Fronto-limbic white matter microstructural changes in psychiatrically healthy adults with childhood trauma.

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Antipsychotic treatment effects and structural MRI brain changes in schizophrenia.

BACKGROUND: Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia. METHODS: A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest. RESULTS: The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms. CONCLUSIONS: We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

The 3-year progression of clinically significant psychotic-like experiences in a general adult population in Lagos, Nigeria.

PURPOSE: The study assessed the 3-year progression of clinically significant psychotic-like experience (CS-PLE) symptoms in an adult general population in terms of stability or remission of symptoms and transition to psychosis. METHODS: Participants (n = 1292) aged 18-65 years with CS-PLE were assessed at baseline for sociodemographic details, family history of mental illness, functioning status, common mental disorders, alcohol, and substance use disorders. Three years later they were reassessed for diagnosis of psychosis, presence or remission of PLE symptoms, and contact with mental health services. RESULTS: The mean age of the participants at baseline in years was 36.56 (SD = 11.66) and there were 855 (66.2%) females. By the 3rd year follow-up, 95 (7.3%) had transited to psychosis, while 850 (65.5%) had persistent CS-PLE symptoms and the rest 347 (27.2%) were in remission. Only history of mental illness in the immediate family (HR 4.81, 95% CI 1.40-16.47, P = 0.013) and regular use of cannabis at less than 18 years of age (HR 0.65, 95% CI 0.55-0.77, P < 0.001) were the independent predictors of conversion to psychosis at 3 years. CONCLUSION: The rate of TTP in the non-clinical population with elevated risk may be lower than that earlier reported in the western literature. Interventions aimed at preventing transition to psychosis in high risk groups must pay attention to early onset users of cannabis and those with family history of mental illness.

Childhood trauma exposure and reward processing in healthy adults: A functional neuroimaging study.

The association between childhood trauma exposure and risk of developing psychopathology may in part be mediated by the effects of chronic stress on dopaminergic neurotransmission. However, little is known about the differential effects of distinct trauma types on reward processing, particularly in adults without concurrent medical or psychiatric disorders. We examined the association of childhood trauma exposure, including the differential effects of abuse and neglect, with reward processing in healthy adults (n = 114). Functional magnetic resonance imaging during a monetary incentive delay task was used to assess neural activity in the ventral striatum and orbitofrontal cortex in relation to reward anticipation and reward outcome, respectively. Exposure to childhood trauma, including abuse and neglect, was assessed using the Childhood Trauma Questionnaire-Short Form. We found a significant effect for abuse on ventral striatal activation during reward anticipation, adjusting for age, sex, scanner site, educational level, and household monthly income. There were no effects for abuse or neglect, independently or combined, on orbitofrontal cortex activation during reward outcome. Our findings suggest differential effects of childhood abuse on ventral striatum activation during reward anticipation in healthy adults.

Cognitive insight is associated with perceived body weight in overweight and obese adults.

BACKGROUND: Accurate perception of body weight is necessary for individuals with a high body mass index (BMI) to initiate strategies to improve their health status. Furthermore, identifying factors that influence accurate body weight perception can assist in designing appropriate educational and weight management programs. We therefore aimed to investigate whether levels of cognitive functioning and insight influence the ability to correctly judge body weight. METHODS: One hundred and eighty four overweight and obese adults who participated in a cross- sectional case-control study and were controls in the aforementioned study were included. The study was conducted in Cape Town, South Africa. Demographic, weight-related, neuropsychiatric, neurocognitive and cognitive insight measures were administered. Regression analysis was conducted to determine the factors associated with correct weight perception. RESULTS: The final regression model explained 52.3% of variation in accurate perception of body weight and was significant (p ≤ 0. 001). The model correctly classified 79.3% of individuals who were able to correctly and incorrectly judge their weight. Adults with higher BMI, and lower self-certainty, those who reported that they had gained weight in the previous year and those who were told by a healthcare professional to lose or maintain a healthy weight were more likely to correctly judge their weight. CONCLUSION: Some aspects of cognitive insight (self-certainty) but not cognitive functioning were associated with perception of body weight in this sample. Awareness of recent weight changes, higher BMI and advice from of health care professionals were also significantly associated with perception of body weight, while demographic variables were not. Understanding the factors that contribute to the correct perception of weight is important in identifying appropriate health interventions that may address the burden of associated non-communicable diseases in overweight and obese individuals.

Spontaneous and emergent extrapyramidal syndromes in Black Africans with first-episode schizophrenia and first exposure to antipsychotics.

