Understanding the link between anxiety symptoms and suicidal ideation and behaviors in outpatients with bipolar disorder.

BACKGROUND: Prior studies suggest an association between anxiety comorbidity and suicidal ideation and behaviors in bipolar disorder. However, the nature of this association remains unclear. METHODS: We examined a range of anxiety symptoms, including panic, phobic avoidance, anxiety sensitivity, worry and fear of negative evaluation, in 98 patients with bipolar disorder. We predicted that each anxiety dimension would be linked to greater suicidal ideation and behavior as measured by Linehan's Suicide Behaviors Questionnaire (SBQ), greater depressive rumination, and poorer emotional processing and expression. RESULTS: Each anxiety dimension except fear of negative evaluation was associated with greater SBQ score, greater rumination, and lower levels of emotional processing in univariate analyses. Depressive rumination was a significant predictor of higher SBQ scores in a stepwise multivariate model controlling for age, gender, bipolar subtype, and bipolar recovery status; the association between the anxiety symptom dimensions and SBQ score was found to be redundant with depressive rumination. Emotional processing emerged as protective against suicidal ideation and behaviors in men only, while emotional expression was a significant predictor of lower SBQ scores for women and for the full sample; however, emotional expression was not significantly correlated with anxiety symptoms. Confirmatory analyses examining only those in recovery or recovered (n=68) indicated that the link between rumination and suicidality was not explained by depression. LIMITATIONS: Interpretation is limited by the cross-sectional study design. CONCLUSIONS: These findings indicate that increased ruminations may mediate the association between anxiety and suicidal ideation/behavior. In men, lower emotional processing may also play a role in this relationship.

The association of comorbid anxiety disorders with suicide attempts and suicidal ideation in outpatients with bipolar disorder.

Individuals with bipolar disorder are at increased risk for suicide attempts and completion. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk individuals nor has its treatment been integrated into suicide prevention strategies. In this study, ancillary to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 120 outpatients with bipolar disorder completed detailed assessment of suicidal ideation and behaviors. We examined the association of current and lifetime comorbid anxiety disorders with suicidal ideation and behaviors univariately and with adjustment for potential confounders in regression models. Lifetime anxiety disorders were associated with a more than doubling of the odds of a past suicide attempt, and current anxiety comorbidity was associated with a more than doubling of the odds of current suicidal ideation. Individuals with current anxiety disorders had more severe suicidal ideation, a greater belief suicide would provide relief, and a higher expectancy of future suicidal behaviors. However, some of these associations appeared to be better accounted for by measures of bipolar severity including an earlier age at bipolar onset and a lack of current bipolar recovery. Comorbid anxiety disorders may play a role in characteristics of bipolar disorder that then elevate risk for suicidal ideation and attempts. While further research is needed to establish the precise nature of these associations, our data support that the presence of comorbid anxiety disorders in individuals with bipolar disorder should trigger careful clinical assessment of suicide risk.

Inositol augmentation of lithium or valproate for bipolar depression.

OBJECTIVE: Despite promising new therapies, bipolar depression remains difficult to treat. Up to half of patients do not respond adequately to currently approved treatments. This study evaluated the efficacy of adjunctive inositol for bipolar depression. METHODS: Seventeen participants with DSM-IV criteria for bipolar depression and a 17-item Hamilton Rating Scale for Depression (HRSD) > or =15 on proven therapeutic levels of lithium or valproate for >2 weeks were randomized to receive double-blind inositol or placebo for 6 weeks. At the end of double-blind treatment, subjects were eligible for an 8-week open-label trial of inositol. RESULTS: Response was defined a priori as >50% reduction in the HRSD and a Clinical Global Impression of 1-2. Four of nine subjects (44%) on inositol and zero of eight subjects on placebo met response criteria (p = 0.053). There was no difference between groups in the average change score for the HRSD or Young Mania Rating Scale (YMRS). Response to inositol was highly variable. Of nine subjects randomized to inositol, two had >50% worsening in HRSD scores at the end of treatment, three had no change and four had >50% improvement. Those who had worsening in depressive symptoms on inositol had significantly higher scores at baseline on the YMRS total score and irritability, disruptive/aggressive behavior and unkempt appearance items. CONCLUSIONS: There was a trend for more subjects on inositol to show improvement in bipolar depression symptoms, but, on average, inositol was not more effective than placebo as an adjunct for bipolar depression. Baseline levels of anger or hostility may be predictive of clinical response to inositol.

A double-blind, placebo-controlled trial of adjunctive donepezil in treatment-resistant mania.

