A double-blind,randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes

BACKGROUND: Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes. METHOD: Twenty-three patients who had experienced at least 1 major depressive episode that was resistant to at least 1 prior trial of antidepressant therapy were selected. These patients were treated with fluoxetine, 20 mg/day, and concomitantly randomly assigned to receive either lamotrigine (N = 13) or placebo (N = 10) for 6 weeks. The dose of lamotrigine was titrated upward from 25 mg/day to 100 mg/day. Patients suffering from bipolar II disorder (N = 8) or from major depressive disorder (N = 15) (DSM-IV criteria) were enrolled, resulting in heterogeneity of the sample. The primary outcome measure was Hamilton Rating Scale for Depression score. Data were collected from 2000-2001. RESULTS: Lamotrigine was statistically superior to placebo on the Clinical Global Impressions scale at endpoint, both in absolute terms (mean +/- SD Clinical Global Impressions-Severity of Illness scores: lamotrigine, 2.15 +/- 1.28; placebo, 3.40 +/- 1.17; p =.0308) and using a responder analysis, with response defined as a Clinical Global Impressions-Improvement score of 2 or less (lamotrigine, 84.62% [N = 11]; placebo, 30.00% [N = 3]; p =.013). The effect of lamotrigine on Clinical Global Impressions scale scores was seen in both major depressive disorder and bipolar II disorder. Lamotrigine, however, failed to separate statistically from placebo on the Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale. This failure to differentiate on a primary outcome measure is essentially a negative study result. This result is most likely an artifact of the small sample size used and the resultant limited power of the study. CONCLUSION: The results of this trial add to the literature suggesting potential efficacy of the antidepressant profile of lamotrigine. In addition, this study points to a possible role of lamotrigine as an augmentation agent in depression.     

Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials

OBJECTIVES: The efficacy of lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression. METHODS: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100-400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7-10 weeks. RESULTS: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery-Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. CONCLUSIONS: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.     

A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression

BACKGROUND: Lamotrigine has demonstrated efficacy for the acute treatment of depression in bipolar I patients in a placebo-controlled, monotherapy study. We describe the results of a 52-week, open-label continuation of that trial. METHOD: Patients meeting DSM-IV criteria for bipolar I disorder with a current major depressive episode who completed a 7-week, double-blind study of bipolar depression were offered 1 year of open-label lamotrigine therapy (flexible doses of 100-500 mg/day) in a continuation study. To maintain the acute study blind, the first 3 weeks of the continuation study remained blinded while patients previously randomly assigned to placebo were titrated to a lamotrigine dose of 50 mg/day. Patients who had been randomly assigned to lamotrigine continued at their fixed doses. Beginning at week 4, all patients received open-label lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications were permitted during the open-label phase. Effectiveness (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale) and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The study was conducted from June 1996 to December 1998. RESULTS: Of 135 patients completing the acute study, 124 (92%) entered the continuation study: 77 had received lamotrigine and 47 had received placebo in the acute study. The mean duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187 mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and sustained improvement from baseline was seen in mean observed MADRS scores (p <.05). The proportion of patients achieving remission (MADRS score < or = 11) by week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less frequently than in the preceding year. Headache was the most common drug-related adverse event. CONCLUSION: During 1 year of open-label therapy with lamotrigine as adjunctive therapy or monotherapy, bipolar I patients experienced sustained improvement in depressive symptoms without evidence of mood destabilization.     

Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone

OBJECTIVE: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.     

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group

BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.     

Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind,placebo‐controlled trial in rapid‐cycling bipolar disorder

Kemp DE, Gao K, Fein EB, Chan PK, Conroy C, Obral S, Ganocy SJ, Calabrese JR. Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder.
Bipolar Disord 2012: 14: 780–789. © 2012 John Wiley & Sons A/S. Objectives: A substantial portion of the morbidity associated with rapid‐cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add‐on therapy for rapid‐cycling bipolar depression non‐responsive to the combination of lithium plus divalproex. Methods: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18–65 years with DSM–IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double‐blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery‐Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed‐models analysis. Results: During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non‐adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double‐blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was ?8.5 ± 1.7 points for lamotrigine and ?9.1 ± 1.5 points for placebo (p = not significant; mixed‐models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. Conclusions: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double‐blind treatment.     

