Antimanic efficacy of topiramate in 11 patients in an open trial with an on-off-on design

BACKGROUND: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. METHOD: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. RESULTS: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. CONCLUSION: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.     

奥卡西平和碳酸锂治疗双相障碍躁狂发作患者的对照研究

目的：比较奥卡西平和碳酸锂治疗双相障碍躁狂发作的疗效和安全性。方法：70例双相障碍躁狂发作患者随机分为奥卡西平组和碳酸锂组各35例,分别给予奥卡西平和碳酸锂治疗8周。以Bech-Rafaelsen躁狂量表（BRMS）、临床疗效总评量表-病情严重程度（CGI-SI）以及治疗中出现的症状量表（TESS）评定疗效及不良反应。结果：两组治疗后BRMS、CGI-SI评分均较治疗前显著下降（P〈0.05或P〈0.01）;两组间比较差异无统计学意义（P〉0.05）;两组不良反应均为轻度。结论：奥卡西平治疗双相障碍躁狂发作的疗效与碳酸锂相当,不良反应轻。     

Oxcarbazepine treatment of refractory bipolar disorder: a retrospective chart review

Objective: To determine if oxcarbazepine is effective as treatment for refractory bipolar illness in a naturalistic setting.

Methods: All charts of out-patients treated with oxcarbazepine (n=13) were reviewed and clinical response assessed retrospectively using the Clinical Global Impression of Improvement (CGI-I) rating scale. All patients had failed treatment with at least one previous mood stabilizer.

Results: Mild improvement was seen in 46% (n=6) and moderate improvement in 16% (n=2). Fifty-four percent (n=7) of the total sample discontinued treatment because of adverse effects.

Conclusion: Oxcarbazepine may possess mild to moderate mood-stabilizing properties in this refractory, mostly depressed, bipolar sample. This naturalistic study is limited by its uncontrolled nature.     

Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double‐blind randomized controlled trial

Objective: The purpose of this study was to evaluate the efficacy of adding folic acid to sodium valproate in the acute phase of mania. Method: Following a double‐blind randomized controlled trial, 88 clinically manic patients with diagnosis of type I bipolar disorder (BID) were divided randomly into two groups (case and control). The case group was treated with folic acid and sodium valproate and the control group with sodium valproate and placebo. The severity of mania was assessed using the Young Mania Rating Scale (YMRS) at the beginning and end of the first, second and third weeks of the study. Results: The case group’s mean manic YMRS measurements (SD) before the initiation of therapy and in the first, second and third weeks of treatment were 34.0 ± 7.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 respectively. The control group’s measurements were 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.5 and 10.1 ± 1.1. There was a statistically significant difference in YMRS scaling results between the case and control groups after 3 weeks of treatment (7.1 ± 0.9 vs. 10.1 ± 1.1, P = 0.005). Conclusion: Based on our findings, folic acid seems to be an effective adjuvant to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.     

Zotepine loading in acute and severely manic patients: a pilot study

OBJECTIVES: In clinical practice patients with severe mania (agitation, insomnia and aggressive behaviour) still receive effective, but often not well tolerated typical antipsychotics. The aim of this study was to test the first-generation atypical antipsychotic zotepine regarding its antimanic efficacy, tolerability and to find an adequate dosage for a loading strategy. METHOD: Twelve patients (seven male) with an acute and severe manic episode, according to DSM-IV, received zotepine loading in individual dosages (up to 600 mg/day) over a maximum period of 3 weeks. Clinical efficacy was measured using the Young-Mania Rating Scale (Y-MRS) total score. Response was defined as a 50% reduction in the Y-MRS score. Safety was assessed by systematic collection of data on side effects and weight; Hamilton Rating Scale for Depression (HAM-D) scores were used to detect a switch into depression. RESULTS: Two patients dropped out of the study after 2 days. Nine of ten patients (baseline mean Y-MRS: 45 +/- 7) were classified as responders, with five of them responding within 4 days. One patient did not respond sufficiently. No switch into a depressive episode occurred. CONCLUSIONS: This open pilot study suggests that zotepine with a median daily dosage of 250 mg/day is effective with a rapid therapeutic effect in severely manic patients. In general, patients tolerated the drug well; dose-dependent extrapyramidal side effects, an increase in weight and autonomic side effects occurred to a lesser degree. This is the first study assessing zotepine monotherapy in manic patients. Controlled studies are warranted.     

