Rapid cycling affective disorders: A clinical review

Rapid Cycling Affective Disorders: A Clinical Review Renato D. Alarcon Different issues pertaining to the study of Rapid Cycling Affective Disorders @CAD) are examined. WAD’s appear to be relatively infrequent, even though their clinical characterization does not differ from the conventional affective disorders. RC can be classified as early onset and late onset, according to time of appearance; spontaneous and induced (by pharmacological or nonpharmaCOlOgiCal agents), according to causation; and ultra-rapid (48 hours) and classical (three days to 12 weeks), according to cycle length. Case reports seem to show that the ultra-rapid cyclers may have clear differences when compared with the classical rapid cyclers: elderly male patients seem to start their affective picture with RC, whereasyounger female patients are predominantly classical rapid cyclers. The inducers seem to be far less specific and the response to treatment far less consistent in the ultra-rapid cyclers. The most widely accepted etiopathogenic theory ascribes an important role to thyroid hypofunction, probably precipitated by lithium treatment. The review, however, suggests that this theory may explain only a minority of cases. Treatment approaches remain tentative, inconsistent and even conflicting with the proposed etiopathogeneses. Clearly, terminological precisions, well defined clinical samples, neurohormonal and psychophysiological tests, and epidemiological designs, can and should help elucidate the key question of whether RCAD is an autonomous clinical condition or simply one end in the spectrum of cyclicity. @ 1985 by Grune & Stratton,

Inc.

T

HE SYSTEMATIC clinical study of rapid cycling affective disorders (RCAD’S) dates back to only ten years.’ Although clinical descriptions resembling presentday notions of RCAD are found in the early references to manic-depressive illness, and extensive studies of single patients were published throughout the 60’s and the early 70’s, Z-6 mention of the concept is either conspicuously absent or barely present in two major contemporary psychiatric textbooks’.* in two recent comphrehensive reviews.“m13 This volumes on affective disorders,‘,1° and in two phenomenological paper attempts to compile all the material published in recent years on this subject, review the original descriptions, examine the clinical characterization of the disorder, the induction of rapid cycling, existing etiopathogenetic and therapeutic approaches, and finally, assess some of the most critical issues confronting this area of clinical inquiry. HISTORICAL

BACKGROUND

Paschalis et a1.r3 include a comprehensive list of RCAD cases published mostly in the European literature during the first four decades of this century. In their review on the natural course of affective disorders, Zis and GoodwinI allude indirectly to the limited reference of RCAD cases in the works of Kraepelin, Bleuler, and other renowned clinicians. In fact, Kraepelin I6 discusses only one such case when analyzing the type of clinical course in manic-depressive insanity. The concepts psychosis found in 4%‘* to 18%19of bipolar patients, of “circular”” manic-depressive

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Address reprint requests to Renoto D. Alarcon, M.D.. M.P.H.. University oJ’ Alubamu,

@ 1985by

Univerrify Hospital 3N Room 390,

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0010-440X/85/2606ooO5$03.W/0

522

ComprehensivePsychiatry, Vol. 26,No. 6,(November/December)

1985

RAPID CYCLING AFFECTIVE

523

DISORDERS

and “chronic” manic-depressive illness described in 5% to 20% of different samples,z0.2’ quite probably include observations on rapid cycling but there is no specific mention of the phenomenon. Lundquist” and StenstedtZ3 describe very few cases in the Scandinavian literature. Rennie” confirms the increasing number of affective episodes with age, and asserts that bipolar patients present more attacks than unipolars, a finding later restated and expanded by Perris’> who found that female bipolars cycle more frequently than male bipolars. These last two findings have particular relevance to the understanding of rapid cycling. The first formal mention of RCAD’s as a distinctive group was made by Dunner and Fieve’ in discussing clinical factors in lithium prophylaxis failure. They defined rapid cyclers as those patients who presented at least four affective episodes (depressive, manic, or hypomanic) per year, and found that ten of 12 such patients were lithium nonresponders. Their definition of rapid cycling has been conventionally accepted by all authors working on the subject. Later, Dunner et al.?’ specified that the four or more affective episodes per year were supposed to be present “prior to an initiation of lithium prophylactic therapy,” a qualification that has since been abandoned as RC has been described (or rediscovered) in many long-term, long-treated (with lithium and other medications) bipolar patients. In their second paper, these authors compared RC’s with non-RC’s and concluded that the two groups are not distinguishable on the basis of symptoms, age of onset, or family history. Another paper by Dunner et al.?’ reaffirms these notions, emphasizing that his sample originated from an outpatient clinic and that it included only bipolar patients. Indeed, a number of authors have also described rapid cycling unipolar patients,?x,2’ a situation that tests the limits of the new nosological sategories,“’ as will be discussed in the following text. The relatively small number of case reports published since the mid-70’s reflects the fact that RC is indeed an unusual clinical phenomenon. Moreover, the case descriptions seem to mark a shift away from the original definition of rapid cycling although without abandoning it completely. The emphasis of the case reports is on the induction of rapid cycling by a number of pharmacological and nonpharmacological agents, many times in the context of long-term, regularly cycling affective disorders. Some of these case reports have laid the ground for the first etiopathogenetic elaborations about the RC phenomenon. CLINICAL

