Effect of Chronic Phenelzine Treatment on REM Sleep: Report of Three Patients Hans-Peter Landolt, Ph.D. and Lieselotte Posthuma de Boer, M.S.

Antidepressants belonging to the class of monoamine oxidase (stages 1–4) were not changed. In contrast, EEG theta inhibitors (MAOI) such as phenelzine have long been known frequency activity (TFA, power within 4.75–8.0 Hz) during a to drastically suppress REM sleep. Sleep and the 5-min wake interval recorded prior to the sleep episodes was electroencephalogram (EEG) in sleep and waking were studied initially enhanced, and tended to correlate negatively with the in three depressed patients at regular time intervals before, percentage of REM sleep (p ϭ .06). This observation indicates during and after 6 to 18 months of phenelzine treatment. While that compensatory REM sleep mechanisms may occur in REM sleep was initially eliminated in all patients, short REM wakefulness during chronic MAOI treatment. sleep episodes reappeared after three to six months of [Neuropsychopharmacology 25:S63–S67, 2001] medication. Total sleep time and EEG slow-wave activity © 2001 American College of Neuropsychopharmacology. (SWA, spectral power within 0.75–4.5 Hz) in nonREM sleep Published by Elsevier Science Inc.

KEY WORDS: Monoamine oxidase inhibitor (MAOI); Sleep MAOI administration is associated with persistent ab- EEG; Wakefulness; Slow-wave activity; Theta activity sence of REM sleep, we studied sleep and the EEG in sleep and waking in three depressed patients at regular The monoamine oxidase inhibitor (MAOI) phenelzine time intervals before, during and after 6 to 18 months of is an effective “first generation” antidepressant capable phenelzine treatment. of virtually abolishing rapid-eye-movement (REM) sleep at a therapeutic dose range (Akindele et al. 1970; Wyatt et al. 1971a,b; Dunleavy and Oswald 1973; Landolt et al. 2001). Although early studies suggested METHODS that REM sleep deprivation was psychologically harm- Patients ful (Dement 1960), a few patients with depression or Patient PM. This 35-year-old woman suffered from narcolepsy have been treated safely and successfully major depressive disorder (MDD) with loss of interest or with phenelzine for prolonged periods of time (Wyatt pleasure, insomnia, feelings of worthlessness, dimin- et al. 1971a,b). While complete REM sleep suppression ished ability to concentrate, recurrent thoughts of death, for as long as seven months has been described, no and suicidal ideation. She also met criteria for general- study has so far investigated the effects of the drug on ized anxiety disorder. Structured clinical psychiatric di- sleep and the sleep electroencephalogram (EEG) for agnostic interview according to DSM-IV (SCID) revealed longer treatment periods. To examine whether chronic a history of two previous episodes of major depression, which were treated with psychotherapy and fluoxetine. From the University of California at San Diego, Department of The patient denied a history of manic/hypomanic epi- Psychiatry, VA San Diego Healthcare System, San Diego, California, sodes and abuse of alcohol or drugs. Her mother and a USA Address correspondence to: Hans-Peter Landolt, Ph.D., Institute maternal uncle suffered from bipolar disorder. of Pharmacology and Toxicology, University of Zürich, Winterthur- erstrasse,190, 8057 Zürich, Switzerland, Tel.: ϩ41-1-635-5953, Fax: Patient RH. The SCID diagnosis of this 37-year old ϩ41-1-635-5707, E-mail: [email protected] man consisted of MDD, single episode. His symptoms

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S64 H.-P. Landolt and L. Posthuma de Boer NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5

were severe and included depressed mood, loss of in- Table 1. Schedule of Phenelzine Treatment terest or pleasure, psychomotor retardation, lack of en- Patient PM Patient RH Patient CS ergy, worthlessness, difficulty thinking or concentrat- Phase of ing, and suicidal ideation. Mood disturbances started at treatment Week mg/day Week mg/day Week mg/day age 10 and met formal criteria of MDD since age 15; Baseline –1 – –1 – –4 – they were never treated. Secondary SCID diagnoses in- Subchronic 1 15–45 1 15–45 1 15–30 cluded alcohol, cannabis and cocaine dependence in 2–3 30 2 60 2 45 sustained full remission. The family history was nega- 4–5 45 3–18 75 3–18 60 tive for psychiatric disorders. 6–18 60 Chronic 19–23 60 19–75 75 19–21 60 Patient CS. The SCID of this 56-year old man re- 24–30 75 Ͼ22 45 vealed the single diagnosis of MDD with depressed Tapering/ Withdrawal 31 45–15 76–79 60–15 mood, lack of interest or pleasure, insomnia, psycho- 32 – 80 – motor retardation, feelings of worthlessness, and di- minished ability to think or concentrate. Three previous Week: week of treatment; mg/day: daily dose of phenelzine. major depressive episodes at ages 20, 48, and 51 were treated with trazodone, fluoxetine and buspirone, re- spectively. The patient had no family history of psychi- Kales (1968), and the EEG was subjected to power spec- atric disorders. tral analysis (Landolt et al. 2001).

