Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ).

OBJECTIVES: This report describes the first comparative double-blind, placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ) as adjunctive treatments in rapid cycling bipolar disorder. METHODS: Thirty-two treatment-resistant, rapid cycling patients who had failed a trial of lithium were randomized into three treatment arms: L-T4 , T3 , or placebo. They were followed for ≥4 months with weekly clinical and endocrine assessments. RESULTS: There were no statistically significant differences between the groups in age, gender, duration of illness, or thyroid status. Markov chain analyses were employed to assess treatment effects on cycling patterns among mood states (euthymia, depression, mania, and mixed). Within groups, post-treatment the L-T4 group spent significantly less time depressed or in a mixed state and greater time euthymic. The T3 and placebo groups did not differ significantly pre- and post-treatment in any mood state, although the pattern of effects was the same for the T3 group as for the L-T4 group. Between groups, the L-T4 group had a significantly greater increase in time euthymic and decrease in time in the mixed state than the placebo group. Other group differences were not significant, although they were in the expected direction. CONCLUSIONS: The findings in this first double-blind study directly comparing the effects of L-T4 and T3 therapy against placebo provide evidence for the benefit of adjunctive L-T4 in alleviating resistant depression, reducing time in mixed states and increasing time euthymic. Adjunctive T3 did not show statistically significant evidence of benefit over placebo in reducing the time spent in disturbed mood states.

Assessing bipolar disorder in the older adult: the GERI-BD toolbox.

INTRODUCTION: The evidence base regarding characteristics of older adults with bipolar disorder (BD) remains limited. The NIH-funded multicenter study Acute Pharmacotherapy of Late-Life Mania (GERI-BD) assessed various clinical domains before and during mood stabilizer treatment in older adults participating in a 9-week, double-blind randomized controlled trial. We describe the rationale for selecting these instruments. METHODS: Domains and instruments were selected on the basis of the study design and the participants. The investigators' experience in clinical trials involving young adults with BD or older adults with major depressive disorder, along with open studies of older adults with BD, contributed to the selection process. RESULTS: We identified domains and selected instruments that could be used to assess the participants given their diagnostic, treatment history, and medical and mood state characteristics. They were also intended to measure tolerability and efficacy and permit examination of potential moderating and mediating factors. CONCLUSIONS: Decisions regarding the assessment domains to be included in the clinical trial highlight the challenges facing researchers studying drug treatments for older adults with BD, or more generally, mood disorders. We suggest that the domains and instruments selected by GERI-BD investigators constitute a "toolbox" that can be customized for other investigators. Copyright © 2017 John Wiley & Sons, Ltd.

Social support in late life mania: GERI-BD.

OBJECTIVE: Using the database of the National Institute of Mental Health-sponsored acute treatment of late life mania study (GERI-BD), we assessed the role of social support in the presentation of late life bipolar mania. METHODS: In the first 100 subjects randomized in geriatric BD, we explored the demographic, clinical, and social support characteristics (assessed using the Duke Social Support Index) and aspects of manic presentation. We selected two dependent variables: symptom severity, as determined by the Young Mania Rating Scale (YMRS) at baseline, and duration of episode. We selected nine potential independent variables on the basis of Pearson correlation coefficients. We derived two final models using multiple regression analysis employing an iterative process. RESULTS: In our severity model, being married was associated with a higher YMRS score (p = 0.05), whereas higher social interaction scores with non-family members were associated with a lower YMRS score (p = 0.011). In the episode duration model, longer duration was associated with a higher Hamilton Depression Rating Scale score (p = 0.03) and higher social interaction scores with non-family members (p = 0.0003), younger age (p = 0.04), higher number of persons in one's family social network (p = 0.017), and higher instrumental support scores (p = 0.0062). CONCLUSIONS: In late life mania, more social interaction with one's community appears to be associated with less severe symptoms at presentation for treatment, however, it can also be associated with slightly longer the duration of episode. Two aspects of the Duke Social Support Index are associated with a shorter episode duration prior to seeking treatment: being part of a larger family network and a having a higher level of instrumental support prior to treatment. The Instrumental Support Subscale measures the degree of assistance that is available for the respondent in performing daily tasks. These findings suggest that in older adults with BD, close social interactions and support are important in limiting the length of the illness episode prior to treatment. Social interactions involving non-family members may be less important in moderating the intensity of the symptoms at presentation.

