Novel therapeutic targets for bipolar disorder

2017 ◽  
Author(s):  
Ioline D. Henter ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Mood Disorders ◽  
Bipolar Depression ◽  
Nmda Antagonist ◽  
Excitatory Neurotransmitter ◽  
Residual Symptoms ◽  
Antidepressant Effects ◽  
The Central Nervous System ◽  
Depressive Episodes

The long-term course of bipolar disorder (BD) comprises recurrent depressive episodes and persistent residual symptoms for which standard therapeutic options are scarce and often ineffective. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders and in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in major depressive disorder (MDD) and BD. This chapter reviews the clinical evidence supporting the use of novel glutamate receptor modulators for treating BD—particularly bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics.

scholarly journals Magnetic Seizure Therapy for Unipolar and Bipolar Depression: A Systematic Review

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Eric Cretaz ◽  
André R. Brunoni ◽  
Beny Lafer
Keyword(s):  
Bipolar Disorder ◽  
Side Effects ◽  
Mood Disorders ◽  
Bipolar Depression ◽  
Eligibility Criteria ◽  
Magnetic Seizure Therapy ◽  
Antidepressant Effects ◽  
Depressive Episodes ◽  
Cognitive Side Effects ◽  
Review Current

Objective. Magnetic seizure therapy (MST) is a novel, experimental therapeutic intervention, which combines therapeutic aspects of electroconvulsive therapy (ECT) and transcranial magnetic stimulation, in order to achieve the efficacy of the former with the safety of the latter. MST might prove to be a valuable tool in the treatment of mood disorders, such as major depressive disorder (MDD) and bipolar disorder. Our aim is to review current literature on MST.Methods. OVID and MEDLINE databases were used to systematically search for clinical studies on MST. The terms “magnetic seizure therapy,” “depression,” and “bipolar” were employed.Results. Out of 74 studies, 8 met eligibility criteria. There was considerable variability in the methods employed and samples sizes were small, limiting the generalization of the results. All studies focused on depressive episodes, but few included patients with bipolar disorder. The studies found reported significant antidepressant effects, with remission rates ranging from 30% to 40%. No significant cognitive side effects related to MST were found, with a better cognitive profile when compared to ECT. Conclusion. MST was effective in reducing depressive symptoms in mood disorders, with generally less side effects than ECT. No study focused on comparing MST to ECT on bipolar depression specifically.

Antidepressant Effects of Atypical Antipsychotics

CNS Spectrums ◽  
2003 ◽  
Vol 8 (S12) ◽  
pp. 6-8
Author(s):  
Roy H. Perlis
Keyword(s):  
Atypical Antipsychotics ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Case Series ◽  
Depression Score ◽  
Antidepressant Effects ◽  
Open Treatment ◽  
Depressive Episodes ◽  
Hamilton Rating Scale

Studies have shown that there is some efficacy for a number of agents, most notably lithium, in treating bipolar depression. However, the studies also highlight the unfortunate reality that many patients fail to respond adequately to first-line therapies and that there is a need to identify additional options for patients and clinicians. The atypical antipsychotics clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole, have been the focus of increased interest in the treatment of bipolar depression.The use of antipsychotics in the treatment of depressive episodes is not a particularly novel idea. In 1982, Robertson and Trimble reviewed 34 studies examining the use of typical antipsychotics to augment an antidepressant and noticed modest but generally consistent benefits. More widespread use of these agents in the management of depression has been limited, however, because of concerns about the long-term risk of tardive dyskinesia and the induction of extrapyramidal symptoms that often mimic depressive symptoms.Clozapine, the first of the atypicals, was applied initially in the treatment of schizophrenia and schizoaffective disorder, where antidepressant effects were noted during open treatment. Subsequent case series described some benefit in dysphoric manias in bipolar disorder as well.Much of the inditect evidence for antidepressant effects of the atypicals came from studies in major depressive disorder (MDD). For example, a series of eight patients with MDD who failed treatment with a selective serotonin reuptake inhibitor (SSRI) achieved marked and rapid response when risperidone was added to the SSRI. All patients remitted within 1 week; Hamilton Rating Scale for Depression score in these patients declined from a mean of 20.5 to a mean of 2.4 (Slide 11). A subsequent series of 30 patients yielded similar results.

