Christina Demopulos

Frontal lobe gray matter density decreases in bipolar I disorder.

BACKGROUND This study was conducted to explore differences in gray and white matter density between bipolar and healthy comparison groups using voxel-based morphometry (VBM). METHODS Brain magnetic resonance imaging was performed for 39 subjects with bipolar I disorder and 43 comparison subjects. Images were registered into a proportional stereotaxic space and segmented into gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping was used to calculate differences in gray and white matter density between groups. RESULTS Bipolar subjects had decreased gray matter density in left anterior cingulate gyrus (Brodmanns area [BA] 32, 7.3% decrease), an adjacent left medial frontal gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects. CONCLUSIONS The observation of a gray matter density decrease in the left anterior cingulate, which processes emotions, in bipolar subjects is consistent with prior reports that used region-of-interest analytic methods. Decreased gray matter density in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions, supports nondominant hemisphere dysfunction as a component of bipolar disorder.

Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder

BACKGROUND Prior work reported elevated gray matter (GM) lactate and Glx (glutamate + glutamine + GABA) concentrations in unmedicated patients with bipolar disorder (BP) compared with healthy controls (HC). This study examined whether lithium (Li) and valproic acid (VPA) treatment modulated these chemicals. METHODS A subset of previously reported BP patients were treated with Li (n = 12, 3.6 +/- 1.9 months) or VPA (n = 9, 1.4 +/- 1.7 months) and compared untreated HC subjects (n = 12, 2.9 +/- 2.4 months) using proton echo-planar spectroscopic imaging. Regression analyses (voxel gray/white composition by chemistry) were performed at each time point, and change scores computed. Metabolite relaxation and regions of interest (ROI) were also examined. RESULTS Across treatment, Li-treated BP subjects demonstrated GM Glx decreases (Li-HC, p =.08; Li-VPA p =.04) and GM myo-inositol increases (Li-HC p =.07; Li-VPA p =.12). Other measures were not significant. Serum Li levels were positively correlated with Glx decreases at the trend level. CONCLUSIONS Li treatment of BP was associated with specific GM Glx decreases and myo-inositol increases. Findings are discussed in the context of cellular mechanisms postulated to underlie Li and VPA therapeutic efficacy.

Donepezil in treatment-resistant bipolar disorder

BACKGROUND A considerable percentage of patients with bipolar disorder do not respond or do not tolerate conventional treatment. Cholinesterase (ChE) inhibitors have been suggested to possess depressogenic and antimanic properties. METHODS We report a case series of treatment-resistant bipolar patients (n = 11) to whom we administered the ChE inhibitor donepezil. Four patients met criteria for current manic episode, 5 for mixed episode, 1 for hypomanic episode, and 1 for major depressive episode. Donepezil was added to current medication on an openlabel basis. Ratings were based on a retrospective chart review. RESULTS Of the 11 patients, 6 (54.5%) demonstrated marked improvement (improvement in CGI-S > or = 2), 3 (27.2%) demonstrated slight improvement, 1 did not respond, and 1 did not tolerate the medication. Among those patients who had marked improvement (i.e., responders, n = 6), improvement was observed within 2 weeks or less in 5 of them (83%). Patients experienced only minor side effects. CONCLUSIONS These pilot data suggest the efficacy and safety of donepezil in the treatment of bipolar disorder. To our knowledge this is the first published report on the use of donepezil in the treatment of mood disorders. Controlled, randomized, double-blind studies are necessary to validate these preliminary observations.

Additional Findings on the Association Between Anxiety Sensitivity and Hypochondriacal Concerns: Examination of Patients with Major Depression

Hypochondriacal concerns ranging from disease phobias to bodily preoccupations are common among patients with panic disorder. In a previous study of patients with panic disorder, we found that, of a number of symptom dimensions examined, anxiety sensitivity was the strongest predictor of hypochondriacal concerns. This finding has been the topic of subsequent debate in the anxiety literature, with concerns raised whether true hypochondriacal concerns were confounded with typical panic-related concerns. To clarify this issue, we now report on the association between anxiety sensitivity and hypochondriacal concerns in 100 patients with major depression and no history of panic disorder. Consistent with our previous study, we found that of the symptoms examined--anxiety sensitivity, depressed mood, anxious mood, somatic symptoms, and anger/hostility--anxiety sensitivity was the strongest predictor of hypochondriacal concerns. Findings are discussed in relation to the role of catastrophic interpretations of somatic symptoms in depression, panic disorder, and hypochondriasis.

Hypochondriacal concerns in depressed outpatients.

The relationship between hypochondriacal concerns, as assessed by the Illness Attitude Scales, and depressive symptoms was examined in a sample of 100 drug-free outpatients with major depressive disorder. These patients were treated with fluoxetine for 8 weeks, and the effect of treatment on hypochondriacal symptoms was examined. All patients were administered the Structured Clinical Interview for DSM-III-R, the Hamilton Depression Rating Scale, the Symptom Questionnaire, and the Personality Disorders Questionnaire-Revised. We found little relationship between severity of depressive symptoms and hypochondriacal concerns. Measures of anxiety, somatic symptoms, and psychological distress were more consistently related to these concerns. Similarly, patients with either histrionic personality disorder or a lifetime history of panic disorder had greater hypochondriacal concerns than patients without these diagnoses. After open treatment with fluoxetine, the degree of hypochondriacal concern showed statistically significant decreases, which were only partly related to the degree of change in depression and anxiety severity. Our findings suggest that the presence of hypochondriacal concerns among depressed outpatients is more closely related to the presence of anxiety than depressive symptoms. The relatively small impact of an acute course of antidepressant treatment on hypochondriacal concerns in our sample suggests that these concerns may be enduring characteristics modulated only to a limited extent by short term pharmacological alterations of affective state.

Effect of lithium on phosphoinositide metabolism in human brain: A proton decoupled 31P magnetic resonance spectroscopy study

BACKGROUND The objective of our study was to evaluate whether lithium increases brain phosphomonoester (PME) levels in human subjects. METHODS Proton decoupled (31)P magnetic resonance spectra were obtained from eight healthy volunteers before and after the administration of lithium carbonate, 450 mg b.i.d., for 7 and 14 days. RESULTS Pairwise comparisons of the mole percent PME revealed a significant increase from baseline at day 7 and day 14 of lithium administration. CONCLUSIONS An increase in PME concentration with 7 and 14 days of lithium administration in the human brain in vivo was observed. Because the inositol-1-monophosphate contributes to the PME peak, this result suggests that some of the initial actions of lithium may occur through a reduction of myo-inositol, which in turn may initiate a cascade of secondary changes at different levels of signal transduction process and gene expression in brain, effects that are ultimately responsible for the therapeutic benefits of lithium.