Acute bipolar I affective episode presentation across life span.

OBJECTIVES: There is a paucity of evidence on bipolar I acute symptoms' presentation in the elderly individuals compared to younger patients. The current literature provides little, and at times conflicting, information on age-related bipolar disorder (BD) symptom presentation. This article aims to compare symptom profile by age group among patients with bipolar I in an acute affective episode as evaluated in outpatient settings. METHODS: The current analyses include all Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) participants with a lifetime diagnosis of bipolar I disorder. We compared the presence and severity of acute mood elevation (mania and hypomania) and acute depression symptoms between younger (20-59 years old) and older individuals (older than or equal to 60 years). RESULTS: With the exception of distractibility, all acute depression symptoms presented with comparable frequency and severity between younger and older individuals. No statistical significance was found regarding the presence of psychotic symptoms between the 2 groups, with symptoms reported by 11.2% of younger versus 9.4% older individuals, χ(2) (1, N = 1541) = 0.03, P = .74. No significant effects were found for mood elevation severity between the 2 age groups. Psychotic symptoms were reported in 12.7% versus 15.2%, χ(2) (1, N = 658) = 0.07, P = .65, and irritability in 97.7% versus 97.8%, χ(2) (1, N = 651) = 0.00, P = 1.00, in the younger and older group, respectively. CONCLUSION: We found no statistically significant association between age and symptoms presentation of acute depression and mood elevation among patients with BD I. Acute BD I affective states present with similar profile and severity in old and young patients.

Correlates of treatment response in depressed older adults with bipolar disorder.

AIMS: To identify baseline clinical factors associated with acute treatment response in depressed older adults with bipolar disorder (BD) receiving lamotrigine. METHODS: Secondary analysis of a multisite, 12-week, open-label, uncontrolled study of add-on lamotrigine in 57 adults 60 years and older with BD I or II depression. Measures included the Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Cardiometabolic risk was measured with total serum cholesterol and the Cumulative Illness Rating Scale-Geriatric (CIRS-G) item #13 (endocrine/metabolic burden). Neurocognitive (executive) function was evaluated using the Trail Making Test. RESULTS: Greater reduction in MADRS from baseline was associated with higher baseline cardiometabolic burden at 6 and 9 weeks and lower YMRS scores at 9 weeks. At 12 weeks, improvement in the MADRS from baseline was no longer significantly related to baseline cardiometabolic burden or YMRS scores. A longitudinal mixed model of MADRS scores corroborated these findings with a significant finding of time-by-baseline cholesterol level interaction. In a subset of participants, better baseline executive function was related to greater improvement in the MADRS at 9 weeks but not at 6 or 12 weeks. Among all participants, higher baseline YMRS scores were related to greater likelihood of dropout. CONCLUSIONS: Lamotrigine appears to work best in depressed elderly patients with BD who have high cardiometabolic risk and low level of mania. Agents like lamotrigine that act primarily on neuroprogressive pathways involving oxidative stress, neurotrophins, and inflammation may be particularly effective in individuals with BD who have significant cardiometabolic burden because of their effects on shared vulnerability factors in BD and medical illness.

Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report.

AIMS: This is a multisite, 12-week, open-label trial of lamotrigine augmentation in 57 older adults (≥ 60 years; mean ± SD age = 66.5 ± 6.7 years) with either type I or type II bipolar depression. METHODS: Primary outcome measure was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule II (WHO-DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess side effects. RESULTS: A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. CONCLUSIONS: In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression.

Effectiveness of adjunctive antidepressant treatment for bipolar depression.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

The relationship of bipolar disorder lifetime duration and vascular burden to cognition in older adults.

