652
BIOL PSYCHIATRY 1992;32:652-667
Periodicity of Episode Occurrences in Rapid Cycling Affective Disorders Rokuro Mizukawa, Mikiko Iitsuka, Hidebumi Hazama, Kaoru Ueda, Joji Tsushima, Tokuro Sugihara, and Wakako Kaneda
We analyzed the medical records of nine patients with severe rapid cycling affective disorders (RCAD), and determined the cycle of mania occurrences by calculating the period between two successive onsets of mania for each patient. Using the cycle as the index we devised a cycle-oriented diagram by dividing the observation period by the i~.~dexcycle, and visually studied the mode of episode occurrences. In seven patients, the onset of mania generally followed the index cycle, but sometimes shifted from the day estimated by the index cycle. The shift seemed to be caused by a cycle other than the index cycle, which appeared temporarily in the course. The period between two successive onsets of mania was often several times longer than the index cycle length. In patients with RCAD, some sort of periodic rhythms may possibly control the course of episode occurrences on a continuing basis.
Introduction The natural course of affective disorders notably differs among patients and even with the same patient (Zis and Goodwin 1979; Cutler and Post 1982). This fact causes complications in judging the effect of psychotropic drugs or psychological factors on the occurrence and cessation of affective episodes (e.g., Angst 1988; Schou 1988; Ellicott et al 1990). Physiological or biochemical evidence corresponding to the course of episode occurrences is meager. There are indications that citcadian rhythm disturbances underlie affective disorders, especially rapid cycling affective disorders (RCAD) (Wehr et ai 1983; Sack et al 1987). The change in biological rhythms, such as body temperature or the sleep-wake cycle, is certainly an important factor in the onset and cyclic recurrences of episodes; however, whether the change in biological rhythms primarily causes affective disorders remains uncertain, Periodicity of episode occurrences in psychotic disease has been vigorously studied from the earliest days: such studies as described by Slater (1938) in manic-depressive psychosis, or by Gjessing and Gjessing (1961) in periodic catatonia, are well known.
From the Department of Neuro-Psychiaa'y, Faculty of Medicine, Tottori University, Yonago, Japan. Address reprint requests to Rokuro Mizukawa, MD, Department of Neuro-Psychiau'y, Faculty of Medicine, Tottori University, 36-1, Nishi-machi, Yonago 683, Japan Received April 17, 1991; revised July 3, 1992.
@ 1992 Society of Biological Psychiatry
0006-32231921505.00
Episode Periodicity in RCAD
nlOLPSYCHIATRY 1992;32:652-66"/
653
We previously reported the case of a female patient who had regular alternating recurrences of mania and depression for 35 years without intervals of remission (Mizukawa et al 1991). As she grew older, the duration of each episode increased from 21 to 28 days, but the regularity of the cycling was maintained, and was not affected by therapeutic drugs or psychological factors. Based on this case study, we deduced that in RCAD, biological rhythms in cycling of mania and depression would continue regularly throughout the whole course, including the periods of remission. Our inference is that some sort of periodicity may possibly be found in episode occurrences in RCAD. Clinical courses in nine patients with RCAD were analyzed. In each case, the diagram of the patient's course was divided by the cycle of episode occurrences that seemed to be intrinsic to each patient. The mechanism of cyclic recurrences was then studied.
Materials and Methods
Subjects Qualifications in selecting patients were as ~ollows: First, both maaic and depressive episodes recurred clearly and frequently, and the manic episode was severe enough to require hospitalization (bipolar I). Second, detailed data were available, in which the onset day, end day, duration of an episode, and ~he remission period were clear. Lastly, at least six manic episodes appeared within the observation period. Clinical data were obtained from doctors of five university-related institutions---that is, Yasugi Daiichi Hospital, Saihaku Hospital, Shimane Prefectual Koryo Hospital, Nishikawa Hospital, and Tajima Hospital. Initially, clinical records of 28 patients were considered, but many of them were excluded because of the lack of detailed qualifying data. In some cases especially, there were frequent cessations of treatment, or incomplete clinical records during depressive phases. All qualifications were satisfied by only nine patients (three men and six women), who had severe symptoms and present or prior long hospitalizations. All patients were categorized as having DSM-III-R bipolar disorder, and diagnosed with RCAD because episodes of affective illness recurred four times or more per year (Dunner and Fieve 1974).
Determination of the Episode The onset day and duration of an episode were determined retrospectively by two doctors (one of the authors and the therapist in charge), from doctor's charts and daily nursing notes when patients were in the hospital and from doctor's charts when patients were out of the hospital. A manic episode was determined to appear when living activities increased, sleeping hours decreased, and talkativeness was noticeable. A depressed episode was determined to occur when activities decreased, most time was spent in bed, and complaints of a depressed mood were articulated. When the symptoms caused patients difficulties in joining ward-planned activities or in taking part in their primary social lives, patients were determined to be in phase even when the symptoms were not severe. The symptoms were defined to be in remission when a euthymic mood and normal behaviors were described on the chart, or when patients' adjustment in the ward or to their social lives was good. There were occasions when minor mood changes were noted even during the
654
eIOt. PSYCHIATRY 1992;J2:652-~i67
R. Mizukawa et al
remission period; but we regarded the occasions to be out of phase because there were no problems in behavior or adjustment. The observation period was from the time of study (July to September 1990) retroactive to the earliest time for which precise information was available concerning the onset and duration of episodes.
Determination of the Cycle in Episode Occurrences To set up the cycle for each patient, which would constitute the base in analyzing the course of episode occurrences, we used the following procedures. First, the days of onset and end of each episode, manic u~-depressive, were specified from clinical charts during the whole observation period. Second, the period between two successive onsets of mania was calculated day by day throughout the observation period. To the obtained data, the nonlinear regression technique (Ralston and Jennrich 1979) and spectral analysis were applied, and the cycle of onset of mania was calculated. Lastly, when four or more successive data fell within the ranges of _ 15% of the value of the cycle calculated with the nonlinear regression technique, the successive data were regarded as representing the regular cycle, and the mean regular cycle length was calculated by using the successive data.
