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.

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.

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

Two Neuroanatomical Signatures in Schizophrenia: Expression Strengths Over the First 2 Years of Treatment and Their Relationships to Neurodevelopmental Compromise and Antipsychotic Treatment.

BACKGROUND AND HYPOTHESIS: Two machine learning derived neuroanatomical signatures were recently described. Signature 1 is associated with widespread grey matter volume reductions and signature 2 with larger basal ganglia and internal capsule volumes. We hypothesized that they represent the neurodevelopmental and treatment-responsive components of schizophrenia respectively. STUDY DESIGN: We assessed the expression strength trajectories of these signatures and evaluated their relationships with indicators of neurodevelopmental compromise and with antipsychotic treatment effects in 83 previously minimally treated individuals with a first episode of a schizophrenia spectrum disorder who received standardized treatment and underwent comprehensive clinical, cognitive and neuroimaging assessments over 24 months. Ninety-six matched healthy case-controls were included. STUDY RESULTS: Linear mixed effect repeated measures models indicated that the patients had stronger expression of signature 1 than controls that remained stable over time and was not related to treatment. Stronger signature 1 expression showed trend associations with lower educational attainment, poorer sensory integration, and worse cognitive performance for working memory, verbal learning and reasoning and problem solving. The most striking finding was that signature 2 expression was similar for patients and controls at baseline but increased significantly with treatment in the patients. Greater increase in signature 2 expression was associated with larger reductions in PANSS total score and increases in BMI and not associated with neurodevelopmental indices. CONCLUSIONS: These findings provide supporting evidence for two distinct neuroanatomical signatures representing the neurodevelopmental and treatment-responsive components of schizophrenia.

The trajectories and correlates of two negative symptom subdomains in first-episode schizophrenia.

BACKGROUND: Recent studies suggest a two-factor structure for negative symptoms as assessed by the Positive and Negative Syndrome Scale (PANSS) in schizophrenia, namely experiential and expressive subdomains. Little is known about their clinical correlates and treatment trajectories. OBJECTIVES: We sought to replicate the two factor-analysis derived subdomains for PANSS negative symptoms in schizophrenia and to assess their independent demographic, premorbid and treatment-related characteristics. METHODS: This was a longitudinal study of 106 minimally treated participants with a first episode of a schizophrenia spectrum disorder who received treatment with flupenthixol decanoate 2-weekly injections over two years. Factor analysis was used to characterize the PANSS negative symptom subdomains and linear mixed-effect models for continuous repeated measures were constructed to assess the temporal relations between the negative symptom subdomains and premorbid and treatment related variables. RESULTS: Factor analysis confirmed a two-factor solution for experiential and expressive subdomains of negative symptoms, although they were strongly correlated. The treatment response trajectories for the two subdomains did not differ significantly, and neither subdomain was significantly associated with our premorbid variables. We found significant main effects for disorganised symptoms and extrapyramidal symptoms on the expressive subdomain, and for disorganised symptoms and depressive symptoms on the experiential subdomain. Post-hoc testing indicated that reductions in HDL-cholesterol levels were associated with less improvement in both expressive and experiential subdomain scores. CONCLUSION: The two negative symptom subdomains are closely related, have similar premorbid correlates and respond similarly to antipsychotic treatment. Depression affects the experiential subdomain, whereas extrapyramidal symptoms affect the expressive subdomain.

The associations of cannabis and methamphetamine use with cognitive performance over the first 2 years of treatment in schizophrenia spectrum disorders.

AIM: Cognitive deficits are a core feature of schizophrenia, and comorbid substance use may be a contributory factor. Methamphetamine use has been associated with cognitive impairment in schizophrenia, while associations with cannabis use are less clear-cut. This study aimed to investigate the associations of cannabis and methamphetamine use with cognitive performance in first-episode schizophrenia spectrum disorders over the first 2 years of treatment. METHODS: This was a longitudinal cohort study in 81 patients treated with flupenthixol decanoate according to a standardized protocol over 24 months. Cognitive performance was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Cognitive Consensus Battery at four time points, and urine testing for cannabis and methamphetamine was conducted at six time points. We used linear mixed-effect models for repeated measures to assess visit-wise changes in composite cognitive scores in patients (n = 91) compared to matched controls without psychiatric or medical disorders (n = 100). Linear regression models were constructed to examine pre-treatment and end-point effects in patients. RESULTS: Compared to controls, patients exhibited greater cognitive impairments at baseline, which improved with treatment, but remained significantly lower throughout. The number of positive methamphetamine, but not cannabis, tests predicted less cognitive improvement in patients. CONCLUSIONS: Our findings suggest a negative association between methamphetamine and cognition, but not cannabis.

The course and concomitants of depression in first-episode schizophrenia spectrum disorders: A 24-month longitudinal study.

