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Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.
This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.
Imprecise nomenclature
Post et al1 coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.
In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.2 Geller and colleagues3 proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.
Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.4
A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.
Table 1
Differential diagnosis in suspected URC
| Phenomenon | Considerations for assessment |
|---|---|
| Mixed episodes in bipolar I disorder, or mixed depressive episodes in bipolar II disorder | DSM-IV-TR mixed episodes entail the co-occurrence of manic and depressive symptoms during the same episode without an intervening period of recovery. ICD-10 includes “rapid alternation of manic, hypomanic or depressive symptoms…from day to day or even hour to hour” in its definition of a mixed episode |
| Distress responses to acute environmental adversities (eg, adjustment disorders with mixed disturbance of emotions and conduct) | One would expect an absence of corresponding sleep-wake cycle changes or speech-language and psychomotor disturbances |
| Intoxication/withdrawal from psychoactive substances or drug-induced mental status changes (eg, corticosteroids, amphetamine, cocaine); a history of substance abuse also may be associated with development of URC in BD patients4 | Substance-induced mood fluctuations caused by intoxication/withdrawal can mimic affective cycling |
| Disinhibition states and frontal lobe syndromes as seen in traumatic brain injury and other CNS disorders, such as multiple sclerosis | Assess for signs of perseveration and history of head trauma or neurologic damage from cumulative toxic-metabolic insults (eg, chronic alcoholism) |
| Autonomic hyperarousal, emotional volatility, and hyperreactivity to environmental stresses, suggestive of PTSD | Determine the presence of a trauma history and review whether DSM-IV-TR symptoms and associated features of PTSD exist, including re-experiencing/reliving and avoidance, as well as paranoid thinking, dissociation, and nightmares |
| Recurrent mood shifts related to premenstrual dysphoric disorder may mimic URC. Other endocrine dysfunctions also may present with URC (eg, thyroid or ovarian malignancies) | Affirm the independent presence of BD before inferring its manifestations solely from premenstrual mood changes |
| Trait affective instability associated with borderline personality disorder | Trait mood instability is more chronic and enduring than episodic, and would not be expected to occur in tandem with signs of psychomotor activation that define mania/hypomania |
| BD: bipolar disorder; ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th revision; PTSD: posttraumatic stress disorder; URC: ultra-rapid cycling | |
Duration criteria
Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.5 More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.6 Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.7 In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)8 that involve continual (ultradian) mood cycling in as many as 80% of cases.9
Is URC a valid construct?
A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.
Studies by our group10 and others11 have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.
A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.
Borderline personality disorder
A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,12 others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.
Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,13 in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.
Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation14; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.15 Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,16 whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.
See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.
Treatment considerations
No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.
Broadly speaking, treatment for URC, similar to RC, pragmatically involves:
- identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
- treating medical comorbidities such as hypothyroidism
- optimizing treatment with mood stabilizing agents
- exercising caution when using antidepressants (see below).
Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group17 compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.
Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al18) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al19 found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.
Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.
Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.27 No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.
Table 2
Evidence-based treatments for ultra-rapid cycling BD
| Intervention | Strength of evidence | Comment |
|---|---|---|
| Antidepressant elimination | Cycling frequency may lengthen during antidepressant-free periods among patients with RC20; long-term (up to 1 year) antidepressant use in RC patients may increase the likelihood of depressive recurrences19 | Findings based mostly on small sample sizes; no controlled trials of antidepressant cessation as an intervention specifically for URC |
| Lithium | Single case report of ECT-induced URC resolved by lithium augmentation during continued ECT22 | No large-scale or randomized trials |
| Carbamazepine | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies among patients with RC |
| Divalproex | Single case report describing resolution of a 48-hour cycle after augmentation of lithium with divalproex23 | No large-scale or randomized trials |
| Lamotrigine | Single case report of 100 mg/d lamotrigine augmentation to divalproex yielded 8 months of remission in a 25-year-old man with BD II and a long-standing pattern of 3 days of hypomania followed by 5 days of depression24 | No large-scale or randomized trials |
| Topiramate | Single case report in URC describing reduction of cycling frequency over 3 years25 | Multiple large scale placebo-controlled studies in bipolar mania have been negative |
| Second-generation antipsychotics | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies in RC |
| Combinations of ≥2 mood stabilizing drugs | No controlled trials or case reports | Combining multiple anti-cycling agents is intuitively logical but largely unstudied |
| Nimodipine | 1 unipolar and 11 BD patients treated in randomized, off-on-off-on fashion (begun at 90 mg/d, increased up to 720 mg/d, mean duration of 12 weeks on active drug)26 | Response in 5 of 9 completers. Findings await replication with larger sample sizes |
| Hypermetabolic thyroid hormone (levothyroxine) | Findings from a small (N = 11) study of adjunctive high-dose levothyroxine (0.15 to 0.4 mg/d, with dosages increased by 0.05 to 0.1 mg/d every 1 to 2 weeks); an unspecified subgroup had “a very rapid cycling pattern” (reviewed by Bauer et al21) | 10 of 11 RC patients had reductions in depressive symptoms, 5 of 7 had improvement from baseline manic symptoms (observation period >60 days) |
| ECT | Case reports of improvement with ECT in refractory RC that was presumed secondary to tricyclic antidepressants | Reports of induction of URC by ECT22; whether or not ECT would more likely improve or exacerbate cyclicity for a given patient may require empirical determination |
| BD: bipolar disorder; BD II: bipolar II disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | ||
Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:
- number of days euthymic
- number of days with depression
- number of days with abnormal mood elevation
- number of occasions in which moods of both polarities occur on the same day.
Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.
Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.
Table 3
Tips for managing suspected ultra-rapid cycling BD
| Do’s | Don’ts |
|---|---|
| Ascertain a history of ≥1 lifetime manic or hypomanic episode to diagnose BD | Diagnose BD solely on the presence of rapid mood fluctuations |
| Determine the presence of changes in sleep, energy, speech-language, and related behavior as correlates of mood to differentiate syndromes from isolated variation in mood | Ignore constellations of associated signs and symptoms of mania/hypomania |
| Obtain patient history to assess for head trauma or other medical and neurologic events that could have affective or other psychiatric manifestations | Disregard possible medical etiologies for new-onset affective dysregulation |
| Ascertain the resolution of 1 episode before counting the resurgence of symptoms as constituting a new episode; a waxing and waning course may reflect illness chronicity with incomplete recovery rather than true cyclicity | Misidentify incomplete recovery from an existing episode as the occurrence of new multiple episodes, which would inflate false-positive cases of RC or URC |
| Advise patients to refrain from alcohol or illicit substances that could destabilize mood | Assume that comorbid alcohol or illicit substance abuse will remit only after mood stabilization has been achieved, rather than the reverse |
| Monitor changes in sleep-wake cycles and the effects of erratic sleep or sleep deprivation on mood | Ignore the effects of poor sleep hygiene on mood |
| Minimize antidepressant exposure in patients with RC or URC | Continue long-term antidepressant maintenance therapy in patients with manic or mixed features or ongoing oscillations between mania/hypomania and depression |
| Assure euthyroid status and consider the potential utility of hypermetabolic levothyroxine | Assume that RC or URC will resolve solely by normalizing or optimizing thyroid function |
| Use rational, pharmacodynamically nonredundant anti-cycling drugs | Ignore the cumulative burden of adverse effects of multiple drugs |
| Consider the potential role for ECT as a strategy to arrest URC during any phase of BD | Assume ECT has value only during acute depressive phases of BD |
| Use prospective mood charting to document the evolution of mood changes over time, particularly when gauging treatment efficacy | Rely solely on impressionistic recall of mood states or polarity changes as reflecting distinct phasic changes |
| BD: bipolar disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | |
Table
Rapid cycling and ultra-rapid cycling BD: A comparison
| Construct | Rapid cycling | Ultra-rapid cycling |
|---|---|---|
| Bipolar I vs II | Predominantly BD IIa | No systematic data |
| Sex | Predominantly women | No systematic data |
| Longitudinal course | May be a transient phenomenon that can occur at any timeb or an enduring phenomenon that may persist for yearsc | Ultradian patterns may be more common across the first several episodes among pediatric BD patientsd |
| Age at onset | Associated with younger age at onsete | May be more evident in prepubescent onset mood disordersd; ultradian cycling more likely when onset occurs before age 13 than in adulthoode |
| Diurnal variation in mood | Morning-to-evening mood switches usually involve depression to mania/hypomania, with the opposite typifying evening-to-morning mood switchesf | Not reported |
| Relationship to environmental stresses | Life stresses may precede initial affective episodes but may be less important as subsequent episodes arise with increasing automaticity | No systematic data |
| Relationship to menstrual cycle | Despite case reports and self-reported links between RC and menstrual mood exacerbations, prospective data do not identify associations between RC and menstrual patternsg,h | No systematic data |
| Subclinical hypothyroidism | Bauer and Whybrow identified hypothyroidism independent of lithium use in 60% of 30 rapidly cycling BD patients, with evidence of improvement in a separate study of 11 RC patients given suprametabolic levothyroxine (reviewed by Bauer et ali) | No systematic data |
| Relationship to psychosis | Nonea | No systematic data |
| Relationship to antidepressant use | Naturalistic observations suggest RC may occur later in the illness course as a result of antidepressant use.c Small open case series data suggest shorter intermorbid intervals on antidepressants with longer intervals off antidepressants.j RC patients often receive antidepressants, but causal relationships are not well-documented.k Some case-control data dispute links between antidepressant use and RCl | No specific published cases |
| Considerations for suicide risk | RC linked with more serious suicide attemptsl | Suicide attempts may be associated with cycling within an episodem or rapid shifting in moodn |
| Time course for judging treatment efficacy | Efforts to diminish acute affective instability may be measured over the course of days to weeks | By definition, treatment of RC involves relapse prevention over the course of 1 year |
| BD: bipolar disorder; RC: rapid cycling | ||
| References a. Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program. Am J Psychiatry. 2004;161(10):1902-1908. b. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131. c. Koukopoulos A, Sani G, Koukopoulos AE, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord. 2003;73(1-2):75-85. d. Geller B, Tillman R, Bolhofner K, et al. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry. 2008;65(10):1125-1133. e. Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7):864-872. f. Feldman-Naim S, Turner EH, Leibenluft E. Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58(2):79-84. g. Leibenluft E, Ashman SB, Feldman-Naim S, et al. Lack of relationship between menstrual cycle phase and mood in a sample of women with rapid cycling bipolar disorder. Biol Psychiatry. 1999;46(4):577-580. h. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184. i. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162. j. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411. k. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377. l. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914-920. m. Fawcett J, Scheftner W, Clark D, et al. Clinical predictors of suicide in patients with major affective disorders: a controlled prospective study. Am J Psychiatry. 1987;144(1):35-40. n. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448. | ||
From a biologic perspective, a handful of preliminary studies have examined genetic markers or familial patterns that might be related to rapid cycling (RC) or ultra-rapid cycling (URC). These include a reported link between URC and the low activity variant of the catechol-o-methyltransferase gene polymorphism in a small group of patients with velo-cardio-facial syndrome,a although this finding was not replicated in a larger sample.a Other preliminary reports on RC have implicated both the long (l) and short (s) allelic variants of the serotonin transporter gene (SLC6A4), the val66met variant of the brain-derived neurotrophic factor gene, and the circadian cryptochrome 2 (CRY2) gene (reviewed by Bauer et alb). These candidate loci have been examined in RC but not URC.