Index Cycle and Cycle-Oriented Diagram For patients having the regular cycle, we devised a diagram of clinical course for each patient to study episode occurrences, based on the mean regular cycle (integral number). For patients not having the regular cycle, cycles analyzed with the two statistical methods were compared: the one that was visually more appropriate for observing the clinical course was selected in drawing the diagram. This selected cycle was determined to be the index cycle for the observation period. On analysis of the diagram, we paid much attention to the position of the onset day of mania, to the interval between two successive mania onsets, to the course of manic and depressive episodes during the above-noted interval, and, in addition, to the relation of these characteristics to treatment, seasonality, and psychological factors. When a patient showed no episode during a period that was twice or more that of the index cycle, this period was thought to be an actual remission period. Lastly, the Rayleigh test (Batschelet 1981) was applied to some of the obtained data for statistical analysis.
Patient Characteristics and Observation Period Table 1 shows clinical features and outlines of course in the nine patients. There was no specific tendency due to age or to age at the onset of illness, but six patients had family histories of psychiatric disease. Symptoms were severe in all patients, and all had repeated hospitalizations and discharges. Aged patients did show a decrease in their ability to adjust socially, and the periods of their latest hospitalizations were prolonged. Patients received, unsystematically, various treatments from their therapists in charge. The dose of neuroleptic drugs was controlled according to the severity of symptoms in all patients. Mood stabilizers such as lithium carbonate or carbamazepine were administered to some patients when needed. No patients were associated with obvious somatic disease. Thyroid functions were all within normal limits. The mean observation period for the nine patients was 3.6 years (range, 1.1-8.5 years):
Episode Periodicity in RCAD
BIOLPSYCHIATRY 1992;32:652-667
655
Table 1. Clinical Features and Outlines of Course in Nine Patients with RCAD No. of subjects
Age (yr)
I 2 3 4 5 6 7 8 9
67 30 46 70 28 55 63 70 51
Gender
Age of onset (yr)
Total hospitalization period (yr)
F F F M F M F F M
35 17 17 33 18 33 36 47 22
20.0 3.5 18.2 5.4 1.3 8.5 16.8 19.8 14.5
Family history (relationship) Bipolar (brother) Schizophrenia (father) Suicide (mother) None Bipolar (aunt) Schizophrenia (cousin) None None Suicide (brother)
Observation period (yr)
No. of manic episodes
2.3 2.5 3.4 4.4 I. ! 2.5 4.5 8.5 3.3
14 16 11 7 1! 9 11 18 10
F -- female;M = male; yr != years,
all but three patients were hospitalized during the whole observation period. Of the three patients (2, 5, and 6), patient 2 was out of the hospital for a total of 11 months, during which time her family always accompanied her to the outpatient clinic, and any change in her symptoms was reported. Patient 5 did not visit the outpatient clinic regularly during 4 of the 5 months when she was out of the hospital; and no precise data were available for these 4 months. The outpatient period for patient 6 was only 2 months. Of the nine patients, only one patient (patient 5) had a gap in the observation period.
Results Table 2 shows the calculated values of cycle of mania onsets and the determined index cycle in all patients. A regular cycle was observed in five patients. Cycle values obtained from nonlinear regression were similar in patients 1, 5, 6, and 7 to the values obtained with spectral analysis; intermediate in p+~tients 2 and 4; and was about half the spectraldetermined cycle length in patient 8.
Mode of Episode Occurrences Patient I (Female). Figure 1 shows the course of patient 1 on an annual basis. Manic and depressive episodes recur almost alternately with short periods of remission. In Figure 2, the course is divided by her index cycle, which was determined to be 49 days. To show the continuity of cycles and the course more clearly, we double plotted the cycle.. oriented diagram by adding on the right side what followed the course shown on the left side. The left of the diagram clearly shows regular appearances of mania onsets between lines A and H on the cycle of about 49 days. Thereafter, the manic episode skips over line I, and appears again at the left of line J. The next manic episode to appear follows the index cycle (line K). But the ~+~extskips over line L, and appears in the middle of line M, returning to the day estimated according to the 49-day cycle. Thereafter, line Q shows a similar onset day to that in line J. In Figure 2, the double-plotted course indicates that onset days of mania may cut the diagram transversely between lines A and Q from right to left. Thus, the double-plotted diagram shows the probability that a cycle other than the 49-day cycle may occur with this patient together with the 49-day cycle in the
656
R. Mizukawa et al
eIOL PSYCHIATRY 1992;32:652-667
Table 2. Statistical Analysis of Cycle Duration and Determined Index Cycle Cycle (days) No. of subjects
No. of data
Nonlinear regression analysis
Spectral analysis°
Mean regular cycle (N)b
Index cycle¢ (days)
1 2 3 4 5 6 7 8 9
13 15 10 6 I0 8 10 17 9
49.2 33.9 63.5 60.7 30.0 78.1 173.2 88.7 54.0
50, 74 29. 38 107, 81, 56 56, 67 30, 26 83, 58 165 185, 92 50, 57, 38
49.4 (5) 32.8 (5) m -29.2 (5) 78.5 (5) 177.2 (6) ---
49 33 56 61 29 79 177 185 54
"Ordered by decreasing power. bMean of four or more successive data that fell within the ranges of ¢ 15% of the value of cycle calculated with the nonlinear regression analysis, (N) = number of successive cycles analyzed, "The index cycle (integral number) was determined with the mean regular cycle in pati.nts I, 2, 5, 6, and 7; and with comparison of the data obtained with the nonlinear regression analysis and spectral analysis in patients 3, 4, 8. and 9.
course of episode occurrences. This second cycle could be a temporary cycle, and/or could act on the whole course.
