Maintenance Therapy For Bipolar Disorder Research Articles

Comparative effectiveness of valproic acid in different serum concentrations for maintenance treatment of bipolar disorder: A retrospective cohort study using target trial emulation framework.

SummaryBackgroundThere is a lack of consensus on the optimal serum valproic acid (VPA) concentration for maintenance therapy in bipolar disorder (BD). We aimed to investigate the association between serum VPA levels and risk of mood episode recurrence.MethodsWe enrolled patients with BD from multiple medical institutions in Taiwan between January 1, 2001 and December 31, 2019. Patients were divided into three groups according to their serum VPA concentrations (< 50 μg/ml, 50–74 μg/ml, and 75–104 μg/ml). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) compared times to mood episode recurrence using the < 50 μg/ml group as reference. A systematic review found relevant articles published before February 2022 (PROSPERO: CRD42022309661), and corresponding results were compared.FindingsThis cohort included 896 patients for an intention-to-treat analysis. Compared with the < 50 μg/ml group, a non-significantly lower risk of mood episode recurrence was found in the 50–74 μg/ml (aHR, 95% CI: 0·86, 0·71–1·05) and 75–104 μg/ml (0·91, 0·71–1·18) groups. A per-protocol analysis of 481 patients found a significant risk reduction in the 50–74 μg/ml group (0·76, 0·60–0·97), with inconclusive results in the ≥ 75 μg/ml group (1·03, 0·73–1·46). A meta-analysis including two studies (254 patients) and our cohort found a similar significantly lower risk of mood episode recurrence in the 50–74 μg/ml group (HR, 95% CI: 0·83, 0·69–0·99), while risk reduction in the 75–99 μg/ml group (0·62, 0·26–1·48) did not differ significantly from that in the < 50 μg/ml group or the 50–74 μg/ml group.InterpretationThe combined results of this cohort and previous studies suggest that VPA between 50–74 μg/ml may be a more effective concentration to prevent acute mood episodes during maintenance therapy in patients with BD compared with VPA < 50 μg/ml.FundingMinistry of Science and Technology, Taiwan, and Chang Gung Medical Research Project.

Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial

BackgroundThe optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. MethodsIn a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. ResultsNo significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. LimitationsA low rate of relapse events precluded detection of any statistically significant difference between groups. ConclusionsThe study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

Aripiprazole adjunct treatment in bipolar I or II disorder, depressed state: a 2-year clinical study.

The symptomatic course of bipolar disorder (BPD) is chronic and dominated by depression. As recurrence rates are high, maintenance therapy is required. Although efficacious, mood stabilizers may be hampered by poor adherence, and second-generation antipsychotic medications may be associated with weight gain and metabolic abnormalities. There is evidence to suggest that aripiprazole is beneficial in major depressive disorder and BPD with depression. We therefore investigated 2-year clinical outcomes with aripiprazole adjunct therapy at 5 to 15 mg once daily alongside a mood stabilizer in 40 patients with BPD. All patients experienced marked improvements in Montgomery-Åsberg Depression Rating Scale scores by 6 weeks and substantial reductions in Clinical Global Impressions Scale scores by 6 months. All patients were able to return to optimal or premorbid functioning by 6 months to 1 year. By 1 year, all patients made a complete functional recovery on the Sheehan Disability Scale. Improvements were maintained on all measures up to 2 years. There were minimal adverse events, all of which decreased during therapy. Our findings indicate that aripiprazole adjunct treatment is safe and effective as an acute and maintenance therapy for BPD. However, the findings will need to be replicated by larger studies.

Olanzapine discontinuation emergent recurrence in bipolar disorder.

Objective:The efficacy of atypical antipsychotics including olanzapine in acute treatment of manic episode has been established, whereas its role in maintenance treatment is not clear.Materials and Methods:Thirteen patients of bipolar disorder who were on regular treatment with mood stabilizer and subsequently relapsed into mania or depressive episode after discontinuation of olanzapine were studied for various socio-demographic and clinical factors using retrospective chart review.Results:There was no correlation found between the period of tapering olanzapine, time to recurrence of episode after discontinuation, and the dosage of olanzapine at the time of discontinuation. The predominant early signs of relapse after discontinuation of olanzapine included sleep disturbance (72.7%), lack of insight for change in behavior (72.7%), irritability (54.5%), and elevated mood (45.5%).Conclusion:Mood stabilizer alone as a maintenance therapy of bipolar disorder may be inadequate for long-term management. A low dose of olanzapine along with mood stabilizers might be useful for prevention of recurrence in bipolar disorder.

