Brief Psychiatric Rating Scale Positive Symptom Research Articles

Long-Term Outcome of Clozapine in Treatment-Resistant Schizophrenia.

The favorable effect of clozapine on psychotic symptoms in patients with treatment-resistant (TR) schizophrenia (SCZ) in short-term studies is well established. However, prospective studies of the long-term outcome of clozapine treatment on psychopathology, cognition, quality of life, and functional outcome in TR-SCZ are limited. Here, we have examined the long-term (mean duration of follow-up 14 years) effects of clozapine on those outcomes in a prospective, open label study in 54 TR-SCZ patients. Assessments were performed at baseline, 6 weeks, 6 months, and at the last follow-up. Brief Psychiatric Rating Scale (BPRS) total, positive symptoms, and anxiety/depression at the last follow-up improved significantly from baseline, as well as from the 6-month evaluation ( P < 0.0001), with a 70.5% responder rate (≥20% improvement at the last follow-up from baseline). Quality of Life Scale (QLS) total improved by 72% at the last follow-up, with 24% of patients rated as having "good" functioning compared with 0% at baseline. Suicidal thoughts/behavior was significantly reduced at the last follow-up from the baseline. No significant change in negative symptoms was found at the last follow-up in the total sample. Short-term memory function declined at the last follow-up from baseline, but there was no significant change in processing speed. The QLS total showed a significant negative correlation with BPRS positive symptoms but not with cognitive measures, or negative symptoms, at the last follow-up. For patients with TR-SCZ, improving psychotic symptoms with clozapine seems to have a more significant impact than negative symptoms or cognition on improving psychosocial function.

Successful high dose antipsychotic treatment with cariprazine in patients on the schizophrenia spectrum: Real-world evidence from a Spanish hospital setting.

Real-world evidence fills in an important gap by providing data on the effectiveness and tolerability of new medications in everyday patients. In this data collection form a Spanish hospital, the effectiveness and tolerability of cariprazine were evaluated in 14 patients who were admitted to the hospital due to an acute episode of schizophrenia or schizoaffective disorder. The collected data included demographic characteristics, history of disorder and previous treatment, and details of cariprazine therapy such as dosing, side effects and measurements of effectiveness via scales. Difference between admission and discharge on the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) scale scores were evaluated using the Wilcoxon Signed-Rank test. Significant improvement was detected in nearly all patients (one patient dropped out) as measured by the BPRS Total, Negative symptom, Positive symptom, and Hostility scores. At admission, patients were markedly-moderately ill and at discharge the severity was reduced to borderline ill and normal according to the CGI-S. The CGI-Improvement scale also indicated very much and much improvement at discharge. Importantly, patients left the hospital with high doses of cariprazine, i.e., 7.5 mg/day or even 9.0 mg/day, but this did not cause safety problems; cariprazine well-tolerated as only a few patients experienced side effects such as akathisia. The results provide novel evidence regarding the tolerability and effectiveness of cariprazine in high doses patients on the schizophrenia spectrum.

Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia.

BACKGROUNDInsulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia.AIMTo determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ.METHODSIn this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTSIn patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = −0.4972, P = 0.001), PANSS-PSS (r = −0.4034, P = 0.028), and PANSS-NSS (r = −0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia.CONCLUSIONDisrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.

Single-Session Dance/Movement Therapy for Thought and Behavioral Dysfunction Associated With Schizophrenia: A Mixed Methods Feasibility Study.

This purposes of this mixed methods feasibility study were to determine whether people with schizophrenia in an inpatient psychiatric facility were able to complete the research protocol, and to obtain preliminary treatment effects of a single-session dance/movement therapy (DMT) intervention versus verbal treatment as usual (TAU). Thirty-two participants were randomized to a 45-minute DMT or verbal TAU session. Data were collected quantitatively using the Brief Psychiatric Rating Scale (BPRS) and qualitatively through open-ended interviews. Results indicated that participants in the DMT group had statistically significant symptom reduction compared with those in the TAU group in overall BPRS scores (effect size [ES] = 0.67), psychological discomfort (ES = 0.64), negative symptoms (ES = 0.67), and positive symptoms (ES = 0.55). No statistical significance was shown for resistance. Qualitative findings substantiate the quantitative findings, however, show divergence regarding resistance. Participants in the DMT group expressed feeling in control, less angry, and motivated for treatment.

