Combination Of Mood Stabilizers Research Articles

Treatment-resistant bipolar disorder

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.

P.2.e.009 Body weight changes in patients with acute mania treated with combination of mood stabilizer and atypical antipsychotic or typical antipsychotic

P.2.e.009 Body weight changes in patients with acute mania treated with combination of mood stabilizer and atypical antipsychotic or typical antipsychotic

Long-Term Combination Therapy Versus Monotherapy With Lithium and Carbamazepine in 46 Bipolar I Patients

Despite wide clinical use of mood-stabilizer combinations for long-term treatment of patients with bipolar disorder, research on risks and benefits of this practice is limited. We found 14 small, usually brief, clinical trials of maintenance treatment with lithium plus carbamazepine. These trials suggest added benefit of combination treatment over use of either agent alone but also indicate the need for further studies. In a post hoc analysis, we reviewed the course of 46 patients with DSM-IV-diagnosed bipolar I disorder identified as not improving during long-term monotherapy in a mood disorders clinic, comparing days per year hospitalized in 3 consecutive time periods: before prophylactic treatment, during monotherapy with lithium (N = 31) or carbamazepine (N = 15), and during their combined use (N = 46). Secondary outcome measures were rates of hospitalization, time to first recurrence of an affective episode, use of adjunctive treatments, and adverse effects. We compared outcomes with nonparametric bivariate methods and tested predictive factors by multiple regression. Subjects showed significant reductions in hospitalized days per year during combination therapy, averaging a decrease of 55.9% (p = .004). Among secondary outcomes, hospitalizations per year fell by 36.1%, and median time to recurrence nearly doubled during combination therapy. Rates of adverse effects increased 2.5-fold, compared with monotherapy, and use of adjunctive psychotropic agents increased by 21.9%. Combining lithium with carbamazepine yielded substantial benefit but more adverse effects.

P.1.040 Combination of mood stabilizer with quetiapine for treatment of acute bipolar disorder: An open label study

P.1.040 Combination of mood stabilizer with quetiapine for treatment of acute bipolar disorder: An open label study

Obsessive-Compulsive–Bipolar Comorbidity

Notwithstanding the emerging literature on comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorder, relatively few systematic data exist on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice. The sample comprised 68 patients with comorbid DSM-IV diagnoses of OCD and major depressive episode admitted and treated at the day-hospital in the Department of Psychiatry at the University of Pisa (Pisa, Italy) during a 3-year period (January 1995-December 1998). Thirty-eight patients (55.8%) showed lifetime comorbid bipolar disorder (12 [31.6%] bipolar I and 26 [68.4%] bipolar II). Diagnoses and clinical features were collected by means of structured (Structured Clinical Interview for DSM-IV) and semistructured interviews (OCD-Interview). Assessments of drug treatments, clinical outcome, and adverse effects were made prospectively as part of routine clinical care throughout the course of their day-hospitalization. In contrast with non-bipolar OCD patients, OCD-bipolar patients showed a more episodic course with a greater number of concurrent major depressive episodes. They reported a significantly higher rate of sexual obsessions and significantly lower rate of ordering rituals. Furthermore, they reported more frequent current comorbidity with panic disorder-agoraphobia and abuse of different substances (alcohol, sedatives, nicotine, and coffee). Drug treatment with clomipramine and, to a lesser extent, with selective serotonin reuptake inhibitors was associated with hypomanic switches in OCD-bipolar patients, especially in those not concomitantly treated with mood stabilizers. A combination of multiple mood stabilizers was necessary in 16 OCD-bipolar patients (42.1%) and a combination of mood stabilizers with atypical antipsychotics was required in 4 cases (10.5%). OCD-bipolar patients tended to show a less positive outcome for mood symptomatology and general functioning. Three patients required hospitalization for severe mixed episode. In a tertiary care center, comorbidity between OCD and bipolar disorder is a significant clinical problem affecting a large number of patients and has a substantial impact on the clinical characteristics and treatment outcome of both disorders.

Treatment-resistant bipolar disorder.

Over the last few years, the number of potential pharmacotherapies for bipolar disorder has greatly expanded. Yet the database for virtually all these newer treatments consists of case reports and case series. Among these newer treatments, recently released anticonvulsants are most promising. Lamotrigine has already shown efficacy for treating bipolar depression, while gabapentin's efficacy has yet to be documented in a controlled study. Alone among its medication class, topiramate, another anticonvulsant, is associated with weight loss. Novel antipsychotics are effective in treating acute mania. With the exception of clozapine, their efficacy as true mood stabilizers is still unknown. Utilizing combinations of mood stabilizers is common and appropriate but demands knowledge of potential pharmacokinetic interactions. Other approaches for treatment resistant bipolar disorder include high-dose thyroid hormones, calcium channel blockers, electroconvulsive therapy, and omega-3 fatty acids. Finally, the efficacy of adjunctive psychosocial strategies is a topic of active investigation.

