Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999–2001 at the age of 33–35 years. A follow-up was conducted 9 years later during 2008–2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions.

Antipsychotic medication may associate with brain structure changes. More long-term follow-up studies taking into account illness severity measures are needed to make definitive conclusions.

BackgroundProgressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators.MethodParticipants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age = 34.7, SD = 0.77) and at follow-up (mean age = 43.4, SD = 0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA.ResultsSchizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction.ConclusionOur findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.

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High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.

HighlightsWomen lost more total brain volume than men during 8.5 years follow-up in midlife.Women showed greater brain reduction in bilateral brain regions with and without co-varying for total brain volume loss.Men exhibited greater brain reduction in mid-line brain regions after correcting for the total brain volume loss.

Objective: Schizophrenia has one of the highest heritability estimates in psychiatry, but the geneticallybased underlying neuropathology has mainly remained unclear. We conducted a multimodal coordinatebased meta-analysis (CBMA) to investigate brain structural and functional alterations in individuals with high familial risk for schizophrenia, i.e. in first-degree relatives of schizophrenia patients (FRs). Methods:We conducted a systematic literature search from two electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results:When compared to healthy controls, FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks. In VBM studies, there were no differences in grey matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. Finally, by utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the grey matter.

Unlike some previous investigators, we found no association between cumulative dose of lifetime antipsychotic medication and brain morphological changes in this population-based sample. However, longer continuous time without antipsychotic medication preceding the MRI scan associated with increased gray matter volume.