T118. A CROSS-SECTIONAL STUDY ON OUTCOMES OF INDIVIDUALS WITH FIRST HOSPITALIZATION AND PSYCHOSIS SPECTRUM DISORDER DIAGNOSIS

BackgroundAcute psychosis is one of the most frequent causes of hospital admission. One of the major challenges is how to manage with negative symptoms. Clinical efficacy of treatment of patients at their first hospitalization has been evaluated in several studies.We carried out a cross sectional study focusing on the different outcomes considering the clinical relevance of positive and negative symptoms.MethodsWe analyzed all the admissions and discharges of patients at their first psychiatric hospitalization after psychosis onset (diagnosed with ICD-9 criteria) in our inpatient psychiatric acute unit of Policlinico Tor Vergata, (located in a suburb of Rome) considering the period of time between January 2017 and September 2019. We characterized all patients according to age, ethnicity, socioeconomic status, substance use/abuse, violent behaviours, voluntary or compulsory treatment, length of hospitalization and use of long acting injection (LAI). We included 73 patients (out of 626 admissions, 12%) with a diagnosis of spectrum psychosis disorder at first hospitalization.We used items 10–11 and 16–17 from the Brief Psychiatric Rating Scale (BPRS) to obtain two groups of patients with different clinical features. Based on the score of these items, patients were divided into two groups: group One characterized by prevalent positive symptomatology and group Two characterized by negative symptoms. Then, we compared clinical outcomes through BPRS, days of Hospital stay and Clinical Global Impression at the end of the hospitalization.ResultsIn our study we found out that patients with BPRS prevalent negative symptoms had longer hospital stays (mean 17.29 days); patients with BPRS positive prevalent symptoms had a mean stay of 15 days. Group Two patients used LAI treatment less frequently (37% of the times) compared to group One, which was treated with LAI 63% of the cases. At discharge, group Two had still higher scores in the Global Improvement Scale compared to group One.DiscussionOur study confirms that the use of antipsychotic therapy does not improve negative symptoms. Moreover, psychosis characterized by negative symptoms has a worse outcomes. Furthermore, considering their first hospitalization, it is interesting to note that our participants’ mean age was 37.98 years old, much higher than the one reported in literature. Since our Hospital is located in a very peripheral area of Rome, where social disadvantage represents a critical issue, we hypothesized different reasons to explain this data such as lower level of education, marginalization and socioeconomic adversity that might increase difficulties to access to health care services. In conclusion, further studies are needed to find more useful and alternative treatments and to deepen relationship between sociodemographic context and the time of their first psychiatric assessment.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Clinical correlates of paliperidone palmitate and aripiprazole monohydrate prescription for subjects with schizophrenia-spectrum disorders: findings from the STAR Network Depot Study.

This study, based on the 'Servizi Territoriali Associati per la Ricerca' (STAR) Network Depot Study nationwide baseline data, explored whether individual symptoms severity and clusters might influence the prescription of paliperidone palmitate 1-month (PP1M) vs. aripiprazole monohydrate. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology and relevant symptoms clusters. Drug Attitude Inventory, 10 items, was used to test attitude towards medications. Adherence to treatments was rated according to the Kemp seven-point scale. We assessed for eligibility 451 individuals and, among them, we included 195 subjects (n = 117 who started PPM1 and n = 78 aripiprazole monohydrate). Individuals were comparable in terms of age, gender, treatment years, recent hospitalizations, previous long-acting injectable antipsychotic treatments, additional oral treatments, attitude toward drugs, medication adherence, and alcohol/substance-related comorbidities. Subjects starting PP1M presented higher BPRS overall (P = 0.009), positive (P = 0.015), and negative (P = 0.010) symptom scores compared to subjects starting aripiprazole monohydrate. Results were confirmed by appropriate regression models and propensity score matching analysis. No differences were found comparing the other BPRS subscale scores: affect, resistance, and activation. Clinicians may be more prone to prescribe PPM1, rather than aripiprazole monohydrate, to subjects showing higher overall symptom severity, including positive and negative symptoms. No additional clinical factors influenced prescribing attitudes in our sample.

