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Effects of lithium carbonate on sleep
J. psychiat.Rex.,1974,Vol.10,pp. 133-146.PergamonPress.Printedin GreatBritain.
EFFECTS OF LITHIUM CARBONATE ON SLEEP D. A. CHERNIK, C. COCHRANE* and J. MENDELS Depression Research Unit, Department of Psychiatry, University of Pennsylvania and the Philadelphia Veterans Administration Hospital, Philadelphia, Pennsylvania 19104, U.S.A. (Received 24 July 1972) (Revised 12 April 1973)
LITHIUM carbonate is now widely used for the treatment of mania,ls2 the prophylaxis of recurrent mania and depression2-4 and, to an extent, in the treatment of selected depressed patients. 5- 7 There is a clear trend towards the increased use of lithium for more patients and for longer periods of time.s Since depressed and manic patients have a significant sleep disturbance and. as it has been suggested that there may be significant associations between these sleep changes and both the clinical syndromes and the antidepressant drug effects,s-13 it seemed important to determine the effect of lithium on sleep (both acutely and chronically). Further, if lithium, which is now being used chronically for many patients, were to adversely affect sleep, then these patients may experience long-term sleep alterations of unknown implications. It is also of interest to determine what, if any, are the correlations between lithium’s therapeutic and prophylactic effects and its influence on the disturbed sleep pattern of these patients. Depressed patients (as a group) have a reduction in total sleep time, more awakenings during the night and less stage 4 sleep. 11, 14- 21In addition, Mendels and Hawkins17,22 have reported that depressed patients take longer to fall asleep and wake significantly earlier in the morning and have increased amounts of stage 1 sleep. Reports on the amount of stage 1 REM sleep obtained by depressed patients are conflicting. Some studies report a reduction in REM sleep during depression, *I4817*20, 23-25 others report normal or even slightly increased REM sleep time with depression26p 27 with an earlier REM sleep onset1s,26 and an increase in phasic REM sleep elements such as eye movements. l s Later reports by MENDELS et aLa 2s*3olikewise reflect a relatively high percentage of REM sleep as well as a pressure to achieve REM sleep in some (but not all) depressed patients. Two previous studies31* 32 of the effects of lithium carbonate on sleep offer apparently contradictory results, although the different findings may be a function of the dose administered and the subjects studied. BREBBIA et al.31 administered 750 mg/24 hr lithium carbonate for 8 days to three control subjects and to three manic patients with plasma levels ranging between 0.34 and 0.46 mEq/l. The plasma levels are below those regarded as being in the therapeutic or prophylactic range. 2,8 They reported no uniform change in sleep pattern associated with the drug. KUPFER et al.,32on the other hand, reported a significant increase in delta wave sleep (stages 3 and 4 combined) and a significant decrease in stage 1 *Department of Psychology, The Bowman Gray School of Medicine of Wake Forest University, Behavioral Sciences Center, Winston-Salem, North Carolina, 27103. 133
134
D. A. CHJXR~K,C. COCHRANEand J. MENDELS
REM sleep with 1200 or 1800 mg/24 hr of lithium carbonate given to seven patients (one depressed, two manic and four hypomanic inpatients), with plasma lithium levels ranging from 0.70 to 1.30 mEq/l. Further, they reported a reduction (not significant) in REM sleep intensity per minute of REM time and a significant increase in REM sleep latency. Actual sleep time was not affected. Two subjects, who did not have any delta wave sleep during baseline, also did not have any delta sleep during lithium administration, The effect of lithium withdrawal was studied on one patient. This patient exhibited a sharp drop in delta wave sleep from 50 to 9 min per night together with an increase in stage 1 REM sleep. The study of KUPFER et aZ.s2 covered a relatively short time period. They obtained an average of 13 sleep recordings from each subject with a minimum of 3 baseline and 3 lithium nights per subject. On the basis of this study, one cannot determine whether or not these effects are enduring. Further, six of their seven subjects were manic or hypomanic, raising the question of whether or not the effects of lithium on sleep which they reported, are specific for this clinical syndrome. METHOD
We have studied the effects of lithium carbonate on the sleep of 15 male patients with affective disorders and two non-depressed psychiatric patients (see Table 1). Each patient was evaluated and classified on the basis of independent agreement by two psychiatrists. The patients were characterized by at least one previous hospitalization for depression TABLE1. PATIENTCHARACTERISTICS
Age
Manic depressives HS 27 RM 37
Number of nights studied in sleep laboratory at specified plasma lithium levels (mEq/l) Baseline
< 0.70
0.71-1.10
0 12
0
14
t3
6 WC 47 5 2 BS 41 0 JH 48 26 10 3 AR 51 7 0 JC 53 0 7 JD 55 13 3 ws 57 7 12 JG 61 7 5 BB 64 0 Uniphasic depressives JL 43 40 1 4 JM 49 10 0 GG 53 21 JS 60 4 1 Psychiatric (non-depressed) patients RP 43 4 16 2 5 OM 62 86 Total nights studied: 167 Note: Adaptation nights are excluded
Clinical status
> 1.10
6
14 11 15 4 18 6 3 8 13
14 0 0 17 32 14 5 0 3
7 17 4 3
5 1 0 0
2 3
0 0
137
106
Lithium carbonate (mg/24 hr)
Outpatient (asymptomatic) Mixed manic and depressed (concurrent) Depressed Outpatient (asymptomatic) Depressed Manic Hypomanic Depressed Depressed Depressed Outpatient (asymptomatic)
2100 900-1800
Depressed Depressed Depressed Depressed
1200 1500 1200-l 500 1200
1800-2400 1200-1500 1200-1500 1500-3300 1500-2700 60&1500 1200-l 500 900-1500 1200-1500
1200 900
EFFECTS OF LITHJIJM CARBONATE ON SLEEP
135
together with the clinical syndrome of “endogetious depression”* as described elsewhere.l* The 15 patients with affective disorders included 11 manic-depressed (biphasic) and four uniphasic patients. We are using these terms (biphasic and uniphasic) as they have no theoretical bias with regard to polarity or other relationship between manic and depressive states.33, s4, 37They are equivalent to the terms bipolar and unipolar. Uniphasic depressive illness was diagnosed if there was no history of previous manic episodes and if there was no history of any other significant psychiatric abnormality or organic brain syndrome. In order to determine if lithium’s effect on sleep is independent of its effect on the sleep and clinical course of depressed patients, we administered 900 and 1200 mg, respectively, to two non-depressed psychiatric patients. These two patients were neither depressed nor schizophrenic. They can best be described as having character disorders (passive dependent or inadequate personality type) with superimposed mixed neurotic symptomatology (anxiety and phobic symptoms). These symptoms varied from day to day and were responsive to environmental changes. While data from two subjects is not sufficient to allow for definitive conclusions, these preliminary observations are of some interest. The 17 subjects were studied for a total of 496 nights. Four of the subjects entered the study while receiving lithium. Of these four subjects, three were studied as outpatients only (while in remission). The remaining 13 patients had received no medication for at least 8 weeks prior to the study. All the hospitalized patients, including the two psychiatric controls, slept in their regular hospital rooms in a special research ward designed for the study of affective disorders. These rooms are connected by cable to the monitoring equipment. The patients were studied in the sleep laboratory for periods ranging from 33 to 74 nearly consecutive nights. Standard sleep recordings38 included the electroencephalogram (EEG), electro-oculogram (EOG) and submental muscle activity (EMG). The EEG record is a C, referred to a mastoid. In addition, electrodes were placed at the outer canthus of each eye for a bipolar recording of the phasic integrated potential (PIP).? The first night of the series was an adaptation night and the sleep records obtained from this night were not scored. Records were scored for stages of sleep according to standardized procedures38 with the scorer blind as to subject, clinical condition, and medication if any. The dose of lithium carbonate (900 to 3370 mg/24 hr) varied with the clinical state, plasma level and clinical response of the individual patients. No other drugs were administered during the baseline or study periods. Lithium carbonate was discontinued on a double blind basis for three patients. We were, therefore, able to compare their baseline (premeditation) sleep pattern with the mid-treatment-no-lithium period (when lithium was withdrawn and placebo substituted). This allowed us to consider to what extent the changes in sleep pattern might be caused by changes in the patient’s clinical status, as opposed to a direct pharmacological effect from lithium. At the same time, we were able to determine whether there were any changes in *The term endogenous depression is used to designate a clinical syndrome, the origins of which are undetermined at this time. It is not used to imply etiology. We suggestedlO that these clinical features may represent the core of the syndrome of depression lo, 3*. This view has recently been supported by COPELAND et ~1.~~and the conclusions are similar to those of ROBINSet ~1.~~in their concept of “primary depressive illness”. tPIPs may be the human analogue to PGO spikes in the cat.3Qs 4o
