Marine omega-3 fatty acids and mood disorders--linking the sea and the soul. 'Food for Thought' I

Hegarty BD, Parker GB. Marine omega‐3 fatty acids and mood disorders – linking the sea and the soul. Objective: While there has long been interest in any nutritional contribution to the onset and treatment of mood disorders, there has been increasing scientific evaluation of several candidate nutritional and dietary factors in recent years. In this inaugural study of our ‘Food for Thought’ series, we will overview the evidence for any role of omega‐3 fatty acids (FA) in regulating mood. Method: Relevant literature was identified through online database searches and cross‐referencing. Results: Plausible mechanisms exist by which omega‐3 FA may influence neuronal function and mood. Cross‐sectional studies demonstrate an association between omega‐3 fatty acid deficiency and both depressive and bipolar disorders. Studies investigating the efficacy of omega‐3 fatty acid supplementation for mood disorders have however provided inconsistent results. The proportion of treatment studies showing a significant advantage of omega‐3 supplementation has dropped over the last 5 years. However, the vast heterogeneity of the trials in terms of constituent omega‐3 FAs, dose and length of treatment makes comparisons of these studies difficult. Conclusion:  More research is required before omega‐3 supplementation can be firmly recommended as an effective treatment for mood disorders. Whereas increased omega‐3 FA intake may alleviate depressive symptoms, there is little evidence of any benefit for mania.     

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.     

Why antidepressants are not antidepressants: STEP‐BD,STAR*D,and the return of neurotic depression

The widely held clinical view of ‘antidepressants’ as highly effective and specific for the treatment of all types of depressive disorders is exaggerated. This sobering conclusion is supported by recent findings from the NIMH‐sponsored STEP‐BD and STAR*D projects. Antidepressants have limited short‐term efficacy in unipolar depressive disorders and less in acute bipolar depression; their long‐term prophylactic effectiveness in recurrent unipolar major depression remains uncertain, and is doubtful in recurrent bipolar depression. These limitations may, in part, reflect the excessively broad concept of major depression as well as unrealistic expectations of universal efficacy of drugs considered ‘antidepressants.’ Treatment‐refractory depression may reflect failure to distinguish depressive conditions, particularly bipolar disorder, that are inherently less responsive to antidepressants. Antidepressants probably should be avoided in bipolar depression, mixed manic‐depressive states, and in neurotic depression. Expectations of antidepressants for specific types of patients with symptoms of depression or anxiety require critical re‐evaluation. A revival of the concept of neurotic depression would make it possible to identify patients with mild‐to‐moderate, chronic or episodic dysthymia and anxiety who are unlikely to benefit greatly from antidepressants. Diagnostic criteria for a revival of the concept of neurotic depression are proposed.     

Anticonvulsants in bipolar disorder.

In recent years, a number of anticonvulsants have been more rigorously investigated for their potential mood-stabilizing properties. They are heterogeneous in their mechanisms of action and in their efficacy in the various mood states in bipolar illness (Table 3). At present, evidence from well-controlled studies supports the role of DIV and CBZ in the treatment of acute mania. DIV seems to have better efficacy than lithium in mixed mania or mania associated with depressive symptoms and is recommended as a first-line pharmacologic option in acutely manic or mixed manic patients. Neither CBZ nor DIV have robust evidence supporting their efficacy in the treatment of acute bipolar depression, although DIV clearly possesses beneficial effects on depressive symptomatology and prophylaxis against depressive episodes during long-term treatment. Results from a large study indicate that LAM has significant efficacy in bipolar depression without the associated risks of cycle acceleration or manic/hypomanic switches. LAM should be considered a primary option in patients with bipolar depression and in bipolar II patients with rapid cycling. DIV is recommended as a first-line option in bipolar I patients with rapid cycling. LAM has proven efficacy in the prophylaxis of bipolar I disorder and should be considered along with lithium or DIV as treatment of choice in the long-term management of bipolar disorder. For the other anticonvulsants, including CBZ and OXC, there is still inadequate evidence of efficacy as monotherapy in the long-term management of bipolar disorder. Even less data exist for other available AEDs, and consensus is growing that someAEDs (eg, GBP) have little or no specific effect in bipolar disorder. Despite the progress made in the past decade, a wider therapeutic armamentarium is critically needed, because a large proportion of bipolar patients do not respond to acute treatments during a manic or depressive episode and have frequent relapse and recurrences during long-term treatment. As additional AEDs become available, rigorously designed and large-scale studies examining AEDs as monotherapy and AEDs in combination therapies versus placebo must be undertaken to assess efficacy and safety more adequately to provide better guidance for the clinician faced with the management of this challenging mood disorder.     

