Dysmyelination could be part of the pathophysiology of schizophrenia spectrum (SCZ) and bipolar disorders (BPD), yet few studies have examined myelination of the cerebral cortex. The ratio of T1- and T2-weighted magnetic resonance images (MRI) correlates with intracortical myelin. We investigated the T1w/T2w-ratio and its age trajectories in patients and healthy controls (CTR) and explored associations with antipsychotic medication use and psychotic symptoms.

Patients with SCZ (n = 64; mean age = 30.4 years, s.d. = 9.8), BPD (n = 91; mean age 31.0 years, s.d. = 10.2), and CTR (n = 155; mean age = 31.9 years, s.d. = 9.1) who participated in the TOP study (NORMENT, University of Oslo, Norway) were clinically assessed and scanned using a General Electric 3 T MRI system. T1w/T2w-ratio images were computed using an optimized pipeline with intensity normalization and field inhomogeneity correction. Vertex-wise regression models were used to compare groups and examine group × age interactions. In regions showing significant differences, we explored associations with antipsychotic medication use and psychotic symptoms.

No main effect of diagnosis was found. However, age slopes of the T1w/T2w-ratio differed significantly between SCZ and CTR, predominantly in frontal and temporal lobe regions: Lower T1w/T2w-ratio values with higher age were found in CTR, but not in SCZ. Follow-up analyses revealed a more positive age slope in patients who were using antipsychotics and patients using higher chlorpromazine-equivalent doses.

While we found no evidence of reduced intracortical myelin in SCZ or BPD relative to CTR, different regional age trajectories in SCZ may suggest a promyelinating effect of antipsychotic medication.

The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects.

A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism.

The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation.

Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

Combination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported.

Patients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study.

In total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: −16.2 [−18.5, −14.0] and −0.9 [−1.0, −0.8], respectively).

OLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.

Patients treated by neuroleptics often develop neuroleptic-induced parkinsonism (NIP) to a varying extent. The reasons for this are discussed controversially in the literature. Previous transcranial sonography (TCS) findings of the substantia nigra (SN) in patients with idiopathic Parkinson’s disease suggest a correlation of echogenicity with nigrostriatal dysfunction.

One hundred psychiatric patients receiving neuroleptics were included. They underwent clinical examination for NIP (Simpson and Angus-scale) and, independently, TCS of the SN. History of smoking habits and medication were taken from the patient’s chart.

We found a significant positive association of the prevalence of NIP with age (P < 0.01) and the echogenic area of the SN (P < 0.05). Neither type nor dosage of the neuroleptics was found to have any significant impact on the occurrence of NIP. Smokers displayed lower prevalence of NIP (P < 0.05) and lower EPS scores (P < 0.01).

These findings suggest that age and increased size of SN echogenicity are possible risk factors for NIP. In contrast, smoking seems to have a certain protecting effect.

To see if patient satisfaction with psychotropics (PSP) could be used as a patient-oriented outcome variable in the evaluation of PSP drugs in clinical epidemiological studies, relationships between PSP, clinical status, QoL, compliance and the type of antipsychotic were analyzed. Elements of validation of PSP were also assessed.

In a 6-month prospective study, 933 schizophrenic outpatients with initiation or change to their antipsychotic treatment were enrolled. Psychiatrists completed five CGI-SCH scales (positive, negative, cognitive, depressive and global), hospitalization, compliance, and prescription variables. Patients completed PSP, EuroQoL scales, sexual function and compliance variables.

A satisfactory structural equation model was obtained showing significant relationships PSP/compliance (coef. = 0.16), QoL/PSP (coef. = 0.37), clinical status/QoL (coef. = 0.61), clinical status/compliance (coef. = 0.09). Patients receiving olanzapine were more satisfied than patients receiving other atypicals (coef. =0 12) and had better clinical status than patients treated with typicals (coef. = 0.08). Evolution of PSP was related to clinical status, QoL, and continuation of treatment (all P < 001). Sensitivity to change of PSP was moderate (effect size = 0.2).

PSP produced consistent results in relation to validated outcome variables. However, a single-item measure was not sufficiently sensitive to change. Multi-item questionnaires evaluating different dimensions are needed.

Sexual dysfunction in patients with schizophrenia can reduce quality of life and treatment compliance. This report will compare the effects of selected atypical and typical antipsychotics on sexual function in a large, international population of outpatients with schizophrenia who were treated over 1 year.

Outpatients with schizophrenia, who initiated or changed antipsychotic treatment, and entered this 3-year, prospective, observational study were classified according to the monotherapy prescribed at baseline: olanzapine (N = 2638), risperidone (N = 860), quetiapine (N = 142) or haloperidol (N = 188).

Based on patient perception, the odds of experiencing sexual dysfunction during 1 year of therapy was significantly lower for patients treated with olanzapine and quetiapine when compared to patients who received risperidone or haloperidol (all P ≤ 0.001). Females on olanzapine (14%) or quetiapine (8%) experienced a lower rate of menstrual irregularities, compared to females on risperidone (23%) or haloperidol (29%). Significant discordance was evident between patient reports and psychiatrist perception of sexual dysfunction, with psychiatrists underestimating sexual dysfunction (P ≤ 0.001).

These findings indicate clinically relevant differences exist in the sexual side effect profiles of these selected antipsychotics. These factors should be considered when selecting the most appropriate treatment for outpatients with schizophrenia.

This article presents the long-term results in terms of antipsychotic medication maintenance and factors influencing it in a representative sample of patients with schizophrenia recruited in the SOHO study within Spain.

