Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort.

OBJECTIVE: The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage. METHODS: A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years [range = 18-90]) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data. RESULTS: Most participants were living with bipolar I disorder (n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I (p = 2.0E-26) and females (p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine. CONCLUSION: Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.

Fabrication and Characterization of Clozapine Nanoemulsion Sol-Gel for Intranasal Administration.

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, it causes many adverse drug reactions (ADRs), which lead to poor treatment outcomes. Nose-to-brain (N2B) drug delivery offers a promising approach to reduce peripheral ADRs by minimizing systemic drug exposure. The aim of the present study was to develop and characterize clozapine-loaded nanoemulsion sol-gel (CLZ-NESG) for intranasal administration using high energy sonication method. A range of oils, surfactants, and cosurfactants were screened with the highest clozapine solubility selected for the development of nanoemulsion. Pseudoternary phase diagrams were constructed using a low-energy (spontaneous) method to identify the microemulsion regions (i.e., where mixtures were transparent). The final formulation, CLZ-NESG (pH 5.5 ± 0.2), comprising 1% w/w clozapine, 1% w/w oleic acid, 10% w/w polysorbate 80/propylene glycol (3:1), and 20% w/w poloxamer 407 (P407) solution, had an average globule size of ≤30 nm with PDI 0.2 and zeta potential of -39.7 ± 1.5 mV. The in vitro cumulative drug release of clozapine from the nanoemulsion gel at 34 °C (temperature of nasal cavity) after 72 h was 38.9 ± 4.6% compared to 84.2 ± 3.9% with the control solution. The permeation study using sheep nasal mucosa as diffusion barriers confirmed a sustained release of clozapine with 56.2 ± 2.3% cumulative drug permeated after 8 h. Additionally, the histopathological examination found no severe nasal ciliotoxicity on the mucosal tissues. The thermodynamic stability studies showed that the gel strength and viscosity of CLZ-NESG decreased after temperature cycling but was still seen to be in "gel" form at nasal temperature. However, the accelerated storage stability study showed a decrease in drug concentration after 3 months, which can be expected at elevated stress conditions. The formulation developed in this study showed desirable physicochemical properties for intranasal administration, highlighting the potential value of a nanoemulsion gel for improving drug bioavailability of clozapine for N2B delivery.

Colorectal, cervical and prostate cancer screening in Australians with severe mental illness: Retrospective nation-wide cohort study.

OBJECTIVE: People with severe mental illness have similar cancer incidence, but higher mortality than the general population. Participation in cancer screening may be a contributing factor but existing studies are conflicting. The aim of this study was to investigate the frequency of colorectal, prostate and cervical cancer screening among people with and without severe mental illness in Australia, who have access to universal health care. METHODS: We followed three cohorts using de-identified data from a random 10% sample of people registered for Australia's universal health care system: those aged 50-69 years ( n = 760,058) for colorectal cancer screening; women aged 18-69 years ( n = 918,140) for cervical cancer screening and men aged 50-69 years ( n = 380,238) for prostate cancer screening. We used Poisson regression to estimate incidence rate ratios and 95% confidence intervals for the association between severe mental illness and rates of faecal occult blood testing, pap smears and prostate-specific antigen testing. RESULTS: Having severe mental illness was associated with a 17% reduction in rates of pap smear (incidence rate ratio = 0.83, 95% confidence interval: 0.82-0.84) and prostate-specific antigen testing (incidence rate ratio = 0.83, 95% confidence interval: 0.81-0.85), compared to the general population. By contrast, incidence rates of faecal occult blood testing were only lower in people with severe mental illness among the participants who visited their general practitioner less than an average of five times per year (incidence rate ratio = 0.83, 95% confidence interval = [0.73, 0.94]). CONCLUSION: Our results suggest that differences in screening frequency may explain some of the mismatch between cancer incidence and mortality in people with severe mental illness and indicate that action is required to improve preventive screening in this very disadvantaged group.

Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX).

