Emergency department presentations for deliberate self-harm and suicidal ideation in 25-39 years olds following agency-notified child maltreatment: results from the Childhood Adversity and Lifetime Morbidity (CALM) study.

AIMS: To compare prospective reports of child maltreatment (CM) with emergency department (ED) presentations for deliberate self-harm (DSH) and suicidal ideation in individuals aged between 25 and 39 years old. METHODS: Linked records between the Mater-University of Queensland Study of Pregnancy birth cohort and Queensland administrative health data were used, which included notifications to child protection agencies for CM. ED presentations for individuals aged between 25 and 39 years of age for suicidal ideation, suicidal behaviour or poisoning by paracetamol or psychotropic medications where the intention was unclear were examined using logistic regression analyses. RESULTS: A total of 609 (10.1%) individuals were the subject of one or more CM notifications for neglect or physical, sexual or emotional abuse before the age of 15 years. Of these, 250 (4.1%) presented at least once to ED for DSH and/or suicidal ideation between 25 and 39 years of age. In adjusted analysis, any notification of CM was associated with significantly increased odds of presenting to ED for these reasons (aOR = 2.80; 95% CI = 2.04-3.84). In sensitivity analyses, any notification of CM increased the odds of the combined outcome of DSH and suicidal ideation by 275% (aOR = 2.75; 95% CI = 1.96-4.06) and increased the odds of DSH alone by 269% (aOR = 2.69; 95% CI = 1.65-4.41). CONCLUSIONS: All CM types (including emotional abuse and neglect) were associated with ED presentations for DSH and suicidal ideation in individuals between 25 and 39 years of age. These findings have important implications for the prevention of DSH, suicidal ideation and other health outcomes. They also underscore the importance of trauma-informed care in ED for all individuals presenting with DSH and suicidal ideation.

An assessment of psychological distress and professional burnout in mental health professionals in Australia during the COVID-19 pandemic.

OBJECTIVE: To examine psychological distress and professional burnout in a cohort of Australian mental healthcare workers during the COVID-19 pandemic. METHODS: This study examined a multi-disciplinary cohort of mental healthcare workers in a large metropolitan service in Australia. Demographic information as well as information on employment and individual's personal experience of the COVID-19 pandemic was collected and correlated with cross-sectional assessments of anxiety, depression and professional burnout using validated clinical questionnaires. RESULTS: Mental healthcare workers reported high levels of anxiety, depression, and professional burnout. Participants reported some reduction in anxiety since the early phases of the pandemic, but the reduction was more modest in mental healthcare workers identifying as being "vulnerable" employees. CONCLUSION: Despite the low numbers of COVID-19 cases, mental healthcare workers in Australia report significant levels of psychological distress and professional burnout during the pandemic.

Physical health trajectories of young people commenced on clozapine.

OBJECTIVES: Clozapine is the most effective antipsychotic medication, but it has the highest propensity for metabolic side effects. A clozapine clinic was established within an early intervention for psychosis service to facilitate the timely commencement of clozapine and to manage the associated adverse effects. This study describes the changes in the weight, body mass index (BMI), waist circumference and blood pressure after 6 months in young people commenced on clozapine. METHOD: This was a prospective cohort study of all young people, aged 15-24 years, commenced on clozapine within an early intervention service in Melbourne, Australia, between 01.04.2016 and 30.06.2018. Continuous data were analyzed with paired t-test and categorical with Wilcoxon signed-rank test. RESULTS: Twenty-six young people received 6 months of treatment with clozapine, of whom the mean age was 19.8 years (s.d. ±3.1) and 66.7% were male. After 6 months, the mean weight gain was 5.1 kg (s.d. ±10.1 kg) and over half (53.8%) gained clinically significant weight. The proportion of young people classified as either overweight or obese rose from 69.2% to 88.5% (p = 0.006). The proportion of young people with a waist circumference above the recommended parameters increased from 57.9% to 78.9% (p = 0.008). Hypertension was present in 30%, and after 6 months, 45% had hypertension (p = 0.64). Metformin was prescribed to 34.6%, typically to those with the greatest and most rapid weight gain. CONCLUSION: Among young people with treatment resistant psychosis, clozapine is associated with significant metabolic side effects in the early stages of commencement. More interventions aimed at attenuating this weight gain are needed.

Impact of smoking behavior on clozapine blood levels - a systematic review and meta-analysis.