136
D. A. CHERNIK, C. C~CHRANEand J. MENDELS
sleep as a result of drug withdrawal. Plasma intraerythrocyte (RBC) lithium levels were determined routinely by atomic absorption spectroscopy for RBC values*l and by flame photometry (Instrumentation Labs; model 143) for plasma values. Several recent reports42, 43 suggest that RBC values may provide a more accurate reflection of lithium distribution and biological activity in the central nervous system than do plasma Li-values. A specially trained group of nurses rated each inpatient daily on a variety of mood and behavioral items.44 Our nurses have demonstrated a high degree of inter-rater reliability. Four independent ratings were obtained every day. The depression rating, derived from this scale, which we used in this report, is termed the “total depression score”. This is obtained by summing the scores applied to five separate items: depression; verbal thoughts of feeling worthless; verbalized thoughts about death or suicide; verbal thoughts of feeling helpless; and sad facial expression. In addition, the patients completed a self-rating depression inventory45 twice weekly. RESULTS
Table 1 describes some of the features of the 17 male patients we have studied. Tables 2 and 3 show the individual patient’s mean percentage values of delta wave and stage 1REM sleep during baseline (no drug), low (< 0.70 mEq/l), medium (0.70 to 1.10 mEq/l) and high (> 1.10 mEq/l) plasma lithium levels. Change scores (plus or minus) reflect the changes which occurred between each ascending level (two adjacent groups). Each value is compared with the preceding value. A plus or minus sign indicates whether the second value is larger or smaller than the first. The results were evaluated using a z-score (two-tailed). In these TABLE 2. PERCENTAGE
OF DELTA SLEEP AT VARYINGPLASMALITHIUMLEVELS(mEq/l)
Plasma lithium concn
Manic depressives
Baseline
< 0.70
JC WC
5.7
7.0
1.7 13.3 0.0 4.0 0.0 0.1
1.4 11.3 0.4 7.6 0.0 0.2 1.2 3.7
JH !zf JD ws JG BS BB HS Unipolar JM JL GG JS Non-depressed OM RP Total changes
0~71-1~10 9.6 74 5.1 20.0 2.5 14.5 0.1 0.2 4.6 8.4 33.7
0.1 24 15.4 2.2
0.3 2.8 6.6
6.6 5.9 17.4 3.8
0.4 0.0
0.0 0.3
0.0 1.1
Changes
by ascending levels -
> 1.10
+
15.9 18.2
:
0 0
:
1
: 0 0 0.5 0.5 0 1 0
3 2 1 1
0 1 0 1
0.5 2
1.5 0
29.5
7.5
20.1 15.1 15.6 0.4
6.2 41-4 10.2 3.1
: 2.5 1.5 :
137
EFFECTSOFLITHIUM CARBONATE ONSLEEP TABLE3. PERCENTAGE OFREM Manic depressives
< 0.70
25.9 22.1 32.1
25.9 20.6 27.4 37.1 28.7 20.0 21.1 20.1 18.6
!F JD WS JG BS BB HS Unipolar JM JL GG JS Non-depressed OM RP Total changes
32.0 195 24.7
PLASMA LITHIUM LEVELS (mEq/l)
Plasma lithium concn 0~71-1~10 > l-10
Baseline
JC WC JH
SLEEP AT VARYING
17.2 16.1 17.8 21.2 19.6 24.0 17.1 19.6 20.0 14.6 13.6
30.3 25.8 21.0 20.8
27.2 22.7 21.3
19.0 28.1 16.0 18.9
28.4 18.3
29.3 15.7
17.4 13.3
13.7 11.5 17.9 19.9 197 16.5 21.0 9.5 23.6 26.3
Changes by ascending levels + 0
0.5 0 0 1 0 1 0 0 1 0
1 2.5 2 3 2 3
1 1 0 1
2 2 1 1
1 0 7.5
1 2
295
tables, intrasubject comparisons were made. Two subjects were manic (AR) and hypomanic (JC), three were asymptomatic, ten were depressed and the remaining two patients were psychiatric controls. There was a progressive increase in the percentage of delta wave sleep and a progressive decrease in the percentage of stage 1 REM sleep with increasing plasma lithium levels (p < 0.005, sign test). A similar, significant trend was obtained using RBC lithium concentrations of less than 0.30 mEq/l, 0.30-0.70 mEq/l and > 0.70 mEq/l. Further analyses were performed to assess the significance and type of change in sleep measures with changing plasma values. Matched pair t-teats were done between successive lithium groups (low and medium plasma lithium concentrations; medium and high plasma lithium concentrations) using: (a) all the subjects who had values in two columns and, (b) 5 patients who had a full range of plasma lithium values. Each of the 5 patients’ sleep data was further analyzed to see if there was a significant linear regression of the respective sleep measures on plasma lithium values, and analyses of variance were performed including a test of whether the combined data of the five patients showed a significant linear trend as a function of increasing plasma ranges (see Table 4). The results are as follows : Delta wave sleep. There were significant increases in mean percentage delta wave sleep with increasing plasma lithium levels (p -=c0.05, matched pair t-test). Analysis of variance for the combined data showed that the means significantly fitted a linear trend (p < 0905). Four of the five patients showed individually significant positive regression slopes with delta wave sleep increasing as plasma lithium increased.* The following linear equation was *Ah five patients showed individuallysignificant positive regression slopes when RBC lithium concentrations were substituted for plasma values.
138
D. A. CHERNIK, C. C~CHRANE and J. MENDELS TABLE 4. MEAN PER CENT DELTA WAVE SLEEPAND STAGE 1 REMVALUES FOR: (a) ALL PATIENTS IN A GIVEN PLASMA Li RANGE, (b) FIVE PATIENTS WITH A FULL RANGE OF PLASMA VALUES Plasma lithium < Delta wave sleep patients Five patients
All
Stage 1 REM All patients Five patients
0.70
concn
0.71-1.10
\?/A)
*
3.29 5.02
10.65 10.98
17.21 15.32,
24.56 26.50
18.04 19.98
17.28 18.44
sleep
derived by averaging the slopes and intercepts for these patients : D’ = 7.74 plasma lithium plus 2.98, where the predicted value of per cent delta wave sleep equals 7.74-times the given plasma lithium level plus the constant 2.98. In other words, delta wave sleep increased 7.74 units with each unit increase in plasma lithium. Table 4 shows the mean per cent of delta wave sleep for (a) all patients in a given column and, (b) the five patients used for analyses of variance and regression analyses. It can be seen that both sets of data confirm the impression of a steeply rising linear dose curve within the range of plasma lithium concentrations studied. Stage 1 REM sleep. The decrease in mean percent of stage 1 REM sleep when plasma lithium rose from the lowest plasma lithium levels to the medium range was significant (p < 0.01) but that between the middle and highest range was not. The combined data for the five patients showed a highly significant linear trend (p < 0.001). Further, four of the 5 patients showed a significant negative regression slope with per cent stage 1 REM sleep decreasing as plasma lithium increased. The equation reads : R’ = - 0.042 plasma lithium plus 1.69. While the linear regression model does significantly fit the data, the lack of a significant difference between REM sleep means for medium and high plasma lithium groups suggests that a linear regression may better describe the low-medium range of lithium concentrations whereas the medium-high group relationship may be asymptotic. Changes in stage 1 REM sleep and delta wave sleep with long-term lithium carbonate administration. Figs. l-3 illustrate the changes over time in stage 1 REM sleep and in delta wave sleep with the administration of lithium. These three subjects (JD, JM and RM) were studied for 51, 37 and 43 nights, respectively. Stage 1 REM and delta wave sleep are expressed as a percentage of the actual sleep time in the upper two graphs. Plasma lithium levels and lithium dose are indicated in the third and fourth graphs and depression ratings are given in the bottom graph. There was an alteration in both stage 1 REM sleep and in delta wave sleep in association with lithium administration, whereas alterations in depression rating scores were not consistently associated changes in these two sleep stages. Comparison of the relative eflects of lithium and severity of depression on sleep stages. The per cent of stage 1 REM sleep was significantly decreased (p < 0.01) and per cent delta wave sleep was significantly increased (p < 0031) with the administration of lithium carbonate in each of three patients for whom the severity of the depression (as measured
139
EFFECTS OF LITHIUMCARBONATE ON SLEEP REM%
(of actual
Plasma
lithium
sleep)
(mEq/-l)
:f[
fl
Hospitalization Nights r?!Tz (from dateof admission)
p
Throughout Cl -zv
0
9
FIG. 1. Longitudinal study of rapid eye movement (REM) sleep and delta wave sleep in relation to lithium carbonate administration to a 55-year-old uniphasic, recurrent depressive (J.D.). REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph.
by DepreSsion Inventory Scores) did not change (see Table 5) which provide further support for the thesis that changes in stage 1 REM and delta wave sleep which occur with the administration of lithium carbonate are not the result of clinical change. TABLE5. CGMPABISON OF STAGE 1 REM ANDDELTAWAVESLEEP(%) DURINGDRUGFREEPERIODSANDLITHIUM CARBONATE PERIODS (Beck depression scores held constant) Delta wave sleep (%)
Stage 1 REM (%) Subject
RM @I* O-3) JD @I” 10-15) JM (DI* 28-31)
Drug free
Lithium carbonate (plasma Li > 0.70 n-JEo/l)
t
Drag free
Lithium carbonate (plasma Li > 0.70 mFq/l)
t
10.526’1-
30.64340
l&8&3.37
12.0761’
5.ozt3.30
20.3k6.31
34.2rt6.02
21.4rt4.71
6.904t
4.8 f2.56
15*0&5*22
7.234t
25~813.68
18*4&3.49
4377*
O-6&0*50
8.5 f3.30
7.101 t
*DI = Depression inventory scores. *p = 0.01, two-tailed f-test. tp = 0,001, two-tailed f-test.