CHARACTERISTICS

The range of yearly affective episodes in RC patients goes from the minimum of four included in the original definition’ to more than 20 if the cycle length and/ or the symptom-free interval are shorter than the average. As for the incidence of RC among patients with affective disorders, the consensus seems to be that it is a relatively infrequent occurrence. Dunner and Fieve’ found that 13% of their bipolar outpatients were rapid cyclers. Wehr and Goodwin” assert that centers specializing in lithium treatment or in the management of “difficult” cases are bound to report higher incidences. The fact that the most frequent means of publishing on RC in medical and psychiatric journals is the brief case report attests to the RC’s relative scarcity. This is why the very high number (118) of RCAD patients presented by an Italian groupJ’,j3 is intriguing, even if we agree with their opinion that clinicians

524

RENATO D. ALARCON

are more aware of the phenomenon now, and that the increased use of tricyclics enhances the chances of RC occurrence. The retrospective method of their study, has probably inflated the frequency in their series, as subjective judgments were made in reviewing hospital charts over a presumed long period of time. The length of an affective cycle can be as short as 48 hours or as long as 12 weeks. Rapid cyclers as a group seem to have a longer duration of bipolar illness than that of the “conventional” cyclers, which obviously means a higher number of prior affective episodes.34 The original reports on RCAD1,3S indicate 30 years as the approximate mean age of onset. Kukopulos et a1.34 encounter that the age of onset of RC in previously conventional cyclers-approximately 42 years-is the same at which RC’s “from the beginning” start presenting clinical symptoms, thus suggesting an internal, age-related modulation triggering the RC phenomena. The few reports on periodicity and time of mood change2+5~29,3h stress the stability of these parameters. Mood change almost always seems to take place during the last third of the night, when the patient is still asleep. An exception to this is the 48-hour cycler reported by Paschalis et a1.l4 Some authors34.37 contend that the appearance of hypomanic episodes-pharmacologically induced or not-in a patient not previously known to present them, may mark the onset of rapid cyclicity. Rapid cycling occurs much more frequently in women and among them, in the postpartum or menopausal periods. 1,34Patients on lithium who present signs and symptoms of lithium-induced hypothyroidism are apparently more prone to develop 38*39 it is interesting to note that postpartum women also rapid cyclicity than others; present occasional evidence of low thyroid function. Authors agree on the observation that RCAD occurs more frequently in bipolars than in unipolars. Kukopulos et al34 studied the premorbid temperament of their rapid cyclers and, although the majority were considered normal, traits of cyclothymic40 and hyperthymic4’ temperaments predominated in more than 85% of the sample; while this is not different in conventional cyclers, cyclothymics appear to develop RCAD from the beginning of their clinical symptoms whereas hyperthymic would be the “late onset” rapid cyclers’ premorbid style. Cyclothymia and seasonal episodes have been recently brought into clinical focus as clinical variants of affective disorders.4z-U The actual clinical symptoms of the RCAD phases do not differ from those of the conventional, regular or “slow” cyclers. There are no differences in life events, family history, or phase sequence. Dunner and Fieve’ stress the need for more family studies, since evidence of familial rapid cycling would help to demonstrate that RCAD is a unique form of bipolar illness. Greden et al.” obtained positive dexamethasone suppression test (DST) results (nonsuppression) during the depressive episodes in three cases of RC. Recently, Muscettola et a1.45 found that a group of RC’s had the lowest urinary MHPG excretion rate in a sample of bipolar patients, although the number was too small to extract any conclusions, and the work rather decries the use of MHPG as a clinical indicator. Finally, the finding of a poor response to lithium among RC patients provided the initial impetus for the study of RCAD. Of interest is the observation that RC’s may present mixed affective crises30 during lithium therapy rather than attacks of mania and depression.46

RAPID CYCLING

AFFECTIVE

525

DISORDERS

TYPES OF RAPID CYCLING Not all RC patients follow an identical pattern of clinical presentation. In fact. some clear differences can be ascertained when studying the time of appearance of RC with respect to the history of the affective disorder as such, the possible causal factors and even the cycle length (Table 1). Whether these differences represent parameters of RCAD subtyping remains to be seen.

According to Time of Appearance In terms of its appearance within the context of a bipolar affective disorder, RC can be classified as early onset, ie, the affective disorder actually starting with raptd cycles, and late onset, ie, RC appearing after a period (lasting at times, years) of “slow” or regular cycles.+’ Kukopulos et al.‘l found in their sample conventional, of 118 patients, that 32 (ten men and 22 women) were RC’s from the beginning of their illness, most of them Bipolar II. These authors found that the average age of onset of RC in 32 patients was very similar to the age of onset of rapid cyclicity in previously conventional cyclers (40 to 43 years); that is to say that the other 86 patients in the sample had about ten to 12 years of “slow” cycles before becoming rapid cyclers. This clearly suggests that some biological changes in the life cycle might have a significant role in disrupting cycle rhythms and triggering a wave of rapid cycling.JX.“”

