Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Making meaning of multimorbidity and severe mental illness: A viewpoint.

People living with severe mental illness, such as schizophrenia and bipolar affective disorder, frequently experience poorer physical health compared to those without mental illness. This issue has hitherto been approached through the disease-centred construct of comorbidity, where subsequent conditions are viewed as secondary to an 'index condition'. In contrast, this Viewpoint sets out to explain why multimorbidity, a patient-centred concept that instead refers to the coexistence of multiple chronic illnesses, is a more versatile and robust framework for tackling the issue of poor physical health in people with severe mental illness. In establishing this argument, this Viewpoint has sought to address three key areas. First, this article will discuss the epidemiology of both physical and psychiatric multimorbidity, with respect to how they manifest at greater frequency and at younger ages in people with severe mental illness. Second, the profound consequences of this multimorbidity burden will be explored, with respect to the 'three D's' of death (premature mortality), disability (functional impacts) and deficit (health-economic impacts). Finally, the utility of multimorbidity as a framework will be illustrated through a proposal for a three-dimensional multimorbidity construct composed of (1) quantity, (2) severity and (3) duration of an individual's chronic illnesses. Consequently, this Viewpoint aims to capture why it is necessary for modern psychiatry to grasp the concept of multimorbidity to facilitate holistic healthcare for people living with severe mental illness.

Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis.

BACKGROUND: Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response. AIMS: Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice. METHOD: We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response. RESULTS: We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223-558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine. CONCLUSIONS: Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Breast cancer treatment disparities in patients with severe mental illness: A systematic review and meta-analysis.

OBJECTIVE: The incidence and mortality rates of breast cancer in individuals with pre-existing severe mental illness (SMI), such as schizophrenia, bipolar disorder, and major depression, are higher than in the general population. Reduced screening is one factor but there is less information on possible barriers to subsequent treatment following diagnosis. METHODS: We undertook a systematic review and meta-analysis on access to guideline-appropriate care following a diagnosis of breast cancer in people with SMI including the receipt of surgery, endocrine, chemo- or radiotherapy. We searched for full-text articles indexed by PubMed, EMBASE, PsycInfo and CINAHL that compared breast cancer treatment in those with and without pre-existing SMI. Study designs included population-based cohort or case-control studies. RESULTS: There were 13 studies included in the review, of which 4 contributed adjusted outcomes to the meta-analyses. People with SMI had a reduced likelihood of guideline-appropriate care (RR = 0.83, 95% CI = 0.77-0.90). Meta-analyses were not possible for the other outcomes but in adjusted results from a single study, people with SMI had longer wait-times to receiving guideline-appropriate care. The results for specific outcomes such as surgery, hormone, radio- or chemotherapy were mixed, possibly because results were largely unadjusted for age, comorbidities, or cancer stage. CONCLUSIONS: People with SMI receive less and/or delayed guideline-appropriate care for breast cancer than the general population. The reasons for this disparity warrant further investigation, as does the extent to which differences in treatment access or quality contribute to excess breast cancer mortality in people with SMI.

Self-reported child maltreatment and cardiometabolic risk in 30-year-old adults.

BACKGROUND: Childhood maltreatment (CM) is associated with both dietary fat intake and obesity in later life. There is less information on associations with metabolic risk factors and specific types of CM such as physical, sexual and emotional abuse, as well as neglect. AIMS: To assess the association between five types of self-reported CM and a range of obesity and metabolic indicators in a subsample of a birth cohort. METHODS: This was a study of 1689 adults born in a major metropolitan maternity hospital in Australia and followed up 30 years later. Body mass index, bioimpedance and fasting lipid levels/insulin resistance were measured. Details on self-reported CM were collected using the Child Trauma Questionnaire. We adjusted for birth weight, parental income and relationship at participants' birth, as well as maternal age and alcohol or tobacco use. We also adjusted for participants' smoking, depression, educational level, marital and employment status at follow up. RESULTS: One-fifth reported maltreatment (n = 362), most commonly emotional neglect (n = 175), followed by emotional abuse (n = 128), physical neglect (n = 123), sexual (n = 121) and physical abuse (n = 116). On adjusted analyses, there were significant associations for CM, particularly neglect or emotional abuse, and one or more of the following outcomes: obesity, the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio and HDL levels. Results for other outcomes were more equivocal. CONCLUSIONS: Of child maltreatment types, emotional abuse and neglect show the strongest associations with obesity and several cardiometabolic risk factors, therefore highlighting the public health importance of early intervention to reduce childhood adversity.

A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders.

