Jennifer C. Hoblyn

Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder

This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative 18F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.

Dorsolateral and dorsomedial prefrontal gray matter density changes associated with bipolar depression

Mood states are associated with alterations in cerebral blood flow and metabolism, yet changes in cerebral structure are typically viewed in the context of enduring traits, genetic predispositions, or the outcome of chronic psychiatric illness. Magnetic resonance imaging (MRI) scans were obtained from two groups of patients with bipolar disorder. In one group, patients met criteria for a current major depressive episode whereas in the other no patient did. No patient in either group met criteria for a current manic, hypomanic, or mixed episode. Groups were matched with respect to age and illness severity. Analyses of gray matter density were performed with Statistical Parametric Mapping software (SPM5). Compared with non-depressed bipolar subjects, depressed bipolar subjects exhibited lower gray matter density in the right dorsolateral and bilateral dorsomedial prefrontal cortices and portions of the left parietal lobe. In addition, gray matter density was greater in the left temporal lobe and right posterior cingulate cortex/parahippocampal gyrus in depressed than in non-depressed subjects. Our findings highlight the importance of mood state in structural studies of the brain-an issue that has received insufficient attention to date. Moreover, our observed differences in gray matter density overlap metabolic areas of change and thus have implications for the conceptualization and treatment of affective disorders.

Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder

The corticolimbic dysregulation hypothesis of bipolar disorder suggests that depressive symptoms are related to dysregulation of components of an anterior paralimbic network (anterior cingulate, anterior temporal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus, and amygdala) with excessive anterior limbic activity accompanied by diminished prefrontal activity. In younger patients, such abnormalities tend to resolve with remission of depression, but it remains to be established whether the same is true for older patients. This was a cross-sectional, between-subjects design conducted with 16 euthymic, medicated patients with bipolar disorder (10 type I, six type II) and 11 age-matched healthy controls. All participants were over age 50. Our main outcome measures were relative rates of cerebral metabolism derived from a resting (18)flourodeoxyglucose positron emission tomography scan in specified regions of interest in the corticolimbic network. Resting metabolic rates in bipolar patients were significantly greater than in controls in bilateral amygdalae, bilateral parahippocampal gyri, and right anterior temporal cortex (BA 20, 38); they were significantly lower in bipolar patients than in controls in the bilateral dorsolateral prefrontal cortices (BA 9, 10, 46). The evidence of corticolimbic dysregulation observed is consistent with the hypothesis that bipolar disorder entails progressive, pernicious neurobiological disruptions that may eventually persist during euthymia. Persistent corticolimbic dysregulation may be related to residual affective, behavioral, and cognitive symptoms in older patients with bipolar disorder, even when not experiencing syndromal mood disturbance.

Neurocognitive Costs and Benefits of Psychotropic Medications in Older Adults

Psychotropic medications are widely used in older adults and may cause neurocognitive deficits. Older adults are at increased risk of developing adverse effects because of age-related pharmacodynamic and pharmacokinetic changes. This article provides a comprehensive review of the undesirable, and at times beneficial, effects of psychotropic medications. The review covers a wide range of medications that impair executive function, memory, and attention, as well as a much smaller group of medications that lead to improved neurocognitive function. Some of the most commonly used psychotropic medications in older adults, namely, antidepressants, sedatives, and hypnotics, are among the drugs that most consistently lead to cognitive impairments. Medications with anticholinergic properties almost invariably lead to neurocognitive dysfunction, despite symptom improvement. The neurocognitive costs and benefits of psychiatric medications should be considered in the context of disease treatment in older adults. (J Geriatr Psychiatry Neurol 2007;20:199—214)

