Abstracts for Bipolar Disorder

Given space limitations and varying reprint permission policies, not all of the influential publications the editors considered reprinting in this issue could be included. This section contains abstracts from additional articles the editors deemed well worth reviewing.

Clinical Course of Children and Adolescents with Bipolar Spectrum Disorders

Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Ivengar S, Keller M

Archives of General Psychiatry February 2006; 63(2):175–183

Context: Despite the high morbidity associated with bipolar disorder (BP), few studies have prospectively studied the course of this illness in youth. Objective: To assess the longitudinal course of BP spectrum disorders (BP-I, BP-II, and not otherwise specified [BP-NOS]) in children and adolescents. Design: Subjects were interviewed, on average, every 9 months for an average of 2 years using the Longitudinal Interval Follow-up Evaluation. Setting: Outpatient and inpatient units at 3 university centers. Participants: Two hundred sixty-three children and adolescents (mean age, 13 years) with BP-I (n = 152), BP-II (n = 19), and BP-NOS (n = 92). Main Outcome Measures: Rates of recovery and recurrence, weeks with syndromal or subsyndromal mood symptoms, changes in symptoms and polarity, and predictors of outcome. Results: Approximately 70% of subjects with BP recovered from their index episode, and 50% had at least 1 syndromal recurrence, particularly depressive episodes. Analyses of weekly mood symptoms showed that 60% of the follow-up time, subjects had syndromal or subsyndromal symptoms with numerous changes in symptoms and shifts of polarity, and 3% of the time, psychosis. Twenty percent of BP-II subjects converted to BP-I, and 25% of BP-NOS subjects converted to BP-I or BP-II. Early-onset BP, BP-NOS, long duration of mood symptoms, low socioeconomic status, and psychosis were associated with poorer outcomes and rapid mood changes. Secondary analyses comparing BP-I youths with BP-I adults showed that youths significantly more time symptomatic and had more mixed/cycling episodes, mood symptom changes, and polarity switches. Conclusions: Youths with BP spectrum disorders showed a continuum of BP symptom severity from subsyndromal to full syndromal with frequent mood fluctuations. Results of this study provide preliminary validation for BP-NOS.

Genetic Variation of Brain-derived Neurotrophic Factor (BDNF) in Bipolar Disorder: Case-control Study of Over 3000 Individuals From the UK

Green EK, Raybould R, Macqregor S, Hyde S, Young AH, O’Donovan MC, Owen MJ, Kirov G, Jones L, Jones I, Craddock N

The British Journal of Psychiatry January 2006; 188:21–25

Background: Brain-derived neurotrophic factor (BDNF) influences neuronal survival, proliferation and plasticity. Three family-based studies have shown association of the common Valine (Val) allele of the Val66Met polymorphism of the BDNF gene with susceptibility to bipolar disorder. Aims: To replicate this finding. Method: We genotyped the Val66Met polymorphism in our UK White bipolar case-control sample (n = 3062). Results: We found no overall evidence of allele or genotype association. However, we found association with disease status in the subset of 131 individuals that had experienced rapid cycling at some time (P = 0.004). We found a similar association on re-analysis of our previously reported family-based association sample (P < 0.03, one-tailed test). Conclusions: Variation at the Val66Met polymorphism of BDNF does not play a major role in influencing susceptibility to bipolar disorder as a whole, but is associated with susceptibility to the rapid-cycling subset of the disorder.

Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Bowden CL, Collins MA, McElrov SL, Calabrese JR, Swann AC, Weisler RH, Wozniak PJ

Neuropsychopharmacology October 2005; 30(10):1932–1939

Euphoric and mixed (dysphoric) manic symptoms have different response patterns to divalproex and lithium in acute mania treatment, but have not been studied in relationship to maintenance treatment outcomes. We examined the impact of initial euphoric or dysphoric manic symptomatology on maintenance outcome. Randomized maintenance treatment with divalproex, lithium, or placebo was provided for 372 bipolar I patients, who met improvement criteria during open phase treatment for an index manic episode. The current analysis grouped patients according to the index manic episode subtype (euphoric or dysphoric), and evaluated the impact on maintenance treatment outcome. The rate of early discontinuation due to intolerance during maintenance treatment was higher for initially dysphoric patients (N = 249) than euphoric patients (N = 123; 15.7 vs 7.3%, respectively; p = 0.032). Both lithium (23.2%) and divalproex (17.1%) were associated with more premature discontinuations due to intolerance than placebo (4.8%; p = 0.003 and 0.02, respectively) in the initially dysphoric patients. Among initially euphoric patients, treatment with lithium was associated with significantly more premature discontinuations due to intolerance compared to placebo (18.2 vs 0%; p = 0.03), and divalproex was significantly (p = 0.05) more effective than lithium, but not placebo in delaying time to a depressive episode. Initial euphoric mania appeared to predispose to better outcomes on indices of depression and overall function with divalproex maintenance than with either placebo or lithium. Dysphoric mania appeared to predispose patients to more side effects when treated with either divalproex or lithium during maintenance therapy.

