Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review

Background: Data from several studies suggest that medications, such as ketoconazole, which lower cortisol levels, may be effective for major depressive disorder (MDD). As with MDD, the manic, depressive, and mixed phases of bipolar disorder are frequently associated with elevated cortisol levels. The literature on the use of cortisol-lowering strategies in mood disorders is reviewed, and a case series illustrating the use of ketoconazole in bipolar depression is presented. Methods: For the review, the MEDLINE and PSYCHINFO databases were searched, as were the bibliographies of pertinent articles to find papers on the use of cortisol-lowering agents in patients with mood disorders. In our open-label case series (n=6), ketoconazole (up to 800 mg/day) as an add-on therapy was given to patients with treatment-resistant or intolerant bipolar I or II disorders with current symptoms of depression. Results: Several case reports and small open studies suggest that cortisol-lowering agents may be useful for patients with depression. Two recent placebo-controlled trials of ketoconazole on patients with MDD report conflicting results. In our case series, all three patients who received a dose of at least 400 mg/day had substantial reductions in depressive symptoms. None had significant increases in mania. However, cortisol levels were not lowered in any of the subjects. Conclusions: The literature suggests that cortisol-lowering medications may be effective for a subset of depressed patients. Our preliminary findings suggest that ketoconazole may be useful in some patients with bipolar depression. Larger clinical trials are needed to confirm our observations.     

Electroconvulsive therapy: an effective therapy of medication-resistant bipolar disorder

OBJECTIVES: We report our experience with a medication-refractory patient with bipolar I disorder, who remained clinically stable under continuation electroconvulsive therapy (C-ECT). We found ECT to be effective in providing functionality for a patient when various medications had failed. METHODS AND RESULTS: A 53-year-old woman with a 31-year history of recurrent manic and depressive episodes poorly responsive to medications warranted an ECT trial. Remission was achieved after 12 treatments and C-ECT at weekly intervals was used as maintenance therapy. C-ECT was continued for 37 months and 85 treatments, and discontinued when anesthetic difficulties precluded further treatment. Three months after the last ECT, she was readmitted in a severe manic relapse. Restarting ECT caused rapid remission. There are no signs of cognitive deterioration during C-ECT. CONCLUSION: Long-term C-ECT is an effective and safe prophylactic treatment in individual treatment-resistant patients with bipolar disorder.     

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.     

Lamotrigine therapy in treatment-resistant menstrually-related rapid cycling bipolar disorder: a case report

AIMS/OBJECTIVES: To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms. METHODS: Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software. RESULTS: As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months. CONCLUSION: This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.     

A two-illness model of bipolar disorder

The current approach to mood disorders is that bipolar disorder, comprising both mania and depression, is a discreet illness distinct from unipolar depression. This formulation has profoundly influenced the approach to understanding the biology and etiology of these disorders, as well as the manner in which the various phases of bipolar disorder are treated. Our new model suggests that bipolar disorder comprises two distinct illnesses, mania and depression, and that bipolar depression is no different from unipolar depression. Studies of clinical syndromes, course of illness, family history and genetics, biological factors, and treatment response data directly or indirectly support this new model.     

Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients

Valentí M, Pacchiarotti I, Rosa AR, Bonnín CM, Popovic D, Nivoli AMA, Murru A, Grande Í, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.
Bipolar Disord 2011: 13: 145–154. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder. Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow‐up (n = 60) with subjects who had never experienced a mixed episode (n = 84) regarding clinical variables. Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p < 0.001), the use of serotonin norepinephrine reuptake inhibitors (p = 0.041), switch rates (p = 0.010), and years spent ill (p = 0.022) were significantly associated with the occurrence of at least one mixed episode during follow‐up. Conclusions: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors.     

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.     

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.     

Treatment of aggression with risperidone in children and adolescents with bipolar disorder: a case series

OBJECTIVES: To evaluate the effectiveness and safety of risperidone in children and adolescents with bipolar disorder characterized by aggression and mania, despite treatment with mood stabilizers. METHODS: A retrospective chart review of patients seen in an outpatient pediatric mood disorders clinic over an 18-month period was performed. Data were extracted from charts of patients who had a diagnosis of bipolar disorder with aggression that was uncontrolled on a mood stabilizer; as a result, these patients had risperidone added to their regimen. RESULTS: Four boys (aged 7-15 years) and two girls (aged 8 and 14 years) were treated with risperidone (mean dosage, 0.85 mg/day) for 3-16 months. Aggressive behavior improved in all patients after risperidone was started and remained improved for the duration of follow-up. Other symptoms of mania also improved. Risperidone was generally well tolerated. Sedation and akathisia were reported in one patient. CONCLUSIONS: The addition of risperidone to a mood stabilizer may improve aggression and other symptoms of mania in pediatric patients with bipolar disorder who do not respond adequately to a mood stabilizer alone. The long-term efficacy and safety of this regimen should be evaluated in a controlled clinical trial.     

Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study

Chaves OC, Lombardo LE, Bearden CE, Woolsey MD, Martinez DM, Barrett JA, Miller AL, Velligan DI, Glahn DC. Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study.
Bipolar Disord 2011: 13: 118–123. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. Methods: A total of 29 individuals with DSM‐IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow‐up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. Results: At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three‐month follow‐up period, HAMD scores changed by 6 points on average [range: ?10 to +18] and YMRS scores changed by 5.31 points on average [range ?11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. Conclusions: Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.     

Evidence-based options for treatment-resistant adult bipolar disorder patients

Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ. Evidence‐based options for treatment‐resistant adult bipolar disorder patients. Bipolar Disord 2012: 14: 573–584. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. Methods: We performed a literature review of the research findings related to treatment‐resistant BD reported through February 2012. Results: Therapeutic trials for treatment‐resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive‐dysthymic‐dysphoric‐mixed phases of BD and long‐term prophylaxis. Therapeutic trials for treatment‐resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N‐methyl‐D‐aspartate (NMDA)] antagonists, dopamine agonists, calcium‐channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation—all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium‐channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive‐behavior therapy have some support for long‐term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. Conclusions: Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow‐up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow‐up.     

Circadian activity rhythm abnormalities in ill and recovered bipolar I disorder patients

OBJECTIVES: Most physiological indicators of bipolar disorder (BPD) reflect current acute illness, and rarely have proved to be state-independent. Activity rhythms are highly abnormal in acute phases of BPD; we compared circadian activity rhythms in BPD I patients during ill and recovered states to those of normal controls to test the hypothesis that some abnormalities may persist. METHODS: We compared 36 adult DSM-IV BPD I patients during acute mania or mixed states, and during full and sustained clinical recovery, to 32 healthy controls of similar age and sex distribution, using wrist-worn, piezoelectric actigraphic monitoring for 72 h and computed cosinor analysis of circadian activity rhythms. RESULTS: We verified expected major differences between manic or mixed-state BPD I patients and matched normal controls, including phase advances averaging 2.1 h in ill BPD I patients and 1.8 h in recovered patients. Moreover, recovered BPD patients differed highly significantly from controls in several measures, including acrophase advance, higher percentage of nocturnal sleep, and lower average daily activity (mesor). Actigraphic measures among recovered BPD patients were independent of ratings of mania (on the Young Mania Rating Scale), depression (on the Hamilton Depression Rating Scale), or rating-scale scored subjective distress, as well as the type and dose of concurrent psychotropic medication. CONCLUSIONS: These findings suggest that abnormal activity rhythms, including sustained phase advances, may represent enduring (trait) characteristics of BPD patients even during clinical recovery. If verified, such indices may be useful in supporting diagnoses and as an objective phenotype for genetic or other biological studies.     

Serum lithium levels and the outcome of maintenance therapy of bipolar disorder

A literature review was conducted to locate studies that compared different serum lithium levels in the long‐term treatment of patients with bipolar disorder and articles about factors that may affect serum lithium levels. Patients with bipolar disorder on long‐term treatment with lithium are typically maintained at serum lithium concentrations between 0.6 and 1.0 mEq/L. Although there are individual exceptions, serum lithium levels below 0.6 mEq/L have been shown in controlled clinical trials to be less effective in preventing relapses than levels within this range, whereas levels much above 1.2 mEq/L can lead to toxicity. Differences in efficacy between levels within the accepted range have not been established. However, higher levels are associated with greater side effects, which can lead to poor compliance. Interindividual variation in pharmacokinetics and pharmacodynamics, as well as such external factors as diet and concomitant medications, can affect serum lithium levels.     

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

Objectives:  Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD.
Methods:  Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls.
Results:  Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses.
Conclusions:  These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.