340
CHERNIK,C.COCHRANE and J. MENDELS
D.A. REM %(of
actual
jr
J.M.
sleep)
-Lq
Delta%(of
actual
j
_
Plasma
lithium
sleep)
_“,_\& (rnEQ/l)
,I
r
Lithium
”
“i
dose (mg)
Depression
raiings
30 *o 10
ni-
Hospitalization Nights (from + doteof “2 admission)
Throughout “,
on
“p
“,
$ rz
FIG.2. Longitudinal study of rapid eye movement (REM) sleep and delta wave sleep in relation to lithium carbonate administration to a 49-year-old uniphasic depressive (J.M.). REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph. DISCUSSION
This study provides support for the initial conclusions of KUPFER et al.32 and extends their findings. In their study of the acute effects of lithium on sleep, they reported a significant decrease in per cent stage 1 REM with a significant increase in per cent delta wave sleep in five of the seven patients studied. For the remaining two, who were among the oldest of the group, delta sleep was entirely lacking throughout the study. In this study we were concerned with the longer term effects of lithium on sleep. Our depressed patients were studied for periods ranging up to 74 nights.* In our patient group, lithium carbonate administration significantly increased per cent delta wave sleep, reduced per cent stage 1 REM sleep and increased the latency to the first REM period without affecting actual time asleep. The changes were significantly related to plasma lithium levels, with higher plasma lithium levels associated with greater changes in delta and REM sleep. While there was a significant linear trend between the two sleep measures and plasma lithium levels, the lack of a significant t between the higher plasma lithium ranges and *Sleep data were discarded if lithium levels were not available.
EFFECTSOF LITHIUMCARBONATEON SLEEP
141
R.M.
REM
%Iof
actual
i_ithiumdose
sleep)
(mg)
Hospiiolizntion -----Throughout Nights (from *v dcte of admission\
B
FIG. 3. Longitudinal study of rapid eye movement (RPM) sleep and delta wave sleep in relation to lithium carbonate administration to a 37-year-old manic-depressive (RM) during both hypomanic and depressed phases. REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph.
per cent REM sleep makes it necessary to qualify the statement regarding linearity. A linear regression model does significantly fit both the REM and delta sleep data, but the curve for REM sleep is better described as dropping steeply and then levelling off at higher (> l-10 mEq/l) plasma lithium values. With the small number of subjects studied thus far, it is appropriate to wait for more data before deciding whether the REM-dose curve is linear or asymptotic. Tables 3 and 4 include sleep values on one patient who was hypomanic (JC) and another who was manic during the study. The hypomanic had sleep values similar to that of the depressed patients studied in our laboratory with more than 6.5 hr of sleep per night. The manic patient, on the other hand, averaged 105 min of sleep per night. In spite of the greatly reduced sleep, this subject did experience an increase in his per cent delta wave sleep with increasing plasma lithium levels suggesting that the effect of lithium carbonate on sleep is nob specific to one clinical state, We have presented our findings in terms of plasma lithium values as this is the general practice at this time. However, as noted we also measured REC lithium concentration in our patients. We found that there was a higher correlation between EEG sleep patterns and
142
D. A. C~RNM,
C. C~CHRANE
and J. MENDELS
RBC lithium concentrations than between EEG sleep pattern and plasma lithium values. Of the five patients for whom we had sleep recordings over a wide range of plasma and RBC lithium levels, four showed a higher correlation between delta wave sleep and RBC concentrations, three showed a higher correlation between stage 1 REM sleep and RBC concentrations as opposed to individual correlations between delta wave sleep and stage 1 REM sleep and plasma lithium concentrations. In keeping with this there is the report that changes in the waking EEG in subjects receiving lithium, were significantly correlated with RBC lithium concentrations, but riot with plasma lithium concentrations,42 again suggesting that RBC lithium may be a more sensitive measure of lithium activity in the central nervous system than plasma lithium measures. Should this preliminary observation be confirmed, it would be in keeping with our finding that the RBC concentration of lithium is higher in some depressed patients, who do respond to lithium treatment, as compared with depressed patients who do not respond to lithium treatment,46 and our finding that RBC lithium concentrations may provide a better index of brain lithium concentrations than plasma lithium concentrations.43 It is possible that lithium carbonate affects the sleep of manic-depressive patients differently from uniphasic depressed patients or psychiatric controls. However, the latter two groups in this study were too small to make a meaningful statement in this regard. It is interesting that the two uniphasic depressed patients had essentially normal amounts of REM sleep (23.6 and 23.1 per cent, respectively) with plasma lithium concentrations in excess of 1.10 mEq/l whereas all of the biphasic patients had less REM sleep (values ranging from 9.6 to 2@4 per cent, with a mean of 15.3 per cent) at similar lithium levels. Lithium carbonate appeared to normalize the sleep of the majority of patients studied. The premeditation sleep of all but one subject was characterized by low amounts of delta wave sleep. There was an increase in delta wave sleep in most patients with the administration of lithium carbonate. Half of the patients had elevated levels of REM sleep during the baseline period with individual subject mean values ranging up to 32.1 per cent of actual sleep time.3o Lithium carbonate decreased stage 1 REM sleep, frequently decreasing REM sleep below normal levels. It should be noted that none of these patients had been taking any medication for at least 8 weeks prior to the sleep study, although one subject (JM) had been drinking heavily for 10 days prior to the sleep recordings. Thus, the elevated levels of REM sleep could not be a rebound caused by previous drug-induced REM sleep deprivation (with the possible exception of the subject who had been drinking prior to the study). There seemed to be a limit to the effect of lithium on REM sleep. While there was a significant difference between per cent stage 1 REM sleep at low and medium plasma lithium levels, there was not a significant difference between REM sleep means for medium and high plasma lithium groups (see Table 4). On the other hand, there was a significant linear trend (p < 0.005) between increases in mean percentage delta wave sleep and increasing plasma lithium levels, including a significant difference (p < 0.05) between delta wave sleep at medium and high plasma lithium levels. Although a plateau effect, similar to that observed for REM sleep, may occur at some higher plasma level this did not emerge with the range of lithium values observed here.
EFFE~S OF LITHIUMCARBONATE ON SLEEP
143
Two of the three subjects who did not show an increase in delta sleep with lithium administration were the psychiatric control subjects. It is possible that the lack of significant changes in stage 1 REM and delta wave sleep reported by BREBBIA et aL31 may therefore have been a function of the subjects studied rather than of lithium dose and plasma lithium levels. In the Brebbia et al. study, comparative sleep measures with and without lithium carbonate were obtained on a small group (3 subjects) of normal controls (the remitted manic-depressed subjects were studied only during lithium administration). It is therefore possible that lithium affects the sleep of normal subjects differently from that of subjects with manic-depressed or recurrent depressive illness. Neither of our two psychiatric controls nor the three normal subjects studied by BREBBIA et al. 31exhibited a noticeable increase in delta wave sleep with the administration of lithium carbonate. We have also noted that controls do not appear to tolerate lithium carbonate as well as do patients. In a separate study which involved the administration of 1200 mg of lithium carbonate to eight healthy normal subjects for 10 days, four subjects discontinued the study after only a few days because of side effects (abnormal cramps, malaise, weakness, and tiredness). All subjects were members of the staff and presumably well motivated. One must consider the possibility that the change in quality of sleep found in this study was in response to a change in the patient’s clinical status. However, this does not seem to be the case because, (a) the increase in delta wave sleep and the decrease in stage 1 REM sleep frequently occurred within 24 hr after the initiation of lithium carbonate therapy (although it usually took 6 or 7 days before there was a consistent change), (b) there was a reversal in the sleep indices in three patients who had been withdrawn from lithium during the course of treatment within two days after drug withdrawal, (c) we compared the sleep of three patients while taking lithium with their sleep during a drug free period, selecting periods with equivalent depression inventory ratings (see Table 5). There was a significant change in both stage 1 REM sleep and delta wave sleep with the administration of lithium carbonate even though the patient’s clinical state was similar during the two periods. Thus, it appears unlikely that clinical improvement per se produced the observed changes in stage 1 REM and delta wave sleep. While a REM rebound (an increase in REM sleep which purportedly makes up for the previous loss in REM sleep) has been reported to occur following the withdrawal of most REM-suppressing drugs, 47-4s there was no evidence of a REM rebound in two patients who were studied 12 and 13 nights following lithium withdrawal. SUMMARY
The effect of lithium carbonate on the sleep of 17 psychiatric patients was studied for 496 nights. Lithium carbonate appeared to normalize the sleep of depressed patients, significantly increasing the low baseline levels of per cent delta wave sleep and significantly decreasing the somewhat elevated levels of per cent stage 1 REM sleep. Analyses of variance showed that the combined subjects’ means for per cent delta wave sleep and per cent stage 1 REM sleep were linearly related to plasma lithium levels. There were significant positive and negative regression slopes for per cent delta and REM sleep with increasing plasma lithium levels. There was some indication that changes in stage 1 REM sleep may reach a plateau at which point no further decrease in per cent REM
