Desynchronized sleep and MHPG excretion: an inverse correlation

412

Brain Research, 61 (1973) 412-416 © Elsevier ScientificPublishing Company, Amsterdam - Printed in The Netherlands

Desynchronized deep and MHPG excretion: an inverse correkltion

ERNEST HARTMANN ANO JOSEPH J. SCHILDKRAUT Sleep and Dream Laboratory, Boston State Hospital and Department of Psychiatry, Tufts University School of Medicine, Boston, Mass. 02111 and ( J.J.S.} Neuropsychopharmacology Laboratory, Massachusetts Mental Health Center and Department of Psychiatry, Harvard Medical School, Cambridge, Mass. 02138 (U.S.A.)

(Accepted June 27th, 1973)

There has been much recent interest in possible relationships between electroencephalographically defined states of sleep and catecholamines (norepinephrine and dopamine) in the brain. Pharmacological studies in animals and man indicate that there may be an inverse relationship between the levels or activity of central catecholamines and the amount of time spent in desynchronized sleep (D-time). Thus D-time has been found to be greatly reduced by amphetamines ~°,27, monoamine oxidase inhibitorsl,ls, 39, most tricyclic antidepressant drugs 8,11,4°, and L-DOPA zs, all of which increase levels or activity of catecholamines in the brain. Similarly, manias and hypomanias which may be associated with increased central catecholaminergic activity 31 are associated with extremely low D-time, measured absolutely or as a percentage of total sleep time 1°. Conversely, D-time can be increased by the administration of reserpine 9,14, alpha-methylparatyrosine lz,37, or 6-hydroxydopamine 1~, each of which, by very different mechanisms, produces a decreased level or availability of catecholamines in the brain. However, not all studies are in agreement15,16. For instance, the effects of alphamethylparatyrosine on sleep are not totally consistent across species 2,17,24,36 and studies of the effects of the phenothiazines, thought to act as blockers of dopamine and possibly norepinephrine receptors in the brain, have been inconclusive 7,19,21,28. Moreover reserpine, given intraperitoneally, can decrease D-time in the cat ~5 but recent studies demonstrate that D-time is increased when the drug is given intrathecally 3z. It is difficult to examine directly the relationship between central catecholamines and D-time in man. Many studies have examined catecholamines or their metabolites in blood, urine, or cerebrospinal fluid, but it is not clear to what extent central catecholaminergic activity is reflected by these measures. However, recent studies in the animals suggest that an appreciable fraction of 3-methoxy-4-hydroxyphenylglycol (MHPG) excreted in urine may derive from the metabolism of norepinephrine in the brain 22,23,29,3°, and that urinary M H P G excretion may thus provide an index of central noradrenergic activity. It has therefore been of interest to

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study the relationship of MHPG excretion and sleep measures, especially D-time, in man. In the present study we examined the relationship between D-sleep and MHPG excretion in a group of patients with depressions or hypomanias as part of a long term investigation of catecholamine metabolism and sleep in patients hospitalized for treatment of affective disorders. Twenty-four-hour urine samples were collected regularly (daily when possible) for the determination of MHPG (see ref. 4). All-night electroencephalographic recordings were obtained in each patient approximately once/week throughout the course of hospitalization, and scored according to the usual sleep laboratory procedures 2~. From the total group of patients studied thus far, 13 were chosen on the basis of having drug-free periods during which adequate urine collections and sleep studies were available, beginning at least 1 week after the last administration of any psychoactive medication; one patient was studied during two different episodes, one depressive and the other hypomanic. Intersubject Pearson product-moment correlations were computed using a mean value for urinary M H P G and a mean value for each sleep measure for each patient during the drug-free period. Fig. 1 illustrates an inverse relationship between D-time and MHPG excretion across all 14 episodes of illness (12 depressive and 2 hypomanic episodes). The inverse correlation between D-time and MHPG excretion was statistically significant when examined in all 14 episodes of illness as well as in the 12 episodes of depressions (Table I). D-time calculated as percent of total sleep (D-time percent) shows approximately the same correlations with MHPG excretion, whereas slow-wave sleep and total sleep show no statistically significant relationship with MHPG excretion. We questioned whether age might conceivably account for the negative relationship between MHPG excretion and D-time, since there is a tendency for D-time to decrease slightly with age in adults, and in our total group of depressed patients M H P G was positively correlated with age (r = 0.55). However, in a large group of normal subjects other investigators found no correlation between MHPG excretion and ageL 2500

