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.     

An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression

OBJECTIVE: The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. METHOD: This was an 8-week open-label trial of lamotrigine with 20 adolescents ages 12-17 years (mean age 15.8; 7 boys, 13 girls) with diagnoses of bipolar disorder I, II, or not otherwise specified, who were experiencing a depressive episode. Lamotrigine was begun at 12.5 to 25 mg/day. Primary response criteria was a 1 or a 2 on the Clinical Global Impression-Improvement at week 8. A secondary criterion was at least a 50% decrease in Children's Depression Rating Scale-Revised scores. RESULTS: Nineteen subjects completed the trial. The mean final dose was 131.6 mg/day. Seven subjects were taking other psychotropic medications. Sixteen subjects (84%) responded by primary criteria, and 12 (63%) responded to our secondary criteria. Eleven subjects (58%) were considered in remission at week 8. Young Mania Rating Scale and Overt Aggression Scale-Modified scores also decreased significantly during the trial. There was no significant weight change, rash, or other adverse effects during the trial. CONCLUSIONS: Adolescents with bipolar depression appeared to respond to lamotrigine treatment, whether as adjunctive therapy or monotherapy, with decreases in depression, mania, and aggression. Larger, placebo-controlled studies of lamotrigine are needed in this population.     

Acute treatment of bipolar depression with adjunctive zonisamide: a retrospective chart review

BACKGROUND: This retrospective chart review evaluated the use of zonisamide as adjunctive treatment in patients with bipolar depression. METHOD: The charts of outpatients with bipolar I or II disorder treated with adjunctive zonisamide were reviewed. The efficacy of zonisamide was assessed via comparison of physician-rated Global Assessment of Functioning (GAF) and Clinical Global Impression of Severity (CGI-S) Scale scores at baseline and after 6 weeks of therapy using paired t-tests. Patients who scored < or = 2 on the CGI-S after 6 weeks of zonisamide therapy were considered good responders to zonisamide. RESULTS: Charts for 12 patients (four men and eight women) with a mean (+/- SD) age of 39.6 (+/- 7.6) years were evaluated. Patients received a mean (+/- SD) zonisamide dosage of 236 (+/- 68) mg/day. Mean GAF scores significantly improved from 44.0 at baseline to 59.3 at week 6 (P = 0.05). Mean CGI-S scores improved from 4.54 at baseline to 3.42 at week 6, but the change was not statistically significant. Six patients (50.0%) were considered responders to zonisamide. Four patients discontinued zonisamide therapy, two for an adverse event (sedation) and two for lack of efficacy. CONCLUSIONS: Zonisamide may be a useful adjunctive treatment for some patients with bipolar depression. Conclusions from this study are limited due to its retrospective design. Further investigation of zonisamide in the treatment of bipolar depression is warranted.     

A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression

OBJECTIVE: Olanzapine-fluoxetine combination has shown efficacy in the acute treatment of depressive episodes in patients with bipolar I disorder. The present analyses examined the efficacy and safety of longer term treatment with olanzapine-fluoxetine combination or olanzapine monotherapy in a 6-month open-label extension study. METHOD: 376 patients with DSM-IV bipolar I disorder, depressed, who completed an acute trial entered the open-label study and received 1 week of olanzapine monotherapy (5-20 mg/day). At all subsequent visits, patients could choose between olanzapine monotherapy or olanzapine-fluoxetine combination (6/25, 6/50, or 12/50 mg/day). Three treatment groups were defined retrospectively according to the medication course taken from week 1: olanzapine, olanzapine-fluoxetine combination, or switched. The efficacy measures were the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Bipolar Version, and Young Mania Rating Scale. The study was conducted from July 2000 to May 2002. RESULTS: Among patients who started in remission, MADRS total scores did not change significantly from baseline to endpoint in the olanzapine-fluoxetine combination (0.8) or olanzapine (0.3) groups, but increased slightly in the switched (2.3, p = .02) group. For patients who started in nonremission, MADRS total scores decreased significantly in all groups (olanzapine-fluoxetine combination: -5.7, p = .001; olanzapine: -11.6, p = .004; switched: -6.4, p = .015). The majority of patients who entered the study in nonremission achieved remission (MADRS total score < or = 12) during the trial (olanzapine-fluoxetine combination: 66.7%, olanzapine: 64.7%, switched: 62.5%). The overall rate of depressive relapse was 27.4%, and the overall incidence of mania emergence was 5.9%. CONCLUSIONS: The present findings suggest that long-term treatment with olanzapine-fluoxetine combination may be a useful option for the management of depressive symptoms and carries a low risk of mania emergence.     

Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report

Sajatovic M, Gildengers A, Al Jurdi RK, Gyulai L, Cassidy KA, Greenberg RL, Bruce ML, Mulsant BH, Ten Have T, Young RC. Multisite, open‐label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report.
Bipolar Disord 2011: 13: 294–302. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Aims: This is a multisite, 12‐week, open‐label trial of lamotrigine augmentation in 57 older adults (≥ 60 years; mean ± SD age = 66.5 ± 6.7 years) with either type I or type II bipolar depression. Methods: Primary outcome measure was change from baseline on the Montgomery–Åsberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM‐D), Clinical Global Impression–Bipolar version (CGI‐BP), and the WHO‐Disability Assessment Schedule II (WHO‐DAS II). The Udvalg for Kliniske Undersøgelser (UKU) was used to assess side effects. Results: A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM‐D, CGI‐BP, and in most domains on the WHO‐DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. Conclusions: In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression.     

Content-specificity of dysfunctional cognitions for patients with bipolar mania versus unipolar depression: a preliminary study

OBJECTIVE: Dysfunctional beliefs or cognitions are considered to be fundamental to both the phenomenology and pathogenesis of depression. However, the cognitive aspects of mania have not been as thoroughly investigated. We sought to compare the maladaptive beliefs and cognitions of 23 bipolar manic or hypomanic patients, 28 patients with unipolar major depression, and 24 normal adults. METHOD: The Cognition Checklist for Mania (CCL-M) was used to assess the beliefs. This 61-item self-report instrument is scored for seven subscales measuring (a) self-importance, (b) interpersonal grandiosity, (c) inappropriate spending, (d) excitement and risk-taking, (e) interpersonal frustrations, (f) goal-driven activity, and (g) past or future outlooks on life, and also yields a total score. RESULTS: The mean CCL-M total score of the bipolar-manic patients was significantly higher than the mean CCL-M total score of the unipolar-depressed patients, and the patients' mean CCL-M total score was also higher than that of the normal adults. The mean scores of the subscales measuring excitement and past and future memories and expectations were also significantly higher for the bipolar-manic than unipolar-depressed patients. CONCLUSIONS: Bipolar-manic patients endorse with maladaptive beliefs and cognitions that are associated with mania more than do unipolar-depressed patients and normal adults. The implications for the early identification of cognitions associated with prodromal states of mania, and for psychotherapeutic interventions, are discussed.     

Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study

INTRODUCTION: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. LIMITATIONS: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.     

Efficacy of milnacipran on cognitive dysfunction with post-stroke depression: preliminary open-label study

The aim of this study was to assess the therapeutic efficacy of the serotonin norepinephrine reuptake inhibitor (SNRI), milnacipran, on both cognitive impairment and depression in post-stroke depression (PSD) patients. A total of 18 PSD patients, approximately 3 months after stroke, were divided into two groups, milnacipran and control. A total of 10 patients were assigned to the milnaciprane group and eight were assigned to control group. Their cognitive impairment and mood symptoms were measured using the Mini-Mental State Examination (MMSE) and Hamilton Depression Rating Scale (HAM-D) both at the time of admission and at discharge, an interval of approximately 3 months. This study examined the changes in both MMSE and HAM-D scores during the study period. A significant time-by-group interaction for results of the MMSE was observed, although there was no significant difference between the two groups on the HAM-D. Amelioration of cognitive impairment was greater in the milnacipran group than the control group. For PSD patients, milnacipran is effective in improving cognitive dysfunction.     

Olanzapine in the treatment of depression with psychotic features: A prospective open-label study