Effectiveness of lamotrigine in bipolar disorder in a clinical setting

OBJECTIVE To assess lamotrigine effectiveness in bipolar disorder (BD) patients in a clinical setting. METHOD Open lamotrigine was naturalistically administered to outpatients at the Stanford University BD Clinic assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and monitored longitudinally with the STEP-BD Clinical Monitoring Form. RESULTS One hundred and ninety-seven patients (64 BD I, 110 BD II, 21 BD NOS, 2 Schizoaffective Bipolar Type, mean+/-SD age 42.2+/-14.4 years, 62% female) had 200 trials of lamotrigine. Lamotrigine was combined with a mean of 2.1+/-1.5 other psychotropic medications, most often during euthymia or depressive symptoms. Mean lamotrigine duration was 434+/-444 days, and mean final dose was 236+/-132mg/day without valproate, and 169+/-137mg/day with valproate. Lamotrigine was discontinued in only 26.5% of trials at 255+/-242 days, most often due to inefficacy, and seldom due to adverse effects. In 31.5% of trials lamotrigine was continued 264+/-375 days with no subsequent psychotropic added. In 42.0% of trials lamotrigine was continued 674+/-479 days, but had subsequent psychotropic added at 146+/-150 days, most often for anxiety/insomnia and depressive symptoms. In 145 trials started at Stanford, lamotrigine primarily yielded relief of depressive symptoms or maintained euthymia. In 55 trials in which lamotrigine was started prior to Stanford, lamotrigine primarily maintained euthymia. Lamotrigine was generally well tolerated, with no serious rash, and only 3.5% discontinuing due to benign rash. CONCLUSION In a cohort of bipolar disorder outpatients commonly with comorbid conditions, and most often receiving complex combination therapy, lamotrigine had a low (26.5%, with an overall mean duration of treatment of 434 days) discontinuation rate, suggesting effectiveness in BD in a clinical setting.

Resting Prefrontal Hypometabolism and Paralimbic Hypermetabolism Related to Verbal Recall Deficits in Euthymic Older Adults With Bipolar Disorder

OBJECTIVES To evaluate deficits of delayed free recall in euthymic older patients with bipolar disorder and relate deficits to resting cerebral metabolism. DESIGN Two group, between subjects. SETTING Outpatient. PARTICIPANTS Participants included 16 older adult (mean age, 58.7 years; SD = 7.5) euthymic outpatients with bipolar disorder (10 Type I and 6 Type II) and 11 healthy comparison subjects (mean age, 58.3 years; SD = 5.2). MEASUREMENTS All participants received resting positron emission tomography with (18)flurodeoxyglucose and, within 10 days, delayed free verbal recall testing with the California Verbal Learning Test II. RESULTS Patients with bipolar disorder, relative to healthy comparison subjects, had significantly poorer delayed free verbal recall. In patients with bipolar disorder, relative to healthy comparison subjects, prefrontal hypometabolism (dorsolateral prefrontal cortex) and paralimbic hypermetabolism (hippocampus, parahippocampal gyrus, and superior temporal gyrus) was associated with recall deficits in patients with bipolar disorder. Prefrontal and limbic metabolism were inversely related. CONCLUSION Our findings demonstrate an association between prefrontal hypometabolism and paralimbic hypermetabolism and verbal memory deficits in euthymic older patients with bipolar disorder. Verbal memory deficits may be a clinical consequence of corticolimbic dysregulation in bipolar disorder, even during euthymia. This suggests that such dysregulation and related deficits could be bipolar disorder traits.

Metabolic evidence of corticolimbic dysregulation in bipolar mania

Findings from previous research on the neural substrates of mania have been variable, in part because of heterogeneity of techniques and patients. Though some findings have been replicated, the constellation of neurophysiological changes has not been demonstrated simultaneously. We sought to determine resting state cerebral metabolic changes associated with relatively severe acute mania. Resting positron emission tomography with (18)fluorodeoxyglucose was performed in bipolar disorder patients with severe mania and in healthy controls. Statistical parametric mapping was used to determine regions of differential metabolism. Relative to controls, bipolar disorder patients with mania exhibited significantly decreased cerebral metabolism in both the dorsolateral prefrontal regions and the precuneus. Conversely, manic patients exhibited significant hypermetabolism in the parahippocampal complex, temporal lobe, anterior cingulate, and subgenual prefrontal cortex compared with controls. These results demonstrate simultaneous resting limbic/paralimbic hypermetabolism and prefrontal hypometabolism during mania. The findings support the hypothesis of corticolimbic dysregulation as a crucial contributor to the pathophysiology of bipolar disorder.

