Rapid Cycling Bipolar Patients Research Articles

Electroconvulsive Therapy (ECT) in Bipolar Disorder Patients with Ultra-Rapid Cycling and Unstable Mixed States.

Background and Objectives: Unstable mixed episodes or rapid switching between opposite affective poles within the scope of short cycles was first characterized in 1967 by S. Mentzos as complex polymorphous states with chaotic overlap of manic and depressive symptoms. Well-known examples include antidepressant-induced mania/hypomania and rapid/ultra-rapid/ultradian cycling, when clinicians observe an almost continuous mixed state with a constant change of preponderance of manic or depressive symptoms. Achieving stable remission in these cases is challenging with almost no data on evidence-based treatment. When mood stabilizers are ineffective, electroconvulsive therapy (ECT) has been suggested. Objectives: After reviewing the evidence from available literature, this article presents our own clinical experience of ECT efficacy and tolerability in patients with ultra-rapid cycling bipolar disorder (BD) and unstable mixed states. Materials and Methods: We conducted an open, one-year observational prospective study with a “mirror image” design, including 30 patients with rapid and ultra-rapid cycling BD on long-term mood stabilizer treatment (18 received lithium carbonate, 6 on valproate and 6 on carbamazepine) with limited effectiveness. A bilateral ECT course (5–10 sessions) was prescribed for regaining mood stability. Results: ECT was very effective in 12 patients (40%) with a history of ineffective mood stabilizer treatment who achieved and maintained remission; all of them received lithium except for 1 patient who received carbamazepine and 2 with valproate. Nine patients (30%) showed partial response (one on carbamazepine and two on valproate) and nine patients (30%) had no improvement at all (four on carbamazepine and two on valproate). For the whole sample, the duration of affective episodes was significantly reduced from 36.05 ± 4.32 weeks in the year prior to ECT to 21.74 ± 12.14 weeks in the year post-ECT (p < 0.001). Depressive episodes with mixed and/or catatonic features according to DSM-5 specifiers were associated with a better acute ECT response and/or long-term mood stabilizer treatment outcome after ECT. Conclusions: ECT could be considered as a useful option for getting mood instability under control in rapid and ultra-rapid cycling bipolar patients. Further randomized trials are needed to confirm these results.

Daily ratings of mood and sleep duration over 3.3 years are associated with the lunar illumination cycle in a rapid cycling bipolar patient.

Previous reports from a single research group have described changes in mood in rapid cycling bipolar patients that are associated with the lunar cycle. In many cases, there is more positive mood around the time of the full moon, and more negative mood around the time of the new moon, in accordance with the lunar illumination cycle period of ~29.5 days (the equivalent of two spring-neap cycles).

Characterization of rapid cycling bipolar patients presenting with major depressive episode within the BRIDGE-II-MIX study.

The "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as rapid cycling (RC). Psychiatric symptoms, socio-demographic, and clinical variables were collected from a sample of 2811 MDE patients, of which 726 (25.8%) were diagnosed with bipolar disorder (BD). The characteristics of bipolar patients with RC (BD-RC) and without (BD-NRC) RC were compared. Of 726 BD patients, 159 (21.9%) met DSM-5 criteria for RC. BD-RC group presented a higher number of lifetime depressive episodes (p<0.001) with shorter duration of depressive episodes, and more psychiatric comorbidities, as well as higher rates of atypical features (p=0.016) and concomitant (hypo)manic symptoms (irritable mood (p=0.001); risky behavior (p=0.005); impulsivity (p=0.006); and psychomotor agitation (p=0.029)). Patients with RC had a worse functioning (p=0.033), more obesity (p=0.003), and were significantly more likely to be treated with three or more drugs (p=0.007). Important clinical differences between bipolar patients with and without a RC include more depressive morbidity, higher incidence of anxiety disorders, addiction, bulimia, and borderline personality disorder, as well as atypical features during depression and symptoms such as irritability, risky behavior, impulsivity, and agitation. RC patients had poorer functioning than patients without RC, more obesity, and had to be treated with more drugs.

A composite peripheral blood gene expression measure as a potential diagnostic biomarker in bipolar disorder.