Patient 2 (Female). Figure 3 shows the yearly diagram for this patient. Figure 4 represents the double plot of a diagram based on her 33-day cycle, During the recurring episodes, two long (actual) remission periods each extending 3 - 4 months are noted. Despite the long remissions, manic episodes recur around the days estimated with the 33-day cycle. From lines N to P and lines P to R, the observed cycle is prolonged to about twice the calculated index cycle. During the period between lines N and R, a depressive episode takes place in the later part of lines O and Q, in which a manic episode is to be expected.
J,,n
19881
Dee
'
:
:
m
a
Q
a ,
~ .
m
LAdmisaion
1989'
I
I
.
Mania
Figure !. Course of effective episodes on an annual basis in patient 1.
Depression
Episode Periodicity in RCAD
BIOL PSYCHIATRY 1992;32:652-667
657
~. May, 198B
A
~-Me v, 1988
B
C D E
I
/
f 1989
F G .a.
H ,Jl,,
l
a "_........ ~
', ..... l:]
if!
K ~,..,..,.....,....._~
L
.,v..~
1
t,,,,%
,e
H N _
0
i
P
#. l g ~ l
_
~ ~
ma~
r ,
~
' ,
I ~
~
. ..........................
|
fdrdrt,-
..............................
JuJ. J99u -~
0
(mg)
.htl, l!lqO
0
10
20
Depression
30
40
49
10
20
30
40
49 (days)
Hani a
"¢~-~X"////////////~
LOnset of Iqania
Figure 2. Double-plotted cycle-oriented diagram for patient 1. In the single diagram, the course is divided by her index cycle of 49 days. Cycles in the course are alphabetized outside the left of the figure from upper (A) to bottom (Q). Onset days of mania appear almost in the middle of each line, except in lines J, K, and Q. The relation between cycle change and administered drugs was not clear.
The double-plotted course in Figure 4 shows a definite cycle change in lines X to B': In a rough estimation, the interval between onsets of mania in lines Y to B' (56 days and 52 days respectively) was about twice the interval in lines X to Y (25 days). Similar cycle change is observed in lines A to D (25 days and 77 days). These intervals between onsets of mania in lines A to D and X to B' were near to multiples of the index cycle. The mode of episode occurrences thus double plotted indicates that patient 2 may have two cycles that is, the 33-day cycle and another cycle related to 25 days. The two attempted suicides that caused bone fractures, and a series of sessions of electroconvulsive therapy (Figure 4) did not change the periodicity of episode occurrences. The cycle change after line M corresponded with the period when blood lithium concentration remained as high as 0.9 to 1.2 mEq/L owing to the increase in the lithium carbonate dose. The two long remission periods did not seem to correlate with treatment. There had
658
BIOLPSYCHIATRY
R. Mizukawa et al
1992;32:652-667
Jan
i988
Dec
A
"I -
I
~. AdmissionCAdm)
DischargeCDis) !
1989
A A
'- A d m
~'~Dis
~- Adm
I
I
Dis
1990'l
+- Ad= Figure 3. Yearlycourse of affective episodes in patient 2.
been similar remission periods in the course before the start of observation. The menstrual cycle was nearly absent owing to the administration of psychotropic drugs. Patient 3 (Female). The mode of episode occurrences was complicated in patient 3. Figure 5 shows two cycles of 59 days, four cycles of about ! 12 days (twice the index cycle), and two cycles of about 168 days (three times the index cycle). In comparison with the 112-day cycle pattern, manic or depressive episodes in the 59-day cycle pattern were shortened, and remission periods in the 168-day cycle pattern were prolonged. The cycle change between lines K and P was temporary. The pattern o¢ mania onsets in the whole course double plotted in Figure 5 was similar to that of patient 1. The observed cycle change seemed to be unrelated to administered drugs. Patiem 4 (Male). Figure 6 shows only one occurrence of mania that was in accordance with the patient's index cycle, whereas the other cycles were prolonged about two, three, five, and six times the index cycle. The pattern of episode occurrences in patient 4 resembled that of patient 3. Patients 3 and 4 also shared in common the administration of combined low-dose antidepressants during almost all depressive episodes. But effects of the drugs on the course were not clear. Patient 5 (Female). At the age of 18 years, this patient had fallen into excited and irritable states cc,inciding with her menstrual periods for about 6 months. She was in remission after a 3-month hospitalization, and lived without treatment over a period of about 8 years. After she bore her second child at the age of 26, pure manic and depressive episodes again occurred, and she was rehospitalized. Figure 7 shows a full diagram of the later course (lines A'-R'), together with the early course (lines A-F). The index cycle was 29 days, but v,e used 30 days as the horizontal axis unit throughout. The index cycle in the early course was 31 days. Despite the long remission and differences in symptoms, both index cycles could be regarded as similar in length. In Figure 7, a manic episode occurs in lines A' through C'. This prolonged episode delayed the next onset of mania by 85 days (three times that of the index cycle). Administration of antidepressants seemed not to affect the course of episode occurrences in this patient. In the later course, three menses were related to onsets of manic episodes. For the last year, however, patient 5 had no menses, and was diagnosed by a gynecologist as amenorrheic, due to neuroleptic drugs.
Episode Periodicity in
RCAD
BIOL PSYCHIATRY 1992;32:652-667
iF J a i l , I~.IIIB
IF Jan, 1988 A
B ...........C: ~, C
I rt ....... ~ I'
~ ~
-
~
~
D E
....
O
H
~
C~
O K
- :'= : : : -
k ~;- . . . . . . . .
.........
n
........~ .
-=---~--
/
I,I
-
g
659
~---
C
-
I
~' I ~ ~m e, . - ,, ,
I J o
"
""
C ~
~l
°
o ~
-, FO
,-,
I
-':: -
-,. .. f l.qm} ......... - ...........................
L .- ................... . ~ :
I ............ ~- ']~,',,~ ~ ' i| .... . ........... .. ............. .. ........... .. ............. . . . . . . ..,.. ~
........... 4 ......... :.-'~'. . -~ -
r4-
~.
1
o,
-
-
,
c-
i
- ...........
I
P Q
R s T U V
.I I !l!~t) 11'
B
I ~Y.](} "~
"4" O3
,~,ar
g
O
!