Family history of alcohol dependence and antidepressant response to an N‐methyl‐D‐aspartate antagonist in bipolar depression

Luckenbaugh DA, Ibrahim L, Brutsche N, Franco‐Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N‐methyl‐d ‐aspartate antagonist in bipolar depression. Bipolar Disord 2012: 14: 880–887. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. Objectives: Both ketamine and ethanol are N‐methyl‐d ‐aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine’s antidepressant and perceptual effects in individuals with bipolar depression. Methods: A post hoc analysis was conducted on 33 subjects with DSM–IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double‐blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post‐infusion. The primary outcome measure was Montgomery‐Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first‐degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. Results: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. Conclusions: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic‐based therapies for depression.     

Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled,double-blind study

BACKGROUND: Mood stabilizers appear to be more potent in treating mania than depression. The anticonvulsant lamotrigine has been shown to be effective for bipolar depression. This study examines putative antidepressive properties of lamotrigine in a mainly unipolar routine clinical patient population. METHOD: Forty patients with a depressive episode (DSM-IV criteria) requiring psychiatric intervention received lamotrigine or placebo using a fixed dose escalation scheme with a target dose of 200 mg/day for 9 weeks. Additionally, all patients were treated with paroxetine. Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions scale (CGI) ratings were used to monitor therapeutic efficacy. RESULTS: Adjunctive treatment with lamotrigine did not result in a significant difference in HAM-D total score at the endpoint of the study when compared with paroxetine alone. However, lamotrigine demonstrated significant efficacy on core depressive symptoms as reflected by HAM-D items 1 (depressed mood; p = .0019), 2 (guilt feelings; p = .0011), and 7 (work and interest; p = .049) and the CGI-Severity of Illness scale (p < .0001). Patients receiving lamotrigine had fewer days on treatment with benzodiazepines and fewer withdrawals for treatment failure. Lamotrigine appeared to accelerate the onset of action of the antidepressant. Two patients on lamotrigine treatment developed neutropenia, and 1 developed a benign rash. There was no detectable pharmacokinetic interaction between lamotrigine and paroxetine. CONCLUSION: Lamotrigine might have antidepressive properties in unipolar patients and may accelerate onset of action when given in combination with typical antidepressants.     

Social support and social strain in inter-episode bipolar disorder

Eidelman P, Gershon A, Kaplan K, McGlinchey E, Harvey AG. Social support and social strain in inter‐episode bipolar disorder.
Bipolar Disord 2012: 14: 628–640. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objectives: This study focused on social support and social strain and their cross‐sectional associations with instabilities in sleep and social rhythms in inter‐episode bipolar disorder (BD). Methods: Thirty‐five adults diagnosed with inter‐episode BD type I and 38 healthy controls completed measures of perceived social support and social strain. Group differences in support and strain were examined. Within the BD group, instabilities in sleep and social rhythms were assessed with 28 days of daily diary and actigraphy. Correlation and regression analyses were used to examine cross‐sectional and prospective associations between social support, social strain, instabilities in sleep and social rhythms, and mood symptoms. Results: The BD group reported lower social support and higher social strain than the control group. Additionally, social strain was positively correlated with manic and depressive symptoms in the BD group. Furthermore, there was a cross‐sectional association between social support and more stable sleep on actigraphy in the BD group, although social support did not predict future sleep instability. Conclusions: These results indicate that inter‐episode BD is associated with deficient social support and elevated social strain compared to controls, and that this may be due to persistent inter‐episode mood symptoms. Social strain may be particularly important given its association with manic and depressive symptoms. The results also raise the possibility that sleep instability is related to poor social support in BD.     

Risk factors related to lifetime suicide attempts in acutely admitted bipolar disorder inpatients