URC has not been examined as a familial entity, although in the National Institute of Mental Health Collaborative Depression Study, DSM-IV-TR RC did not occur with elevated frequency in bipolar pedigrees.c Rapid mood switches—abrupt rather than gradual transitions from one affective pole to another—appear to be only slightly, nonsignificantly more common in first-degree bipolar relatives of BD patients who themselves have rapid rather than gradual transitions from one affective pole to the other.d
Neuroimaging studies in BD seldom focus on subpopulations with RC or URC, and have been confined mainly to case reports that have yielded limited, non-generalizable observations, such as state-dependent variations in prefrontal activity during tasks of facial recognition (reviewed by Bauer et alb).
References
a. Papolos DF, Veit S, Faedda GL, et al. Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry. 1998;3(4):346-349.
b. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
c. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131.
d. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448.
Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time
In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression
Related Resources
- American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
- Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.
Drug Brand Names
- Carbamazepine • Equetro, Tegretol
- Divalproex • Depakote
- Lamotrigine • Lamictal
- Levothyroxine • Synthroid
- Lithium • Lithobid
- Nimodipine • Nimotop
- Topiramate • Topamax
Disclosures
Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.
Acknowledgment
The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.
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17. Goldberg JF, Bowden CL, Calabrese JR, et al. Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder. Biol Psychiatry. 2008;63(1):125-130.
18. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377.
19. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380.
20. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184.
21. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
22. Zavorotnyy M, Diemer J, Patzelt J, et al. Occurrence of ultra-rapid cycling during electroconvulsive therapy in bipolar depression. World J Biol Psychiatry. 2009;10(4 Pt 3):987-990.
23. Lepkifker E, Iancu I, Dannon P, et al. Valproic acid in ultra-rapid cycling: a case report. Clin Neuropharmacol. 1995;18(1):72-75.
24. Woo YS, Chae JH, Jun TY, et al. Lamotrigine added to valproate successfully treated a case of ultra-rapid cycling bipolar disorder. Psychiatry Clin Neurosci. 2007;61(1):130-131.
25. Karama S, Lal S. Adjunctive topiramate in ultradian cycling bipolar disorder: case report with 3-year follow-up. Eur Psychiatry. 2006;21(4):280-281.
26. Pazzaglia PJ, Post RM, Ketter TA, et al. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res. 1993;49(3):257-272.
27. Reilly-Harrington NA, Deckersbach T, Knauz R, et al. Cognitive behavioral therapy for rapid-cycling bipolar disorder: a pilot study. J Psychiatr Pract. 2007;13(5):291-297.
Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.
This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.
Imprecise nomenclature
Post et al1 coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.
In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.2 Geller and colleagues3 proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.
Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.4
A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.
Table 1
Differential diagnosis in suspected URC
| Phenomenon | Considerations for assessment |
|---|---|
| Mixed episodes in bipolar I disorder, or mixed depressive episodes in bipolar II disorder | DSM-IV-TR mixed episodes entail the co-occurrence of manic and depressive symptoms during the same episode without an intervening period of recovery. ICD-10 includes “rapid alternation of manic, hypomanic or depressive symptoms…from day to day or even hour to hour” in its definition of a mixed episode |
| Distress responses to acute environmental adversities (eg, adjustment disorders with mixed disturbance of emotions and conduct) | One would expect an absence of corresponding sleep-wake cycle changes or speech-language and psychomotor disturbances |
| Intoxication/withdrawal from psychoactive substances or drug-induced mental status changes (eg, corticosteroids, amphetamine, cocaine); a history of substance abuse also may be associated with development of URC in BD patients4 | Substance-induced mood fluctuations caused by intoxication/withdrawal can mimic affective cycling |
| Disinhibition states and frontal lobe syndromes as seen in traumatic brain injury and other CNS disorders, such as multiple sclerosis | Assess for signs of perseveration and history of head trauma or neurologic damage from cumulative toxic-metabolic insults (eg, chronic alcoholism) |
| Autonomic hyperarousal, emotional volatility, and hyperreactivity to environmental stresses, suggestive of PTSD | Determine the presence of a trauma history and review whether DSM-IV-TR symptoms and associated features of PTSD exist, including re-experiencing/reliving and avoidance, as well as paranoid thinking, dissociation, and nightmares |
| Recurrent mood shifts related to premenstrual dysphoric disorder may mimic URC. Other endocrine dysfunctions also may present with URC (eg, thyroid or ovarian malignancies) | Affirm the independent presence of BD before inferring its manifestations solely from premenstrual mood changes |
| Trait affective instability associated with borderline personality disorder | Trait mood instability is more chronic and enduring than episodic, and would not be expected to occur in tandem with signs of psychomotor activation that define mania/hypomania |
| BD: bipolar disorder; ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th revision; PTSD: posttraumatic stress disorder; URC: ultra-rapid cycling | |
Duration criteria
Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.5 More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.6 Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.7 In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)8 that involve continual (ultradian) mood cycling in as many as 80% of cases.9
Is URC a valid construct?
A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.
Studies by our group10 and others11 have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.
A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.
Borderline personality disorder
A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,12 others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.
Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,13 in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.
Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation14; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.15 Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,16 whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.
