Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.

BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.     

A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression

Swartz HA, Frank E, Cheng Y. A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression. Bipolar Disord 2012: 14: 211–216. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: The differential roles of psychotherapy and pharmacotherapy in the management of bipolar (BP) II depression are unknown. As a first step toward exploring this issue, we conducted a pilot study to evaluate the feasibility and acceptability of comparing a BP‐specific psychotherapy [Interpersonal and Social Rhythm Therapy (IPSRT)] to quetiapine as treatments for BP‐II depression. Methods: Unmedicated individuals (n = 25) meeting DSM‐IV criteria for BP‐II disorder, currently depressed, were randomly assigned to weekly sessions of IPSRT (n = 14) or quetiapine (n = 11), flexibly dosed from 25–300 mg. Participants were assessed with weekly measures of mood and followed for 12 weeks. Treatment preference was queried prior to randomization. Results: Using mixed effects models, both groups showed significant declines in the 25‐item Hamilton Rating Scale for Depression [F(1,21) = 44, p < 0.0001] and Young Mania Rating Scale [F(1,21) = 20, p = 0.0002] scores over time but no group‐by‐time interactions. Dropout rates were 21% (n = 3) and 27% (n = 3) in the IPSRT and quetiapine groups, respectively. Overall response rates (defined as ≥ 50% reduction in depression scores without an increase in mania scores) were 29% (n = 4) in the IPSRT group and 27% (n = 3) in the quetiapine group. Measures of treatment satisfaction were high in both groups. Treatment preference was not associated with outcomes. Conclusions: Outcomes in participants with BP‐II depression assigned to IPSRT monotherapy or quetiapine did not differ over 12 weeks in this small study. Follow‐up trials should examine characteristics that predict differential response to psychotherapy and pharmacotherapy.     

Antidepressant monotherapy for bipolar type II major depression

Objectives:  Bipolar type II (BP II) disorder is thought to be distinct from BP I disorder on genetic and biological grounds, and it is not merely a milder form of the illness. It affects 1.5–2.5% of the US adult population, and is characterized by highly recurrent depressive episodes with a substantial morbidity from alcoholism and non-affective psychopathology, and a higher suicide rate than either BP I or unipolar depression. Treatment recommendations for BP II depression are based upon concerns over drug-induced manic-switch episodes, and suggest using either a mood stabilizer alone or a combination of an SSRI plus a mood stabilizer. Recent evidence, however, indicates that the rate of manic switch episodes may be modest in BP II patients. Recent studies have provided evidence that antidepressant monotherapy may be an effective initial and long-term treatment for BP II major depression with a low manic-switch rate.
Methods:  In this article, we review the recent literature on BP II disorder, with a focus on the treatment of BP II major depression.
Results:  We present a summary of data from recent studies by our group and others indicating that antidepressant monotherapy for BP II depression may be safe and effective with a low manic-switch rate.
Conclusion:  Antidepressant monotherapy may be beneficial for some patients with BP II major depression.     

Interpersonal and social rhythm therapy for adolescents with bipolar disorder: treatment development and results from an open trial

Background: In adolescents and adults, bipolar disorder (BD) is associated with significant morbidity, mortality, and impairment in psychosocial and occupational functioning. IPSRT is an empirically supported adjunctive psychotherapy for adults with bipolar disorder, which has been shown to help delay relapse, speed recovery from a bipolar depressive episode, and increase occupational and psychosocial functioning in adults with BD. This study is designed to describe the adolescent‐specific developmental adaptations made to IPSRT (i.e., IPSRT‐A) and to report the results from an open trial of IPSRT‐A with 12 adolescents with a bipolar spectrum disorder. Method: Interpersonal and Social Rhythm Therapy was adapted to be developmentally relevant to adolescents with bipolar disorder. Twelve adolescents (mean age 16.5±1.3 years) diagnosed with a bipolar spectrum disorder participated in 16–18 sessions of adjunctive IPSRT‐A over 20 weeks. Manic, depressive, and general symptoms and global functioning were measured at baseline, monthly during treatment, and at post‐treatment. Adolescent satisfaction with treatment was also measured. Results: Feasibility and acceptability of IPSRT‐A were high; 11/12 participants completed treatment, 97% of sessions were attended, and adolescent‐rated satisfaction scores were high. IPSRT‐A participants experienced significant decreases in manic, depressive, and general psychiatric symptoms over the 20 weeks of treatment. Participants' global functioning increased significantly as well. Effect sizes ranged from medium‐large to large. Conclusions: IPSRT‐A appears to be a promising adjunctive treatment for adolescents with bipolar disorder. A current randomized controlled trial is underway to examine effects of adjunctive IPSRT‐A on psychiatric symptoms and psychosocial functioning. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Quetiapine monotherapy for bipolar depression

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called "unipolar" depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers - antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration.     