144
D. A.
CHERNIK, C. COCHRANE
and J. MENDELS
sleep occurs in spite of increasing plasma lithium levels, whereas per cent delta wave sleep showed a significantly linear trend as a function of increasing plasma ranges. The sleep changes frequently occurred within 24 hr after the initiation of lithium carbonate treatment. The withdrawal of lithium during the study was associated with an immediate change in both per cent stage 1 REM and delta wave sleep in the direction of baseline values in spite of sustained clinical improvements, strongly suggesting that the changes in sleep were directly related to the presence of lithium rather than to clinical change. There was no apparent rebound in stage 1 REM sleep when the drug was withdrawn. AcknowZedgements-l%is study was supported by NIMH grant MH17551 and research funds from the Veterans Administration. We are grateful for the assistance of A. Frazer, Ph.D., who provided the lithium measures; of K. Roden and S. Bembry, the recording technicians; and of F. Beckman, M. Stevens, S. Leet and S. Suls for their assistance in scoring EEG records. We also appreciate the invaluable assistance of B. Dougherty and A. Teichman in compiling the data for statistical analysis. We gratefully acknowledge the assistance of Drs. Robert Stolberg, Pat Ciccone, and Kenneth Sandler, as well as the entire nursing staff of 7 East for making this study possible. REFERENCES 1. CADE,J. F. J. Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2,349, 1949. 2. SCHOU, M. Lithium in psychiatric therapy and prophylaxis. J. psychiat. Res. 6, 67, 1968. 3. BAASTRLJP, P. C. and SCHOU,M. Lithium as a prophylactic agent: Its effect against recurrent depressions and manic depressive psychosis. Archs gen. Psychiat. 16, 162, 1967. 4. BAASTRUP,P. C., POULSEN,J. C., SCHOU, M., TXOMSEN,K. and AMDISEN, A. Prophylactic lithium: Double blind discontinuation in manic depressive and recurrent depressive disorders. Lancet ii, 326, 1970. 5. DYSON,W. L. and MENDELS,J. Lithium and depression. Curr. Ther. Res. 10,601,1968. 6. GOODWIN,F. K., MURPHY, D. L. and BUNNEY,JR., W. E. Lithium carbonate treatment in depression and mania. Archs gen. Psychiat. 21,486, 1969. 7. MENDELLS,J., SECLJNDA,S. K. and DYSON, W. L. A controlled study of the antidepressant effects of lithium. Archs gen. Psychiat. 26, 154, 1972. 8. MENDELS,J. and SECUNDA,S. K. (Editors), Lithium and Medicine. Gordan & Breach, New York, 1972. 9. DETRE, T. The depressive group of illnesses: Sleep disorders and psychosis. Can. Psychiat. Ass. J. 2, 169, 1966, Suppl. 10. MENDELS,J. and GXHRANE, C. The nosology of depression: The endogenous-reactive concept. (Suppl.) Am. J. Psychiat. 124, 1, 1968. 11. MENDELS,J. and CHERNIK,D. A. Psychophysiological studies of sleep in depressed patients: An overview. In: Proc. of Ann. Conf. Current Concerns in Clinical Psychology, FOWLES, C. D. (Editor), University of Iowa Press, in press. 12. AK~NDELE,M. O., EVANS,J. I. and OSWALD,I. Mono-amine oxidase inhibitors, sleep and mood, EEG Clin. Neurophysiol. 29,47, 1970. 13. WYATT,R. J., FRAM, D. H., KUPFER, D. J. and SNYDER,F. Total prolonged drug-induced REM sleep suppression in anxious-depressed patients. Archs gen. Psychiat. 24, 145, 1971. 14. GRESHAM,S., AGNEW, H. and WILLIAMS,R. The sleep of depressed patients. An EEG and eye movement study. Archs gen. Psychiat. 12, 503, 1965. 15. ZUNG, W. W. K., WILSON, W. P. and DODSON,W. E. Effect of depressive disorders on sleep EEG responses. Archs gen. Psychiat. 10,439, 1964. 16. HAUTKINS,D. R. and MENDELS,J. Sleep disturbance in depressive syndromes. Am. J. Psychiat. 123,682, 1966. 17. MENDELS,J. and HAWKINS,D. R. Sleep and depression: A controlled EEG study. Archs gen. Psychiat. 16,344, 1967. 18. MENDELS,J. and HAWKINS,D. R. Sleep and depression: A follow-up study. Archs gen. Psychiat. 16, 536, 1967. 19. MENDELS,J. and HAWK~S, D. R. Sleep and depression: Further considerations. Archs gen. Psychiat. 19, 445, 1968.
EFFECTSOF LITHIUMCARBONATE ON SLEEP 20. SNYDER,F. Electrographic studies of sleep in depression. In: Computers and Electronic Psvchiatrv, KLINE. N. S. and LASKE.E. (Editors). v. 272. Grune & Stratton. N.Y., 1968. 21. Low;, F. H.; CLE~B~RN,J. M. and MC&RE, D.‘J.* Sleep patterns in depression. i. Nerv. 153, 10, 1971. 22. MENDELS,J. and HAWKINS,D. R. Sleep and Depression-IV. Longitudinal studies. J. Nerv. 153, (4), 251, 1971. 23. GREEN,W. J. and STAJDUHAR,P. P. The effect of ECT on the sleepdream cycle in a psychotic
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Meat. Dis. Ment. Dis.
depression.
J. Nerv. Ment. Dis. 143, 123, 1966. 24. VOGEL,G. W. REM deprivation-III.
Dreaming and psychosis. Archs. Gen. Psychiat. l&312,1968. 25. VOGEL,G. W., TRAULX, A. C., BEN-H• RIN, P. and MEYERS,G. M. REM deprivation-II. The effects on depressed patients. Archs gen. Psychiat. 18, 301, 1968. 26. HARTMANN,E. Longitudinal studies of sleep and dream patterns in manic-depressive patients. Archs gen. Psychiat. 19, 312, 1968. 27. VAUGHAN,T., WYATT, R. J. and GREEN, R. Changes in REM sleep of chronically anxious depressed patients given alphamethylparatyrosine (AMPT). Psychophysiology, 9, 96, 1972 (Abstract). 28. SNYDER,F. NIH studies of EEG sleep in affective illness. In: Recent Advances in the Psychobiology of the Depressive Illnesses. WILLIAMS,T. A., KATZ, M. M. and SH[ELD,J. A. (Editors), p. 171, U.S. Government Printing Office, Washington, D.C., 1972. 29. MENDELS,J. and HAWKINS, D. R. Sleep studies in depression. In: Recent Advances in the Psychobiology of the Depressive Illnesses. WILLIAMS,T. A., KATZ, M. M. and SHIELD,J. A. (Editors), p. 145, U.S. Government Printing Office, Washington, DC., 1972. 30. MENDELS,J. and CHERNIK,D. A. REM sleep and depression. Meeting of the Assoc. Psychophysiological Study of Sleep, New York, May, 1972. 31. BREBBIA,D. R., ALTSCJXJLER,K. and KLINE, N. S. Lithium and the electroencephalogram during sleep. Dis. of the Nerv. Syst. 30, 541, 1969. 32. KUPFER, D. J., WYATT,R. J., GREENSPAN,K. and SNYDER,F. Lithium carbonate and sleep in affective illness. Archs gen. Psychiat. 23, 35, 1970. 33. WHYBROW,P. C. and MENDELS,J. Toward a biology of depression: Some suggestions from neurophysiology. Am. J. Psychiat. 125, 1491, 1969. 34. MENRELS,J. Concepts of Depression. Wiley, New York, 1970.
