Augmentation of clozapine with ECT: a retrospective case analysis

Objective:We sought to assess the effectiveness of clozapine augmentation with ECT (C+ECT) in patients with clozapine-resistant schizophrenia. Methods:We conducted a retrospective review of electronic health records to identify patients treated with C+ECT. We determined the response to C+ECT and the rate of rehospitalisation over the year following treatment with C+ECT. Results:Forty-two patients were treated with C+ECT over a ten year period. The mean age of the patients at initiation of ECT was 46.3 (SD=8.2) years (range 27-62 years). The mean number of ECTs given was 10.6(SD = 5.3)(Range 3-25) with the majority receiving twice weekly ECT. Seventy six percent of patients (n=32) showed a Clinical Global Impression improvement score (CGI-I) of≤3 (at least minimally improved) following C+ECT. The mean number of ECT treatments was 10.6 (SD = 5.3) (range 3-25) with the majority receiving twice weekly ECT. Sixty four percent of patients experienced no adverse events. Response to C+ECT was not associated with gender, age, duration of illness, or duration of clozapine treatment.Seventy five percent of responders remained out of hospital over the course of one-year follow up, while 70% of those with no response to C+ECT were not admitted to hospital. Three patients received maintenance ECT, one of whom was rehospitalised. Conclusion:This study lends support to emerging evidence for the effectiveness of C+ECT in clozapine resistant schizophrenia. These results are consistent with the results of a meta-analysis and the only randomised controlled trial (RCT) of this intervention. Further RCTs are required before this treatment can be confidently recommended

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

Correlates of vitamin D in psychotic disorders:A comprehensive systematic review

People with psychosis have high prevalence of low vitamin D levels but the correlates and relevance of this deficiency are unclear. A systematic search of major databases from inception to 03/2016 was undertaken investigating correlates of vitamin D in people with psychosis. Data was summarised with a best evidence synthesis. Across 23 included studies (n=1,770 psychosis, n= 8,171 controls) a mean difference in vitamin D levels between both groups of −11.14 ng/ml ±0.59 was found. 53 unique correlations between vitamin D and outcomes in people with psychosis were identified. The evidence base was broadly equivocal although season of blood sampling (67% of studies found a positive correlation with warmer seasons) and parathyroid hormone (100% of studies found a negative correlation) were associated with vitamin D levels. The most commonly non-correlated variables were: BMI (83% found no correlation), age (73%), gender (86%), smoking (100%), duration of illness (100%) and general assessment of functioning score (100%). In conclusion, whilst many unique correlates have been investigated, there is weak and inconclusive evidence regarding the consistency and meaning of the correlates of vitamin D levels in people with psychosis. Future longitudinal studies should consider the correlates of vitamin D in people with psychosi

Predicting Affect Classification in Mental Status Examination Using Machine Learning Face Action Recognition System: A Pilot Study in Schizophrenia Patients

Classifying patients’ affect is a pivotal part of the mental status examination. However, this common practice is often widely inconsistent between raters. Recent advances in the field of Facial Action Recognition (FAR) have enabled the development of tools that can act to identify facial expressions from videos. In this study, we aimed to explore the potential of using machine learning techniques on FAR features extracted from videotaped semi-structured psychiatric interviews of 25 male schizophrenia inpatients (mean age 41.2 years, STD = 11.4). Five senior psychiatrists rated patients’ affect based on the videos. Then, a novel computer vision algorithm and a machine learning method were used to predict affect classification based on each psychiatrist affect rating. The algorithm is shown to have a significant predictive power for each of the human raters. We also found that the eyes facial area contributed the most to the psychiatrists’ evaluation of the patients’ affect. This study serves as a proof-of-concept for the potential of using the machine learning FAR system as a clinician-supporting tool, in an attempt to improve the consistency and reliability of mental status examination

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor:A Systematic Review

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. METHODS/PROCEDURES: We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. FINDINGS/RESULTS: We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count IMPLICATIONS/CONCLUSIONS: Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.</p

Effect of vitamin D supplementation on outcomes in people with early psychosis

Importance People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, −1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, −0.98; 95% CI, −2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, −0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, −1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, −0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, −2.09; 95% CI, −4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, −1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, −4.60 to 4.94); Global Assessment of Function disability score (mean difference, −0.01; 95% CI, −5.25 to 5.23), or Calgary Depression Scale score (mean difference, −0.39; 95% CI, −2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration isrctn.org Identifier: ISRCTN1242484

New approaches to antipsychotic medication adherence – safety, tolerability and acceptability

Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability

Hepatitis, Interstitial Nephritis, and Pancreatitis in Association With Clozapine Treatment:A Systematic Review of Case Series and Reports

PURPOSE/BACKGROUND: Clozapine is the criterion standard in treatment-resistant schizophrenia. We sought to review data on several inflammatory effects associated with clozapine, specifically interstitial nephritis, hepatitis, and pancreatitis. METHODS/PROCEDURES: We conducted a systematic review to identify studies, published up until December 2017, describing clozapine-induced hepatitis, nephritis, and pancreatitis. The primary objective was to characterize the clinical characteristics associated with each of the specific inflammatory reactions to clozapine. FINDINGS/RESULTS: We identified 42 cases of inflammatory reactions associated with clozapine treatment- 20 :cases of clozapine-induced hepatitis, 11 cases of nephritis, and 11 of pancreatitis. The mean (SD) age was 38.8 (11.9) years. The mean (SD) dose of clozapine used was 252.4 (133.7) mg. Time to onset of pancreatitis (17.9 [11.2] days; range 4-35 days) was shorter than that for hepatitis (34.2 [20.1] days; range, 12-90 days) and nephritis (27.9 [27.0]; range, 8-90 days) but was not statistically significant (F = 2.267, P = 0.117). The mean (SD) time to recovery was shorter for cases of pancreatitis (15.7 [18.4] days) compared with cases of hepatitis (25.9 [16.5] days) and nephritis (24.5 [18.9] days). Three cases with hepatitis died. Seven of the cases had a clozapine rechallenge (hepatitis [n = 3], nephritis [n = 1], pancreatitis [n = 3]), with 5 having a recurrence at a mean (SD) onset of 3.5 (2.5) days (range, 1-7 days); 2 hepatitis cases were successfully rechallenged. IMPLICATIONS/CONCLUSIONS: Clozapine-induced hepatitis, nephritis, and pancreatitis are uncommon adverse events, reflected in the paucity of case studies in the literature. Early recognition of the signs and symptoms of clozapine-associated hepatitis, nephritis, and pancreatitis is important, as when identified, clozapine should be urgently discontinued. Clozapine is associated with evidence of benign inflammatory processes; the extent to which hepatitis, and other inflammatory reactions, may be on a continuum with these more benign and self-limiting reactions is unclear, and this can only be resolved by prospectively following cohorts of clozapine-treated patients.</p