OBJECTIVES: There is an increasing interest in combining psilocybin or methylenedioxymethamphetamine with psychological support in treating psychiatric disorders. Although there have been several recent systematic reviews, study and participant numbers have been limited, and the field is rapidly evolving with the publication of more studies. We therefore conducted a systematic review of PubMed, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, Embase, and CINAHL for randomised controlled trials of methylenedioxymethamphetamine and psilocybin with either inactive or active controls. METHODS: Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least 2 weeks following drug administration, Quality was independently assessed using the Cochrane risk of bias assessment tool and Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: There were eight studies on methylenedioxymethamphetamine and six on psilocybin. Diagnoses included post-traumatic stress disorder, long-standing/treatment-resistant depression, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease. The most information and strongest association was for the change in methylenedioxymethamphetamine scores compared to active controls in post-traumatic stress disorder (k = 4; standardised mean difference = -0.86; 95% confidence interval = [-1.23, -0.50]; p < 0.0001). There were also small benefits for social anxiety in adults with autism. Psilocybin was superior to wait-list but not niacin (active control) in life-threatening disease anxiety or depression. It was equally as effective as escitalopram in long-standing depression for the primary study outcome and superior for most of the secondary outcomes in analyses uncorrected for multiple comparisons. Both agents were well tolerated in supervised trials. Trial quality varied with only small proportions of potential participants included in the randomised phase. Overall certainty of evidence was low or very low using the Grading of Recommendations Assessment, Development and Evaluation framework. CONCLUSION: Methylenedioxymethamphetamine and psilocybin may show promise in highly selected populations when administered in closely supervised settings and with intensive support.

Anti-glutamic acid decarboxylase antibody screening in first-episode psychosis.

OBJECTIVE: The Royal Australian and New Zealand College of Psychiatrists recommends screening for a range of antibodies in first-episode psychosis, including anti-glutamic acid decarboxylase antibodies. Glutamic acid decarboxylase antibody-associated encephalitis occurs with high antibody titres and may cause cognitive dysfunction, seizures and psychiatric symptoms. However, glutamic acid decarboxylase antibodies are more frequently found in lower titre in association with other autoimmune disorders (such as diabetes mellitus type 1) and in healthy individuals. The utility of testing unselected populations of consumers with psychosis is unclear. The psychiatric manifestations of this disorder are also poorly described. METHODS: First, systematic review of cohort and case-control studies that tested for IgG glutamic acid decarboxylase antibodies in psychiatric populations was conducted. Random-effects meta-analysis of odds ratio for antibody positivity in cases with psychosis and controls assessed prevalence. Second, literature review of all published cases and case series of glutamic acid decarboxylase antibody-associated limbic encephalitis was assessed for frequency and description of psychotic symptoms. RESULTS: There were 17 studies, in which 2754 individuals with psychotic disorders were tested for glutamic acid decarboxylase IgG antibodies. Thirty-one consumers with psychosis (0.7%) had positive glutamic acid decarboxylase antibodies compared to 24 controls (1.0%), all at low titre and not fulfilling diagnostic criteria for autoimmune encephalitis. Meta-analysis found no significant difference in rates of glutamic acid decarboxylase antibody positivity (odds ratio = 1.8, 95% confidence interval: [0.90, 3.63]). Literature review found 321 cases of glutamic acid decarboxylase antibody-associated limbic encephalitis, with psychosis in 15 (4.3%) cases. Clinical screening would have identified all cases that presented to psychiatric services. CONCLUSION: Glutamic acid decarboxylase antibodies were uncommon in consumers with psychosis, with no significant difference in prevalence from controls and no cases of encephalitis identified. In cases with established glutamic acid decarboxylase antibody-associated limbic encephalitis, psychotic symptoms were uncommon and identifiable by clinical assessment. Targeted antibody testing guidelines should be further considered.

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.

Renewal of academic psychiatry without addressing gender equity will render it Jurassic rather than endangered.

While two editorials have raised concerns about the decline in Australian academic psychiatry, for a genuine rejuvenation to ever occur, we will need to re-examine how women can be better included in this important endeavour. While attainment of fellowship has reached gender parity, academic psychiatry has disappointingly lagged, with 80% of its senior leadership roles across Australia and New Zealand still held by men, with a similar situation in the United Kingdom and the United States as well as many other countries. Encouraging women into academic psychiatry is not only critical to progress as a profession but also will help address the current blindness to sex differences in biological psychiatry, as well the social impact of restrictive gender norms and the effects of gender-based violence on mental health. This potentially creates opportunities for significant gains and insights into mental disorders. However, addressing the barriers for women in academia requires tackling the entrenched disparities across salaries, grant funding, publications, teaching responsibilities, keynote invitations and academic promotions alongside the gender-based microaggressions, harassment and tokenism reported by many of our female academics. Many women must grapple with not just a 'second shift' but a 'third shift', making the burden of an academic career unreasonable and burnout more likely. Addressing this is no easy task. The varied research in academic medicine reveals no quick fixes, although promoting gender equity brings significant potential benefits. Areas such as academic psychiatry need to recognise our community's growing discomfort with workplaces that choose to maintain status quo. Gender equity must be a critical part of any quest to revive this important area of practice for our profession.

