Evidence-Based Principles for Bipolar Disorder Treatment

Pharmacological Treatment of Adult Bipolar Disorder

Baldessarini RJ, Tondo L, Vázquez GH

Mol Psychiatry 2019; 24(2):198–217

We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.

Antiepileptic Drugs and Fetal Malformation: Analysis of 20 Years of Data in a Pregnancy Register

Vajda FJE, Graham JE, Hitchcock AA, et al.

Seizure 2019 Feb; 65:6–11

PURPOSE: This paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. METHOD: Over 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analyzed using conventional statistical techniques, confidence interval methods, and logistic regression. RESULTS: By 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy. There were (i) dose-related increased incidences of pregnancies carrying fetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (Pc<c.05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the fetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that preconception folate supplementation reduced the hazard of AED-associated fetal malformation. AED polytherapy did not increase fetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. CONCLUSIONS: If it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.

Copyright © 2018. Published by Elsevier Ltd. Used by permission.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Acute and Long-Term Treatment of Mixed States in Bipolar Disorder

Grunze H, Vieta E, Goodwin GM, et al.

World J Biol Psychiatry 2018; 19:2–58

OBJECTIVES: Although clinically highly relevant, the recognition and treatment of bipolar mixed states has played only an underpart in recent guidelines. This WFSBP guideline has been developed to supply a systematic overview of all scientific evidence pertaining to the acute and long-term treatment of bipolar mixed states in adults. METHODS: Material used for these guidelines is based on a systematic literature search using various data bases. Their scientific rigor was categorized into six levels of evidence (A-F), and different grades of recommendation to ensure practicability were assigned. We examined data pertaining to the acute treatment of manic and depressive symptoms in bipolar mixed patients, as well as data pertaining to the prevention of mixed recurrences after an index episode of any type, or recurrence of any type after a mixed index episode. RESULTS: Manic symptoms in bipolar mixed states appeared responsive to treatment with several atypical antipsychotics, the best evidence resting with olanzapine. For depressive symptoms, addition of ziprasidone to treatment as usual may be beneficial; however, the evidence base is much more limited than for the treatment of manic symptoms. Besides olanzapine and quetiapine, valproate and lithium should also be considered for recurrence prevention. LIMITATIONS: The concept of mixed states changed over time, and recently became much more comprehensive with the release of DSM-5. As a consequence, studies in bipolar mixed patients targeted slightly different bipolar subpopulations. In addition, trial designs in acute and maintenance treatment also advanced in recent years in response to regulatory demands. CONCLUSIONS: Current treatment recommendations are still based on limited evidence, and there is a clear demand for confirmative studies adopting the DSM-5 specifier with mixed features concept.

Reprinted with permission from Taylor & Francis.

Adjunctive Bright Light Therapy for Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Trial

Sit DK, McGowan J, Wiltrout C, Diler RS, Dills JJ, Luther J, Yang A, Ciolino J.D., Seltman H, Wisniewski SR, Terman M, Wisner KL.

Am J Psychiatry 2018 Feb 1; 175(2):131–139

OBJECTIVE: Patients with bipolar disorder have recurrent major depression, residual mood symptoms, and limited treatment options. Building on promising pilot data, the authors conducted a 6-week randomized double-blind placebo-controlled trial to investigate the efficacy of adjunctive bright light therapy at midday for bipolar depression. The aims were to determine remission rate, depression symptom level, and rate of mood polarity switch, as well as to explore sleep quality. METHOD: The study enrolled depressed adults with bipolar I or II disorder who were receiving stable dosages of antimanic medication (excluding patients with hypomania or mania, mixed symptoms, or rapid cycling). Patients were randomly assigned to treatment with either 7,000-lux bright white light or 50-lux dim red placebo light (N=23 for each group). Symptoms were assessed weekly with the Structured Interview Guide for the Hamilton Depression Scale With Atypical Depression Supplement (SIGH-ADS), the Mania Rating Scale, and the Pittsburgh Sleep Quality Index. Remission was defined as having a SIGH-ADS score of 8 or less. RESULTS: At baseline, both groups had moderate depression and no hypomanic or manic symptoms. Compared with the placebo light group, the group treated with bright white light experienced a significantly higher remission rate (68.2% compared with 22.2%; adjusted odds ratio=12.6) at weeks 4–6 and significantly lower depression scores (9.2 [SD=6.6] compared with 14.9 [SD=9.2]; adjusted β=-5.91) at the endpoint visit. No mood polarity switches were observed. Sleep quality improved in both groups and did not differ significantly between them. CONCLUSIONS: The data from this study provide robust evidence that supports the efficacy of midday bright light therapy for bipolar depression.