X Y Z A'
0 CD 0
O .~jejep.~
O
B' 0
~.p.P.epjep,~
,111|, l¢lql} "~ ,hll, ialql(l a~
I
I
10
20
......
: A.(~Xal)ine(7,~-lS(l mq)
(rag)
I
30 33
: Suicide Attempt/Bone Fracture
10
20
30 33
(days)
A : E1ectroconvulslve Therapy
Figure 4. Double-plotted diagram of the course for patient 2 divided by her 33-day index cycle. The period ( + ) between two manic onsets is prolonged approximately twice the 33-day cycle. The increase in dose amount of lithium carbonate might have affected on the cycle change.
Patient 6 (Male). The index cycle for this patient (Figure 8) was determined to be 79 days. But the course between lines B and D shows no manic episode; instead, there were two depressive episodes, followed by a remission period. Using the later course to analyze the pattern of episode occurrences between lines A and E, the depressive episodes and remission period in lines B to D occupy the periods when manic episodes were to be expected. The observation period was limited with this patient, and it could not be decided whether the period between the two successive onsets of mania (294 days) in lines A and E was a fourfold prolongation of the period indicated by the index cycle. Patient7 (Female)• The index cycle for thispatientwas 177 days, and manic episodes occurred every 6 months in a relativelyregularpattern (Figure 9). The periodicityis lost in line H. The double-plotted diagram shows that the period of each manic episode in lines E and F have been prolonged as much as 5 months. The two manic episodes in line G look as if the manic episode in line F have separated into two portions. However, no
660
BIOL PSYCHIATRY 1992;32:652-667
R. Mizukawa et al
Admitted in Oct. 1982 i . , . .............. z~ . . . . . .~-#, " [" . . . . . . . . . . . . . . .
Ir A p r . 1 9 8 7 .... --..~ L~ __-:-.~=_..-=-~
A B C D E F G H
'i
.....
~ ..o=
-..
#~
I
J K
"
L . M N
0 P
""
. . . . ~ '" ~ ~ ' J l
..... ~( ~ , o "
Ofl,q
O
...............
_-, . . . . . . . . . . . . . . . . ~ ' ~ - - ~
.'~- :".'"=::':":':':.~:'-:-:-I • .CF
I
,.o
,
•
:
,
f'~m
i
El
.
N fl) I3 ...............
i
0 R
S T U V
•
'
.
........
|...........
•
,
,
.
~
•
. . . . . . . :Mtxforote Ik)."e ^,,.. l,,,.) ~
0
II
I
20
40
56
I
I
20
40
(m~t)
56 (days)
Figure 5. Course of illness in patient 3 on the 56-day index cycle. The diagram is double-plotted. The period between two onsets of mania is about two (+) and three (#) times the 56-day cycle. Cessation of antidepressants did not induce onset of mania, because antidepressants were always stopped after depressive symptoms remitted or after a manic episode appeared.
factor(s) related to the change could be obtained. In line I, the manic episode reappears around the day estimated form the early course.
Patient 8 (Female). Manic episodes recurred eight times over 4 yeats, generally by turns on a regular basis in summer and winter seasons. Then, 275 days elapsed before the next manic episode took place in the autumn, and another 165 days before the next episode in the spring. The course during the above period was similar to the course in patient 1 between lines A and K (Figure 2). For the successive 3 years, eight episodes of mania appeared, but with little relationship to the index cycle (185 days) nor with seasonality. No factors were remarkable during the time when the mode of onset changed. Characteristics in symptoms did not differ between the early course when seasonality was noted and the later course when the seasonality was lost. The type and dosage of drugs used did not greatly differ between the early and later periods of the course. Patient 9 (Male). In patient 9, the interval between two successive mania onsets varied greatly (e.g., 36, 339, 44, and 186 days), with little relationship between the index cycle (54 days) and the actual onsets of illness.
E~,is,xle Periodicity in RCAD
F-Mar.
A
BIOL PSYCHIATRY 1992"32:652-667
Admission
1986
661
I J.
B
C D E
T
.....
m
I,q[tZ
-
"~
N
8
1]
F G H
-,
E!
I
N
N
J K L
•1o
"o
"~
I~mH 3
H N
0 P Q
|
w
!
, @ - - . . ~ t
qllq I'
R
S T U V t4 X
Figtwe 6. Diagram for patient 4. The intervals between two successive onsets of mania are much varied, each being near to several times longer than the index cycle length. Low amounts of antidepressants (maprotiline) were given in most of depressive episodes.
I i
JL.
.................
~.~mamai'a~l~ A
I q r l f ) ..~
Y Z A' ~ 0
(rag)
10
20
30
40
50
61
(days)
The relationship of episode occurrences in nine RCAD patients to those indicated by the index cycle is summarized as follows: (1) In seven of the nine patients, most onset days of mania followed the index cycle. (2) In three patients (1, 2, and 3), the onset of mania temporarily shifted from the day estimated by the index cycle; however, the onset day of mania finally returned to the day near the primarily estimated day. This change was presumably caused by a cycle other than the index cycle, which appeared temporarily in the course. (3) For five patients (2, 3, 4, 5, and 6), the period between two successive onsets of mania was often several times longer than that of the index cycle. (4) For patient 7, the change in cyclicity of the mania onset seemed to be caused by separation of a manic episode that had previously occurred as one continuous episode. In two patients, the index cycle was poorly correlated with the actual cycles observed (patients 8 and 9).
Rayleigh Test Onset days of mania that changed from the days estimated with the index cycle appeared to return to the estimated day. To test this observation statistically, we selected patients 1, 2, 5, and 6, who showed both the regular cycle (e.g,, lines A-F in patient 1), and more than one instance when the interval between two successive mania onsets was 1.5 or more times the index cycle (e.g., lines H-J in patient 1). Nonlinear regression was
662
BIOL PSYCHIATRY
R. Mizukawa et al
1992;32:652-667
A
B C
D E
.
.
.
.
.
.
.