Clinical implications of predominant polarity and the polarity index in bipolar disorder: a naturalistic study

Predominant polarity (PP) is an important variable in maintenance treatment of bipolar disorder (BD). This study aimed at determining the role of polarity index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. Two hundred and fifty-seven of 604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing the ratio of number needed to treat (NNT) for depression prevention to NNT for mania prevention, was calculated for patients' current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. One hundred and forty-three patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics' PI, and mood stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse, and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia, and suicide attempts. The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD.

A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder

A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder

Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder

Over one half of bipolar patients have been reported to be more prone to either depressive or manic relapses. This study aimed to define profiles of drugs used for maintenance treatment of bipolar disorder (BD) by the means of Polarity Index.Polarity Index is a new metric indicating the relative antimanic versus antidepressive preventive efficacy of drugs. Polarity Index was retrieved by calculating Number Needed to Treat (NNT) for prevention of depression and NNT for prevention of mania ratio, as emerging from the results of randomized placebo-controlled trials. Included trials were randomized and double blind, with a minimal duration of 24weeks, assessing effectiveness of a mood stabilizer or antipsychotic drug alone or in combination with a mood stabilizing agent versus a placebo comparator in BD maintenance treatment.Polarity Index value above 1.0 indicates a relative greater antimanic prophylactic efficacy, number below 1.0 a relative greater antidepressive efficacy. The polarity index for the drugs used in maintenance therapy for bipolar disorder was 12.09 for risperidone, 4.38 for aripiprazole, 3.91 for ziprasidone, 2.98 for olanzapine, 1.39 for lithium, 1.14 for quetiapine, and 0.40 for lamotrigine. Polarity index of valproate and oxcarbazepine may not be reliable due to the failure of their maintenance trials.The polarity index provides a measure of how much antidepressant versus antimanic a drug is in bipolar disorder prophylaxis, and may guide the choice of maintenance therapy in bipolar patients.

A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder

Background Bipolar disorder is a chronic, recurrent disorder with a significant negative impact on quality of life. Effective treatments are available for acute mania. In contrast, there is a lack of consensus on the treatment of acute bipolar depression and long treatment options for bipolar disorder require more study. Aripiprazole is FDA approved for the treatment of acute mania. This paper reviews current data on the efficacy of aripiprazole in the treatment of acute bipolar depression and in maintenance therapy of bipolar disorder. Methods PubMed and abstracts of recent conferences were searched for randomized, double-blind studies that investigated the efficacy of aripiprazole in acute bipolar depression or maintenance therapy of bipolar disorder. Results Two studies assessed the efficacy of aripiprazole monotherapy in the treatment of acute bipolar depression. These showed that although aripiprazole significantly reduced depressive symptoms early in treatment, the results were not significantly different from placebo at the primary end point of week 8. As to long-term treatment, aripiprazole was superior to placebo in delaying time to relapse for manic episodes, but not for depressive episodes after 26 and 100 weeks of maintenance therapy. Aripiprazole was as effective as lithium, and adjunctive aripiprazole with lithium or valproate was more effective than placebo plus lithium or valproate, in preventing a manic relapse. Reductions in manic and mixed relapse rates compared to placebo were achieved in a study combining aripiprazole with lamotrigine; however, the results were not statistically significant. Similar to other maintenance studies, depressive relapse rates were not significantly reduced compared to placebo. Limitations Negative findings for aripiprazole in the treatment of acute bipolar depression have been attributed to high study doses, rapid titration, and high placebo rates. A recent post-hoc analysis demonstrated that aripiprazole was more effective in patients with severe depressive symptoms, particularly for patients on a lower dose. Further research is needed to confirm this finding. The inability of aripiprazole to reduce the time to depressive relapse during maintenance therapy may be due to the recruitment of patients with an index manic episode and a consequent lower incidence of depressive relapses. Therefore, studies using a depression index episode are needed to appropriately evaluate relapse prevention. Conclusions Although aripiprazole has proven efficacy for acute mania and the prevention of mania, the evidence available thus far does not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. Further studies with appropriate doses and a depressive index episode are needed to clarify the role of aripiprazole in bipolar disorder.

Assessment of Medication Adherence in a Cohort of Patients with Bipolar Disorder

This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. Of 1,831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach.

