A 6-Month, Double-Blind, Maintenance Trial of Lithium Monotherapy Versus the Combination of Lithium and Divalproex for Rapid-Cycling Bipolar Disorder and Co-Occurring Substance Abuse or Dependence

Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 01/2009; 70(1):113-21. DOI: 10.4088/JCP.07m04022
Source: PubMed


To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder and comorbid substance abuse and/or dependence.
A 6-month, double-blind, parallel-group comparison was carried out in patients who met DSM-IV criteria for (1) bipolar I or II disorder; (2) alcohol, cannabis, or cocaine abuse within the last 3 months or dependence within the last 6 months; (3) rapid cycling during the 12 months preceding study entry; and (4) a history of at least 1 manic, hypomanic, or mixed episode within 3 months of study entry and who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy. The study was conducted at an outpatient mood disorders program between October 1997 and October 2006.
Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%, nonresponse: 25%, intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% (N = 17) relapsed (24% [N = 4] into depression and 76% [N = 13] into a manic/hypomanic/mixed episode), 26% (N = 8) completed the study, and 19% (N = 6) were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (not significant). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% (N = 9) and 53% (N = 8), respectively. The rate of depressive relapse in both arms was 13% (N = 2), while the rate of relapse into a manic, hypomanic, or mixed episode was 44% (N = 7) for lithium monotherapy and 40% (N = 6) for the combination of lithium and divalproex.
A small subgroup of patients in this study stabilized after 6 months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of rapid-cycling bipolar disorder in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.
clinical Identifier: NCT00194129.

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    • "Patients with BPD I and alcohol dependence completed a few days of stabilisation on lithium, after which valproate or placebo was added for 24 weeks (Salloum et al., 2005) (Ib) The lithium plus valproate group had a significantly lower proportion of heavy drinking days (p = 0.02) and a trend toward fewer drinks per heavy drinking day (p = 0.055) than the lithium plus placebo group, although manic and depressive symptoms improved equally in both groups. In the other trial, patients with BPD I or II and alcohol, cannabis or cocaine abuse or dependence entered a 6-month stabilisation 'open' phase with lithium and valproate, followed by a blinded 6-month 'maintenance' phase comparing this combination with lithium alone (Kemp et al., 2009) (Ib). Only 31 of the 145 patients were randomised in the maintenance phase, and the combination was not superior in improving any of their chosen outcome measures including 'time to treatment' for a mood episode or time to discontinuation with medication. "
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    • "One study found decreased cannabis use among patients in a small sample of adolescents treated with lithium but there are no other data to support the conclusion that lithium is effective in decreasing cannabis use (Geller et al., 1998). One RCT of lithium and divalproex vs. lithium alone found some evidence of effectiveness for reducing use of cannabis and cocaine among comorbid bipolar patients (Kemp et al. 2009). However, the sample in this study was quite small sample because only 20% of patients were able to be randomized to trial following a stabilization period. "
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    • "Equally scarce is literature regarding optimal medications for individuals with comorbid bipolar and alcohol use disorders. Randomized, placebo-controlled trials of medications for patients with comorbid bipolar and alcohol use disorders have been few and have focused primarily on medications used for mood stabilization such as lithium and divalproex (Geller et al., 1998; Salloum et al., 2005; Kemp et al., 2009) or the atypical antipsychotic quetiapine (Brown et al., 2008; Stedman et al., 2010). These studies have suggested that divalproex may reduce heavy drinking (Salloum et al., 2005) and that quetiapine may improve depressive symptoms (Brown et al., 2008) in individuals with co-occurring alcoholism and bipolar disorder. "
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