OBJECTIVE: Tobacco smoking significantly impacts clozapine blood levels and has substantial implications on individual efficacy and safety outcomes. By investigating differences in clozapine blood levels in smoking and non-smoking patients on clozapine, we aim to provide guidance for clinicians how to adjust clozapine levels for patients on clozapine who change their smoking habits. METHODS: We conducted a meta-analysis on clozapine blood levels, norclozapine levels, norclozapine/clozapine ratios, and concentration to dose (C/D) ratios in smokers and non-smokers on clozapine. Data were meta-analyzed using a random-effects model with sensitivity analyses on dose, ethnic origin, and study quality. RESULTS: Data from 23 studies were included in this meta-analysis with 21 investigating differences between clozapine blood levels of smokers and non-smokers. In total, data from 7125 samples were included for the primary outcome (clozapine blood levels in ng/ml) in this meta-analysis. A meta-analysis of all between-subject studies (N = 16) found that clozapine blood levels were significantly lower in smokers compared with non-smokers (Standard Mean Difference (SMD) -0.39, 95% confidence interval (CI) -0.55 to -0.22, P < 0.001, I2  = 80%). With regard to the secondary outcome, C/D ratios (N = 16 studies) were significantly lower in the smoker group (n = 645) compared with the non-smoker group (n = 813; SMD -0.70, 95%CI -0.84 to -0.56, P < 0.00001, I2  = 17%). CONCLUSION: Smoking behavior and any change in smoking behavior is associated with a substantial effect on clozapine blood levels. Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking. Reductions should be informed by clozapine steady-state trough levels and a close clinical risk-benefit evaluation.

Evaluation of the proposed anti-N-methyl-d-aspartate receptor encephalitis clinical diagnostic criteria in psychiatric patients.

OBJECTIVE: The gold standard for diagnosing anti-NMDAR encephalitis is demonstration of the antibody in CSF. Clinical diagnostic criteria have been proposed for when this is not available in a timely manner which is evaluated, in this study, for a psychiatric population. METHODS: This study retrospectively assessed the proposed criteria in patients presenting to psychiatric services for the first time with known anti-NMDAR antibody status. Antibody-positive cases were derived from the literature (conception to December 2019) and a state-wide (Queensland, Australia) cohort. Antibody-negative cases were derived from a service-wide (Metro South, Queensland, Australia) cohort of psychiatric cases which underwent antibody testing for routine organic screening. Sensitivity and specificity were calculated at 1 week following admission and the point of discharge. RESULTS: The proposed criteria were applied to 641 cases (500 antibody-positive and 141 antibody-negative), demonstrating a sensitivity which increased from around 19% after 1 week to 49% by the point of discharge. Specificity was 100% at both time points. The mean average time to become positive using the proposed criteria was 19.5 days compared to 34.9 days for return of antibody testing. CONCLUSIONS: High specificity of the proposed criteria, seen in this study, suggests that cases which are positive can be considered for expedited commencement of treatment. However, if clinical suspicion is high despite criteria being negative, it is essential to test CSF for anti-NMDAR antibody.

Community-care unit model of residential mental health rehabilitation services in Queensland, Australia: predicting outcomes of consumers 1-year post discharge.

AIMS: Community care units (CCUs) are a model of residential psychiatric rehabilitation aiming to improve the independence and community functioning of people with severe and persistent mental illness. This study examined factors predicting improvement in outcomes among CCU consumers. METHODS: Hierarchical regression using data from a retrospective cohort (N = 501) of all consumers admitted to five CCUs in Queensland, Australia between 2005 and 2014. The primary outcome was changed in mental health and social functioning (Health of the Nation Outcome Scale). Secondary outcomes were disability (Life Skills Profile-16), service use, accommodation instability, and involuntary treatment. Potential predictors covered service, consumer, and treatment characteristics. Group-level and individualised change were assessed between the year pre-admission and post-discharge. Where relevant and available, the reliable and clinically significant (RCS) change was assessed by comparison with a normative sample. RESULTS: Group-level analyses showed statistically significant improvements in mental health and social functioning, and reductions in psychiatry-related bed-days, emergency department (ED) presentations and involuntary treatment. There were no significant changes in disability or accommodation instability. A total of 54.7% of consumers demonstrated reliable improvement in mental health and social functioning, and 43.0% showed RCS improvement. The majority (60.6%) showed a reliable improvement in psychiatry-related bed-use; a minority demonstrated reliable improvement in ED presentations (12.5%). Significant predictors of improvement included variables related to the CCU care (e.g. episode duration), consumer characteristics (e.g. primary diagnosis) and treatment variables (e.g. psychiatry-related bed-days pre-admission). Higher baseline impairment in mental health and social functioning (ß = 1.12) and longer episodes of CCU care (ß = 1.03) increased the likelihood of RCS improvement in mental health and social functioning. CONCLUSIONS: CCU care was followed by reliable improvements in relevant outcomes for many consumers. Consumers with poorer mental health and social functioning, and a longer episode of CCU care were more likely to make RCS improvements in mental health and social functioning.