Clozapine causes obesity and type 2 diabetes (T2DM). Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exenatide) can counter clozapine-associated GLP-1 dysregulation in animals, and may be beneficial in people on clozapine. This randomized, controlled, open-label, pilot trial evaluated weekly exenatide for weight loss among clozapine-treated obese adults with schizophrenia, with or without T2DM. A total of 28 outpatients were randomized to once-weekly extended-release subcutaneous exenatide or usual care for 24 weeks. The primary outcome was proportion of participants with >5% weight loss. All 28 participants completed the study; 3/14 in the exenatide group and 2/14 in the usual care group had T2DM. Six people on exenatide achieved >5% weight loss vs one receiving usual care (P = .029). Compared with usual care, participants on exenatide had greater mean weight loss (-5.29 vs -1.12 kg; P = .015) and body mass index reduction (-1.78 vs -0.39 kg/m2 ; P = .019), and reduced fasting glucose (-0.34 vs 0.39 mmol/L; P = .036) and glycated haemoglobin levels (-0.21% vs 0.03%; P = .004). There were no significant differences in other metabolic syndrome components. Exenatide may be a promising therapeutic agent for glycaemic control and weight loss in clozapine-treated people with obesity, and could assist in reducing clozapine-associated cardio-metabolic morbidity and mortality.

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. METHODS: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. CONCLUSIONS: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Identifying characteristics and practices of multidisciplinary team reviews for patients with severe mental illness: a systematic review.

OBJECTIVES: Multidisciplinary teams in mental health receive limited guidance, leading to inconsistent practices. We undertook a systematic review of the characteristics and practices of multidisciplinary team reviews for patients with severe mental illness or in relevant mental health service settings. METHODS: Sources published since 2000 were located via academic database and web searches. Results were synthesised narratively. RESULTS: A total of 14 sources were analysed. Important characteristics and practices identified included routine monitoring and evaluation, good communication, equality between team members, and clear documentation practices. Success factors included defined leadership and clear team goals. Four sources described considerations for patients with complex clinical needs, including allocating sufficient time for discussion, maintaining connections with community providers, and ensuring culturally sensitive practices. CONCLUSIONS: No single best practice model was found, due to variations in team caseload, casemix, and resourcing levels. However, key ingredients for success were proposed. Sources were mostly descriptive; there remains a lack of evidence-based guidance regarding multidisciplinary team review characteristics and practices.

The Mental Health of Older Persons After Human-Induced Disasters: A Systematic Review and Meta-Analysis of Epidemiological Data.

BACKGROUND: Older people are increasingly "in harm's way" following human-induced disasters (HIDs). There is debate in the literature as to the relative impact of disasters on their psychological health compared with other age groups. Natural disasters and HIDs are thought to affect survivors differentially, and this may extend to older adults as a group. In the absence of existing systematic reviews, we aimed to synthesize the available evidence and conduct meta-analyses of the effects of HIDs on the psychological health of older versus younger adults. METHODS: A meta-analysis was conducted on papers identified through a systematic review. The primary outcomes measured were post-traumatic stress disorder (PTSD), depression, anxiety disorders, adjustment disorder, and psychological distress. RESULTS: We identified 11 papers from 10 studies on HIDs (N = 26,753), of which 8 had sufficient data for a random-effects meta-analysis. Older adults were 2.85 times less likely to experience PTSD symptoms following HID (95% CI: 1.42-5.70) when compared with younger adults. There was no statistically significant difference in terms of anxiety and depressive symptoms. CONCLUSION: Health and emergency services need to be increasingly prepared to meet the psychological needs of older people, given the global rise in the numbers of older adults affected by disasters of all kinds. Preliminary evidence suggests that old age may be a protective factor for the development of PTSD in the wake of HID.

Mental health implications for older adults after natural disasters--a systematic review and meta-analysis.