According to Causation RCAD patients can be classified as those who present a spontaneous appearance of the clinical phenomenon,J7,‘x and those whose RC’s seem clearly induced by a pharmacological or nonpharmacological agent. It must be clear that spontaneous presentation does not necessarily mean early onset appearance for there are reports of well known but untreated bipolar patients, who without any outside precipitant, progress toward rapid cycling.- ‘05’ These patients, then, could be appropriately classified as late onset, spontaneous RC’s, according to the two parameters discussed SO far. Conversely, some early onset cases have been clearly triggered by psychotropics or other pharmacological agents. While most of the RC-inducing factors are pharmacological (see following text). there are other factors whose study may throw some light into the etiopathogenesis of rapid cycling. Table 1. Types of Rapid Cycling Affective According

to: Time of Appearance *Early onset *Late onset Causation *Spontaneous *Externally Induced Cycle length *Ultra-rapid cyclers Wassrcal rapid cyclers

Disorders

526

According

RENATO D. ALARCON

to Cycle Length

The estimation of cycle length may be a crucial differentiating factor of the RC patient population as a whole. Historically, the first reports on RCAD were about patients who we could in fact call now ultra-rapid cyclers due to an unusually short cycle length of 48 hours. 2,3 Later, cycles lasting days to weeks were called “classical” rapid cyclers,37 namely those who fit Dunner & Fieve’s’ seminal definition. The pertinent question is whether these two types are substantially different or simply represent both ends of a clinical spectrum. To complicate matters, there are reports of mixed RC’s according to cycle length3s4s46 which would indirectly confirm the unitary character of the rapid cycling phenomenon in spite of some differences in presentation. Nevertheless, it is extremely important to examine and compare every possible parameter since some authors have reported on differences in time of appearance, 52.14therapeutic response,53s32 and possible etiopathogenesis.54,55

RAPID CYCLING-INDUCING

AGENTS

Rapid cycling can be induced by a variety of factors. This is the main subject of a number of case reports published in the last two decades and listed in Table 2. The table does not include patients reported by Greden et a1.,37Dunner & Fieve,’ Wehr et al.,” Kripke et al.,48 and Reginaldi et a1.,32 either because of incomplete data, or because of the considerable number of patients studied in the samples. One patient from the Potter et al. seriesS6 is not included as she was reported earlier by Extein et al.54 Actually, the remarks of Bunney et al.@’about the advantages of the case study method are applicable to the selection of the cases included in the table. RC inducers can be grouped as pharmacological and nonpharmacological. (Table 3) The former include a variety of agents, tricyclic antidepressants being the most frequently reported. Siris et aL5’ were the first to report a case of imipramineinduced rapid cycling. Extein et al.54 make the interesting distinction of RC’s induced by a noradrenergic (desipramine) but not a serotonergic (zimelidine) antidepressant. Their patient, a 57-year old bipolar II woman with a 25-year history was admitted with a seven-year course of intractable rapid cycles associated with the use of imipramine and isocarboxazid, a MAOI. The drug trials themselves were similar in doses and blood levels of the two medications but differed in the crucial variable of time of exposure: at least 17 weeks on desipramine and only five on zimelidine. The question of whether a longer treatment on the serotonergic agent could have evolved into a RC pattern remains unanswered. Dibenzepin, a dibenzazepine antidepressant, has also been reported as triggering RCAD in two late onset bipolar cases, ages 70,58 and 6359 years. Reginaldi et a13* found 45 (of 108) RC patients probably induced by tricyclics, 30 of them after one year on antidepressant treatments. These authors relate rapid cycling induction to the phenomenon of “pharmacological hypomania.“40,42,60 Their hypothesis sounds somewhat tautological: rapid cyclicity occurs because tricyclic antidepressants trigger a postdepression hypomania, shorten the depressive phase and eliminate the posthypomanic free interval so that “hypomania itself precipitates a new depression when it is strengthened by the action of antidepressants.”

57

Gelenberg

Doerr et al., 1979

et al., 1978

39

Post et al., 1977

56

43

47

1972

1965

Age

Gerner et al., 1976

Kupfer & Heninger,

Jenner et al., 1967

Bunney & Hartmann,

Author(s)/Year

M

F

M

Sex

13 yrs.?

Onset

1 yr.

35 yrs.

Onset

Onset

Onset

Onset

Onset

RC Appearance

1 % yrs.

23 yrs.

4 yrs.

2 yrs.

Length of Illness

Table 2. Case Reports

weeks

days

48 hours

48 hours

2-6

4-6

48 hours

48 hours

48 hours

Cycle Length

Affective __ Family History

None

None

3 maternal relatives with bipolar disease Not reported

Not reported

Son, suicidal Daughter, moody

Not reported

of Rapid Cycling

/,,m

“I

I

Not reported

Unknown

Unknown

Piribedil

Not reported

Children leaving, suggestions of hysterectomy Unknown (Head Injury?)

Probable RC Inducer

Disorders

*.,

1

..,

Not reported

Amitriptyline

Not reported

Pimozide, Li and Trifluoperazine

Nothing helped

Not reported

Medication (not named)

Effective Treatment

+

_

,,,

,.,

,*

(contmued)

Switch correlates found in activity, sleep pattern, and MHPG levels. Unipolar. Poor response to isocarboxazid, slightly low RAIU. Increased T, and T,, blunted TSH. No relation with CS excretion Unipolar, elevated UFC in depression, normalization when improved

Episodes were not “pure”. High 17OHCS in depression, low in mania Mild to moderate intensity of episodesOccasional paranoid ideas. Increased Tyramine and hydroxyphenylacetic acid excretion Increased early morning awakening and decreased REM sleep in depression. REM deprivation did not abolish cyclicity Dopamine involvement in mania (and RC?) only

Observations

i

22 yrs. 7 yrs.

