Treatment with psychostimulants and atomoxetine in people with psychotic disorders: reassessing the risk of clinical deterioration in a real-world setting.

BACKGROUND: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine. AIMS: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before. METHOD: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year. RESULTS: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001). CONCLUSIONS: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

Problem gambling in psychotic disorders: A systematic review and meta-analysis of prevalence.

INTRODUCTION: Problem gambling (PBG) is more common in people with mental health disorders, including substance use, bipolar, and personality disorders, than in the general population. Although individuals with psychotic disorders might be expected to be more vulnerable to PBG, fewer studies have focused on this comorbidity. The aim of this review was to estimate the prevalence of PBG in people with psychotic disorders. METHODS: Medline (Ovid), EMBASE, PsycINFO (Ovid), CINAHL, CENTRAL, Web of science, and ProQuest were searched on November 1, 2023, without language restrictions. Observational and experimental studies including individuals with psychotic disorders and reporting the prevalence of PBG were included. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal for systematic reviews of prevalence data. The pooled prevalence of PBG was calculated using a fixed effects generalized linear mixed model and presented through forest plots. RESULTS: Of 1271 records screened, 12 studies (n = 3443) were included. The overall prevalence of PBG was 8.7% (95% CI = 7.8%-9.7%, I2 = 69%). A lower prevalence was found in studies with a low risk of bias (5.6%; 95% CI = 4.4%-7.0%) compared with studies with a moderate risk of bias (10.4%; 95% CI = 9.2%-11.7%). Different methods used to assess PBG also contributed to the heterogeneity found. CONCLUSION: This meta-analysis found substantial heterogeneity, partly due to the risk of bias of the included studies and a lack of uniformity in PBG assessment. Although more research is needed to identify those at increased risk for PBG, its relatively high prevalence warrants routine screening for gambling in clinical practice.

Problem gambling among people with first-episode psychosis: protocol for a prospective multicenter cohort study.

BACKGROUND: The limited available data suggest that the prevalence of problem gambling is increased among young adults with first-episode psychosis, possibly due in part to several risk factors for problem gambling that are common in this population. Aripiprazole, a widely used antipsychotic drug, has also been linked to cases of problem gambling, but causality remains uncertain. Although the consequences of problem gambling further hinder the recovery of people with first-episode psychosis, there is a paucity of research about this comorbidity and its risk factors. Additionally, to our knowledge, no screening instrument for problem gambling tailored to these individuals exists, contributing to its under-recognition. Further, treatment approaches for problem gambling adapted to this population are at an embryonic stage, while existing treatments effectiveness remains to be documented. Using an innovative screening and assessment procedure for problem gambling, this study aims to identify risk factors for problem gambling among people with first-episode psychosis and to document the effectiveness of standard treatment approaches. METHODS: This is a multicenter prospective cohort study conducted in two first-episode psychosis clinics, including all patients admitted between November 1st, 2019, and November 1st, 2023, followed for up to 3 years until May 1st, 2024. These 2 clinics admit approximately 200 patients annually, for an expected sample size of 800 individuals. The primary outcome is the occurrence of a DSM-5 diagnosis of gambling disorder. All patients are screened and evaluated for problem gambling using a systematic procedure at admission, and every 6 months thereafter. Socio-demographic and clinical variables are prospectively extracted from the patients' medical records. The nature and effectiveness of treatments for problem gambling offered to affected individuals are also documented from medical records. Survival analyses with Cox regression models will be used to identify potential risk factors for problem gambling. Descriptive statistics will document the effectiveness of treatments for problem gambling in this population. DISCUSSION: A better understanding of potential risk factors for problem gambling among people with first-episode psychosis will allow for better prevention and detection of this neglected comorbidity. Results of this study will also hopefully raise clinicians' and researchers' awareness and serve as the basis to adapted treatments that will better support recovery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05686772. Retrospectively registered, 9 January 2023.

Gaming Disorder and Psychotic Disorders: A Scoping Review.

