1. Rapid cycling refers to 4 or more mood episodes within a year with no required period of remission between episodes. 2. Treatment is challenging as rapid cycling is relatively resistant to pharmacological treatment, though the goal is significant symptom reduction rather than complete prevention. 3. Treatment involves identifying and addressing potential contributing factors like medical illnesses or substances, stopping antidepressants, adding a mood stabilizer like lithium or valproate, and sometimes combining agents with anti-manic and antidepressant properties.

1. RAPID CYCLING
BIPOLAR DISORDERS
Dr. Rajeev Ranjan Raj
1

2. Outline
• Introduction
• Historical background
• Definition and nosological status
• Types of rapid cycling
• Clinical characteristics
• Etiopathogenesis(including Rapid cycling inducing agents )
• Management
• Conclusion
2

3. Introduction
• In bipolar disorders, there is great variability in the frequency
of episode recurrences and duration.
• In addition to random spontaneous cycles, a spectrum of rapid
cycle frequency has been observed in which the tendency for
mania and depression to recur regularly and frequently are
very much pronounced.
• It occurs in 5% to 15% of patients with bipolar disorder (APA,
1994; Kaplan and Sadock, 1995).
• 3

4. HISTORICAL BACKGROUND
• Kahlbaum - “circular” manic-depressive psychosis
(1931)
• Astrup’s chronic manic depressive illness (1959)
• The first formal mention of Rapid cycling affective
disorders as a distinctive group was made by Dunner
and Fieve (1974) in discussing clinical factors in
lithium prophylaxis failure.
4

5. DEFINITION AND NOSOLOGICAL
STATUS
• Dunner and Fieve (1974) defined rapid cyclers as those patients
who presented at least four affective episodes per year.
 The following criteria are the important features of their
definition: -
1) four and more episodes of depression, mania or hypomania must
occur in the previous 12 months;
2) a euthymic interval is not required between a manic and
depressive episode to be counted as two episodes;
3) numbers of episodes are tabulated, rather that number of cycles;
4) episodes are demarcated by a switch to an episode of opposite
polarity or by a period of remission.
5

6. • The conceptualization of rapid cycling is introduced
for the first time in (DSM-IV), which accepts Dunner
and Fieve definition of rapid cycling as a course
specifier, with slight modification:
• “Episodes are demarcated either by partial or full
remission for at least two months or a switch to an
episode of opposite polarity.”
6

7. • Kramlinger and Post (1996) defined rapid alteration of
episodes occurring within the course several days (ultrarapid
cycling), to distinct, abrupt mood shifts of less than 24 hours
duration that showed much faster frequencies (Ultra-ultra
rapid or ultradian cycling)
• The concept has not been given acceptance in ICD-10.
However rapid alteration of manic, hypomanic and depressive
symptoms has been included in Bipolar Affective disorder,
current episode mixed (F31.6).
7

8. TYPES OF RAPID CYCLING
• According to time of onset:
• Early onset: Affective disorder actually starting with rapid cycles.
Kukopulos et al.,(1983) found 23% of rapid cyclers as early onset
rapid cyclers
• Late onset: Rapid cycling appearing after a period of conventional
slow cycles.
• According to causation:
• Spontaneous: Patients presenting spontaneous appearance of
clinical phenomenon.
• Externally induced: Rapid cycling induced by pharmacological or
nonpharmacological factors.
8

9. • According to cycle length:
• Classical rapid cycling: Cycle length from 3
days to 12 weeks.
• Ultra rapid cycling: Cycle length of less than
48 hours.
• Ultra ultra rapid cycling: Cycle length of less
than 24 hours.
9

10. EPIDEMIOLOGY
• 5% to 15% in patients with bipolar affective disorder (APA,
1994; Kaplan and Sadock, 1995).
• Adulthood (Coryel et al 1992; Persad et al 1996) with original
reports indicating 30 years as the approximate mean age of
onset.
• However rapid cycling in children and adolescents (Geller et al.,
1995) and in elderly (Nakamura and Kinosita, 1994) have been
reported.
• It occurs more frequently in women (70%-90%), mostly in
postpartum and menopausal period (Kukopulos et al., 1983).
10

11. ETIOPATHOGENESIS
• Studies on the etiopathogenesis of rapid cycling have been
tentative, mostly hypothetical and are still inconclusive.
 Rapid cycling inducing agents:
• Pharmacological factors and nonpharmacological factors.
A. Pharmacological factors:
 Tricyclic antidepressants
 SSRI
 Cyproheptadine (a serotinergic receptor antagonist): Gold et al.,
1980.
 Lithium carbonate: Kukopulos et al., 1980.
 L-dopa: Ko et al., 1981.
 Monoamine oxidase inhibitors: Mattson et al., 1981.
11

12. B. Nonpharmacological factors
 Electroconvulsive therapy
 Pregnancy
 Multiple sclerosis
 Cerebral sarcoidosis
 Graves’ disease
 Subarachnoid hemorrhage
 Cerebrovascular accident
 Hypothyroidism
12

13.  Age
 Kindling phenomena
 Female gender
 Premorbid temperament
 Hypothyroidism
 Dysregulation of circadian activity- altered sleep cycle can
provoke rapid cycling in bipolar disorder
13