See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.
Treatment considerations
No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.
Broadly speaking, treatment for URC, similar to RC, pragmatically involves:
- identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
- treating medical comorbidities such as hypothyroidism
- optimizing treatment with mood stabilizing agents
- exercising caution when using antidepressants (see below).
Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group17 compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.
Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al18) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al19 found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.
Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.
Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.27 No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.
Table 2
Evidence-based treatments for ultra-rapid cycling BD
| Intervention | Strength of evidence | Comment |
|---|---|---|
| Antidepressant elimination | Cycling frequency may lengthen during antidepressant-free periods among patients with RC20; long-term (up to 1 year) antidepressant use in RC patients may increase the likelihood of depressive recurrences19 | Findings based mostly on small sample sizes; no controlled trials of antidepressant cessation as an intervention specifically for URC |
| Lithium | Single case report of ECT-induced URC resolved by lithium augmentation during continued ECT22 | No large-scale or randomized trials |
| Carbamazepine | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies among patients with RC |
| Divalproex | Single case report describing resolution of a 48-hour cycle after augmentation of lithium with divalproex23 | No large-scale or randomized trials |
| Lamotrigine | Single case report of 100 mg/d lamotrigine augmentation to divalproex yielded 8 months of remission in a 25-year-old man with BD II and a long-standing pattern of 3 days of hypomania followed by 5 days of depression24 | No large-scale or randomized trials |
| Topiramate | Single case report in URC describing reduction of cycling frequency over 3 years25 | Multiple large scale placebo-controlled studies in bipolar mania have been negative |
| Second-generation antipsychotics | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies in RC |
| Combinations of ≥2 mood stabilizing drugs | No controlled trials or case reports | Combining multiple anti-cycling agents is intuitively logical but largely unstudied |
| Nimodipine | 1 unipolar and 11 BD patients treated in randomized, off-on-off-on fashion (begun at 90 mg/d, increased up to 720 mg/d, mean duration of 12 weeks on active drug)26 | Response in 5 of 9 completers. Findings await replication with larger sample sizes |
| Hypermetabolic thyroid hormone (levothyroxine) | Findings from a small (N = 11) study of adjunctive high-dose levothyroxine (0.15 to 0.4 mg/d, with dosages increased by 0.05 to 0.1 mg/d every 1 to 2 weeks); an unspecified subgroup had “a very rapid cycling pattern” (reviewed by Bauer et al21) | 10 of 11 RC patients had reductions in depressive symptoms, 5 of 7 had improvement from baseline manic symptoms (observation period >60 days) |
| ECT | Case reports of improvement with ECT in refractory RC that was presumed secondary to tricyclic antidepressants | Reports of induction of URC by ECT22; whether or not ECT would more likely improve or exacerbate cyclicity for a given patient may require empirical determination |
| BD: bipolar disorder; BD II: bipolar II disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | ||
Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:
- number of days euthymic
- number of days with depression
- number of days with abnormal mood elevation
- number of occasions in which moods of both polarities occur on the same day.
Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.
Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.
Table 3
Tips for managing suspected ultra-rapid cycling BD
| Do’s | Don’ts |
|---|---|
| Ascertain a history of ≥1 lifetime manic or hypomanic episode to diagnose BD | Diagnose BD solely on the presence of rapid mood fluctuations |
| Determine the presence of changes in sleep, energy, speech-language, and related behavior as correlates of mood to differentiate syndromes from isolated variation in mood | Ignore constellations of associated signs and symptoms of mania/hypomania |
| Obtain patient history to assess for head trauma or other medical and neurologic events that could have affective or other psychiatric manifestations | Disregard possible medical etiologies for new-onset affective dysregulation |
| Ascertain the resolution of 1 episode before counting the resurgence of symptoms as constituting a new episode; a waxing and waning course may reflect illness chronicity with incomplete recovery rather than true cyclicity | Misidentify incomplete recovery from an existing episode as the occurrence of new multiple episodes, which would inflate false-positive cases of RC or URC |
| Advise patients to refrain from alcohol or illicit substances that could destabilize mood | Assume that comorbid alcohol or illicit substance abuse will remit only after mood stabilization has been achieved, rather than the reverse |
| Monitor changes in sleep-wake cycles and the effects of erratic sleep or sleep deprivation on mood | Ignore the effects of poor sleep hygiene on mood |
| Minimize antidepressant exposure in patients with RC or URC | Continue long-term antidepressant maintenance therapy in patients with manic or mixed features or ongoing oscillations between mania/hypomania and depression |
| Assure euthyroid status and consider the potential utility of hypermetabolic levothyroxine | Assume that RC or URC will resolve solely by normalizing or optimizing thyroid function |
| Use rational, pharmacodynamically nonredundant anti-cycling drugs | Ignore the cumulative burden of adverse effects of multiple drugs |
| Consider the potential role for ECT as a strategy to arrest URC during any phase of BD | Assume ECT has value only during acute depressive phases of BD |
| Use prospective mood charting to document the evolution of mood changes over time, particularly when gauging treatment efficacy | Rely solely on impressionistic recall of mood states or polarity changes as reflecting distinct phasic changes |
| BD: bipolar disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | |
Table
Rapid cycling and ultra-rapid cycling BD: A comparison
| Construct | Rapid cycling | Ultra-rapid cycling |
|---|---|---|
| Bipolar I vs II | Predominantly BD IIa | No systematic data |