BACKGROUND: There is a growing interest in understanding the impact of video games in the clinical field, given that their excessive use could be associated with health issues. Particularly, gaming disorder (GD) is considered as an addictive behavioral disorder. Clinicians widely recognize the comorbidity of gaming and psychotic disorders (PDs). Furthermore, association between addictive (i.e., substance use disorders) and PDs are well recognized by clinicians. It seems of high interest to explore GD among people with PDs. To this day, little is known about the consequences of GD in vulnerable populations. OBJECTIVES: The aim of this scoping review was to summarize the available research on the comorbidity between GD and PD and to identify the knowledge gaps in this field. METHODS: We used Levac's six-stage methodology for scoping review. Two-hundred and forty-two articles from seven databases were identified. Eight articles respected our inclusion and exclusion criteria. RESULTS: No available study has assessed the prevalence or incidence of GD among patients with PDs. The cases reported highlight the possibility that excessive video gameplay or abrupt gaming disruption could trigger psychosis in some patients. CONCLUSION: The results highlight a significant lack of knowledge concerning PDs associated with GD as only a few reported cases and one empirical study exposed the potential association between those conditions.

Association between previous and future antipsychotic adherence in patients initiating clozapine: real-world observational study.

BACKGROUND: Although recognised as the most effective antipsychotic for treatment-resistant schizophrenia, clozapine remains underused. One reason is the widespread concern about non-adherence to clozapine because of poor adherence before initiating clozapine. AIMS: To determine if prior poor out-patient adherence to treatmentbefore initiating clozapine predisposes to poor out-patient adherence to clozapine or to any antipsychotics (including clozapine) after its initiation. METHOD: This cohort study included 3228 patients with schizophrenia living in Quebec (Canada) initiating (with a 2-year clearance period) oral clozapine (index date) between 2009 and 2016. Using pharmacy data, out-patient adherence to treatment was measured by the medication possession ratio (MPR), over a 1-year period preceding and following the index date. Five groups of patients were formed based on their prior MPR level (independent variable). Two dependent variables were defined after clozapine initiation (good out-patient adherence to any antipsychotics and to clozapine only). Along with multiple logistic regressions, state sequence analysis was used as a visual representation of antipsychotic-use trajectories over time, before and after clozapine initiation. RESULTS: Although prior poor adherence to antipsychotics was associated with poor adherence after clozapine initiation, the absolute risk of subsequent poor adherence remained low, regardless of previous adherence level. Most patients adhered to their treatment after initiating clozapine (>68% to clozapine and >84% to any antipsychotics). CONCLUSIONS: Despite the fact that poor adherence prior to initiating clozapine is widely recognised by clinicians as a barrier for the prescription of clozapine, the current study supports the initiation of clozapine in all eligible patients.

Clozapine Rechallenge or Continuation Despite Neutropenia, an Extended Follow-up of a Consecutive Quebec Case Series.

BACKGROUND: Clozapine is the most efficacious antipsychotic for treatment-resistant schizophrenia. However, clozapine-induced neutropenia may warrant treatment discontinuation, hindering recovery. Several case reports describe clozapine rechallenge or continuation despite neutropenia, although many are subject to selective reporting, with incomplete information and short follow-up periods. Thus, consecutive case series, devoid of such bias, with long-term comprehensive follow-up are needed to better assess this practice. This study aimed to describe consecutively the evolution of every patient in the Québec City catchment area for whom clozapine was either reintroduced after neutropenia during a previous clozapine trial or was maintained despite a first neutropenia. METHODS: Patients were identified through clozapine's national hematological monitoring database and their medical records between January 1, 2000, and October 22, 2017. RESULTS: Twenty-three patients were identified, 8 continued clozapine despite neutropenia, while 15 discontinued clozapine and attempted rechallenge; among the latter, 4 patients were successfully rechallenged after agranulocytosis without the use of granulocyte colony-stimulating factors, which is the largest published consecutively. A total of 6 patients experienced further neutropenia episodes. Every patient who had a neutropenia recurrence also had a possible explanation for neutropenia other than exposure to clozapine. After a median follow-up of 4.8 years, 16 patients were still on clozapine and 3 cases discontinued because of a hematological event. CONCLUSIONS: This study adds further data on the subject of clozapine rechallenge or continuation despite neutropenia. Clozapine rechallenge after agranulocytosis may be less perilous than first thought, but a systematic review on this specific subject is needed.