Study Protocol, Phenelzine Treatment and Polygraphic Recordings RESULTS The study protocol was approved by the local Institu- Treatment Response and Visually Scored Sleep tional Review Board (IRB), and written informed con- Variables sent was obtained prior to the study. The patients were seen weekly for clinical visits (bi-weekly after remis- All patients remitted from depression by week 5 on sion). They were instructed to keep a regular sleep- phenelzine (HRSD and BDI scores р 10; Table 2). The wake cycle and to avoid daytime naps. A total of 60 treatment response was especially impressive in RH, nocturnal sleep episodes scheduled at their habitual who had been severely depressed for 20 years prior to bedtimes were recorded in the sleep laboratory during the study. a drug-free baseline night prior to initiation of antide- The sleep profiles and the time course of EEG slow- pressant therapy, at 2 to 4-week intervals during wave activity (SWA, power within 0.75–4.5 Hz) of rep- phenelzine treatment, and at 3 to 7-day intervals during resentative nights of PM and RH in all treatment phases dose tapering and withdrawal (patients PM and RH). are illustrated in Figure 1. REM sleep was completely The data of two recordings (one in RH and one in CS) eliminated in all patients by day 43 of pharmacother- were lost because of technical difficulties. apy. In PM, REM sleep was essentially absent for six In all patients, open-labeled treatment with the months except for short REM sleep episodes (range: MAOI phenelzine was initiated after the baseline night, 4–28 min) during the fifth month on phenelzine (Figure 1). and individual daily doses of 15–75 mg were prescribed REM sleep disappeared again after increasing the dose according to clinical considerations (Table 1). To verify of the drug. In RH, REM sleep was initially eliminated compliance, the patients were instructed to check off a for five months. Various amounts of REM sleep (range: box in a drug diary after medication intake. The treat- 9–134 min) were detected in most sleep recordings dur- ment period was arbitrarily subdivided into a sub- ing the remainder of pharmacotherapy. In CS, REM chronic (1–18 weeks) and chronic (Ͼ18 weeks) phase. sleep was absent for three months. Thereafter, REM Nine EEGs (the data of the C3-A2 derivation are re- sleep episodes of various durations (range: 1–53 min) ported here), submental EMG, bipolar EOG and ECG reappeared in most sleep recordings. The suppression were recorded by a portable amplifier system during a of REM sleep was accompanied by increased amount of 5-min wake interval prior to lights-out (starting at 10:05 stage 2 (PM), slow wave sleep (stages 3 & 4) and/or P.M. Ϯ 20 min [SD] in PM, 10:23 P.M. Ϯ 23 min in RH, wakefulness after sleep onset (WASO; RH and CS). To- and 10:27 P.M. Ϯ 42 min in CS), and the entire sleep epi- tal sleep time (TST) was not affected (Table 2). sode. The detailed procedures of data recording and Phenelzine treatment in PM was stopped because of signal conditioning have been described previously weight gain and edema. Tapering the dose gave rise to (Landolt et al. 2001). Each recording night was pre- an impressive REM sleep rebound, for example a 2-h ceded by at least one adaptation night. The sleep stages sleep onset REM sleep period and more than were visually scored according to Rechtschaffen and three hours of REM sleep (46% of TST) in the third

NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5 Phenelzine and REM sleep S65

Table 2. Visually Scored Sleep Variables, Theta Frequency Activity in Waking, and Mood Ratings (Means Ϯ SD)

REM sleep WASO TFA HRSD BDI (%) Stage 2 (%) SWS (%) (%) TST (min) (␮V2/Hz)

