Changes in immunoglobulin levels during clozapine treatment in schizophrenia.

BACKGROUND AND HYPOTHESIS: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored. DESIGN: This prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS). RESULTS: IgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: ß = -32.66, 95% CI = -62.38, -2.93, p = 0.03; IgG: ß = -63.96, 95% CI = -118.00, -9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: ß = -23.48, 95% CI = -39.56, -7.42, p = 0.004; 24 weeks: ß = -33.12, 95 %CI = -50.30, -15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03). CONCLUSIONS: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Severe Alprazolam Withdrawal With Delirium and Psychosis: A Case Report and Literature Review.

ABSTRACT: In our report, and review of the literature, we present an important clinical lesson for the recognition and treatment of alprazolam withdrawal with complicated delirium and psychosis, and present a strong case for future treatment algorithms. Our case is unique due to the severity of behavioral disturbance associated with acute psychosis secondary to alprazolam withdrawal and the significant quantity of alprazolam consumed. The use of high cumulative doses of longer-acting benzodiazepines resulted in rapid improvement in symptoms with full resolution of psychosis. Within 4 days of treatment in hospital, delirium and psychosis had fully resolved. Detoxification continued in the community and the patient was followed up in clinic for monitoring of mental state. There was no recurrence of psychotic symptoms.

Augmentation of clozapine with ECT: a retrospective case analysis.

OBJECTIVE: We sought to assess the effectiveness of clozapine augmentation with Electroconvulsive therapy (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 10-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 per cent of patients (n = 32) showed a Clinical Global Impression-Improvement (CGI-I) score 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 per cent 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 per cent of responders remained out of hospital over the course of 1-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.

Hospitalisation and length of hospital stay following first-episode psychosis: systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Reducing hospitalisation and length of stay (LOS) in hospital following first episode psychosis (FEP) is important, yet reliable measures of these outcomes and their moderators are lacking. We conducted a systematic review and meta-analysis to investigate the proportion of FEP cases who were hospitalised after their first contact with services and the LOS in a hospital during follow-up. METHODS: Studies were identified from a systematic search across major electronic databases from inception to October 2017. Random effects meta-analyses and meta-regression analyses were conducted. RESULTS: 81 longitudinal studies encompassing data for 23 280 FEP patients with an average follow-up length of 7 years were included. 55% (95% CI 50.3-60.5%) of FEP cases were hospitalised at least once during follow-up with the pooled average LOS of 116.7 days (95% CI 95.1-138.3). Older age of illness onset and being in a stable relationship were associated with a lower proportion of people who were hospitalised. While the proportion of hospitalised patients has not decreased over time, LOS has, with the sharpest reduction in the latest time period. The proportion of patients hospitalised during follow-up was highest in Australia and New Zealand (78.4%) compared to Europe (58.1%) and North America (48.0%); and lowest in Asia (32.5%). Black ethnicity and longer duration of untreated psychosis were associated with longer LOS; while less severe psychotic symptoms at baseline were associated with shorter LOS. CONCLUSION: One in two FEP cases required hospitalisation at least once during a 7-year follow-up with an average length of hospitalisation of 4 months during this period. LOS has declined over time, particularly in those countries in which it was previously longest.

Effect of lifestyle, medication and ethnicity on cardiometabolic risk in the year following the first episode of psychosis: prospective cohort study.

BACKGROUND: The first episode of psychosis is a critical period in the emergence of cardiometabolic risk. AIMS: We set out to explore the influence of individual and lifestyle factors on cardiometabolic outcomes in early psychosis. METHOD: This was a prospective cohort study of 293 UK adults presenting with first-episode psychosis investigating the influence of sociodemographics, lifestyle (physical activity, sedentary behaviour, nutrition, smoking, alcohol, substance use) and medication on cardiometabolic outcomes over the following 12 months. RESULTS: Rates of obesity and glucose dysregulation rose from 17.8% and 12%, respectively, at baseline to 23.7% and 23.7% at 1 year. Little change was seen over time in the 76.8% tobacco smoking rate or the quarter who were sedentary for over 10 h daily. We found no association between lifestyle at baseline or type of antipsychotic medication prescribed with either baseline or 1-year cardiometabolic outcomes. Median haemoglobin A1c (HbA1c) rose by 3.3 mmol/mol in participants from Black and minority ethnic (BME) groups, with little change observed in their White counterparts. At 12 months, one-third of those with BME heritage exceeded the threshold for prediabetes (HbA1c >39 mmol/mol). CONCLUSIONS: Unhealthy lifestyle choices are prevalent in early psychosis and cardiometabolic risk worsens over the next year, creating an important window for prevention. We found no evidence, however, that preventative strategies should be preferentially directed based on lifestyle habits. Further work is needed to determine whether clinical strategies should allow for differential patterns of emergence of cardiometabolic risk in people of different ethnicities.