Finseth PI, Morken G, Andreassen OA, Malt UF, Vaaler AE. Risk factors related to lifetime suicide attempts in acutely admitted bipolar disorder inpatients.
Bipolar Disord 2012: 14: 727–734. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objective: The main aim of this study was to assess possible clinical characteristics of acutely admitted bipolar I disorder (BD‐I) and bipolar II disorder (BD‐II) inpatients at high risk of suicide by comparing patients who had made one or several serious suicide attempts with patients who had not. Methods: A total of 206 consecutive patients (mean age 42 ± 15 years; 54.9% women) with DSM–IV diagnosed BD‐I (n = 140) and BD‐II (n = 66) acutely admitted to a single psychiatric hospital department from November 2002 through June 2009 were included. Using a detailed retrospective questionnaire, patients with a history of a serious suicide attempt were compared to those with no history of a suicide attempt. Results: Ninety‐three patients (45.1%) had a history of one or more serious suicide attempts. These constituted 60 (42.9%) of the BD‐I patients and 33 (50%) of the BD‐II patients (no significant difference). Lifetime suicide attempt was associated with a higher number of hospitalizations due to depression (p < 0.0001), antidepressant (AD)‐induced hypomania/mania (p = 0.033), AD‐ and/or alcohol‐induced affective episodes (p = 0.009), alcohol and/or substance use (p = 0.002), and a family history of alcohol abuse and/or affective disorder (p = 0.01). Suicide attempt was negatively associated with a higher Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Positive Subscale score (p = 0.022) and more hospitalizations due to mania (p = 0.006). Conclusions: The lifetime suicide attempt rate in BD inpatients is high. Risk factors of suicide attempts were: (i) a predominant depressive course of illness, (ii) comorbid alcohol and substance use disorders, and (iii) a history of AD‐ and/or alcohol‐induced affective episodes. Risk‐reducing factors were a preponderant manic or psychotic course of the illness. These risk factors may be signs of a clinical subgroup at risk of suicidal behaviour, and seem to be important for suicide risk assessment in acutely admitted BD patients.     

Lamotrigine use in geriatric patients with bipolar depression.

OBJECTIVE: To study the effectiveness of adding lamotrigine to the treatment of inpatient geriatric patients with bipolar disorder (BD) who were in the depressed phase and had been on lithium and valproate for at least 3 months. METHOD: Lamotrigine was started at 25 mg given at bedtime, with weekly incremental increases of 12.5 mg daily until a total dosage of either 75 mg or 100 mg was obtained. Improvement was measured by clinical interview and Hamilton Depression Rating Scale (HDRS) scores. Patients were reassessed at 6 weeks, and if their HDRS score had decreased by at least 50%, they were considered to have improved. RESULTS: The study group comprised 5 women with an average age of 71.5 years (range 65 to 85). Four had rapid-cycling BD, and 1 had mixed BD. All patients had early age of onset, as judged by their first contact with a psychiatrist or their first hospitalization. The average initial HDRS score was 27 (range 20 to 35). Of the patients, 3 out of the 5 had remission of symptoms, as judged by clinical interview and reduction of their HDRS score by 50%. At 3 months follow-up, these 3 patients had not required rehospitalization and were doing well. Lamotrigine was well tolerated, and none of the patients developed a rash. One patient did develop coarse hand tremor that improved when the lamotrigine dosage was decreased. CONCLUSIONS: Lamotrigine in conjunction with lithium and valproate may be effective in treating geriatric patients with BD and depression.     

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium,lamotrigine or placebo and paroxetine

van der Loos MLM, Mulder P, Hartong EGThM, Blom MBJ, Vergouwen AC, van Noorden MS, Timmermans MA, Vieta E, Nolen WA, for the LamLit Study Group. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine. Objective: In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non‐responders. Method: Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non‐responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment. Results: After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non‐responders to placebo. Conclusion: Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non‐responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non‐responders to lithium plus placebo.     

Lamotrigine vs. lamotrigine plus divalproex in randomized,placebo‐controlled maintenance treatment for bipolar depression

Bowden CL, Singh V, Weisler R, Thompson P, Chang X, Quinones M, Mintz J. Lamotrigine vs. lamotrigine plus divalproex in randomized, placebo‐controlled maintenance treatment for bipolar depression. Objective: To compare the maintenance efficacy of lamotrigine (Lam) to combination therapy of Lam + divalproex ER (Div) in recently depressed patients with bipolar disorder (BD). Method: We randomized 86 BD I or II patients in a major depressive episode to 8 months of double‐blind treatment with Lam + placebo or Lam + Div. To be eligible for randomization, patients had to achieve control of both depressive and manic symptoms during an open phase that included both Lam and Div. Results: Time to depressive episode did not differ significantly by Kaplan–Maier survival analysis (χ² = 1.82, df = 1, P = 0.18). However, several secondary outcomes did show significant differences. The proportion of Lam + placebo patients who had at least one Montgomery–Asberg Depression Rating Scale (MADRS) score ≥15 during the maintenance phase was 67% (30/45) compared with 44% (18/41) for the Lam + Div group (χ² = 4.51, P = 0.03). Among BD I patients assigned to Lam + placebo, 71.4% (25/35) had at least one visit with MADRS score ≥15 compared with 36.7% (11/30) among Lam + Div patients (χ² = 7.89, df = 1, P = 0.005). Conclusion: Lam + Div generally provided greater maintenance efficacy than Lam alone for depressive indices in recently depressed BD patients.     

