Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series

OBJECTIVE: Previous studies and case observations have suggested that dopamine agonists (DAAs) such as pramipexole (PPX) and ropinirole (RPN) might be effective for major depression, but their adjunctive use in treatment-resistant bipolar II depression has not yet been specifically addressed. METHOD: A chart review was conducted on 18 patients with a DSM-III-R bipolar NOS (Bipolar II) major depressive episode who were admitted to the day-hospital of the Department of Psychiatry at the University of Pisa. DAAs were added to ongoing treatments with conventional antidepressants and mood stabilizers to which patients had no responded after a period of at least 8 weeks. Clinical state and adverse effects were assessed at each visit. Final improvement in CGI scores of 1 or 2 were considered as responders. RESULTS: Mean DAA trial duration was 17.6 (sd = 7.8, range 4-34) weeks, with a mean final dose of 1.23+/-0.32 mg/day (range, 0.75-1.50mg/day) for PPX, and 2.97+/-0.99mg/day (range, 1.50-5.00mg/day) for RPN. DAAs were well tolerated and did not show any negative interaction with concomitant psychotropic medications. Only one patient became worse (final CGI = 5), and had to interrupt PPX due to nausea, increased agitation and irritability. Eight patients (44.4%) were considered responders (4 with PPX and 4 with RPN): 5 showed marked improvement (CGI = 1), and 3 showed moderate improvement (CGI = 2); another 5 (27.8%) manifested a transient response not sustained up to the end. The initial and final scores of CGI severity scale for all patients (responders and non-responders combined) were, respectively, 5.33+/-0.7 and 3.94+/-1.3 (mean +/- S.D). The mean change according to the CCI severity scale was statistically significant (t=4.74. p < 0.0002). CONCLUSION: From the results, PPX and RPN appear to be well tolerated and potentially useful in the adjunctive treatment of drug-resistant bipolar II depression.     

Adjunctive gabapentin for treatment-resistant insomnia of bipolar disorder: a case report

We report a case with bipolar II disorder having mixed features, in which refractory insomnia persisted. We diagnosed his case as mixed depression with mood fluctuations because increased impulsivity and buying sprees became remarkable, with diminished ability to think or concentrate. Switching to carbamazepine and risperidone improved his mood fluctuations and impulsivity. Nevertheless, his intermittent awakening (fragmentation of the sleep-wake rhythm), related dysfunctional beliefs, anxiety about sleep, and mild impulsivity persisted. The addition of various benzodiazepine sleeping drugs, bromovalerylurea, and antipsychotics did not improve insomnia. His intractable insomnia was markedly responsive to gabapentin, engendering further improvement of mood symptoms. Eventually, its efficacy achieved his reinstatement at work. Results of this case suggest the clinical use of gabapentin for treating bipolar disorder, especially in cases with intractable insomnia, which is a very important point in the symptoms and therapeutics of bipolar disorder.     

Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression

Objective: To study the clinical effect of a single ketamine infusion, 0.5?mg/kg body weight, in bipolar depressive patients receiving mood-stabilising drugs, not improving on antidepressants. Previously, in such patients, we had found a correlation between clinical efficacy, serum brain-derived neurotrophic factor and vitamin B12 levels and a rapid improvement in neurocognitive performance.

Methods: The study included 53 patients (13 men, 40 women), aged 22–81 years, receiving ≥1 mood-stabilising medications of the first and/or second generation. Pre-infusion depression intensity on the Hamilton Depression Rating Scale (HDRS) was 23.4?±?4.6 points and the assumed criterion for response was a reduction of ≥50% in the HDRS score after 7 days.

Results: Twenty-seven subjects (51%) met a criterion for response, more frequently males (77%) than females (43%). Responders did not differ from non-responders as to age, illness onset, duration of depressive episode, type of bipolar illness, family history of psychiatric illness, personal/family history of alcoholism or using lithium, quetiapine or a combination of these mood stabilisers.

Conclusions: The results confirm a rapid antidepressant effect of ketamine infusion in a considerable proportion of those patients with bipolar depression receiving mood-stabilising drugs. Apart from male gender, no other clinical factors were predictors of response.     

