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.

Sex and gender associations with indicators of neurodevelopmental compromise in schizophrenia spectrum disorders.

BACKGROUND: It has been proposed that sex and gender differences described in schizophrenia can be explained from a neurodevelopmental perspective. AIM: In this study, we examined the associations of biological sex and gender role endorsement with putative indicators of neurodevelopmental compromise. METHODS: We used the Bem Sex Role Inventory to calculate masculinity scores in 77 patients with a first episode of a schizophrenia spectrum disorder, and selected the following indicators of neurodevelopmental compromise: family history of schizophrenia, obstetric complications, premorbid functioning, neurological soft signs, and cognitive function. Secondary objectives included the moderating effects of age of onset of illness, substance use and negative symptoms on these associations. RESULTS: There were no significant sex differences across any of the indicators of neurodevelopmental compromise. However, lower masculinity scores correlated significantly with poorer premorbid adjustment, sensory integration deficits and worse overall cognitive performance. Stepwise linear regression identified poorer premorbid adjustment in early adolescence and lower verbal learning scores as independent predictors of lower masculinity scores. In contrast to sex, gender showed several associations with indicators of neurodevelopmental compromise. CONCLUSIONS: Lower masculinity scores may represent part of a phenotype for a neurodevelopmental anomaly that places some individuals on a pathway to schizophrenia.

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.

Childhood trauma and hippocampal subfield volumes in first-episode schizophrenia and healthy controls.

Childhood trauma and schizophrenia are both associated with neuroanatomical abnormalities in the hippocampus, a stress-sensitive structure vulnerable to developmental insults. However, few studies have evaluated the effects of childhood trauma exposure on hippocampal morphometry in minimally treated first-episode schizophrenia patients. Here we aim to investigate the associations of childhood trauma with hippocampal subfield volumes in a cohort of antipsychotic-naive or minimally treated first-episode schizophrenia spectrum disorder patients and matched controls. 79 patients with first-episode schizophrenia spectrum disorder and 82 matched controls completed the childhood trauma questionnaire and underwent MRI assessment. Hippocampal subfields were reconstructed using FreeSurfer 6.0. We considered inter-correlations between the various subfields, by entering them as dependent variables into a multivariate analysis of co-variance (MANCOVA), modeling for interactions between diagnosis, childhood trauma total score and gender while controlling for substance use, scanner sequence and age. MANCOVA revealed a significant interaction between sex, childhood trauma total scores and diagnosis across hippocampal sub-regions (p = 0.012). Bonferroni corrected post-hoc analysis revealed a significant sex*diagnosis*childhood trauma score interaction for the hippocampal fissure (F(1,161) = 9.485,p = .002). Hippocampal fissure size showed a positive relationship with CA structures as well as whole hippocampal size in the larger sample. Findings from the present study suggest that childhood trauma exposure exerts illness-specific effects on hippocampal structures in female patients with first-episode schizophrenia, consistent with increased stress sensitivity in this group.

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.

Childhood Trauma Associated White Matter Abnormalities in First-Episode Schizophrenia.

Schizophrenia is associated with brain connection irregularities within and between brain regions. Childhood trauma increases the risk of schizophrenia suggesting that the relationships between childhood trauma and brain connectivity requires further investigation. Here, we examine the relationship between childhood trauma (as measured by the Childhood Trauma Questionnaire) and fractional anisotropy (FA) in 54 minimally treated first-episode schizophrenia (FES) patients and 51 community matched controls. Patients who experienced high levels of trauma had significantly lower FA in the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and inferior fronto-occipital fasciculus (IFOF) compared with controls who experienced high levels of childhood trauma. A history of childhood sexual abuse in patients was associated with lower FA in the IFOF, ILF, SLF, and forceps major compared with patients without a history of sexual abuse. However, patients who had experienced childhood emotional neglect had higher FA in the right SLF compared to patients with low levels of emotional neglect. Our findings highlight altered cortico-limbic circuitry in FES patients compared with controls and differential effects of childhood emotional neglect and sexual abuse on white matter in patients. Although stress-related white matter (WM) pathways appear to be involved in both schizophrenia and otherwise healthy controls previously exposed to childhood trauma, the pattern of disruption of WM integrity in FES patients appears to be distinct.