomes of schizophrenia is challenging to assess in a clinical trial setting. The objective of this study is to draw on the results of the ACTIONS study to highlight the challenges faced while conducting the economic evaluation. The ACTIONS study (n=62), a multicenter, double-blind, randomized, placebo-controlled trial, sought to establish the clinical and cost-effectiveness of augmenting antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. Patients with schizophrenia on continuing, stable antipsychotic medication with persistent negative symptoms were followed for 12 months. A within-trial economic evaluation was conducted. The importance of measuring outcomes that are sensitive to changes, and assess productivity loss and carer burden are imminent. While the clinical analysis found trend towards improved outcomes in terms of avolition/amotivation, there was no evidence of improvement either in the EQ-5D-3L or ICECAP-A measures. This questions if these measures are able to capture additional changes in the negative symptoms alongside the improvement in positive symptoms. After adjusting for baseline differences, there was no statistically significant difference between arms in any cost category, except non-mental health inpatient costs but was this due to the infrequent occurrence of non-mental health hospital use. Costing brought up issues of potential selection imbalance at randomization and representativeness in terms of employment, substance abuse, and residency in psychiatric institutions. Small sample size, randomization imbalance respective of health economic factors, lack of adherence to medications and doctor visits, and loss-to-follow-up due to changing residency status of the patients pose additional challenges of assessing the outcomes and costs of schizophrenia patients for economic evaluation. Future clinical studies in schizophrenia should consider including employment, substance abuse, and current residential status in the study inclusion/exclusion criteria in order to reduce variability in the costs.

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ² tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (p_uncorrected = 0.008, p_corrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

Short-term Effects of Risperidone Monotherapy on Spontaneous Brain Activity in First-episode Treatment-naïve Schizophrenia Patients: A Longitudinal fMRI Study.

It is unclear whether abnormal spontaneous neural activation patterns found in chronic schizophrenia patients (CSP) are part of the pathogenesis of disease, consequences of chronic illness, or effects of antipsychotic treatment. We performed a longitudinal resting-state functional magnetic resonance imaging (fMRI) study in 42 treatment-naïve first-episode schizophrenia patients (FESP) at baseline and then after 8-weeks of risperidone monotherapy, and compared the findings to 38 healthy volunteers. Spontaneous brain activity was quantified using the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) and compared between patients and controls. Pretreatment, patients exhibited higher fALFF in left caudate compared with controls. After treatment, patients had elevated fALFF in bilateral putamen and right caudate, and increased ReHo in right caudate and left putamen. Greater increase of fALFF in the left putamen correlated with less improvement in positive symptoms. Thus, abnormalities of spontaneous neural activity in chronic schizophrenia is at least partly due to a medication effect. The observed post-treatment increase in striatal intrinsic activity may reflect counter-therapeutic functional adaptation to dopamine D2 receptor occupancy required for medication effects on psychosis.

Physician and patient benefit-risk preferences from two randomized long-acting injectable antipsychotic trials.

PurposeTo quantify clinical trial participants’ and investigators’ judgments with respect to the relative importance of efficacy and safety attributes of antipsychotic treatments for schizophrenia, and to assess the impact of formulation and adherence.MethodsDiscrete-choice experiment surveys were completed by patients with schizophrenia and physician investigators participating in two phase-3 clinical trials of paliperidone palmitate 3-month long-acting injectable (LAI) antipsychotic. Respondents were asked to choose between hypothetical antipsychotic profiles defined by efficacy, safety, and mode of administration. Data were analyzed using random-parameters logit and probit models.ResultsPatients (N=214) and physicians (N=438) preferred complete improvement in positive symptoms (severe to none) as the most important attribute, compared with improvement in any other attribute studied. Both respondents preferred 3-month and 1-month injectables to oral formulation (P<0.05), irrespective of prior adherence to oral antipsychotic treatment, with physicians showing greater preference for a 3-month over a 1-month LAI for nonadherent patients. Physicians were willing to accept treatments with reduced efficacy for patients with prior poor adherence. The maximum decrease in efficacy (95% confidence interval [CI]) that physicians would accept for switching a patient from daily oral to 3-month injectable was as follows: adherent: 9.8% (95% CI: 7.2–12.4), 20% nonadherent: 25.4% (95% CI: 21.0–29.9), and 50% nonadherent: >30%. For patients, adherent: 10.1% (95% CI: 6.1–14.1), nonadherent: the change in efficacy studied was regarded as unimportant.ConclusionImprovement in positive symptoms was the most important attribute. Patients and physicians preferred LAIs over oral antipsychotics, with physicians showing a greater preference for 3-month over 1-month LAI. Physicians and patients were willing to accept reduced efficacy in exchange for switching a patient from an oral formulation to a LAI.