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder

BACKGROUND: The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. METHOD: During an 8- to 16-week open-label phase, lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. The primary outcome measure was time from randomization to intervention (addition of pharmacotherapy) for any mood episode (depressive, manic, hypomanic, or mixed). Data were gathered from September 1997 to August 2001. RESULTS: Time to intervention for any mood episode was statistically superior (p = .029) for both lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode (p = .047). The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77%, lithium 86%, and placebo 72%. Headache was the most frequent adverse event for all 3 treatment groups. CONCLUSION: Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with lamotrigine predominantly effective against depression and lithium predominantly effective against mania.     

Lamotrigine and hemodialysis in bipolar disorder: case analysis of dosing strategy with literature review

Kaufman KR. Lamotrigine and hemodialysis in bipolar disorder: case analysis of dosing strategy with literature review.
Bipolar Disord 2010: 12: 446–449. © 2010 The Author. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Medical conditions and associated procedures/treatments may impact therapeutic blood levels of pharmacologic agents in the illnesses we treat. The use of anti‐epileptic drugs in the treatment of psychiatric disorders, most commonly bipolar disorders, and epilepsy is a case in point. This report addresses the impact of hemodialysis on lamotrigine efficacy in bipolar disorder. Method: Case analysis with literature review. Results: A bipolar disorder patient stabilized on lamotrigine 200 mg total daily dose was admitted to the hospital with end‐stage renal disease. With three consecutive days of hemodialysis, treatment‐emergent hypomanic features were noted by the patient and confirmed in psychiatric consultation. When lamotrigine was increased to 250 mg total daily dose, the bipolar features remitted. Conclusion: Lamotrigine titration may be required in bipolar disorder patients undergoing hemodialysis secondary to the associated hemodialysis extraction factor. Therapeutic drug monitoring is recommended in these patients.     

A double-blind, placebo-controlled study of memantine in the treatment of major depression

OBJECTIVE: This study was designed to assess possible antidepressant effects of memantine, a selective N-methyl-D-aspartate (NMDA) receptor antagonist in humans. METHOD: In a double-blind, placebo-controlled study, 32 subjects with major depression were randomly assigned to receive memantine (5-20 mg/day) (N=16) or placebo (N=16) for 8 weeks. Primary efficacy was assessed by performance on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The linear mixed models for total MADRS scores showed no treatment effect. CONCLUSIONS: In an 8-week trial, the low-to-moderate-affinity NMDA antagonist memantine in doses of 5-20 mg/day was not effective in the treatment of major depressive disorder.     

A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report

Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double‐blind, placebo‐controlled clinical trial of acamprosate in alcohol‐dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord 2012: 14: 54–63. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Background: Alcohol use disorders commonly co‐occur with bipolar disorder and are associated with a more severe course of bipolar illness, yet treatment research in this important clinical population is scarce. The current study assessed the effects of acamprosate on alcohol use and mood symptoms in subjects with co‐occurring bipolar disorder and active alcohol dependence. Methods: Thirty‐three adults meeting criteria for bipolar I or bipolar II disorder and current alcohol dependence were randomized to receive add‐on acamprosate (1998 mg/day) or placebo while concurrently maintained on mood stabilizing medications. Participants were assessed weekly for frequency and quantity of alcohol consumption and general clinical severity for eight weeks. Depressive symptoms, manic symptoms, and alcohol craving were assessed biweekly. Biomarkers of alcohol use were assessed at study baseline and endpoint. Results: Of the 33 subjects randomized, 23 (69.7%) completed all active phase visits. Over the trial as a whole, no statistically significant treatment differences were detected in drinking outcomes. Post‐hoc analysis revealed lower Clinical Global Impression scores of substance use severity in acamprosate‐treated participants in weeks 7–8 of the trial. No significant differences in depressive symptoms, manic symptoms, or adverse events were observed between groups. Conclusions: Acamprosate was well‐tolerated, with no worsening of depressive or manic symptoms, and appeared to confer some clinical benefit in study completers in the last two weeks of the trial. Larger studies of longer duration are required to fully explore the utility of acamprosate in this population.     

Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study

Chou Y‐H, Wang S‐J, Lin C‐L, Mao W‐C, Lee S‐M, Liao M‐H. Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study.
Bipolar Disord 2010: 12: 312–318. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD. Methods: Twenty‐eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery‐Åsberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight‐week period. Single photon emission computed tomography with the radiotracer ¹²³I‐ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome. Results: The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three‐way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = ?0.742, p = 0.014) only. Conclusions: Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.     

拉莫三嗪治疗精神分裂症和双相抑郁及重性抑郁症耐受性与敏感性的文献分析

目的 分析拉莫三嗪在精神分裂症、双相抑郁和重性抑郁症急性期治疗中耐受性与敏感性.方法 选择符合急性期、随机双盲、安慰剂对照的关于拉莫三嗪治疗急性期精神分裂症、双相抑郁和重性抑郁症的临床试验进行分析;以不良事件引起治疗终止发生率为拉莫三嗪的耐受性指标,以皮疹和头痛为敏感性指标.分别计算拉莫三嗪(200 mg/d)事件发生率相对于安慰剂事件发生率增加(ARI),以及拉莫三嗪(200 mg/d)治疗相对于安慰剂治疗所致1例不良事件发生前需要治疗的患者数(NNH);显著性检验以95%可信区间(95%CI)表示.结果 (1)难治性精神分裂症4项、双相抑郁4项、难治性双相抑郁1项和重性抑郁症3项临床试验被分析;(2)在难治性精神分裂症、双相抑郁及难治性双相抑郁、重性抑郁症的急性治疗期,与安慰剂比较,拉莫三嗪(200 mg/d)相关不良事件引起治疗终止NNH(95%CI)依次为323(-23～20)、-47(-17～60)、-34(-10～22)和-32(-14～158)例,皮疹依次为133(-51～29)、-46(-18～83)、51(-16～10)和-31(-15～1208)例,头痛依次为-26(-11～61)、-168(-16～19)、-28(-6～9)和53(-24～13)例,差异无统计学意义(95%CI包括0).结论 拉莫三嗪单药或增效治疗精神分裂症、双相抑郁和重性抑郁症具有良好的耐受性与安全性.

Abstract：

Objective To compare the tolerability and sensitivity of lamotrigine in the treatment of schizophrenia, bipolar depression and major depressive disorder (MDD). Methods Data from randomized,double-blind, placebo-controlled trials of lamotrigine adjunctive or monotherapy in the acute treatment of treatment-resistant schizophrenia, bipolar depression, and MDD were used. The discontinuation due to adverse events (DAEs) was used as an index of tolerability. The reported headache and occurrence of rash were used as indexes of sensitivity. Absolute risk increase (ARI) and number needed to harm (NNH) of lamotrigine at dose of 200 mg/d relative to placebo for DAEs, headache, and rash were estimated with 95% confidence interval (CI) to reflect the magnitude of variance. Results Four trials in treatment-resistant schizophrenia, 4 in bipolar depression, 1 in treatment-resistant bipolar depression and 3 in major depressive disorder were analyzed. In the acute treatment of treatment-resistant schizophrenia, bipolar depression or treatment-resistant bipolar depression and major depressive disorder, lamotrigine 200 mg/d did not significantly increase the risk for DAEs [NNH 95% CI respectively as 323(-23 to 20) ,-47(-17 to 60), -34(-10 to 22) and-32(-14 to 158)], rash [NNH 95% CI respectively as 133 (-51 to 29),-46(-18 to 83), 51 (-16 to 10) and -31 (-15 to 1208)] and headache [NNH 95% CI respectively as -26(-11 to 61),-168 (-16 to 19),-28 (-6 to 9) and 53 (-24 to 13)] relative to placebo. Conclusion The available data indicate patients with schizophrenia, bipolar depression and major depressive disorder tolerate lamotrigine 200 mg/d as well as placebo and have a similar sensitivity to lamotrigine as to placebo.