From unipolar depression to bipolar illness: 29 who changed

We studied 29 patients who were admitted to a psychiatric hospital for depression, never had had a previous mania, and developed the mania in follow-up. When compared to patients who were stable unipolars, the potential bipolars had a history of more episodes prior to their onset of mania, more hospital admissions, more marked self-reproach and guilt; in follow-up, they had more hospitalizations.     

Gabapentin augmentation therapy in bipolar depression

Background:  Gabapentin (GBP) may be useful in bipolar disorders, including as adjunctive therapy for bipolar depression, although controlled studies suggest inefficacy as primary treatment for mania or treatment-resistant rapid cycling.
Methods:  We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed [28-item Hamilton Depression Rating Scale (HDRS) >18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years; current depressive episode duration was 18.0 weeks. Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global Impression – Severity (CGI-S) ratings were obtained.
Results:  Overall, HDRS ratings decreased 53% from 32.5 ± 7.7 at baseline to 16.5 ± 12.8 at week 12 (p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS decrease=50%) with HDRS decreasing 78% from 27.9 ± 6.2 to 6.2 ± 4.5 (p < 0.0001). Eight of 22 (36%) patients remitted (HDRS≥8). In non-responders, HDRS decreased from 38.0 ± 5.4 to 28.9 ± 6.7 (p=0.005). Ten of 13 (77%) mild to moderately depressed (baseline HDRS >18 and <35) patients responded, while only two of nine patients (22%) with severe depression (HDRS ≥ 35) responded (p < 0.03). Both groups, however, had similar, statistically significant HDRS decreases. GBP was well tolerated.
Conclusion:  Open adjunctive GBP was effective and well tolerated in patients with mild to moderate bipolar depression. This open pilot study must be viewed with caution, and randomized controlled studies are warranted.     

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.     

The distinction of bipolar II disorder from bipolar I and recurrent unipolar depression: results of a controlled family study

The aim of the study was to differentiate bipolar II, bipolar I and recurrent unipolar depression by their familial load for affective disorders. Eighty bipolar, 108 unipolar, 80 control subjects and interviewed first-degree relatives were diagnosed according to Research Diagnostic Criteria using the Schedule for Affective Disorders and Schizophrenia – lifetime version. The morbid risks for bipolar I disorder were equivalent in relatives of bipolar I (3.6%) and bipolar II (3.5%) subjects and lower in relatives of unipolar subjects (1.0%). The morbid risks of relatives for bipolar II disorder distinguished bipolar II subjects (6.1%) from bipolar I subjects (1.8%), from unipolar depressives (0.3%) and from controls (0.5%). To promote further evaluation, bipolar II disorder should be included in DSM-IV as a distinct diagnostic category.     

Postpartum bipolar depression: a case study

PURPOSE. This case study of a 29‐year‐old married woman with postpartum bipolar depression demonstrates the importance of an accurate differential diagnosis when evaluating a patient presenting with symptoms of postpartum depression. CONCLUSION. Although many of the signs and symptoms of unipolar depression and bipolar depression are identical, there are some important differences. Careful evaluation of symptoms and a thorough psychiatric history leads to accurate diagnosis and successful treatment outcomes. PRACTICE IMPLICATIONS. All women presenting with postpartum depression should be screened for bipolar disorder as the treatment of bipolar depression differs substantially from unipolar depression.     

The treatment of bipolar depression

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.

Methods: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.

Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.

Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.     

Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression - low manic switch rate

Objectives:  Current guidelines for the initial treatment of bipolar type II (BP II) major depressive episode (MDE) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor (SSRI). This recommendation is the result of concern over antidepressant-induced manic switch episodes. However, recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy.
Methods:  As part of a randomized, double-blind, placebo-controlled relapse-prevention study of fluoxetine monotherapy in BP II MDE, 37 patients received open-label fluoxetine 20 mg every day for up to 8 weeks. Outcome measures included the Hamilton Depression Rating (HAM-D 17) rating and the Young Mania Rating (YMR) scale.
Results:  Eleven of 23 patients (48%) who completed 8 weeks of fluoxetine treatment showed a HAM-D 17 reduction of ≥50%, while 14 (38%) of all treated patients had ≥50% reduction in baseline HAM-D 17 score. Using a conservative YMR score of ≥8 to identify hypomanic symptoms, the frequency of patients with YMR score ≥8 during fluoxetine did not differ from that seen during the screen and baseline period. Only three patients (7.3%) had symptoms suggestive of hypomania, and only one patient stopped treatment because of a rapid mood swing into depression.
Limitations:  Fluoxetine was given at a fixed dose of 20 mg everyday. Fluoxetine was prescribed in an open-label manner, and the sample size was limited.
Conclusions:  These observations support the findings of a low manic switch rate during SSRI monotherapy of BP II MDE, and suggest that fluoxetine monotherapy may be a safe and effective initial treatment of BP II MDE.     