An open-label, rater-blinded, augmentation study of aripiprazole in treatment-resistant depression

Background: About 30% to 46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. While treatment-resistant depression commonly refers to nonresponse or partial response to at least 2 adequate trials with antidepressants from different classes, due to variability in terminology, a staging system based on prior treatment response has been suggested. Aripiprazole is a novel atypical antipsychotic with partial agonism at dopamine D(2) and serotonin 5-HT(1A) receptors and antagonism at the 5-HT(2) receptors. The present study evaluated whether augmentation with aripiprazole would be beneficial and tolerable in patients with treatment-resistant MDD who had failed 1 or more trials of antidepressants. Method: In an open-label, rater-blinded study conducted from March 2003 through December 2003, 10 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 1 antidepressant were prescribed aripiprazole (10-30 mg/day) for 6 weeks. The dose of preexisting antidepressants remained unchanged. Treatment response was defined as a 50% or greater reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) scales. Results: Eight of 10 patients had failed 2 or more antidepressant trials. The mean daily dose of aripiprazole was 13.21 mg. Intent-to-treat analysis showed that mean ± SD HAM-D scores reduced significantly from baseline (23.0 ± 8.1) to end of treatment (8.1 ± 6.0) (p < .001). There was a significant reduction in CGI-I (p < .05) and a trend toward decrease in CGI-S (p = .06) score. Seventy percent of the subjects were responders and 30% achieved remission. Common adverse effects were akathisia (20%), nausea (20%), and restlessness (20%). Conclusions: The study indicates the potential utility of aripiprazole as an augmenting agent in treatment-resistant depression, particularly in those who had failed 2 or more antidepressant trials. Adequately powered, randomized controlled trials are necessary to evaluate the role of aripiprazole in treatment-resistant depression.     

Donepezil in treatment-resistant bipolar disorder.

BACKGROUND: A considerable percentage of patients with bipolar disorder do not respond or do not tolerate conventional treatment. Cholinesterase (ChE) inhibitors have been suggested to possess depressogenic and antimanic properties. METHODS: We report a case series of treatment-resistant bipolar patients (n = 11) to whom we administered the ChE inhibitor donepezil. Four patients met criteria for current manic episode, 5 for mixed episode, 1 for hypomanic episode, and 1 for major depressive episode. Donepezil was added to current medication on an openlabel basis. Ratings were based on a retrospective chart review. RESULTS: Of the 11 patients, 6 (54.5%) demonstrated marked improvement (improvement in CGI-S > or = 2), 3 (27.2%) demonstrated slight improvement, 1 did not respond, and 1 did not tolerate the medication. Among those patients who had marked improvement (i.e., responders, n = 6), improvement was observed within 2 weeks or less in 5 of them (83%). Patients experienced only minor side effects. CONCLUSIONS: These pilot data suggest the efficacy and safety of donepezil in the treatment of bipolar disorder. To our knowledge this is the first published report on the use of donepezil in the treatment of mood disorders. Controlled, randomized, double-blind studies are necessary to validate these preliminary observations.     

Aripiprazole augmentation in treatment-resistant depression.

BACKGROUND: Evidence is accumulating to support the use of atypical neuroleptics as adjunctive treatment for refractory mood disorders, although there are currently no published data on the efficacy of an atypical neuroleptic in treatment-resistant depression when a previous trial of drug from the same class has failed. The authors hypothesized that aripiprazole would be efficacious in augmenting antidepressant treatment in resistant patients with non-psychotic unipolar depression who had previously failed a trial of another atypical neuroleptic. METHODS: This study was a retrospective chart review of the efficacy of aripiprazole augmentation in 30 treatment-resistant unipolar depression patients who had failed multiple previous antidepressant trials and had also failed augmentation with at least one other atypical neuroleptic. Prospective Global Assessment of Functioning and Clinical Global Impressions-Improvement scores were completed on each patient throughout treatment. RESULTS: Utilizing an intent-to-treat analysis (including 9 patients who dropped out prior to completion of 6 weeks), 46.7% (14/30) patients were rated much improved or very much improved with treatment. This improvement negatively correlated with Thase-Rush staging of treatment resistance. GAF scores also showed a significant improvement. Six of the 14 patients who initially improved subsequently relapsed (yielding a long-term net response rate of 26.7%). CONCLUSION: Aripiprazole may be effective as an antidepressant augmentation agent in highly treatment resistant patients who had failed a prior trial of another atypical neuroleptic.     

Adjunctive topiramate in bipolar II disorder.

We evaluated the efficacy and safety of adjunctive topiramate in bipolar II patients who were either treatment-resistant to or unable to tolerate lithium, carbamazepine or valproate. Nineteen DSM-IV bipolar II patients received increasing doses of open-label topiramate as adjunctive therapy for their hypomanic (n=15) or depressive (n=4) symptoms. Sixteen patients completed the 12-week follow-up. There were highly significant improvements in YMRS, HDRS and CGI-BP-M scores (p=0.0001). Of the fifteen hypomanic patients, eight (53%) were rated as responders to topiramate (50% reduction in YMRS scores), and five (33%) met criteria for remission (YMRS score pound 8). Two of the four patients with a depressive episode at study entry (50%) were rated as responders (50% reduction in HDRS score), and one (25%) achieved remission (HDRS score pound 6). Topiramate was generally well tolerated. One third of the patients experienced weight loss. These preliminary results suggest that adjunctive topiramate may be useful in treating bipolar II disorder.     

Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression

Anhedonia—which is defined as diminished pleasure from, or interest in, previously rewarding activities—is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine''s anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia.     

阿立哌唑治疗难治性精神分裂症患者的疗效和安全性

目的:探讨阿立哌唑治疗门诊难治性精神分裂症患者的疗效和安全性。方法:204例入组患者符合中国精神障碍分类与诊断标准第3版精神分裂症的诊断标准,且符合难治性精神分裂症的标准。所有患者接受为期8周的阿立哌唑开放性治疗,在基线、治疗2、4和8周采用阳性与阴性症状量表(PANSS)评定疗效,采用治疗中出现的症状量表(TESS)评定不良反应。结果:阿立哌唑治疗4周开始起效,治疗8周,有效率为55.4%。治疗4和8周,患者PANSS总分减分率有统计学意义(t=2.44,P<0.05;t=3.61,P<0.01),PANSS阳性分减分率有统计学意义(t=3.53,P<0.05;t=3.89,P<0.01),PANSS阴性分减分率有统计学意义(t=3.19,P<0.05;t=4.02,P<0.01)。主要不良反应为焦虑、头晕头痛、失眠、恶心呕吐、嗜睡等。结论:阿立哌唑对于难治性精神分裂症患者的治疗具有一定的疗效,不良反应少,耐受性较好。     

Aripiprazole augmentation in treatment-resistant bipolar depression: early response and development of akathisia

There is growing evidence that atypical antipsychotics may be effective in the treatment of acute bipolar depression. Results from randomized, placebo-controlled trials support the use of quetiapine monotherapy and a combination of olanzapine-fluoxetine in the depressed phase of bipolar disorder, while only limited data exists regarding the use of aripiprazole in this population. To assess the potential effectiveness of aripiprazole in treating acute bipolar depression, a chart review was conducted on 12 patients with treatment-resistant bipolar disorder (I, II, and not otherwise specified [NOS]) who received aripiprazole augmentation for the relief of an acute major depressive episode. After 8 weeks of treatment, 4 of 12 (33%) patients demonstrated a response, defined as a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score. In addition, 5 of 12 (42%) patients newly developed akathisia. This report, though limited by its small sample size and naturalistic design, suggests that the usefulness of aripiprazole in the treatment of bipolar depression may be limited by akathisia.     

Adjunctive gabapentin treatment of bipolar disorder.

INTRODUCTION: The aim of this study was to analyze the effectiveness of gabapentin administration to bipolar patients who had an incomplete response to other mood stabilizers. SUBJECTS AND METHODS: Twenty-two RDC bipolar 1 and II patients were assessed by means of the SADS and entered if they gave their consent to participate. All them had suffered from frequent relapses, subsyndromal features (mostly depressive) and incomplete response to other drugs. They all received open-label increasing doses of gabapentin until clinical response. The patients were assessed through the CGI-BP and a specific questionnaire at baseline and at 12 weeks of follow-up. RESULTS: Six out of the 22 patients dropped out for various reasons (four because of relapse, one because of side effects and one more because of poor compliance). Eight of the 16 patients that completed the 12-week follow-up showed at least two stages of improvement in the CGI. Using the last observation-carried forward analysis, the improvement was statistically significant for the depression subscale, and apparently related to social functioning, irritability and anxiety. Only one patient dropped out because of intolerance (mild rash). The mean dose of gabapentin was 1,310 mg/day. CONCLUSION: Gabapentin may be a useful drug for the add-on treatment of bipolar patients with poor response to other mood stabilizers. Gabapentin may improve depressive residual symptoms such as irritability, social withdrawal or anxiety. These results should be confirmed in randomized clinical trials.     

Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression

Background

Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first-line therapeutic options, resulting in treatment-resistant bipolar depression (B-TRD). Esketamine, the S-enantiomer of ketamine, has recently been approved for treatment-resistant depression (TRD), but no data are available on its use in B-TRD.

Objectives

To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B-TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B-TRD, focusing on the average risk of an affective switch.

Methods

Thirty-five B-TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery-Asberg Depression Rating Scale/MADRS, Hamilton-depression scale/HAM-D, Hamilton-anxiety scale/HAM-A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up.

Results

A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B-TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B-TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment-emergent affective switch.

Conclusions

Our results supported the effectiveness and tolerability of esketamine in a real-world population of subjects with B-TRD. The low risk of manic switch in B-TRD patients confirmed the safety of this treatment.