Dermatology Precautions and Slower Titration Yield Low Incidence of Lamotrigine Treatment-emergent Rash

Ketter TA, Wang PW, Chandler RA, Alarcon AM, Becker OV, Nowakowska C, O’Keeffe CM, Schumacher MR

The Journal of Clinical Psychiatry May 2005; 66(5):642–645

Objective: To assess treatment-emergent rash incidence when using dermatology precautions (limited antigen exposure) and slower titration during lamotrigine initiation. Method: We assessed rash incidence in 100 patients with DSM-IV bipolar disorder instructed, for their first 3 months taking lamotrigine, to avoid other new medicines and new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy/oak. Lamotrigine was not started within 2 weeks of a rash, viral syndrome, or vaccination. In addition, lamotrigine was titrated more slowly than in the prescribing information. Patients were monitored for rash and clinical phenomena using the Systematic Treatment Enhancement Program for Bipolar Disorder Clinical Monitoring Form. Descriptive statistics were compiled. Results: No patient had serious rash. Benign rash occurred in 5 patients (5%) and resolved uneventfully in 3 patients discontinuing and 2 patients continuing lamotrigine. Two patients with rash were found to be not adherent to dermatology precautions. Therefore, among the remaining patients, only 3/98 (3.1%) had benign rashes. Conclusion: The observed rate of benign rash was lower than the 10% incidence in other clinical studies. The design of this study confounds efforts to determine the relative contributions of slower titration versus dermatology precautions to the low rate of rash. Systematic studies are needed to confirm these preliminary findings, which suggest that adhering to dermatology precautions with slower titration may yield a low incidence of rash with lamotrigine.

Two-year Outcomes for Interpersonal and Social Rhythm Therapy in Individuals with Bipolar I Disorder

Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T

Archives of General Psychiatry September 2005; 62(9):996–1004

Context: Numerous studies have pointed to the failure of prophylaxis with pharmacotherapy alone in the treatment of bipolar I disorder. Recent investigations have demonstrated benefits from the addition of psychoeducation or psychotherapy to pharmacotherapy in this population. Objective: To compare 2 psychosocial interventions: interpersonal and social rhythm therapy (IPSRT) and an intensive clinical management (ICM) approach in the treatment of bipolar I disorder. Design: Randomized controlled trial involving 4 treatment strategies: acute and maintenance IPSRT (IPSRT/IPSRT), acute and maintenance ICM (ICM/ICM), acute IPSRT followed by maintenance ICM (IPSRT/ICM), or acute ICM followed by maintenance IPSRT (ICM/IPSRT). The preventive maintenance phase lasted 2 years. Setting: Research clinic in a university medical center. Participants: One hundred seventy-five acutely ill individuals with bipolar I disorder recruited from inpatient and outpatient settings, clinical referral, public presentations about bipolar disorder, and other public information activities. Interventions: Interpersonal and social rhythm therapy, an adaptation of Klerman and Weissman’s interpersonal psychotherapy to which a social rhythm regulation component has been added, and ICM. Main Outcome Measures: Time to stabilization in the acute phase and time to recurrence in the maintenance phase. Results: We observed no difference between the treatment strategies in time to stabilization. After controlling for covariates of survival time, we found that participants assigned to IPSRT in the acute treatment phase survived longer without a new affective episode (P = .01), irrespective of maintenance treatment assignment. Participants in the IPSRT group had higher regularity of social rhythms at the end of acute treatment (P<.001). Ability to increase regularity of social rhythms during acute treatment was associated with reduced likelihood of recurrence during the maintenance phase (P = .05). Conclusion: Interpersonal and social rhythm therapy appears to add to the clinical armamentarium for the management of bipolar I disorder, particularly with respect to prophylaxis of new episodes.

A Placebo-controlled 18-month Trial of Lamotrigine and Lithium Maintenance Treatment in Recently Manic or Hypomanic Patients with Bipolar I Disorder

Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group

Archives of General Psychiatry April 2003; 60(4):392–400

Background: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. Methods: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100–400 mg daily), lithium (0.8–1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. Results: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P = .02; lithium vs placebo, P = .006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P = .02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P = .006). The most common adverse event reported for lamotrigine was headache. Conclusions: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.