TRIAL REGISTRATION: clinicaltrials.gov NCT00852592

Complex Psychotropic Polypharmacy in Bipolar Disorder Across Varying Moodpolarities: A Prospective Cohort Study of 2712 Inpatients

Golden JC, Goethe JW, Woolley S.B.

J Affect Disord 2017, Oct 15; 221:6–10

BACKGROUND: It is common for patients with bipolar disorder (BP) to receive multiple psychotropics, but few studies have assessed demographic and clinical features associated with risk for receiving complex psychotropic polypharmacy. METHODS: This longitudinal cohort study examined 2712 inpatients with a DSM-IV clinical diagnosis of BP to assess associations between complex polypharmacy (defined as≥4 psychotropics) and demographic and clinical features; associations with risk of rehospitalization were also examined. Logistic regressions were performed with the sample as a whole and with each of four DSM-IV BP subtypes individually. RESULTS: Complex polypharmacy was present in 21.0%. BP-I depressed patients were more likely to receive complex regimens than BP-I manic, BP-I mixed or BP-II patients. In the sample as a whole, variables significantly associated with complex polypharmacy included female, white, psychotic features and a codiagnosis of borderline personality, posttraumatic stress or another anxiety disorder. The only examined medication not significantly associated with complex polypharmacy was lithium, although only in BP-I depressed and BP-I mixed. Complex polypharmacy was associated with rehospitalization in BP-I mania within 15 and 30 days post index hospitalization. LIMITATIONS: All data were from one clinical facility; results may not generalize to other settings and patient populations. CONCLUSIONS: BP-I depression may pose a greater treatment challenge than the other BP subtypes. Lithium may confer an overall advantage compared with other medications in BP-I depressed and BP-I mixed. Further research is needed to guide pharmacotherapy decisions in BP patients.

Copyright © 2017 Elsevier B.V. All rights reserved. Used by permission.

Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8-Year Prospective Study of 50,000 Patients With Bipolar Disorder

Song J, Sjölander A, Joas E, et al.

Am J Psychiatry 2017 Aug 1; 174:795–802

OBJECTIVE: Conclusions regarding lithium's antisuicidal effect for bipolar disorder have been limited due to nonrepresentative subjects and potential confounding factors, including varying severity of illness. Findings regarding the effect of valproate, the most common alternative to lithium, are inconsistent for suicidal behavior. This study investigated the associations of these two drugs with the risk of suicide-related events, and possible differences between drugs, by using within-individual designs in a register-based longitudinal cohort. METHOD: Through linkage of multiple Swedish national registers, 51,535 individuals with bipolar disorder were followed from 2005 to 2013 for treatment with lithium and valproate. Stratified Cox regression was used to estimate the hazard ratios of suicide-related events during treated periods compared with untreated periods. For significant associations between medication and suicide-related events, the population attributable fraction was estimated to assess the public health impact for patients with bipolar disorder. RESULTS: During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78–0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89–1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4%−20%) of suicide-related events could have been avoided if patients had taken lithium during the entire follow-up. CONCLUSIONS: The results suggest that lithium should be considered for patients with bipolar disorder with suspected suicidal intentions, although risk for suicide is only one of the considerations when providing clinical care.

Reprinted with permission from American Psychiatric Association Publishing.

Optimal Duration of Risperidone or Olanzapine Adjunctive Therapy to Mood Stabilizer Following Remission of a Manic Episode: A CANMAT Randomized Double-Blind Trial

Yatham LN, Beaulieu S, Schaffer A, et al.

Mol Psychiatry 2016; 21:1050–1056

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (N=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, subgroup analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2ckg in the 52-weeks group compared with a weight loss of 0.2ckg in the 0-weeks and 0.1ckg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Reprinted with permission from Springer Nature (Springer), copyright ©2016.