OBJECTIVES: We describe the cognitive function of older adults presenting with bipolar disorder (BD) and mania and examine whether longer lifetime duration of BD is associated with greater cognitive dysfunction. We also examine whether there are negative, synergistic effects between lifetime duration of BD and vascular disease burden on cognition. METHODS: A total of 87 nondemented individuals with bipolar I disorder, age 60 years and older, experiencing manic, hypomanic, or mixed episodes, were assessed with the Dementia Rating Scale (DRS) and the Framingham Stroke Risk Profile (FSRP) as a measure of vascular disease burden. RESULTS: Subjects had a mean (SD) age of 68.7 (7.1) years and 13.6 (3.1) years of education; 50.6% (n = 44) were females, 89.7% (n = 78) were white, and 10.3% (n = 9) were black. They presented with overall and domain-specific cognitive impairment in memory, visuospatial ability, and executive function compared to age-adjusted norms. Lifetime duration of BD was not related to DRS total score, any other subscale scores, or vascular disease burden. FSRP scores were related to the DRS memory subscale scores, but not total scores or any other domain scores. A negative interactive effect between lifetime duration of BD and FSRP was only observed with the DRS construction subscale. CONCLUSIONS: In this study, lifetime duration of BD had no significant relationship with overall cognitive function in older nondemented adults. Greater vascular disease burden was associated with worse memory function. There was no synergistic relationship between lifetime duration of BD and vascular disease burden on overall cognition function. Addressing vascular disease, especially early in the course of BD, may mitigate cognitive impairment in older age.

Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD.

AIM: This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients. METHOD: There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions. RESULTS: Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria. CONCLUSIONS: A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia.

OBJECTIVE: Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. METHODS: We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS). RESULTS: Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. CONCLUSIONS: Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.

GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder.

(Reprinted with permission from Am J Psychiatry 2017; 174:1086-1093).

The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD.

OBJECTIVE: In a naturalistic follow-up of adult bipolar patients, the authors examined the contributions of demographic, phenomenological, and clinical variables, including antidepressant use, to prospectively observed mood episode frequency. METHOD: For 1,742 bipolar I and II patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), episodes of mood disorders were evaluated for up to 1 year of treatment. RESULTS: At entry, 32% of the patients met the DSM-IV criteria for rapid cycling in the prestudy year. Of the 1,742 patients, 551 (32%) did not complete 1 year of treatment. Among the 1,191 patients remaining, those with prior rapid cycling (N=356) were more likely to have further recurrences, although not necessarily more than four episodes per year. At the end of 12 months, only 5% (N=58) of the patients could be classified as rapid cyclers; 34% (N=409) had no further mood episodes, 34% (N=402) experienced one episode, and 27% (N=322) had two or three episodes. Patients who entered the study with earlier illness onset and greater severity were more likely to have one or more episodes in the prospective study year. Antidepressant use during follow-up was associated with more frequent mood episodes. CONCLUSIONS: While DSM-IV rapid cycling was prospectively observed in only a small percentage of patients, the majority of these patients had continued recurrences at lower but clinically significant rates. This suggests that cycling is on a continuum and that prevention of recurrences may require early intervention and restricted use of antidepressants.

Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program.

CONTEXT: Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder. OBJECTIVE: To examine the benefits of 4 disorder-specific psychotherapies in conjunction with pharmacotherapy on time to recovery and the likelihood of remaining well after an episode of bipolar depression. DESIGN: Randomized controlled trial. SETTING: Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder. Patients A total of 293 referred outpatients with bipolar I or II disorder and depression treated with protocol pharmacotherapy were randomly assigned to intensive psychotherapy (n = 163) or collaborative care (n = 130), a brief psychoeducational intervention. INTERVENTIONS: Intensive psychotherapy was given weekly and biweekly for up to 30 sessions in 9 months according to protocols for family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy. Collaborative care consisted of 3 sessions in 6 weeks. MAIN OUTCOME MEASURES: Outcome assessments were performed by psychiatrists at each pharmacotherapy visit. Primary outcomes included time to recovery and the proportion of patients classified as well during each of 12 study months. RESULTS: All analyses were by intention to treat. Rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions. Patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care (hazard ratio, 1.47; 95% confidence interval, 1.08-2.00; P = .01). Patients in intensive psychotherapy were 1.58 times (95% confidence interval, 1.17-2.13) more likely to be clinically well during any study month than those in collaborative care (P = .003). No statistically significant differences were observed in the outcomes of the 3 intensive psychotherapies. CONCLUSIONS: Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression. Future studies should compare the cost-effectiveness of models of psychotherapy for bipolar disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.

Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a "recovered" status in the systematic treatment enhancement program for bipolar disorder.