Antipsychotic medication exposure, clozapine, and pneumonia: results from a self-controlled study.

OBJECTIVE: By using a self-controlled design, we investigated whether antipsychotic medication exposure was associated with increased pneumonia risk and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications. METHODS: Through nationwide health registers, we identified all out-patients with schizophrenia initiating antipsychotic treatment. First, we estimated whether antipsychotic-naïve patients with schizophrenia increased their risk of pneumonia after initiation of either a first- or second-generation antipsychotic medication using a one-year mirror-image model. Afterward, similar analyses were made for individual second-generation antipsychotics. Lastly, the rate of pneumonia for patients initiated on clozapine was compared to patients commenced on other second-generation antipsychotics. RESULTS: In total, 8355 antipsychotic-naïve patients with schizophrenia were initiated on a first-generation antipsychotic medication; 0.95% of the patients had developed pneumonia before exposure, compared to 0.68% after exposure (P = 0.057). Similar findings were made for the 8001 antipsychotic-naïve patients with schizophrenia initiated on second-generation antipsychotic medications, with 0.56% developing pneumonia before exposure compared to 0.55% after exposure (P = 1.00). Second-generation antipsychotic medications did not increase the pneumonia risk, except for risperidone (increased by 0.32%; P = 0.007) and clozapine, which gave the largest absolute increase in pneumonia risk although not significant (increased by 0.64%; P = 0.10). The rate of pneumonia was higher after initiation of clozapine than for other second-generation antipsychotic medications. CONCLUSION: Most antipsychotic medications were not found to increase the risk of pneumonia. Clozapine exposure might be associated with increased risk of developing pneumonia.

The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days: a mirror image cohort study.

BACKGROUND: Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation. AIMS: The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine. METHODS: All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2 years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement. RESULTS/OUTCOMES: There was a significant reduction in bed days (29.55 days vs 24.46 days, p < 0.001) and admissions (2.27 vs 1.87 < 0.001) associated with clozapine commencement. This remained significant among clozapine continuers, but not among those with early cessation. Longer duration on clozapine was associated with greater reductions in psychiatric bed days and admissions. Age, sex and time to clozapine commencement, indigeneity and country of origin did not impact outcomes. CONCLUSION/INTERPRETATION: Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions.

Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder. METHOD: A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018. RESULTS: There were 706 cases of anti-NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period. CONCLUSION: The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification.

Meta-analysis examining the epidemiology of clozapine-associated neutropenia.

BACKGROUND: Clozapine is associated with life-threatening neutropenia. There are no previous meta-analyses of the epidemiology of clozapine-associated neutropenia. OBJECTIVES: To determine the cumulative incidence of mild, moderate and severe neutropenia, incidence of death related to severe neutropenia, case fatality rate of neutropenia and the longitudinal incidence of neutropenia following exposure to clozapine. DATA SOURCES: A systematic search of Medline, EMBASE and PsycINFO using search terms [clozapine OR clopine OR zaponex OR clozaril] AND [neutropenia OR agranulocytosis]. METHODS: Random effects meta-analysis to determine event rates and longitudinal incidence of events per 100 person-years of exposure. RESULTS: A total of 108 studies were included. The incidence of clozapine-associated neutropenia was 3.8% (95% CI: 2.7-5.2%) and severe neutropenia 0.9% (95% CI: 0.7-1.1%). The incidence of death related to neutropenia following prescription of clozapine was 0.013% (95% CI: 0.01-0.017%). The case fatality rate of severe neutropenia was 2.1% (95% CI: 1.6-2.8%). The peak incidence of severe neutropenia occurred at one month of exposure and declined to negligible levels after one year of treatment. CONCLUSION: Severe neutropenia associated with clozapine is a rare event and occurs early with a substantial decline in risk after one year of exposure. Death from clozapine-associated neutropenia is extremely rare. Implications for haematological monitoring are discussed.

Adverse cardiac events in out-patients initiating clozapine treatment: a nationwide register-based study.

OBJECTIVE: Using national Danish registers, we estimated rates of clozapine-associated cardiac adverse events. Rates of undiagnosed myocarditis were estimated by exploring causes of death after clozapine initiation. METHOD: Through nationwide health registers, we identified all out-patients initiating antipsychotic treatment (January 1, 1996-January 1, 2015). Rates of clozapine-associated myocarditis and pericarditis within 2 months from clozapine initiation and rates of cardiomyopathy within 1-2 years from clozapine initiation were compared to rates for other antipsychotics. Mortality within 2 months from clozapine initiation was extracted. RESULTS: Three thousand two hundred and sixty-two patients of a total 7932 patients initiated clozapine as out-patients (41.12%). One patient (0.03%) developed myocarditis, and no patients developed pericarditis within 2 months from clozapine initiation. Two (0.06%) and four patients (0.12%) developed cardiomyopathy within 1 and 2 years respectively. Rates were similar for other antipsychotics. Twenty-six patients died within 2 months from clozapine initiation. Pneumonia (23.08%) and stroke (11.54%) were the main causes of death. We estimated the maximum rate of clozapine-associated fatal myocarditis to 0.28%. CONCLUSION: Cardiac adverse effects in Danish out-patients initiating clozapine treatment are extremely rare and these rates appear to be comparable to those observed for other antipsychotic drugs.

