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
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 trials.gov Identifier: NCT00194129.
Available from: David J Nutt
- "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. "
[Show abstract] [Hide abstract]
ABSTRACT: The British Association for Psychopharmacology guidelines for the treatment of substance abuse, harmful use, addiction and comorbidity with psychiatric disorders primarily focus on their pharmacological management. They are based explicitly on the available evidence and presented as recommendations to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback from participants. The guidelines primarily cover the pharmacological management of withdrawal, short- and long-term substitution, maintenance of abstinence and prevention of complications, where appropriate, for substance abuse or harmful use or addiction as well management in pregnancy, comorbidity with psychiatric disorders and in younger and older people.
Available from: Denis Daley
- "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. "
[Show abstract] [Hide abstract]
ABSTRACT: To update clinicians on the latest in evidence-based treatments for substance use disorders (SUD) and non-substance use disorders among adults and suggest how these treatments can be combined into an evidence-based process that enhances treatment effectiveness in comorbid patients.
Articles were extracted from Pubmed using the search terms "dual diagnosis," "comorbidity" and "co-occurring" and were reviewed for evidence of effectiveness for pharmacologic and psychotherapeutic treatments of comorbidity.
Twenty-four research reviews and 43 research trials were reviewed. The preponderance of the evidence suggests that antidepressants prescribed to improve substance-related symptoms among patients with mood and anxiety disorders are either not highly effective or involve risk due to high side-effect profiles or toxicity. Second generation antipsychotics are more effective for treatment of schizophrenia and comorbid substance abuse and current evidence suggests clozapine, olanzapine and risperidone are among the best. Clozapine appears to be the most effective of the antipsychotics for reducing alcohol, cocaine and cannabis abuse among patients with schizophrenia. Motivational interviewing has robust support as a highly effective psychotherapy for establishing a therapeutic alliance. This finding is critical since retention in treatment is essential for maintaining effectiveness. Highly structured therapy programs that integrate intensive outpatient treatments, case management services and behavioral therapies such as Contingency Management (CM) are most effective for treatment of severe comorbid conditions.
Creative combinations of psychotherapies, behavioral and pharmacological interventions offer the most effective treatment for comorbidity. Intensity of treatment must be increased for severe comorbid conditions such as the schizophrenia/cannabis dependence comorbidity due to the limitations of pharmacological treatments.
Available from: James J Prisciandaro
- "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. "
[Show abstract] [Hide abstract]
ABSTRACT: Despite the high prevalence and detrimental impact of alcoholism on bipolar patients, the diagnostic and treatment factors associated with better or worse clinical outcomes in alcohol-dependent patients with bipolar disorder are not well understood. The present study investigated the prospective impact of baseline psychiatric comorbidities and treatment regimens on clinical outcomes in bipolar alcoholics. Data were drawn from an 8-week randomized controlled clinical trial of acamprosate for individuals (n=30) with co-occurring bipolar disorder and alcohol dependence. Depressive and manic symptoms, and alcohol craving and consumption were monitored longitudinally using standardized instruments. Path analysis was used to estimate the prospective associations between patient characteristics and outcomes. More than 50% of patients were diagnosed with at least one anxiety (76.7%) or drug dependence disorder (60.0%). Comorbid anxiety disorders were prospectively associated with increased depressive symptoms and alcohol use. Participants were prescribed an average of 2.6 psychotropic medications at baseline. Antipsychotics and anticonvulsants were prospectively associated with increased alcohol use; anticonvulsants and benzodiazepines were associated with increased alcohol craving. Antidepressants were associated with increased depressive symptoms. Conversely, lithium was associated with decreased alcohol craving and depressive symptoms. The findings from the present study suggest areas for future research in this population.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.