Gene expression in peripheral blood has the potential to inform on pathophysiological mechanisms and has emerged as a viable avenue for the identification of biomarkers. Here, we aimed to identify gene expression candidate genes and to explore the potential for a composite gene expression measure as a diagnostic and state biomarker in bipolar disorder. First, messenger RNA levels of 19 candidate genes were assessed in peripheral blood mononuclear cells of 37 rapid cycling bipolar disorder patients in different affective states (depression, mania and euthymia) during a 6–12-month period and in 40 age- and gender-matched healthy control subjects. Second, a composite gene expression measure was constructed in the first half study sample and independently validated in the second half of the sample. We found downregulation of POLG and OGG1 expression in bipolar disorder patients compared with healthy control subjects. In patients with bipolar disorder, upregulation of NDUFV2 was observed in a depressed state compared with a euthymic state. The composite gene expression measure for discrimination between patients and healthy control subjects on the basis of 19 genes generated an area under the receiver-operating characteristic curve of 0.81 (P<0.0001) in sample 1, which was replicated with a value of 0.73 (P<0.0001) in sample 2, corresponding with a moderately accurate test. The present findings of altered POLG, OGG1 and NDUFV2 expression point to disturbances within mitochondrial function and DNA repair mechanisms in bipolar disorder. Further, a composite gene expression measure could hold promise as a potential diagnostic biomarker.

Reduced mRNA expression of PTGDS in peripheral blood mononuclear cells of rapid-cycling bipolar disorder patients compared with healthy control subjects.

Background:Disturbances related to the arachidonic acid cascade and prostaglandin metabolism may be involved in the pathophysiology of bipolar disorder, as supported by a recent genome-wide association study meta-analysis; however, evidence from clinical studies on a transcriptional level is lacking. Two enzymes in the arachidonic acid cascade are the prostaglandin D synthase (PTGDS), which catalyzes the conversion of prostaglandin H2 to prostaglandin D2 (PGD2), and the aldo-keto reductase family 1 member C3 (AKR1C3), which catalyzes the reduction of PGD2. We aimed to test the hypothesis that mRNA expression of PTGDS and AKR1C3 is deregulated in rapid-cycling disorder patients in a euthymic or current affective state compared with healthy control subjects, and that expression alters with affective states.Methods: PTGDS and AKR1C3 mRNA expression in peripheral blood mononuclear cells was measured in 37 rapid-cycling bipolar disorder patients and 40 age- and gender-matched healthy control subjects using reverse transcription quantitative real-time polymerase chain reaction. Repeated measurements of PTGDS and AKR1C3 mRNA expression were obtained in various affective states during 6–12 months and compared with repeated measurements in healthy control subjects.Results:Adjusted for age and gender, PTGDS mRNA expression was down-regulated in rapid-cycling bipolar disorder patients in a euthymic, depressive, and manic/hypomanic state compared with healthy control subjects. No difference in PTGDS mRNA expression was observed between affective states. AKR1C3 mRNA expression did not differ between bipolar disorder patients in any affective state or in comparison with healthy control subjects.Conclusions:The results suggest a role for aberrantly-regulated PTGDS mRNA expression in rapid-cycling bipolar disorder. The sample size was limited; replication of the findings in larger, independent samples is warranted to further explore the role of the arachidonic acid cascade and prostaglandin metabolism as a potential therapeutic target in bipolar disorder.

Elevated levels of IL-6 and IL-18 in manic and hypomanic states in rapid cycling bipolar disorder patients.

Inflammatory system dysregulation may be involved in the pathophysiology of bipolar disorder with peripheral cytokine levels varying between affective states; however, the evidence is based primarily on case-control studies and limited by methodological issues. The objectives of the present study were to assess alterations of peripheral cytokine levels between affective states in rapid cycling bipolar disorder patients and to compare these with levels in healthy control subjects. In a longitudinal design, repeated measurements of plasma levels of IL-6, IL-10, IL-18, IL-1β and TNF-α were obtained in affective states of varying polarity during 6-12 months in 37 rapid cycling bipolar disorder patients and compared with repeated measurements in 40 age- and gender matched healthy control subjects, using rigorous laboratory-, clinical- and statistical methodology. Adjusting for demographical, clinical- and lifestyle factors, levels of IL-6 (p<0.05) and IL-18 (p<0.005) were significantly elevated in rapid cycling bipolar disorder patients in a manic/hypomanic state, compared with a depressed and a euthymic state. Compared with healthy control subjects, unadjusted levels of IL-6 (p<0.05) and IL-18 (p<0.05) were elevated in manic/hypomanic bipolar disorder patients. Levels of IL-10 and IL-1β were undetectable in the majority of samples; high TNF-α assay variability was found. The results support a role for altered peripheral immune response signaling in rapid cycling bipolar disorder and suggest that IL-6 and IL-18 could be markers of manic episodes.