BACKGROUND: Natural disasters affect the health and well-being of adults throughout the world. There is some debate in the literature as to whether older persons have increased risk of mental health outcomes after exposure to natural disasters when compared with younger adults. To date, no systematic review has evaluated this. We aimed to synthesize the available evidence on the impact of natural disasters on the mental health and psychological distress experienced by older adults. DESIGN: A meta-analysis was conducted on papers identified through a systematic review. The primary outcomes measured were post-traumatic stress disorder (PTSD), depression, anxiety disorders, adjustment disorder, and psychological distress. RESULTS: We identified six papers with sufficient data for a random effects meta-analysis. Older adults were 2.11 times more likely to experience PTSD symptoms and 1.73 more likely to develop adjustment disorder when exposed to natural disasters when compared with younger adults. CONCLUSIONS: Given the global rise in the number of older adults affected by natural disasters, mental health services need to be prepared to meet their needs following natural disasters, particularly around the early detection and management of PTSD.

Successful rechallenge with clozapine after treatment associated eosinophilia.

OBJECTIVE: Eosinophilia has been associated with the use of clozapine. Where clozapine associated eosinophilia develops, and is associated with organ specific damage, clozapine is usually ceased. In cases of treatment associated eosinophilia without evidence of organ specific damage, clozapine would also typically be withdrawn. There are small numbers of reports in the literature describing patients who have had a successful rechallenge of clozapine having previously stopped treatment due to eosinophilia without associated organ specific inflammation. We report the case of a man who underwent a successful retrial of clozapine. METHOD: Case from authors' clinical practice reviewed. RESULTS: We present the case of a young man with treatment resistant schizophrenia who underwent a successful re-challenge of clozapine, having previously ceased treatment due to an eosinophilia associated with treatment. CONCLUSION: We believe that the current report provides further evidence that it may be unnecessary to cease treatment in all patients who develop an eosinophilia without organ dysfunction whilst on clozapine. Furthermore, where clozapine has been ceased due to an eosinophilia without evidence of organ specific inflammation, clozapine rechallenge with increased haematological monitoring should be considered.

Frequency and quality of mental health treatment for affective and anxiety disorders among Australian adults.

OBJECTIVES: To describe the frequency, type and quality of mental health treatment among Australian adults with past-year affective and/or anxiety disorders. DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of data for 8831 adults aged 16-85 years interviewed for the 2007 National Survey of Mental Health and Wellbeing, of whom 17% (n = 1517) met International Classification of Diseases, 10th revision (ICD-10) criteria for a past-year affective and/or anxiety disorder. MAIN OUTCOME MEASURES: Three levels of mental health treatment received in the past year: (1) any consultation with a health professional for mental health; (2) any evidence-based intervention (antidepressant medication, mood stabiliser medication, cognitive behaviour therapy and/or psychotherapy); and (3) minimally adequate treatment (a "dose" of an evidence-based intervention above a minimum threshold, consistent with treatment guidelines). RESULTS: Of participants with past-year affective and/or anxiety disorders, 39% sought professional help for mental health, 26% received an evidence-based treatment, and 16% received minimally adequate treatment. After controlling for clinical factors including type and severity of disorder, the odds of all levels of treatment were lower among younger adults (16-29 years) compared with middle-aged adults, and the odds of receiving an evidence-based treatment or minimally adequate treatment were lower among people who consulted a general practitioner only compared with a mental health professional. CONCLUSIONS: Closing the gap in treatment quality requires strategies to increase the use of evidence-based interventions, and to ensure these are delivered in sufficient doses. Research to elucidate why some patients are at increased risk of inadequate treatment, and the aspects of treatment that contribute to inadequate care, is indicated.

Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study.

BACKGROUND AND HYPOTHESIS: The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. STUDY DESIGN: A total of 1021 participants (41.0% female; aged 46.2 ±â€…10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. STUDY RESULTS: Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. CONCLUSIONS: Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol-Gels for Intranasal Administration.