| Sex | Predominantly women | No systematic data |
| Longitudinal course | May be a transient phenomenon that can occur at any timeb or an enduring phenomenon that may persist for yearsc | Ultradian patterns may be more common across the first several episodes among pediatric BD patientsd |
| Age at onset | Associated with younger age at onsete | May be more evident in prepubescent onset mood disordersd; ultradian cycling more likely when onset occurs before age 13 than in adulthoode |
| Diurnal variation in mood | Morning-to-evening mood switches usually involve depression to mania/hypomania, with the opposite typifying evening-to-morning mood switchesf | Not reported |
| Relationship to environmental stresses | Life stresses may precede initial affective episodes but may be less important as subsequent episodes arise with increasing automaticity | No systematic data |
| Relationship to menstrual cycle | Despite case reports and self-reported links between RC and menstrual mood exacerbations, prospective data do not identify associations between RC and menstrual patternsg,h | No systematic data |
| Subclinical hypothyroidism | Bauer and Whybrow identified hypothyroidism independent of lithium use in 60% of 30 rapidly cycling BD patients, with evidence of improvement in a separate study of 11 RC patients given suprametabolic levothyroxine (reviewed by Bauer et ali) | No systematic data |
| Relationship to psychosis | Nonea | No systematic data |
| Relationship to antidepressant use | Naturalistic observations suggest RC may occur later in the illness course as a result of antidepressant use.c Small open case series data suggest shorter intermorbid intervals on antidepressants with longer intervals off antidepressants.j RC patients often receive antidepressants, but causal relationships are not well-documented.k Some case-control data dispute links between antidepressant use and RCl | No specific published cases |
| Considerations for suicide risk | RC linked with more serious suicide attemptsl | Suicide attempts may be associated with cycling within an episodem or rapid shifting in moodn |
| Time course for judging treatment efficacy | Efforts to diminish acute affective instability may be measured over the course of days to weeks | By definition, treatment of RC involves relapse prevention over the course of 1 year |
| BD: bipolar disorder; RC: rapid cycling | ||
| References a. Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program. Am J Psychiatry. 2004;161(10):1902-1908. b. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131. c. Koukopoulos A, Sani G, Koukopoulos AE, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord. 2003;73(1-2):75-85. d. Geller B, Tillman R, Bolhofner K, et al. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry. 2008;65(10):1125-1133. e. Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7):864-872. f. Feldman-Naim S, Turner EH, Leibenluft E. Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58(2):79-84. g. Leibenluft E, Ashman SB, Feldman-Naim S, et al. Lack of relationship between menstrual cycle phase and mood in a sample of women with rapid cycling bipolar disorder. Biol Psychiatry. 1999;46(4):577-580. h. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184. i. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162. j. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411. k. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377. l. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914-920. m. Fawcett J, Scheftner W, Clark D, et al. Clinical predictors of suicide in patients with major affective disorders: a controlled prospective study. Am J Psychiatry. 1987;144(1):35-40. n. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448. | ||
From a biologic perspective, a handful of preliminary studies have examined genetic markers or familial patterns that might be related to rapid cycling (RC) or ultra-rapid cycling (URC). These include a reported link between URC and the low activity variant of the catechol-o-methyltransferase gene polymorphism in a small group of patients with velo-cardio-facial syndrome,a although this finding was not replicated in a larger sample.a Other preliminary reports on RC have implicated both the long (l) and short (s) allelic variants of the serotonin transporter gene (SLC6A4), the val66met variant of the brain-derived neurotrophic factor gene, and the circadian cryptochrome 2 (CRY2) gene (reviewed by Bauer et alb). These candidate loci have been examined in RC but not URC.
URC has not been examined as a familial entity, although in the National Institute of Mental Health Collaborative Depression Study, DSM-IV-TR RC did not occur with elevated frequency in bipolar pedigrees.c Rapid mood switches—abrupt rather than gradual transitions from one affective pole to another—appear to be only slightly, nonsignificantly more common in first-degree bipolar relatives of BD patients who themselves have rapid rather than gradual transitions from one affective pole to the other.d
Neuroimaging studies in BD seldom focus on subpopulations with RC or URC, and have been confined mainly to case reports that have yielded limited, non-generalizable observations, such as state-dependent variations in prefrontal activity during tasks of facial recognition (reviewed by Bauer et alb).
References
a. Papolos DF, Veit S, Faedda GL, et al. Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry. 1998;3(4):346-349.
b. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
c. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131.
d. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448.
Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time
In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression
Related Resources
- American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
- Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.
Drug Brand Names
- Carbamazepine • Equetro, Tegretol
- Divalproex • Depakote
- Lamotrigine • Lamictal
- Levothyroxine • Synthroid
- Lithium • Lithobid
- Nimodipine • Nimotop
- Topiramate • Topamax
Disclosures
Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.
Acknowledgment
The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.
Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.
This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.
Imprecise nomenclature
Post et al1 coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.
In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.2 Geller and colleagues3 proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.
Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.4
A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.