INTRODUCTION: Because there is a high rate of partial response to standard thymoleptic medication, novel augmentation strategies for treatment-resistant bipolar disorder are needed. In an open trial, donepezil augmentation was associated with improvement in manic symptoms in 9 of 11 subjects. METHOD: We conducted a 6-week, double-blind, placebo-controlled trial of donepezil for treatment-resistant bipolar mania. Eligible subjects had a Young Mania Rating Scale (YMRS) score of at least 15 despite two or more weeks of proven therapeutic levels of lithium or valproate. Subjects who completed the trial were eligible for an 8-week open trial of donepezil. Subjects were started on donepezil 5 mg/day and were eligible for dose increase to 10 mg/day after 4 weeks. RESULTS: Twelve subjects were enrolled. Eleven subjects received at least 1 week of study medication and were included in the analysis. No subjects in the donepezil group (0/6) and 60% (3/5) in the placebo group met response criteria of >30% reduction in YMRS score (Fisher's Exact p = 0.061). YMRS scores were higher at trial endpoint in the donepezil group 20.17 (3.66) compared with the placebo group [11.20 (4.60), Z = -2.476, p = 0.01]. There were no differences at trial endpoint in Hamilton Rating Scale for Depression (HAM-D) or Brief Psychiatric Rating Scale (BPRS) scores in either the intent-to-treat or the completer analyses. CONCLUSIONS: Donepezil does not appear to be an effective adjunctive treatment for refractory manic symptoms. The strength of the conclusion of this trial is limited by the possibility of a false-negative result due to the small sample.

Lithium-induced alterations in nucleoside triphosphate levels in human brain: a proton-decoupled 31P magnetic resonance spectroscopy study.

We examined how lithium's demonstrated effects on various cellular processes in human brain would be reflected in the (31)P magnetic resonance spectra of living human beings with respect to brain high-energy phosphate metabolites. Eight healthy volunteers received a baseline (31)P magnetic resonance spectroscopy (MRS) scan, after which they received lithium carbonate, 900 mg/day, for 14 days. Follow-up MRS scans were obtained on day 7 and on day 14. We detected a lithium-induced decrease in alpha-, beta-, gamma- and total nucleoside triphosphate NTP levels with chronic administration of lithium. On day 7, significant decreases were noted in gamma-NTP (14%) and total NTP (11%) levels. There was a trend for a decrease in beta-NTP (11%) levels. On day 14, significant decreases were noted in alpha-NTP (7%) and total NTP (8%) levels. There was a trend for a decrease in beta-NTP (16%) levels. Lithium caused a 25% reduction in inorganic phosphate (P(i)) levels on day 14. The theoretical relevance of the lithium-induced alterations on brain high-energy phosphates to the lithium-induced modifications of neuroplasticity is discussed.

Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder.

OBJECTIVE: The authors hypothesized that changes in brain membrane composition resulting from omega-3 fatty acid administration in patients with bipolar disorder would result in greater membrane fluidity, as detected by reductions in T(2) values. METHOD: Women with bipolar disorder (N=12) received omega-3 fatty acids for 4 weeks. A cohort of bipolar subjects (N=9) and a group without bipolar disorder (N=12) did not receive omega-3 fatty acids. T(2) values were acquired at baseline and after 4 weeks. RESULTS: Bipolar subjects who received omega-3 fatty acids had significant decreases in T(2). There was a dose-dependent effect when the bipolar omega-3 fatty acid group was subdivided into high- and low-dose cohorts. CONCLUSIONS: Omega-3 fatty acids lowered T(2) values, consistent with the hypothesis that the fluidity of cell membranes was altered. Further studies are needed to clarify the significance of alterations in brain physiology induced by omega-3 fatty acids, as reflected in T(2) values.

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.

Brain metabolic alterations in medication-free patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) has substantial morbidity and incompletely understood neurobiological underpinnings. OBJECTIVE: To investigate brain chemistry in medication-free individuals with BD. DESIGN: Two-dimensional proton echo-planar spectroscopic imaging (PEPSI) (32 x 32, 1-cm(3) voxel matrix) acquired axially through the cingulate gyrus was used to quantify regional brain chemistry. SETTING: The Center for Anxiety and Depression at the University of Washington in Seattle and the Bipolar Research Programs at McLean Hospital and the Massachusetts General Hospital in Boston. PARTICIPANTS: Thirty-two medication-free outpatients with a diagnosis of BD type I (BDI) or BD type II (BDII), predominantly in a depressed or mixed-mood state, were compared with 26 age- and sex-matched healthy controls. MAIN OUTCOME MEASURES: Tissue type (white and gray) and regional analyses were performed to evaluate distribution of lactate; glutamate, glutamine, and gamma-aminobutyric acid (Glx); creatine and phosphocreatine (Cre); choline-containing compounds (Cho); N-acetyl aspartate; and myo-inositol. Chemical relationships for diagnosis and mood state were evaluated. RESULTS: Patients with BD exhibited elevated gray matter lactate (P =.005) and Glx (P =.007) levels; other gray and white matter chemical measures were not significantly different between diagnostic groups. Isolated regional chemical alterations were found. An inverse correlation between 17-item Hamilton Depression Rating Scale scores and white matter Cre levels was observed for BD patients. CONCLUSIONS: Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.