.
r. ^
BIOL PSYCHIATRY 1992;32:652-667
Periodicity of Episode Occurrences in Rapid Cycling Affective Disorders Rokuro Mizukawa, Mikiko Iitsuka, Hidebumi Hazama, Kaoru Ueda, Joji Tsushima, Tokuro Sugihara, and Wakako Kaneda
We analyzed the medical records of nine patients with severe rapid cycling affective disorders (RCAD), and determined the cycle of mania occurrences by calculating the period between two successive onsets of mania for each patient. Using the cycle as the index we devised a cycle-oriented diagram by dividing the observation period by the i~.~dexcycle, and visually studied the mode of episode occurrences. In seven patients, the onset of mania generally followed the index cycle, but sometimes shifted from the day estimated by the index cycle. The shift seemed to be caused by a cycle other than the index cycle, which appeared temporarily in the course. The period between two successive onsets of mania was often several times longer than the index cycle length. In patients with RCAD, some sort of periodic rhythms may possibly control the course of episode occurrences on a continuing basis.
Introduction The natural course of affective disorders notably differs among patients and even with the same patient (Zis and Goodwin 1979; Cutler and Post 1982). This fact causes complications in judging the effect of psychotropic drugs or psychological factors on the occurrence and cessation of affective episodes (e.g., Angst 1988; Schou 1988; Ellicott et al 1990). Physiological or biochemical evidence corresponding to the course of episode occurrences is meager. There are indications that citcadian rhythm disturbances underlie affective disorders, especially rapid cycling affective disorders (RCAD) (Wehr et ai 1983; Sack et al 1987). The change in biological rhythms, such as body temperature or the sleep-wake cycle, is certainly an important factor in the onset and cyclic recurrences of episodes; however, whether the change in biological rhythms primarily causes affective disorders remains uncertain, Periodicity of episode occurrences in psychotic disease has been vigorously studied from the earliest days: such studies as described by Slater (1938) in manic-depressive psychosis, or by Gjessing and Gjessing (1961) in periodic catatonia, are well known.
From the Department of Neuro-Psychiaa'y, Faculty of Medicine, Tottori University, Yonago, Japan. Address reprint requests to Rokuro Mizukawa, MD, Department of Neuro-Psychiau'y, Faculty of Medicine, Tottori University, 36-1, Nishi-machi, Yonago 683, Japan Received April 17, 1991; revised July 3, 1992.
@ 1992 Society of Biological Psychiatry
0006-32231921505.00
Episode Periodicity in RCAD
nlOLPSYCHIATRY 1992;32:652-66"/
653
We previously reported the case of a female patient who had regular alternating recurrences of mania and depression for 35 years without intervals of remission (Mizukawa et al 1991). As she grew older, the duration of each episode increased from 21 to 28 days, but the regularity of the cycling was maintained, and was not affected by therapeutic drugs or psychological factors. Based on this case study, we deduced that in RCAD, biological rhythms in cycling of mania and depression would continue regularly throughout the whole course, including the periods of remission. Our inference is that some sort of periodicity may possibly be found in episode occurrences in RCAD. Clinical courses in nine patients with RCAD were analyzed. In each case, the diagram of the patient's course was divided by the cycle of episode occurrences that seemed to be intrinsic to each patient. The mechanism of cyclic recurrences was then studied.
Materials and Methods
Subjects Qualifications in selecting patients were as ~ollows: First, both maaic and depressive episodes recurred clearly and frequently, and the manic episode was severe enough to require hospitalization (bipolar I). Second, detailed data were available, in which the onset day, end day, duration of an episode, and ~he remission period were clear. Lastly, at least six manic episodes appeared within the observation period. Clinical data were obtained from doctors of five university-related institutions---that is, Yasugi Daiichi Hospital, Saihaku Hospital, Shimane Prefectual Koryo Hospital, Nishikawa Hospital, and Tajima Hospital. Initially, clinical records of 28 patients were considered, but many of them were excluded because of the lack of detailed qualifying data. In some cases especially, there were frequent cessations of treatment, or incomplete clinical records during depressive phases. All qualifications were satisfied by only nine patients (three men and six women), who had severe symptoms and present or prior long hospitalizations. All patients were categorized as having DSM-III-R bipolar disorder, and diagnosed with RCAD because episodes of affective illness recurred four times or more per year (Dunner and Fieve 1974).
Determination of the Episode The onset day and duration of an episode were determined retrospectively by two doctors (one of the authors and the therapist in charge), from doctor's charts and daily nursing notes when patients were in the hospital and from doctor's charts when patients were out of the hospital. A manic episode was determined to appear when living activities increased, sleeping hours decreased, and talkativeness was noticeable. A depressed episode was determined to occur when activities decreased, most time was spent in bed, and complaints of a depressed mood were articulated. When the symptoms caused patients difficulties in joining ward-planned activities or in taking part in their primary social lives, patients were determined to be in phase even when the symptoms were not severe. The symptoms were defined to be in remission when a euthymic mood and normal behaviors were described on the chart, or when patients' adjustment in the ward or to their social lives was good. There were occasions when minor mood changes were noted even during the
654
eIOt. PSYCHIATRY 1992;J2:652-~i67
R. Mizukawa et al
remission period; but we regarded the occasions to be out of phase because there were no problems in behavior or adjustment. The observation period was from the time of study (July to September 1990) retroactive to the earliest time for which precise information was available concerning the onset and duration of episodes.
Determination of the Cycle in Episode Occurrences To set up the cycle for each patient, which would constitute the base in analyzing the course of episode occurrences, we used the following procedures. First, the days of onset and end of each episode, manic u~-depressive, were specified from clinical charts during the whole observation period. Second, the period between two successive onsets of mania was calculated day by day throughout the observation period. To the obtained data, the nonlinear regression technique (Ralston and Jennrich 1979) and spectral analysis were applied, and the cycle of onset of mania was calculated. Lastly, when four or more successive data fell within the ranges of _ 15% of the value of the cycle calculated with the nonlinear regression technique, the successive data were regarded as representing the regular cycle, and the mean regular cycle length was calculated by using the successive data.