Rapid cycling in bipolar disorder: a systematic review.

THE long-term course of bipolar disorder is typified by recurring mood episodes of opposite polarity as well as mixed states. Rapid-cycling bipolar disorder refers to the presence of at least 4 mood episodes in the previous 12 months that meet the criteria for manic, hypomanic, or major depressive episode. The purpose of this study was to synthesize data regarding prevalence, clinical correlates, and familial/genetic aspects related to rapid cycling in bipolar disorder. we searched the MEDLINE database through September 7, 2013 for articles regarding rapid cycling in bipolar disorder. Searches were performed using the keywords rapid cycling or rapid-cycling. The search strategy was augmented through the inspection of reference lists of relevant review articles. Eligible articles included original studies in English on rapid-cycling bipolar patients according to the criteria defined by the Diagnostic and Statistical Manual of Mental Disorders. This study followed the recommendations of the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses statement. The initial search returned 2,715 articles; 2,594 were excluded for several reasons (not aligned with objectives, pertaining to bipolar disorder but not focusing on rapid cycling, case reports, and case series). The final review included 119 articles. Two investigators (K.N.F. and D.D.) independently reviewed articles for eligibility. Final decisions regarding eligibility were made by consensus following the full-text review. The literature suggests that rapid cycling affects a significant proportion of bipolar patients and is related to a longer course of illness, an earlier age at onset, and more illegal drug and alcohol abuse and increased suicidality. Year prevalence of rapid cycling among all bipolar patients ranges between 5%-33.3%, while lifetime prevalence ranges between 25.8%-43%.The etiology remains unclear, although a causal or triggering role for the use of antidepressants and hypothyroidism is implicated. Rapid cycling seems to represent a transitory phenomenon rather than a stable pattern that characterizes the individual patient and probably is related to a worse outcome. Rapid cycling is a frequent, although underrecognized, condition in bipolar disorder, and it constitutes a worsening of the primary disorder. There is no good evidence that rapid cycling represents a discrete subtype. Early recognition of this pattern can lead to better treatment strategy and improvement of the long-term course. Conceptualizing rapid cycling according to Research Domain Criteria will be an important advance.

Elevated levels of plasma brain derived neurotrophic factor in rapid cycling bipolar disorder patients.

Impaired neuroplasticity may be implicated in the pathophysiology of bipolar disorder, involving peripheral alterations of the neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). Evidence is limited by methodological issues and is based primarily on case-control designs. The aim of this study was to investigate whether BDNF and NT-3 levels differ between patients with rapid cycling bipolar disorder and healthy control subjects and whether BDNF and NT-3 levels alter with affective states in rapid cycling bipolar disorder patients. Plasma levels of BDNF and NT-3 were measured in 37 rapid cycling bipolar disorder patients and in 40 age- and gender matched healthy control subjects using enzyme-linked immunosorbent assay (ELISA). In a longitudinal design, repeated measurements of BDNF and NT-3 were evaluated in various affective states in bipolar disorder patients during a 6-12 months period and compared with repeated measurements in healthy control subjects. Careful attention was given to standardization of all procedures and adjustment for potential confounders of BDNF and NT-3. In linear mixed models, adjusting for demographical and lifestyle factors, levels of BDNF were significantly elevated in bipolar disorder patients in euthymic- (p<0.05), depressed- (p<0.005) and manic/hypomanic (p<0.005) states compared with healthy control subjects. Within bipolar disorder patients, adjusting for medication, there was no significant difference in BDNF levels between affective states, with equally elevated levels present in euthymic-, depressive- and manic/hypomanic patients. Levels of BDNF were higher in patients with longer duration of illness compared with patients with shorter duration of illness. We found no difference in NT-3 levels between bipolar disorder patients in any affective state compared with healthy control subjects and no difference in NT-3 levels between affective states in bipolar disorder patients. The results suggest that BDNF may be a marker related to illness stage in bipolar disorder, not varying with affective states in rapid cycling bipolar disorder patients. Due to the nature of comparison, it cannot be excluded that the finding of elevated BDNF levels in bipolar disorder patients compared with healthy controls could be influenced by medication.