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 (Brodmann's 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.

Low-field magnetic stimulation in bipolar depression using an MRI-based stimulator.

OBJECTIVE: Anecdotal reports have suggested mood improvement in patients with bipolar disorder immediately after they underwent an echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) procedure that can be performed within clinical MR system limits. This study evaluated possible mood improvement associated with this procedure. METHOD: The mood states of subjects in an ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief Affect Scale, a structured mood rating scale, immediately before and after an EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects with bipolar disorder, and actual EP-MRSI was administered to a comparison group of healthy subjects. The characteristics of the electric fields generated by the EP-MRSI scan were analyzed. RESULTS: Mood improvement was reported by 23 of 30 bipolar disorder subjects who received the actual EP-MRSI examination, by three of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14 healthy comparison subjects who received actual EP-MRSI. Significant differences in mood improvement were found between the bipolar disorder subjects who received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects who received actual EP-MRSI, between the healthy subjects and the bipolar disorder subjects and to a lesser extent between the unmedicated bipolar disorder subjects and the bipolar disorder subjects who were taking medication. The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of depression (1-500 V/m) and also extended uniformly throughout the head, unlike the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train of monophasic trapezoidal gradient pulses, differed from that used in rTMS. CONCLUSIONS: These preliminary data suggest that the EP-MRSI scan induces electric fields that are associated with reported mood improvement in subjects with bipolar disorder. The findings are similar to those for rTMS depression treatments, although the waveform used in EP-MRSI differs from that used in rTMS. Further investigation of the mechanism of EP-MRSI is warranted.

Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy.

OBJECTIVES: Oral choline administration has been reported to increase brain phosphatidylcholine levels. As phospholipid synthesis for maintaining membrane integrity in mammalian brain cells consumes approximately 10-15% of the total adenosine triphosphate (ATP) pool, an increased availability of brain choline may lead to an increase in ATP consumption. Given reports of genetic studies, which suggest mitochondrial dysfunction, and phosphorus (31P) magnetic resonance spectroscopy (MRS) studies, which report dysfunction in high-energy phosphate metabolism in patients with bipolar disorder, the current study is designed to evaluate the role of oral choline supplementation in modifying high-energy phosphate metabolism in subjects with bipolar disorder. METHODS: Eight lithium-treated patients with DSM-IV bipolar disorder, rapid cycling type were randomly assigned to 50 mg/kg/day of choline bitartrate or placebo for 12 weeks. Brain purine, choline and lithium levels were assessed using 1H- and 7Li-MRS. Patients received four to six MRS scans, at baseline and weeks 2, 3, 5, 8, 10 and 12 of treatment (n = 40 scans). Patients were assessed using the Clinical Global Impression Scale (CGIS), the Young Mania Rating Scale (YRMS) and the Hamilton Depression Rating Scale (HDRS) at each MRS scan. RESULTS: There were no significant differences in change-from-baseline measures of CGIS, YMRS, and HDRS, brain choline/creatine ratios, and brain lithium levels over a 12-week assessment period between the choline and placebo groups or within each group. However, the choline treatment group showed a significant decrease in purine metabolite ratios from baseline (purine/n-acetyl aspartate: coef = -0.08, z = -2.17, df = 22, p = 0.030; purine/choline: coef = -0.12, z = -1.97, df = 22, p = 0.049) compared to the placebo group, controlling for brain lithium level changes. Brain lithium level change was not a significant predictor of purine ratios. CONCLUSIONS: The current study reports that oral choline supplementation resulted in a significant decrease in brain purine levels over a 12-week treatment period in lithium-treated patients with DSM-IV bipolar disorder, rapid-cycling type, which may be related to the anti-manic effects of adjuvant choline. This result is consistent with mitochondrial dysfunction in bipolar disorder inadequately meeting the demand for increased ATP production as exogenous oral choline administration increases membrane phospholipid synthesis.

Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study.

OBJECTIVE: The authors' goal was to determine if there is an association between brain-to-serum lithium ratios and age. METHOD: Lithium-7 magnetic resonance spectroscopy was used to measure in vivo brain lithium levels in nine children and adolescents (mean age=13.4 years, SD=3.6) and 18 adults (mean age=37.3, SD=9.1) with bipolar disorder. RESULTS: Serum and brain lithium concentrations were positively correlated. Younger subjects had lower brain-to-serum concentration ratios than adults: 0.58 (SD=0.24) versus 0.92 (SD=0.36). The brain-to-serum concentration ratio correlated positively with age. CONCLUSIONS: These observations suggest that children and adolescents may need higher maintenance serum lithium concentrations than adults to ensure that brain lithium concentrations reach therapeutic levels.