Alternatives to antidepressants in treating acute bipolar depression

Major depressive episodes and subsyndromal depressive symptoms are associated with significant psychosocial impairment for patients with bipolar disorder. However, insufficient evidence exists to support the efficacy of antidepressants for treating bipolar depression. Alternative pharmacotherapies have been approved for the treatment of bipolar depressive episodes, and adjunctive psychosocial interventions have proven efficacy when used with pharmacotherapy.     

A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders

Mantere O, Isometsä E, Ketokivi M, Kiviruusu O, Suominen K, Valtonen HM, Arvilommi P, Leppämäki S. A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders.
Bipolar Disord 2010: 12: 271–284. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To test two hypotheses of psychiatric comorbidity in bipolar disorder (BD): (i) comorbid disorders are independent of BD course, or (ii) comorbid disorders associate with mood. Methods: In the Jorvi Bipolar Study (JoBS), 191 secondary‐care outpatients and inpatients with DSM‐IV bipolar I disorder (BD‐I) or bipolar II disorder (BD‐II) were evaluated with the Structured Clinical Interview for DSM‐IV Disorders, with psychotic screen, plus symptom scales, at intake and at 6 and 18 months. Three evaluations of comorbidity were available for 144 subjects (65 BD‐I, 79 BD‐II; 76.6% of 188 living patients). Structural equation modeling (SEM) was used to examine correlations between mood symptoms and comorbidity. A latent change model (LCM) was used to examine intraindividual changes across time in depressive and anxiety symptoms. Current mood was modeled in terms of current illness phase, Beck Depression Inventory (BDI), Young Mania Rating Scale, and Hamilton Depression Rating Scale; comorbidity in terms of categorical DSM‐IV anxiety disorder diagnosis, Beck Anxiety Inventory (BAI) score, and DSM‐IV‐based scales of substance use and eating disorders. Results: In the SEM, depression and anxiety exhibited strong cross‐sectional and autoregressive correlation; high levels of depression were associated with high concurrent anxiety, both persisting over time. Substance use disorders covaried with manic symptoms (r = 0.16–0.20, p < 0.05), and eating disorders with depressive symptoms (r = 0.15–0.32, p < 0.05). In the LCM, longitudinal intraindividual improvements in BDI were associated with similar BAI improvement (r = 0.42, p < 0.001). Conclusions: Depression and anxiety covary strongly cross‐sectionally and longitudinally in BD. Substance use disorders are moderately associated with manic symptoms, and eating disorders with depressive mood.     

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.     

Lithium and anticonvulsants in bipolar depression

For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder.     

Challenges in the diagnosis and treatment of pediatric bipolar depression

There has been great public and academic interest in the diagnosis and treatment of bipolar disorders (BD) in children and adolescents over the past decade, originally in the US, but now extending internationally. Much of the interest in pediatric BD has focused on the unique manifestation of mania in younger populations. Depression is often overlooked, both as a topic, and as a clinical reality, in these children. While it is becoming clear that adults with BD spend the majority of their symptomatic time in depressive rather than manic episodes, less is known about the pediatric experience of bipolar depression. However, children and adolescents with BD clearly do experience significant depressive symptoms as well as depressive episodes, and therefore early recognition and treatment is necessary. This review addresses what is known about the prevalence, presentation, and treatment of depressive symptoms and episodes in youth with BD, and includes a discussion about the recognition and treatment of bipolar depressive episodes that occur before the first manic episode.     

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.     

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.     

The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) who have rapid cycling features are often treatment refractory. Clear and conclusive evidence regarding effective treatments for this group is not available. METHODS: Patients with diagnoses of refractory bipolar disorder who were currently experiencing manic, mixed, depressive, or hypomanic episodes were treated with lamotrigine as add-on therapy (60 patients) or monotherapy (15 patients). We compared the efficacy of lamotrigine in the 41 rapid cycling and 34 non-rapid cycling patients with BD. RESULTS: Improvement from baseline to last visit was significant among both rapid cycling and non-rapid cycling patients for both depressive and manic symptomatology. For patients entering the study in a depressive episode, improvement in depressive symptomatology was equivalent in the two groups. Among patients entering the study in a manic, mixed, or hypomanic episode, those with rapid cycling improved less in manic symptomatology than did non-rapid cycling patients. Among rapid cycling patients with initial mild-to-moderate manic symptom severity, improvement was comparable to that in non-rapid cycling subjects; however, the subset of rapid cycling patients with severe initial manic symptomatology had little improvement in mania. Rapid cycling patients had earlier onset and more lifetime episodes of mania, depression, and mixed mania. CONCLUSIONS: Lamotrigine was generally effective and well tolerated in this group of previously non-responsive, rapid cycling bipolar patients.     