Combination Therapy Versus Monotherapy for Bipolar Disorder

Patients experiencing breakthrough manic or mixed episodes during maintenance therapy for bipolar disorder should first be assessed to ensure they are receiving an optimal dose of the first-line medication. If further intervention is needed, one option is to combine an atypical antipsychotic and a mood stabilizer. The decision to use a particular combination should be made on the basis of the efficacy, tolerability, and safety of each medication for individual patients. Psychosocial therapy as an adjunct to medication is also useful in delaying relapse.

Is Cognitive-Behavioural Therapy More Effective Than Psychoeducation in Bipolar Disorder?

Psychosocial research in bipolar disorder (BD) has not yet assessed the relative benefits of a short course of psychoeducation (PE), compared with a longer course of cognitive-behavioural therapy (CBT) containing psychoeducational principles. This pilot study evaluated the efficacy and added benefit of adding a course of CBT to a standard course of brief PE, as maintenance therapy for BD. Seventy-nine consenting adult men and women with BD on stable medication regimens, who were in full or partial remission from an index episode (BD I = 52; BD II = 27), were randomized to receive either 7 sessions of individual PE, or 7 sessions of PE followed by 13 additional individual sessions of CBT. Weekly mood and medication adherence was rated using the National Institute of Mental Health's Life Chart Method, while psychosocial functioning and mental health use were assessed monthly. Forty-six participants completed the entire study. Participants who received CBT in addition to PE experienced 50% fewer days of depressed mood over the course of one year. Participants who received PE alone had more antidepressant increases compared with those who received CBT. There were no group differences in hospitalization rates, medication adherence, psychosocial functioning, or mental health use. Pilot data from this real-world study suggest that even after medication treatment has been optimized, a longer course of adjunctive CBT may offer some additional benefits over a shorter course of PE alone for the maintenance treatment of BD. Larger randomized controlled trials with equal treatment lengths are indicated.

Valproate effective maintenance therapy in bipolar disorder

Valproate effective maintenance therapy in bipolar disorder

The Importance of Facilitating Adherence in Maintenance Therapy for Bipolar Disorder

Treatment goals for patients with bipolar disorder differ depending on the phase in which the patient presents. During maintenance treatment, the goal of therapy should be for patients to become stable and improve their quality of life. However, the most challenging barrier to effective treatment of bipolar disorder is patient nonadherence with clinician-recommended therapy. A strong treatment alliance between patients and clinicians to provide good social support can help patients adhere to treatment.

Risperidone long-acting injectable for maintenance therapy in bipolar disorder: An open-label pilot study

Objective. To investigate the maintained efficacy of antipsychotic therapy in stable patients with bipolar disorder transitioned directly to risperidone long-acting injectable (RLAI). Methods. Within a large multi-centre European trial (StoRMi), adults with bipolar I disorder (DSM-IV) stable on a medication regimen for ≥1 month, but requiring a change of antipsychotic therapy, received injections of RLAI 25mg i.m. (increased to 37.5 or 50 mg if necessary), every 14 days for 6 months. Results. Sixteen patients were included in this subgroup analysis. Reasons for changing to RLAI included non-compliance (eight patients), insufficient efficacy (four patients) and side effects (three patients), associated with previous therapy. Twelve patients completed the 6-month trial. The most common dosage at endpoint was 25mg (seven patients). Disease symptoms (CGI Disease Severity) were significantly reduced from baseline to endpoint (P=0.0225). Patient satisfaction with treatment increased from baseline to endpoint, with 36% of patients rating their treatment satisfaction as “very good” versus 0% at baseline. Mean total score of ESRS improved from baseline to endpoint. Conclusion. Patients with bipolar disorder showed maintained symptom control over a 6-month treatment period with RLAI. Controlled studies in this population are required.

P.3.c.051 Aripiprazole maintenance therapy in bipolar disorder: a placebo-controlled, 74-week extension of a 26-week study (CN138-010)

P.3.c.051 Aripiprazole maintenance therapy in bipolar disorder: a placebo-controlled, 74-week extension of a 26-week study (CN138-010)

P.7.c.004 Valproate in the treatment of acute mania in adolescents with bipolar disorder

The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients.In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1 mg (n = 164), 0.4 mg (n = 160), or 0.8 mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo.No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon.A low rate of relapse events precluded detection of any statistically significant difference between groups.The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

Usefulness of long-acting injectable risperidone during 12-month maintenance therapy of bipolar disorder