Objective. Depression with psychotic features is a severe subtype of major depression associated with the presence of delusions, hallucinations and specific neurobiological features. Despite clinical consensus and guideline recommendations, data comparing the efficacy of combining antipsychotics with antidepressants compared to antidepressants alone remain inconclusive. The aim of the study was to investigate effectiveness and tolerability of the atypical antipsychotic olanzapine in acute depression with psychotic features. Methods. Seventeen inpatients with major depressive disorder with psychosis (MDDp) were treated with a combination of an antidepressant and olanzapine for 6 weeks in a prospective open-label study. Depressive and psychotic symptoms, extrapyramidal and general side effects were assessed every 2 weeks. Sixteen patients were eligible for final analysis. Results. The Brief Psychiatric Rating Scale (BPRS) showed a 30% symptom reduction after week 2, a 45% symptom reduction after week 4 and no considerable improvement thereafter. Depressive symptoms (Bech–Rafaelsen Melancholia Scale, BRMS) receded by 37% after week 2 and 50% after week 4. No extrapyramidal side effects occurred. Conclusion. Olanzapine is effective and tolerable in combination with an antidepressant in an MDDp inpatient sample. The results concur with data supporting good efficacy in negative and depressive symptoms of patients with schizophrenic and schizoaffective diseases.     

An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.

BACKGROUND: Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. METHODS: This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of >/=20 received riluzole (50-200 mg/day) for 8 weeks. RESULTS: Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. CONCLUSIONS: Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.     

An open-label study of nefazodone treatment of major depression in patients with congestive heart failure.

OBJECTIVES: To evaluate the feasibility of screening and recruiting patients with major depression and congestive heart failure (CHF) in a tertiary care cardiology hospital and to obtain preliminary efficacy, tolerability, and safety data for nefazodone treatment of a major depressive episode in CHF patients. METHOD: We conducted a 12-week, open-label trial of nefazodone given in dosages up to 600 mg daily. We assessed patients at baseline, 1, 2, 4, 8, and 12 weeks. Measures used were the 17-item Hamilton Depression Rating Scale (HDRS), the Clinical Global Impression Scale, the Beck Depression Inventory, Spielberger's State-Trait Anxiety Inventory, and the Minnesota Living with Heart Failure Questionnaire. We also obtained pre- and poststudy ECGs, 24-hour Holter monitor recordings, and plasma levels of norepinephrine. RESULTS: After screening 443 CHF patients, 28 patients with major depression met study eligibility criteria. The 23 patients who completed 4 or more weeks of medication showed significant improvement on all depression scales and in quality of life. Of 19 subjects who completed the full 12-week trial, 74% experienced a decline of 50% or more on HDRS scores. The completers also showed a significant reduction in heart rate, an increase in QT intervals (but not in the QTc), and a marginally significant decrease in plasma norepinephrine. There were no changes in heart rate variability. CONCLUSIONS: It is feasible to screen and recruit CHF patients with major depression for an anti-depressant trial. Nefazodone seems sufficiently safe, tolerable, and efficacious to justify a larger, placebo-controlled trial.     

Newer treatment studies for bipolar depression

Objective:  Depressive symptoms of bipolar disorder have more negative impact on a patient's life than manic symptoms. This review focused on the emerging efficacy data for treatments in bipolar depression.
Methods:  English-language literature cited in Medline was searched with terms bipolar depression, clinical trial, and trial. Randomized, placebo-controlled trials of newer studies with older agents and all studies with newer or novel agents were prioritized. Open-label studies of novel agents presented at major scientific meetings were also included.
Results:  Olanzapine, olanzapine–fluoxetine combination (OFC), and quetiapine were superior to placebo in the acute treatment of bipolar depression. Lamotrigine only significantly reduced core symptoms of depression compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood stabilizer (MS) had superiority to placebo in reducing depressive symptoms. Topiramate augmentation of an MS was equally as effective as Bupropion-SR. Patients treated with an MS responded well to the addition of agomelatine, a melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol and repetitive transcranial magnetic stimulation did not separate from placebo. Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to placebo in preventing depressive relapses. All agents were relatively well tolerated.
Conclusions:  Olanzapine, OFC, and quetiapine are effective in the acute treatment of bipolar depression. Compared with lithium and divalproex, lamotrigine is more effective in preventing bipolar depression. Larger controlled studies of the other agents in the acute and maintenance treatment of bipolar depression are warranted.     

Add-on quetiapine for bipolar depression: a 12-month open-label trial.