14. MANAGEMENT OF RAPID CYCLING
• Lithium;
• Anticonvulsants (carbamazepine, valproate, lamotrigine,
gabapentin, and topiramate);
• Benzodiazepines, especially clonazepam and lorazepam;
• Atypical antipsychotics (clozapine, resperidone, and
olanzepine);
• L-type calcium channel blockers (nimodepine,
amlodepine,and isradepine);
• Thyroid hormone usually thyroxine.
14

15. • Lithium: Statistics from several studies have placed the
percentage of rapid cyclers at 5%to 15% with as many as 72%
to82% of these exhibiting poor response to lithium (Calabrese
et al., 1993).
• Carbamazepine: Data from several studies support the use of
carbamazepine along with adjunctive medications for rapid
cycling with response rate for acute treatment being 32% for
depression and 52% for mania and prophylactic rate of 57%
for depression and 59% for mania (Calabrese et al., 1995).
Calabrese et al., 1995 suggested marked antimanic efficacy
and poor to moderate antidepressant properties.
15

16. • Valproate: Calabrese et al., (1990) found evidence of
augmentation of lithium with valproate in 66% of patients
receiving combination therapy and concluded that valproate
has a marked efficacy for manic and mixed states but minimal
to moderate antidepressant properties.
• Predictors of positive outcome for acute and prophylactic
mania were:
• (1)the presence of a family history of a mood disorder;
• (2) being lithium naïve;
• (3) BP 2 designation;
• (4) mixed states.
16

17.  Predictors of negative outcome :
• (1) severity of mania;
• (2) increasing episodes frequencies;
• (3) increasing severity of mania during natural
course of illness.
17

18. • Lamotrigine: Calabrese et al., (2000) indicate lamotrigine
monotherapy to be useful treatment for some patient with
rapid cycling (41% of patient with lamotrigine v/s 26% with
placebo were stable without relapse for 6 months). Frye et al.,
(2000) found prevalence of marked antidepressant response on
lamotrigine (45% v/s 19% on placebo).
• Topiramate: Marcotte (1998) found topiramate might be
useful in mood disorder unresponsive to traditional therapy.
Topiramate might be selected to control manic or hypomanic
breakthrough.
• 18

19. • Atypical antipsychotics: Olanzepine was found to be
effective in reducing symptoms of mania and well tolerated in
patients with rapid cycling (Sanger et al., 2002). Quetiapine
could be an effective treatment for rapid cycling patients
(Vieta et al., 2002). Clozapine produced marked improvement
in mood and psychotic symptoms in resistant bipolar patients
and presence of rapid cycling did not clinical outcome
(Calabrese et al., 1996).
• Benzodiazepines: Clonazepam is an excellent as needed
medication to treat daytime mood variation and in some ends
up as the most effective mood stabilizer.
19

20. • Thyroid supplementation: Preliminary data indicate
thyroid supplementation may be useful in augmenting the
prophylactic efficacy of partial responders to lithium,
carbamazepine, and valproate (Bauer al., 1990). Mood
stabilizers augmented with enough T4 to raise the free
thyroxine index to approximately 1.5 times the upper limits of
the normal range are likely to produce positive therapeutic
effects. Thus a normal thyroid status should not discourage
clinicians from pursuing thyroid supplementation.
• .
20

21. • Other agents: Choline and inositol, fatty acid moities of those
lipoproteins making up cell membranes and /or participating in
second messenger systems, have also been added to treatment
regimens for rapid cycling. There are spotty reports of success
(Stoll et al. 1996) L-type calcium channel blockers especially
nimodipine are used in ultradian cycling. Antidepressants
should be used only in refractory depressive episodes and
MAO inhibitors, reversible MAO inhibitors or bupropion
should be selected.
•
21

22. 22

23. SUMMARY OF RAPID CYCLING
• Occurrence of ≥ 4 mood disturbances in a year
• Episodes are demarcated either by partial/ full remission for
atleast 2 months or a switch to opposite polarity.
• Relatively resistant to most pharmacological treatment.
• Realistic goal  Significant reduction of symptoms than complete
prevention of symptoms.
• Despite growing therapeutic armamentarium - remains one of the
greatest challenge. 23

24. Rapid cycling
• 1st
look for - factors promoting cycling - hypothyroidism, drugs,
alcohol, hormonal treatment, endocrine disturbances.
• Anti depressants should be stopped & mood stabilizer added.
• Treatment - Valproate > Lithium, alternative - Lamotrigine
• Combining mood stabilizer agent which have predominantly anti
manic & anti depressive properties - promising.
24

25. Rapid cycling
Suggested algorithm (Yatham et al)
• Allow every new treatment/ combination sufficient time to exhibit its
efficacy.
25

26. Experimental drugs
• Calcium channel blockers- Verapamil, Diltiazem showed mixed
responses.
• Nimodipine- Improvement in ultrarapid bipolar (Pazzaglia et al, 98)
• Magnesium sulphate- Improvement noted in severe, treatment
resistant manic episode (Heiden et al, 99)
• Tamoxifen- found to be effective in a small series of patients (Manji
& Chen, 02), probably because of its Phophokinase C inhibition.
• Ώ 3 Fatty acids, Eicosapentanoic acid (EPA)- Unknown benefit.
26

27. Summary of medications
Agent Manic Mixed Depressive Maintenance
Lithium
+
+ +
Divalproate + + +
Carbamazepine + +
Lamotrigine + +
Olanz/Floux +
Olanzapine + + +
Risperidone + +
Quetiapine + +
Aripiprazole + + +
Ziprasidone + +
Lurasidone +
ECT + + +/-
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