Microstructural changes of the nucleus accumbens due to increase of estradiol level during menstrual cycle contribute to recurrent manic episodes—A single case study

We examined a rapid-cycling bipolar disorder patient who demonstrated manic episode regularly at around day 7 of the menstrual cycle. We hypothesize that gonadal hormones may induce a state-dependent change in cerebral microstructure and function. Following this hypothesis, the serum levels of estradiol and progesterone were analyzed and diffusion tensor imaging data were examined between the manic and euthymic states of the patient. Estradiol levels increased in the late follicular phase at manic state when compared to the luteal or early follicular phase at euthymic state. DTI results showed that the patient had increased fractional anisotropy values at manic state in the bilateral nucleus accumbens (NAc) and its connected areas, which is a major projection field of the mesolimbic dopamine (DA) system, perhaps reflecting microstructural changes due to neuronal activation related to manic episodes. According to these results, we consider that the mesolimbic DA system of this patient has hypersensitivity to estradiol, and elevation of the estradiol level increases the activity of the dopaminergic system, which in turn may contribute to recurrent manic episodes. Our findings provide a clue for understanding how fluctuations in gonadal hormone may amplify or ameliorate the symptomatology of psychiatric disorders related to the menstrual cycle.

Suicide risk in rapid cycling bipolar patients

Background Rapid-cycling (RC) is a course modifier of bipolar disorder which often implicates a poor prognosis. However, the relationship of RC with suicidal features as a marker of impairment has been understudied. Methods Three hundred and five patients ( n = 305) were included in a naturalistic, systematic prospective study in a single site setting. Patients with rapid-cycling (RC) were defined as having four or more manic, mixed or depressive episodes in the year prior to baseline assessment. The two groups were compared regarding clinical and sociodemographic variables, paying special attention to suicidal features. Statistical methods consisted of chi-square statistic for the comparison of categorical data, and Student's t test for dimensional variables normally distributed. Also, a General Linear Model was used to study the main effect of different sociodemographic and clinical variables on suicidality. All statistics were two-tailed, and significance was set at p less than 0.05. Results Fifty-five patients (18%) were classified as RC, whilst 250 (82%) were considered as nonrapid-cycling (NRC). No significative difference was found in the prevalence of RC amongst bipolar I and II patients. RC was associated with depressive onset of bipolar disorder. The number of suicide attempts was significantly higher amongst RC (RC mean 0.82 [SD 1.85] vs. NRC 0.44[SD 0.94] t = 2.09, p = 0.37). Nonetheless, no significative differences were found between RC and NRC regarding the percentage of suicide attempters. On the other hand patients that presented RC showed a marked increase of lifetime history of suicidal ideation (Chi 2 = 4.363, p = 0.039). Finally, there were not any differences between RC patients and NRC in family history of suicide. Discussion Bipolar patients with RC are more likely to attempt suicide. Intensive treatment of this marker should be considered.

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Electroencephalographic Cerebral Dysrhythmic Abnormalities in the Trinity of Nonepileptic General Population, Neuropsychiatric, and Neurobehavioral Disorders

Subclinical electroencephalographic epileptiform discharges in neurobehavioral disorders are not uncommon. The clinical significance and behavioral, diagnostic, and therapeutic implications of this EEG cerebral dysrhythmia have not been fully examined. Currently the only connotation for distinctive epileptiform electroencephalographic patterns is epileptic seizures. Given the prevailing dogma of not treating EEGs, these potential aberrations are either disregarded as irrelevant or are misattributed to indicate epilepsy. This article reappraises the literature on paroxysmal EEG dysrhythmia in normative studies of the "healthy" nonepileptic general populations, neuropsychiatry, and in neurobehavioral disorders. These EEG aberrations may be reflective of underlying morpho-functional brain abnormalities that underpin various neurobehavioral disturbances.

Clinical response of quetiapine in rapid cycling manic bipolar patients and lactate level changes in proton magnetic resonance spectroscopy

The aim of the current study was to evaluate the relationship between quetiapine's effect on the improvement of mood symptoms in bipolar patients and brain metabolite level changes as measured by proton magnetic resonance spectroscopy ( 1H-MRS). Rapid cycling bipolar patients in the manic state were recruited and treated with quetiapine for 12 weeks. Clinical assessment was performed using the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression-Severity scale (CGI-S) at baseline and weekly intervals during the 12-week period. In order to evaluate metabolite level changes over time, 1H-MRS scans were acquired at baseline and week 12. There were significant reductions in YMRS scores (by 43.0%), HDRS scores (by 27.5%) and CGI-S score (by 44.6%) over the 12 week-period. Lactate levels significantly decreased over the 12-week study period (22.4%). This change in lactate levels was more prominent in quetiapine responders than in non-responders. Additionally, there was a positive correlation between changes in lactate levels and those in YMRS scores ( r = 0.52, p = 0.003). Our findings suggest that quetiapine's antimanic and antidepressant efficacy in patients with rapid cycling bipolar disorder may potentially be related to decreased lactate levels in frontal regions of the brain.