JS01-04 - Rational optimization of bipolar disorders’ treatment

2011 ◽  
Vol 26 (S2) ◽  
pp. 1998-1998
Author(s):  
E. Vieta
Keyword(s):  
Bipolar Disorder ◽  
Healthy Lifestyle ◽  
Bipolar Depression ◽  
Treatment Options ◽  
Bipolar Disorders ◽  
Mood Stabilizer ◽  
Evidence Base ◽  
Term Therapy ◽  
Depressive Episodes

Bipolar disorder is difficult to treat. There are several options to treat acute mania, but combination of two or more drugs is the rule rather than the exception, indicating the limitations of currently available therapies. The evidence base for the treatment of bipolar depression is much weaker, and again combination is the rule. Although patients with bipolar disorder may experience resolution of symptoms with acute treatment, many will continue to experience impaired functioning due to the episodic, chronic, and progressive nature of the illness. Maintenance therapy is needed for a variety of reasons, including prevention of relapse, reduction of subthreshold symptoms, decreasing the risk of suicide, and reducing the frequency of rapid cycling and mood instability. Although long-term therapy is usually required to maintain or improve functioning and quality of life, it has been a significant challenge to identify clinically effective treatments for long-term management. There are few currently-available, well-tolerated treatment options that are effective in all phases of bipolar disorder and which prevent recurrence of manic and/or depressive episodes. Questions concerning when to discontinue one of the drugs when two or more are used, or how to switch from one mood stabilizer to another, have not been addressed in clinical trials. Electroconvulsive therapy may be effective in treatment resistant cases and can be used as maintenance when pharmacotherapy is not enough. Psychoeducation may help to enhance treatment adherence and healthy lifestyle. A rational combination of the above mentioned strategies may help to optimize the outcome of this challenging condition.

Rethinking the Treatment Paradigm for Bipolar Depression: The Importance of Long-Term Management

CNS Spectrums ◽  
2004 ◽  
Vol 9 (S9) ◽  
pp. 11-18 ◽  
Author(s):  
Claudia F. Baldassano ◽  
Christos A. Ballas ◽  
John P. O'Reardon
Keyword(s):  
Bipolar Disorder ◽  
Maintenance Therapy ◽  
Bipolar Depression ◽  
Open Label ◽  
Randomized Controlled Studies ◽  
Treatment Paradigm ◽  
Bipolar Patients ◽  
Depressive Episodes ◽  
Term Management

ABSTRACT:The need for long-term management of bipolar disorder is evident. Bipolar patients spend more time depressed than manic; however, few agents used for maintenance therapy of bipolar disorder have demonstrated good efficacy in delaying relapse into depression. This article provides a comprehensive review of open-label and randomized, controlled studies examining prophylactic efficacy in bipolar disorder, especially bipolar depression. Lithium, considered the gold standard for bipolar disorder maintenance therapy may be more effective in delaying manic relapse than in delaying depressive relapse. Evidence for the efficacy of divalproex and carbamazepine in delaying depressive relapse is yet to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time to depressive relapse. Unpublished studies show ohnzapine's efficacy in preventing manic recurrence, while its efficacy in preventing depressive recunence is yet to be proven. As patients with bipohr disorder are prone to experiencing depressive episodes, more attention needs to be focused on preventing depressive relapse. To date, three agents—lithium, lamotrigine, and olanzapine—have been shown to have prophylactic benefits in treating this highly recunent disorder.

scholarly journals Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Maximilian Pilhatsch ◽  
Thomas J Stamm ◽  
Petra Stahl ◽  
Ute Lewitzka ◽  
Anne Berghöfer ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Phenotypic Expression ◽  
Anxiety Symptoms ◽  
Controlled Study ◽  
Double Blind ◽  
Comorbid Anxiety ◽  
Depressed Patients ◽  
Depressive Episodes

Abstract Background Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression. Methods Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI). Results Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877). Conclusions This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839

Bipolar disorder and comorbid obsessive-compulsive disorder is associated with higher rates of anxiety and impulse control disorders

2010 ◽  
Vol 22 (2) ◽  
pp. 81-86 ◽  
Author(s):  
Cilly Klüger Issler ◽  
Emel Serap Monkul ◽  
José Antonio de Mello Siqueira Amaral ◽  
Renata Sayuri Tamada ◽  
Roseli Gedanke Shavitt ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Obsessive Compulsive Disorder ◽  
Impulse Control ◽  
Severe Form ◽  
Impulse Control Disorders ◽  
Tic Disorders ◽  
Obsessive Compulsive ◽  
Residual Symptoms ◽  
Compulsive Disorder ◽  
Depressive Episodes

Issler CK, Monkul ES, Amaral JAMS, Tamada RS, Shavitt RG, Miguel EC, Lafer B. Bipolar disorder and comorbid obsessive-compulsive disorder is associated with higher rates of anxiety and impulse control disorders.Objective:Although bipolar disorder (BD) with comorbid obsessive-compulsive disorder (OCD) is highly prevalent, few controlled studies have assessed this comorbidity. The objective of this study was to investigate the clinical characteristics and expression of comorbid disorders in female BD patients with OCD.Method:We assessed clinically stable female outpatients with BD: 15 with comorbid OCD (BD+OCD group) and 15 without (BD/no-OCD group). All were submitted to the Structured Clinical Interview for DSM-IV, with additional modules for the diagnosis of kleptomania, trichotillomania, pathological gambling, onychophagia and skin picking.Results:The BD+OCD patients presented more chronic episodes, residual symptoms and previous depressive episodes than the BD/no-OCD patients. Of the BD+OCD patients, 86% had a history of treatment-emergent mania, compared with only 40% of the BD/no-OCD patients. The following were more prevalent in the BD+OCD patients than the BD/no-OCD patients: any anxiety disorder other than OCD; impulse control disorders; eating disorders; and tic disorders.Conclusion:Female BD patients with OCD may represent a more severe form of disorder than those without OCD, having more depressive episodes and residual symptoms, and being at a higher risk for treatment-emergent mania, as well as presenting a greater anxiety and impulse control disorder burden.