F

30

46 41

40

Siris et al., 1979

Wehr & Goodwin,

5 yrs?

1 yr.

F F

F

46 53

29

Potter et al., 1982

5 yrs.

6 mos.

F

24

Extein et al., 1982

Onset?

Onset?

1 month

Not reported

Not reported

4 weeks

days

with unipolar depression Not reported

Father, paternal

Positive (not specified)

6 weeks

30-40

2 weeks

weeks

5 yrs.

39 yrs.

l-6

52 days

7 yrs.

8 yrs.

58

42 days 18 days

12 days (onset?)

Not reported

Mother, brother with MDI Depression in mother ECT: 48 hour cycles Not reported Not reported

5 weeks

7 yrs.

weeks

Not reported

6 weeks

16 mos.

l-2

Family History

Table 2. (continued) -

Cycle Length

RC Appearance

3 yrs.

3 yrs.

25 yrs.

Cutler 8 Post, 1982

1979

F

57

Dunner, 1979 (representative case) Extein et al., 1979

2 yrs.

F

27

-

Sex

Age

Author(s)/Year

Length of Illness

Li, neuroleptics, propranolol

lmipramine and Li

Unknown

Desipramine

None

Clorgyline Li Clorgyline Li

and

and

L-thyroxine*

Unknown

Li Chlorpromazine and Li

Amitriptyline lmipramine

lmipramine Lithium? Not reported

Li(lmipramine continued)

Li and neuroleptics Li*

Effective Treatment

lmipramine

Desipramine

ECT?

Probable RC inducer

Sleep Deprivation alleviated depressions Li-induced hypothyroidism. Carbamazepine and LThyroxine failed Amphetamine abuse, hysterical personality. Poor response to Li, L-Thyroxine and Clorgyline

Prior use of TCA’s History of hypothyroidism and estrogen therapy for amenorrhea Li-induced hypothyroidism Patient from prepsychopharmacologica era. RC interspersed with more prolonged episodes Unipolar depression. Increased TSH response to TRH

2 Postpartum depressions. 48-hour hypomania Unipolar?

Depression and hypomania Improvement with sleep deprivation

Observations

~-

32

50

55

Alarcon et al., 1985

Kanter et al.. 1984

Post et al., 1984

72

F

53

1984

7 yrs.

29

Kellner. 1984

Oppenheim,

3 yrs.

53

Jones et al., 1984

22 yrs.

15 yrs.

3 yrs.

10 yrs.

25 yrs.

4 mos 26 yrs.

70 36

Leibow, 1983

12 yrs.

2 yrs.

1982

F

30

Oppenheim,

35

Onset

Onset

Onset

Onset

6 yrs.

Onset?

Onset

Onset 21 yrs.

18 mos.

Onset

weeks

weeks

weeks

days

Not reported

2-3

I-3

3-9

4 weeks

4 weeks

2-8

None

Not reported

None

Mother, maternal grandmother, Bipolar Drsorder None

None Father, paternal grandmother, brother, all bipolar Father, 2 sisters, 1 brother, depressed and suicidal None

3 paternal aunts depressed

IO days

48 hours 4 days

Not reported

35 days

Unknown

Conjugated estrogen Estrogen, ?phenylpropanolamrne TCA’s

MS?

MS?

TCA

Dibenzepin Pregnancy?

and ? Li

Unknown

Carbamazepine

Carbamazepine

D/C inducers, lithium

D/C estrogen

Nothing helped

Nothing helped

Nothing helped

Li L-Thyroxine

Clorgyline, carbamazeprne and thioridazine D/C both

Diabetes

Delirium with carbamazepinehaloperidol combination Relatively high doses needed. Phenytoin and valproic acid failed

Unipolar. severe and resistant Concomitant euthyroid hyperthyroxinemia

Only depressive relapses. Poor response to Li and Amitriptyline Hypomanic rebound? Poor response to Li, imipramine, antipsychotics, and Carbamazepine. Euthyroid Unipolar depression. Poor response to ECT maintenance, imipramine, or neuroleptics Abnormal CAT Scan, Theta EEG. Diagnosis of “atypical mania” Lithium and TCA’s failed

Lr-induced insipidus

530

RENATO D. ALARCON

Table 3. Types of Rapid Cycling-Inducing

Agents

Pharmacological

lTricyclic

antidepressants (imipramine, desipramine, *Monoamine oxidase inhibitors *Other antidepressants (dibenzoxazepine) lL-Dopa ‘Piribedil (dopamine receptor stimulant) ‘Cyproheptadine (Serotonin receptor antagonist) *Conjugated estrogens l?Lithium

amitriptyline,

nortriptyline)

