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Background: Several single‐site alcohol treatment clinical trials have demonstrated efficacy for immediate‐release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended‐release (GE‐XR) (HORIZANT®), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). Methods: Men and women (n = 346) who met DSM‐5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double‐blind GE‐XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. Results: The GE‐XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol‐related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side‐effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. Conclusions: Overall, GE‐XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE‐XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions. Gabapentin enacarbil extended‐release (GE‐XR) (HORIZANT) at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with alcohol use disorder, including the primary outcome – the percentage of subjects with no heavy drinking days (PSNHDD). There was no significant difference between GE‐XR and placebo on PSNHDD across trial months and across the entire maintenance period (Weeks 2 to 25) (all ps > 0.05). [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) spectrum and alcohol use disorders (AUDs) commonly occur together. Comorbidity between the two conditions predisposes patients to elevated risks of adverse outcomes, including hospitalization and suicide, compared with either condition alone. Despite the consistent relationship observed between BD and AUD, the underlying cause remains incompletely characterized. Few trials conducted have been able to identify promising interventions for patients with these disease states. The antipsychotic quetiapine has been evaluated most commonly as a therapeutic agent for patients with BD and AUD followed by naltrexone and acamprosate. Randomized controlled trials of quetiapine have consistently reported a lack of efficacy for the treatment of patients with BD and AUD. Trials of acamprosate have also been negative but small in size. Results of the sole randomized controlled trial of naltrexone have found large treatment effect sizes, but no statistically significant difference between treatment groups. Other agents including the antipsychotic aripiprazole, mood stabilizing agents including lamotrigine, lithium, and divalproex, and the antiepileptic agent topiramate have also been evaluated for the treatment of BD and AUD with mixed findings. The lone statistically significant treatment effect was observed in a randomized, placebo-controlled trial of divalproex added on to lithium which demonstrated a reduction in alcohol use. This review summarizes the available clinical evidence and current guideline recommendations for the treatment of comorbid BD and AUD, and provides discussion and recommendations based on the current literature. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder is associated with a very high prevalence of alcohol-related disorders. However, few studies have examined treatment in this population. Preclinical research suggests a role for the flavonoid icariin in mood and addictive disorders. In this open-label pilot study, we investigated the feasibility and safety of using icariin for persons with bipolar disorder and alcohol abuse or dependence.Methods: Ten participants with bipolar I or bipolar II disorders, currently depressed, and with active alcohol abuse or dependence were given open-label icariin of up to 300 mg/day for 8 weeks using a flexible dosing strategy. Participants were assessed using the Hamilton Rating Scale for Depression (HAMD), Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), Hamilton Rating Scale for Anxiety (HAMA), and Young Mania Rating Scale (YMRS). Standard drinks, heavy drinking days, and drinking days were also quantified. Baseline and exit data were analyzed using the Wilcoxon Signed Rank Test.Results: We observed a significant decrease in the HAMD (p = 0.012, d = 0.8), QIDS (p = 0.017, d = 0.7), and HAMA (p = 0.005, d = 1.4) scores. Heavy drinking days (p = 0.034, d = 1.1) and standard drinks (p = 0.038, d = 0.8) also decreased significantly. Icariin was well tolerated and no participants withdrew due to side-effects.Conclusion: Results from this uncontrolled study suggest icariin may decrease depressive symptoms and reduce alcohol consumption in persons with bipolar disorder and alcohol use. Improvement in mood and alcohol use was similar to that observed in an open-label trial of naltrexone in this population. Controlled trials, but at this point not routine clinical use, of icariin seem warranted. [ABSTRACT FROM AUTHOR]

Objective: Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use.Method: A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale.Results: In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed.Conclusions: Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit. [ABSTRACT FROM AUTHOR]

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered. [ABSTRACT FROM AUTHOR]

Background Alcohol dependence is common in bipolar disorder ( BPD) and associated with treatment nonadherence, violence, and hospitalization. Quetiapine is a standard treatment for BPD. We previously reported improvement in depressive symptoms, but not alcohol use, with quetiapine in BPD and alcohol dependence. However, mean alcohol use was low and a larger effect size on alcohol-related measures was observed in those with higher levels of alcohol consumption. In this study, efficacy of quetiapine in patients with BPD and alcohol dependence was examined in patients with higher mean baseline alcohol use than in the prior study. Methods Ninety outpatients with bipolar I or II disorders, depressed or mixed mood state, and current alcohol dependence were randomized to 12 weeks of sustained release quetiapine (to 600 mg/d) add-on therapy or placebo. Drinking was quantified using the Timeline Follow Back method. Additional assessment tools included the Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology- Self- Report, Young Mania Rating Scale, Penn Alcohol Craving Scale, liver enzymes, and side effects. Alcohol use and mood were analyzed using a declining-effects random-regression model. Results Baseline and demographic characteristics in the 2 groups were similar. No significant between-group differences were observed on the primary outcome measure of drinks per day or other alcohol-related or mood measures ( p > 0.05). Overall side effect burden, glucose, and cholesterol were similar in the 2 groups. However, a significant weight increase was observed with quetiapine at week 6 (+2.9 lbs [ SE 1.4] quetiapine vs. −2.0 lbs [ SE 1.4], p = 0.03), but not at week 12. Scores on the Barnes Akathisia Scale increased significantly more ( p = 0.04) with quetiapine (+0.40 [ SE 0.3]) than placebo (−0.52 [ SE 0.3]) at week 6 but not week 12. Retention (survival) in the study was similar in the groups. Conclusions Findings suggest that quetiapine does not reduce alcohol consumption in patients with BPD and alcohol dependence. [ABSTRACT FROM AUTHOR]