Mental Health Collaborative Care and its Role in Primary Care Settings

Bipolar depression is considered the most difficult-to-treat phase of bipolar disorder, in relation to its pervasiveness and efficacy and/or tolerability limitations of available treatments. Indeed, most mood stabilizers and atypical antipsychotics are not as effective in ameliorating depressive compared with manic symptoms, and entail substantial tolerability limitations. However, the use of antidepressants is highly controversial, as their efficacy appears less robust in bipolar compared with unipolar depression. In addition, antidepressants, in spite of generally having adequate somatic tolerability, in BD may be associated with a higher risk of manic/hypomanic switch, suicidality and rapid cycling. Among alternative pharmacological strategies, compounds with stimulant and pro-dopaminergic effects, such as methylphenidate, modafinil, armodafinil and pramipexole, have showed potential antidepressant activity, even though their use in clinical practice has been limited by the paucity of controlled evidence. This article seeks to review available evidence about the use of the aforementioned compounds in the treatment of bipolar depression. Findings from reviewed studies suggested that pro-dopaminergic compounds, such as pramipexole and stimulants/stimulant-like agents, deserve consideration as adjunctive therapies in bipolar depressed patients, at least in some subgroups of patients. Nevertheless, caution regarding their use is recommended as further clinical trials with larger samples and longer follow-up periods are necessary to clarify the roles of these medications in bipolar depression.     

Depression in bipolar disorder versus major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions

Moreno C, Hasin DS, Arango C, Oquendo MA, Vieta E, Liu S, Grant BF, Blanco C. Depression in bipolar disorder versus major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Bipolar Disord 2012: 14: 271–282. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: To compare the clinical features and course of major depressive episodes (MDEs) occurring in subjects with bipolar I disorder (BD‐I), bipolar II disorder (BD‐II), and major depressive disorder (MDD). Methods: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (2001–2002), a nationally representative face‐to‐face survey of more than 43000 adults in the USA, including 5695 subjects with lifetime MDD, 935 with BD‐I and lifetime MDE, and 494 with BD‐II and lifetime MDE. Differences on sociodemographic characteristics and clinical features, course, and treatment patterns of MDE were analyzed. Results: Most depressive symptoms, family psychiatric history, anxiety disorders, alcohol and drug use disorders, and personality disorders were more frequent—and number of depressive symptoms per MDE was higher—among subjects with BD‐I, followed by BD‐II, and MDD. BD‐I individuals experienced a higher number of lifetime MDEs, had a poorer quality of life, and received significantly more treatment for MDE than BD‐II and MDD subjects. Individuals with BD‐I and BD‐II experienced their first mood episode about ten years earlier than those with MDD (21.2, 20.5, and 30.4 years, respectively). Conclusions: Our results support the existence of a spectrum of severity of MDE, with highest severity for BD‐I, followed by BD‐II and MDD, suggesting the utility of dimensional assessments in current categorical classifications.     

Emerging roles of new antipsychotics in bipolar disorders

Recent years have seen the emergence of important new treatment options for bipolar disorders (BD), including new anticonvulsants and antipsychotics. New antipsychotics have displaced older ones, based on their superior tolerability, and emerging evidence of efficacy in BD. All new antipsychotics, including risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, have recent placebo-controlled data showing acute mania efficacy. Data demonstrating olanzapine efficacy in acute BD depression and utility in longer-term treatment of BD are emerging. Taken together, the wealth of new data suggesting BD efficacy with new antipsychotics suggest that these agents as a class will have an increasingly important role in the management of BD. Additional research should help determine the validity of this notion.     

Assessing bipolar disorder in the older adult: the GERI‐BD toolbox

Introduction

The evidence base regarding characteristics of older adults with bipolar disorder (BD) remains limited. The NIH‐funded multicenter study Acute Pharmacotherapy of Late‐Life Mania (GERI‐BD) assessed various clinical domains before and during mood stabilizer treatment in older adults participating in a 9‐week, double‐blind randomized controlled trial. We describe the rationale for selecting these instruments.