Nonpharmacological

l?Electroshock

l?Pregnancy

lTCA withdrawal l?Multiole Sclerosis

Wehr and Goodwin3’ described three female bipolar I and two bipolar II patients whose RC was induced by maintenance tricyclic antidepressants during observation periods lasting from several months to over one year. The five cases are not homogeneous however, and data on their pre-NIMH treatments are sketchy. Case 1 for instance had been treated for many years with TCA’s but there were no reports of RC until the close observation in the research setting took place. Case 2, on the other hand, was already a RC for at least three years before entering the hospital, and during that time was maintained on neuroleptics, TCA’s, lithium and even one course of ECT; the study period proved that imipramine induced rapid cycling but did not rule out the possible effect of the other agents. Interestingly enough, this case did not seem to develop RC when on phenelzine, in contrast with Mattson and Seltzer’9 finding in a 17 year-old male adolescent. Case 2 had also a history of treatment for hypothyroidism but was found euthyroid, whereas Case 3 showed persistently elevated TSH levels. This patient presented rapid cycles during periods of continuous administration of imipramine and lithium carbonate. Lithium seems also involved in the rapid cycling of Case 4, and MAO inhibitors appear also inducing RC in Case 5. In general, the multiple prehospitalization treatments make the exclusive attribution of RC induction to TCA’s questionable. The very fact that RC has been observed before the psychopharmacological era4’ speaks in favor of other possible sources generating the RC pattern Silberman & Post62 also report a case of a 45 year-old woman who presented several episodes per year during a three-year trial of lithium. Gerner et a163discuss the case of a 47 year old man who developed rapid cycling when given piribedil, a dopamine receptor stimulant. The authors postulate a dopaminergic role in mania, a claim made later by Ko et al.M Although their point is well taken, Gerner et aP3 do not explain the persistance of RC even after discontinuation of piribedil, nor do they comment on the short-lived four-week antimanic effects of the dopamine receptor blocker pimozide. By the same token, Ko et a1.64cite a patient who experienced rapid cycling for at least one year before L-dopa was administered, and even though L-dopa clearly shortened the cycle length, its effect was not only the intended induction of hypomania but the production of true manic-depressive cycles.

RAPID CYCLING

AFFECTIVE

DISORDERS

531

Cyproheptadine, a serotonin receptor antagonist, caused rapid cycling in a 41year old woman, as reported by Gold et al 50. . the same patient however had been reported, although part of the clinical data differed. as presenting RC secondary to the use of TCA’s;” this suggests additional, perhaps complementary, RC-inducing mechanisms. Finally, another pharmacological inducer seems to be a conjugated estrogen, as reported by Oppenheim36 and Alarcon et al.Jb Nonpharmacological inducers include a variety of agents. Electroshock has been indirectly incriminated. 5*,65Pregnancy is specifically mentioned in at least one case report;b6 this is, of course, conceptually compatible with estrogen-induced RC. The abrupt discontinuation of long-term TCA treatment (imipramine) induced RC in of the case report however a 53-year old unipolar woman. 55 A close examination reveals one brief cycle (two weeks) which improved with fluoxetine, and even while on this antidepressant the patient’s mood began deteriorating again; the phenomenon repeated itself when she was later placed on amitriptyline. The authors view this case as a “rebound effect” but such claim cannot be solidly substantiated. Kellner et al.67 report the most intriguing type of nonpharmacological RC inducer: Two RC patients found to have multiple sclerosis. Prior to being so diagnosed both patients had of course been treated with numerous medications. The authors recognize that the association may be just coincidental and, in any case, clear nosological objections can be raised in regard to the diagnosis of major bipolar affective disorders in these cases.3o A further inspection of the tables shows some interesting features. The greater majority of cases in which a family history was reported contained relatives with affective disorders, with only two exceptions where schizophrenia was noted. Only seven cases were reported as unipolar and, in general, the clinical manifestations encompass the whole spectrum of affective psychopathology, from psychotic depression or mania to cyclothymia, from severe suicidal behavior to episodes of very mild intensity. Only one patient was electroencephalographically studied and the diagnosis of atypical mania was made. Only one patient had a previous history of postpartum depressions. Eight of 37 cases presented a cycle frequency of 48 hours, therefore corresponding to what we have called ultra-rapid cyclers. Although the sample is by no means representative, the comparison of the ultra-rapid cyclers and the “classical” rapid cyclers shows some interesting distinctions. Seven of the eight ultra-rapid cyclers were men? whereas 27 of 29 “classical” rapid cyclers were women. In two females, cycle frequency was not recorded. The mean age of the eight ultra-rapid cyclers was 66 v 43 in the “classical” rapid cyclers. Five of the eight ultra-rapid cyclers (62.5%) presented the rapid cycling at the outset of their affective disorder, as opposed to only 12 of the 29 “classical” rapid cyclers (42.8%). The length of illness does not seem to be an important differentiating feature of these two subgroups. The inducers seem to be far less specific and the response to treatment far less consistent in the ultra-rapid cyclers than in the conventional cyclers. It is, therefore, highly suggestive that ultra-rapid cyclers may be an entirely different subgroup than the more conventional rapid cyclers. Elderly male patients seem to start their affective symptoms with this peculiar clinical phenomenon. Biological factors, reflected on sex and age differences, linger on as possible physiopathological bases for rapid cycling types. Numerous reports in the literature confirm the significant influence of the aging process on a variety of physiological regulatory functions.