Index Cycle and Cycle-Oriented Diagram For patients having the regular cycle, we devised a diagram of clinical course for each patient to study episode occurrences, based on the mean regular cycle (integral number). For patients not having the regular cycle, cycles analyzed with the two statistical methods were compared: the one that was visually more appropriate for observing the clinical course was selected in drawing the diagram. This selected cycle was determined to be the index cycle for the observation period. On analysis of the diagram, we paid much attention to the position of the onset day of mania, to the interval between two successive mania onsets, to the course of manic and depressive episodes during the above-noted interval, and, in addition, to the relation of these characteristics to treatment, seasonality, and psychological factors. When a patient showed no episode during a period that was twice or more that of the index cycle, this period was thought to be an actual remission period. Lastly, the Rayleigh test (Batschelet 1981) was applied to some of the obtained data for statistical analysis.
Patient Characteristics and Observation Period Table 1 shows clinical features and outlines of course in the nine patients. There was no specific tendency due to age or to age at the onset of illness, but six patients had family histories of psychiatric disease. Symptoms were severe in all patients, and all had repeated hospitalizations and discharges. Aged patients did show a decrease in their ability to adjust socially, and the periods of their latest hospitalizations were prolonged. Patients received, unsystematically, various treatments from their therapists in charge. The dose of neuroleptic drugs was controlled according to the severity of symptoms in all patients. Mood stabilizers such as lithium carbonate or carbamazepine were administered to some patients when needed. No patients were associated with obvious somatic disease. Thyroid functions were all within normal limits. The mean observation period for the nine patients was 3.6 years (range, 1.1-8.5 years):
Episode Periodicity in RCAD
BIOLPSYCHIATRY 1992;32:652-667
655
Table 1. Clinical Features and Outlines of Course in Nine Patients with RCAD No. of subjects
Age (yr)
I 2 3 4 5 6 7 8 9
67 30 46 70 28 55 63 70 51
Gender
Age of onset (yr)
Total hospitalization period (yr)
F F F M F M F F M
35 17 17 33 18 33 36 47 22
20.0 3.5 18.2 5.4 1.3 8.5 16.8 19.8 14.5
Family history (relationship) Bipolar (brother) Schizophrenia (father) Suicide (mother) None Bipolar (aunt) Schizophrenia (cousin) None None Suicide (brother)
Observation period (yr)
No. of manic episodes
2.3 2.5 3.4 4.4 I. ! 2.5 4.5 8.5 3.3
14 16 11 7 1! 9 11 18 10
F -- female;M = male; yr != years,
all but three patients were hospitalized during the whole observation period. Of the three patients (2, 5, and 6), patient 2 was out of the hospital for a total of 11 months, during which time her family always accompanied her to the outpatient clinic, and any change in her symptoms was reported. Patient 5 did not visit the outpatient clinic regularly during 4 of the 5 months when she was out of the hospital; and no precise data were available for these 4 months. The outpatient period for patient 6 was only 2 months. Of the nine patients, only one patient (patient 5) had a gap in the observation period.
Results Table 2 shows the calculated values of cycle of mania onsets and the determined index cycle in all patients. A regular cycle was observed in five patients. Cycle values obtained from nonlinear regression were similar in patients 1, 5, 6, and 7 to the values obtained with spectral analysis; intermediate in p+~tients 2 and 4; and was about half the spectraldetermined cycle length in patient 8.
Mode of Episode Occurrences Patient I (Female). Figure 1 shows the course of patient 1 on an annual basis. Manic and depressive episodes recur almost alternately with short periods of remission. In Figure 2, the course is divided by her index cycle, which was determined to be 49 days. To show the continuity of cycles and the course more clearly, we double plotted the cycle.. oriented diagram by adding on the right side what followed the course shown on the left side. The left of the diagram clearly shows regular appearances of mania onsets between lines A and H on the cycle of about 49 days. Thereafter, the manic episode skips over line I, and appears again at the left of line J. The next manic episode to appear follows the index cycle (line K). But the ~+~extskips over line L, and appears in the middle of line M, returning to the day estimated according to the 49-day cycle. Thereafter, line Q shows a similar onset day to that in line J. In Figure 2, the double-plotted course indicates that onset days of mania may cut the diagram transversely between lines A and Q from right to left. Thus, the double-plotted diagram shows the probability that a cycle other than the 49-day cycle may occur with this patient together with the 49-day cycle in the
656
R. Mizukawa et al
eIOL PSYCHIATRY 1992;32:652-667
Table 2. Statistical Analysis of Cycle Duration and Determined Index Cycle Cycle (days) No. of subjects
No. of data
Nonlinear regression analysis
Spectral analysis°
Mean regular cycle (N)b
Index cycle¢ (days)
1 2 3 4 5 6 7 8 9
13 15 10 6 I0 8 10 17 9
49.2 33.9 63.5 60.7 30.0 78.1 173.2 88.7 54.0
50, 74 29. 38 107, 81, 56 56, 67 30, 26 83, 58 165 185, 92 50, 57, 38
49.4 (5) 32.8 (5) m -29.2 (5) 78.5 (5) 177.2 (6) ---
49 33 56 61 29 79 177 185 54
"Ordered by decreasing power. bMean of four or more successive data that fell within the ranges of ¢ 15% of the value of cycle calculated with the nonlinear regression analysis, (N) = number of successive cycles analyzed, "The index cycle (integral number) was determined with the mean regular cycle in pati.nts I, 2, 5, 6, and 7; and with comparison of the data obtained with the nonlinear regression analysis and spectral analysis in patients 3, 4, 8. and 9.
course of episode occurrences. This second cycle could be a temporary cycle, and/or could act on the whole course.
