Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

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.

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.

Depressive symptoms and quality of life prior to metabolic surgery in Cape Town, South Africa.

Background: Depression has been shown to have a negative impact on the outcomes of metabolic surgery and quality of life (QOL). Currently, there are limited data on mental distress and QOL in metabolic surgery candidates in South Africa. Aim: This study aimed to determine the prevalence of depressive symptoms at the time of presurgical assessment in participants undergoing metabolic surgery. Setting: The Obesity and Metabolic Surgery Initiative at Tygerberg Hospital. Methods: We conducted pre-operatively a retrospective cross-sectional study on patients who underwent metabolic surgery from September 2017 to September 2019. Participants were profiled in terms of metabolic parameters, depressive symptoms and QOL. Results: Of the 157 participants assessed, 88% were female with a body mass index in the super obese range. Twenty-two percent of participants had depressive symptoms. Metabolic surgery candidates with depressive symptoms had a significantly poorer overall QOL score compared with those without depressive symptoms. When controlling for all other variables, an increase in QOL score was shown to decrease the odds of current depressive symptoms, whilst back pain on non-narcotic medication and having had a stroke were found to increase the odds of current depressive symptoms. Conclusion: This study highlights the complex interplay between metabolic, clinical and psychiatric factors in patients undergoing metabolic surgery. The study highlights the vital role of a psychiatrist as part of a multidisciplinary team pre- and post-operatively in the early identification of depressive symptoms. Psychiatrists may have an important role to play as part of the multidisciplinary team in metabolic surgery, including screening for mental health problems pre- and post-operatively, providing psychoeducation and relevant pharmacological treatment and psychotherapy where needed. Contribution: This study expands our limited knowledge of psychiatric comorbidity (in particular depressive symptoms and associated factors) in people undergoing metabolic surgery in low- and middle-income countries.

Prevalence and associated factors of depression among older adults in rural Tanzania.

OBJECTIVES: Depression is the commonest mental disorder in older adults worldwide, affecting 7% of the world's older population and accounting for 5.7% of years lived with disability among adults aged over 60 years. We conducted a secondary data analysis to determine the point prevalence, associated risk factors and treatment gap for DSM-IV depression among older adults in the Hai District, rural Tanzania. METHODS: The primary data source was a cross-sectional two-stage community-based dementia study where older adults aged ≥70 years (n = 296) were fully-assessed for dementia and depression in the second stage. Age-adjusted prevalence of depression was determined based on the WHO standard population using the Direct Method. Univariate and multivariate logistic regression models were performed. RESULTS: Of the 296 older adults assessed for depression, 48 were diagnosed with depression based on Diagnostic and Statistical Manual of Mental Disorders-IV criteria. The median (Inter Quartile Range; QR) age was 80 (75-88) years. Age-adjusted point prevalence of depression was 21.2% (95% CI: 16.6-21.9) and the treatment gap for depression was 100%. There was reduced odds of depression in older adults who rated their physical health as good or very good (adjusted odds ratio [AOR] = 0.22; 95%CI: 0.10-0.46; p < 0.001), or moderate (AOR 0.26; 95%CI: 0.10-0.66; p = 0.005). CONCLUSIONS: Depression in older adults is associated with physical health status and there is an alarmingly high treatment gap. Future research on depression in older adults should focus on effective interventions to address physical morbidity, psychosocial factors and the treatment gap.

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.

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

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

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.

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.

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.

Validation of the Montreal cognitive assessment against the RBANS in a healthy South African cohort.