532

RENATO D. ALARCON

ETIOPATHOGENESIS The work of Bunney et a1.“)@-70 and Gjessing” on the “switch process” in manicdepressive illness laid the foundations of our scientific understanding of this clinical phenomenon. Biochemical, neurophysiological, and behavioral observations were assembled to postulate the transition from depression into mania and vice versa. Factors such as TCA’s, MAOI’s, levodopa, ECT, and environmental stresses were implicated in the production of the switch from depression to mania or hypomania, whereas lithium and phenothiazines determined the cessation of mania and its passage into hypomania before a new depression without associated stresses ensued. In spite of its exclusive reliance on catecholamines, the concept of a “switch” outlined by these articles is still useful to understand the functional sequence and basis of the clinical changes. The authors hypothesized enzymatic changes leading to an increased synthesis or release of monoamines, alterations in receptor site sensitivity or a dysfunction in presynaptic or postsynaptic neuronal structures as the underlying responsible factors. Interestingly enough, they also postulated the possible existence of a number of different manic illnesses, did not believe much in “directly spontaneous swings into depression from mania,” and suggested both an underlying and a superimposed dysfunction rather than a pathological continuum, to explain the clinical switches. Studies on the etiopathogenesis of RC have been tentative, mostly hypothetical, and are still inconclusive. An example of this situation are the findings of Naylor et a1.72 that low RBC Na-K ATPase activity and high RBC Na concentration in mania, and low Na and ATP concentration in depression in four mentally retarded rapid cyclers. Their findings ran counter those from nonmentally retarded, conventional bipolar but are difficult to interpret, and may be “related but out of That phase with the clinical state,” which renders them weak and inconclusive. membrane phenomena and ions are involved, however, is a workable assumption in the light of the lithium role in bipolar conditions and findings of calcium effects on the affective picture.” Neurotransmitters such as norepinephrine (NE), serotonin, and dopamine have also been implicated. The different hypotheses, however, are mostly the result of case reports, noted by their unusualness rather than their generalizability. Thus, Gold et a1.5o postulate a serotonin-mediated circadian desynchronization or, put another way, oscillations in central serotonergic function with resulting excess secondary to HPA activation in the depressive phase, and defect in mania or hypomania. These authors also raise the issue of “predisposition toward rapid mood cycling in response to pharmacological challenge. ” In this connection, Dilsaver and Greden,74 and Dilsaver et a1.75 apply their “cholinergic-monoaminergic interaction theory,” a dysfunctional imbalance between the two systems, to the production of tricyclic-induced rapidly cycling bipolar illness: The depressive phase would result from cholinergic hyperfunction and functional denervation of monoaminergic networks, and the manic from the reverse phenomena. Gerner et a1.63speculate about a dopaminergic component of mood fluctuations, and idea later reformulated by Ko et al.M who reported induction of RC during treatment with L-Dopa. Recent evidence against the predominant or exclusive role of dopamine in schizophrenia76.77 stemmed from studies of this neurotransmitter in nonschizophrenic phychosis. ‘* Among the catecholamines, NE has long been con-

RAPID CYCLING AFFECTIVE

DISORDERS

533

its participation in RC as sidered key in the production of affective disorders; 79~80 hypothesized by 0ppenheim36 would be based on the reports of estrogen rapidly increasing the bioavailability of central norepinephrine, thus producing a “switch” by acting on the increased receptor sensitivity secondary to reduced neurotransmitter availability during the preceding depressive phase. By and large, much attention has been paid to a hypothalamic-pituitary-thyroid (HPT) axis disfunction as a possible etiopathogenetic source of RC.This view was by Whybrow and conceptually advanced by Hertz,“’ and recently supported Prange’s** monograph. The general consensus seems to be that most RC patients do have some evidence of at least “subclinical hypothyroidism” as reported by Cowdry et al.3x in a retrospective study of 43 bipolar patients. An elevated TSH level is said to be an effective indicator of such a state. This report followed a paper by Cho et al.*’ on the association between lithium-induced hypothyroidism and RC; and Wehr and Goodwin’s3’ which reportedly found three of five female RC patients have hypothyroidism. Extein et al.R4 suggest that the TSH stimulation test could even be a better test of the predisposition to RC. The general hypothesis is that thyroid hormones regulate the periodicity of biological clocks through direct neurohormonal or hormonal effects, through general effects on metabolic processes, or through effects on neurotransmitter systems influencing circadian rhythms. The latter is confirmed by increased turnover of brain catecholamines and increased sensitivity of brain catecholamine receptors to thyroxine;39J2 a relative deficiency of thyroid hormones produces a relative predominance of a-adrenergic over ,!$ adrenergic receptors and may then be associated with a reduction in central and peripheral NE turnover. Low levels of urinary MHPG make individuals susceptible to early switches. 15*45Moreover, abruptly fluctuating levels of thyroid hormone (even within the normal range) would upset the homeostasis of CNS adrenergic receptors producing rapid alteration of mood in a predisposed individual.67 Thus, the notion of an impaired regulation of oscillatory systems possibly secondary to oscillatory changes in thyroid statu$‘.‘” 1s crucial in the pathogenetic formulation of RC’s. However, circadian rhythms are internally determinedI and environmentally dependent,4 as well. Furthermore, the thyroid-based hypothesis does not explain why prolonged lithium therapy in most patients, even when causing hypothyroidism, does not necessarily lead to RC: lithium carbonate has been used as and is still suggested to be one of the treatments of choice for RC.‘.27 There are reports of RC in euthyroid patients*” and in patients with the so-called euthyroid hyperthyroxinemia.s6,46 Clearly, however, this is up to now the most comprehensive etiopathogenetic formulation of RC: HPT axis, other neurohormonal connections, neurotransmitters, membrane phenomena, and neurophysiological predispositions aided by factors such as age, sex, length of illness, and medications, interact to provoke either a clear predisposition toward or an actual appearance of rapid cycling. The DST evidence on RC is uneven. Greden et al.!’ report a preponderance of abnormal DST in depressive episodes, with normalization during manic, hypomanic or euthymic periods in these RC patients. They noted consistent associations between menstrual cycles and DST abnormalities in two patients. Schaffer*’ writes about a case in which DST showed actually normal results during both depressive and manic phases, and does not explain why his patient was kept on desipramine when she presented clear manic symptoms. Finally, Kellner et al.h7 raise the question