T191. RANDOMIZED DOUBLE-BLIND FEASIBILITY STUDY OF A GLUTEN-FREE DIET IN PEOPLE WITH SCHIZOPHRENIA AND ELEVATED ANTIGLIADIN ANTIBODIES (AGA IGG)

BackgroundDeconstructing schizophrenia is important, since different disorders within the syndrome may have distinct pathophysiological mechanisms and treatment targets. Emerging evidence suggests inflammation may play a role in at least a subgroup of people with this illness. One specific subgroup with known inflammation is a group with elevations in antigliadin antibodies (AGA IgG). These elevations (>20 U) are found in about 1/3 of people with schizophrenia. Gliadin is a protein found in wheat, barley and rye. This subgroup with AGA IgG elevations may be distinct as they have fewer positive symptoms, higher kynurenic acid levels, and may benefit from a gluten free diet. The effectiveness of gluten removal has been controversial with mixed results in previous studies, however no former study has examined gluten removal in those with high AGA IgG, that is, the population who may be expected to benefit.MethodsSixteen people with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder and who also had elevated AGA IgG (≥20 U) were recruited and admitted to an inpatient unit for a 5-week randomized double blind trial. Participants were randomized in a double blind fashion to either a diet containing gluten or a complete strictly enforced gluten free diet. This was accomplished by given 10 gm of gluten flour or 10 gm of rice flour daily in a protein shake, with all meals for all participants being standardized and gluten free. Participants had cooking classes, received cookbooks, and went on shopping trips for gluten free foods and meals. Participants were rated on the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS) and the MATRICS Cognitive Battery (MCCB) at baseline and 5 weeks. The study was not powered to find a treatment effect, but designed to examine the feasibility of conducting an inpatient gluten removal study and examine trends in treatment as measured by Cohen’s D effect size (ES) differences.ResultsFourteen of 16 people completed the 5-week trial and all tolerated the diet (2 discontinued early in the trial for housing and administrative reasons). The mean age of participants was 37.9 ± 13.2 years, 56% male and 75% African-American. During the clinical trial, participants receiving the gluten free diet had an improvement in negative symptoms as compared to placebo (treatment difference) with an ES=0.53. There was no improvement in BPRS total score or positive symptoms. The MCCB composite score did not improve, but an ES=0.6 was noted in the domain of attention favoring the gluten free diet. The AGA IgG levels decreased by 35% in the five weeks in the gluten free diet group relative to a 17% decrease in the gluten containing group. It is also important to note that the correlation between the change in SANS total score and AGA IgG in the gluten free group (r=0.57) was strong and notably different than the correlation between the change in SANS total score and AGA IgG in the gluten containing group (r=-0.017), suggesting a possible marker of treatment effect. Adverse effects were similar between treatment groups.DiscussionThis is the very first study of a gluten free diet in schizophrenia with elevated AGA IgG. This feasibility study suggests that removal of gluten is associated with improvement in negative symptoms and attention, but not positive symptoms. Participants tolerated the diet. The feasibility study provided data to design the now ongoing fully powered confirmatory double-blind trial in people with schizophrenia with negative symptoms using a higher gluten amount (30 grams daily) and with aims to examine associated mechanisms, with targets of inflammation, neuroimaging and gut permeability.

Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression.