Patient 2 (Female). Figure 3 shows the yearly diagram for this patient. Figure 4 represents the double plot of a diagram based on her 33-day cycle, During the recurring episodes, two long (actual) remission periods each extending 3 - 4 months are noted. Despite the long remissions, manic episodes recur around the days estimated with the 33-day cycle. From lines N to P and lines P to R, the observed cycle is prolonged to about twice the calculated index cycle. During the period between lines N and R, a depressive episode takes place in the later part of lines O and Q, in which a manic episode is to be expected.
J,,n
19881
Dee
'
:
:
m
a
Q
a ,
~ .
m
LAdmisaion
1989'
I
I
.
Mania
Figure !. Course of effective episodes on an annual basis in patient 1.
Depression
Episode Periodicity in RCAD
BIOL PSYCHIATRY 1992;32:652-667
657
~. May, 198B
A
~-Me v, 1988
B
C D E
I
/
f 1989
F G .a.
H ,Jl,,
l
a "_........ ~
', ..... l:]
if!
K ~,..,..,.....,....._~
L
.,v..~
1
t,,,,%
,e
H N _
0
i
P
#. l g ~ l
_
~ ~
ma~
r ,
~
' ,
I ~
~
. ..........................
|
fdrdrt,-
..............................
JuJ. J99u -~
0
(mg)
.htl, l!lqO
0
10
20
Depression
30
40
49
10
20
30
40
49 (days)
Hani a
"¢~-~X"////////////~
LOnset of Iqania
Figure 2. Double-plotted cycle-oriented diagram for patient 1. In the single diagram, the course is divided by her index cycle of 49 days. Cycles in the course are alphabetized outside the left of the figure from upper (A) to bottom (Q). Onset days of mania appear almost in the middle of each line, except in lines J, K, and Q. The relation between cycle change and administered drugs was not clear.
The double-plotted course in Figure 4 shows a definite cycle change in lines X to B': In a rough estimation, the interval between onsets of mania in lines Y to B' (56 days and 52 days respectively) was about twice the interval in lines X to Y (25 days). Similar cycle change is observed in lines A to D (25 days and 77 days). These intervals between onsets of mania in lines A to D and X to B' were near to multiples of the index cycle. The mode of episode occurrences thus double plotted indicates that patient 2 may have two cycles that is, the 33-day cycle and another cycle related to 25 days. The two attempted suicides that caused bone fractures, and a series of sessions of electroconvulsive therapy (Figure 4) did not change the periodicity of episode occurrences. The cycle change after line M corresponded with the period when blood lithium concentration remained as high as 0.9 to 1.2 mEq/L owing to the increase in the lithium carbonate dose. The two long remission periods did not seem to correlate with treatment. There had
658
BIOLPSYCHIATRY
R. Mizukawa et al
1992;32:652-667
Jan
i988
Dec
A
"I -
I
~. AdmissionCAdm)
DischargeCDis) !
1989
A A
'- A d m
~'~Dis
~- Adm
I
I
Dis
1990'l
+- Ad= Figure 3. Yearlycourse of affective episodes in patient 2.
been similar remission periods in the course before the start of observation. The menstrual cycle was nearly absent owing to the administration of psychotropic drugs. Patient 3 (Female). The mode of episode occurrences was complicated in patient 3. Figure 5 shows two cycles of 59 days, four cycles of about ! 12 days (twice the index cycle), and two cycles of about 168 days (three times the index cycle). In comparison with the 112-day cycle pattern, manic or depressive episodes in the 59-day cycle pattern were shortened, and remission periods in the 168-day cycle pattern were prolonged. The cycle change between lines K and P was temporary. The pattern o¢ mania onsets in the whole course double plotted in Figure 5 was similar to that of patient 1. The observed cycle change seemed to be unrelated to administered drugs. Patiem 4 (Male). Figure 6 shows only one occurrence of mania that was in accordance with the patient's index cycle, whereas the other cycles were prolonged about two, three, five, and six times the index cycle. The pattern of episode occurrences in patient 4 resembled that of patient 3. Patients 3 and 4 also shared in common the administration of combined low-dose antidepressants during almost all depressive episodes. But effects of the drugs on the course were not clear. Patient 5 (Female). At the age of 18 years, this patient had fallen into excited and irritable states cc,inciding with her menstrual periods for about 6 months. She was in remission after a 3-month hospitalization, and lived without treatment over a period of about 8 years. After she bore her second child at the age of 26, pure manic and depressive episodes again occurred, and she was rehospitalized. Figure 7 shows a full diagram of the later course (lines A'-R'), together with the early course (lines A-F). The index cycle was 29 days, but v,e used 30 days as the horizontal axis unit throughout. The index cycle in the early course was 31 days. Despite the long remission and differences in symptoms, both index cycles could be regarded as similar in length. In Figure 7, a manic episode occurs in lines A' through C'. This prolonged episode delayed the next onset of mania by 85 days (three times that of the index cycle). Administration of antidepressants seemed not to affect the course of episode occurrences in this patient. In the later course, three menses were related to onsets of manic episodes. For the last year, however, patient 5 had no menses, and was diagnosed by a gynecologist as amenorrheic, due to neuroleptic drugs.
Episode Periodicity in
RCAD
BIOL PSYCHIATRY 1992;32:652-667
iF J a i l , I~.IIIB
IF Jan, 1988 A
B ...........C: ~, C
I rt ....... ~ I'
~ ~
-
~
~
D E
....
O
H
~
C~
O K
- :'= : : : -
k ~;- . . . . . . . .
.........
n
........~ .
-=---~--
/
I,I
-
g
659
~---
C
-
I
~' I ~ ~m e, . - ,, ,
I J o
"
""
C ~
~l
°
o ~
-, FO
,-,
I
-':: -
-,. .. f l.qm} ......... - ...........................
L .- ................... . ~ :
I ............ ~- ']~,',,~ ~ ' i| .... . ........... .. ............. .. ........... .. ............. . . . . . . ..,.. ~
........... 4 ......... :.-'~'. . -~ -
r4-
~.
1
o,
-
-
,
c-
i
- ...........
I
P Q
R s T U V
.I I !l!~t) 11'
B
I ~Y.](} "~
"4" O3
,~,ar
g
O
!