scholarly journals Age at onset, course of illness and response to psychotherapy in bipolar disorder: results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

2014 ◽  
Vol 44 (16) ◽  
pp. 3455-3467 ◽  
Author(s):  
A. Peters ◽  
L. G. Sylvia ◽  
P. V. da Silva Magalhães ◽  
D. J. Miklowitz ◽  
E. Frank ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Collaborative Care ◽  
Bipolar Depression ◽  
Age At Onset ◽  
Number Needed To Treat ◽  
Systematic Treatment ◽  
Illness Duration ◽  
Bipolar Patients ◽  
Depressive Episodes ◽  
Intensive Psychotherapy

Background.The course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients' prior courses of illness are related to responses to psychotherapy.Method.Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy with collaborative care (a three-session psycho-educational intervention). We assessed whether the number of previous mood episodes, age of illness onset, and illness duration predicted or moderated the likelihood of recovery and time until recovery from a depressive episode in patients in the two treatments.Results.Independently of treatment condition, participants with one to nine prior depressive episodes were more likely to recover and had faster time to recovery than those with 20 or more prior depressive episodes. Participants with fewer than 20 prior manic episodes had faster time to recovery than those with 20 or more episodes. Longer illness duration predicted a longer time to recovery. Participants were more likely to recover in intensive psychotherapy than collaborative care if they had 10–20 prior episodes of depression [number needed to treat (NNT) = 2.0], but equally likely to respond to psychotherapy and collaborative care if they had one to nine (NNT = 32.0) or >20 (NNT = 9.0) depressive episodes.Conclusions.Number of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression.

scholarly journals Repetitive transcranial magnetic stimulation in the treatment of bipolar disorder

2020 ◽  
Vol 10 ◽  
pp. 204512532097379
Author(s):  
Danielle Hett ◽  
Steven Marwaha
Keyword(s):  
Bipolar Disorder ◽  
Transcranial Magnetic Stimulation ◽  
Side Effects ◽  
Magnetic Stimulation ◽  
Sleep Problems ◽  
Bipolar Depression ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Controlled Trial ◽  
Total N ◽  
Depressive Episodes

Bipolar disorder (BD) is a debilitating mood disorder marked by manic, hypomanic and/or mixed or depressive episodes. It affects approximately 1–2% of the population and is linked to high rates of suicide, functional impairment and poorer quality of life. Presently, treatment options for BD are limited. There is a strong evidence base for pharmacological (e.g., lithium) and psychological (e.g., psychoeducation) treatments; however, both of these pose challenges for treatment outcomes (e.g., non-response, side-effects, limited access). Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, is a recommended treatment for unipolar depression, but it is unclear whether rTMS is an effective, safe and well tolerated treatment in people with BD. This article reviews the extant literature on the use of rTMS to treat BD across different mood states. We found 34 studies in total ( N = 611 patients), with most assessing bipolar depression ( n = 26), versus bipolar mania ( n = 5), mixed state bipolar ( n = 2) or those not in a current affective episode ( n = 1). Across all studies, there appears to be a detectable signal of efficacy for rTMS treatment, as most studies report that rTMS treatment reduced bipolar symptoms. Importantly, within the randomised controlled trial (RCT) study designs, most reported that rTMS was not superior to sham in the treatment of bipolar depression. However, these RCTs are based on small samples ( NBD ⩽ 52). Reported side effects of rTMS in BD include headache, dizziness and sleep problems. Ten studies ( N = 14 patients) reported cases of affective switching; however, no clear pattern of potential risk factors for affective switching emerged. Future adequately powered, sham-controlled trials are needed to establish the ideal rTMS treatment parameters to help better determine the efficacy of rTMS for the treatment of BD.

Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data

CNS Spectrums ◽  
2005 ◽  
Vol 10 (6) ◽  
pp. 1-2 ◽  
Author(s):  
Terence A. Ketter ◽  
David L. Ginsberg ◽  
Hagop S. Akiskal ◽  
Paul E. Keck ◽  
Richard H. Weisler ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Weight Gain ◽  
Drug Interactions ◽  
Bipolar Depression ◽  
Panel Discussion ◽  
Current Data ◽  
Clinical Implications ◽  
Good Tolerability ◽  
Long Term Treatment

AbstractThis monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S1) ◽  
pp. 1-2 ◽  
Keyword(s):  
Bipolar Disorder ◽  
Weight Gain ◽  
Drug Interactions ◽  
Bipolar Depression ◽  
Panel Discussion ◽  
Current Data ◽  
Clinical Implications ◽  
Good Tolerability ◽  
Long Term Treatment

ABSTRACTThis monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight. *) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

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