35. COPELAND,J. R. M., COOPER,J. E., KENDE~, R. E. and GOURLAY,A. J. Differences in usage of diagnostic labels amongst psychiatrists in the British Isles. Br. J. Psychiat 118,629, 1971. 36. ROBINS,E. and GUZE, S. Classification of affective disease: The primary-secondary, the endogenousreactive, and the neurotic-psychotic concepts. In: Recent Advances in the Psychobiology of the Depressive Illnesses. WILLIAMS,T. A., KATZ, M. M. and SHIELD,J. A. (Editors), p. 283, U.S. Government Printing Office, Washington, D.C., 1972. 37. MENDELS,J. Lithium and depression. In: Lithium: Its Role in Psychiatric Research and Treatment. GERSHON,S. and SHOPSIN,B. (Editors), p. 253, Raven Press, New York, 1973. 38. RECHTSCHAF~~N, A. and KALES, A. (Editors). A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. U.S. Government Printing Office, Public Health Service, Washington, D.C., 1968. 39. RECHTSCHAFFEN, A., MOL~NARI,S., WATSON,R. and WINCOR,M. Z. Extra-ocular potentials: A possible indicator of PGO activity in the human. Psychophysiology 7,336,1971 (Abstract). 40. RECH~SCHAPFEN, A. and CHERNJK, D. A. The effect of REM deprivation on periorbital spike activity in NREM sleep. Psychophysiology 9, 128, 1972. 41. FRAZER, A., SECUNDA,S. K. and MENDELS,J. A method for the determination of sodium, potassium, magnesium and lithium concentrations in erythrocytes. Clin. Chim. Acta 36,499,1972. 42. ZAKOWSKA-DABROWSKA, T. and RYBAKOWSKI,J. Lithium-induced EEG changes. Relation to lithium level in serum and red blood cells. Acta Psychiat. Stand. in press. 43. FRAZER, A., MENDELS,J., SECUNDA, S., COCHRANE,C. and B~ANCHI,C. P. The prediction of brain lithium concentrations from plasma or erythrocyte measures. J. psychiat. Res. 10, 1, 1973. 44. BUNNEY,JR., W. E. and HAMIXJRG,D. A. Methods for reliable longitudinal observation of behavior: Developments of a method for systematic observation of emotional behavior on a psychiatric ward. Archs gen. Psychiat. 9, 280, 1963. 45. BECK, A. T., WARD, C. H., MPNDELSON,M., MOCK, J. and ERBAUGH,J. K. An inventory for measuring depression. Archs gen. Psychiat. 4, 561, 1961. 46. MENDELS,J. and FRAZER, A. Intracellular lithium concentration and clinical response: Towards a membrane theory of depression. J. psychiat. Res. 10,9,1973.
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47. OSWALD, I. and PRIEST,R. G. Five weeks to escape the sleeping-pill habit. Br. Med. J. 2,1093,1965. 48. OSWALD, I. Sleep and dependence on amphetamine and other drugs. In: Sleep: Physiology and PathoL ogy, a Symp. KALES, A. (Editor), p. 317, Lippincott, Philadelphia, 1968. 49. KALES, A., MALSTROM,E. J., SCHAXW,M. B. and RUBIN, R. T. Psychophysiological and biochemical changes following use and withdrawal of hypnotics. In: Sleep: Physiology and Pathology, a Symp. KALES, A. (Editor), p. 331, Lippincott, Philadelphia, 1968.
EFFECTS OF LITHIUM CARBONATE ON SLEEP D. A. CHERNIK, C. COCHRANE* and J. MENDELS Depression Research Unit, Department of Psychiatry, University of Pennsylvania and the Philadelphia Veterans Administration Hospital, Philadelphia, Pennsylvania 19104, U.S.A. (Received 24 July 1972) (Revised 12 April 1973)
LITHIUM carbonate is now widely used for the treatment of mania,ls2 the prophylaxis of recurrent mania and depression2-4 and, to an extent, in the treatment of selected depressed patients. 5- 7 There is a clear trend towards the increased use of lithium for more patients and for longer periods of time.s Since depressed and manic patients have a significant sleep disturbance and. as it has been suggested that there may be significant associations between these sleep changes and both the clinical syndromes and the antidepressant drug effects,s-13 it seemed important to determine the effect of lithium on sleep (both acutely and chronically). Further, if lithium, which is now being used chronically for many patients, were to adversely affect sleep, then these patients may experience long-term sleep alterations of unknown implications. It is also of interest to determine what, if any, are the correlations between lithium’s therapeutic and prophylactic effects and its influence on the disturbed sleep pattern of these patients. Depressed patients (as a group) have a reduction in total sleep time, more awakenings during the night and less stage 4 sleep. 11, 14- 21In addition, Mendels and Hawkins17,22 have reported that depressed patients take longer to fall asleep and wake significantly earlier in the morning and have increased amounts of stage 1 sleep. Reports on the amount of stage 1 REM sleep obtained by depressed patients are conflicting. Some studies report a reduction in REM sleep during depression, *I4817*20, 23-25 others report normal or even slightly increased REM sleep time with depression26p 27 with an earlier REM sleep onset1s,26 and an increase in phasic REM sleep elements such as eye movements. l s Later reports by MENDELS et aLa 2s*3olikewise reflect a relatively high percentage of REM sleep as well as a pressure to achieve REM sleep in some (but not all) depressed patients. Two previous studies31* 32 of the effects of lithium carbonate on sleep offer apparently contradictory results, although the different findings may be a function of the dose administered and the subjects studied. BREBBIA et al.31 administered 750 mg/24 hr lithium carbonate for 8 days to three control subjects and to three manic patients with plasma levels ranging between 0.34 and 0.46 mEq/l. The plasma levels are below those regarded as being in the therapeutic or prophylactic range. 2,8 They reported no uniform change in sleep pattern associated with the drug. KUPFER et al.,32on the other hand, reported a significant increase in delta wave sleep (stages 3 and 4 combined) and a significant decrease in stage 1 *Department of Psychology, The Bowman Gray School of Medicine of Wake Forest University, Behavioral Sciences Center, Winston-Salem, North Carolina, 27103. 133
134
D. A. CHJXR~K,C. COCHRANEand J. MENDELS
REM sleep with 1200 or 1800 mg/24 hr of lithium carbonate given to seven patients (one depressed, two manic and four hypomanic inpatients), with plasma lithium levels ranging from 0.70 to 1.30 mEq/l. Further, they reported a reduction (not significant) in REM sleep intensity per minute of REM time and a significant increase in REM sleep latency. Actual sleep time was not affected. Two subjects, who did not have any delta wave sleep during baseline, also did not have any delta sleep during lithium administration, The effect of lithium withdrawal was studied on one patient. This patient exhibited a sharp drop in delta wave sleep from 50 to 9 min per night together with an increase in stage 1 REM sleep. The study of KUPFER et aZ.s2 covered a relatively short time period. They obtained an average of 13 sleep recordings from each subject with a minimum of 3 baseline and 3 lithium nights per subject. On the basis of this study, one cannot determine whether or not these effects are enduring. Further, six of their seven subjects were manic or hypomanic, raising the question of whether or not the effects of lithium on sleep which they reported, are specific for this clinical syndrome. METHOD
We have studied the effects of lithium carbonate on the sleep of 15 male patients with affective disorders and two non-depressed psychiatric patients (see Table 1). Each patient was evaluated and classified on the basis of independent agreement by two psychiatrists. The patients were characterized by at least one previous hospitalization for depression TABLE1. PATIENTCHARACTERISTICS
Age
Manic depressives HS 27 RM 37
Number of nights studied in sleep laboratory at specified plasma lithium levels (mEq/l) Baseline
< 0.70
0.71-1.10
0 12
0
14
t3
6 WC 47 5 2 BS 41 0 JH 48 26 10 3 AR 51 7 0 JC 53 0 7 JD 55 13 3 ws 57 7 12 JG 61 7 5 BB 64 0 Uniphasic depressives JL 43 40 1 4 JM 49 10 0 GG 53 21 JS 60 4 1 Psychiatric (non-depressed) patients RP 43 4 16 2 5 OM 62 86 Total nights studied: 167 Note: Adaptation nights are excluded
Clinical status
> 1.10
6
14 11 15 4 18 6 3 8 13
14 0 0 17 32 14 5 0 3
7 17 4 3
5 1 0 0
2 3
0 0
137
106
Lithium carbonate (mg/24 hr)
Outpatient (asymptomatic) Mixed manic and depressed (concurrent) Depressed Outpatient (asymptomatic) Depressed Manic Hypomanic Depressed Depressed Depressed Outpatient (asymptomatic)
2100 900-1800
Depressed Depressed Depressed Depressed
1200 1500 1200-l 500 1200
1800-2400 1200-1500 1200-1500 1500-3300 1500-2700 60&1500 1200-l 500 900-1500 1200-1500
1200 900
EFFECTS OF LITHJIJM CARBONATE ON SLEEP
135