Short-term and long-term treatment for bipolar patients: beyond the guidelines

This clinical review considers the different symptomatic forms of bipolar disorders and the influence of the clinical subtype on treatment. Therapy is required both to manage the various types of acute episodes of mania or depression and to prevent recurrence. For the latter purpose, continuous long-term or even lifetime prophylaxis may be required, continuing on after control of the acute episode. In this context, the roles and potential side-effects of lithium, divalproex sodium and carbamazepine, alone and in combination, are summarized, along with the proper use of antipsychotic drugs. The selection of mood-stabilizing agent or drug combination depends on the clinical manifestations of bipolar disorder, family history and previous treatment history of the patient. Particular caution must be exercised in those with a history of antidepressant-induced switches; many such patients appear prone to course aggravation and even rapid-cycling and will often need combined mood-stabilizer combinations.

Mood Stabilizer Combinations for Bipolar Disorder

Back to table of contents Previous article Next article Letter to the EditorFull AccessMood Stabilizer Combinations for Bipolar DisorderR. WALTER LOVELL, M.D., R. WALTER LOVELLSearch for more papers by this author, M.D., Buckley, Wash.Published Online:1 Jun 1999https://doi.org/10.1176/ajp.156.6.980aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: The article by Marlene P. Freeman, M.D., and Andrew L. Stoll, M.D., on combinations of mood stabilizers for treatment of bipolar disorder (1) noted the potentially dangerous interaction of lamotrigine with valproate. Unfortunately, the authors failed to mention that the risk of severe and at times fatal rashes associated with lamotrigine is much higher in the pediatric population. Readers should have been reminded of the one in 50 to one in 100 chance of life-threatening rashes associated with the use of lamotrigine in children and adolescents under 16 years. The product information monograph bears a boxed warning emphasizing that lamotrigine is not approved for use in patients below the age of 16 years.

Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients.

Recent investigations have suggested that the antimanic agents divalproex sodium and carbamazepine may each hasten hospital discharge and be especially beneficial in treating mixed-state mania. This study retrospectively compared the time to remission for pure versus mixed manic bipolar inpatients who were taking lithium, divalproex, or carbamazepine, or their combination, under naturalistic conditions. Records were reviewed for 120 bipolar inpatients from 1991 to 1995. Research DSM-III-R diagnoses of pure or mixed mania were assigned along standardized guidelines. Data were obtained on daily symptoms, medication doses, and blood levels. Weekly improvement was evaluated by Kaplan-Meier survival analysis of Clinical Global Impressions scale scores. Variables associated with "remission" versus "nonremission" were examined by logistic regression. Mixed mania (N = 70) was more common than pure mania (N = 50). No significant differences were observed in the time to remission for mixed or pure manic bipolar patients who took lithium compared with those who took divalproex or carbamazepine. In patients who remained symptomatic with lithium as a single-agent mood stabilizer despite therapeutic serum lithium levels, the addition of a second mood stabilizer led to rapid symptom improvement. Among all medication subgroups, the speed with which patients achieved therapeutic blood levels of any of these agents significantly affected the time to remission. Mixed manic bipolar patients taking lithium, divalproex, or carbamazepine under naturalistic conditions remit at comparable rates. Those failing to respond to single-agent mood stabilizers often receive combinations of mood stabilizers. However, delays in optimizing a medication regimen may attenuate short-term outcome, regardless of the mood stabilizer selected. Rapid achievement of therapeutic blood levels of any antimanic agent appears to be strongly related to swift symptom remission.

Mood stabilizer combinations: a review of safety and efficacy.

Polypharmacy is common in the treatment of refractory bipolar disorder. The purpose of this article is to review the safety and efficacy of mood stabilizers in combinations. A manual and computer (MEDLINE) search was performed for combinations of the most commonly used mood-stabilizing agents. The authors review safety and efficacy data on the more frequently encountered combinations of established and putative mood stabilizers. There have been few controlled studies of the use of combinations of mood stabilizers. The interactions of such combinations are sometimes complex, often very useful, and potentially dangerous. One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. The safest and most efficacious mood stabilizer combinations appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action.

Chronobiological approach for treatment-resistant rapid cycling affective disorders

A subgroup of patients who experience four or more major mood swings per year has been identified as rapid cyclers (Dunner and Fieve 1974). This subgroup is now believed to account for a significant proportion of treatment-resistant bipolar patients. Such rapid cycling has been indicated to be not only exacerbated, but possibly caused by the use of conventional antidepressants such as tricyclics (Wehr and Goodwin 1979). We applied phototherapy and vitamin BL2 coadministration to two patients with nonseasonal rapid cycling affective disorders, whose manic-depressive phases were uncontrollable for several years by various combinations of mood stabilizers as well as thyroid hormone. After these chronobiological treatments, their sleepwake rhythms became normal and their manic-depressive episodes became markedly suppressed. We presented some characteristic findings in their biological rhythms, and also discussed the usefulness of the chronobiological approach for treatment-resistant rapid cyclers.