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Rapid Cycling Bipolar Disorder: Update on Phenomenology and Treatment
Aditi Mehta, MD; Joseph R. Calabrese, MD Medscape Psychiatry & Mental Health. 2005;8(2) ©2005 Medscape
The rapid cycling pattern of bipolar disorder was first noted by Kraepelin in the early 1900s. In 1974, Dunner and Fieve identified rapid cycling as a specific entity that could quite possibly predict nonresponse to treatment. Many independent studies confirmed the existence of rapid cycling and, finally, in 1994, following a meta-analysis by Bauer and colleagues, the rapid cycling specifier was included in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association. The DSM-IV defines rapid cycling bipolar disorder as a pattern of presentation accompanied by 4 or more mood episodes in a 12-month period, with a typical course of mania or hypomania followed by depression or vice versa. The episodes must be demarcated by a full or partial remission lasting at least 2 months or by a switch to a mood state of opposite polarity. Research shows that it is common for rapid cyclers to have frequent brief depressive episodes that do not necessarily meet duration criteria for full depressive episodes as per DSM-IV.
Some investigators have further classified rapid cycling into ultrarapid (cycling every few days) and ultradian (cycling that occurs daily).[6,7] Kraepelin referred to these patterns of cycling as being the inherent mood lability seen in almost all patients with bipolar disorder; consequently, these additional specifiers have never been incorporated into the DSM-IV. Initially, investigators hypothesized that rapid cycling predicted poor response to individual medications, but more recent data suggest that this entity is also accompanied by higher rates of recurrence and is more likely to be a nonspecific predictor of poor outcome, such as is the case for psychosis.[8,9]
Demographics and Risk Factors
A review of several studies demonstrates a wide range in prevalence rates (13% to 56%),[10,11] which may be due to confusion regarding interpretations of rapid cycling and recruitment bias. Rapid cycling patients usually tend to be younger, with illness onset before the age of 17 years. Women are more likely than men to be rapid cyclers, with prevalence rates of 70% (range, 58% to 92%) or even higher.[12,16,17] The higher prevalence of rapid cycling in women could be attributed to increased occurrence of hypothyroidism or menstrual cycle irregularities. Some researchers have asserted that hypothyroidism can cause rapid cycling,[18-20] while others question this theory.[21,22] According to Calabrese and colleagues, rapid cycling is predominant in patients with bipolar II, which usually manifests as depression at onset. Since women are more prone to depression, they often may be diagnosed with rapid cycling. Additionally, rapid cycling may be induced by the use of antidepressant drugs,[24,25] especially in women. Finally, in patients with no psychiatric history, rapid cycling can emerge after varying kinds of trauma to the brain, such as subarachnoid hemorrhage, diffuse cerebral damage following closed head injury, or focal temporal pole damage.
In a recent review article by Papadimitriou and colleagues, rapid cycling was described as rare in unipolar patients, but considerably more common in bipolar patients. Rapid cyclers also suffer higher morbidity, which is evident in more serious suicide attempts, more frequent hospitalizations, and a greater tendency to seek treatment later in the course of illness. Episodes also consist of more severe depression, less severe mania, and fewer psychoses compared with nonrapid cyclers. In addition, rapid cyclers usually have a prior history of rapid cycling, substance abuse, and childhood physical and/or sexual abuse.[5,13] A family history of bipolar disorder, depression, and substance abuse usually exists as well. In contrast to some other researchers, Kupka noted bipolar I disorder subtype to be more prevalent than bipolar II subtype in rapid cycling patients. In short-term clinical trials, patients with rapid cycling tend to be placebo-responsive, but the available long-term data suggest that this pattern of presentation predicts poor long-term outcome.
Course of Illness
In the early years of the 20th century, Kraepelin reported an association between cycle length and the progression of illness. Later research revealed that as the number of affective episodes increases, the length of each cycle decreases[30-32] and eventually stabilizes after 4-6 episodes. Patients with a higher frequency of cycling usually spend more time in mania and hypomania with every subsequent episode, while depressive episodes appear to be unaffected by the frequency of cycling. This observation, however, is inconsistent with the growing impression that highly recurrent treatment-refractory depression is the hallmark of rapid cycling bipolar disorder.