Psychotic depression has no Food and Drug Administration-approved treatment. Patients demonstrate significant dysregulation of the hypothalamic-pituitary-adrenal axis providing a biologically targeted treatment opportunity. The purpose of this study was to explore the clinical and biological effects of short-duration (7-day) glucocorticoid receptor antagonism with mifepristone and the role of mifepristone plasma levels in patients with psychotic depression. This double-blind, randomized study took place at 34 US clinical research centers and included patients with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder, severe, with psychotic features. Patients underwent daily, observed, in-clinic administration of oral study drug (mifepristone 1200 mg or placebo) for days 1 to 7 of the 56-day trial, followed by treatment with a single Food and Drug Administration-approved antidepressant on days 8 to 56. The following scales were administered on days 0, 7, 14, 28, 42, and 56: Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale, Hamilton Rating Scale for Depression, and Columbia-Suicide Severity Rating Scale. The primary end point was a categorical analysis evaluating the proportion of patients with 50% or greater reduction from baseline in BPRS Positive Symptom Subscale score on both days 7 and 56, demonstrating early and durable response. Cortisol and adrenocorticotropic hormone were measured on days 0, 7, 28, and 56. Mifepristone plasma levels were assessed on days 0 and 7. An interim analysis indicated that the primary efficacy end point was unlikely to be met, and the study was stopped early with 292 of the planned 450 patients enrolled. Although the primary end point was not met, in a secondary prespecified analysis, patients who attained a mifepristone plasma level of 1637 ng/mL or greater (defined a priori and termed the high plasma level; 66.7% of patients) demonstrated statistically significant reductions in psychotic symptoms compared with patients who received placebo starting on day 28. This group also showed nonsignificant, numeric superiority on Hamilton Rating Scale for Depression improvement. No significant improvements were observed in the low-mifepristone group (<1637 ng/mL) versus the placebo group. There were no significant differences in Columbia-Suicide Severity Rating Scale suicidality ratings between groups. Mifepristone 1200 mg daily for 7 days was safe and well tolerated, allowing most treated patients to achieve the a priori defined therapeutic plasma level of 1637 ng/mL, the mifepristone level associated with biological effect and clinical benefit.

Clozapine augmented with risperidone in treatment-resistant schizophrenia

IntroductionThe evolution of various pharmacological therapies for schizophrenia has given rise to several pharmacological models for the neuroreceptor targets of antipsychotics and the influence of various neuroreceptors on specific symptoms and side effects.ObjectivesExperience in clinical practice affirms clozapine's position as the treatment of choice for patients with treatment-refractory schizophrenia. Unlike clozapine, risperidone has a more targeted profile of neurotransmitter binding, with particular predilection for dopamine and serotonin receptors. Risperidone is, to date, the most extensively documented clozapine augmentation agent.AimThe aim was to evaluate clinical efficacy, safety and tolerability of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.MethodsIn a randomized, double-blind, placebo-controlled 8-week trial, 10 patients unresponsive or partially responsive to 300 mg/day of clozapine monotherapy (n = 5) received a steady dose of 450 mg/day clozapine combined with or up to 4 mg/day of risperidone (n = 5). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression (CGI) improvement scale.ResultsFrom baseline to week 4 and week 8, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine monotherapy group. Clozapine/risperidone treatment did not induce additional weight gain or agranulocytosis compared with clozapine monotherapy treatment.ConclusionsClozapine augmentation with risperidone appears to be well tolerated, safe and may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.Disclosure of interestThe authors have not supplied their declaration of competing interest.

SU16. Predictors of Treatment Response of Adjunct Minocycline to Clozapine in Refractory Schizophrenia

Background: Accumulating evidence suggests minocycline (MINO) is effective as an adjunct treatment in schizophrenia. We previously reported significant improvement in avolition, anxiety/depression and working memory and a trend for positive symptoms and total Brief Psychiatric Rating Scale (BPRS) scores with MINO in a double-blind, placebo-controlled trial. We also found a >30% reduction in total BPRS scores in 25% of the MINO group compared to 4% in placebo (P = .04). Here we examine variables associated with symptom improvements. Methods: Participants with persistent positive symptoms of schizophrenia and schizoaffective disorder, despite adequate clozapine dosing, were randomized to receive adjunct MINO (100-mg BID) (N = 29) or placebo (N = 23). Both the BPRS and the Schedule for the Assessment of Negative Symptoms (SANS) were assessed biweekly in this 10-week trial. We examined demographic variables, duration of illness, baseline symptoms, serum cytokine levels, and CLZ blood levels to BPRS and SANS changes using Spearman’s correlation coefficients. Results: Symptom improvements were not related to demographic variables except that a shorter duration of illness related to SANS improvement in the MINO group (P = .04). Baseline total BPRS was associated with greater BPRS reduction (r = −0.51, P < .001), stronger in the MINO group than in placebo (difference in line slopes (F(1,45) = 5.13, P = .03). A greater increase in IFN-gamma with MINO was associated with a greater decrease in BPRS positive symptoms (r = −0.45, P = .02). SANS total score improvement was associated with an increase in TNF-alpha (r = −0.4, P = .045) and a trend for increased IFN-gamma (r = −0.38, P = .053). Lastly, CLZ levels were not related to BPRS; however, a greater decrease in CLZ levels related to a improvement in the SANS total score in the MINO group (r = 0.48, P = .01). In the placebo group, higher total CLZ was associated with greater SANS (difference in line slopes F(1, 42) = 4.43, P = .04). Conclusion: Variables associated with improvement on BPRS and positive symptoms include a higher baseline BPRS score and an increase in IFN-gamma levels. Variables associated with negative symptom improvement include shorter duration of illness, a decrease in CLZ levels, an increase in TNF-alpha, and trend for increase in IFN-gamma levels. These data suggest that despite MINO increasing CLZ levels (data not shown here) this does not contribute to MINO’s treatment effect. More research is needed to help define predictors of treatment response to MINO in larger samples.