BACKGROUND: Mild cognitive impairment (MCI) represents an intermediate state between normal cognition and dementia. Early detection and treatment of reversible contributing factors to progressive cognitive decline currently forms the cornerstone of management. As the population at risk of developing dementia is projected to increase significantly in many low- and middle-income countries where health care services continue to operate under clinical and human resource constraints, there is a need for low-cost, quick and reliable screening tools. The Montreal cognitive assessment (MoCA) was developed as a brief screening tool with high sensitivity and specificity for detecting MCI. The initial validation sample for the MoCA consisted of English and French speaking Canadians. Studies undertaken in a variety of countries show that the reliability and validity of the MoCA in screening for MCI is good; however, it has been recommended that some item modification and adjustment of cut-offs for the diagnosis of MCI in these populations may be needed to account for cultural differences.To date, no studies have evaluated the MoCA in the South African population. We aimed to compare the validity of the MoCA to the RBANS, evaluate the effectiveness of the MoCA as a screening tool for MCI and generate normative data for the MoCA. METHODS: A cross-sectional observational study comprising a sample of 370 cognitively healthy males and females aged 18 years and older of mixed race (Coloured ethnicity) who were administered the MoCA and RBANS during screening. RESULTS: The MoCA showed acceptable internal consistency (Cronbach's alpha of 0.624). MoCA scores were significantly associated with gender (r = -0.199, p = 0.000), and correlated with age (r = -0.203, p = 0.000) and education (r = 0.326, p = 0.000). There was a strong correlation between total scores on the MoCA and RBANS (r = 513; p = 0.000), indicating good criterion-related validity. The MoCA also showed good agreement with the RBANS according to the Bland-Altman plot. ROC statistics demonstrated that the performance of the MoCA for predicting MCI compared to the RBANS was fair with an AUC of 0.794. Using the recommended cut-off score of 26, the MoCA showed high sensitivity (94.23%) but low specificity (28.16%). When the cut-off score was lowered to 23, the sensitivity was 75% and specificity 66.77%, while a cut-off of 24 demonstrated a sensitivity of 84.62% and a specificity of 52.53%. CONCLUSION: Although the MoCA appears fairly reliable at identifying MCI in this population, our findings suggest that some modification to certain domains and items is needed to improve the differentiation between normal ageing and MCI. Until such time that a culturally adapted version of the MoCA has been developed and validated for this population, we suggest lowering the cut-off score to 24 in order to reduce false-positive diagnoses of MCI.

Prevalence and clinical correlates of police contact prior to a first diagnosis of schizophrenia.

BACKGROUND: Little is known about the reasons why people with schizophrenia have contact with police, especially prior to the first episode of illness. AIM: To investigate the prevalence and correlates of police contact in first-episode schizophrenia. METHODS: The prevalence and type of police contact was established among all 110 patients presenting to psychiatric services in one catchment area during a first episode of schizophrenia and among 65 non-mentally ill controls, by participant and collateral interview and from records. Socio-demographic and clinical characteristics were also recorded and the two groups compared. RESULTS: The first episode of schizophrenia patients had more contact with police than controls, despite the higher prevalence of conduct disorder symptoms among the controls. The patients were not, however, more likely to be incarcerated or arrested. Among the patients, over half of the police call-outs occurred during the period of untreated psychosis. Positive psychotic symptoms were independently associated with police contact, after allowing for socio-demographics. CONCLUSIONS: As over a third of people in a first episode of schizophrenia had been in contact with the police - more than twice the proportion among non-psychotic controls - and contact was associated with untreated positive psychotic symptoms, better early detection and treatment of psychosis seems indicated. In the meantime, police services may be playing an important role in reducing the duration of untreated psychosis. Copyright © 2015 John Wiley & Sons, Ltd.

The identification of novel genetic variants associated with antipsychotic treatment response outcomes in first-episode schizophrenia patients.

BACKGROUND: Although antipsychotics are integral to the treatment of schizophrenia, drug efficacy varies between patients. Although it has been shown that antipsychotic treatment response outcomes are heritable, our understanding of the genetic factors that are involved remains incomplete. Therefore, this study aims to use an unbiased scan of the genome to identify the genetic variants contributing toward antipsychotic treatment response outcomes. MATERIALS AND METHODS: This study utilized whole-exome sequencing of patients on extreme ends of the treatment response spectrum (n=11) in combination with results from previous antipsychotic studies to design a panel of variants that were genotyped in two well-characterized first-episode schizophrenia cohorts (n=103 and 87). Association analyses were carried out to determine whether these variants were significantly associated with antipsychotic treatment response outcomes. RESULTS: Association analyses in the discovery cohort identified two nonsynonymous variants that were significantly associated with antipsychotic treatment response outcomes (P<2.7 × 10(-5)), which were also significantly associated with the corresponding treatment response outcome in an independent replication cohort. Computational approaches showed that both of these nonsynonymous variants--rs13025959 in MYO7B (E1647D) and rs10380 in MTRR (H622Y)--were predicted to impair the functioning of their corresponding protein products. CONCLUSION: The use of whole-exome sequencing in a subset of patients from a well-characterized cohort of first-episode schizophrenia patients, for whom longitudinal depot treatment response data were available, allowed for (i) the removal of confounding factors related to treatment progression and compliance and (ii) the identification of two genetic variants that have not been associated previously with antipsychotic treatment response outcomes and whose results were applicable across different classes of antipsychotics. Although the genes that are affected by these variants are involved in pathways that have been related previously to antipsychotic treatment outcomes, the identification of these novel genes will play an important role in improving our understanding of the specific variants involved in antipsychotic treatment response outcomes.

Rate and predictors of non-response to first-line antipsychotic treatment in first-episode schizophrenia.