The effects of antipsychotic discontinuation or maintenance on the process of recovery in remitted first-episode psychosis patients - A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The optimal duration of antipsychotic treatment following remission of first-episode psychosis (FEP) is uncertain, considering potential adverse effects and individual variability in relapse rates. This study aimed to investigate the effect of antipsychotic discontinuation compared to continuation on recovery in remitted FEP patients. METHODS: CENTRAL, MEDLINE (Ovid), Embase, and PsycINFO databases were searched on November 2, 2023, with no language restrictions. RCTs evaluating antipsychotic discontinuation in remitted FEP patients were selected. The primary outcome was personal recovery, and secondary outcomes included functional recovery, global functioning, hospital admission, symptom severity, quality of life, side effects, and employment. Risk of bias was assessed using the Cochrane risk-of-bias tool 2, and the certainty of evidence was evaluated with GRADE. Meta-analysis used a random-effect model with an inverse-variance approach. RESULTS: Among 2185 screened studies, 8 RCTs (560 participants) were included. No RCTs reported personal recovery as an outcome. Two studies measured functional recovery, and discontinuation group patients were more likely to achieve functional recovery (RR 2.19; 95% CIs: 1.13, 4.22; I2 = 0%; n = 128), although evidence certainty was very low. No significant differences were found in hospital admission, symptom severity, quality of life, global functioning, or employment between the discontinuation and continuation groups. CONCLUSIONS: Personal recovery was not reported in any antipsychotic discontinuation trial in remitted FEP. The observed positive effect of discontinuation on functional recovery came from an early terminated trial and an RCT followed by an uncontrolled period. These findings should be interpreted cautiously due to very low certainty of evidence.

Sex-specific immune mechanisms in PTSD symptomatology and risk: A translational overview and perspectives.

Altered immune function in patients with posttraumatic stress disorder (PTSD) may play a role in the disorder pathophysiology and onset. Women are more likely to develop PTSD, suggesting potential sex-specific inflammatory mechanisms underlying the dichotomous prevalence and risk of PTSD in men and women. In this review we examine the available literature to better assess the state of knowledge in the field. In humans, increased systemic inflammation is found in both men and women with PTSD, but seems to be at a greater extend in women. Despite the existence of few clinical studies taking account of sex as a factor in the observed immune changes in PTSD, challenges in the study of sex-specific immune function in humans include: controlling for confounding variates such as the type of trauma and the ethnicity; and limited methodologies available to study central nervous system (CNS)-relevant changes. Thus, preclinical studies are a valuable tool to provide us with key insights on sex-specific peripheral and CNS immune mechanisms underlying PTSD. Available preclinical studies reported increased systemic and CNS inflammation, as well as elevated trafficking of monocytes from the periphery to the brain in both male and female rodents. To date, psychological trauma-induced inflammation is more robust in female vs male rodents. Limitations of preclinical studies include animal models hardly applicable to female rodents, and hormonal changes across estrus phases that may affect immune function. The present review: (1) highlights the key findings from both human and animal studies, (2) provides guidance to address limitations; and (3) discusses the gap of knowledge on the complex intertwined interaction between the brain, neurovascular, and systemic units.

Impact of gaming disorder on first episode psychosis patients' evolution: Protocol for a multicentered prospective study.

