The Canadian Journal of Psychiatry

One in every 4 individuals born with a 22q11.2 microdeletion will develop schizophrenia. Thirty years of clinical genetic testing capability have enabled detection of this major molecular susceptibility for psychotic illness. However, there is limited literature on the treatment of schizophrenia in individuals with a 22q11.2 microdeletion, particularly regarding the issue of treatment resistance.

From a large, well-characterized adult cohort with a typical 22q11.2 microdeletion followed for up to 25 years at a specialty clinic, we studied all 107 adults (49 females, 45.8%) meeting the criteria for schizophrenia or schizoaffective disorder. We performed a comprehensive review of lifetime (1,801 patient-years) psychiatric records to determine treatments used and the prevalence of treatment-resistant schizophrenia (TRS). We used Clinical Global Impression–Improvement (CGI-I) scores to compare within-individual responses to clozapine and nonclozapine antipsychotics. For a subgroup with contemporary data (n = 88, 82.2%), we examined antipsychotics and dosage at the last follow-up.

Lifetime treatments involved on average 4 different antipsychotic medications per individual. Sixty-three (58.9%) individuals met the study criteria for TRS, a significantly greater proportion than for a community-based comparison (42.9%; χ² = 10.38, df = 1, p < 0.01). The non-TRS group was enriched for individuals with genetic diagnosis before schizophrenia diagnosis. Within-person treatment response in TRS was significantly better for clozapine than for nonclozapine antipsychotics (p < 0.0001). At the last follow-up, clozapine was the most common antipsychotic prescribed, followed by olanzapine, risperidone, and paliperidone. Total antipsychotic chlorpromazine equivalent dosages were in typical clinical ranges (median: 450 mg; interquartile range: 300, 750 mg).

The results for this large sample indicate that patients with 22q11.2 microdeletion have an increased propensity to treatment resistance. The findings provide evidence about how genetic diagnosis can inform clinical psychiatric management and could help reduce treatment delays. Further research is needed to shed light on the pathophysiology of antipsychotic response and on strategies to optimize outcomes.

Real-world treatment of schizophrenia in adults with a 22q11.2 microdeletion

Tobacco smoking is the leading cause of preventable death among individuals with serious mental illness (SMI) but few persons with SMI are offered smoking cessation treatment. The purpose of this study was to pilot-test a multicomponent intervention to increase the delivery of evidence-based smoking cessation treatment in community mental health clinics (CMHCs).

This study was carried out at five CMHCs in Maryland involving clinicians who participated in training in smoking cessation. Other implementation activities included the provision of a treatment protocol, coaching, expert consultation, and organizational strategy meetings. The primary outcome was a change in clinicians’ knowledge and self-efficacy about smoking cessation. Secondary outcomes included documentation of evidence-based smoking cessation practices including assessment of smoking status and readiness to quit, and provision of smoking cessation treatment over the course of the 12-month intervention period.

A total of 91 clinicians participated in the study. Data were available on 6,011 clients. Clinicians’ scores on the knowledge and self-efficacy measures increased modestly over the course of the implementation period. Overall, 57% of clients had their smoking status assessed; 81% of current smokers were evaluated about their willingness to quit; 82% of those willing to quit within 90 days received behavioral counseling, and 36% were prescribed or given smoking cessation pharmacotherapy. Clinicians rated the smoking cessation program highly in terms of acceptability, appropriateness, and feasibility.

Clinicians at CMHCs were engaged by and participated in training and implementation activities around smoking cessation practices which they then delivered to a substantial portion of clients in their care. The results of this study provide important data for the future planning of testing implementation strategies to scale up tobacco cessation treatment in this population in outpatient mental health settings.

Implementing Smoking Cessation Treatment in Community Mental Health Clinics.

To establish whether the risk of psychotic disorders in cannabis users changes with time following cannabis cessation using data from the European Network of National Networks studying Gene–Environment Interactions in Schizophrenia (EU-GEI) case–control study.

The EU-GEI case–control study collected data from first episode psychosis patients and population controls across sites in Europe and Brazil between May 2010 and April 2015. Adjusted logistic regressions were applied to examine whether the odd of psychosis case status changed: (1) with time following cannabis cessation and (2) across different cannabis use groups.