Clozapine Rechallenge Following Neuroleptic Malignant Syndrome: A Systematic Review.

PURPOSE/BACKGROUND: Neuroleptic malignant syndrome (NMS) has been described with most antipsychotics, most commonly first generation. Clozapine has also been associated with NMS. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing (a) clozapine rechallenge following suspected NMS associated with clozapine, (b) clozapine use after suspected NMS associated with another antipsychotic, and (c) rechallenge with nonclozapine antipsychotics after suspected clozapine-associated NMS. FINDINGS/RESULTS: We identified 51 reports detailing 67 cases. Thirty-eight described clozapine administration after NMS on a nonclozapine antipsychotic; 12 described a clozapine rechallenge after an NMS on clozapine monotherapy; and 17 described the use of nonclozapine antipsychotics after an NMS on clozapine. The outcome of clozapine rechallenge was favorable (no recurrence of NMS) in 92% (n = 11) of cases after an NMS on clozapine and in 79% (n = 30) of those prescribed clozapine following NMS on a nonclozapine antipsychotic. Most (82%; n = 14) cases after NMS on clozapine had no recurrence of NMS on receiving a nonclozapine antipsychotic.No mortality was reported with any of these interventions. IMPLICATIONS/CONCLUSIONS: Our findings suggest that rechallenge following clozapine NMS is possible, and with careful risk-benefit analysis consideration, a clozapine rechallenge can be made. A publication bias in favor of cases in which rechallenge was successful is probable and is an important limitation.

Simple Schizophrenia: A Forgotten Diagnosis in Psychiatry.

Clustering of symptoms to characterize simple schizophrenia is still debated, and support is needed for the characterization of simple schizophrenia as a syndrome. We conducted a systematic review to identify all cases of simple schizophrenia published until December 2017. We identified 42 cases of simple schizophrenia, 57% of which met all three diagnostic criteria (ICD-10, DSM-4 research criteria, and Black and Boffeli's criteria for simple schizophrenia). The mean age at first contact with clinical services was 30.1 (SD = 11.6) years, with a mean delay of 7.4 (SD = 6.8) years from symptom onset to first presentation. An insidious onset and negative symptoms were characteristic features in all cases. Social withdrawal, alogia, blunted affect, lack of initiative/interest, and functional impairment were found in more than 85% of cases. Our findings contribute to greater awareness and understanding of simple schizophrenia, and have the potential to reawaken interest in this clinically distinct subgroup.

Brain-relevant antibodies in first-episode psychosis: a matched case-control study.

BACKGROUND: There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). METHODS: Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case-control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. RESULTS: VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. CONCLUSIONS: This case-control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context.

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.

Remission and recovery from first-episode psychosis in adults: systematic review and meta-analysis of long-term outcome studies.

BackgroundRemission and recovery rates for people with first-episode psychosis (FEP) remain uncertain.AimsTo assess pooled prevalence rates of remission and recovery in FEP and to investigate potential moderators.MethodWe conducted a systematic review and meta-analysis to assess pooled prevalence rates of remission and recovery in FEP in longitudinal studies with more than 1 year of follow-up data, and conducted meta-regression analyses to investigate potential moderators.ResultsSeventy-nine studies were included representing 19072 patients with FEP. The pooled rate of remission among 12301 individuals with FEP was 58% (60 studies, mean follow-up 5.5 years). Higher remission rates were moderated by studies from more recent years. The pooled prevalence of recovery among 9642 individuals with FEP was 38% (35 studies, mean follow-up 7.2 years). Recovery rates were higher in North America than in other regions.ConclusionsRemission and recovery rates in FEP may be more favourable than previously thought. We observed stability of recovery rates after the first 2 years, suggesting that a progressive deteriorating course of illness is not typical. Although remission rates have improved over time recovery rates have not, raising questions about the effectiveness of services in achieving improved recovery.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

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 < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred. 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.