Acute treatment of bipolar depression with adjunctive zonisamide: a retrospective chart review

BACKGROUND: This retrospective chart review evaluated the use of zonisamide as adjunctive treatment in patients with bipolar depression. METHOD: The charts of outpatients with bipolar I or II disorder treated with adjunctive zonisamide were reviewed. The efficacy of zonisamide was assessed via comparison of physician-rated Global Assessment of Functioning (GAF) and Clinical Global Impression of Severity (CGI-S) Scale scores at baseline and after 6 weeks of therapy using paired t-tests. Patients who scored < or = 2 on the CGI-S after 6 weeks of zonisamide therapy were considered good responders to zonisamide. RESULTS: Charts for 12 patients (four men and eight women) with a mean (+/- SD) age of 39.6 (+/- 7.6) years were evaluated. Patients received a mean (+/- SD) zonisamide dosage of 236 (+/- 68) mg/day. Mean GAF scores significantly improved from 44.0 at baseline to 59.3 at week 6 (P = 0.05). Mean CGI-S scores improved from 4.54 at baseline to 3.42 at week 6, but the change was not statistically significant. Six patients (50.0%) were considered responders to zonisamide. Four patients discontinued zonisamide therapy, two for an adverse event (sedation) and two for lack of efficacy. CONCLUSIONS: Zonisamide may be a useful adjunctive treatment for some patients with bipolar depression. Conclusions from this study are limited due to its retrospective design. Further investigation of zonisamide in the treatment of bipolar depression is warranted.     

Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania

Although lithium and carbamazepine used alone are effective in treating acute mania, some patients do not respond adequately to either of these medications used alone. We assessed, under double-blind conditions, a potential synergism between carbamazepine and lithium in the acute treatment of mania. Six of 7 manic patients who had previously been largely refractory to lithium alone, and who still showed substantial mania after several weeks of double-blind treatment with carbamazepine, improved following the blind addition of lithium. The clinical and theoretical implications of the response to this combination treatment are discussed.     

Acute antimanic efficacy and safety of intravenous valproate loading therapy: an open-label study

This open-label study investigated whether acute antimanic effects and safety of intravenous valproate loading therapy is superior to oral valproate loading. Eighteen patients with DSM-IV diagnosis of either bipolar affective disorder or schizomania who met the study criteria were recruited (9 in the intravenous and 9 in the oral valproate group). Psychopathology was assessed with the scale for manic and mixed states on days 0 and 4. A checklist was used for the assessment of side effects. The results showed about 36% reduction in total mean manic scores with intravenous valproate loading; however, statistically, the degree of reduction in manic scores was comparable between the groups. A nonsignificant increase in the rate of adverse events was noted in the intravenous group. Despite its limitations, this study suggests that acute antimanic effects of both intravenous and oral valproate loading are comparable.     

Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies

Objectives: Serotonin (5-hydroxytryptamine, 5-HT) was implicated in the pathophysiology of manic-depressive illness as early as 1958. Although extensive evidence has accumulated since then to support 5-HT's role in depression, relatively fewer studies examined its role in mania. The purpose of this paper was to review and summarize the current state of knowledge on the role of 5-HT in mania and its treatment.

Methods: We systemically reviewed clinical studies of 1) 5-HT function in mania and 2) 5-HT in the mechanism of action of mood stabilizers, including lithium and anticonvulsants.

Results: Review showed that cerebrospinal fluid, postmortem, platelet, neuroendocrine challenge, and tryptophan depletion studies provided some evidence to support the hypothesis that a 5-HT deficit is involved in mania and that enhancement of 5-HT neurotransmission exerts a mood-stabilizing effect.

Conclusions: There is some evidence from clinical studies for the contribution of 5-HT in mania and in the mechanism of action of mood stabilizers. However, it is very likely that other neurotransmitters also play important roles. Future directions for research include 1) in vivo study of 5-HT receptor subtypes using positron emission tomography, 2) investigation of the interaction between 5-HT and other neurotransmitter systems, and 3) determination of the relationships between diagnostic subtypes of mania and 5-HT function and other neurotransmitter systems.     

The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder

Objectives: Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post‐traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder.

Methods: The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid‐cycling bipolar disorder are summarized. Preliminary data from one pilot dose‐finding, double‐blind, random‐assignment, placebo‐controlled, 3‐week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered.

Results: The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24‐h half‐life, and minimal drug interactions. Open clinical studies suggest a 50–65% response for refractory bipolar mania, and a 40–56% response for refractory bipolar depression in mainly add‐on treatment. Open clinical studies of topiramate for rapid‐cycling subjects and those for comorbid bulimia, substance abuse, post‐traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y‐MRS total scores) of the placebo‐controlled, random assignment parallel group phase II dose‐finding study were not statistically significant. However, once the antidepressant‐associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post‐hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y‐MRS change scores as compared to placebo (p<0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word‐finding difficulty. Weight loss may be seen in several topiramate‐treated subjects with bipolar disorder.