Antiglucocorticoid and related treatments for psychosis.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development and relapse of psychotic disorders. Elevated cortisol secretion has been positively linked with symptom severity in people with psychosis. Antiglucocorticoid and related drugs that target the HPA axis may be useful for the treatment of individuals with psychosis. 1. To determine the effects of antiglucocorticoid and related drugs for the treatment of psychosis, when used alone or in combination with antipsychotic medication.2. To determine whether the effects of these medications differs between those in a prodromal phase or first episode of psychosis, and those with more established illness. We searched the Cochrane Schizophrenia Group's Trials Register (August 2009 and April 2014). Randomised controlled trials (RCTs) comparing antiglucocorticoid and related drugs compared to placebo (either as a sole treatment or as an adjunct to atypical antipsychotics, typical antipsychotics, antidepressants or other combination treatment) for people with a primary diagnosis of a psychotic disorder, or for individuals at high risk of developing a psychotic disorder. Review authors independently selected trials, assessed methodological quality and extracted data. We used a fixed-effect meta-analysis. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and standardised mean differences (SMDs) with 95% CIs for continuous measures. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table. We included 11 studies that randomly assigned 509 people with schizophrenia, schizoaffective disorder or psychotic depression. No trials were conducted in patients at their first episode of psychotic illness and none included populations at high risk for developing psychosis. Our pre-stated outcomes of interest were mental state, global state, general functioning, adverse effects and quality of life.Two trials compared antiglucocorticoid drugs (mifepristone) versus placebo as sole treatment. Limited data from one trial showed no difference in the proportion responding to mifepristone when mental state was assessed immediately post intervention using the Brief Psychiatric Rating Scale (BPRS) (n = 5, 1 RCT, MD -5.20, 95% CI -17.91 to 7.51; very low-quality evidence); depressive symptoms (Hamilton Rating Scale for Depression (HAMD) total) were also similar between groups (n = 5, 1 RCT, MD 1.67, 95% CI -16.44 to 19.78; very low-quality evidence). However, a significant difference favoured treatment at short-term follow-up for global state (30% reduction in total BPRS, n = 221, 1 RCT, RR 0.58, 95% CI 0.38 to 0.89; low-grade quality evidence). This effect was also seen for short-term positive psychotic symptoms (50% reduction in BPRS positive symptom subscale, n = 221, 1 RCT, RR 0.60, 95% CI 0.43 to 0.84; low-grade quality evidence). Participants receiving mifepristone experienced a similar overall number of adverse effects as those receiving placebo (n = 226, 2 RCTs, RR 0.92, 95% CI 0.77 to 1.09; moderate-quality evidence). No data on general functioning or quality of life were available.One trial compared an antiglucocorticoid, dehydroepiandrosterone (DHEA), as an adjunct to atypical antipsychotic treatment to adjunctive placebo. Data for main outcomes of interest were of low quality, and analysis of useable data showed no significant effects of treatment on mental state or adverse effects. Data on global state, general functioning and quality of life were not available.Data from six trials comparing antiglucocorticoid drugs as an adjunct to combination treatment versus adjunctive placebo showed no significant differences between groups in mean endpoint scores for overall psychotic symptoms (n = 171, 6 RCTs, SMD 0.01, 95% CI - 0.29 to 0.32) or positive psychotic symptoms (n = 151, 5 RCTs, SMD -0.07, 95% CI - 0.40 to 0.25). Data from three trials showed no differences between groups in mean endpoint scores for negative symptoms (n = 94, 3 RCTs, MD 2.21, 95% CI -0.14 to 4.55). One study found improvements in global state that were similar between groups (n = 30, 1 RCT, RR 0.58, 95% CI 0.32 to 1.06; very low-quality evidence). In this comparison, pooled results showed that antiglucorticoids caused a greater overall number of adverse events (n = 199, 7 RCTs, RR 2.66, 95% CI 1.33 to 5.32; moderate quality evidence), but no quality of life data were available. Good evidence is insufficient to conclude whether antiglucocorticoid drugs provide effective treatment for psychosis. Some global state findings suggest a favourable effect for mifepristone, and a few overall adverse effect findings favour placebo. Additional large randomised controlled trials are needed to justify findings.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

