Shelley J. Hill

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.

Toward interaction of affective and cognitive contributors to creativity in bipolar disorders: A controlled study

BACKGROUND Enhanced creativity in bipolar disorder patients may be related to affective and cognitive phenomena. METHODS 32 bipolar disorder patients (BP), 21 unipolar major depressive disorder patients (MDD), 22 creative controls (CC), and 42 healthy controls (HC) (all euthymic) completed the Revised Neuroticism Extraversion Openness Personality Inventory (NEO), the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), the Myers-Briggs Type Inventory (MBTI); the Barron-Welsh Art Scale (BWAS), the Adjective Check List Creative Personality Scale, and the Figural and Verbal Torrance Tests of Creative Thinking. Mean scores were compared across groups, and relationships between temperament/personality and creativity were assessed with bivariate correlation and hierarchical multiple linear regression. RESULTS BP and CC (but not MDD) compared to HC had higher BWAS-Total (46% and 42% higher, respectively, p<0.05) and BWAS-Dislike (83% and 93% higher, p<0.02) scores, and higher MBTI-Intuition preference type rates (78% vs. 50% and 96% vs. 50%, p<0.05). BP, MDD, and CC, compared to HC, had increased TEMPS-A-Cyclothymia scores (666%, 451% and 434% higher, respectively, p<0.0001), and NEO-Neuroticism scores (60%, 57% and 51% higher, p<0.0001). NEO-Neuroticism and TEMPS-A Cyclothymia correlated with BWAS-Dislike (and BWAS-Total), while MBTI-Intuition continuous scores and NEO-Openness correlated with BWAS-Like (and BWAS-Total). LIMITATIONS Relatively small sample size. CONCLUSIONS We replicate the role of cyclothymic and related temperaments in creativity, as well as that of intuitive processes. Further studies are needed to clarify relationships between creativity and affective and cognitive processes in bipolar disorder patients.

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.

Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course

BACKGROUND Gene-environment interactions may contribute to bipolar disorder (BD) clinical course variability. We examined effects of brain-derived neurotrophic factor (BDNF) val66met genotype and early life stress (ELS) upon illness severity and chronicity in adult BD patients. METHODS 80 patients (43 BD I, 33 BD II, 4 BD not otherwise specified, mean ± SD age 46.4 ± 14.0 years, 63.7% female) receiving open evidence-based and measurement-based care in the Stanford Bipolar Disorders Clinic for at least 12 months underwent BDNF val66met genotyping and completed the Childhood Trauma Questionnaire. BDNF met allele carrier genotype and history of childhood sexual and physical abuse were evaluated in relation to mean prior-year Clinical Global Impressions-Bipolar Version-Overall Severity of Illness (MPY-CGI-BP-OS) score and clinical and demographic characteristics. RESULTS BDNF met allele carriers (but not non-met allele carriers) with compared to without childhood sexual abuse had 21% higher MPY-CGI-BP-OS scores (3.5 ± 0.7 versus 2.9 ± 0.7, respectively, t = -2.4, df = 28, p = 0.025) and 35% earlier BD onset age (14.6 ± 5.7 versus 22.8 ± 7.9 years, respectively, t = 3.0, df = 27, p = 0.006). Regression analysis, however, was non-significant for a BDNF-childhood sexual abuse interaction. LIMITATIONS small sample of predominantly female Caucasian insured outpatients taking complex medication regimens; only one gene polymorphism considered. CONCLUSIONS Between group comparisons suggested BDNF met allele carrier genotype might amplify negative effects of ELS upon BD illness severity/chronicity, although with regression analysis, there was not a significant gene-environment interaction. Further studies with larger samples are warranted to assess whether BDNF met allele carriers with ELS are at risk for more severe/chronic BD illness course.

Childhood-compared to adolescent-onset bipolar disorder has more statistically significant clinical correlates

BACKGROUND The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue. METHODS BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients. RESULTS Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics. LIMITATIONS Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall. CONCLUSIONS Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

American tertiary clinic-referred bipolar II disorder compared to bipolar I disorder: More severe in multiple ways, but less severe in a few other ways

BACKGROUND Prevalence and relative severity of bipolar II disorder (BDII) vs. bipolar I disorder (BDI) are controversial. METHODS Prevalence, demographics, and illness characteristics were compared among 260 BDII and 243 BDI outpatients referred to the Stanford University BD Clinic and assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation. RESULTS BDII vs. BDI outpatients had statistically similar prevalence (51.7% vs. 48.3%), and in multiple ways had more severe illness, having significantly more often: lifetime comorbid anxiety (70.8% vs. 58.4%) and personality (15.4% vs. 7.4%) disorders, first-degree relative with mood disorder (62.3% vs. 52.3%), at least 10 prior mood episodes (80.0% vs. 50.9%), current syndromal/subsyndromal depression (52.3% vs. 38.4%), current antidepressant use (47.3% vs. 31.3%), prior year rapid cycling (33.6% vs. 13.4%), childhood onset (26.2% vs. 16.0%), as well as earlier onset age (17.0±8.6 vs. 18.9±8.1 years), longer illness duration (19.0±13.0 vs. 16.1±13.0), and higher current Clinical Global Impression for Bipolar Disorder-Overall Severity (4.1±1.4 vs. 3.7±1.5). However, BDII vs. BDI patients significantly less often had prior psychosis (14.2% vs. 64.2%), psychiatric hospitalization (10.0% vs. 67.9%), and current prescription psychotropic use, (81.5% vs. 93.0%), and had a statistically similar rate of prior suicide attempt (29.5% vs. 32.1%). LIMITATIONS American tertiary bipolar disorder clinic referral sample, cross-sectional design. CONCLUSIONS Further studies are warranted to determine the extent to which BDII, compared to BDI, can be more severe in multiple ways but less severe in a few other ways, and contributors to occurrence of more severe forms of BDII.

Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000–2011

OBJECTIVE To assess mood stabilizer (MS) and second-generation antipsychotic (SGA) prescribing trends in bipolar disorder (BD) outpatients referred to a bipolar disorder specialty clinic over the past 12 years. METHOD BD outpatients referred to the Stanford University Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prescription rates for MSs and SGAs were compared during the first (2000-2005) and second (2006-2011) six years. RESULTS Among 597 BD patients (mean±SD age 35.4±8.6 years; 58.1% female; 40.7% Type I, 43.6% Type II, and 15.7% Type Not Otherwise Specified; taking 2.6±1.7 prescription psychotropic medications), lamotrigine, quetiapine, and aripiprazole usage more than doubled, from 14.7% to 37.2% (p<0.0001), 7.2% to 19.7% (p<0.0001), and 3.1% to 10.9% (p=0.0003), respectively, while olanzapine and risperidone use decreased by more than half from 15.0% to 6.6% (p=0.0043), and from 8.7% to 3.8% (p=0.039), respectively. SGA use increased from 34.1% to 44.8% (p=0.013), although MS use continued to be more common (in 65.2% for 2006-2011). Use of other individual MSs and SGAs and MSs as a class did not change significantly. CONCLUSIONS Over 12 years, in patients referred to a BD specialty clinic, lamotrigine, quetiapine, and aripiprazole use more than doubled, and olanzapine and risperidone use decreased by more than half. Tolerability (for lamotrigine, aripiprazole, olanzapine, and risperidone) more than efficacy (for quetiapine) differences may have driven these findings. Additional studies are needed to explore the relative influences of enhanced tolerability versus efficacy upon prescribing practices in BD patients.

First controlled treatment trial of bipolar II hypomania with mixed symptoms: Quetiapine versus placebo

OBJECTIVES To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ≥2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Superior chronic tolerability of adjunctive modafinil compared to pramipexole in treatment-resistant bipolar disorder

BACKGROUND Suboptimal outcomes are common in bipolar disorder (BD) pharmacotherapy, and may be mitigated with novel adjunctive agents such as modafinil (a low-affinity dopamine transport inhibitor) and pramipexole (a dopamine D2/D3 receptor agonist). While uncontrolled long-term effectiveness data have been reported for these treatments, reports specifically assessing their comparative acute versus chronic tolerability in BD are lacking. Such information, particularly in relation to discontinuation causes, has substantial relevance, providing initial indications to clinicians which treatment may be better tolerated, and to researchers which agent ought to be assessed in longer-term controlled trials. METHODS BD 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 adjunctive modafinil or pramipexole, and somatic/psychiatric intolerability discontinuation rates were compared. RESULTS Among 63 BD outpatients (mean ± SD age 43.5 ± 14.3 years, 60.3% female, 42.9% type I, 44.4% type II, 12.7% type not otherwise specified), taking 3.5 ± 1.5 (median 3) concurrent prescription psychotropics, adjunctive modafinil (n=24) for 626.9 ± 863.9 (286) days versus pramipexole (n=39) for 473.7 ± 613.4 (214; p=0.51) days yielded a 26.0% lower somatic/psychiatric intolerability discontinuation rate (12.5% vs. 38.5%; p<0.05), with most of the difference accounted for by more pramipexole somatic intolerability discontinuations, due to nausea and sedation, after the first 12 weeks of treatment. LIMITATIONS No placebo comparison group. Small sample of predominantly female Caucasian insured outpatients, taking complex concurrent medication regimens. CONCLUSIONS Further studies are warranted to assess our preliminary observation that modafinil, compared to pramipexole, may be better tolerated for longer-term BD treatment.

Divalproex extended-release in acute bipolar II depression

BACKGROUND Divalproex extended-release (divalproex-ER) is effective in acute mania, and limited data suggest divalproex may have efficacy in acute bipolar depression. METHODS A 7-week, open-label trial of divalproex-ER monotherapy or adjunctive therapy was conducted in 28 outpatients (15 female, mean age 36.7+/-9.1, and mean duration of illness 22.1+/-11.1 years) with bipolar II depression (39% with rapid cycling course of illness within the prior year). Divalproex-ER was generally given as a single dose at bedtime, starting at 250mg and increased by 250mg every 4 days to symptom relief or adverse effects. Efficacy was assessed using weekly prospective Montgomery Asberg Depression Rating Scale (MADRS) scores. RESULTS Overall, mean divalproex-ER final doses and serum concentrations were 1469mg/day and 80.1microg/mL, respectively. Mean MADRS scores (last observation carried forward) decreased significantly from baseline in patients in the overall group (from 30.1 to 15.2, p<.00001). The overall response rate was 54%. Divalproex-ER therapy was generally well tolerated, with no early discontinuations due to adverse events. LIMITATIONS This study is limited by a small sample size and an open-label study design with no placebo control. CONCLUSIONS Divalproex-ER as monotherapy and adjunctive therapy was well tolerated and yielded an overall response rate of 54% in bipolar II depression. Based on the results of this pilot study, randomized, double-blind, placebo-controlled studies of divalproex-ER in bipolar II depression are warranted.