Table 1
Differential diagnosis in suspected URC
| Phenomenon | Considerations for assessment |
|---|---|
| Mixed episodes in bipolar I disorder, or mixed depressive episodes in bipolar II disorder | DSM-IV-TR mixed episodes entail the co-occurrence of manic and depressive symptoms during the same episode without an intervening period of recovery. ICD-10 includes “rapid alternation of manic, hypomanic or depressive symptoms…from day to day or even hour to hour” in its definition of a mixed episode |
| Distress responses to acute environmental adversities (eg, adjustment disorders with mixed disturbance of emotions and conduct) | One would expect an absence of corresponding sleep-wake cycle changes or speech-language and psychomotor disturbances |
| Intoxication/withdrawal from psychoactive substances or drug-induced mental status changes (eg, corticosteroids, amphetamine, cocaine); a history of substance abuse also may be associated with development of URC in BD patients4 | Substance-induced mood fluctuations caused by intoxication/withdrawal can mimic affective cycling |
| Disinhibition states and frontal lobe syndromes as seen in traumatic brain injury and other CNS disorders, such as multiple sclerosis | Assess for signs of perseveration and history of head trauma or neurologic damage from cumulative toxic-metabolic insults (eg, chronic alcoholism) |
| Autonomic hyperarousal, emotional volatility, and hyperreactivity to environmental stresses, suggestive of PTSD | Determine the presence of a trauma history and review whether DSM-IV-TR symptoms and associated features of PTSD exist, including re-experiencing/reliving and avoidance, as well as paranoid thinking, dissociation, and nightmares |
| Recurrent mood shifts related to premenstrual dysphoric disorder may mimic URC. Other endocrine dysfunctions also may present with URC (eg, thyroid or ovarian malignancies) | Affirm the independent presence of BD before inferring its manifestations solely from premenstrual mood changes |
| Trait affective instability associated with borderline personality disorder | Trait mood instability is more chronic and enduring than episodic, and would not be expected to occur in tandem with signs of psychomotor activation that define mania/hypomania |
| BD: bipolar disorder; ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th revision; PTSD: posttraumatic stress disorder; URC: ultra-rapid cycling | |
Duration criteria
Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.5 More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.6 Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.7 In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)8 that involve continual (ultradian) mood cycling in as many as 80% of cases.9
Is URC a valid construct?
A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.
Studies by our group10 and others11 have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.
A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.
Borderline personality disorder
A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,12 others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.
Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,13 in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.
Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation14; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.15 Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,16 whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.
See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.
Treatment considerations
No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.
Broadly speaking, treatment for URC, similar to RC, pragmatically involves:
- identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
- treating medical comorbidities such as hypothyroidism
- optimizing treatment with mood stabilizing agents
- exercising caution when using antidepressants (see below).
Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group17 compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.
Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al18) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al19 found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.
Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.
Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.27 No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.
Table 2
Evidence-based treatments for ultra-rapid cycling BD
| Intervention | Strength of evidence | Comment |
|---|---|---|
| Antidepressant elimination | Cycling frequency may lengthen during antidepressant-free periods among patients with RC20; long-term (up to 1 year) antidepressant use in RC patients may increase the likelihood of depressive recurrences19 | Findings based mostly on small sample sizes; no controlled trials of antidepressant cessation as an intervention specifically for URC |
| Lithium | Single case report of ECT-induced URC resolved by lithium augmentation during continued ECT22 | No large-scale or randomized trials |
| Carbamazepine | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies among patients with RC |
| Divalproex | Single case report describing resolution of a 48-hour cycle after augmentation of lithium with divalproex23 | No large-scale or randomized trials |
| Lamotrigine | Single case report of 100 mg/d lamotrigine augmentation to divalproex yielded 8 months of remission in a 25-year-old man with BD II and a long-standing pattern of 3 days of hypomania followed by 5 days of depression24 | No large-scale or randomized trials |
| Topiramate | Single case report in URC describing reduction of cycling frequency over 3 years25 | Multiple large scale placebo-controlled studies in bipolar mania have been negative |
| Second-generation antipsychotics | No controlled trials or case reports | Possible anti-cycling benefits relevant for URC could be inferred from post hoc studies in RC |
| Combinations of ≥2 mood stabilizing drugs | No controlled trials or case reports | Combining multiple anti-cycling agents is intuitively logical but largely unstudied |
| Nimodipine | 1 unipolar and 11 BD patients treated in randomized, off-on-off-on fashion (begun at 90 mg/d, increased up to 720 mg/d, mean duration of 12 weeks on active drug)26 | Response in 5 of 9 completers. Findings await replication with larger sample sizes |
| Hypermetabolic thyroid hormone (levothyroxine) | Findings from a small (N = 11) study of adjunctive high-dose levothyroxine (0.15 to 0.4 mg/d, with dosages increased by 0.05 to 0.1 mg/d every 1 to 2 weeks); an unspecified subgroup had “a very rapid cycling pattern” (reviewed by Bauer et al21) | 10 of 11 RC patients had reductions in depressive symptoms, 5 of 7 had improvement from baseline manic symptoms (observation period >60 days) |
| ECT | Case reports of improvement with ECT in refractory RC that was presumed secondary to tricyclic antidepressants | Reports of induction of URC by ECT22; whether or not ECT would more likely improve or exacerbate cyclicity for a given patient may require empirical determination |
| BD: bipolar disorder; BD II: bipolar II disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | ||
Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:
- number of days euthymic
- number of days with depression
- number of days with abnormal mood elevation
- number of occasions in which moods of both polarities occur on the same day.
Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.
Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.