Psychosis risk declined following cessation of cannabis use (β = −0.002; 95% CI −0.004 to 0.000; P = 0.067). When accounting for duration of use, this effect remained (β = −0.003; 95% CI −0.005 to −0.001; P = 0.013). However, in models adjusting for frequency and potency of use the result was not significant. Analysis of different cannabis use groups indicated that ex-users who stopped 1 to 4 weeks previously had the highest risk for psychotic disorder compared to never users (OR = 6.89; 95% CI 3.91–12.14; P < 0.001); risk declined for those who stopped 5 to 12 weeks previously (OR = 2.70; 95% CI 1.73–4.21; P < 0.001) and 13 to 36 weeks previously (OR = 1.53; 95% CI 1.00–2.33; P = 0.050). Ex-users who stopped 37 to 96 weeks (OR = 1.01; 95% CI 0.66–1.57; P = 0.949), 97 to 180 weeks (OR = 0.73; 95% CI 0.45–1.19; P = 0.204), and 181 weeks previously or more (OR = 1.18; 95% CI 0.76–1.83; P = 0.456) had similar psychosis risk to those who had never-used cannabis.

Risk of psychotic disorder appears to decline with time following cannabis cessation, receding to that of those who have never used cannabis after 37 weeks or more of abstinence. Although, preliminary results suggest that frequent users of high potency types of cannabis might maintain an elevated risk compared to never users even when abstaining for longer than 181 weeks.

Electroconvulsive therapy (ECT) is an evidence-based treatment for schizophrenia when anti-psychotic medications do not sufficiently control symptoms of psychosis or rapid response is required. Little is known about how it is used in routine clinical practice. The aim of this study was to identify the association of demographic and clinical characteristics with administration of ECT for schizophrenia spectrum disorders (SSD).

Among psychiatric inpatients with a diagnosis of SSD in Ontario, Canada (2006–2023), patient-level socio-demographic and clinical characteristics were described in those who did and did not receive ECT. We used multi-variable logistic regression to assess the association between patient-level characteristics and administration of ECT during index hospitalization.

From 164,632 admissions, 2,168 (1.3%) involved exposure to ≥1 inpatient ECT procedure. Compared to those not receiving ECT, those receiving ECT were older, had higher rates of pre-admission medication use, medical and psychiatric comorbidities, outpatient mental health service use, but lower rates of substance use disorders. In the multi-variable logistic regression model, patient-level characteristics most strongly associated with receiving inpatient ECT were the presence of catatonia (odds ratio [OR]: 5.83; 95% confidence interval [95% CI]: 4.01–8.46), comorbid depression (OR: 2.49; 95% CI: 2.07–2.98), obsessive-compulsive disorder (OR: 2.16; 95% CI: 1.55–3.00), while characteristics most strongly associated with not receiving inpatient ECT were myocardial infarction (OR: 0.44; 95% CI: 0.20–0.95) and family conflict towards patient (OR: 0.47; 95% CI: 0.31–0.71). Neither severity of psychotic symptoms, non-command auditory hallucinations nor delusions were associated with administration of ECT.

While characteristics associated with the use of ECT are generally consistent with the indications for ECT (e.g., catatonia, mood disorders), ECT is rarely used amongst individuals with SSD. Severity of psychotic symptoms was not associated with the use of inpatient ECT suggesting an opportunity to increase the use of ECT in this population.

Patient characteristics associated with receiving electroconvulsive therapy in schizophrenia and other psychotic illnesses

The majority of patients with schizophrenia experience dramatic improvement in psychotic symptoms when treated with antipsychotic medication. Maintenance treatment can prevent relapses but problems with medication adherence limit effectiveness. Long-acting injectable antipsychotics (LAIs) provide an opportunity to establish adherence but challenges remain in ensuring that the dose selected is therapeutic. Therapeutic drug monitoring has not been established as valuable for LAIs in the maintenance treatment of schizophrenia. This exploratory study was undertaken to describe plasma paliperidone levels in outpatients treated with the LAI paliperidone palmitate and to determine whether paliperidone levels are associated with subjective experience on medication and side effects.

Twenty-one outpatients with schizophrenia receiving treatment with LAI paliperidone consented to participation in this study. Blood samples were obtained for measurement of paliperidone and prolactin levels at the first visit. A second paliperidone level was obtained at the time of the next injection for 18 of the participants. Clinical rating scales were administered at the first visit to assess illness severity, attitudes regarding medication, subjective well-being and side effects.

Paliperidone levels were highly correlated at the two time points (ρ = .85; P < .001). Mean paliperidone level at the first visit was 34.9 ng/ml and ranged from 5.1 to 73.9 ng/ml. Higher paliperidone levels were correlated with higher prolactin levels (ρ = 0.59, P < .01) and lower sexual desire (ρ = −.58, P < .01).

We demonstrated that paliperidone levels can be measured reliably in patients receiving LAI paliperidone. Higher plasma levels were associated with higher prolactin levels and reduced sexual desire but not with measures of subjective experience on medications or other side effects. Measurement of paliperidone levels in patients treated with paliperidone palmitate may have the potential to minimize the dose of medication prescribed and, in turn, the severity of sexual side effects.

Can the Dosing of Long-Acting Injectable Paliperidone for the Treatment of Schizophrenia Be Improved by Measuring Drug Levels?