BackgroundThe N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. MethodsData from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7. ResultsPearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. LimitationsSecondary data analysis, combined diagnostic groups, potential unblinding. ConclusionsAmong the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Clinical Correlates and Description Profiles of Antipsychotic Polypharmacy for Patients with Schizophrenia

ObjectivesZZDespite increasing use of antipsychotic polypharmacy (APP), few studies have in- vestigated APP for Korean patients with schizophrenia. The aim of this study was to identify the sociodemographic and clinical correlates and recent prescription profiles of APP in schizophrenia patients. MethodsZZA total of 297 schizophrenia patients were recruited and interviewed using standard- ized assessment instruments in Seoul National Hospital. Differences in demographic and clinical characteristics between APP and antipsychotic monopharmacy (APM) groups were analyzed. The prescriptions of psychotropic drugs were collected by a review of medical records. ResultsZZIn comparison with the APM group, the APP group showed association with earlier onset, lower employment rate, and higher scores for Clinical Global Impression-Severity and Brief Psychiatric Rating Scale (BPRS) (p<0.001). In particular, the BPRS positive (p<0.001) and affective symptom scores (p<0.001) of the APP group were higher those of the APM group. The most frequent combination pattern of APP was second generation antipsychotics (SGA)+SGA, followed by SGA+first generation antipsychotics (FGA), and SGA+SGA+FGA. For antipsychotics, it was risperidone+quetiapine, followed by clozapine+risperidone, risperidone+sulpiride, and risperidone+haloperidol. ConclusionZZThe current study suggests that the usage of APP for schizophrenia could be re- lated to symptom severity affected by positive and affective symptoms. The prescription profile reflects that the proportion of atypical antipsychotics on APP has increased. J Kor ean Neuropsychiatr Assoc 2014;53(6):370-378

A pilot study on community-based outpatient treatment for patients with chronic psychotic disorders in Somalia: Change in symptoms, functioning and co-morbid khat use

BackgroundIn Low and Middle Income Countries, mental health services are often poorly developed due to the lack of resources and trained personnel. In order to overcome these challenges, new ways of care have been suggested such as a focus on community-based services. In Somalia, the consumption of the natural stimulant khat is highly prevalent, aggravating mental illness. At the same time, mental health care is largely unavailable to the vast majority of the population. In a pilot project, we tested possibilities for effective measures in community-based out-patient mental health care.MethodsThirty-five male patients with chronic psychotic disorders and their carers were involved in a 10-months follow-up study. All of them abused khat. Seventeen outpatients experiencing acute psychotic episodes were recruited from the community and received an intensive six week home-based treatment package. Additionally eighteen patients with chronic psychotic disorders in remission were recruited either following hospital discharge or from the community. In a second phase of the study, both groups received community-based relapse prevention that differed in the degree of the family’s responsibility for the treatment. The treatment package was comprised of psycho-education, low-dose neuroleptic treatment, monthly home visits and counseling. The Brief Psychiatric Rating Scale (BPRS) was applied three times. Additionally, we assessed functioning, khat use and other outcomes.ResultsOf the 35 patients enrolled in the study, 33 participated in the 10-month follow-up. Outpatients improved significantly in the first six weeks of treatment and did not differ from remitted patients at the start of the second treatment phase. In the preventive treatment phase, we find heterogeneous outcomes that diverge between symptom and functioning domains. With the exception of depressive symptoms, symptoms in all patients tended to worsen. The outpatient group had higher BPRS positive and negative symptom scores compared to the remitted group. Levels of functioning in 20 out of 33 patients significantly improved, with small differences between groups. Most patients experienced improvements in basic functioning, such as communication, self-care etc. Khat use could only be reduced in the group of outpatients.ConclusionsCommunity-based out-patient mental health treatment for chronic psychotic disorders has demonstrated positive effects in Somalia and is both feasible and practical, despite facing formidable challenges, e.g. controlling khat intake.