Table 3
Tips for managing suspected ultra-rapid cycling BD
| Do’s | Don’ts |
|---|---|
| Ascertain a history of ≥1 lifetime manic or hypomanic episode to diagnose BD | Diagnose BD solely on the presence of rapid mood fluctuations |
| Determine the presence of changes in sleep, energy, speech-language, and related behavior as correlates of mood to differentiate syndromes from isolated variation in mood | Ignore constellations of associated signs and symptoms of mania/hypomania |
| Obtain patient history to assess for head trauma or other medical and neurologic events that could have affective or other psychiatric manifestations | Disregard possible medical etiologies for new-onset affective dysregulation |
| Ascertain the resolution of 1 episode before counting the resurgence of symptoms as constituting a new episode; a waxing and waning course may reflect illness chronicity with incomplete recovery rather than true cyclicity | Misidentify incomplete recovery from an existing episode as the occurrence of new multiple episodes, which would inflate false-positive cases of RC or URC |
| Advise patients to refrain from alcohol or illicit substances that could destabilize mood | Assume that comorbid alcohol or illicit substance abuse will remit only after mood stabilization has been achieved, rather than the reverse |
| Monitor changes in sleep-wake cycles and the effects of erratic sleep or sleep deprivation on mood | Ignore the effects of poor sleep hygiene on mood |
| Minimize antidepressant exposure in patients with RC or URC | Continue long-term antidepressant maintenance therapy in patients with manic or mixed features or ongoing oscillations between mania/hypomania and depression |
| Assure euthyroid status and consider the potential utility of hypermetabolic levothyroxine | Assume that RC or URC will resolve solely by normalizing or optimizing thyroid function |
| Use rational, pharmacodynamically nonredundant anti-cycling drugs | Ignore the cumulative burden of adverse effects of multiple drugs |
| Consider the potential role for ECT as a strategy to arrest URC during any phase of BD | Assume ECT has value only during acute depressive phases of BD |
| Use prospective mood charting to document the evolution of mood changes over time, particularly when gauging treatment efficacy | Rely solely on impressionistic recall of mood states or polarity changes as reflecting distinct phasic changes |
| BD: bipolar disorder; ECT: electroconvulsive therapy; RC: rapid cycling; URC: ultra-rapid cycling | |
Table
Rapid cycling and ultra-rapid cycling BD: A comparison
| Construct | Rapid cycling | Ultra-rapid cycling |
|---|---|---|
| Bipolar I vs II | Predominantly BD IIa | No systematic data |
| Sex | Predominantly women | No systematic data |
| Longitudinal course | May be a transient phenomenon that can occur at any timeb or an enduring phenomenon that may persist for yearsc | Ultradian patterns may be more common across the first several episodes among pediatric BD patientsd |
| Age at onset | Associated with younger age at onsete | May be more evident in prepubescent onset mood disordersd; ultradian cycling more likely when onset occurs before age 13 than in adulthoode |
| Diurnal variation in mood | Morning-to-evening mood switches usually involve depression to mania/hypomania, with the opposite typifying evening-to-morning mood switchesf | Not reported |
| Relationship to environmental stresses | Life stresses may precede initial affective episodes but may be less important as subsequent episodes arise with increasing automaticity | No systematic data |
| Relationship to menstrual cycle | Despite case reports and self-reported links between RC and menstrual mood exacerbations, prospective data do not identify associations between RC and menstrual patternsg,h | No systematic data |
| Subclinical hypothyroidism | Bauer and Whybrow identified hypothyroidism independent of lithium use in 60% of 30 rapidly cycling BD patients, with evidence of improvement in a separate study of 11 RC patients given suprametabolic levothyroxine (reviewed by Bauer et ali) | No systematic data |
| Relationship to psychosis | Nonea | No systematic data |
| Relationship to antidepressant use | Naturalistic observations suggest RC may occur later in the illness course as a result of antidepressant use.c Small open case series data suggest shorter intermorbid intervals on antidepressants with longer intervals off antidepressants.j RC patients often receive antidepressants, but causal relationships are not well-documented.k Some case-control data dispute links between antidepressant use and RCl | No specific published cases |
| Considerations for suicide risk | RC linked with more serious suicide attemptsl | Suicide attempts may be associated with cycling within an episodem or rapid shifting in moodn |
| Time course for judging treatment efficacy | Efforts to diminish acute affective instability may be measured over the course of days to weeks | By definition, treatment of RC involves relapse prevention over the course of 1 year |
| BD: bipolar disorder; RC: rapid cycling | ||
| References a. Schneck CD, Miklowitz DJ, Calabrese JR, et al. Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program. Am J Psychiatry. 2004;161(10):1902-1908. b. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131. c. Koukopoulos A, Sani G, Koukopoulos AE, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord. 2003;73(1-2):75-85. d. Geller B, Tillman R, Bolhofner K, et al. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry. 2008;65(10):1125-1133. e. Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7):864-872. f. Feldman-Naim S, Turner EH, Leibenluft E. Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58(2):79-84. g. Leibenluft E, Ashman SB, Feldman-Naim S, et al. Lack of relationship between menstrual cycle phase and mood in a sample of women with rapid cycling bipolar disorder. Biol Psychiatry. 1999;46(4):577-580. h. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184. i. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162. j. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411. k. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377. l. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914-920. m. Fawcett J, Scheftner W, Clark D, et al. Clinical predictors of suicide in patients with major affective disorders: a controlled prospective study. Am J Psychiatry. 1987;144(1):35-40. n. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448. | ||
From a biologic perspective, a handful of preliminary studies have examined genetic markers or familial patterns that might be related to rapid cycling (RC) or ultra-rapid cycling (URC). These include a reported link between URC and the low activity variant of the catechol-o-methyltransferase gene polymorphism in a small group of patients with velo-cardio-facial syndrome,a although this finding was not replicated in a larger sample.a Other preliminary reports on RC have implicated both the long (l) and short (s) allelic variants of the serotonin transporter gene (SLC6A4), the val66met variant of the brain-derived neurotrophic factor gene, and the circadian cryptochrome 2 (CRY2) gene (reviewed by Bauer et alb). These candidate loci have been examined in RC but not URC.