Bipolar disorder is associated with very high rates of substance dependence. Cocaine use is particularly common. However, limited data are available on the treatment of this population. A 10-week, randomized, double-blind, placebo-controlled trial of lamotrigine was conducted in 120 outpatients with bipolar disorder, depressed or mixed mood state, and cocaine dependence. Other substance use was not exclusionary. Cocaine use was quantified weekly by urine drug screens and participant report using the timeline follow-back method. Mood was assessed with the Hamilton rating scale for depression, quick inventory of depressive symptomatology self-report, and young mania rating scale. Cocaine craving was assessed with the cocaine-craving questionnaire. Data were analyzed using a random regression analysis that used all available data from participants with at least one postbaseline assessment (n=112). Lamotrigine and placebo groups were similar demographically (age 45.1±7.3 vs 43.5±10.0 years, 41.8% vs 38.6% women). Urine drug screens (primary outcome measure) and mood symptoms were not significantly different between groups. However, dollars spent on cocaine showed a significant initial (baseline to week 1, p=0.01) and by-week (weeks 1-10, p=0.05) decrease in dollars spent on cocaine, favoring lamotrigine. Few positive trials of medications for cocaine use, other than stimulant replacement, have been reported, and none have been reported for bipolar disorder. Reduction in amount of cocaine use by self-report with lamotrigine suggests that a standard treatment for bipolar disorder may reduce cocaine use. A study limitation was weekly assessment of urine drug screens that decreased the ability to detect between-group differences. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence. Methods: Male and female outpatients (21 to 60 years) with a history of bipolar I disorder and alcohol dependence were included in this 12-week, placebo-controlled study. Patients treated with lithium or divalproex (ongoing or assigned at screening) were randomized to receive quetiapine (dosed up to 400 mg/d over 7 days, followed by 300 to 800 mg/d flexible dosing until study end) or placebo. The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 (as derived from the Timeline Followback method). Secondary outcome measures included time to the first consecutive 2 weeks of abstinence, changes from baseline to Week 12 in the proportion of nondrinking days, mean number of standardized drinks per day, and Clinical Global Impressions-Severity of Illness score. Results: Of 362 enrolled patients (mean 38.6 years), 176 were randomized to receive quetiapine and 186 to placebo. The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group. At Week 12, the mean change in the proportion of heavy drinking days was −0.36 with quetiapine and −0.36 with placebo ( p = 0.93). No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups. The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine. Conclusions: The efficacy of quetiapine in the treatment of bipolar disorder is already well established. In this study, however, quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence. [ABSTRACT FROM AUTHOR]

Background: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. Methods: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. Results: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends ( p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. Conclusions: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Corticosteroid excess is associated with impairment in declarative memory and hippocampal changes. In animals, phenytoin blocks the effects of stress on memory and hippocampal histology. Levetiracetam also shows neuroprotective properties in some animal models. This report examines whether levetiracetam prevents mood or cognitive changes secondary to prescription corticosteroids. Materials and methods: Thirty outpatients given systemic corticosteroid therapy for asthma were randomized to either levetiracetam (1500mg/day) or placebo given concurrently with the corticosteroids. Mood was assessed with the Hamilton rating scale for depression (HRSD), Young mania rating scale (YMRS) and activation (ACT) subscale of the internal state scale, declarative memory with the Rey auditory verbal learning test (RAVLT), and attention and executive functioning with the Stroop color and word test at baseline and after approximately 7 days of corticosteroid plus levetiracetam or placebo therapy. Results: Levetiracetam and placebo groups showed significant improvement from baseline to exit on RAVLT total words recalled with a non-significant change on other outcomes. No significant between-group differences were found. Initial prednisone dose showed a significant correlation with change in some cognitive domains. Conclusions: Levetiracetam was well tolerated when combined with prednisone. Significant between-group differences in mood and cognition were not found. [Copyright &y& Elsevier]