together with the clinical syndrome of “endogetious depression”* as described elsewhere.l* The 15 patients with affective disorders included 11 manic-depressed (biphasic) and four uniphasic patients. We are using these terms (biphasic and uniphasic) as they have no theoretical bias with regard to polarity or other relationship between manic and depressive states.33, s4, 37They are equivalent to the terms bipolar and unipolar. Uniphasic depressive illness was diagnosed if there was no history of previous manic episodes and if there was no history of any other significant psychiatric abnormality or organic brain syndrome. In order to determine if lithium’s effect on sleep is independent of its effect on the sleep and clinical course of depressed patients, we administered 900 and 1200 mg, respectively, to two non-depressed psychiatric patients. These two patients were neither depressed nor schizophrenic. They can best be described as having character disorders (passive dependent or inadequate personality type) with superimposed mixed neurotic symptomatology (anxiety and phobic symptoms). These symptoms varied from day to day and were responsive to environmental changes. While data from two subjects is not sufficient to allow for definitive conclusions, these preliminary observations are of some interest. The 17 subjects were studied for a total of 496 nights. Four of the subjects entered the study while receiving lithium. Of these four subjects, three were studied as outpatients only (while in remission). The remaining 13 patients had received no medication for at least 8 weeks prior to the study. All the hospitalized patients, including the two psychiatric controls, slept in their regular hospital rooms in a special research ward designed for the study of affective disorders. These rooms are connected by cable to the monitoring equipment. The patients were studied in the sleep laboratory for periods ranging from 33 to 74 nearly consecutive nights. Standard sleep recordings38 included the electroencephalogram (EEG), electro-oculogram (EOG) and submental muscle activity (EMG). The EEG record is a C, referred to a mastoid. In addition, electrodes were placed at the outer canthus of each eye for a bipolar recording of the phasic integrated potential (PIP).? The first night of the series was an adaptation night and the sleep records obtained from this night were not scored. Records were scored for stages of sleep according to standardized procedures38 with the scorer blind as to subject, clinical condition, and medication if any. The dose of lithium carbonate (900 to 3370 mg/24 hr) varied with the clinical state, plasma level and clinical response of the individual patients. No other drugs were administered during the baseline or study periods. Lithium carbonate was discontinued on a double blind basis for three patients. We were, therefore, able to compare their baseline (premeditation) sleep pattern with the mid-treatment-no-lithium period (when lithium was withdrawn and placebo substituted). This allowed us to consider to what extent the changes in sleep pattern might be caused by changes in the patient’s clinical status, as opposed to a direct pharmacological effect from lithium. At the same time, we were able to determine whether there were any changes in *The term endogenous depression is used to designate a clinical syndrome, the origins of which are undetermined at this time. It is not used to imply etiology. We suggestedlO that these clinical features may represent the core of the syndrome of depression lo, 3*. This view has recently been supported by COPELAND et ~1.~~and the conclusions are similar to those of ROBINSet ~1.~~in their concept of “primary depressive illness”. tPIPs may be the human analogue to PGO spikes in the cat.3Qs 4o
136
D. A. CHERNIK, C. C~CHRANEand J. MENDELS
sleep as a result of drug withdrawal. Plasma intraerythrocyte (RBC) lithium levels were determined routinely by atomic absorption spectroscopy for RBC values*l and by flame photometry (Instrumentation Labs; model 143) for plasma values. Several recent reports42, 43 suggest that RBC values may provide a more accurate reflection of lithium distribution and biological activity in the central nervous system than do plasma Li-values. A specially trained group of nurses rated each inpatient daily on a variety of mood and behavioral items.44 Our nurses have demonstrated a high degree of inter-rater reliability. Four independent ratings were obtained every day. The depression rating, derived from this scale, which we used in this report, is termed the “total depression score”. This is obtained by summing the scores applied to five separate items: depression; verbal thoughts of feeling worthless; verbalized thoughts about death or suicide; verbal thoughts of feeling helpless; and sad facial expression. In addition, the patients completed a self-rating depression inventory45 twice weekly. RESULTS
Table 1 describes some of the features of the 17 male patients we have studied. Tables 2 and 3 show the individual patient’s mean percentage values of delta wave and stage 1REM sleep during baseline (no drug), low (< 0.70 mEq/l), medium (0.70 to 1.10 mEq/l) and high (> 1.10 mEq/l) plasma lithium levels. Change scores (plus or minus) reflect the changes which occurred between each ascending level (two adjacent groups). Each value is compared with the preceding value. A plus or minus sign indicates whether the second value is larger or smaller than the first. The results were evaluated using a z-score (two-tailed). In these TABLE 2. PERCENTAGE
OF DELTA SLEEP AT VARYINGPLASMALITHIUMLEVELS(mEq/l)
Plasma lithium concn
Manic depressives
Baseline
< 0.70
JC WC
5.7
7.0
1.7 13.3 0.0 4.0 0.0 0.1
1.4 11.3 0.4 7.6 0.0 0.2 1.2 3.7
JH !zf JD ws JG BS BB HS Unipolar JM JL GG JS Non-depressed OM RP Total changes
0~71-1~10 9.6 74 5.1 20.0 2.5 14.5 0.1 0.2 4.6 8.4 33.7
0.1 24 15.4 2.2
0.3 2.8 6.6
6.6 5.9 17.4 3.8
0.4 0.0
0.0 0.3
0.0 1.1
Changes
by ascending levels -
> 1.10
+
15.9 18.2
:
0 0
:
1
: 0 0 0.5 0.5 0 1 0
3 2 1 1
0 1 0 1
0.5 2
1.5 0
29.5
7.5
20.1 15.1 15.6 0.4
6.2 41-4 10.2 3.1
: 2.5 1.5 :
137
EFFECTSOFLITHIUM CARBONATE ONSLEEP TABLE3. PERCENTAGE OFREM Manic depressives
< 0.70
25.9 22.1 32.1
25.9 20.6 27.4 37.1 28.7 20.0 21.1 20.1 18.6
!F JD WS JG BS BB HS Unipolar JM JL GG JS Non-depressed OM RP Total changes
32.0 195 24.7
PLASMA LITHIUM LEVELS (mEq/l)
Plasma lithium concn 0~71-1~10 > l-10
Baseline
JC WC JH
SLEEP AT VARYING
17.2 16.1 17.8 21.2 19.6 24.0 17.1 19.6 20.0 14.6 13.6
30.3 25.8 21.0 20.8
27.2 22.7 21.3
19.0 28.1 16.0 18.9
28.4 18.3
29.3 15.7
17.4 13.3
13.7 11.5 17.9 19.9 197 16.5 21.0 9.5 23.6 26.3
Changes by ascending levels + 0
0.5 0 0 1 0 1 0 0 1 0
1 2.5 2 3 2 3
1 1 0 1
2 2 1 1
1 0 7.5
1 2
295
tables, intrasubject comparisons were made. Two subjects were manic (AR) and hypomanic (JC), three were asymptomatic, ten were depressed and the remaining two patients were psychiatric controls. There was a progressive increase in the percentage of delta wave sleep and a progressive decrease in the percentage of stage 1 REM sleep with increasing plasma lithium levels (p < 0.005, sign test). A similar, significant trend was obtained using RBC lithium concentrations of less than 0.30 mEq/l, 0.30-0.70 mEq/l and > 0.70 mEq/l. Further analyses were performed to assess the significance and type of change in sleep measures with changing plasma values. Matched pair t-teats were done between successive lithium groups (low and medium plasma lithium concentrations; medium and high plasma lithium concentrations) using: (a) all the subjects who had values in two columns and, (b) 5 patients who had a full range of plasma lithium values. Each of the 5 patients’ sleep data was further analyzed to see if there was a significant linear regression of the respective sleep measures on plasma lithium values, and analyses of variance were performed including a test of whether the combined data of the five patients showed a significant linear trend as a function of increasing plasma ranges (see Table 4). The results are as follows : Delta wave sleep. There were significant increases in mean percentage delta wave sleep with increasing plasma lithium levels (p -=c0.05, matched pair t-test). Analysis of variance for the combined data showed that the means significantly fitted a linear trend (p < 0905). Four of the five patients showed individually significant positive regression slopes with delta wave sleep increasing as plasma lithium increased.* The following linear equation was *Ah five patients showed individuallysignificant positive regression slopes when RBC lithium concentrations were substituted for plasma values.