Randomised control trial of the effectiveness of an integrated psychosocial health promotion intervention aimed at improving health and reducing substance use in established psychosis (IMPaCT).

BACKGROUND: People with psychosis have a reduced life expectancy of 10-20 years, largely due to cardiovascular disease. This trial aimed to determine the effectiveness of a modular health promotion intervention (IMPaCT Therapy) in improving health and reducing cardiovascular risk in psychosis. METHODS: A multicentre, two arm, parallel cluster RCT was conducted across five UK mental health NHS trusts. Community care coordinators (CC) were randomly assigned to training and supervision in delivering IMPaCT Therapy or treatment as usual (TAU) to current patients with psychosis (cluster). The primary outcome was the physical and mental health subscales of the Short form-36 (SF-36) questionnaire. RESULTS: Of 104 care coordinators recruited, 52 (with 213 patients) were randomised to deliver IMPaCT therapy and 52 (with 193 patients) randomised to TAU. Of 406 patients, 318 (78%) and 301 (74%) attended 12- and 15-month follow-up respectively. IMPaCT therapy showed no significant effect on the physical or mental health component SF-36 scores versus TAU at 12 or 15 months. No effect was observed for cardiovascular risk indicators, except for HDL cholesterol, which improved more with IMPACT therapy than TAU (Treatment effect (95% CI); 0.085 (0.007 to 0.16); p = 0.034). The 22% of patients who received >180 min of IMPACT Therapy in addition to usual care achieved a greater reduction in waist circumference than did controls, which was clinically significant. CONCLUSION: Training and supervising community care coordinators to use IMPaCT therapy in patients with psychosis is insufficient to significantly improve physical or mental health quality of life. The search for effective, pragmatic interventions deliverable in health care services continues. TRIAL REGISTRATION: The trial was retrospectively registered with ISRCTN registry on 23/4/2010 at ISRCTN58667926 ; recruitment started on 01/03/2010 with first randomization on 09.08.2010 ISRCTN58667926 .

Randomised controlled trial to improve health and reduce substance use in established psychosis (IMPaCT): cost-effectiveness of integrated psychosocial health promotion.

BACKGROUND: There is mounting evidence that people with severe mental illness have unhealthy lifestyles, high rates of cardiovascular and metabolic diseases, and greater risk of early mortality. This study aimed to assess the cost-effectiveness of a health promotion intervention seeking to improve physical health and reduce substance use in people with psychosis. METHODS: Participants with a psychotic disorder, aged 18-65 years old and registered on an enhanced care approach programme or equivalent were recruited from community mental health teams in six mental health trusts in England. Participants were randomisation to either standard community mental health team care (treatment as usual) or treatment as usual with an integrated health promotion intervention (IMPaCT). Cost-effectiveness and cost-utility analyses from health and social care and societal perspectives were conducted alongside a cluster randomised controlled trial. Total health and social care costs and total societal costs at 12 and 15 months were calculated as well as cost-effectiveness (incremental cost-effectiveness ratios and cost-effectiveness acceptability curves) at 15 months based on quality of life (SF-36 mental and physical health components, primary outcome measures) and quality adjusted life years (QALYs) using two measures, EQ-5D-3 L and SF-36. Data were analysed using bootstrapped regressions with covariates for relevant baseline variables. RESULTS: At 12-15 months 301 participants had full data needed to be included in the economic evaluation. There were no differences in adjusted health and social care costs (£95, 95% CI -£1410 to £1599) or societal costs (£675, 95% CI -£1039 to £2388) between the intervention and control arms. Similarly, there were no differences between the groups in the SF-36 mental component (-0.80, 95% CI -3.66 to 2.06), SF-36 physical component (-0.68, 95% CI -3.01 to 1.65), QALYs estimated from the SF-36 (-0.00, -0.01 to 0.00) or QALYs estimated from the EQ-5D-3 L (0.00, 95% CI -0.01 to 0.02). Cost-effectiveness acceptability curves for all four outcomes and from both cost perspectives indicate that the probability of the health promotion intervention being cost-effective does not exceed 0.4 for willingness to pay thresholds ranging from £0-£50,000. CONCLUSIONS: Alongside no evidence of additional quality of life/clinical benefit, there is also no evidence of cost-effectiveness. TRIAL REGISTRATION: ISRCTN58667926 . Date retrospectively registered: 23/04/2010. Recruitment start date: 01/03/2010.

