This 6-month, randomized, double-blind, placebo-controlled trial is the first maintenance study in RCBD to compare combination mood stabilizer treatment (lithium and divalproex) with lithium monotherapy. To our knowledge, it is also the first double-blind maintenance trial of RCBD to be conducted in subjects with a co-occurring alcohol and/or drug use disorder. This study complements a 20-month maintenance trial previously conducted by our group comparing double-blind treatment with lithium or divalproex monotherapy in RCBD uncomplicated by SUDs.17
After random assignment, no significant difference was observed on the primary outcome measure of time to relapse into a new mood episode or on the secondary outcome measure of time to discontinuation for any reason. Although a numeric benefit was observed in the estimated hazard ratio (0.72), this value was non-significant and suggests the difference in prophylactic efficacy between lithium monotherapy and the combination of lithium and divalproex is small when used in the maintenance treatment of RCBD comorbid with SUDs.
Similar to other controlled maintenance studies of subjects with bipolar disorder, this trial employed an enriched design requiring subjects to respond to lithium and divalproex prior to entering the double-blind, placebo-controlled phase.17,28–29
This served to enrich the randomized population with compliant subjects tolerant of the medications under investigation, effectively reducing bias due to differences in tolerability. Consistent with this expectation, no dropouts due to adverse events were observed during the double-blind maintenance phase.
In maintenance studies conducted over 6–18 months, rates of discontinuation due to lack of efficacy are higher among trials that employ more rigorous stabilization criteria.28–29
In the present trial, 25% of subjects discontinued due to lack of efficacy, reflective of the requirement for stabilization to be sustained over 4 consecutive weeks (HAM-D ≤ 20, YMRS ≤ 12.5, and GAS ≥51), as well as the difficulty encountered when treating subjects with co-occurring SUDs. Of 149 patients who received open lithium and divalproex, 118 (79%) exited the study prior to randomization to the blinded maintenance phase. The attrition rate in previously conducted maintenance trials of non-substance abusing bipolar patients has ranged from 50–72%.28–30
During open stabilization, 37 patients demonstrated mood symptoms non-responsive to combination treatment with lithium and divalproex. Approximately equal numbers experienced refractory depression or refractory manic/hypomanic/mixed states. This finding is novel and stands in contrast to RCBD populations without co-occurring SUDs, where the predominant mood presentation is depression.17
Furthermore, the majority of subjects relapsed into manic/hypomanic/mixed states as opposed to depression during maintenance phase treatment. This also distinguishes RCBD populations with co-occurring SUDs, as relapse into depression is more prevalent in populations without substance use comorbidity.17
Although depression is regarded as the hallmark of RCBD, manic, hypomanic, or mixed states appear to be the major mood morbidity in the setting of alcohol and/or other SUDs. This observation is supported by other authors who identified a higher rate of mixed states and dysphoric mania among bipolar patients who abuse substances.7,31
Mania was identified as the most common index episode in a post hoc analysis of patients with bipolar disorder and comorbid cannabis abuse,32
and manic or mixed states were the most common presentations among patients with comorbid alcoholism.20
The prevalence of rapid cycling is believed to be highest among females1,33
and those with bipolar II disorder.1
The positive association between females and rapid-cycling may partly be attributed to the greater depressive morbidity experienced by women over their lifetime.34
Contrarily, in this trial the patient composition was weighted toward males and subjects with bipolar I disorder, consistent with previous research identifying these variables to be associated with higher rates of alcohol and drug abuse.2
This suggests the tendency for relapse into manic/hypomanic/mixed states may be more heavily influenced by comorbid substance use than rapid-cycling status per se.
The present study has several strengths, perhaps foremost its attempt to assess mood outcomes in a population with bipolar disorder and co-occurring SUDs. This area has recently been articulated as a priority for clinical investigation by a “call to action” report, given the scarcity of clinical trials addressing substance use comorbidity.35
In fact, bipolar patients with SUDs have been identified as a population exhibiting the greatest level of unmet need, followed closely by those with rapid-cycling.36
The present trial addresses both understudied areas and is highly generalizable to clinical practices, providing the first estimate of the difference in median survival for two commonly used drug regimens.
There is evidence that clinicians under-treat bipolar disorder when a co-morbid SUD is present, as STEP-BD data show nearly half of patients do not receive adequate mood stabilizer treatment. 37
Our findings suggest that combination mood stabilizer therapy can be efficacious and safe when prescribed to substance-abusing individuals with bipolar disorder. Relatedly, Salloum and colleagues20
found the addition of valproate to lithium among individuals with alcohol dependence reduced the number of heavy drinking days and prolonged the time to relapse to sustained heavy drinking. However, divalproex did not reduce depressive or manic symptoms more effectively than lithium alone.20
Collectively, these results emphasize that clinicians should not abandon or delay mood stabilizer treatment as a result of substance use.
The intent of this single-site pilot trial was to generate an estimate of the difference in overall survival between treatment arms for designing a future, large scale maintenance study. Consequently, the lack of power to detect a small difference in overall survival between treatments is a valid but expected methodological limitation. The estimated hazard ratio of 0.72 indicates that patients randomly assigned to combination treatment had a tendency toward lower risk of discontinuation for any reason. Thus, a future study would need to enroll 193–225 subjects per arm in order to achieve statistical power of 0.80 with an alpha set at 0.05, two-tailed. Given the large sample size sample requirement and relatively small effect size demonstrated by this pilot study, it is unlikely that a future, large-scale trial involving these two first-line mood stabilizers will ever be conducted. Furthermore, the high drop-out rate during the open stabilization phase highlights the complexity of treating patients with comorbid RCBD. A further limitation concerns the nominal data on substance use outcomes. We were not able to quantify the change in frequency of alcohol or drug use. In addition, toxicology screens were not collected to verify the presence of a SUD or relapse into substance use. Future maintenance trials of RCBD with co-occurring SUDs should specifically evaluate the quantity and frequency of substance use as a primary outcome measure, in addition to measuring relapse rates and time to relapse.
There is a need for future maintenance studies that combine conventional mood stabilizers with agents able to reduce depression symptoms and also protect against mood elevation. Members of the atypical antipsychotic drug class offer promise of satisfying this unmet need and may also reduce drug and alcohol consumption.38–40
In conclusion, this is the first controlled investigation to compare lithium monotherapy with combination mood stabilizer therapy (lithium plus divalproex) in rapid-cycling presentations of bipolar I or II disorder and co-occurring substance use disorders. The similar time to relapse between treatment arms suggests a small effect size when combining divalproex with lithium. The high rate of dropout observed during the open-label stabilization phase suggests combination therapy with lithium and divalproex will be inadequate for the majority of patients with RCBD and comorbid substance abuse or dependence. Greater efforts are needed to identify adjunctive pharmacotherapy or psychosocial interventions that are effective in such highly comorbid populations.