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of a diffuse multifocal CNS white matter disease (Multiple Sclerosis) associated with rapid cycling, making the implicit search for this condition in RC patients a distinct necessity. SurridgeE8 however, describes intellectual deterioration, euphoria, personality change, and exaggeration of emotional expression as symptoms of MS, whereas depression seems to be predominantly reactive in nature. MANAGEMENT A variety of treatment approaches to RC have been offered in the literature. (Table 4). The original proponents of the concept considered a beneficial effect of lithium in RC “difficult to demonstrate,“’ but three years later stated that although the frequency of attacks may not be changed, the severity and duration of depressive and manic episodes seemed to be ameliorated after prolonged lithium treatment.26 Their suggestions, however, can be applied to bipolar patients in general, and not only rapid cyclers. The lithium tolerance of rapid cyclers is the same as that of also advocated the use of antipsychotic other affective disorder patients. Dunner 26*89 agents or symptomatic antidepressants if deemed necessary. Of interest is the than “classical” rapid cyclers to possible better response of “ultra-rapid-cyclers” lithium treatment as demonstrated by Hanna,53 Naylor,‘* and Paschalis.14 In practical terms, if RC is more frequent in late adulthood, and the symptom-free intervals of bipolar illness decrease with age, Dunner’ss9 suggestion of a readier use of lithium in later-onset bipolars is also applicable to RC’s. Waters and Lapierre5’ reported two cases of RC in which depression was quickly stopped with the administration of tricyclic antidepressants; as soon as the switch occurred, the TCA was discontinued and euthymia persisted from four to ten weeks. Oppenheims8 advocates a similar approach, emphasizing the stage of the cycle at which discontinuation can be effective, “especially if more than six to eight months have passed since the onset of the patient’s current episode.” If a residual depression persists, ECT or lithium might be helpful. To discontinue the offending drug is not without risks,90l91 for, as we have seen, sometimes the very RC-inducing drug can be effective in the management of the condition at different stages. Difficulties in case selection and monitorization of treatments are apparent in this approach, in addition to the relatively short duration of the asymptomatic period. Oppenheim36 presents also a rather unconvincing case for the use of estrogen “as a potentiator of standard antidepressant drugs” in a patient with RC, making the caveat that such potential responders would have to have “known estrogen deficiency.” A similar qualification should be applied, on the basis of the evidence revised here, to the therapeutic use of thyroxine in RC. Stancer and Persad reported good Table 4. Pharmacological

Agents

*Prolonged Lithium treatment *Lithium and antipsychotic (plus symptomatic *Therapeutic use of TCA-induced AC lLevothyroxine (hypermetabolic doses) lCarbamazepine lClorgyline lCalcitonin?

Used in the Treatment

antidepressants)