138
D. A. CHERNIK, C. C~CHRANE and J. MENDELS TABLE 4. MEAN PER CENT DELTA WAVE SLEEPAND STAGE 1 REMVALUES FOR: (a) ALL PATIENTS IN A GIVEN PLASMA Li RANGE, (b) FIVE PATIENTS WITH A FULL RANGE OF PLASMA VALUES Plasma lithium < Delta wave sleep patients Five patients
All
Stage 1 REM All patients Five patients
0.70
concn
0.71-1.10
\?/A)
*
3.29 5.02
10.65 10.98
17.21 15.32,
24.56 26.50
18.04 19.98
17.28 18.44
sleep
derived by averaging the slopes and intercepts for these patients : D’ = 7.74 plasma lithium plus 2.98, where the predicted value of per cent delta wave sleep equals 7.74-times the given plasma lithium level plus the constant 2.98. In other words, delta wave sleep increased 7.74 units with each unit increase in plasma lithium. Table 4 shows the mean per cent of delta wave sleep for (a) all patients in a given column and, (b) the five patients used for analyses of variance and regression analyses. It can be seen that both sets of data confirm the impression of a steeply rising linear dose curve within the range of plasma lithium concentrations studied. Stage 1 REM sleep. The decrease in mean percent of stage 1 REM sleep when plasma lithium rose from the lowest plasma lithium levels to the medium range was significant (p < 0.01) but that between the middle and highest range was not. The combined data for the five patients showed a highly significant linear trend (p < 0.001). Further, four of the 5 patients showed a significant negative regression slope with per cent stage 1 REM sleep decreasing as plasma lithium increased. The equation reads : R’ = - 0.042 plasma lithium plus 1.69. While the linear regression model does significantly fit the data, the lack of a significant difference between REM sleep means for medium and high plasma lithium groups suggests that a linear regression may better describe the low-medium range of lithium concentrations whereas the medium-high group relationship may be asymptotic. Changes in stage 1 REM sleep and delta wave sleep with long-term lithium carbonate administration. Figs. l-3 illustrate the changes over time in stage 1 REM sleep and in delta wave sleep with the administration of lithium. These three subjects (JD, JM and RM) were studied for 51, 37 and 43 nights, respectively. Stage 1 REM and delta wave sleep are expressed as a percentage of the actual sleep time in the upper two graphs. Plasma lithium levels and lithium dose are indicated in the third and fourth graphs and depression ratings are given in the bottom graph. There was an alteration in both stage 1 REM sleep and in delta wave sleep in association with lithium administration, whereas alterations in depression rating scores were not consistently associated changes in these two sleep stages. Comparison of the relative eflects of lithium and severity of depression on sleep stages. The per cent of stage 1 REM sleep was significantly decreased (p < 0.01) and per cent delta wave sleep was significantly increased (p < 0031) with the administration of lithium carbonate in each of three patients for whom the severity of the depression (as measured
139
EFFECTS OF LITHIUMCARBONATE ON SLEEP REM%
(of actual
Plasma
lithium
sleep)
(mEq/-l)
:f[
fl
Hospitalization Nights r?!Tz (from dateof admission)
p
Throughout Cl -zv
0
9
FIG. 1. Longitudinal study of rapid eye movement (REM) sleep and delta wave sleep in relation to lithium carbonate administration to a 55-year-old uniphasic, recurrent depressive (J.D.). REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph.
by DepreSsion Inventory Scores) did not change (see Table 5) which provide further support for the thesis that changes in stage 1 REM and delta wave sleep which occur with the administration of lithium carbonate are not the result of clinical change. TABLE5. CGMPABISON OF STAGE 1 REM ANDDELTAWAVESLEEP(%) DURINGDRUGFREEPERIODSANDLITHIUM CARBONATE PERIODS (Beck depression scores held constant) Delta wave sleep (%)
Stage 1 REM (%) Subject
RM @I* O-3) JD @I” 10-15) JM (DI* 28-31)
Drug free
Lithium carbonate (plasma Li > 0.70 n-JEo/l)
t
Drag free
Lithium carbonate (plasma Li > 0.70 mFq/l)
t
10.526’1-
30.64340
l&8&3.37
12.0761’
5.ozt3.30
20.3k6.31
34.2rt6.02
21.4rt4.71
6.904t
4.8 f2.56
15*0&5*22
7.234t
25~813.68
18*4&3.49
4377*
O-6&0*50
8.5 f3.30
7.101 t
*DI = Depression inventory scores. *p = 0.01, two-tailed f-test. tp = 0,001, two-tailed f-test.
340
CHERNIK,C.COCHRANE and J. MENDELS
D.A. REM %(of
actual
jr
J.M.
sleep)
-Lq
Delta%(of
actual
j
_
Plasma
lithium
sleep)
_“,_\& (rnEQ/l)
,I
r
Lithium
”
“i
dose (mg)
Depression
raiings
30 *o 10
ni-
Hospitalization Nights (from + doteof “2 admission)
Throughout “,
on
“p
“,
$ rz
FIG.2. Longitudinal study of rapid eye movement (REM) sleep and delta wave sleep in relation to lithium carbonate administration to a 49-year-old uniphasic depressive (J.M.). REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph. DISCUSSION
This study provides support for the initial conclusions of KUPFER et al.32 and extends their findings. In their study of the acute effects of lithium on sleep, they reported a significant decrease in per cent stage 1 REM with a significant increase in per cent delta wave sleep in five of the seven patients studied. For the remaining two, who were among the oldest of the group, delta sleep was entirely lacking throughout the study. In this study we were concerned with the longer term effects of lithium on sleep. Our depressed patients were studied for periods ranging up to 74 nights.* In our patient group, lithium carbonate administration significantly increased per cent delta wave sleep, reduced per cent stage 1 REM sleep and increased the latency to the first REM period without affecting actual time asleep. The changes were significantly related to plasma lithium levels, with higher plasma lithium levels associated with greater changes in delta and REM sleep. While there was a significant linear trend between the two sleep measures and plasma lithium levels, the lack of a significant t between the higher plasma lithium ranges and *Sleep data were discarded if lithium levels were not available.
EFFECTSOF LITHIUMCARBONATEON SLEEP
141
R.M.
REM
%Iof
actual
i_ithiumdose
sleep)
(mg)
Hospiiolizntion -----Throughout Nights (from *v dcte of admission\
B
FIG. 3. Longitudinal study of rapid eye movement (RPM) sleep and delta wave sleep in relation to lithium carbonate administration to a 37-year-old manic-depressive (RM) during both hypomanic and depressed phases. REM and delta sleep measurements are expressed as a percentage of the actual sleep period in the two upper graphs. Plasma lithium levels and the dose of lithium carbonate are presented in the middle two graphs and the depression ratings are indicated in the bottom graph.
per cent REM sleep makes it necessary to qualify the statement regarding linearity. A linear regression model does significantly fit both the REM and delta sleep data, but the curve for REM sleep is better described as dropping steeply and then levelling off at higher (> l-10 mEq/l) plasma lithium values. With the small number of subjects studied thus far, it is appropriate to wait for more data before deciding whether the REM-dose curve is linear or asymptotic. Tables 3 and 4 include sleep values on one patient who was hypomanic (JC) and another who was manic during the study. The hypomanic had sleep values similar to that of the depressed patients studied in our laboratory with more than 6.5 hr of sleep per night. The manic patient, on the other hand, averaged 105 min of sleep per night. In spite of the greatly reduced sleep, this subject did experience an increase in his per cent delta wave sleep with increasing plasma lithium levels suggesting that the effect of lithium carbonate on sleep is nob specific to one clinical state, We have presented our findings in terms of plasma lithium values as this is the general practice at this time. However, as noted we also measured REC lithium concentration in our patients. We found that there was a higher correlation between EEG sleep patterns and
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C. C~CHRANE
and J. MENDELS
RBC lithium concentrations than between EEG sleep pattern and plasma lithium values. Of the five patients for whom we had sleep recordings over a wide range of plasma and RBC lithium levels, four showed a higher correlation between delta wave sleep and RBC concentrations, three showed a higher correlation between stage 1 REM sleep and RBC concentrations as opposed to individual correlations between delta wave sleep and stage 1 REM sleep and plasma lithium concentrations. In keeping with this there is the report that changes in the waking EEG in subjects receiving lithium, were significantly correlated with RBC lithium concentrations, but riot with plasma lithium concentrations,42 again suggesting that RBC lithium may be a more sensitive measure of lithium activity in the central nervous system than plasma lithium measures. Should this preliminary observation be confirmed, it would be in keeping with our finding that the RBC concentration of lithium is higher in some depressed patients, who do respond to lithium treatment, as compared with depressed patients who do not respond to lithium treatment,46 and our finding that RBC lithium concentrations may provide a better index of brain lithium concentrations than plasma lithium concentrations.43 It is possible that lithium carbonate affects the sleep of manic-depressive patients differently from uniphasic depressed patients or psychiatric controls. However, the latter two groups in this study were too small to make a meaningful statement in this regard. It is interesting that the two uniphasic depressed patients had essentially normal amounts of REM sleep (23.6 and 23.1 per cent, respectively) with plasma lithium concentrations in excess of 1.10 mEq/l whereas all of the biphasic patients had less REM sleep (values ranging from 9.6 to 2@4 per cent, with a mean of 15.3 per cent) at similar lithium levels. Lithium carbonate appeared to normalize the sleep of the majority of patients studied. The premeditation sleep of all but one subject was characterized by low amounts of delta wave sleep. There was an increase in delta wave sleep in most patients with the administration of lithium carbonate. Half of the patients had elevated levels of REM sleep during the baseline period with individual subject mean values ranging up to 32.1 per cent of actual sleep time.3o Lithium carbonate decreased stage 1 REM sleep, frequently decreasing REM sleep below normal levels. It should be noted that none of these patients had been taking any medication for at least 8 weeks prior to the sleep study, although one subject (JM) had been drinking heavily for 10 days prior to the sleep recordings. Thus, the elevated levels of REM sleep could not be a rebound caused by previous drug-induced REM sleep deprivation (with the possible exception of the subject who had been drinking prior to the study). There seemed to be a limit to the effect of lithium on REM sleep. While there was a significant difference between per cent stage 1 REM sleep at low and medium plasma lithium levels, there was not a significant difference between REM sleep means for medium and high plasma lithium groups (see Table 4). On the other hand, there was a significant linear trend (p < 0.005) between increases in mean percentage delta wave sleep and increasing plasma lithium levels, including a significant difference (p < 0.05) between delta wave sleep at medium and high plasma lithium levels. Although a plateau effect, similar to that observed for REM sleep, may occur at some higher plasma level this did not emerge with the range of lithium values observed here.