Patterns of illness and care over the 5 years following onset of psychosis in different ethnic groups; the GAP-5 study.

PURPOSE: Previous research has not provided us with a comprehensive picture of the longitudinal course of psychotic disorders in Black people living in Europe. We sought to investigate clinical outcomes and pattern of care in Black African and Black Caribbean groups compared with White British patients during the first 5 years after first contact with mental health services for psychosis. METHODS: 245 FEP cases aged 18-65 who presented to psychiatric services in 2005-2010 in South London (UK). Using the electronic psychiatric clinical notes in the South London and Maudsley NHS Foundation Trust (SLaM), extensive information was collected on three domains-clinical, social, and service use. RESULTS: During the 5-year follow-up (mean = 5.1 years, s.d. = 2.4; 1251 person years) after first contact with mental health services, a higher proportion of Black African and Black Caribbean ethnicity had compulsory re-admissions (χ 2 = 17.34, p = 0.002) and instances of police involvement during an admission to a psychiatric unit (χ 2 = 22.82, p < 0.001) compared with White British ethnic group. Patients of Black African and Black Caribbean ethnicity did not differ from the ethnic group in overall functional disability and illness severity, or frequency of remission or recovery during the follow-up period. However, patients of Black ethnicity become increasing socially excluded as their illness progress. CONCLUSIONS: The longitudinal trajectory of psychosis in patients of Black ethnicity did not show greater clinical or functional deterioration than white patients. However, their course remains characterised by more compulsion, and longer periods of admission.

Autoantibodies against voltage-gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta-analysis, and case series.

Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.

Physical multimorbidity and psychosis: comprehensive cross sectional analysis including 242,952 people across 48 low- and middle-income countries.

BACKGROUND: In people with psychosis, physical comorbidities, including cardiovascular and metabolic diseases, are highly prevalent and leading contributors to the premature mortality encountered. However, little is known about physical health multimorbidity in this population or in people with subclinical psychosis and in low- and middle-income countries (LMICs). This study explores physical health multimorbidity patterns among people with psychosis or subclinical psychosis. METHODS: Overall, data from 242,952 individuals from 48 LMICs, recruited via the World Health Survey, were included in this cross-sectional study. Participants were subdivided into those (1) with a lifetime diagnosis of psychosis ("psychosis"); (2) with more than one psychotic symptom in the past 12 months, but no lifetime diagnosis of psychosis ("subclinical psychosis"); and (3) without psychotic symptoms in the past 12 months or a lifetime diagnosis of psychosis ("controls"). Nine operationalized somatic disorders were examined: arthritis, angina pectoris, asthma, diabetes, chronic back pain, visual impairment, hearing problems, edentulism, and tuberculosis. The association between psychosis and multimorbidity was assessed by multivariable logistic regression analysis. RESULTS: The prevalence of multimorbidity (i.e., two or more physical health conditions) was: controls = 11.4% (95% CI, 11.0-11.8%); subclinical psychosis = 21.8% (95% CI, 20.6-23.0%), and psychosis = 36.0% (95% CI, 32.1-40.2%) (P < 0.0001). After adjustment for age, sex, education, country-wise wealth, and country, subclinical psychosis and psychosis were associated with 2.20 (95% CI, 2.02-2.39) and 4.05 (95% CI, 3.25-5.04) times higher odds for multimorbidity. Moreover, multimorbidity was increased in subclinical and established psychosis in all age ranges (18-44, 45-64, ≥ 65 years). However, multimorbidity was most evident in younger age groups, with people aged 18-44 years with psychosis at greatest odds of physical health multimorbidity (OR = 4.68; 95% CI, 3.46-6.32). CONCLUSIONS: This large multinational study demonstrates that physical health multimorbidity is increased across the psychosis-spectrum. Most notably, the association between multimorbidity and psychosis was stronger among younger adults, thus adding further impetus to the calls for the early intervention efforts to prevent the burden of physical health comorbidity at later stages. Urgent public health interventions are necessary not only for those with a psychosis diagnosis, but also for subclinical psychosis to address this considerable public health problem.