This study aimed to assess the safety, tolerability, efficacy, and compliance of a risperidone long-acting injection (RLAI) formulation for the maintenance treatment of stabilized bipolar patients. A prospective, open-label trial of RLAI was conducted for 12 months. Stable bipolar patients ( n = 11) were switched from their existing oral antipsychotic agents to RLAI, and injections were given every 2 weeks. The assessments were performed at baseline and at 6 and 12 months of treatment by using the Young Mania Rating Scale (YMRS), Clinical Global Impressions—Severity of Illness (CGI-S) scale, 17-item Hamilton Rating Scale for Depression (HAM-D), Brief Psychiatric Rating Scale (BPRS), and Extrapyramidal Symptom Rating Scale (ESRS). The satisfaction levels of subjects were evaluated at the end of the study period using a 10-point visual analog scale. Ten patients (90.9%) completed the trial, and no significant changes were seen in the YMRS, HAM-D, and BPRS scores throughout the study. CGI-S and ESRS scores were significantly decreased from the baseline to the post-12-month treatment score. Relapses were not reported by any of the participants. This result indicates that RLAI may be beneficial in the maintenance therapy of stable bipolar patients; however, an adequately powered, randomized, placebo-controlled trial is necessary to draw a definite conclusion about the role of RLAI in the maintenance treatment of bipolar patients.

Comment on "What Happened to Lithium?: Antidepressant Augmentation in Clinical Settings"

Back to table of contents Previous article Next article Letters to the EditorFull AccessComment on “What Happened to Lithium?: Antidepressant Augmentation in Clinical Settings”TAKESHI TERAO MD, Ph. D.,TAKESHI TERAO MD, Ph. D.Search for more papers by this author,Published Online:1 Dec 2006https://doi.org/10.1176/ajp.2006.163.12.2196bAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: I am very surprised at the article by Marcia Valenstein, M.D., M.S., et al. (1) showing that only 1,106 (0.5%) of 244,855 patients with depression received lithium augmentation. On the other hand, the most popular augmenting drugs were a second antidepressant and a second-generation antipsychotic, received by 26,739 (11%) and 17,797 (7%) patients, respectively. Moreover, 9,053 (4%) patients received augmentation with anticonvulsants, while 11,054 (5%) received other augmenting drugs, such as thyroid hormone, stimulants, and buspirone. Taking strong evidence for lithium as an augmenting drug of refractory depression (2) into consideration, I cannot accept the findings by Dr. Valenstein et al. (1) as they are. At least two possibilities are yet to be investigated. The first possibility is that most patients receiving lithium had been apparently and/or automatically diagnosed as suffering from bipolar disorder, which was excluded from their subjects. Because, according to Food and Drug Administration, lithium is indicated in the treatment of manic episodes of manic-depressive illness (i.e., bipolar disorder) and in maintenance therapy of bipolar disorder, but not in augmentation therapy for depression. Therefore, many patients actually receiving lithium augmentation for refractory depression might have been excluded from their analysis. The second possibility is that a significant proportion of patients had discontinued lithium augmentation within 60 days because lithium augmentation can bring about rapid responses in some patients (3) . They also might have been excluded from the subjects. Oita, Japan

Long‐term Use of Atypical Antipsychotics in Bipolar Disorder

Bipolar disorder is a chronic disease that may require lifetime treatment. The maintenance therapy of bipolar disorder can be challenging for the treating clinician. Currently, according to the American Psychiatric Association (APA) guidelines, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, and the antipsychotics are recommended for the maintenance treatment of bipolar disorder. The antipsychotics are recommended to be continued only if the clinician decides that they are necessary for the control of persistent psychosis or for prophylaxis against recurrence. Although the APA guidelines provide sufficient evidence for the use of these mood stabilizers, newer drugs such as the atypical antipsychotics are being investigated for use in the maintenance phase of treatment of bipolar disorder.

Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature

There are an increasing number of pharmacologic therapies for bipolar disorder. Two of these agents, the anticonvulsants carbamazepine (CBZ) and valproate (VPA), were first developed over 30 years ago for the treatment of epilepsy, and subsequent studies demonstrated that they are also effective in the treatment of acute mania and suggest efficacy as maintenance therapy in bipolar disorder. Because VPA and CBZ have been in use for many years, the psychiatric community is familiar with the adverse event profiles of these agents. A review of the clinical data evaluating VPA and CBZ monotherapy for the treatment of acute mania suggests that VPA and CBZ are similarly effective in acute mania. However, when their respective adverse event profiles are considered, VPA may be more tolerable than CBZ for short-term use, while CBZ may be better suited for long-term therapy. Controlled and direct comparative studies, both short and long term, are needed to further clarify the differences between VPA and CBZ.