Should One Use Medications in Combination With Cognitive Training? If So, Which Ones?

In this article, we review current research regarding diagnosis of cognitive impairment in nondemented adults and discuss why medications and cognitive training together may be more beneficial than either alone. We also review potential cognitive enhancers and future research challenges. There are major reasons for such research: (a) Large numbers of older adults without dementia but with cognitive problems are not treatable with current cognitive training techniques; (b) some medications offer a rationale (i.e., cognitive enhancement) and some evidence that they might be a useful adjunct; and (c) there are unanswered questions about which population to target, which medications to use, how to administer them, and issues regarding tolerance and use of appropriate (active) placebo controls. As the number of cognitively impaired older adults grows, it is likely that there will be pressure to treat more broadly with both medications and cognitive training.

Factors Associated With Psychiatric Hospitalization of Individuals Diagnosed With Dementia and Comorbid Bipolar Disorder

The objective was to determine risk factors of psychiatric hospitalization among a Veterans Administration database of patients with dementia and comorbid bipolar disorder (D+BD). Patients with D+BD had a greater prevalence of psychiatric hospitalization (28% vs 4%). The strongest predictor of psychiatric hospitalization was the presence of an alcohol use disorder (51% risk); patients without alcohol use disorders but under the age of 70 had the next highest risk (33% risk). However, patients with an alcohol use disorder had shorter psychiatric hospitalizations than those without. Compared with patients without BD, D+BD patients were more likely to have alcohol use disorders (15% vs 3%) and any other substance use problem (10% vs 1%). In patients diagnosed with dementia and bipolar disorder, the strongest risk factor for psychiatric hospitalization was an alcohol abuse disorder. These findings suggest that disorders with increased frequency in BD affect the course of dementia.

Effectiveness of quetiapine plus lamotrigine maintenance therapy in challenging bipolar disorder patients.

OBJECTIVE Assess quetiapine plus lamotrigine (QTP+LTG) combination maintenance therapy effectiveness in challenging bipolar disorder (BD). METHOD Outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form were naturalistically prescribed QTP+LTG. RESULTS Fifty-four outpatients with challenging BD, taking in addition to QTP+LTG, a mean±SD of 2.1±1.6 (in 63.0% at least 2) other psychotropic and 2.3±1.9 non-psychotropic prescription medications, had QTP+LTG maintenance trials. Median(mean±SD) QTP+LTG duration was 401(730±756) days. Final QTP and LTG doses were 87.5(188±211) and 300(287±108) mg/day, respectively. Half (27/54) of patients discontinued QTP (in 19), LTG (in 6), or QTP+LTG (in 2), after 294(415±414) days - due to side-effects in 10, inefficacy in seven, non-adherence in five, and other reasons in five. 42.6%(23/54) had additional pharmacotherapy intervention for emergent mood symptoms, after 175(261±237) days, with at least one psychotropic added (in 16/54) or substantively (by ≥50%) increased (in 7/54). 55.6%(30/54) had recurrent mood episodes, after 126(187±158) days, most often depressive (in 35.2%), although 64.8%(35/54) were euthymic at final visit taking QTP+LTG. Sedation increased significantly during treatment among those with side-effect discontinuations, and 19.2%(10/52, all having QTP added to LTG) had clinically significant (≥7%) weight gain. LIMITATIONS No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients taking complex concurrent medication regimens. CONCLUSION Additional studies are warranted to confirm our preliminary observation that QTP+LTG maintenance may be effective in patients with challenging BD.