Patient PM Baseline 22 22 12.4 53.7 23.8 17.2 396.3 40.9 Subchronic (n=8) 3.7 Ϯ 2.8 3.0 Ϯ 3.1 2.1 Ϯ 5.5 74.2 Ϯ 11.3 18.1 Ϯ 5.5 10.4 Ϯ 6.3 405.5 Ϯ 34.9 135.2 Ϯ 71.9 Chronic (n=7) 4.3 Ϯ 1.6 0.5 Ϯ .05 1.9 Ϯ 2.6 78.3 Ϯ 4.3 15.0 Ϯ 4.9 4.1 Ϯ 3.3 397.2 Ϯ 21.8 121.9 Ϯ 25.2 Withdrawal (n=6) 7.3 Ϯ 2.5 2.3 Ϯ 0.6 25.6 Ϯ 16.6 45.1 Ϯ 18.3 17.6 Ϯ 2.8 7.8 Ϯ 4.2 378.9 Ϯ 17.1 52.5 Ϯ 20.6 Ͻ Ͻ Ͻ Ͻ F3,21 (p) 19.0 ( 0.001) 29.8 ( 0.001) 8.8 ( 0.001) 9.9 ( 0.001) 1.3 (n.s.) 3.4 (0.04) 1.2 (n.s.) 4.0 (0.02) Patient RH Baseline 28 36 14.4 52.5 24.5 14.5 373.0 53.8 Subchronic (n=7) 6.3 Ϯ 6.2 7.6 Ϯ 9.5 0.1 Ϯ 0.4 52.9 Ϯ 14.2 40.4 Ϯ 15.7 23.8 Ϯ 13.6 343.2 Ϯ 46.8 86.0 Ϯ 35.3 Chronic (n=12) 0.7 Ϯ 0.9 0.1 Ϯ 0.3 6.9 Ϯ 10.3 50.7 Ϯ 11.0 33.7 Ϯ 11.7 17.3 Ϯ 10.1 382.6 Ϯ 47.4 51.0 Ϯ 28.7 Withdrawal (n=6) 0.0 Ϯ 0.0 0.0 Ϯ 0.0 26.7 Ϯ 5.8 48.8 Ϯ 6.8 15.7 Ϯ 7.4 5.0 Ϯ 1.6 446.2 Ϯ 32.9 40.4 Ϯ 22.5 Ͻ Ͻ Ͻ F3,25 (p) 21.2 ( 0.001) 15.7 ( 0.001) 13.6 ( 0.001) 0.2 (n.s.) 4.8 (0.01) 3.8 (0.03) 5.9 (0.004) 3.1 (0.05) Patient CS Baseline 23 27 21.6 60.5 4.0 13.4 310.7 20.4 Subchronic (n=4) 5.6 Ϯ 3.2 2.6 Ϯ 2.7 3.4 Ϯ 3.9 73.3 Ϯ9.6 9.1 Ϯ 10.8 30.4 Ϯ 19.4 342.7 Ϯ 40.2 41.4 Ϯ12.8 Chronic (n=5) 5.6 Ϯ 1.5 2.2 Ϯ0.4 3.5 Ϯ 7.2 69.6 Ϯ 6.0 3.9 Ϯ 3.8 56.8 Ϯ 12.0 310.2 Ϯ 23.7 26.0 Ϯ 12.9 Ͻ Ͻ F2,9 (p) 21.8 ( 0.001) 73.4 ( 0.001) 4.1 (0.07) 1.1 (n.s.) 0.6 (n.s.) 5.0 (0.04) 1.2 (n.s.) 2.2 (n.s.)

HRSD: Hamilton Rating Scale of Depression (24 items). BDI: Beck Depression Inventory. The sleep variables are given in minutes (TST, total sleep time) or as a percentage of TST. SWS: slow wave sleep. WASO: waking after sleep onset. TFA: theta frequency activity (power within 4.75–8.0 Hz) in a 5-min wake period prior to sleep. F and p values: One-way ANOVA with factor ‘treatment phase’ (baseline, subchronic, chronic, withdrawal). n.s.: no significant change. night after withdrawal. A REM sleep rebound occurred vestigating the effect of phenelzine have suggested that also in RH. It was most prominent after one week of REM sleep in humans can be drastically suppressed, or dose tapering, with 162 min of REM sleep (33 % of even completely eliminated, for weeks to months with- TST). Elevated REM sleep levels (Ͼ30%) were observed out obvious adverse effects (Akindele et al. 1970; Wyatt in both patients for approximately two weeks after the et al. 1971a,b; Dunleavy and Oswald 1973; Landolt et al. reduction of phenelzine. In CS, the dose of medication 2001). As pointed out by Horne (2000), these findings was reduced after six months due to complaints of might indicate that (1) the drug substitutes for REM drowsiness and sexual side effects. At present, he is still sleep, (2) the medication affects REM sleep control in treatment, but non-compliance with the dosing mechanisms rather than REM sleep function, or (3) that schedule and non-availability of the PS-1 recording sys- REM sleep has no unique benefit that cannot be met by tem precluded further sleep studies. either nonREM sleep or wakefulness. We found in a small sample of depressed patients who were chronically and successfully treated with EEG Power Spectra in NonREM Sleep and Waking phenelzine that the drug eliminated REM sleep for Phenelzine treatment had no effect on nonREM sleep three to six months. The loss of REM sleep was associ- ϭ (stages 1–4) intensity as quantified by EEG SWA (F3,57 ated with increased duration of stage 2 or SWS, 1.1, p Ͼ .3). Similarly, theta frequency activity (TFA, whereas TST and EEG SWA were not changed. During power within 4.75–8.0 Hz) in nonREM sleep was not continued treatment, episodes of REM sleep reap- ϭ Ͼ changed (F3,57 1.0, p .4). peared in all patients. They occurred at regular time in- Statistical analysis of TFA during the 5-min wake in- tervals during sleep, and coincided roughly with REM terval prior to the sleep episodes revealed a significant sleep periods in the baseline recordings (Figure 1). This effect of ‘treatment phase’, with the highest value observation indicates that the drug is not sufficient to present during subchronic phenelzine administration substitute for REM sleep. ϭ Ͻ (Table 2; F3,57 3.4, p .03). Spearman rank correlation Central nervous mechanisms of adaptation or toler- analysis between the mean percentage of REM sleep ance may have allowed REM sleep to reoccur after sev- and TFA revealed a trend toward a negative correlation eral months of MAOI treatment. The amount of REM ϭ Ϫ ϭ ϭ between these two variables (rs 0.58, p .06, n 11). sleep, however, was still reduced during the chronic phase of medication when compared with baseline (Ta- ble 2). Complete REM sleep disinhibition occurred only DISCUSSION in the phase of treatment where the drug was reduced. It was followed by two weeks of REM sleep rebound, The exact mechanism underlying MAOI-induced sup- which was observed in both patients who were studied pression of REM sleep is unknown. Previous studies in- during dose tapering and withdrawal. This finding in- S66 H.-P. Landolt and L. Posthuma de Boer NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5