Conclusions: Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.     

Anticonvulsants in bipolar disorders: current research and practice and future directions

Objectives:  To determine the clinical effectiveness of drugs with anticonvulsant properties for interventions in persons with bipolar disorder and to place these findings in the context of clinicians' practices and their implications for future research to more effectively manage bipolar disorders.
Methods:  Major electronic databases were searched up to February 2009 for clinical trial data, both original studies and reviews, on drugs with anticonvulsant properties studied for bipolar disorders.
Results:  Valproate, principally as divalproex, has strong evidence for effectiveness in mania, moderately strong evidence for benefits in prophylaxis of recovered states, and recent proof-of-concept evidence for benefits in bipolar depression. Lamotrigine has strong evidence for evidence for effectiveness in maintenance treatment of bipolar disorder, principally for benefits in depressive states. Lamotrigine has been established as ineffective in mania and has lacked efficacy in acute bipolar depression in most randomized trials. Carbamazepine has strong evidence for effectiveness in mania, but lacks adequate studies in other aspects of bipolar disorder treatment. Its adverse effect profile and pharmacokinetic interference with a wide range of drugs, including many employed in bipolar disorder, warrants limitation of use to patients who have responded inadequately to other regimens.
Conclusions:  Three drugs, valproate, lamotrigine, and carbamazepine, have strong evidence-based support for use in clinical states of bipolar disorder. Other anticonvulsant drugs investigated in bipolar disorder either have evidence of lack of benefits in bipolar disorder or have been inadequately studied to determine possible effectiveness.     

Tiagabine in treatment refractory bipolar disorder: a clinical case series

Objectives: Anticonvulsants have provided major treatment advances for patients with bipolar disorder. Many of these drugs, including several with proven efficacy in bipolar mania or depression, enhance the activity of the γ‐amino butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has selective GABAergic activity and is approved for patients with partial epilepsy. Few reports of its potential effectiveness in bipolar disorder, however, have been published. We sought to evaluate the effectiveness of tiagabine added to ongoing medication regimens in patients with bipolar disorder inadequately responsive to or intolerant of usual treatments. Methods: Seventeen treatment‐refractory patients participating in the Stanley Foundation Bipolar Network (SFBN) long‐term follow‐up study were offered open treatment with add‐on tiagabine after discussion of the risks, benefits, other treatment options and giving informed consent. Patients’ clinical symptoms and somatic complaints were closely monitored with SFBN longitudinal and cross‐sectional ratings. Four patients discontinued low‐dose tiagabine prior to the second visit and were excluded from data analysis. Results: Thirteen patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical Global Impression Scale for Bipolar Disorder Overall category, three (23%) patients showed much or very much improvement and 10 (77%) patients showed no change or worsening. Three significant adverse events were noted, including two presumptive seizures. Conclusions: Open add‐on tiagabine for treatment‐refractory patients with bipolar disorder demonstrated limited efficacy with the majority of patients showing no change or worsening of clinical symptoms. In addition, patients experienced serious side‐effects attributed as likely due to the medication, which resolved without lasting consequence when tiagabine was discontinued.     

Two case reports of oral ulcers with lamotrigine several weeks after oxcarbazepine withdrawal

OBJECTIVE: To report two cases of mouth ulcers in lamotrigine patients after oxcarbazepine withdrawal. PATIENTS AND METHODS: The first patient was a 35-year-old woman with bipolar disorder II (BD II) started on lamotrigine and tapered off oxcarbazepine while an inpatient. The second patient was a 36-year-old man with BD II. He was discharged on lamotrigine and oxcarbazepine with the recommendation of a slow withdrawal of oxcarbazepine. RESULTS: Many weeks after hospital discharge and after a stable lamotrigine dose had been established, both patients developed painful mouth ulcers that were diagnosed during outpatient visits. The first patient developed ulcers 39 days after oxcarbazepine was stopped and the ulcers resolved 4 days after lamotrigine discontinuation. The second patient was taking 1200 mg/day of oxcarbazepine and after leaving hospital decreased this to 600 mg/day. Twenty-two days after the oxcarbazepine decrease, he developed oral ulcers that resolved with oxcarbazepine and lamotrigine discontinuation. CONCLUSIONS: Lamotrigine is mainly metabolized by glucuronidation, specifically by the uridine 5'-diphosphate glucuronosyltransferases 1A4 (UGT1A4). Carbamazepine is a UGT1A4 inducer. These two cases suggest that oxcarbazepine may also induce lamotrigine metabolism. The discontinuation or dosage decrease of carbamazepine or oxcarbazepine may be associated with a slow increase of lamotrigine levels over several weeks and thus increase risk of lamotrigine toxicity that may manifest as oral ulcers. Hospital psychiatrists need to be aware that discontinuation of inducers may take several weeks to manifest as side effects.     