Patients with rapid cycling bipolar disorder are difficult to treat, especially if complete mood stabilization is the goal. Rapid cyclers are considered to be in remission if they stop cycling and their functioning returns to near normal in occupational, family, and social settings. Sleep patterns are reliable indicators of relapse, and if these patients have regular sleep, they may avoid cycling into mania. In patients who have never been treated, mood stabilizers such as lithium are the first line of treatment. Permissive definition of mood stabilizers characterizes medications as effective in the long-term management of at least 1 phase of bipolar disorder without worsening any other phase of the illness. Therefore, effective treatment should not precipitate mania, depression, or rapid cycling, and should minimize the burden of treatment-emergent side effects. Sufficient evidence exists to support the use of lithium and lamotrigine in the prevention of cycling in bipolar disorder. Lamotrigine is particularly efficacious in patients with predominant depression and rapid cycling bipolar II, while divalproex is a first-line option in rapid cycling bipolar I.[36,37]
The combination of lithium with carbamazepine, valproate, or lamotrigine for maintenance along with olanzapine as an adjunct also has some support from controlled studies. Quetiapine monotherapy has also shown effectiveness in treating depression in patients with a rapid cycling course.
At least 8 placebo-controlled, randomized trials have demonstrated lithium to be prophylactic in bipolar disorder. A meta-analysis of 16 studies of bipolar disorder by Tondo and colleagues showed that lithium may be considered first-line treatment in the prophylaxis of rapid cycling bipolar disorder. Many studies support the efficacy of lithium as a mood stabilizer,[41-44] particularly in the maintenance of bipolar type II patients. Conversely, other studies have illustrated poor efficacy of lithium in rapid cycling bipolar disorder,[2,24] especially compared with divalproex in the hypomanic and manic phases of rapid cycling bipolar disorder.[2,24,46-48] However, these studies may have been confounded by many variables (eg, concomitant antidepressant use), and therefore cannot be generalized.
Most bipolar type II patients who have not been treated with antidepressants usually show a good response to lithium. Response to lithium improves upon the discontinuation of antidepressant(s). Other factors that need to be considered include gender, cycling history, and past use of lithium in treatment subjects. Women tend to respond better and longer to lithium, even though their serum levels are lower. In addition, the response to lithium is usually lower in individuals with a history of 4 depressive or 12 manic episodes. This phenomenon may be related to neuropsychological changes due to increased incidents of lithium discontinuation. Sometimes, poor response to lithium that is attributed to its poor efficacy actually exists due to treatment refractoriness of these patients as they have been cycling for a long time before lithium was administered.
In an open, prospective study by Calabrese and colleagues, divalproex was markedly effective in mania for 72% of the sample, 94% for mixed states, and 33% for depression. Divalproex has moderate-to-marked acute and prophylactic antimanic properties in rapid cyclers with only modest antidepressant effects. It has proved effective in patients with a family history of affective disorder, no prior lithium therapy, and bipolar II or mixed states. Patients with more frequent or severe mania, or borderline personality disorder, usually do not respond as well. Prior studies indicated that patients with mixed states or rapid cycling respond better to divalproex compared with lithium. Calabrese and colleagues recently reported on a 20-month double-blind study in which both lithium and divalproex had equal effect on time and rate of relapse. At the present time, the emerging consensus is that lithium and divalproex have similar efficacy in the long-term treatment of rapid cycling bipolar disorder.[41,53] Divalproex can sometimes be combined with lithium to improve response.[54,55] However, while the combination of lithium and divalproex administered over 6 months showed marked efficacy in mania for 85% of patients and in depression for 60% of patients, only 50% of patients showed bimodal stabilization.
In an open-label study of lamotrigine as add-on or monotherapy, patients with more severe symptoms of mania did not improve, but subgroups of patients with rapid cycling who also had both depressive and hypomanic symptoms showed significant improvement.[56,57] In the first double-blind, placebo-controlled study of a homogeneous cohort of prospectively enrolled patients with rapid cycling bipolar disorder, lamotrigine monotherapy over a 6-month study period exhibited evidence of mood-stabilizing efficacy, especially in patients with bipolar II. Compared with placebo, lamotrigine at an average dose of 288 ± 94 mg/day showed higher median survival and effectiveness (time to drop out for any reason). When comparing lithium with lamotrigine in bipolar patients, patients taking lamotrigine showed lower rates of rapid cycling. Frye and colleagues compared lamotrigine, gabapentin, and placebo in treatment-refractory patients with a high percentage (92%) of rapid cycling and found marked antidepressant response in lamotrigine-treated patients. Even though lamotrigine has limited efficacy in the manic phase, its moderate-to-marked efficacy in depression and hypomania makes it a good complement to lithium and divalproex in the treatment of rapid cycling. In addition, lamotrigine has a relatively weight-neutral profile, which is a potential advantage over other mood stabilizers such as lithium or divalproex.