Interpersonal psychotherapy for depression with panic spectrum symptoms: a pilot study

Patients whose depression is complicated by a lifetime history of panic symptoms display a poorer treatment response to both psychotherapeutic and pharmacologic interventions. A newly adapted psychosocial treatment for depression with lifetime panic spectrum symptoms was evaluated in an open pilot study.     

重性抑郁障碍或双相障碍患者抑郁发作伴随躁狂症状的临床特征

目的:了解重性抑郁障碍(MDD)或双相障碍抑郁发作患者出现躁狂症状的频率和程度。方法:对52例经简明国际神经精神访谈(MINI)、符合《美国精神障碍诊断与统计手册》第4版(DSMIV)重性抑郁障碍或双相障碍抑郁发作的患者,采用情感障碍评估量表(ADE)评估患者本次抑郁发作中出现的躁狂症状。结果:52例患者中有36例重性抑郁障碍,16例为双相障碍抑郁发作。至少有1条躁狂症状的患者达86.5%(n=45),至少有3条躁狂症状的患者占32.7%(n=17),而没有任何躁狂症状的患者仅占13.5%(n=7)。结论:抑郁发作患者大多存在不同程度的躁狂症状,及时识别这些症状,对诊断与治疗有指导意义。情感障碍评估量表是一个值得应用的评估情感发作的工具。     

Inositol augmentation of lithium or valproate for bipolar depression

OBJECTIVE: Despite promising new therapies, bipolar depression remains difficult to treat. Up to half of patients do not respond adequately to currently approved treatments. This study evaluated the efficacy of adjunctive inositol for bipolar depression. METHODS: Seventeen participants with DSM-IV criteria for bipolar depression and a 17-item Hamilton Rating Scale for Depression (HRSD) > or =15 on proven therapeutic levels of lithium or valproate for >2 weeks were randomized to receive double-blind inositol or placebo for 6 weeks. At the end of double-blind treatment, subjects were eligible for an 8-week open-label trial of inositol. RESULTS: Response was defined a priori as >50% reduction in the HRSD and a Clinical Global Impression of 1-2. Four of nine subjects (44%) on inositol and zero of eight subjects on placebo met response criteria (p = 0.053). There was no difference between groups in the average change score for the HRSD or Young Mania Rating Scale (YMRS). Response to inositol was highly variable. Of nine subjects randomized to inositol, two had >50% worsening in HRSD scores at the end of treatment, three had no change and four had >50% improvement. Those who had worsening in depressive symptoms on inositol had significantly higher scores at baseline on the YMRS total score and irritability, disruptive/aggressive behavior and unkempt appearance items. CONCLUSIONS: There was a trend for more subjects on inositol to show improvement in bipolar depression symptoms, but, on average, inositol was not more effective than placebo as an adjunct for bipolar depression. Baseline levels of anger or hostility may be predictive of clinical response to inositol.     

双相情感障碍抑郁相与单相抑郁发作临床分析

目的:对双相情感障碍抑郁相和单相抑郁发作进行临床分析。方法:对双相情感障碍抑郁相和单相抑郁发作患者各30例进行临床分析。结果:双相情感障碍抑郁相有如下特点:①发病年龄早;②女性多见;③具有“精力过盛”性人格;④一级亲属中有双相障碍的家族史;⑤症状多为非典型抑郁发作或伴有精神病性症状。结论:如首次抑郁发作的症状符合以上特点,则可能以后发展为双相情感障碍,应使用足量心境稳定剂,谨慎使用抗抑郁剂,以免转为躁狂发作。     

Inositol as an add-on treatment for bipolar depression

Objective: Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood–brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression.

Methods: Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I=21; bipolar II=3) were randomly assigned to receive either 12 g of inositol or d -glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged.

Results: Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically non-significant difference. On the Montgomery–Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p=0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered.

Conclusions: These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.     

Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy

Amsterdam JD, Wang G, Shults J. Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Objective: We examine the safety and efficacy of venlafaxine monotherapy in bipolar type II (BP II) patients with major depressive episode (MDE) who were unresponsive to prior lithium monotherapy. We hypothesized that venlafaxine would be superior to lithium with a low hypomanic conversion rate. Method: Seventeen patients who were unresponsive to prior lithium monotherapy were crossed to venlafaxine monotherapy for 12 weeks. The primary outcome was within‐subject change in total Hamilton Depression Rating (HAM‐D) score over time. Secondary outcomes included the change in Young Mania Rating (YMRS) and clinical global impressions severity (CGI/S) and change (CGI/C) scores. Results: Venlafaxine produced significantly greater reductions in HAM‐D (P < 0.0005), CGI/S (P < 0.0005), and CGI/C (P < 0.0005) scores vs. prior lithium. There was no difference in mean YMRS scores between treatment conditions (P = 0.179). Conclusion: Venlafaxine monotherapy may be a safe and effective monotherapy of BP II MDE with a low hypomanic conversion rate in lithium non‐responders.