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

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

Changes in insight among patients with bipolar I disorder: a 2-year prospective study

OBJECTIVES: The aim of this 2-year prospective study was to examine changes in insight among bipolar patients with different clinical courses. METHODS: A cohort of 65 patients with bipolar I disorder in remission was recruited for this study. They received six follow-up assessments over a 2-year period. The Schedule of Assessment of Insight-Expanded version (SAI-E) was used to determine their levels of insight, while the Young Mania Rating Scale (YMRS) and the Hamilton Rating Scale for Depression (HAM-D) were used to determine affective symptoms. Types of changes in insight among bipolar patients were analyzed according to the different clinical courses during the 2-year follow-up period. RESULTS: Insight in consistently stable patients was steady during the 2-year period. Insight decreased during the manic period in patients with only a single manic episode as well as in those with repeated manic episodes. However, insight returned to the pre-episode level for patients with only a single manic episode, but did not for most of the patients with repeated episodes. No changes in insight were observed during depressive episodes for either patients with a single or those with repeated depressive episodes. CONCLUSIONS: The types of insight changes among bipolar patients during the 2-year period were various and depended on the different clinical courses. Frequent mood disturbance episodes may cause patient insight to deteriorate.     

What symptoms predict the diagnosis of mania in persons with severe/profound intellectual disability in clinical practice?

Background While researchers have attempted to address the difficulties of diagnosing affective disorders in the intellectually disabled population, diagnosing bipolar disorder in an individual with severe intellectual disability (ID) remains a challenge. The aim of this study was to identify what symptoms can predict a diagnosis of mania in the intellectually disabled population. Methods Three groups of persons with ID participated in this study: (1) individuals with a bipolar diagnosis who were currently manic; (2) individuals with an Axis I diagnosis other than bipolar disorder; and (3) individuals without an Axis I diagnosis. Two recognized measures of mania (i.e. Diagnostic Assessment for the Severely Handicapped‐Revised and Parent Version of Young Mania Rating Scale) were used to evaluate symptoms of mania. A logistical regression procedure was conducted on mania items to identify which items correctly identify persons with ID who were currently manic. Results Psychomotor agitation, decreased sleep, changes in mood and aggression were significantly related to the diagnosis of mania. Further, psychomotor agitation and disturbed sleep were significant predictors of a diagnosis of mania. Conclusions Problems of sleep and psychomotor agitation should alert clinicians that further assessment of bipolar symptomatology is warranted. Focusing on observable behaviours based on Diagnostic and Statistical Manual of Mental Disorder‐IV criteria can be useful in formulating a diagnosis of bipolar disorder in persons with ID.     

Antidepressant-induced mania: an overview of current controversies

Objective:  The prevalence, characteristics, and possible risk factors associated with antidepressant-induced mania remain poorly described. The present review sought to identify published rates of antidepressant-induced mania and describe risk factors for its emergence.
Methods:  A MedLine search was conducted of journals that focused on mania or hypomania associated with recent antidepressant use. Data from published reports were augmented with relevant findings from recent clinical trials presented at scientific conferences.
Results:  Antidepressant-induced manias have been reported with all major antidepressant classes in a subgroup of about 20–40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant-induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials.
Conclusion:  About one-quarter to one-third of bipolar patients may be inherently susceptible to antidepressant-induced manias. Bipolar patients with a strong genetic loading for bipolar illness whose initial illness begins in adolescence or young adulthood may be especially at risk. Further efforts are needed to better identify high-vulnerability subgroups and differentiate illness-specific from medication-specific factors in mood destabilization.     

Depressive and manic symptoms are not opposite poles in bipolar disorder

Johnson SL, Morriss R, Scott J, Paykel E, Kinderman P, Kolamunnage‐Dona R, Bentall RP. Depressive and manic symptoms are not opposite poles in bipolar disorder. Objective: This study of 236 individuals with bipolar disorders employed longitudinal analyses to determine whether the symptoms of mania and depression can be understood as one dimension (with depression and mania as opposites) or two relatively independent dimensions. Method: Weekly severity ratings of manic and depression were assessed using the Longitudinal Interval Follow‐up Evaluation‐II for 72 weeks. The within‐subjects correlation of manic and depressive severity was examined using random effects regression. Results: Contrary to the one‐dimension model, mania and depression symptoms were not negatively related. Indeed, the correlations of mania with depressive symptoms were quite small. Conclusion: The data suggest that depressive and manic symptoms are not opposite poles. Rather depressive and manic symptoms appear to fluctuate relatively independently within bipolar disorder.