URC has not been examined as a familial entity, although in the National Institute of Mental Health Collaborative Depression Study, DSM-IV-TR RC did not occur with elevated frequency in bipolar pedigrees.c Rapid mood switches—abrupt rather than gradual transitions from one affective pole to another—appear to be only slightly, nonsignificantly more common in first-degree bipolar relatives of BD patients who themselves have rapid rather than gradual transitions from one affective pole to the other.d
Neuroimaging studies in BD seldom focus on subpopulations with RC or URC, and have been confined mainly to case reports that have yielded limited, non-generalizable observations, such as state-dependent variations in prefrontal activity during tasks of facial recognition (reviewed by Bauer et alb).
References
a. Papolos DF, Veit S, Faedda GL, et al. Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry. 1998;3(4):346-349.
b. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
c. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131.
d. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7(5):441-448.
Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time
In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression
Related Resources
- American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
- Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.
Drug Brand Names
- Carbamazepine • Equetro, Tegretol
- Divalproex • Depakote
- Lamotrigine • Lamictal
- Levothyroxine • Synthroid
- Lithium • Lithobid
- Nimodipine • Nimotop
- Topiramate • Topamax
Disclosures
Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.
Acknowledgment
The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.
1. Kramlinger KG, Post RM. Ultra-rapid and ultradian cycling in bipolar affective illness. Br J Psychiatry. 1996;168(3):314-323.
2. Leibenluft E. Severe mood dysregulation irritability, and the diagnostic boundaries of bipolar disorder in youths. Am J Psychiatry. 2011;168(2):129-142.
3. Geller B, Tillman R, Bolhofner K. Proposed definitions of bipolar I disorder episodes and daily rapid cycling phenomena in preschoolers school-aged children, adolescents, and adults. J Child Adolesc Psychopharmacol. 2007;17(2):217-222.
4. Feinman JA, Dunner DL. The effect of alcohol and substance abuse on the course of bipolar affective disorder. J Affect Disord. 1996;37(1):43-49.
5. Maj M, Pirozzi R, Formicola AM, et al. Reliability and validity of four alternative definitions of rapid-cycling bipolar disorder. Am J Psychiatry. 1999;156(9):1421-1424.
6. Jenner FA, Gjessing LR, Cox JR, et al. A manic depressive psychotic with a persistent forty-eight hour cycle. Br J Psychiatry. 1967;113(501):895-910.
7. Zwil AS, McAllister TW, Cohen I, et al. Ultra-rapid cycling bipolar affective disorder following a closed-head injury. Brain Inj. 1993;7(2):147-152.
8. Geller B, Tillman R, Craney JL, et al. Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry. 2004;61(5):459-467.
9. Geller B, Sun K, Zimerman B, et al. Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord. 1995;34(4):259-268.
10. Goldberg JF, Garno JL, Callahan AM, et al. Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability. J Clin Psychiatry. 2008;69(11):1751-1757.
11. Zimmerman M, Ruggero CJ, Chelminski I, et al. Psychiatric diagnoses in patients previously overdiagnosed with bipolar disorder. J Clin Psychiatry. 2010;71(1):26-31.
12. MacKinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1-14.
13. Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder. Demographics diagnosis, family history, and course. Arch Gen Psychiatry. 1992;49(2):126-131.
14. Koenigsberg HW, Harvey PD, Mitropoulou V, et al. Characterizing affective instability in borderline personality disorder. Am J Psychiatry. 2002;159(5):784-788.
15. Henry C, Mitropoulou V, New AS, et al. Affective instability and impulsivity in borderline personality and bipolar II disorders: similarities and differences. J Psychiatr Res. 2001;35(6):307-312.
16. Gottschalk A, Bauer MS, Whybrow PC. Evidence of chaotic mood variation in bipolar disorder. Arch Gen Psychiatry. 1995;52(11):947-959.
17. Goldberg JF, Bowden CL, Calabrese JR, et al. Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder. Biol Psychiatry. 2008;63(1):125-130.
18. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370-377.
19. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380.
20. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179-184.
21. Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder—diagnostic concepts. Bipolar Disord. 2008;10(1 Pt 2):153-162.
22. Zavorotnyy M, Diemer J, Patzelt J, et al. Occurrence of ultra-rapid cycling during electroconvulsive therapy in bipolar depression. World J Biol Psychiatry. 2009;10(4 Pt 3):987-990.
23. Lepkifker E, Iancu I, Dannon P, et al. Valproic acid in ultra-rapid cycling: a case report. Clin Neuropharmacol. 1995;18(1):72-75.
24. Woo YS, Chae JH, Jun TY, et al. Lamotrigine added to valproate successfully treated a case of ultra-rapid cycling bipolar disorder. Psychiatry Clin Neurosci. 2007;61(1):130-131.
25. Karama S, Lal S. Adjunctive topiramate in ultradian cycling bipolar disorder: case report with 3-year follow-up. Eur Psychiatry. 2006;21(4):280-281.
26. Pazzaglia PJ, Post RM, Ketter TA, et al. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res. 1993;49(3):257-272.
27. Reilly-Harrington NA, Deckersbach T, Knauz R, et al. Cognitive behavioral therapy for rapid-cycling bipolar disorder: a pilot study. J Psychiatr Pract. 2007;13(5):291-297.
1. Kramlinger KG, Post RM. Ultra-rapid and ultradian cycling in bipolar affective illness. Br J Psychiatry. 1996;168(3):314-323.
2. Leibenluft E. Severe mood dysregulation irritability, and the diagnostic boundaries of bipolar disorder in youths. Am J Psychiatry. 2011;168(2):129-142.
3. Geller B, Tillman R, Bolhofner K. Proposed definitions of bipolar I disorder episodes and daily rapid cycling phenomena in preschoolers school-aged children, adolescents, and adults. J Child Adolesc Psychopharmacol. 2007;17(2):217-222.
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