OBJECTIVE: The goals of this study were to (i) estimate the rate of non-response to first-line treatment in first-episode schizophrenia, (ii) evaluate other outcomes associated with symptom non-response and (iii) identify demographic, baseline clinical and early treatment response predictors of non-response. METHODS: This was a single-site, longitudinal cohort study assessing the effects of treatment with flupenthixol decanoate according to a standardised protocol over 12 months in patients with schizophrenia, schizophreniform and schizo-affective disorders. RESULTS: Of 126 patients who received at least one dose of study medication, 84 (67%) completed the study. Fifteen (12%) met our predefined criteria for non-response. Non-responders were younger and at baseline had more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS) and lower body mass index. At endpoint, the non-responders were characterised by higher levels of symptomatology in all domains, poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and lower body mass index. The strongest predictors of non-response were more prominent baseline NSS and poor early (7 weeks) treatment response. CONCLUSIONS: Results are consistent with a lower rate of refractoriness to treatment in first-episode schizophrenia compared with multi-episode samples.

The nature of relapse in schizophrenia.

BACKGROUND: Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications. METHODS: We critically review selected literature regarding the nature and underlying neurobiology of relapse. RESULTS: Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis. CONCLUSIONS: Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.

Quetiapine versus other atypical antipsychotics for schizophrenia.

BACKGROUND: In many countries, second-generation ('atypical') antipsychotic drugs have become the first-line drug treatment for people with schizophrenia. It is not clear how the effects of the various second-generation antipsychotic drugs differ. OBJECTIVES: To evaluate the effects of quetiapine compared with other second-generation (atypical) antipsychotic drugs in the treatment of people with schizophrenia and schizophrenia-like psychoses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (May 2010), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing oral quetiapine with other oral forms of atypical antipsychotic medication in people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a random-effects model. We calculated number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For continuous data, we calculated mean differences (MDs), again based on a random-effects model. MAIN RESULTS: Efficacy data tended to favour the control drugs over quetiapine (Positive and Negative Syndrome Scale (PANSS) total score vs olanzapine: 11 RCTs, n = 1486, mean quetiapine endpoint score 3.67 higher, CI 1.95 to 5.39, low quality; vs risperidone: 13 RCTs, n = 2155, mean quetiapine endpoint score 1.74 higher, CI 0.19 to 3.29, moderate quality; vs paliperidone: 1 RCT, n = 319, mean quetiapine endpoint score 6.30 higher, CI 2.77 to 9.83, moderate quality), but the clinical meaning of these data is unclear. No clear mental state differences were noted when quetiapine was compared with clozapine, aripiprazole or ziprasidone. Compared with olanzapine, quetiapine produced slightly fewer movement disorders (7 RCTs, n = 1127, RR use of antiparkinson medication 0.51, CI 0.32 to 0.81, moderate quality) and less weight gain (8 RCTs, n = 1667, RR 0.68, CI 0.51 to 0.92, moderate quality) and glucose elevation, but increased QTc prolongation (3 RCTs, n = 643, MD 4.81, CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (8 RCTs, n = 2163, RR use of antiparkinson medication 0.5, CI 0.36 to 0.69, moderate quality), less prolactin increase (7 RCTs, n = 1733, MD -35.25, CI -43.59 to -26.91) and some related adverse effects but greater cholesterol increase (6 RCTs, n = 1473, MD 8.57, CI 4.85 to 12.29). On the basis of limited data, compared with paliperidone, quetiapine induced fewer parkinsonian side effects (1 RCT, n = 319, RR use of antiparkinson medication 0.64, CI 0.45 to 0.91, moderate quality) and less prolactin increase (1 RCT, n = 319, MD -49.30, CI -57.80 to -40.80) and weight gain (1 RCT, n = 319, RR weight gain of 7% or more of total body weight 2.52, CI 0.5 to 12.78, moderate quality). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n = 522, RR use of antiparkinson medication 0.43, CI 0.2 to 0.93, moderate quality) and less prolactin increase. On the other hand, quetiapine was more sedating and led to greater weight gain (2 RCTs, n = 754, RR 2.22, CI 1.35 to 3.63, moderate quality) and cholesterol increase when compared with ziprasidone. AUTHORS' CONCLUSIONS: Available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks (around 60%). Comparisons with amisulpride, sertindole and zotepine do not exist. Although efficacy data favour olanzapine and risperidone compared with quetiapine, the clinical meaning of these data remains unclear. Quetiapine may produce fewer parkinsonian effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine. Quetiapine appears to have a similar weight gain profile to risperidone, as well as clozapine and aripiprazole (although data are very limited for the latter two comparators). Quetiapine may produce greater weight gain than ziprasidone and less weight gain than olanzapine and paliperidone. Most data that have been reported within existing comparisons are of very limited value because of assumptions and biases within them. Much scope is available for further research into the effects of this widely used drug.