Antipsychotic medications are able to make the hallucinations and delusional thoughts go away for most people who have schizophrenia. Providing the medication in the form of an injection that can be given every few weeks or months can help people with schizophrenia stay well. It can be hard to know what dose of the injectable antipsychotic paliperidone will be best for each person. If the dose is too low, symptoms will return. If the dose is too high, side effects can be difficult to tolerate. This exploratory study was done to see whether measuring the amount of paliperidone in the blood can be used to make sure that the dose is likely to be effective and well tolerated.

People with schizophrenia who were being treated with the long-acting injectable paliperidone had their blood drawn to measure the level of medication just before they received their next injection. Researchers also measured the symptoms and side effects that participants were experiencing to see whether people who had higher levels of paliperidone in their blood had more side effects.

Even at the same dose of medication, some people had very small amounts of medication in their blood and others had much higher amounts. People with higher amounts in their blood experienced less sexual desire.

The amount of paliperidone in the blood is a better measure of how much medication a person is getting than the dose they are given. Measuring paliperidone blood levels may lead to lower doses with fewer sexual side effects. It may make it easier for people with schizophrenia to continue on medication and to stay well.

Currently, there are no effective treatments for functional outcomes (i.e., role and social) and negative symptoms for youth at clinical high-risk (CHR) for psychosis. Investigations into possible mechanisms that may contribute to the improvement of functioning and negative symptoms are needed in CHR research to help inform psychosocial treatments. The present study examined whether functioning and negative symptoms were mediated by asocial beliefs, defeatist beliefs, self-efficacy, maladaptive schemas, anxiety, depression, social cognition, or attenuated psychotic symptoms (APS) in a large clinical trial.

CHR participants (n = 203; 104 females; 99 males) were recruited as part of a three-site randomized control trial comparing group cognitive-behavioural social skills training (CBSST) versus a supportive therapy group. Mediation analyses were conducted to test the relationships between treatment group, mediators (asocial beliefs, defeatist beliefs, self-efficacy, maladaptive schemas, anxiety, depression, social cognition, and APS), and outcome (social and role functioning, and negative symptoms). The mediation analyses employed conditional process path analysis via ordinary least squares regression.

At the end of treatment, but not 12-month follow-up, more severe APS were found to mediate the impact of treatment on negative symptoms, and social and role functioning. The greater the severity of APS, the less likely that CBSST would result in improvement in negative symptoms and social and role functioning. Many of the other variables showed significant associations with social (less for role) functioning and negative symptoms but did not mediate the effect of treatment on these outcomes at the end of treatment or 12-month follow-up.

There were no significant mediators except for APS at the end of treatment. Since more severe APS may result in participants being unable to fully participate in therapy and thus limit their gains, clinical implications may include offering some individual therapy to prepare these young people to benefit from the group treatment.

Formal thought disorders (FTDs), a core feature of schizophrenia, have been subdivided into positive and negative types, and are clinically assessed by examining speech (objective) or patient introspection (subjective). Despite being associated with poorer treatment response and worse outcomes, FTDs have been understudied in patients with schizophrenia, in particular treatment-resistant schizophrenia (TRS) or schizoaffective disorder. We aimed to explore the relationship between the severity of positive and negative FTDs and neurocognition as well as social/occupational functioning in this clinical subgroup.

This was a retrospective chart review conducted at the Clozapine Clinic at the Centre for Addiction and Mental Health, Toronto, Canada. We reviewed charted standardized assessment of FTDs using the Thought and Language Disorder (TALD) scale, neurocognition using the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS), and functioning using the Social and Occupational Functioning Assessment Scale (SOFAS) between October 2022 and June 2023. Following the original factor structure of the TALD, we computed 4- factor scores that combined positive or negative and objective or subjective FTDs. We then explored the correlation between the scores from each TALD factor and the neurocognition and functioning scores.

We analysed data for 23 outpatients on clozapine. After the Bonferroni adjustment, total TALD scores, indicating overall severity of FTDs, were strongly and inversely correlated with SOFAS scores (p < 0.001). A strong inverse correlation was found between the objective positive TALD factor and Letter-Number Span verbal working memory scores, r(21) = −0.63, p < 0.001.

Our results demonstrate the strong relationship between FTDs, neurocognition, and social/occupational functioning in a sample of TRS outpatients. Within the cognitive domains assessed, verbal working memory impairment had the strongest correlation with positive FTDs, such as derailment or tangentiality. These findings highlight the value of employing standardized psychopathological scales for FTDs in clinical practice.

Accelerated brain aging, i.e., the age-related structural changes in the brain appearing earlier than expected from one's chronological age, is a feature that is now well established in schizophrenia. Often interpreted as a feature of a progressive pathophysiological process that typifies schizophrenia, its prognostic relevance is still unclear. We investigate its role in response to antipsychotic treatment in first-episode schizophrenia.