OBJECTIVES: Bipolar disorder (BD) is a disabling and often chronic condition. Patients with BD suffer from depression at least one-third of the time, but they do not always respond well to conventional mood stabilizers. Attempts to treat them with antidepressants can provoke a switch to mania or increased cycling. Our open-label trial aimed to assess the long-term response of patients with bipolar depression to the addition of quetiapine to their usual treatment. Our study also sought to assess the safety and tolerability of quetiapine in patients with BD. METHOD: To meet inclusion criteria for the study, patients had a DSM-IV diagnosis of type I or II BD, were aged 18 years and older, currently suffered from depression with a score of > 18 on the Hamilton Depression Rating Scale (HDRS), and had no change in antidepressant use for at least 3 weeks prior to the study. We added quetiapine to patients' medication and attempted to increase the dosage to at least 400 mg daily. Outcome was measured at baseline and once monthly for 12 months on the HDRS, the Young Mania Rating Scale, the Clinical Global Impression Scale (CGI), and the Abnormal Involuntary Movement Scale. RESULTS: There were 19 patients enrolled in the study (6 men and 13 women), 2 of whom dropped out because they could not tolerate the drug. Seventeen completed at least 2 assessments, and 7 patients completed the full 12-month trial. Data for the 17 patients (that is, last observation carried forward) at 12 months shows HDRS scores reduced from 27.2 to 12.1 and CGI scores reduced from 4.7 to 2.6. CONCLUSIONS: Quetiapine seems to be helpful to and relatively well tolerated by patients with bipolar depression when it is added to their usual treatment. There is, however, a need for controlled trials.     

米氮平与西酞普兰治疗双相抑郁的对照研究

目的:评价米氮平与西酞普兰治疗双相抑郁的疗效及安全性.方法:将符合中国精神障碍分类与诊断标准第3版双相抑郁诊断标准的64例患者随机分为两组,予米氮平(32例)及西酞普兰(32例)分别合并碳酸锂治疗,疗程为12周.采用汉密尔顿抑郁量表(HAMD)、躁狂量表(BRMS)、临床疗效总评量表(CGI)评定疗效,以治疗中出现的症状量表(TESS)评定不良反应.结果:治疗12周后,两组患者HAMD、CGI评分均显著减少(P＜0.05或P＜0.01),BRMS、TESS评分均无明显增加.两组间比较HAMD、CGI、BRMS、TESS评分差异无显著性(P＞0.05).结论:米氮平与西酞普兰治疗双相抑郁均有较好的疗效,不良反应较少,无诱发躁狂病例.     

抑郁症患者的Quisi试验研究

目的　探讨Quisi在抑郁症辅助诊断中的价值。方法　应用德国Quisi仪 ,对 2 4例抑郁症患者 (抑郁症组 )的睡眠脑电进行 2次全夜测试 ,并与 2 1名正常受试者 (正常对照组 )进行对照。结果　 (1)抑郁症组在第 1夜的各项指标中 ,仅总记录时间短于第 2夜 [分别为 (478 1± 2 7 4 )min和(499 5± 2 5 7)min ;P <0 0 1]。 (2 )抑郁症组与正常对照组比较 ,睡眠潜伏期长 [分别为 (34 5± 17 9)min和 (2 3 9± 17 4 )min ;P <0 0 5 ],觉醒时间长 [分别为 (39 8± 2 1 9)min和 (19 3± 14 9)min],睡眠效率低 [分别为 (83 7± 6 9) %和 (93 3± 5 1) % ],睡眠维持率低 [分别为 (88 8± 9 1) %和 (99 8±4 9) % ],REM睡眠潜伏期短 [分别为 (6 9 9± 16 3)min和 (88 6± 15 9)min],第二阶段百分比高 [分别为 (5 5 3± 11 9) %和 (47 5± 7 8) % ;P <0 0 5 ],第三阶段百分比高 [分别为 (8 9± 6 9) %和 (14 1±6 1) % ],REM睡眠百分比低 [分别为 (10 1± 5 9) %和 (16 9± 5 1) % ],伪迹百分比高 [分别为 (3 9±1 3) %和 (1 9± 0 8) % ],P <0 0 5或P <0 0 1。结论　Quisi适合于全夜监测。在缺乏相关设备的基层医院 ,Quisi技术可用于对抑郁症的检测。     

Current issues in the treatment of depression in bipolar disorder patients

Reviewing abstracts of posters and presentations at scientific meetings offers a rapid overview summary of the state of the art of a given discipline and/or disorder, with data presented being available months to years before formal publication occurs. This article reviews selected abstracts of posters presented at the Sixth International Conference on Bipolar Disorder, held in Pittsburgh, PA June 16–18, 2005. The review consists of the consideration of nine published abstracts (of a total of 278 abstracts). The major focus of this review is on the nature and treatment of depression in bipolar disorder patients, and includes information generally not previously circulated to psychiatric professionals.