A Randomized Trial on the Efficacy of Group Psychoeducation in the Prophylaxis of Recurrences in Bipolar Patients whose Disease is in Remission

Colom F, Vieta E, Martinez-Aran A, Reinares M, Goikolea JM, Benabarre A, Torrent C, Comes M, Corbella B, Parramon G, Corominas J

Archives of General Psychiatry April 2003; 60(4):402–407

Background: Studies on individual psychotherapy indicate that some interventions may reduce the number of recurrences in bipolar patients. However, there has been a lack of structured, well-designed, blinded, controlled studies demonstrating the efficacy of group psychoeducation to prevent recurrences in patients with bipolar I and II disorder. Methods: One hundred twenty bipolar I and II outpatients in remission (Young Mania Rating Scale score <6, Hamilton Depression Rating Scale-17 score <8) for at least 6 months prior to inclusion in the study, who were receiving standard pharmacologic treatment, were included in a controlled trial. Subjects were matched for age and sex and randomized to receive, in addition to standard psychiatric care, 21 sessions of group psychoeducation or 21 sessions of nonstructured group meetings. Subjects were assessed monthly during the 21-week treatment period and throughout the 2-year follow-up. Results: Group psychoeducation significantly reduced the number of relapsed patients and the number of recurrences per patient, and increased the time to depressive, manic, hypomanic, and mixed recurrences. The number and length of hospitalizations per patient were also lower in patients who received psychoeducation. Conclusion: Group psychoeducation is an efficacious intervention to prevent recurrence in pharmacologically treated patients with bipolar I and II disorder.

A Randomized Controlled Study of Cognitive Therapy for Relapse Prevention for Bipolar Affective Disorder: Outcome of the First Year

Lam DH, Watkins ER, Hayward P, Bright J, Wright K, Kerr N, Parr-Davis G, Sham P

Archives of General Psychiatry February 2003; 60(2):145–152

Background: Despite the use of mood stabilizers, a significant proportion of patients with bipolar affective disorder experience frequent relapses. A pilot study of cognitive therapy (CT) specifically designed to prevent relapses for bipolar affective disorder showed encouraging results when used in conjunction with mood stabilizers. This article reports the outcome of a randomized controlled study of CT to help prevent relapses and promote social functioning. Methods: We randomized 103 patients with bipolar 1 disorder according to the DSM-IV, who experienced frequent relapses despite the prescription of commonly used mood stabilizers, into a CT group or control group. Both the control and CT groups received mood stabilizers and regular psychiatric follow-up. In addition, the CT group received an average of 14 sessions of CT during the first 6 months and 2 booster sessions in the second 6 months. Results: During the 12-month period, the CT group had significantly fewer bipolar episodes, days in a bipolar episode, and number of admissions for this type of episode. The CT group also had significantly higher social functioning. During these 12 months, the CT group showed less mood symptoms on the monthly mood questionnaires. Furthermore, there was significantly less fluctuation in manic symptoms in the CT group. The CT group also coped better with manic prodromes at 12 months. Conclusion: Our findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.

The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB

Archives of General Psychiatry June 2002; 59(6):530–537

Background: To our knowledge, this is the first prospective natural history study of weekly symptomatic status of patients with bipolar I disorder (BP-I) during long-term follow-up. Methods: Analyses are based on ongoing prospective follow-up of 146 patients with Research Diagnostic Criteria BP-I, who entered the National Institute of Mental Health (Bethesda, Md) Collaborative Depression Study from 1978 through 1981. Weekly affective symptom status ratings were analyzed by polarity and severity, ranging from asymptomatic, to subthreshold levels, to full-blown major depression and mania. Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined. Finally, 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. Results: Patients with BP-I were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up. Depressive symptoms (31.9% of total follow-up weeks) predominated over manic/hypomanic symptoms (8.9% of weeks) or cycling/mixed symptoms (5.9% of weeks). Subsyndromal, minor depressive, and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms (29.9% vs 11.2% of weeks, respectively). Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year. Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder. Conclusions: The longitudinal weekly symptomatic course of BP-I is chronic. Overall, the symptomatic structure is primarily depressive rather than manic, and subsyndromal and minor affective symptoms predominate. Symptom severity levels fluctuate, often within the same patient over time. Bipolar I disorder is expressed as a dimensional illness featuring the full range (spectrum) of affective symptom severity and polarity.