•

2000 ..~ 1 5 0 0

I 0

~_. fO00 500

0

510

i I00

i t50

200

D -TIME (rains)

Fig. 1. M H P G excretion and D-time. As described in the text, average values for M H P G excretion (in/~g/24 h) and D-time (in rain/night) were determined for each of 14 episodes of depressions and hypomanias in 13 patients studied during drug-free periods; a Pearson product-moment correlation was computed (r = --0.70; P < 0.01).

414 TABLE

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I

CORRELATIONS BETWEEN M H P G

EXCRETION AND SLEEP MEASURES

All episodes o f hypomanias or depressions ( N = 14)

MHPG

D-time

D-time percent

Slow-wave sleep

Total sleep

--0.70**

--0.60*

~0.08

--0.16

All episodes o f depressions ( N -- 12)

MHPG * P < 0.05;

D-time

D-time percent

Slow-wave sleep

Total sleep

--0.66*

4.46

--0.15

--0.35

**P < 0.01.

Furthermore when we looked separately at a subgroup of our patients with bipolar depressions (i.e., with histories of manias or hypomanias) there was an even stronger negative correlation between M H P G excretion and D-time, but no correlation between M H P G and age ( M H P G vs. D-time, r = --0.88; M H P G vs. D-time percent, r ~-- --0.89; M H P G vs. age, r = 0.07). We conclude that the relationship between M H P G excretion and D-time is not simply a function of age. Also, we do not think that the inverse correlation between M H P G and D-time can be explained on the basis of differences in anxiety or stress, since we observed no relationship between M H P G excretion and scores for psychic or somatic anxiety, agitation or retardation as measured on the Hamilton Depression Rating Scale s in the group of depressed patients 32. The inverse correlation between D-time and M H P G excretion demonstrated in the present study is consistent with the inverse relationship between D-time and central catecholaminergic activity suggested by pharmacological studies. Our findings may also be related to the results of several previous studies of D-time and urinary catecholamines or metabolites in man. In a small group of patients studied during amphetamine withdrawal, we observed a negative correlation, not reaching statistical significance, between M H P G excretion and D-time 35. Other investigators have demonstrated significant inverse relationships between D-time and urinary excretion of norepinephrine and epinephrine in a long-term study of 3 patients with periodic catatonia 34. And in a small group of manic-depressive patients, urinary excretion of norepinephrine (but not of M H P G ) was found to increase and D-time to decrease during the transition from depression to mania 3. The observation that slow-wave sleep shows no relationship to M H P G excretion is consistent with our previous findings. In these studies we found that synchronized sleep in the rat was entirely unchanged by drugs which produced marked changes in catecholamine levels and D-timO 2,1a. In conclusion, the findings of this study demonstrate an inverse correlation between D-time and the urinary excretion of M H P G in a group of patients with

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affective disorders. It m a y be t h a t patients with affective d i s o r d e r s p r o v i d e an especially g o o d o p p o r t u n i t y to examine this r e l a t i o n s h i p because o f the great range in values o f d e s y n c h r o n i z e d sleep a n d M H P G excretion f o u n d in these patients. However, this relationship should certainly be studied in n o r m a l subjects as well, b o t h u n d e r n a t u r a l c o n d i t i o n s a n d in experiments where an a t t e m p t is m a d e to m a n i p u l a t e one o r the o t h e r o f these variables. This w o r k was s u p p o r t e d in p a r t b y N a t i o n a l Institute o f M e n t a l H e a l t h G r a n t M H 15413.

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