Treating Rapid Cycling Bipolar Disorder with Novel Medications

Background: Brief definition of rapid cycling is the occurrence of at least four mood episodes in a year. It may be seen in patients with bipolar I, or bipolar II disorder. Rapid cycling bipolar disorder is frequently treatment-resistant. There is need for new, effective medications for the treatment of these patients. Objective: Novel anticonvulsants and newer generation of atypical antipsychotics may offer promising alternative treatment to existing mood stabilizers and other medications available for rapid cycling bipolar patients. Method: A computerized (MEDLINE) search was performed to explore the English-language literature on medications that were studied in patients with rapid cycling bipolar disorder. Bipolar disorder and rapid cycling were used as key words while performing the search. The articles, including in press ones were then searched. Results: Lithium has been a predictor of poor response to rapid cycling in earlier studies, while recent studies have demonstrated equal efficacy of lithium, and valproate. In fact, many available medications are not effective in rapid cycling patients. Lithium, lamotrigine and valproic acid and combination of mood stabilizers are likely the most efficacious treatment regimens among all. Efficacy of atypical antipsychotics in combination with mood stabilizers is noted, but this finding has not been consistent across studies. Conclusions: Combination of mood stabilizers might be more effective than use of other treatment regimens in patients with rapid cycling bipolar disorder. There is need for controlled studies evaluating the efficacy of combinations with different mood stabilizers to establish better treatment approaches.

Inositol deficiency diet and lithium effects

A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7-14 days of treatment. These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

Sudden Akathisia After a Ziprasidone Dose Reduction

Back to table of contents Previous article Next article Letter to the EditorFull AccessSudden Akathisia After a Ziprasidone Dose ReductionE. TIMUCIN ORAL, M.D., KURSAT ALTINBAS, M.D., and SIMDEN DEMIRKIRAN, M.D., E. TIMUCIN ORALSearch for more papers by this author, M.D., KURSAT ALTINBASSearch for more papers by this author, M.D., and SIMDEN DEMIRKIRANSearch for more papers by this author, M.D., Istanbul, TurkeyPublished Online:1 Mar 2006https://doi.org/10.1176/appi.ajp.163.3.546AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor:We report five cases of akathisia in female patients with bipolar disorder (who were treated with 80–160 mg/day of ziprasidone) that appeared to occur dramatically after a dose reduction. All of the patients had subjective feelings of motor restlessness. They displayed an irresistible urge to walk or move their legs, and they were evaluated with Barnes Rating Scale for Drug-Induced Akathisia (1). None of these patients had any significant medical conditions related to akathisia.Ms. A was a 27-year-old woman receiving carbamazepine. Because of a mixed episode, 120 mg b.i.d. of ziprasidone was added. After 2 months, ziprasidone was tapered to 80 mg b.i.d., and akathisia developed, with a Barnes rating scale score of 6. Ziprasidone was accordingly discontinued, and 40 mg b.i.d. of propranolol, 20 mg b.i.d. of diazepam, and 4 mg b.i.d. of biperiden were added to her treatment regimen.Ms. B, who had been receiving 200 mg b.i.d. of lamotrigine when psychotic symptoms appeared, was also 27 years old. She did not respond to 3 weeks of ziprasidone, 120 mg b.i.d., and during the tapering process, a sudden and severe akathisia developed, with a Barnes rating scale score of 14. Ziprasidone was discontinued, and the already-mentioned protocol for the treatment of akathisia was applied.Ms. C, a 46-year-old woman had her last manic episode treated with ziprasidone, 160 mg/day. After 4 weeks, her mania disappeared, but depressive symptoms emerged. Decreasing her ziprasidone dose to 120 mg/day was followed by abrupt akathisia, with a Barnes rating scale score of 9. Forty mg b.i.d. of propranolol, 30 mg b.i.d. of diazepam, and 4 mg b.i.d. of biperiden were added to her drug regimen for akathisia.A rapid-cycling bipolar patient, Ms. D, age 61, was the eldest of our five cases. She had been given valproate and ziprasidone until she complained about sedation. Her ziprasidone dose was reduced to 120 mg/day from 160 mg/day, which was also followed by sudden akathisia with a Barnes rating scale score of 14 that responded only to clonazepam, 6 mg/day.Ms. E, who had responded well to lithium prophylaxis but discontinued it because of polyuria, polydipsia, and urinary incontinence, was 48 years old. She refused to take valproate and olanzapine because she experienced hair loss and weight gain. Finally, she agreed to take 40 mg/day of ziprasidone for prophylaxis. But because of the appearance of depressive symptoms, it was also discontinued. This resulted in sudden akathisia with a score on the Barnes rating scale of 12. Her akathisia disappeared totally after treatment with 40 mg/day of propranolol, 4 mg/day of biperiden, and 2 mg/day of alprazolam. Although unexpected, akathisia after ziprasidone dose reduction in our cases was not persistent. Gradual or complete resolution of akathisia with 75% to 100% reduction in Barnes rating scale scores was observed within 7–10 days in all cases.The patients described here remind clinicians of unexpected side effects with second-generation antipsychotics and to consider extrapyramidal syndrome in patients while they are taking or discontinuing their drugs (2).