Bipolar disorder is associated with very high rates of substance abuse. However, few clinical trials are reported in this population. Naltrexone is effective for alcohol dependence, but its safety and efficacy are not established in patients with bipolar disorder and alcohol dependence. A 16-week, open-label, add-on pilot study of naltrexone was conducted in 34 outpatients with bipolar disorder and alcohol dependence. Assessments included the 17-item Hamilton Rating Scale for Depression (HRSD-17), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and an alcohol craving scale. Alcohol use was quantified. Significant improvement was observed in the HRSD-17 and YMRS, and days of alcohol use and craving decreased significantly. Naltrexone was well tolerated. Controlled trials are warranted. Depression and Anxiety 23:492–495, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This article presents information about several studies that are published in the previous issues of the "Journal of Dual Diagnosis." In the first study, researchers examined the use of cognitive behavioral therapy (CBT) combined with an antidepressant in outpatients with active injection drug use. This study suggests that patients with active substance use can respond favorably to interventions for depression including CBT. Another study shows that substance use is common in patients with severe psychiatric illness. This trend appears to hold true in Australia as in the United States.

Background: Data from several studies suggest that medications, such as ketoconazole, which lower cortisol levels, may be effective for major depressive disorder (MDD). As with MDD, the manic, depressive, and mixed phases of bipolar disorder are frequently associated with elevated cortisol levels. The literature on the use of cortisol-lowering strategies in mood disorders is reviewed, and a case series illustrating the use of ketoconazole in bipolar depression is presented. Methods: For the review, the MEDLINE and PSYCHINFO databases were searched, as were the bibliographies of pertinent articles to find papers on the use of cortisol-lowering agents in patients with mood disorders. In our open-label case series (n=6), ketoconazole (up to 800 mg/day) as an add-on therapy was given to patients with treatment-resistant or intolerant bipolar I or II disorders with current symptoms of depression. Results: Several case reports and small open studies suggest that cortisol-lowering agents may be useful for patients with depression. Two recent placebo-controlled trials of ketoconazole on patients with MDD report conflicting results. In our case series, all three patients who received a dose of at least 400 mg/day had substantial reductions in depressive symptoms. None had significant increases in mania. However, cortisol levels were not lowered in any of the subjects. Conclusions: The literature suggests that cortisol-lowering medications may be effective for a subset of depressed patients. Our preliminary findings suggest that ketoconazole may be useful in some patients with bipolar depression. Larger clinical trials are needed to confirm our observations. [ABSTRACT FROM AUTHOR]

Background: Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments. Method: Twenty-eight bipolar patients experiencing manic (n=18), depressive (n=5), or rapid-cycling (n=5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A ‘positive response’ was operationalized as a CGI response of much or very much improved. Results: Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600–3600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7±7.2 days. Patients with classic mania had a mean time to positive response of 25±12 days, and in patients with mixed mania it was 31.8±20.9 days. All of the five patients treated for depression had a positive response within 21±13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation. Conclusions: Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including prescription glucocorticoids, the risk factors of treating with glucocorticoids, and the role of medical illness on the development of the said treatments.

Background: In animal models, corticosteroids are associated with changes in hippocampal structure and functioning that are prevented by glutamate release inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Cushing''s disease and prescription corticosteroid administration are also associated with memory impairment and hippocampal atrophy. Use of NMDA receptor antagonists to attenuate corticosteroid effects in humans has not been investigated. We examine the NMDA receptor antagonist memantine in patients receiving corticosteroids. Methods: Twenty outpatients receiving long-term oral corticosteroid therapy were randomized to 8 weeks of memantine (maximum dose 20 mg/day) and 8 weeks of placebo in a double-blind fashion, with a 4-week washout period between courses. Declarative memory was assessed with the Hopkins Verbal Learning Test (HVLT) and mood with the Hamilton Rating Scale for Depression and Young Mania Rating Scale. Changes in outcome measures were compared during memantine and placebo exposure. Results: Seventeen participants completed both treatment phases and were used in the analysis. Significant improvement (p < .05) in total and delayed recall on the HVLT was observed with memantine as compared with placebo. No significant changes in mood were observed. Conclusions: Memantine therapy was associated with improvement in declarative memory but not mood in patients receiving prescription corticosteroids. [Copyright &y& Elsevier]

The article presents several research on bipolar disorder and substance abuse treatment featured in the 2007 issue of the "Journal of Dual Diagnosis."The research includes "Divalproex utility in bipolar disorder with co-occurring cocaine dependence: A pilot study: Addictive Behaviors," "Naltrexone in patients with bipolar disorder and alcohol dependence: Depression and Anxiety" and "The Challenges of Dual Diagnosis: Managing Substance Abuse in Severe Mental Illness." The primary purpose of the studies are to examine the appropriate treatment of behavioral disorder.