EFFE~S OF LITHIUMCARBONATE ON SLEEP
143
Two of the three subjects who did not show an increase in delta sleep with lithium administration were the psychiatric control subjects. It is possible that the lack of significant changes in stage 1 REM and delta wave sleep reported by BREBBIA et aL31 may therefore have been a function of the subjects studied rather than of lithium dose and plasma lithium levels. In the Brebbia et al. study, comparative sleep measures with and without lithium carbonate were obtained on a small group (3 subjects) of normal controls (the remitted manic-depressed subjects were studied only during lithium administration). It is therefore possible that lithium affects the sleep of normal subjects differently from that of subjects with manic-depressed or recurrent depressive illness. Neither of our two psychiatric controls nor the three normal subjects studied by BREBBIA et al. 31exhibited a noticeable increase in delta wave sleep with the administration of lithium carbonate. We have also noted that controls do not appear to tolerate lithium carbonate as well as do patients. In a separate study which involved the administration of 1200 mg of lithium carbonate to eight healthy normal subjects for 10 days, four subjects discontinued the study after only a few days because of side effects (abnormal cramps, malaise, weakness, and tiredness). All subjects were members of the staff and presumably well motivated. One must consider the possibility that the change in quality of sleep found in this study was in response to a change in the patient’s clinical status. However, this does not seem to be the case because, (a) the increase in delta wave sleep and the decrease in stage 1 REM sleep frequently occurred within 24 hr after the initiation of lithium carbonate therapy (although it usually took 6 or 7 days before there was a consistent change), (b) there was a reversal in the sleep indices in three patients who had been withdrawn from lithium during the course of treatment within two days after drug withdrawal, (c) we compared the sleep of three patients while taking lithium with their sleep during a drug free period, selecting periods with equivalent depression inventory ratings (see Table 5). There was a significant change in both stage 1 REM sleep and delta wave sleep with the administration of lithium carbonate even though the patient’s clinical state was similar during the two periods. Thus, it appears unlikely that clinical improvement per se produced the observed changes in stage 1 REM and delta wave sleep. While a REM rebound (an increase in REM sleep which purportedly makes up for the previous loss in REM sleep) has been reported to occur following the withdrawal of most REM-suppressing drugs, 47-4s there was no evidence of a REM rebound in two patients who were studied 12 and 13 nights following lithium withdrawal. SUMMARY
The effect of lithium carbonate on the sleep of 17 psychiatric patients was studied for 496 nights. Lithium carbonate appeared to normalize the sleep of depressed patients, significantly increasing the low baseline levels of per cent delta wave sleep and significantly decreasing the somewhat elevated levels of per cent stage 1 REM sleep. Analyses of variance showed that the combined subjects’ means for per cent delta wave sleep and per cent stage 1 REM sleep were linearly related to plasma lithium levels. There were significant positive and negative regression slopes for per cent delta and REM sleep with increasing plasma lithium levels. There was some indication that changes in stage 1 REM sleep may reach a plateau at which point no further decrease in per cent REM
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CHERNIK, C. COCHRANE
and J. MENDELS
sleep occurs in spite of increasing plasma lithium levels, whereas per cent delta wave sleep showed a significantly linear trend as a function of increasing plasma ranges. The sleep changes frequently occurred within 24 hr after the initiation of lithium carbonate treatment. The withdrawal of lithium during the study was associated with an immediate change in both per cent stage 1 REM and delta wave sleep in the direction of baseline values in spite of sustained clinical improvements, strongly suggesting that the changes in sleep were directly related to the presence of lithium rather than to clinical change. There was no apparent rebound in stage 1 REM sleep when the drug was withdrawn. AcknowZedgements-l%is study was supported by NIMH grant MH17551 and research funds from the Veterans Administration. We are grateful for the assistance of A. Frazer, Ph.D., who provided the lithium measures; of K. Roden and S. Bembry, the recording technicians; and of F. Beckman, M. Stevens, S. Leet and S. Suls for their assistance in scoring EEG records. We also appreciate the invaluable assistance of B. Dougherty and A. Teichman in compiling the data for statistical analysis. We gratefully acknowledge the assistance of Drs. Robert Stolberg, Pat Ciccone, and Kenneth Sandler, as well as the entire nursing staff of 7 East for making this study possible. REFERENCES 1. CADE,J. F. J. Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2,349, 1949. 2. SCHOU, M. Lithium in psychiatric therapy and prophylaxis. J. psychiat. Res. 6, 67, 1968. 3. BAASTRLJP, P. C. and SCHOU,M. Lithium as a prophylactic agent: Its effect against recurrent depressions and manic depressive psychosis. Archs gen. Psychiat. 16, 162, 1967. 4. BAASTRUP,P. C., POULSEN,J. C., SCHOU, M., TXOMSEN,K. and AMDISEN, A. Prophylactic lithium: Double blind discontinuation in manic depressive and recurrent depressive disorders. Lancet ii, 326, 1970. 5. DYSON,W. L. and MENDELS,J. Lithium and depression. Curr. Ther. Res. 10,601,1968. 6. GOODWIN,F. K., MURPHY, D. L. and BUNNEY,JR., W. E. Lithium carbonate treatment in depression and mania. Archs gen. Psychiat. 21,486, 1969. 7. MENDELLS,J., SECLJNDA,S. K. and DYSON, W. L. A controlled study of the antidepressant effects of lithium. Archs gen. Psychiat. 26, 154, 1972. 8. MENDELS,J. and SECUNDA,S. K. (Editors), Lithium and Medicine. Gordan & Breach, New York, 1972. 9. DETRE, T. The depressive group of illnesses: Sleep disorders and psychosis. Can. Psychiat. Ass. J. 2, 169, 1966, Suppl. 10. MENDELS,J. and GXHRANE, C. The nosology of depression: The endogenous-reactive concept. (Suppl.) Am. J. Psychiat. 124, 1, 1968. 11. MENDELS,J. and CHERNIK,D. A. Psychophysiological studies of sleep in depressed patients: An overview. In: Proc. of Ann. Conf. Current Concerns in Clinical Psychology, FOWLES, C. D. (Editor), University of Iowa Press, in press. 12. AK~NDELE,M. O., EVANS,J. I. and OSWALD,I. Mono-amine oxidase inhibitors, sleep and mood, EEG Clin. Neurophysiol. 29,47, 1970. 13. WYATT,R. J., FRAM, D. H., KUPFER, D. J. and SNYDER,F. Total prolonged drug-induced REM sleep suppression in anxious-depressed patients. Archs gen. Psychiat. 24, 145, 1971. 14. GRESHAM,S., AGNEW, H. and WILLIAMS,R. The sleep of depressed patients. An EEG and eye movement study. Archs gen. Psychiat. 12, 503, 1965. 15. ZUNG, W. W. K., WILSON, W. P. and DODSON,W. E. Effect of depressive disorders on sleep EEG responses. Archs gen. Psychiat. 10,439, 1964. 16. HAUTKINS,D. R. and MENDELS,J. Sleep disturbance in depressive syndromes. Am. J. Psychiat. 123,682, 1966. 17. MENDELS,J. and HAWKINS,D. R. Sleep and depression: A controlled EEG study. Archs gen. Psychiat. 16,344, 1967. 18. MENDELS,J. and HAWKINS,D. R. Sleep and depression: A follow-up study. Archs gen. Psychiat. 16, 536, 1967. 19. MENDELS,J. and HAWK~S, D. R. Sleep and depression: Further considerations. Archs gen. Psychiat. 19, 445, 1968.
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