(1) Background: Clozapine is the most effective antipsychotic. It is, however, associated with many adverse drug reactions. Nose-to-brain (N2B) delivery offers a promising approach. This study aims to develop clozapine-encapsulated thermosensitive sol-gels for N2B delivery. (2) Methods: Poloxamer 407 and hydroxypropyl methylcellulose were mixed and hydrated with water. Glycerin and carbopol solutions were added to the mixture and stirred overnight at 2-8 °C. Clozapine 0.1% w/w was stirred with polysorbate 20 (PS20) or polysorbate 80 (PS80) at RT (25 °C) before being added to the polymer solution. The final formulation was made to 10 g with water, stirred overnight at 2-8 °C and then adjusted to pH 5.5. (3) Results: Formulations F3 (3% PS20) and F4 (3% PS80) were selected for further evaluation, as their gelation temperatures were near 28 °C. The hydrodynamic particle diameter of clozapine was 18.7 ± 0.2 nm in F3 and 20.0 ± 0.4 nm in F4. The results show a crystallinity change in clozapine to amorphous. Drug release studies showed a 59.1 ± 3.0% (F3) and 53.1 ± 2.7% (F4) clozapine release after 72 h. Clozapine permeated after 8 h was 20.8 ± 3.0% (F3) and 17.8 ± 3.1% (F4). The drug deposition was higher with F4 (144.8 ± 1.4 µg/g) than F3 (110.7 ± 2.7 µg/g). Both sol-gels showed no phase separation after 3 months. (4) Conclusions: Binary PS80-P407 mixed micelles were more thermodynamically stable and rigid due to the higher synergism of both surfactants. However, binary mixed PS20-P407 micelles showed better drug permeation across the nasal mucosa tissue and may be a preferable carrier system for the intranasal administration of clozapine.

Australian national trends in stimulant dispensing: 2002-2009.

OBJECTIVE: Internationally there has been an increase in the prescriptions of stimulant medication. The aim of this study was to examine longitudinal national trends of stimulant dispensing in Australia between 2002 and 2009. METHOD: Government databases were retrospectively reviewed for all dispensed stimulant prescriptions between 2002 and 2009. Prescriptions were converted to defined daily dose (DDD)/1000 population/day using census data. Utilization of dexamphetamine and methylphenidate were analysed by source (subsidized or non-subsidized), prescriber (general practitioner, psychiatrist or other specialists), gender and age of patient. RESULTS: Between 2002 and 2009, dispensing of stimulants in Australia increased 87% from 2.93 to 5.47 DDD/1000 population/day. Dexamphetamine remained the most commonly dispensed stimulant, with rates of dispensing falling 13% from 2.02 to 1.75 DDD/1000 population/day. Dispensed prescriptions of methylphenidate increased 300% from 0.45 in 2002 to 1.81 DDD/1000 population/day in 2009, attributable to the availability of long-acting preparations. Dispensing of stimulants to males was four-fold greater than to females. There was substantial dispensing of dexamphetamine to those older than 25 years. CONCLUSIONS: Stimulant dispensing in Australia increased between 2002 and 2009 as a result of increased dispensing of long-acting preparations of methylphenidate. Further research is required to determine if the increase in stimulant dispensing in Australia is clinically appropriate.

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions.

RATIONALE: Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. OBJECTIVE: This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. METHODS: Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. RESULTS: A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). CONCLUSIONS: Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.

Anxiolytic, hypnotic and sedative medication use in Australia.

PURPOSE: New sedative drugs have been marketed in Australia in the last few years. We examined the trends in the prescribing of subsidised anxiolytic, hypnotic and sedative (AHS) medication use in the Australian population from 2002 to 2007. METHODS: We analysed the Medicare Australia and Drug Utilisation Sub-Committee databases for AHS script data from 2002 to 2007 by source, class of prescriber, gender and 5-year age groups. Scripts were converted to defined daily dose per 1000 population per day (DDD/1000 population/day) using Australian Bureau of Statistics population data. RESULTS: Overall use of AHS increased from 23.76 to 24.11 DDD/1000 population/day between 2002 and 2007. Anxiolytic medication utilisation increased as hypnotic medication utilisation decreased. Diazepam was the most widely used anxiolytic followed by alprazolam and oxazepam. Temazepam was the most widely used hypnotic followed by nitrazepam. Medication use was concentrated in those aged > or = 65 years with peak use in those aged 85-89 years. There was substantial use of anxiolytics in those aged 30-65 years. Age-adjusted utilization was higher in females than males. CONCLUSIONS: The prescribing of AHS medications increased slightly over the last half decade. There is growing use of zolpidem on private prescription. The gender differences in use reflect the higher prevalence of anxiety and sleep disorders in women. The very high use of these drugs in elderly people warrants further exploration because of the concomitant increased risks of mortality and morbidity.

