The association of antipsychotic medication and lithium with brain measures in patients with bipolar disorder

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Abstract

There is evidence that brain structure is abnormal in patients with bipolar disorder. Lithium intake appears to ׳normalise׳ global and local brain volumes, but effects of antipsychotic medication on brain volume or cortical thickness are less clear. Here, we aim to disentangle disease-specific brain deviations from those induced by antipsychotic medication and lithium intake using a large homogeneous sample of patients with bipolar disorder type I. Magnetic resonance imaging brain scans were obtained from 266 patients and 171 control subjects. Subcortical volumes and global and focal cortical measures (volume, thickness, and surface area) were compared between patients and controls. In patients, the association between lithium and antipsychotic medication intake and global, subcortical and cortical measures was investigated. Patients showed significantly larger lateral and third ventricles, smaller total brain, caudate nucleus, and pallidum volumes and thinner cortex in some small clusters in frontal, parietal and cingulate regions as compared with controls. Lithium-free patients had significantly smaller total brain, thalamus, putamen, pallidum, hippocampus and accumbens volumes compared to patients on lithium. In patients, use of antipsychotic medication was related to larger third ventricle and smaller hippocampus and supramarginal cortex volume. Patients with bipolar disorder show abnormalities in total brain, subcortical, and ventricle volume, particularly in the nucleus caudate and pallidum. Abnormalities in cortical thickness were scattered and clusters were relatively small. Lithium-free patients showed more pronounced abnormalities as compared with those on lithium. The associations between antipsychotic medication and brain volume are subtle and less pronounced than those of lithium.

Introduction

Efforts to identify the neural circuit involved in bipolar disorder have demonstrated brain abnormalities in these patients. The most consistent finding is a significant enlargement of the ventricles in patients as compared with controls (Hallahan et al., 2011, Emsell and McDonald, 2009). Grey matter reductions, such as cortical thinning or smaller volumes in the frontal and parietal areas of patients with bipolar disorder have also been reported (Rimol et al., 2010, Lan et al., 2014). So far, relatively few studies focused on subcortical structures. Reductions in the left hippocampus and bilateral putamen have been shown in adolescent bipolar spectrum patients relative to controls (MacMaster et al., 2014) while, in contrast, adolescents with type I bipolar disorder show an enlarged putamen (DelBello et al., 2004). In addition, volume reductions in the hippocampus, thalamus, nucleus accumbens (Rimol et al., 2010), and amygdala (DelBello et al., 2004) have been reported.

A widely recognised complicating factor in psychiatric imaging studies investigating the structure of the brain is the intake of psychotropic medication, e.g., lithium, other mood stabilisers (such as anticonvulsants), antidepressants and (typical and atypical) antipsychotic medication. There is consistent evidence implicating that lithium has a ‘normalizing’ effect on brain structural abnormalities (Singh and Chang, 2012, Hafeman et al., 2012). It has been associated with an increase (or normalization) of grey matter volume, particularly in the hippocampus, amygdala, anterior and subgenual cingulate in adult patients (Hafeman et al., 2012). Whereas this effect of lithium is fairly established, there is more debate about the impact of antipsychotic medication on the brain. Studies in patients with schizophrenia have shown that intake of typical antipsychotics increases the volume of the basal ganglia (Navari and Dazzan, 2009). Moreover, caudate volume decreased after changing from haloperidol to clozapine (Scheepers et al., 2001). Some argue that antipsychotics are related to an increase of ventricle size and lower overall brain size and thus contribute to the brain abnormalities observed in schizophrenia (Ho et al., 2011, Moncrieff and Leo, 2010). Others show differential effects of typical and atypical medication, e.g., a higher cumulative intake of typical antipsychotics was found to be associated with more pronounced cortical thinning over time, whereas higher cumulative intake of atypical antipsychotic medication was associated with less pronounced cortical thinning (Van Haren et al., 2011). Here, patients with bipolar disorder can provide a naturalistic model to study the association between antipsychotic medication and brain volumes, as only a minority of patients with bipolar disorder uses antipsychotic medication.

Here, we aim to investigate how brain volume was associated with antipsychotic medication and lithium intake using a large homogeneous sample of patients with bipolar disorder type I.

Section snippets

Participants

In this cross-sectional study, 266 patients with bipolar disorder type I and 171 control subjects participated. The required minimum age was 18 years, and only patients with bipolar disorder type I according to DSM-IV criteria were included. Control subjects did not have bipolar disorder, schizophrenia or any other psychotic disorder, nor had their first-degree relatives.

All participants took part in a NIMH funded study carried out by the University Medical Center Utrecht in a collaboration

Differences between patients and controls

No significant differences were found between patients and controls on gender and handedness distribution. Mean age difference between patients and controls is low, i.e. 2.3 years, but reached trend level significance (p=0.05). Mean age of first symptoms was 24.0 (s.d. 10.9) year. The majority of patients with bipolar disorder used lithium (65.8%) and 45.6% used antipsychotic medication at the time of scanning, with 24.1% of patients using both. For further demographic and clinical information,

Discussion

In one of the largest single-site samples of patients with bipolar disorder type I, we aimed to disentangle the disease-specific brain abnormalities from the ones associated with lithium or antipsychotic medication intake. We found significantly smaller total brain volume and larger lateral and third ventricle volumes in patients with bipolar disorder, irrespective of the current intake of medication. We calculated effect sizes in order to compare our findings to those of recent meta-analyses

Role of the funding source

This study was supported by NIMH grant number: R01 MH090553 (to RAO). The NIMH had no further role in study design, in the collection, analysis and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication.

Preliminary results were presented at the 10th International Conference on Bipolar Disorder, Miami Beach, Florida. The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection

Contributors

Author Lucija Abramovic wrote the manuscript and performed the statistical analyses. Marco Boks provided consultation and support on statistical methods, and assisted with manuscript edits. Diandra Bouter and Caitlyn Kruiper assisted with data collection and segmentation of the MRI scans. Annabel Vreeker, Sanne Verkooijen and Annet van Bergen assisted with data collection. Roel Ophoff and René Kahn served as senior authors and assisted with study design and interpretation of the data. Neeltje

Conflict of interest

The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Acknowledgements

We thank the study participants and also Fiona van den Heiligenberg, Amke Edomskis, Karlijn Schols, Michiel Flik, Juliana Schott, Bart Duin and Diane Ramakers for their help with the data collection. We also thank Ellen Blijenberg for her assistance in data collection and Manabu Kubota for his assistance with the FreeSurfer analyses.

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