Pharmacological interventions for clozapine-induced sinus tachycardia.

BACKGROUND: Clozapine is an efficacious treatment for treatment-resistant schizophrenia; however its use can be limited by side effect intolerability. Sinus tachycardia is a common adverse event associated with clozapine treatment. Various pharmacological treatments are used to control heart rate increase due to clozapine use and can include a decreased rate of clozapine titration, a switch to a different antipsychotic, or treatment with negative chronotropic drugs. OBJECTIVES: To assess the clinical effects and efficacy of pharmacological interventions for clozapine-induced sinus tachycardia.To systematically review the adverse events associated with pharmacological interventions for clozapine-induced sinus tachycardia. SEARCH METHODS: On 23 March 2015, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: Randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced tachycardia. DATA COLLECTION AND ANALYSIS: We independently screened and assessed studies for inclusion using pre-specified inclusion criteria. MAIN RESULTS: The electronic searches located three references. However, we did not identify any studies that met our inclusion criteria. AUTHORS' CONCLUSIONS: With no studies meeting the inclusion criteria, it is not possible to arrive at definitive conclusions. There are currently insufficient data to confidently inform clinical practice. We cannot, therefore, conclude whether specific interventions, such as beta-blockers, are less effective or more effective than standard courses of alternative treatments for tachycardia. This lack of evidence for the treatment of clozapine-induced tachycardia has implications for research and practice. Well-planned, conducted and reported randomised trials are indicated. One trial is currently underway. Current practice outside of well-designed randomised trials should be clearly justified.

Lower Bone Mineral Density at the Hip and Lumbar Spine in People with Psychosis Versus Controls: a Comprehensive Review and Skeletal Site-Specific Meta-analysis.

It remains unclear if differences in bone mineral density (BMD) exist at different skeletal sites between people with schizophrenia and age- and sex-matched healthy controls (HCs). Major databases were searched from inception until February 2016 for studies measuring BMD using dual-energy X-ray absorptiometry (DXA) at any skeletal site in individuals with schizophrenia. Ten studies investigating 827 people with schizophrenia (55.4 % female, 33.8 ± 9.7 years) and 1379 HCs (58.7 % female, 34.7 ± 9.1 years) were included. People with schizophrenia had significantly reduced BMD at the lumbar spine (standardised mean difference adjusted for publication bias (SMD) = -0.950 (95 % CI = -1.23 to -0.66, fail-safe number = 825) and hip (SMD = -0.534, 95 % CI = -0.876 to -0.192, fail-safe number = 186). A higher proportion of hyperprolactinaemia (ß = -0.0102, p < 0.0001) and smokers (ß = -0.0099, p = 0.02) moderated a larger reduced BMD at the lumbar spine. Further research is required to investigate if low bone mass and fractures can be prevented in people with schizophrenia.

Prevalence and Predictors of Clozapine-Associated Constipation: A Systematic Review and Meta-Analysis.

Constipation is a frequently overlooked side effect of clozapine treatment that can prove fatal. We conducted a systematic review and meta-analysis to estimate the prevalence and risk factors for clozapine-associated constipation. Two authors performed a systematic search of major electronic databases from January 1990 to March 2016 for articles reporting the prevalence of constipation in adults treated with clozapine. A random effects meta-analysis was conducted. A total of 32 studies were meta-analyzed, establishing a pooled prevalence of clozapine-associated constipation of 31.2% (95% CI: 25.6-37.4) (n = 2013). People taking clozapine were significantly more likely to be constipated versus other antipsychotics (OR 3.02 (CI: 1.91-4.77), p < 0.001, n = 11 studies). Meta-regression identified two significant study-level factors associated with constipation prevalence: significantly higher (p = 0.02) rates of constipation were observed for those treated in inpatient versus outpatient or mixed settings and for those studies in which constipation was a primary or secondary outcome measure (36.9%) compared to studies in which constipation was not a specified outcome measure (24.8%, p = 0.048). Clozapine-associated constipation is common and approximately three times more likely than with other antipsychotics. Screening and preventative strategies should be established and appropriate symptomatic treatment applied when required.