Effects of Isocarboxazid on Sleep
Authors: Shirakura Katsuyuki 
Published: March 2008

Recent findings on depression and sleep mechanism all suggest that brain MA plays an important role. We conducted an acute/chronic administration, sleep poly‐graphy and behavioral observation using chronic cats in order to investigate the influence of isocarboxazid (ICZ) on the sleep. Concurrently, clinical studies were carried out in three cases in which sleep polygram was recorded continually.

1. Preliminary experiments were performed preceding to animal experiments. In investigating the sleep in animal experiments, it is generally difficult to obtain reliable and stable results, with varied factors exerting influence. Under conditions employed by us, however, it was found that the feeding time and subsequent recording time have a great influence, judging from the individual difference, diurnal change and day‐to‐day change. Following animal experiments were conducted by selecting the feeding time (9.00 p.m.) and recording time (11.00 p.m.‐1.00 a.m.) during which a relatively stable PS % time can be obtained.

2. In the drug‐administration experiments with two cats, ICZ 0.5 mg/kg/day and 1.5 mg/kg/day corresponding to the clinical doses were fixed, and experiment with the acute and chronic administration was performed three times each for each dose.

(a) Except acute administration of 0.5 mg/kg/day, selective initial suppression of PS was observed (p <0.01) from the 2nd day to the 3rd day after administration, and its intensity tended to be almost parallel to the doses. Analysis of PS on the 3rd day with the chronic administration in which stronger initial suppression of PS occurred revealed that no significant difference was observed in the duration of individual PS episode but the incidence was decreased markedly (p <0.01).

(b) In the chronic administration experiment, there appeared a relatively stable period both for PS % time and TS % time subsequent to the initial suppression.

(c) The rebound phenomenon of PS was not found on the acute administration; however, it was observed on the chronic administration with the 2nd day after cessation of the administration as a peak, the intensity of which tended to be parallel to the intensity of the initial suppression.

(d) As to SWS, supression was observed on the 1st day irrespective of the administration acute and chronic; however, no remarkable change was found thereafter.

3. Interesting findings observed on polygram were as follows.

(a) A phenomenon was observed in which the preceding PGO activity appears some two minutes 30 seconds ahead of the PS episode.

(b) The delta band of the hippocampal activity showed a conspicuous sustained intensification,

(c) There was observed a period during which the a band of the same hippocampal activity shows a transient intensification over a little less than six minutes. Further, the behavior of cats at this time did not differ from what it was during SWS.

4. Sleep polygram was recorded on three depressed patients. The PS % time before the administration was shown to be reduced as compared with that on remission in two patients, and inversely it was increased in one patient. As for the clinical course following the chronic administration, a relatively stable period of PS appeared on the 6th day to the 10th day subsequent to the initial suppression of PS the same as in the results obtained with the animal experiments. At about this time the improvement of clinical symptoms and an increase in the quantity of movement were observed in all cases.

5. If it is supposed on the basis of our results that the brain MA metabolism is disturbed by a certain mechanism in the brain process of depressed patients and subsequently the imbalance between the brain CA and IA causes sleep disturbance, the relatively stable period of the PS % time on the administration of MAOI may be considered to have resulted from the brain MA metabolism having reached a new equilibrium. Hence, our inference that this period itself might be related in one form or other to the treatment process.