Patterns of antipsychotic medication use in Australia 2002-2007.

OBJECTIVE: Atypical antipsychotic medications that are primarily used to treat schizophrenia and bipolar disorder cost the Pharmaceutical Benefits Scheme (PBS) AUD$334.4m in 2007. There are indications that they have also been used outside the approved indications to treat behavioural disturbances in the elderly. The aim of the present study was therefore to examine (i) trends in prescribing of subsidized atypical antipsychotic drugs in the Australian population from 2002 to 2007; and (ii) gender and age differences in the utilization of these drugs. METHODS: Government (Medicare Australia) data on numbers of prescriptions, quantity and doses for atypical and typical antipsychotics from 2002 to 2007 were analysed. Defined daily dose per 1000 population per day were estimated for age and sex groups using Australian Bureau of Statistics population data. RESULTS: The proportion of prescribed antipsychotics that were atypical increased from 61% in 2002 to 77% in 2007. In male subjects, olanzapine was most often prescribed between the ages of 25 and 55 years. In female subjects, in contrast, the highest rates of prescribing were in those > or = 75 years. Lower doses of these drugs were prescribed in older adults. CONCLUSIONS: Atypical antipsychotic drugs were most commonly used to treat schizophrenia in younger men and behavioural disturbances in older women with dementia. They appear to have been used outside of the approved indication for schizophrenia and bipolar disorder with significant financial costs to the PBS. Research into the reasons for their extensive use in elderly women is needed to inform more rational prescribing of these medicines.

Pharmacological interventions for smoking cessation among people with schizophrenia spectrum disorders: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: People with schizophrenia have higher rates of smoking than the general population, and lower quit rates. Several randomised controlled trials have investigated the effectiveness of pharmacological interventions for smoking cessation over the past 20 years. We did a systematic review and pairwise and network meta-analysis of smoking abstinence to guide decision making in offering pharmacological interventions for smoking cessation for people with schizophrenia spectrum disorders. METHODS: We systematically reviewed PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and China National Knowledge Infrastructure from inception to Sept 30, 2019, for randomised controlled trials of varenicline, bupropion, and nicotine replacement therapy for smoking cessation for people with schizophrenia spectrum disorders or psychotic disorders who were smokers at the time of study recruitment. Data were extracted from published studies on smoking abstinence outcomes and psychotic symptoms. We did pairwise and network meta-analyses for the primary outcome of smoking abstinence. Sensitivity analyses were done on study inclusion criteria, duration, quality, and location. This study is registered with the international prospective register of systematic reviews PROSPERO, CRD42018102343. FINDINGS: A total of 15 111 records were identified by the database searches, and 163 full-text articles were assessed for eligibility. 145 articles were then excluded for several reasons including insufficient data, or abstracts published in later studies, and 18 studies were included in the meta-analysis. In the pairwise meta-analyses, four studies with 394 participants assessed varenicline (RR 3·75, 95% CI 1·96-7·19, p<0·0001; I2=0%), four studies with bupropion and 292 participants (RR 3·40, 95% CI 1·58-7·34, p=0·0002; I2=0%), and three studies with 561 participants assessed nicotine replacement therapy (RR 4·27, 95% CI 1·71-10·65, p=0·0002; I2=0%). All three treatments were deemed superior to placebo. In the network meta-analysis, varenicline was superior to bupropion (RR 2·02, 95% CI 1·04-3·93; p=0·038) but no significant difference was found between varenicline and nicotine replacement therapy, or bupropion and nicotine replacement therapy. No agents were associated with changes in psychiatric symptoms, but varenicline was associated with higher rates of nausea than was placebo. INTERPRETATION: We found evidence to support use of pharmacological agents for smoking cessation for people with psychosis. Varenicline might be superior to bupropion; however, additional direct testing and combination trials of pharmacological agents for smoking cessation are required to inform clinical decision making for people with psychosis. FUNDING: None.