OBJECTIVES: This study compares prescription patterns between young adults and elderly with bipolar disorder who achieved a recovery status during the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). DESIGN: STEP-BD is a multicenter National Institute of Mental Health-funded project designed to evaluate the longitudinal outcome of patients with bipolar disorder. The STEP-BD study involved extensive assessment across multiple domains including demographic data, diagnosis, symptom severity, treatment, and clinical status. Patients achieved "recovered" status when they experienced eight consecutive weeks without significant symptoms. PARTICIPANTS: The authors analyzed data of all subjects who achieved a recovered status at least once in their participation. MEASUREMENTS: The authors compared treatment regimes and doses among young participants with middle age (N = 3,364), 20-59 years old, and older participants 60 and above (N = 246). RESULTS: Of the 3,615 STEP-BD participants who had a lifetime diagnosis of bipolar subtypes I or II, 67.6% (N = 2442) achieved a recovered status during their participation. A total of 78.5% (N = 193) of older patients recovered compared with 66.8% of the younger cohort. On average, participants who reached a recovered status took 2.05 medications with no difference between age groups. Lithium was prescribed to 37.8% of younger patients compared with only 29.5% of older participants. The mean dosages taken by younger and older patients differed significantly only for lithium, valproate, and risperidone with elderly individuals prescribed lower daily dosages. Significant reduction in lithium dosing was observed among individuals aged 50 and older and among individuals 60 and older for valproate. Although valproate was more often prescribed, 42.1% of recovered bipolar elder achieved recovery with lithium alone compared with only 21.3% of the younger cohort. CONCLUSION: This data shows recovery is achievable in the elderly though more than one medication is often needed regardless of age.

GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder.

OBJECTIVE: Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific randomized controlled trials. The authors describe findings from a first such study of late-life mania. METHOD: The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 inpatients and outpatients age 60 or older with bipolar I disorder who presented with a manic, hypomanic, or mixed episode. Participants were randomly assigned, under double-blind conditions, to treatment with lithium (target serum concentration, 0.80-0.99 mEq/L) or divalproex (target serum valproate concentration, 80-99 µg/mL) for 9 weeks. Participants with an inadequate response after 3 weeks received open adjunctive risperidone. The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium. Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations. Efficacy was assessed with the Young Mania Rating Scale (YMRS). RESULTS: Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score, 3.90; 97.5% CI=1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively). CONCLUSIONS: Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater reduction in mania scores over 9 weeks.

Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

OBJECTIVE: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. METHOD: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. RESULTS: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. CONCLUSIONS: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.

Menstrual dysfunction prior to onset of psychiatric illness is reported more commonly by women with bipolar disorder than by women with unipolar depression and healthy controls.

BACKGROUND: Preliminary reports suggest that menstrual cycle irregularities occur more commonly in women with bipolar disorder and unipolar depression than in the general population. However, it is not always clear whether such abnormalities, reflecting disruption of the hypothalamic-pituitary-gonadal (HPG) axis, are caused by psychotropic treatments or associated with the disorder per se. METHOD: The prevalence of early-onset (within the first 5 postmenarchal years) menstrual cycle dysfunction (menstrual cycle length unpredictable within 10 days or menstrual cycle length<25 days or >35 days) occurring before onset of psychiatric illness was compared between subjects with DSM-IV bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and subjects with DSM-IV unipolar depression or no psychiatric illness participating in the Harvard Study of Moods and Cycles. Data from the Harvard Study of Moods and Cycles were gathered from September 1995 to September 1997, and data from STEP-BD were gathered from November 1999 to May 2001. RESULTS: Early-onset menstrual cycle dysfunction was reported to have occurred in 101/295 women with bipolar disorder (34.2%), 60/245 women with depression (24.5%), and 134/619 healthy controls (21.7%). Women with bipolar disorder were more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=16.58, p<.0001) and depressed women (chi2=6.08, p=.01), while depressed women were not more likely to have early-onset menstrual cycle dysfunction than healthy controls (chi2=0.81, p=.37). CONCLUSIONS: Compared with healthy controls and women with unipolar depression, women with bipolar disorder retrospectively report early-onset menstrual dysfunction more commonly prior to onset of bipolar disorder. Future studies should evaluate potential abnormalities in the hypothalamic-pituitary-gonadal axis that are associated with bipolar disorder.

Sex-specific self-reported mood changes by patients with bipolar disorder.

INTRODUCTION: While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes. METHODS: Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women. RESULTS: The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle. CONCLUSIONS: The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.