BACKGROUND: Persons of African ancestry are thought to carry a higher risk for extrapyramidal syndromes (EPS) in schizophrenia. AIM: We investigated the phenomenon of spontaneous and treatment-emergent EPS in a sample comprising Xhosa (South Africa) and Yoruba (Nigeria) Africans with first-episode schizophrenia and first exposure to antipsychotics. METHODS: The Extrapyramidal Symptom Rating Scale (ESRS) and a variety of validated tools were used for the assessment of participants before, and two-weekly after treatment with low dose flupenthixol decanoate. Participants were followed up for 12 months. Association of EPS with clinical characteristics was investigated using Pearson's correlation and linear regression analyses. RESULTS: Of 88 participants at baseline, 16 (18.1%) had at least one definite EPS prior to antipsychotic exposure and 34 (38.6%) had treatment-emergent EPS. While spontaneous Parkinsonism was associated with negative symptoms (r = 0.2, p = 0.043; ß = 0.6, p = 0.043), treatment-emergent EPS demonstrated non-significant correlations with clinical characteristics. Apart from dyskinesia, the frequency of treatment-emergent EPS decreased over 12 months observation. CONCLUSION: These findings support the hypothesis suggesting that spontaneously occurring Parkinsonism in schizophrenia may be the motor spectrum of negative symptomatology. Future studies of this relationship may lead to early identification of patients who may be more sensitive to EPS.

Factors associated with dropout at 2 years post-initiation of treatment in the first episode of schizophrenia.

BACKGROUND: Prevention of new episodes during the first 2 years after a first episode of schizophrenia (FES) may delay treatment refractoriness and brain morphological changes over time. However, adherence to treatment is characteristically poor in these patients. AIM: The aim of this study was to examine clinical and sociodemographic factors associated with patient dropout in patients with FES. SETTING: This study was set at inpatient and outpatient services at a psychiatric hospital in the Western Cape, between 2007 and 2011. METHODS: Data were collected as part of a prospective longitudinal study, which followed up patients with FES treated with flupenthixol decanoate. We examined the relationship between treatment adherence and sociodemographic and clinical factors at baseline and at 24 months. Unadjusted and adjusted logistic regression models were used to determine adherence variables. RESULTS: A total of 62% of patients completed the 24 months of treatment. Participants with FES and a substance use disorder (dual diagnosis) were at greater risk of dropout (p = 0.01). On univariate analysis, dual diagnosis participants who dropped out were older (p = 0.04) had completed more years of schooling (p = 0.001), older age of onset (p = 0.02) and higher baseline positive symptoms (p = 0.05). On regression analysis, non-completer substance users achieved a higher level of education (odds ratio [OR]: 3.87, confidence interval [CI]: 1.34-11.11, p = 0.01). CONCLUSION: Substance use disorder was associated with non-adherence to follow up in a cohort of FES patients treated with flupenthixol decanoate. Interventions that take into account age, education and baseline positive symptoms may afford the opportunity to influence adherence and patient outcome.

Erratum: Extrapyramidal side effects in first-episode schizophrenia treated with flupenthixol decanoate.

[This corrects the article DOI: 10.4102/sajpsychiatry.v27i0.1568.].

Extrapyramidal side effects in first-episode schizophrenia treated with flupenthixol decanoate.

BACKGROUND: Concern for the development of extrapyramidal side effects (EPSEs) represents a barrier to the routine use of long-acting injectable (LAI) antipsychotic medication in patients with first-episode schizophrenia (FES). Flupenthixol decanoate is a first-generation antipsychotic, which is readily available in the public healthcare system in South Africa. AIM: The aim of this study was to describe the nature, occurrence and severity of EPSEs and their impact on patients with FES over 12 months of treatment with flupenthixol decanoate (fluanxol depot). SETTING: The study was based in Cape Town, South Africa, and patients with FES were recruited from inpatient services at Stikland and Tygerberg Hospitals and surrounding psychiatric clinics. This was a sub-study of a larger study, which examined several outcomes in patients with FES treated with the lowest effective dose of flupenthixol decanoate. METHODS: The Extrapyramidal Symptom Rating Scale (ESRS) was used to assess both subjective experience and objective measures of EPSEs in a cohort of patients with FES (N = 130). The relationship between demographic and clinical risk factors for individual subsets of EPSEs was also determined. RESULTS: In the context of an overall good 12-month tolerability, EPSEs peaked at month 3. Patients with akathisia were more likely to have greater symptoms of depression, and Parkinsonism was predicted by higher Positive and Negative Syndrome Scale scores (independent of medication dosage). Black and white patients showed higher total ESRS and higher subjective ESRS scores, compared with patients of mixed ancestry, and white patients scored higher on Parkinsonism ratings. CONCLUSION: Flupenthixol decanoate is well tolerated in patients with FES. Certain clinical features of schizophrenia may be related to EPSEs. Ethnicity is a socio-cultural construct, and hence the differential risk of EPSEs should be interpreted according to ethnicity. Variations in the environment, diet, substance use and genetics may all affect the pharmacokinetics and pharmacodynamics of psychotropic drugs and warrant further investigation.

Associations of premorbid adjustment with type and timing of childhood trauma in first-episode schizophrenia spectrum disorders.