Early studies of the efficacy of carbamazepine showed that a diagnosis of rapid cycling predicts a positive response to carbamazepine. More recently, this observation has been persuasively refuted by a series of studies. Carbamazepine has been found to have a very limited scope in the treatment of rapid cycling, especially as monotherapy. It has moderate-to-marked efficacy in the manic phase, and poor-to-moderate efficacy in the depressed phase. When carbamazepine was added to another mood stabilizer, particularly lithium, it was more advantageous than monotherapy. It was seen that the response rate in bipolar patients on carbamazepine alone was half that of the response with lithium monotherapy. However, both lithium and carbamazepine achieved earlier response and twice the response rate as lithium alone. Now the use of a congener, oxcarbazepine, has increased in an effort to avoid potential adverse reactions from carbamazepine; however, oxcarbazepine has not been studied enough in the treatment of rapid cycling to make any conclusive statements.
Tohen and colleagues compared olanzapine and the combination of olanzapine plus fluoxetine to placebo in acute bipolar I depression and found that both monotherapy and combination therapy showed significant improvement in depression. In addition, the improvement on combination therapy occurred as early as the first week of treatment and neither therapy caused an elevation in treatment-emergent mania. Recent randomized, double-blind trials comparing the short-term efficacy of olanzapine vs placebo in acute mania have shown good response. The patient population consisted of current rapid cyclers and also those with a history of a rapid cycling course. Vieta and colleagues recently looked at long-term outcomes from pooled data of the prior randomized studies and found that even though the rapid cycling patients are more likely to relapse in the long term, olanzapine improves their overall outcome.
Quetiapine is a bimodal mood stabilizer effective for treatment of both bipolar mania and depression. In an open-label study, quetiapine was found to be effective and well tolerated as monotherapy or as an add-on to a mood stabilizer in treatment of Type I rapid cycling bipolar disorder. In the first randomized, placebo-controlled trial to evaluate the efficacy of quetiapine in depressed patients with and without rapid cycling bipolar disorder, significant improvement was seen independent of the rapid cycling pattern. A 3-month follow-up study in which quetiapine was given to patients on lithium and/or divalproex or concomitant lamotrigine showed improvement in rapid cycling in groups with quetiapine. Additionally, Vieta and colleagues reported that quetiapine is an efficacious add-on therapy to other mood stabilizers for rapid cycling and is more effective for mania. The dosage of quetiapine for acute illness ranged from 720 ± 84 mg/day for mania vs 183 ± 29 mg/day for depression.
A limited number of open-label studies have supported the use of topiramate in rapid cycling bipolar disorders. Double-blinded, placebo-controlled studies have been unable to demonstrate the mood-stabilizing effects of topiramate in general cohorts of patients with bipolar disorder. It has an advantage of reversing increased body weight, however, as well as normalizing glycemic control and blood pressure, which are side effects of some of the other medications for rapid cycling.
Rapid cycling bipolar disorder is defined as 4 or more mood episodes alternating between depression and mania over a 12-month period. Patients with rapid cycling are usually managed through the use of multiple mood stabilizers in combination that target minimizing the frequency of the cycles without worsening any phase of the disorder. Lithium and divalproex are considered first-line treatments for acute and long-term management of rapid cycling in bipolar I (especially for mania) and lamotrigine for bipolar II patients who usually present with depression. Prior notions that lithium is ineffective in rapid cycling are not supported by recently conducted maintenance studies. Other drugs such as olanzapine and quetiapine are currently being studied in the long-term treatment of rapid cycling bipolar disorder. Although the acute treatment of patients with rapid cycling bipolar disorder is satisfactory, the long-term management of this variant of illness is quite challenging, with response rates frequently being very modest and rates of comorbidity quite high. There is emerging evidence to suggest that highly recurrent, treatment-refractory depression is the hallmark of rapid cycling bipolar disorder, and that many patients presenting in this way are being incorrectly diagnosed and treated with selective serotonin reuptake inhibitors used as monotherapy.
Supported by an independent educational grant from GlaxoSmithKline
Aditi Mehta, MD, Resident, Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio
Joseph R. Calabrese, MD, Professor of Psychiatry, Case Western Reserve University School of Medicine; Director, Mood Disorders Program; Director, Division of Ambulatory Care, University Hospitals of Cleveland, Cleveland, Ohio
Disclosure: Aditi Mehta, MD, has disclosed no relevant financial relationships.
Disclosure: Joseph R. Calabrese, MD, has disclosed that he has received grants for clinical research and/or educational activities from Abbott, AstraZeneca, Merck, GlaxoSmithKline, Janssen, Eli Lilly, and Pfizer. Dr. Calabrese has also disclosed that he serves on an advisory board for Abbott, AstraZeneca, Bristol-Myers