We recruited 49 drug-naive patients with schizophrenia who were then treated with risperidone at a standard dose range of 2–6 mg/day. We followed them up for 3 months to categorize their response status. We acquired T1-weighted anatomical images and used the XGboost method to evaluate individual brain age. The brain age gap (BAG) is the difference between the predicted brain age and chronological age.

Patients with FES had more pronounced BAG compared to healthy subjects, and this difference was primarily driven by those who did not respond adequately after 12 weeks of treatment. BAG did not worsen significantly over the 12-week period, indicating a lack of prominent brain-ageing effect induced by the early antipsychotic exposure per se. However, highly symptomatic patients had a more prominent increase in BAG, while patients with higher BAG when initiating treatment later showed lower gains in global functioning upon treatment, highlighting the prognostic value of BAG measures in FES.

Accelerated brain aging is a feature of first-episode schizophrenia that is more likely to be seen among those who will not respond adequately to first-line antipsychotic use. Given that early poor response indicates later treatment resistance, measuring BAG using structural MRI in the first 12 weeks of treatment initiation may provide useful prognostic information when considering second-line treatments in schizophrenia.

Stress and traumatic experiences are well-established risk factors for psychiatric disorders. Stressful events can induce symptoms of anxiety and depression and may lead to overt psychosis, especially when there is an innate biological vulnerability. This study explores the role of the stress-regulating endocannabinoid system, specifically the activity of the enzyme fatty acid amid hydrolase (FAAH), a key regulatory enzyme for endocannabinoids, in association with stress by analysing data from healthy individuals and patients with psychosis.

We performed a post-hoc exploratory analysis on 65 positron emission tomography scans using the selective FAAH radioligand [¹¹C]CURB, encompassing 30 patients with psychosis (6 female) and 35 healthy controls (19 female). The study aimed to examine the association between FAAH activity and stressful life events, assessed through the Recent Life Events, Survey of Life Experiences, and Hassles and Uplifts Scale.

There was a significant difference regarding the number of recent stressors with higher levels in patients compared to healthy subjects (Survey of Life Experiences: t = 4.88, p < 0.001, hassles: t = 3.14, p = 0.003), however there was no significant relationship of brain FAAH activity and stressful life events in any of the applied scales across groups (Recent Life Events: F_1,57= 0.07, p = 0.80; Survey of Life Experiences: F_1,57= 1.75, p = 0.19; hassles: F_1,56= 1.06, p = 0.31). Linear mixed models performed separately for each group revealed that there was a positive association between FAAH activity and Recent Life Events in patients with psychosis only (F_1,25= 8.07, p = 0.009).

Our data reveal a significant disparity in recent stressors between the two groups, and a correlation between brain FAAH activity and stressful life events in patients with psychosis only. This suggests a complex interplay between stress and the endocannabinoid system.

How Stress Affects the Brain’s Endocannabinoid System in Early Psychosis: A PET Study

The pathophysiological mechanisms influencing psychosis spectrum disorders are largely unknown. The glymphatic system, which is a brain waste clearance pathway, has recently been implicated in its pathophysiology and has also been shown to be disrupted in various neurodegenerative and vascular diseases. Initial studies examining the glymphatic system in psychosis spectrum disorders have reported disruptions, but the findings have been confounded by medication effects as they included antipsychotic-treated patients. In this study, we used diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) as a technique to measure the functionality of the glymphatic system in a sample of antipsychotic-minimally exposed patients with psychosis spectrum disorders and healthy controls.

The study included 13 antipsychotic-minimally exposed (2 weeks antipsychotic exposure in the past 3 months/lifetime) patients with psychosis spectrum disorders and 114 healthy controls. We quantified water diffusion metrics along the x-, y-, and z-axes in both projection and association fibres to derive the DTI-ALPS index, a proxy for glymphatic activity. Between-group differences were analyzed using two-way ANCOVA controlling for age and sex. Partial correlations were used to assess the association between the ALPS index and clinical variables.

Analyses revealed that antipsychotic-minimally exposed psychosis spectrum disorder patients had a lower DTI-ALPS index value than healthy controls in both hemispheres and the whole brain (all P < 0.005). Significant differences were also observed between the x and y projections/associations between patients and healthy controls (P < 0.001). Furthermore, we did not find any significant correlations (all P > 0.05) between the DTI-ALPS index with age, body mass index, symptomatology, and metabolic parameters.

This study shows that the glymphatic system is dysregulated in antipsychotic-minimally exposed patients with psychosis spectrum disorders. Understanding the mechanisms that influence the glymphatic system may help to understand the pathophysiology of psychosis spectrum disorders as proper waste clearance is needed for normal brain functioning.