Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study

Abstract

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.

Antipsychotic and benzodiazepine use and brain morphology in schizophrenia and affective psychoses – Systematic reviews and birth cohort study

“…nucleus after controlling for antipsychotic doses and PANSS average score (Huhtaniska et al, 2017b). In this study, lifetime benzodiazepine doses did not associate with the volume of any brain structures in schizophrenia at the age of 43 years, when antipsychotic doses were also taken into account.…”

“…In previous studies of an overlapping NFBC1966 sample, a higher amount of antipsychotic medication predicted total brain volume loss (Veijola et al, 2014) and lateral ventricular volume increase (Huhtaniska et al, 2017b;Veijola et al, 2014), as well as periventricular brain volume reductions at the fourth ventricular edge (Guo et al, 2015) over a 9-year follow-up. In addition to brain findings, higher doses of antipsychotics associated with decline in verbal learning and memory (Husa et al, 2014), and high lifetime doses and antipsychotic polypharmacy associated with poorer outcomes in schizophrenia in the NFBC1966 (Moilanen et al, 2016).…”

“…We have previously published longitudinal findings from NFBC1966 follow-up study performed at ages 34 and 43 years for schizophrenia subjects. In these studies, higher doses of antipsychotic medication over the follow-up was associated with a larger total brain volume loss (Veijola et al, 2014), a degree of periventricular brain reduction at the fourth ventricular edge (Guo et al, 2015), and an increase in lateral ventricles after adjusting for symptom severity (Huhtaniska et al, 2017b). Higher benzodiazepine doses during the follow-up was associated with a volume decrease in the caudate nucleus even after controlling for antipsychotic use and illness severity (Huhtaniska et al, 2017b).…”

“…To extract the brain structure volumes from the MRI images we used an online automated MRI brain volumetry system volBrain (http:// volbrain.upv.es/) (Manjón and Coupé, 2016). Based on previously reported reliability measures (Huhtaniska et al, 2017b) and previous brain imaging findings in psychoses, we selected 10 brain areas to be examined: total brain, total gray matter (GM), cerebrum, cerebral GM, lateral ventricles, caudate, putamen, thalamus, hippocampus, accumbens). Details on the reliability measures and image processing pipeline are described in our previous publication (Huhtaniska et al, 2017b) and briefly in supplementary material.…”

“…When studying medication effects in a non-controlled population, it is important to take into account the possible confounding effects of other medications. To our knowledge, the effect of benzodiazepine use on brain structures has not been studied before in psychoses with the exception of our previous longitudinal study of the Northern Finland Birth Cohort 1966 (NFBC1966) in a smaller sample (Huhtaniska et al, 2017b). Previously benzodiazepine use has been associated with decline in cognition (Baandrup et al, 2017;Fond et al, 2017) and increased mortality (Fontanella et al, 2016) in schizophrenia, and decreased brain plasticity in mice (Curto et al, 2016;Huopaniemi et al, 2004).…”