AIMS: The objective of this study is to underline the impact of Gaming Disorder on the clinical evolution of patients with First Episode Psychosis. The specific aims of the study are to determine the prevalence of gaming disorder among those patients and assess the consequences of gaming on their clinical trajectory. METHODS: This is a prospective multicenter cohort study that will enrol 800 patients diagnosed with a first episode psychosis, with a follow-up period of up to 3 years. Using a systematic screening procedure for gaming disorder, the clinical staff will assess patients gaming habits at admission and every 6 months thereafter. Information from patients' medical records will also be extracted using the same timeframe. RESULTS: The patients' characteristics at admission and during follow-up will be presented in the form of descriptive statistics and compared between different subgroups of patients using uni- and multivariate logistic regression models. Repeated measures ANCOVA will also be performed to analyse the impact of gaming disorders on patients' clinical path as assessed by the Positive and Negative Syndrome Scale and the Clinical Global Impression scale, considering covariates such as psychiatric diagnosis, pharmacological treatment, age, sex/gender, and duration of untreated psychosis. CONCLUSION: These findings will guide the development of prevention, detection, and treatment strategies for the comorbidity between gaming disorder and first episode psychosis, ultimately improving the patients' recovery.

Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: A systematic review.

OBJECTIVES: Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs. METHODS: MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis. RESULTS: Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented. CONCLUSIONS: Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.

Management of Rhabdomyolysis in a Patient Treated with Clozapine: A Case Report and Clinical Recommendations.

Clozapine has a unique efficacy in treatment-resistant schizophrenia. Its use is, however, associated with potential adverse events. Among those, clozapine induced rhabdomyolysis can compromise clozapine treatment. Recommendations surrounding the management of this rare adverse event are limited. We present a case of clozapine-induced rhabdomyolysis. A 20-year-old Caucasian male diagnosed with resistant schizophrenia developed, after a 5-month total exposition and a significant response to treatment, a marked creatine kinase (CK) elevation and important myalgia in the weeks following an increment from 175 to 200 mg of the daily dose of clozapine. This event also coincided with weight training as reported by the patient. The patient was hospitalized, and the clozapine was stopped following the diagnosis of rhabdomyolysis (CK 45,564 U/L). The cause of rhabdomyolysis was thoroughly investigated, and clozapine was held accountable for most. Clozapine cessation led to a severe psychotic relapse. Clozapine rechallenge while strictly monitoring CK was then performed allowing a significant clinical response. Clozapine was pursued despite two other episodes of mild CK elevations observed following weight training. Rhabdomyolysis comes as a rare adverse event of clozapine and its mechanism is poorly understood. Evidence on clozapine rechallenge following this adverse event is lacking and the innocuity of such practice is unknown. The unique aspect of our case report is that a shared decision with the medical team, patient and family led to a proactive clozapine rechallenge. More research is needed to provide robust guidelines and evidenced based approaches for clinicians in such a clinical dilemma.

Real-life effectiveness of transitioning from paliperidone palmitate 1-monthly to paliperidone palmitate 3-monthly long-acting injectable formulation.

Background: Non-adherence to antipsychotics in schizophrenia is associated with an increased risk of psychotic relapse and hospitalization, a risk that is reduced with the use of long-acting injectable (LAI) antipsychotics. Randomized clinical trials (RCTs) have demonstrated the efficacy of paliperidone palmitate 3-monthly (PP3M) for psychotic relapse prevention in schizophrenia, but it remains poorly documented among individuals treated in real-life settings who can benefit the most out of LAIs. Objectives: The objective of this study was to evaluate the effectiveness of PP3M in relapse prevention among patients with schizophrenia. Methods: This is a multicentre retrospective study conducted in four outpatients' clinics across Canada. All consecutive patients with a main diagnosis of schizophrenia who initiated PP3M between June 2016 and March 2020 were included. The primary outcome was psychotic relapse, defined using broad and clinically relevant criteria. Results: Among 178 consecutive patients who were switched to PP3M, the 12-month relapse rate was 18.5% and the relapse-free survival probability was 0.788 (95% confidence interval [CI] = 0.725-0.856). Comorbid diagnoses of personality disorders and substance use disorders were associated with hazard rates (HRs) of 3.6 (95% CI = 1.8-7.3, p < 0.001) and 3.1 (95% CI = 1.6-6.2), respectively. Increased psychopathology severity was associated with an increased likelihood of relapse, while having a job or being in school was protective. Conclusion: These findings reinforce the necessity of conducting research in patients with comorbid psychiatric disorders who are typically underrepresented in RCTs, yet overrepresented in real-life settings, in order to better inform and guide clinical practice.