A systematic review and meta-regression of the prevalence and incidence of perinatal depression.

BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of the disease burden for women of childbearing age, but the burden of MDD attributable to perinatal depression is not yet known. There has been little effort to date to systematically review available literature and produce global estimates of prevalence and incidence of perinatal depression. Enhanced understanding will help to guide resource allocation for screening and treatment. METHODS: A systematic literature review using the databases PsycINFO and PubMed returned 140 usable prevalence estimates from 96 studies. A random-effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates between studies and to guide a subsequent random-effects meta-analysis. RESULTS: The meta-regression explained 31.1% of the variance in prevalence reported between studies. Adjusting for the effects of all other variables in the model, prevalence derived using symptom scales was significantly higher than prevalence derived using diagnostic instruments (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.3-2.0). Additionally, prevalence was significantly higher in women from low and middle income countries compared to women from high income countries (OR 1.8, 95% CI 1.4-2.2). The overall pooled prevalence was 11.9% of women during the perinatal period (95% CI 11.4-12.5). There were insufficient data to calculate pooled incidence. LIMITATIONS: Studies in low income countries were especially scarce in this review, demonstrating a need for more epidemiological research in those regions. CONCLUSIONS: Perinatal depression appears to impose a higher burden on women in low- and middle-income countries. This review contributes significantly to the epidemiological literature on the disorder.

International trends in clozapine use: a study in 17 countries.

OBJECTIVE: There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. METHOD: A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. RESULTS: In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). CONCLUSION: While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

The impact of clozapine on hospital use: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness. METHOD: PubMed, EMBASE, PsycINFO and the Cochrane Schizophrenia Group Trials Register were systematically searched from inception to 12 October 2016. We included all trials and observational studies, except case reports. RESULTS: Thirty-seven studies were included. Clozapine significantly reduced the proportion of people hospitalised compared to control medicines (RR = 0.74; 95% CI: 0.69-0.80, P < 0.001, 22 studies, n = 44 718). There were significantly fewer bed days after clozapine treatment compared to before clozapine treatment in both controlled (MD = -34.41 days; 95% CI: -68.22 to -0.60 days, P = 0.046, n = 162) and uncontrolled studies (MD = -52.86 days; 95% CI: -79.86 days to -25.86 days, P < 0.001, n = 2917). Clozapine and control medicines had a similar time to rehospitalisation (-19.90 days; 95% CI: -62.42 to 22.63 days, P = 0.36). CONCLUSION: Clozapine treatment reduced the number of people hospitalised and the number of bed days after treatment compared with before treatment. Clozapine has the potential to reduce acute hospital use among people with treatment refractory schizophrenia.

Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis.

AIMS: Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables. METHODS: Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators. RESULTS: One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups. CONCLUSIONS: Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Increasing Clozapine Dispensing Trends in Queensland, Australia 2004-2013.

INTRODUCTION: Clozapine is the most effective treatment for treatment-resistant schizophrenia but its use is suboptimal. METHODS: Clozapine dispensing data from Queensland, Australia were extracted (2004-2013). The number of people dispensed clozapine each year and mean maintenance doses were calculated. The 18-week and 5-year cessation and treatment interruption rates were calculated using Kaplan-Meier analysis. RESULTS: Clozapine dispensings increased 36.4% (p<0.001) from 44 to 60 people per 100,000. This was estimated as 8.3% of people with schizophrenia and 33.3% of people with treatment resistant schizophrenia dispensed clozapine in 2013. Mean maintenance dose did not significantly change (364-399 mg) over 5 years of treatment. One in 7 (14.2%) people ceased within the first 3 weeks. 3-quarters (72.7%) reached maintenance therapy. The 5-year actuarial estimate of the proportion of people a) dispensed clozapine was 0.610 (S.E. 0.011) and b) with an interruption to treatment was 0.422 (S.E. 0.013). DISCUSSION: The number of patients being dispensed clozapine increased between 2004 and 2013 but clozapine is still underused. Increased use combined with continued monitoring for adverse effects will improve quality use of clozapine.