Methods

Domains and instruments were selected on the basis of the study design and the participants. The investigators' experience in clinical trials involving young adults with BD or older adults with major depressive disorder, along with open studies of older adults with BD, contributed to the selection process.

Results

We identified domains and selected instruments that could be used to assess the participants given their diagnostic, treatment history, and medical and mood state characteristics. They were also intended to measure tolerability and efficacy and permit examination of potential moderating and mediating factors.

Conclusions

Decisions regarding the assessment domains to be included in the clinical trial highlight the challenges facing researchers studying drug treatments for older adults with BD, or more generally, mood disorders. We suggest that the domains and instruments selected by GERI‐BD investigators constitute a “toolbox” that can be customized for other investigators. Copyright © 2017 John Wiley & Sons, Ltd.     

Antidepressant-associated switches from depression to mania in severe bipolar disorder

OBJECTIVES: To determine whether switching from depression to mania is part of the natural history of bipolar illness or results from antidepressant (AD) treatment by examining bipolar patients with psychosis early in their illness course. METHODS: A multi-facility cohort of 123 first-admission inpatients, aged 15-60 years, with DSM-IV bipolar disorder (BD) with psychotic features, was followed for four years, and 76 individuals experienced at least one episode of depression. Frequency of and risk factors for switches from depression to mania, time to switch, and duration of the subsequent manic episode were examined in relation to AD use (with anti-manic and/or antipsychotic medications). RESULTS: The 76 respondents experienced 113 depressive episodes. Those prescribed ADs had more depressive episodes and spent more time depressed than non-users. A total of 23 depressive episodes in 17 respondents ended in a manic/hypomanic/mixed episode (20%). The time to switch and duration of the subsequent manic episode were not significantly different for the seven respondents and nine episodes involving AD treatment versus the 10 respondents and 14 episodes without ADs. None of the risk factors (age of onset 相似文献   

Discriminating primary clinical states in bipolar disorder with a comprehensive symptom scale

Objective: We assessed the spectrum and severity of bipolar symptoms that differentiated bipolar disorder (BD) clinical states, employing the Bipolar Inventory of Symptoms Scale (BISS) which provides a broader item range of traditional depression and mania rating scales. We addressed symptoms differentiating mixed states from depression or mania/hypomania. Method: One hundred and sixteen subjects who met DSM‐IV‐TR criteria for BD and were currently in a depressed, manic/hypomanic, mixed episode, or recovered state were interviewed using the BISS. Results: A subset of manic items differed between mixed episodes and mania/hypomania or depression. Most anxiety items were more severe in mixed subjects. BISS Depression and Manic subscales differentiated episodes from recovered status. The majority of depression and manic symptoms differentiated mood states in the predicted direction. Mixed episodes had overall greater mood severity than manic/hypomanic episodes or depressed episodes. Conclusion: These results indicate that a small subset of symptoms, several of which are absent in DSM‐IV‐TR criteria and traditional rating scales for bipolar studies, aid in distinguishing mixed episodes from depressive or manic/hypomanic episodes. The results also support the utility of a comprehensive BD symptom scale in distinguishing primary clinical states of BD.     

Brain stimulation treatments in bipolar disorder: A review of the current literature

Objectives. Brain stimulation techniques are non-pharmacologic strategies which offer additional therapeutic options for treatment-resistant depression (TRD). The purpose of this paper is to review the current literature regarding the use of brain stimulation in resistant bipolar disorder (BD), with particular reference to hypomanic/manic symptoms. Methods. Keywords pertaining to the brain simulation techniques used in the treatment of depression (either unipolar or bipolar) along with their role in regard to hypomanic/manic symptoms were used to conduct an electronic search of the literature. Pertinent findings were identi?ed by the authors and reviewed. Results. Brain stimulation techniques represent a valid therapeutic option in TRD. They have been extensively studied in unipolar depression and, to a minor extent, in the depressive phase of BD, showing encouraging but often limited results. With exception of electroconvulsive therapy, the efficacy of brain stimulation in the treatment of manic symptoms of bipolar patients is still uncertain and needs to be fully evaluated. Conclusions. Brain stimulation in BD is derived from its use in unipolar depression. However, there are many important differences between these two disorders and more studies with a systematic approach need to be conducted on larger samples of bipolar patients with treatment-resistant characteristics.