Can improvement in delivery of smoking cessation care be sustained in psychiatry inpatient settings through a system change intervention? An analysis of statewide administrative health data.

OBJECTIVE: This study evaluated maintenance of improved delivery of smoking cessation assistance in adult acute psychiatry inpatient units 3 years post statewide implementation of a system change intervention through analysis of a statewide administrative health dataset. METHOD: Rates of documenting smoking status and providing a brief smoking cessation intervention (the Smoking Cessation Clinical Pathway) in all eligible Queensland public adult acute psychiatry inpatient units (N = 57) during the implementation phase (October 2015-September 2017) of a system change intervention were compared to the maintenance phase (October 2017-October 2020) using interrupted time series analysis. RESULTS: Across implementation and maintenance phases, the percentage of discharges from psychiatry inpatient units that had a smoking status recorded remained high with the statewide average exceeding 90% (implementation phase 93.2%, 95% confidence interval = [92.4, 93.9]; and maintenance phase 94.6%, 95% confidence interval = [94.0, 95.2]). The percentage of discharges statewide with a completed Pathway stabilised during the maintenance phase (change in slope -3.7%, 95% confidence interval = [-5.2, -2.3]; change in level 0.4%, 95% confidence interval = [-7.0, 7.9]). CONCLUSION: An evidence-based smoking cessation intervention implemented with a system change intervention resulted in sustained improvement in addressing smoking in adult inpatient psychiatry units up to 3 years post implementation.

Reversal learning in those with early psychosis features contingency-dependent changes in loss response and learning.

INTRODUCTION: People with psychotic disorders commonly feature broad decision-making impairments that impact their functional outcomes. Specific associative/reinforcement learning problems have been demonstrated in persistent psychosis. But these phenotypes may differ in early psychosis, suggesting that aspects of cognition decline over time. METHODS: The present proof-of-concept study examined goal-directed action and reversal learning in controls and those with early psychosis. RESULTS: Equivalent performance was observed between groups during outcome-specific devaluation, and reversal learning at an 80:20 contingency (reward probability for high:low targets). But when the low target reward probability was increased (80:40) those with early psychosis altered their response to loss, whereas controls did not. Computational modelling confirmed that in early psychosis there was a change in punishment learning that increased the chance of staying with the same stimulus after a loss, multiple trials into the future. In early psychosis, the magnitude of this response was greatest in those with higher IQ and lower clinical severity scores. CONCLUSIONS: We show preliminary evidence that those with early psychosis present with a phenotype that includes altered responding to loss and hyper-adaptability in response to outcome changes. This may reflect a compensatory response to overcome the milieu of corticostriatal changes associated with psychotic disorders.

Frailty and Treatment-Resistant Schizophrenia: A Retrospective Cohort Study.

Frailty, a state of reduced physiological reserve, has not been studied in consumers with treatment-resistant schizophrenia, despite known elevated rates of comorbidity and psychosocial impairment. This study applies a frailty index to the electronic medical records of 78 adults with treatment-resistant schizophrenia, aged 18-64 years, to determine the prevalence and characteristics of frailty (defined as a frailty index score > 0.21). The mean frailty index score was 0.24 (SD = 0.091, range = 0.061-0.54), with 52.6% of the population categorised as frail (40.0% in those aged 18-39 years). Frailty was positively correlated with age and psychiatric illness severity. This study provides novel evidence that individuals with treatment-resistant schizophrenia have a high rate of frailty and become frail at a younger age. Routine frailty assessments could be used to trigger the delivery of appropriate interventions, which have the potential to improve life expectancy and quality of life.

CBTp for people with treatment refractory schizophrenia on clozapine: a systematic review and meta-analysis.

BACKGROUND: Cognitive behavioural therapy for psychosis (CBTp), an effective treatment for people with schizophrenia, may have a role in clozapine refractory schizophrenia. AIMS: A systematic-review and meta-analysis on the impact of CBTp on psychotic symptoms in people on clozapine. METHODS: We searched PubMed, Embase, PsycInfo, CINAHL and Cochrane for randomised control trials of CBTp as augmentation in people with treatment-refractory schizophrenia on clozapine and conducted pair-wise meta-analyses. RESULTS: Four studies met inclusion criteria. On pairwise meta-analyses, the primary outcome of total psychotic symptoms was not significantly altered by CBTp at either therapy endpoint or six to twelve months follow-up. Secondary outcomes showed that CBT improved positive symptoms at both therapy endpoint (SMD -0.33, 95%CI -0.50 to -0.16, p = 0.002, I2 = 0%) and six to twelve months follow-up (SMD -0.20, 95%CI -0.38 to -0.02, p = 0.03, I2 = 0%) though did not alter negative psychotic symptoms at either timepoint. CONCLUSIONS: CBTp may lead to small benefits for positive symptoms refractory to clozapine. Given the low risks associated with CBTp, and the limited alternative options for clozapine refractory schizophrenia, this approach should be considered in this population.

Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis.

Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.

A Systematic Review and Meta-Analysis of the Association Between Periodontal Disease and Severe Mental Illness.

BACKGROUND: Periodontal disease represents a global public health concern, with a disproportionate burden being borne by vulnerable populations. One such group is people with severe mental illness (SMI), and this study examined whether periodontal health is poorer in people with SMI than the general population. METHODS: We conducted a systematic search for studies published before March 2021 on the periodontal health of people with SMI using the following databases: PubMed, PsycINFO, EMBASE, China National Knowledge Infrastructure, and Chongqing VIP. Outcomes were periodontitis, periodontal disease, and shallow and deep periodontal pockets. Results were compared with the general population. RESULTS: Seventeen studies had sufficient data for a random-effects meta-analysis, consisting of 4404 psychiatric patients and 95,411 controls. SMI was associated with an increased prevalence of periodontitis (odds ratio = 1.97, 95% confidence interval [CI] = 1.15-3.35) compared with the general population. People with SMI had 4.28 the odds of having periodontal disease compared with controls (95% CI = 2.54-7.21). They also had 3.65 the odds of shallow pockets (95% CI = 1.80-7.42) and 2.76 the odds of deep pockets (95% CI = 1.10-6.93). CONCLUSIONS: Our findings highlight the increased prevalence and severity of periodontal disease in people with SMI. Oral health is often considered the gateway to overall health and should be a public health priority for this population.

Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis.

BACKGROUND: Treatment-resistant schizophrenia (TRS) is associated with high levels of functional impairment, healthcare usage and societal costs. Cross-sectional studies may overestimate TRS rates because of selection bias. AIMS: We aimed to quantify TRS rates by using first-episode cohorts to improve resource allocation and clozapine access. METHOD: We undertook a systematic review of TRS rates among people with first-episode psychosis and schizophrenia, with a minimum follow-up of 8 weeks. We searched PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews, and meta-analysed TRS rates from included studies. RESULTS: Twelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1-27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5-30.0%, P < 0.001) among first-episode schizophrenia cohorts. Subgroup sensitivity analyses by location of recruitment, TRS definition, study quality, time of data collection and retrospective versus prospective data collection did not lead to statistically significant differences in heterogeneity. In a meta-regression, duration of follow-up and percentage drop-out did not significantly affect the overall TRS rate. Men were 1.57 times more likely to develop TRS than women (95% CI 1.11-2.21, P = 0.010). CONCLUSIONS: Almost a quarter of people with first-episode psychosis or schizophrenia will develop TRS in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third. These high rates of TRS highlight the need for improved access to clozapine and psychosocial supports.

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.

Risk factors for clozapine-induced myocarditis and cardiomyopathy: A systematic review and meta-analysis.

OBJECTIVE: Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and meta-analysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy. METHODS: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale. RESULTS: Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature. CONCLUSION: Concurrent use of sodium valproate increases the odds of clozapine-induced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.

Treatment strategies for clozapine-induced nocturnal enuresis and urinary incontinence: a systematic review.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia but is associated with significant adverse drug reactions, including nocturnal enuresis and urinary incontinence. This side effect can be burdensome and lead to medication nonadherence and psychotic relapse. Evidence to guide treatment of clozapine-induced nocturnal enuresis and urinary incontinence is sparse. We therefore aimed to synthesize the evidence base to guide management for clinicians, patients, and their carers. METHODS: We systematically searched PubMed, Embase, PsycInfo, CINAHL, and the Cochrane Trial Registry databases from inception to May 2021 for publications on management of clozapine-induced nocturnal enuresis and urinary incontinence using a PROSPERO preregistered search strategy. RESULTS: We identified 22 case reports and case series describing 74 patients. Interventions included clozapine dose reduction, nonpharmacological treatment, and pharmacological treatments. Among pharmacological treatments, desmopressin, oxybutynin, trihexyphenidyl, tolterodine, imipramine, amitriptyline, ephedrine, pseudoephedrine, aripiprazole, and verapamil were associated with complete resolution of nocturnal enuresis and urinary incontinence. Balancing evidence for effectiveness against risk of adverse effects, we developed a management framework for clozapine-induced nocturnal enuresis and urinary incontinence. CONCLUSIONS: Following assessment of urological, psychiatric, pharmacological, and common comorbid medical issues, first-line treatments should be nonpharmacological, including bathroom alarms, voiding before bedtime, and nocturnal fluid restriction. If these interventions do not provide adequate relief, aripiprazole should be trialed. Desmopressin may be considered for severe refractory cases, but monitoring for hyponatremia is essential.