[Psychopharmacology of First Episode Psychosis: An Approach Based on Recovery]. / Une approche de la psychopharmacologie des premiers épisodes psychotiques axée sur le rétablissement.

Objectives Individuals with first-episode psychosis (FEP) are poorly represented in clinical trials leading to drug approval. As a result, there is a relative paucity of empirical data to guide the psychopharmacological treatment of these youths. This article provides a synthesis of this literature, informed by the authors' clinical experience in treating FEP over the past 25 years. Methods This selective review of the literature focuses on the psychopharmacological treatment of FEP and includes both randomized trials and observational studies. It is organized around the following themes for FEP: response and remission rates; relapse rates; specifics regarding susceptibility to adverse events; comparisons of efficacy, safety and relapse prevention among various molecules and dosage forms; recommendations for duration of treatment; approach to treatment resistance; and use of clozapine. For each of these themes, research data are interpreted and supplemented by commentary based on the authors' clinical experience, with a strong focus on the individual's recovery. Results Symptom remission is achieved in approximately 75% of individuals during the initial treatment of a FEP, its maintenance being a very strong predictor of functional recovery. The rate of psychotic relapse during the three years following a FEP is about 60%, the problem of adherence to treatment being the main cause of these relapses. The FEP population is distinguished by a greater propensity for adverse events, including weight gain and extrapyramidal reactions. With the exception of treatment-resistant FEP, no clear difference has been demonstrated in the efficacy of the various molecules, but they do differ in their adverse events profile and formulations. As such, the use of long-acting injectable antipsychotics (LAIs) is superior to oral agents in preventing relapse. While the guidelines recommend continued treatment for 18 months after remission is achieved, these recommendations are based on empirical data that are still unclear, necessitating the use of a shared-decision approach with the patient and his/her family. In the group of people who do not achieve a satisfactory response after two trials of antipsychotics, clozapine is effective in up to 80% of people. Conclusions The FEP population is characterized by a high response rate, relapses frequently related to non-adherence to treatment, and increased susceptibility to adverse events. Tailoring pharmacological treatment for FEP aims at sustained remission of all symptom dimensions combined with proactive management of adverse events, including through judicious use of LAIs and clozapine.

Clozapine rechallenge following neutropenia using granulocyte colony-stimulating factor: A Quebec case series.

BACKGROUND: Clozapine has a unique efficacy profile among individuals suffering from treatment-resistant schizophrenia, but is associated with hematological side effects. The use of granulocyte colony-stimulating factors (G-CSF) to allow clozapine continuation or rechallenge has emerged as a promising option, but evidence is still scarce. AIM: To describe the largest case series so far published regarding this practice. METHOD: A national clozapine hematological monitoring database was consulted to identify all patients who had had neutrophil count <1.5 × 109/L since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who had received at least one dose of G-CSF, such as filgrastim, while being exposed to clozapine. All data were collected retrospectively, using patients' medical files, from January to July 2019. RESULTS: Using G-CSF, three out of eight patients could maintain clozapine despite neutropenia episodes that otherwise would have required treatment discontinuation. The only side effect reported was mild short-lived back pain, over a mean 3-year follow-up period. In all but one case, filgrastim was used on an "as-needed" basis at doses of 300 mcg administered subcutaneously. CONCLUSION: These results suggest that the "as-needed" use of G-CSF is well-tolerated and may allow clozapine rechallenge in some well-selected patients, adding to the paucity of data regarding long-term safety and efficacy of this strategy. More research may help to better define potential candidates and optimal regimen of such practice.