BACKGROUND: Childhood trauma may contribute to poorer premorbid social and academic adjustment which may be a risk factor for schizophrenia. AIM: We explored the relationship between premorbid adjustment and childhood trauma, timing of childhood trauma's moderating role as well as the association of clinical and treatment-related confounders with premorbid adjustment. SETTING: We conducted a secondary analysis in 111 patients with first-episode schizophrenia (FES) disorders that formed part of two parent studies, EONKCS study (n =73) and the Shared Roots study (n =38). METHODS: Type of childhood trauma was assessed with the Childhood Trauma Questionnaire, short-form and premorbid adjustment using the Premorbid Adjustment Scale. Timing of childhood trauma was assessed using the Life Events Checklist and life events timeline. Linear regression analyses were used to assess the moderating effect of timing of childhood trauma. Clinical and treatment-related confounders were entered into sequential hierarchical regression models to identify independent predictors of premorbid adjustment across key life stages. RESULTS: Childhood physical neglect was associated with poorer premorbid academic functioning during childhood and early adolescence, and poorer premorbid social functioning during early and late adolescence. By hierarchical regression modelling (r 2 = 0.13), higher physical neglect subscale scores (p = 0.011) independently predicted poorer premorbid social adjustment during early adolescence. Timing of childhood trauma did not moderate the relationship between childhood trauma and premorbid functioning. CONCLUSION: In patients with FES, childhood physical neglect may contribute to poorer premorbid social functioning during early adolescence. This may provide us with an opportunity to identify and treat at-risk individuals earlier.

Correction to: Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations.

An amendment to this paper has been published and can be accessed via the original article.

Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations.

BACKGROUND: The novel coronavirus pandemic calls for a rapid adaptation of conventional medical practices to meet the evolving needs of such vulnerable patients. People with coronavirus disease (COVID-19) may frequently require treatment with psychotropic medications, but are at the same time at higher risk for safety issues because of the complex underlying medical condition and the potential interaction with medical treatments. METHODS: In order to produce evidence-based practical recommendations on the optimal management of psychotropic medications in people with COVID-19, an international, multi-disciplinary working group was established. The methodology of the WHO Rapid Advice Guidelines in the context of a public health emergency and the principles of the AGREE statement were followed. Available evidence informing on the risk of respiratory, cardiovascular, infective, hemostatic, and consciousness alterations related to the use of psychotropic medications, and drug-drug interactions between psychotropic and medical treatments used in people with COVID-19, was reviewed and discussed by the working group. RESULTS: All classes of psychotropic medications showed potentially relevant safety risks for people with COVID-19. A set of practical recommendations was drawn in order to inform frontline clinicians on the assessment of the anticipated risk of psychotropic-related unfavorable events, and the possible actions to take in order to effectively manage this risk, such as when it is appropriate to avoid, withdraw, switch, or adjust the dose of the medication. CONCLUSIONS: The present evidence-based recommendations will improve the quality of psychiatric care in people with COVID-19, allowing an appropriate management of the medical condition without worsening the psychiatric condition and vice versa.

Variation within voltage-gated calcium channel genes and antipsychotic treatment response in a South African first episode schizophrenia cohort.

Voltage-gated calcium channels have been implicated in schizophrenia aetiology; however, little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Twelve regulatory variants within seven genes were shown to be significantly associated with treatment outcome. Most notably, the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.

Factors associated with poor satisfaction with treatment and trial discontinuation in chronic schizophrenia.

IntroductionDespite consistently high discontinuation rates due to withdrawal of consent (WOC) and insufficient therapeutic effect (ITE) in schizophrenia trials, insight into the underlying factors contributing to poor satisfaction with treatment and dropout is limited. A better understanding of these factors could help to improve trial design and completion rates. METHODS: Using data from 1,136 trial participants with schizophrenia or schizoaffective disorder, we explored associations between predictor variables with (1) dropout due to WOC and ITE and (2) satisfaction with treatment among patients and investigators by means of hierarchic multiple regression analyses. RESULTS: ITE was associated with poor clinical improvement, poor investigator satisfaction with treatment, and poor patient insight into their own disease, whereas WOC only showed a meaningful association with poor patient satisfaction with treatment. Investigator satisfaction with treatment appeared most strongly associated with Positive and Negative Syndrome Scale (PANSS) positive factor endpoint scores, whereas patient satisfaction with treatment was best predicted by the endpoint score on the PANSS emotional distress factor. The occurrence of severe side effects showed no meaningful association to satisfaction with treatment among investigators and patients, and neither did a patient's experienced psychopathology, nor their self-rating of functional impairment. CONCLUSIONS: Whereas trial discontinuation due to ITE is associated with poor treatment effectiveness, a patient's decision to withdraw from an antipsychotic trial remains unpredictable and may occur even when the investigator observes a global clinical improvement and is satisfied with the treatment.

Prolactin, flupenthixol decanoate and first episode schizophrenia - clinical and laboratory correlates.

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.

The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder.

Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web-server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage-gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well-characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder-specific. And unique disorder-specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross-disorder commonalities in order to realise actionable and translatable results to combat mental health disorders.