Depressive symptoms are common in schizophrenia and have been associated with both favourable and unfavourable outcomes. We studied the longitudinal course of depressive symptoms and explored their temporal relationships with other manifestations of the illness and its treatment. This longitudinal cohort study included 126 antipsychotic naïve or only briefly treated patients with first-episode schizophrenia spectrum disorders treated with a long-acting antipsychotic over 24 months. Depressive symptoms were assessed at three monthly intervals using the Calgary Depression Scale for Schizophrenia and changes over time were assessed using linear mixed-effect models for continuous repeated measures. Depressive symptoms were most prominent at baseline with highly significant reductions during the first three months of treatment and maintenance of improvement thereafter. Most improvement occurred with antipsychotic treatment alone, with few patients requiring additional antidepressants. We also found that depressive symptoms were associated with positive symptoms, better insight and poorer quality of life, but not with negative symptoms, extrapyramidal symptoms, substance use or cumulative antipsychotic dose.There were few differences between patients who met criteria for depression during the acute phase of treatment and those in the post-acute phase.

Early recovery in the first 24 months of treatment in first-episode schizophrenia-spectrum disorders.

Studies assessing the treatment outcomes in first-episode schizophrenia have reported mixed results. While symptom improvement is frequently robust, when other domains are considered outcomes are generally poorer. We explored response trajectories, rates and predictors of recovery in the domains of core psychopathology, clinician-rated social and occupational functioning and patient-rated quality of life over 24 months of treatment in 98 patients with first-episode schizophrenia spectrum disorders who were treated with a long-acting antipsychotic medication. There was robust improvement in core psychopathology (effect size d = 3.36) and functionality (d = 1.78), with most improvement occurring within the first six months of treatment. In contrast, improvement in subjective quality of life was less marked (d = 0.37) and slower, only reaching significance after 12 months of treatment. Symptom remission was achieved by 70% of patients and over half met our criteria for functional remission and good quality of life. However, only 29% met the full criteria for recovery. Patients who met the recovery criteria had better premorbid adjustment, were less likely to be of mixed ethnicity and substance use emerged as the only modifiable predictor of recovery. Only 9% of our sample achieved both functional remission and good quality of life despite not being in symptom remission. We found high rates of symptom remission, functional remission and good quality of life in patients, although relatively few achieved recovery by meeting all three of the outcome criteria. Symptom remission is not a necessary prerequisite for functional remission and good quality of life, although few non-remitters achieve other recovery criteria.

Changes in insight over the first 24 months of treatment in schizophrenia spectrum disorders.

BACKGROUND: While insight in schizophrenia improves with treatment, significant impairments often persist. The degree of persistence is not well characterised. AIMS: We assessed patient and clinician-rated changes in insight in acutely ill, minimally treated first-episode schizophrenia spectrum disorder patients over 24 months of standardised treatment with a depot antipsychotic. METHOD: This single arm open label longitudinal cohort study included 105 participants with first-episode schizophrenia, schizophreniform or schizoaffective disorder. Insight was assessed at months 0, 6, 12 and 24 using the patient-rated Birchwood Insight Scale (BIS) and clinician-rated global insight item of the Positive and Negative Syndrome Scale (PANSS). Changes in insight over time were assessed using linear mixed-effect models for continuous repeated measures. Relationships between insight and psychopathology, functionality, cognition and quality of life were assessed with regression models. RESULTS: There was significant improvement over time for the PANSS insight item (p < 0.0001). However, the only significant improvement for the BIS was with the Need for Treatment subscale (p = 0.01). There were no significant improvements noted for the Symptom Attribution (p = 0.7) and Illness Awareness (p = 0.2) subscales, as well as the BIS Total score (p = 0.6). Apart from depressive symptoms at baseline, there were no significant predictors of patient-rated insight. CONCLUSIONS: Clinicians should note that, even when treatment is assured and response is favourable, fundamental impairments in patient-rated insight persist.

Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries.

Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption.

Clinical relevance of apolipoprotein E genotyping based on a family history of Alzheimer's disease.

Having a family history of Alzheimer' s disease (AD) may potentiate cumulative risk associated with phenotypic expression of the ε-4 allele of the apolipoprotein E (APOE) gene. In this study, we compared the genotype distribution and allele frequencies of APOE ε-2 (rs7412) and ε -4 (rs429358) in 537 South African individuals participating in a chronic disease screening program, in order to establish whether AD family history modulates the expression of their dyslipidemic effects. Significant differences in the genotype distribution for APOE ε-2 (p=0.034) as well as APOE ε-4 (p=0.038) were found between study participants with (n=67) and without (n=470) a family history of AD. LDL cholesterol levels were inversely associated with physical activity in the study group with a positive family history of AD (p<0.001) but not in those with a negative family history of AD (p=0.257). Similar to its existing use in the diagnosis of monogenic dyslipidemias such as familial hypercholesterolemia, clinical inquiry regarding family history was identified as an important determinant of eligibility for APOE genotyping performed in the context of chronic disease risk management. To our knowledge, this is the first study to demonstrate the modulating influence of AD family history on expression of a dyslipidemic phenotype associated with the APOE ε-4 allele. Our findings provide the scientific rationale supporting a novel clinical application for APOE genotyping as a means of identifying a genetic subgroup of dyslipidemic patients set to derive the greatest benefit from early lifestyle-based interventions aimed at decreasing cumulative risk for cardiovascular disease and prevention of AD later in life.