Annet H. van Bergen

DNA methylation signatures of mood stabilizers and antipsychotics in bipolar disorder.

AIM In view of the potential effects of psychiatric drugs on DNA methylation, we investigated whether medication use in bipolar disorder is associated with DNA methylation signatures. EXPERIMENTAL PROCEDURES Blood-based DNA methylation patterns of six frequently used psychotropic drugs (lithium, quetiapine, olanzapine, lamotrigine, carbamazepine, and valproic acid) were examined in 172 bipolar disorder patients. After adjustment for cell type composition, we investigated gene networks, principal components, hypothesis-driven genes and epigenome-wide individual loci. RESULTS Valproic acid and quetiapine were significantly associated with altered methylation signatures after adjustment for drug-related changes on celltype composition. CONCLUSION Psychiatric drugs influence DNA methylation patterns over and above cell type composition in bipolar disorder. Drug-related changes in DNA methylation are therefore not only an important confounder in psychiatric epigenetics but may also inform on the biological mechanisms underlying drug efficacy.

Cognitive enhancing agents in schizophrenia and bipolar disorder

Cognitive dysfunction is a core feature of schizophrenia and is also present in bipolar disorder (BD). Whereas decreased intelligence precedes the onset of psychosis in schizophrenia and remains relatively stable thereafter; high intelligence is a risk factor for bipolar illness but cognitive function decreases after onset of symptoms. While in schizophrenia, many studies have been conducted on the development of cognitive enhancing agents; in BD such studies are almost non-existent. This review focuses on the pharmacological agents with putative effects on cognition in both schizophrenia and bipolar illness; specifically agents targeting the dopaminergic, cholinergic and glutamatergic neurotransmitter pathways in schizophrenia and the cognitive effects of lithium, anticonvulsants and antipsychotics in BD. In the final analysis we conclude that cognitive enhancing agents have not yet been produced convincingly for schizophrenia and have hardly been studied in BD. Importantly, studies should focus on other phases of the illness. To be able to treat cognitive deficits effectively in schizophrenia, patients in the very early stages of the illness, or even before - in the ultra-high risk stages - should be targeted. In contrast, cognitive deficits occur later in BD, and therefore drugs should be tested in BD after the onset of illness. Hopefully, we will then find effective drugs for the incapacitating effects of cognitive deficits in these patients.

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

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.

The effectiveness of restarted lithium treatment after discontinuation: reviewing the evidence for discontinuation-induced refractoriness

We sought to determine whether the risk of relapse in patients with bipolar disorder is higher after discontinuation and restart of lithium treatment as compared to continuous lithium treatment in these same patients.

The relationship between brain volumes and intelligence in bipolar disorder

OBJECTIVES Bipolar disorder type-I (BD-I) patients show a lower Intelligence Quotient (IQ) and smaller brain volumes as compared with healthy controls. Considering that in healthy individuals lower IQ is related to smaller total brain volume, it is of interest to investigate whether IQ deficits in BD-I patients are related to smaller brain volumes and to what extent smaller brain volumes can explain differences between premorbid IQ estimates and IQ after a diagnosis of BD-I. METHODS Magnetic resonance imaging brain scans, IQ and premorbid IQ scores were obtained from 195 BDI patients and 160 controls. We studied the relationship of (global, cortical and subcortical) brain volumes with IQ and IQ change. Additionally, we investigated the relationship between childhood trauma, lithium- and antipsychotic use and IQ. RESULTS Total brain volume and IQ were positively correlated in the entire sample. This correlation did not differ between patients and controls. Although brain volumes mediated the relationship between BD-I and IQ in part, the direct relationship between the diagnosis and IQ remained significant. Childhood trauma and use of lithium and antipsychotic medication did not affect the relationship between brain volumes and IQ. However, current lithium use was related to lower IQ in patients. CONCLUSIONS Our data suggest a similar relationship between brain volume and IQ in BD-I patients and controls. Smaller brain volumes only partially explain IQ deficits in patients. Therefore, our findings indicate that in addition to brain volumes and lithium use other disease factors play a role in IQ deficits in BD-I patients.

An actigraphy study investigating sleep in bipolar I patients, unaffected siblings and controls

OBJECTIVES Disturbances in sleep and waking patterns are highly prevalent during mood episodes in bipolar disorder. The question remains whether these disturbances persist during phases of euthymia and whether they are heritable traits of bipolar disorder. The current study investigates objective sleep measures in a large sample of bipolar I patients, non-affected siblings and controls. METHODS A total of 107 bipolar disorder I patients, 74 non-affected siblings, and 80 controls were included. Sleep was measured with actigraphy over the course of 14 days. Seven sleep parameters were analyzed for group differences and their relationship with age at onset, number of episodes and psychotic symptoms using linear mixed model analysis to account for family dependencies. RESULTS Patients had a longer sleep duration and later time of sleep offset compared to the non-affected siblings but these differences were entirely attributable to differences in mood symptoms. We found no difference between patients and controls or siblings and controls when the analyses were restricted to euthymic patients. None of the bipolar illness characteristics were associated with sleep. LIMITATIONS Medication use was not taken into account which may have influenced our findings and controls were younger compared to non-affected siblings. CONCLUSIONS In the largest study to date, our findings suggest that recovered bipolar I patients and their siblings do not experience clinically significant sleep disturbances. Sleep disturbances are primarily a reflection of current mood state, but are unrelated to the course of the disorder.

White matter disruptions in patients with bipolar disorder

Bipolar disorder (BD) patients show aberrant white matter microstructure compared to healthy controls but little is known about the relation with clinical characteristics. We therefore investigated the relation of white matter microstructure with the main pharmacological treatments as well its relation with IQ. Patients with BD (N = 257) and controls (N = 167) underwent diffusion tensor imaging (DTI) and comprehensive clinically assessments including IQ estimates. DTI images were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) and Mean Diffusivity (MD) were determined. Patients had significantly lower FA and higher MD values throughout the white matter skeleton compared to controls. Within the BD patients, lithium use was associated with higher FA and lower MD. Antipsychotic medication use in the BD patients was not associated with FA but, in contrast to lithium, was associated with higher MD. IQ was significantly positively correlated with FA and negatively with MD in patients as well as in controls. In this large DTI study we found evidence for marked differences in FA and MD particularly in (but not restricted to) corpus callosum, between BD patients and controls. This effect was most pronounced in lithium-free patients, implicating that lithium affects white matter microstructure and attenuates differences associated with bipolar disorder. Effects of antipsychotic medication intake were absent in FA and only subtle in MD relative to those of lithium. The abnormal white matter microstructure was associated with IQ but not specifically for either group.

Poster #S103 HIGH EDUCATIONAL PERFORMANCE IS A DISTINCT FEATURE OF BIPOLAR DISORDER COMPARED TO SCHIZOPHRENIA

ness, but lower level of neurocognitive reasoning, and less depression, which in turn impacts patient-reported assessment of well-being overall. Improvement in insight over time was longitudinally associated with reduction in uncooperativeness symptoms. These results support the importance of reducing impairments in insight and cognition both for functional performance and willingness to accept treatments.