P-1306 - Impruvment on clozapine and valproate thetrapy among male schizophrenic patients

Introduction Clozapine is indicated for thetreatment of refractory schizophrenia. Objectives Aim of the study was to investigate improvement among schizophrenic male patients after augmentation on clozapine with valproate. Method Study group consisted of 24 male, aged 19 to 46 years inpatients and outpatients diagnosed with schizophrenia (DSM-IV criteria) and who had received a single antipsychotic clozapine for at least 4 weeks and with total score of at least 45 on the BPRS. Because no responsive or only partially responsive to clozapine, patients were treated with comminuted therapy clozapine and valproate. The Brief Psychiatric Rating Scale (BPRS), among others: SANS, ASEX, subscale on sexual function of the UKU Side Effects Rating Scale, were administered in at two-week intervals for 8 weeks. Study exclusion criteria: somatic conditions, Depressive/ subdepressive symptoms, substance abuse; patients did not take medications to improve erectile dysfunction or other medications unless prescribed antipsychotic. Results Mean BPRS total and positive symptom subscale scores decreased significantly from baseline to week 4 and week 8 in BPRS total score on to baseline, as were reductions in SANS scores. After 2 weeks on comminuted therapy clozapine and valprote, ASEX scores was decreased. (p = 0, 01). In patients under clozapine therapy, orgasmic, ejaculatory and erectile dysfunction is more common compared with comminuted therapy clozapine and valproate after 4 weeks (p Conclusions In patients with a suboptimal response to clozapine, the addition of valproate improved overall and positive symptoms of schizophrenia and may provide additional benefit in sexual dysfunction.

A Double-Blind, Randomized Study Comparing the Efficacy and Safety of Sertindole and Risperidone in Patients With Treatment-Resistant Schizophrenia

The comparative efficacy of second-generation antipsychotics has yet to be fully elucidated in patients with treatment-resistant schizophrenia. The objective of this study was to examine the efficacy and safety of sertindole, compared to risperidone, in this patient population. In this multicenter, phase 3, randomized, double-blind, parallel-group study, only patients with DSM-IV schizophrenia who had failed an adequate antipsychotic treatment within the previous 6 months and who had not responded positively to haloperidol during screening were eligible for enrollment. The primary efficacy variable was change in Positive and Negative Syndrome Scale (PANSS) from baseline to final assessment. Weekly assessments included the PANSS, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impressions (CGI) scale. The study was conducted between June 1996 and April 1998. Of the 321 patients randomly assigned to double-blind treatment, 217 patients completed the study (sertindole, n/n = 142/216 [66%]; risperidone, n/n = 75/105 [71%]). The main reason for withdrawal in both groups was ineffective therapy. The between-group difference in PANSS total score was not statistically significant and both groups showed improvement, with mean changes of -18.6 in the sertindole group and -20.9 in the risperidone group based on observed cases and -12.0 and -19.0, respectively, based on the last-observation-carried-forward method for inputing missing data. There were no statistically significant differences between the groups in any of the secondary end points: PANSS positive and negative subscales, CGI scores, BPRS total scores and positive symptom subscale scores, and SANS total scores. Patients reported similar levels of adverse events and treatment-emergent adverse events (TEAEs), except for extrapyramidal syndrome-related TEAEs, which were more common in the risperidone-treated group. Prolongation of the QTc interval was observed significantly more frequently with sertindole treatment. Sertindole and risperidone are effective and well-tolerated in patients with treatment-resistant schizophrenia. Sertindole offers an alternative treatment option for refractory patients in Europe given its good EPS profile, favorable metabolic profile, and comparable efficacy to risperidone.