Combination Treatment of Clozapine and Topiramate in Resistant Rapid-Cycling Bipolar Disorder

Several open-label studies or case reports have suggested the effectiveness of clozapine or topiramate in the treatment of resistant rapid-cycling bipolar patients, but none of these publications report the long-term effectiveness of these two agents in combination. The authors present a 38-year-old woman with a 22-year history of rapid-cycling bipolar I disorder who failed to respond satisfactorily to various somatic therapies, including combination therapy for complex regimens and a course of bilateral electroconvulsive therapy, but finally responded well to a combination treatment of clozapine and topiramate. Such a combination therapy led the patient to a complete remission for more than 3 years without inducing side effects such as weight gain, hyperglycemia, type II diabetes mellitus, or hyperlipidemia. In addition, she had a weight loss of 12 kg over the past 3 years. This case suggests that the combination treatment of clozapine and topiramate can be safe and effective in some resistant rapid-cycling bipolar patients.

Comparison of Rapid-Cycling and Non–Rapid-Cycling Bipolar I Manic Patients During Treatment With Olanzapine

Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments, and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine. We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects. RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p < .0001), and more likely to have familial bipolar disorder (p < .0001), abused substances (p = .01), more previous hospitalizations (p = .004), and many more illness episodes (p < .001). In initial blinded trial outcomes, relative responses (> or = 50% improvement of mania) to olanzapine/placebo were similar in RC and non-RC subjects, though early responses to olanzapine favored RC over non-RC subjects (p = .003), and long-term outcomes favored non-RC subjects (p = .05). Fewer RC subjects achieved strictly defined initial symptomatic remission (p = .014) within a year; RC subjects were more likely to experience recurrences (p = .002), especially of depressive illness (< .001), and had more rehospitalizations (p = .01) and suicide attempts (p = .03). RC bipolar I patients showed major initial differences and more rapid initial clinical changes, especially toward depression, with less favorable long-term outcomes than non-RC cases during treatment with olanzapine. Inclusion of RC bipolar disorder patients can complicate therapeutic trials, but these patients require further study for differential responsiveness to innovative treatments with methods of assessing clinical response that take their mood instability into account.

Phenomenology of Rapid-Cycling Bipolar Disorder: Data From the First 500 Participants in the Systematic Treatment Enhancement Program

OBJECTIVE: This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status. METHOD: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. CONCLUSIONS: Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

A multicentre study of the efficacy and safety of topiramate in mania

The aim of the current study was to evaluate the relationship between quetiapine's effect on the improvement of mood symptoms in bipolar patients and brain metabolite level changes as measured by proton magnetic resonance spectroscopy (1H-MRS). Rapid cycling bipolar patients in the manic state were recruited and treated with quetiapine for 12 weeks. Clinical assessment was performed using the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression-Severity scale (CGI-S) at baseline and weekly intervals during the 12-week period. In order to evaluate metabolite level changes over time, 1H-MRS scans were acquired at baseline and week 12. There were significant reductions in YMRS scores (by 43.0%), HDRS scores (by 27.5%) and CGI-S score (by 44.6%) over the 12 week-period. Lactate levels significantly decreased over the 12-week study period (22.4%). This change in lactate levels was more prominent in quetiapine responders than in non-responders. Additionally, there was a positive correlation between changes in lactate levels and those in YMRS scores (r = 0.52, p = 0.003). Our findings suggest that quetiapine's antimanic and antidepressant efficacy in patients with rapid cycling bipolar disorder may potentially be related to decreased lactate levels in frontal regions of the brain.