of RCAD

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535

results in five of seven euthyroid women; in two of the five, however, phenytoin and chlorpromazine, respectively, were given daily. Leibowbb also presents a RC euthyroid patient helped by L-Thyroxine. Yet, Cowdry et a1.j’ insist that RC is related to overt or covert thyroid deficiencies and that for thyroid therapy to be effective, it may be necessary to completely suppress the production of endogenous thyroid hormone. Moreover, these authors recognize that “reestablishing a chemically and clinically euthyroid state is only sometimes effective in stopping rapid cycling” except if “a vigorous perturbation of the HPT axis” is present. Kukopulos et a1.34 contend that the ideal treatment should be to allow the depression to end spontaneously, with the occasional addition of anxiolytics and sleeping medication if needed. Post et a1.92.93and Kanter et a1.94report on RC cases treated with carbamazepine and showing good clinical response; this anticonvulsant, used successfully in conventional bipolars, could be a promising agent in the treatment of RC although more documentation is necessary. Emrich et aL9> report poor results with sodium valproate, another anticonvulsant. Recently Potter et al.5h advocate the use of clorgyline, a selective MAO-A inhibitor, in the treatment of refractory rapid cyclers. Three of their five cases, however, received other drugs (lithium, carbamazepine, and thioridazine) and a fourth patient showed no clinical response. Finally, the use of calcitoninqb or calcium-related medications in RC is theoretically possible but has not yet been put to clinical use in rapid cycling. Of heuristic importance is the observation of switches out of depression into mania or hypomania, as a result of sleep loss in RC patients.” DISCUSSION The central question in attempting a review of RCAD is whether it is simply one end of the spectrum of recurrent affective disorders or rather, an autonomous entity. Unfortunately, this review cannot provide a clear answer because of the confusing language utilized by different clinicians, and the changing nature of the course of a bipolar disorder, particularly since the advent of psychopharmacological agents.9R,oq The most accepted conceptualization of RC views it as a clinical state in some affective disorder patients, mostly bipolar, of spontaneous occurrence in some, induced by a variety of agents in most others. related to thyroid dysfunction in only a sub-group of such patients, some of them probably on lithium therapy, and presenting clear management difficulties. Conversely, there are also RC’s who are unipolar, euthyroid, off-lithium, and relatively manageable. Our review suggests, however, that the so-called ultra-RC’s (cycle length of 48 hours or less) have characteristics that distinguish them from the classical RC’s. Such features include the nature of the clinical symptoms, age and sex of the patients, family history, types of inducers, and response to treatment. In fact the cycle length may establish the sharpest differential criterion for those who may advocate the existence of at least two types of rapid cyclers. Every clinician may have seen conventional cyclers who occasionally present more than three episodes per year and then return to their “slow” cyclicity. Does that make them rapid cyclers? Or is this simply a transient, time-limited clinical occurence? Clearly, followup studies will help to decide these critical questions. Terminological clarifications are in order. The definition of a cycle is not universally agreed upon as for instance, Dunner et al.’ say it is the time interval

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between two manic episodes, and Wehr and Goodwin-” describe it as the total number of days in each pair of consecutive manic and depressive phases. When does one start to count the episode or episodes that are going to constitute a cycle? Is a cycle necessarily a “biphasic” or a “triphasic” affair as when a depressive episode is insensibly preceded and followed by hypomanic or manic episodes? Many authors, particularly in the prepharmacological era, wrote about chronic manicdepressive illness, and some more recent workers may have taken such name as being synonymous with rapid cycling bipolar affective disorder. This is not necessarily so however, since chronicity implies a criterion of duration rather than cycle frequency. Likewise, the term “circular” manic-depression has to do with the “switch” phenomenon rather than the number of episodes or cycles in a given period of time. Some authors ascribe the concept of “pharmacological hypomania” to RC3*; the two phenomena, however, are not necessarily related since pharmacological hypomania was strictly linked to the use of TCA’s and RC can be precipitated by a variety of inducers. Furthermore, Akiska140*‘00has not reported RC cases in his various studies. On the other hand, RC does not imply necessarily the occurrence of Major Bipolar Disorder, since in fact both depression and elation can present rather mild intensity, or be better defined as Bipolar II.3o In its current structure, DSM-III does not include operational criteria for this clinical phenomenon. It can, therefore, be concluded that if RC is to be adequately defined, its relationship with all the other related terms will also have to be clearly elucidated. The long list of pharmacological and nonpharmacological agents reported as RC-inducers, implicates compounds and processes sometimes functionally different if not clearly antagonistic, such as TCA’s and MAOI’s, three different neurotransmitters (dopamine, norepinephrine, and serotonin), and conditions such as pregnancy, hypothyroidism, and MS. Clinical observations concur in singling out a number of RC patients who, at one point in their clinical course, progress from regular cycling to rapid cycling; such patients may or may not be receiving tricyclics at the time that they progress to rapid cycling. The key question is, of course, what makes them convert to rapid cycling? There is evidence of occurence of RC before the pharmacological era. What induced them then? Was an intercurrent subclinical hypothyroidism responsible? Diagnostically, the clinical description and a close longitudinal observation are still the best tools. However, the TSH measurement and a good drug intake history which includes the list of RC-inducers appears mandatory. The treatment area is also confusing, as some of the very agents implicated in RC-induction have also been successfully used in controlling it. At this point, however, carbamazepine, clorgyline, and perhaps levothyroxine appear to be the most promising therapeutic agents in selected cases. There is disagreement as to the heuristic value of RC. Greden et al.-” see it clearly as a valuable “experiment in nature” allowing the relatively quick study of biochemical, hormonal, and neurophysiological variables in mood disorders. Naylor for the et al.,‘* and Reid and Naylor6 on the other hand, express disappointment myriad of intercurrent variables which compromise an adequate time-clinical stateexperimental variable correlation. Clearly, the current knowledge of RC has only scratched the surface of this phenomenon. Better, consensually accepted definitions will help to elucidate nosological, taxonomic, clinical, pathogenetic, and therapeutic issues pertaining to this condition.

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DISORDERS

ACKNOWLEDGMENT The author wishes to thank Drs. John R. Shirrlff and Edward E. Kern Arthur M. Freeman III and William G. Walter-Ryan for their comments. provided

for their assistance, Secretarial

suPPorr

and Wa

by Ms. Toni Hulsey.

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