The SOHO was a prospective, 3-year observational study of the outcomes of schizophrenia treatment in outpatients who initiated therapy or changed to a new antipsychotic performed in 10 European countries with a focus on olanzapine. The Kaplan–Meier method was used to analyse the time to treatment discontinuation and the Cox proportional hazards model to investigate correlates of discontinuation.

In total, 1688 patients were included in the analyses. Medication maintenance at 3 years varied with the antipsychotic prescribed, being highest with clozapine (57.6%, 95% CI 39.2–74.5), followed by olanzapine (48.3%, 95% CI 45.1–51.5); and lowest with quetiapine (19.0%, 95% CI 13.0–26.3). Treatment discontinuation was significantly less frequent with olanzapine than with risperidone (p = 0.015), depot typical (p = 0.001), oral typical antipsychotics (p < 0.001) or quetiapine (p < 0.001); but not than with clozapine (p = 0.309). Longer maintenance was also associated with higher social abilities and better cognitive status at baseline; in contrast, a shorter time to discontinuation was associated with the need for mood stabilisers during follow-up. This study emphasises the different value of antipsychotics in day-to-day clinical practice, as some of them were associated with longer medication maintenance periods than others. This study has some limitations because of possible selection and information biases derived from the non-systematic, non-randomised allocation to treatments and the existence of unobserved covariates that may influence the outcome.

The evidence informing the management of cardiovascular risk in patients with psychiatric disorders is weak.

This cohort study used data from all patients, aged ≥ 30, registered in 140 primary care practices (n = 524,952) in London to estimate the risk of developing diabetes, hypertension, hyperlipidemia, tobacco consumption, obesity, and physical inactivity, between 2005 and 2015, for patients with a previous diagnosis of schizophrenia, depression, anxiety, bipolar or personality disorder. The role of antidepressants, antipsychotics and social deprivation in these associations was also investigated. The age at detection of cardiovascular risk factor was compared between patients with and without psychiatric disorders. Variables, for exposures and outcomes, defined from general practitioners records, were analysed using multivariate regression.

Patients with psychiatric disorders had an increased risk for cardiovascular risk factors, especially diabetes, with hazard ratios: 2.42 (2.20–2.67) to 1.31 (1.25–1.37), hyperlipidemia, with hazard ratios: 1.78 (1.60–1.97) to 1.25 (1.23–1.28), and obesity. Antidepressants, antipsychotics and social deprivation did not change these associations, except for smoking and physical inactivity. Antidepressants were associated with higher risk of diabetes, hypertension and hyperlipidemia. Antipsychotics were associated with a higher risk of diabetes. Antidepressants and antipsychotics were associated with lower risk of other risk factors. Patients with psychiatric conditions have later detection of cardiovascular risk factors. The interpretation of these results should acknowledge the lower rates of detection of risk factors in mentally ill patients.

Cardiovascular risk factors require special clinical attention among patients with psychiatric disorders. Further research could study the effect of antidepressants and antipsychotics on cardiovascular risk factors.

The Antipsychotic Long-acTing injection in schizOphrenia (ALTO) study was a non-interventional study across several European countries examining prescription of long-acting injectable (LAI) antipsychotics to identify sociodemographic and clinical characteristics of patients receiving and physicians prescribing LAIs. ALTO was also the first large-scale study in Europe to report on the use of both first- or second-generation antipsychotic (FGA- or SGA-) LAIs.

Patients with schizophrenia receiving a FGA- or SGA-LAI were enrolled between June 2013 and July 2014 and categorized as incident or prevalent users. Assessments included measures of disease severity, functioning, insight, well-being, attitudes towards antipsychotics, and quality of life.

For the 572 patients, disease severity was generally mild-to-moderate and the majority were unemployed and/or socially withdrawn. 331/572 were prevalent LAI antipsychotic users; of whom 209 were prescribed FGA-LAI. Paliperidone was the most commonly prescribed SGA-LAI (56% of incident users, 21% of prevalent users). 337/572 (58.9%) were considered at risk of non-adherence. Prevalent LAI users had a tendency towards better insight levels (PANSS G12 item). Incident FGA-LAI users had more severe disease, poorer global functioning, lower quality of life, higher rates of non-adherence, and were more likely to have physician-reported lack of insight.

These results indicate a lower pattern of FGA-LAI usage, reserved by prescribers for seemingly more difficult-to-treat patients and those least likely to adhere to oral medication.

Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set.

The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed.

GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain.

The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

Patients with major mental illness are recognised to be at risk of premature death for a multitude of reasons. This initiative aimed to improve the physical health monitoring of patients prescribed depot antipsychotic medication in a catchment area of ~36 000 in Ireland.

International best practice recommends monitoring of blood tests, physical parameters such as weight, BMI, waist circumference and blood pressure, and side effects of patients prescribed antipsychotic medication. A clinic was established to target these interventions.

A cohort of patients receiving antipsychotics in long-acting injectable form was chosen. A twice-yearly, multidisciplinary health monitoring clinic was established. Evaluation involved an audit of medical records which measured the proportion of those attending the clinic who had blood test monitoring and physical parameters recorded.

Before the clinic’s implementation, 30% of patients had evidence of some blood test monitoring, 9% had evidence of complete blood testing and one patient had evidence of physical health parameters having been recorded. One year after the implementation 78% of patients had evidence of some blood test monitoring, 61% had evidence of full blood test monitoring and 100% had evidence of physical parameters recorded.

The clinic was positively received by patients, and led to improved teamwork. Recommendations include organising concurrent psychiatric and phlebotomy clinics so that patients may avail of psychiatric review and blood testing at a single appointment. As a result of the increased focus on physical health monitoring, a similar project is planned to target all patients prescribed antipsychotics.