Pituitary volume and early treatment response in drug-naïve first-episode psychosis patients

Background An early response to antipsychotic treatment in patients with psychosis has been associated with a better course and outcome. However, factors that predict treatment response are not well understood. The onset of schizophrenia and related disorders has been associated with increased levels of stress and hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. This study examined whether pituitary volume at the onset of psychosis may be a potential predictor of early treatment response in first-episode psychosis (FEP) patients. Methods We investigated the relationship between baseline pituitary volume and symptomatic treatment response over 12 weeks using mixed model analysis in a sample of 42 drug-naïve or early treated FEP patients who participated in a controlled dose-finding study of quetiapine fumarate. Logistic regression was used to examine predictors of treatment response. Pituitary volume was measured from magnetic resonance imaging scans that were obtained upon entry into the trial. Results Larger pituitary volume was associated with less improvement in overall psychotic symptoms (Brief Psychiatric Rating Scale (BPRS) P = 0.031) and positive symptoms (BPRS positive symptom subscale P = 0.010). Regardless of gender, patients with a pituitary volume at the 25th percentile (413 mm 3) were approximately three times more likely to respond to treatment by week 12 than those at the 75th percentile (635 mm 3) (odds ratio = 3.07, CI: 0.90–10.48). Conclusion The association of baseline pituitary volumes with early treatment response highlights the importance of the HPA axis in emerging psychosis. Potential implications for treatment strategies in early psychosis are discussed.

Clinical response to risperidone in relation to plasma drug concentrations in acutely exacerbated schizophrenic patients

There are no data indicating a clear relationship between the clinical effect of risperidone and plasma drug concentration. In this study, 51 patients with acutely exacerbated schizophrenia received 6 mg risperidone/day for 4 weeks. A clinical evaluation using the Brief Psychiatric Rating Scale (BPRS) and Udvalg for Klinicke Undersøgelser (UKU) side effect rating scale were performed at baseline and each week. Significant (P < 0.05) correlations were found between plasma concentrations of risperidone and improved total BPRS scores, positive and cognitive symptoms. Plasma concentrations of the active moiety were significantly (P < 0.05) correlated with improved total BPRS scores. Improved score and percent improvement in anxiety-depression subscale were significantly (P < 0.01) correlated with plasma concentrations of the active moiety. The sum of total UKU side effect scores from 1 to 4 weeks was significantly correlated with plasma concentration of both risperidone (rs = 0.319, P < 0.05) and active moiety (rs = 0.373, P < 0.01). The sum of the psychic subgroup scores was significantly correlated with plasma concentrations of active moiety (rs = 0.318, P < 0.05). Results suggest that plasma drug concentrations are, to some extent, associated with improved scores in some psychopathological schizophrenic symptoms and sedative side effects. These findings should be replicated with a larger patient sample.

Medication status affects the relationship of symptoms to prepulse inhibition of acoustic startle in schizophrenia

Inhibition of the acoustic startle response by a smaller preliminary nonstartling stimulus is termed prepulse inhibition (PPI). Schizophrenia patients have impairments in PPI that may not fully normalize even when they are clinically stable on medication, particularly typical antipsychotics. There is evidence that more severe symptoms are associated with more severe PPI abnormalities, but the effect of antipsychotics on this relationship is not clear. Seventy-three male schizophrenia patients underwent acoustic startle and PPI testing. Symptom ratings were performed using the Brief Psychiatric Rating Scale (BPRS) and its subscales. Fifty-two subjects were treated with antipsychotic medication at time of testing; 21 were unmedicated. For all subjects, PPI was negatively correlated with the BPRS psychological discomfort subscale but not with BPRS total symptoms, BPRS positive symptoms or BPRS negative symptoms. For medicated subjects analyzed separately, there were no correlations with BPRS total scores or any subscales. For the unmedicated subjects analyzed separately, there were significant correlations of lower PPI with greater severity of BPRS total symptoms, positive symptoms and the psychological discomfort subscale. These data indicate that more severe symptoms are associated with lower PPI, but that medication status is an important factor in the relationship between symptom severity and sensorimotor gating.