X Y Z A'
0 CD 0
O .~jejep.~
O
B' 0
~.p.P.epjep,~
,111|, l¢lql} "~ ,hll, ialql(l a~
I
I
10
20
......
: A.(~Xal)ine(7,~-lS(l mq)
(rag)
I
30 33
: Suicide Attempt/Bone Fracture
10
20
30 33
(days)
A : E1ectroconvulslve Therapy
Figure 4. Double-plotted diagram of the course for patient 2 divided by her 33-day index cycle. The period ( + ) between two manic onsets is prolonged approximately twice the 33-day cycle. The increase in dose amount of lithium carbonate might have affected on the cycle change.
Patient 6 (Male). The index cycle for this patient (Figure 8) was determined to be 79 days. But the course between lines B and D shows no manic episode; instead, there were two depressive episodes, followed by a remission period. Using the later course to analyze the pattern of episode occurrences between lines A and E, the depressive episodes and remission period in lines B to D occupy the periods when manic episodes were to be expected. The observation period was limited with this patient, and it could not be decided whether the period between the two successive onsets of mania (294 days) in lines A and E was a fourfold prolongation of the period indicated by the index cycle. Patient7 (Female)• The index cycle for thispatientwas 177 days, and manic episodes occurred every 6 months in a relativelyregularpattern (Figure 9). The periodicityis lost in line H. The double-plotted diagram shows that the period of each manic episode in lines E and F have been prolonged as much as 5 months. The two manic episodes in line G look as if the manic episode in line F have separated into two portions. However, no
660
BIOL PSYCHIATRY 1992;32:652-667
R. Mizukawa et al
Admitted in Oct. 1982 i . , . .............. z~ . . . . . .~-#, " [" . . . . . . . . . . . . . . .
Ir A p r . 1 9 8 7 .... --..~ L~ __-:-.~=_..-=-~
A B C D E F G H
'i
.....
~ ..o=
-..
#~
I
J K
"
L . M N
0 P
""
. . . . ~ '" ~ ~ ' J l
..... ~( ~ , o "
Ofl,q
O
...............
_-, . . . . . . . . . . . . . . . . ~ ' ~ - - ~
.'~- :".'"=::':":':':.~:'-:-:-I • .CF
I
,.o
,
•
:
,
f'~m
i
El
.
N fl) I3 ...............
i
0 R
S T U V
•
'
.
........
|...........
•
,
,
.
~
•
. . . . . . . :Mtxforote Ik)."e ^,,.. l,,,.) ~
0
II
I
20
40
56
I
I
20
40
(m~t)
56 (days)
Figure 5. Course of illness in patient 3 on the 56-day index cycle. The diagram is double-plotted. The period between two onsets of mania is about two (+) and three (#) times the 56-day cycle. Cessation of antidepressants did not induce onset of mania, because antidepressants were always stopped after depressive symptoms remitted or after a manic episode appeared.
factor(s) related to the change could be obtained. In line I, the manic episode reappears around the day estimated form the early course.
Patient 8 (Female). Manic episodes recurred eight times over 4 yeats, generally by turns on a regular basis in summer and winter seasons. Then, 275 days elapsed before the next manic episode took place in the autumn, and another 165 days before the next episode in the spring. The course during the above period was similar to the course in patient 1 between lines A and K (Figure 2). For the successive 3 years, eight episodes of mania appeared, but with little relationship to the index cycle (185 days) nor with seasonality. No factors were remarkable during the time when the mode of onset changed. Characteristics in symptoms did not differ between the early course when seasonality was noted and the later course when the seasonality was lost. The type and dosage of drugs used did not greatly differ between the early and later periods of the course. Patient 9 (Male). In patient 9, the interval between two successive mania onsets varied greatly (e.g., 36, 339, 44, and 186 days), with little relationship between the index cycle (54 days) and the actual onsets of illness.
E~,is,xle Periodicity in RCAD
F-Mar.
A
BIOL PSYCHIATRY 1992"32:652-667
Admission
1986
661
I J.
B
C D E
T
.....
m
I,q[tZ
-
"~
N
8
1]
F G H
-,
E!
I
N
N
J K L
•1o
"o
"~
I~mH 3
H N
0 P Q
|
w
!
, @ - - . . ~ t
qllq I'
R
S T U V t4 X
Figtwe 6. Diagram for patient 4. The intervals between two successive onsets of mania are much varied, each being near to several times longer than the index cycle length. Low amounts of antidepressants (maprotiline) were given in most of depressive episodes.
I i
JL.
.................
~.~mamai'a~l~ A
I q r l f ) ..~
Y Z A' ~ 0
(rag)
10
20
30
40
50
61
(days)
The relationship of episode occurrences in nine RCAD patients to those indicated by the index cycle is summarized as follows: (1) In seven of the nine patients, most onset days of mania followed the index cycle. (2) In three patients (1, 2, and 3), the onset of mania temporarily shifted from the day estimated by the index cycle; however, the onset day of mania finally returned to the day near the primarily estimated day. This change was presumably caused by a cycle other than the index cycle, which appeared temporarily in the course. (3) For five patients (2, 3, 4, 5, and 6), the period between two successive onsets of mania was often several times longer than that of the index cycle. (4) For patient 7, the change in cyclicity of the mania onset seemed to be caused by separation of a manic episode that had previously occurred as one continuous episode. In two patients, the index cycle was poorly correlated with the actual cycles observed (patients 8 and 9).
Rayleigh Test Onset days of mania that changed from the days estimated with the index cycle appeared to return to the estimated day. To test this observation statistically, we selected patients 1, 2, 5, and 6, who showed both the regular cycle (e.g,, lines A-F in patient 1), and more than one instance when the interval between two successive mania onsets was 1.5 or more times the index cycle (e.g., lines H-J in patient 1). Nonlinear regression was
662
BIOL PSYCHIATRY
R. Mizukawa et al
1992;32:652-667
A
B C
D E
.
.
.
.
.
.
.
.
r. ^