Figure 1. Sleep profiles and EEG slow-wave activity (SWA, power within 0.75–4.5 Hz; C3-A2 derivation) of representative nights of patients PM and RH in baseline, during subchronic and chronic phenelzine treatment, and in the first night after withdrawal. W: wakefulness (including movement time [MT]). N: nonREM sleep (stages 1–4). R: REM sleep. The curves of SWA were smoothed by a 3-point moving average. Artifacts and data of W and MT were excluded. The calibration marks at the left of the y-axes of the bottom panels represent 103 ␮V2.

dicates that the suppression of REM sleep was not tients whose compliance could not be verified by deter- merely due to the absence of electrophysiological signs mination of phenelzine blood plasma levels, the find- of this sleep state. Nevertheless, two weeks of rebound ings indicate that REM sleep reoccurs in a cyclic appear unlikely to be long enough to regain all REM manner within sleep episodes after several months of sleep, which had been lost during the months of absence during chronic MAOI treatment. This observa- phenelzine treatment. It has previously been hypothe- tion has implications for hypotheses regarding the reg- sized that accumulated REM sleep pressure may be re- ulation and function of REM sleep. duced and/or replaced by wakefulness (Endo et al. 1998; Horne 2000). The enhancement of TFA in waking during treatment and its weak inverse relationship with ACKNOWLEDGMENTS REM sleep is consistent with this view, and may be evi- dence for compensatory REM sleep mechanisms occur- We wish to dedicate this manuscript to Dr. J. Christian Gillin ring during wakefulness. and thank him cordially for his generous support. We thank Although the present data need to be interpreted R. Wong, A. Schlosser and D. Sweat for their help with data cautiously because they were obtained in only a few pa- collection, Drs. E. Raimo and B. Schnierow for clinical care, NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5 Phenelzine and REM sleep S67

Dr. A. A. Borbély for lending us two PS-1 recording systems, vation in humans: effects on sleep and sleep EEG. Am J and Drs. P. Achermann, C. Kopp and I. Tobler for comments Physiol 274:R1186–R1194 on the manuscript. The study was supported by the Swiss Na- tional Science Foundation (823A-0566161), the National Insti- Horne JA (2000): REM sleep-by default? Neurosci Biobehav tute of Mental Health (MH38738), the UCSD MHCRC Rev 24:777–797 (MH30914), the General Clinical Research Center (M01- RR00827), the Department of Veterans Affairs, and the UCSD Landolt HP, Raimo EB, Schnierow BJ, Kelsoe JR, Rapaport Fellowship in Psychopharmacology and Psychobiology. MH, Gillin JC (2001): Sleep and sleep electroencephalo- gram in depressed patients treated with phenelzine. Arch Gen Psychiatry 58:268–276 REFERENCES Rechtschaffen A, Kales A (eds) (1968): A manual of stan- dardized terminology, techniques and scoring system for sleep stages of human sleep. Washington, D.C.: Pub- Akindele MO, Evans JI, Oswald I (1970): Mono-amine oxi- lic Health Service, U.S. Government Printing Office dase inhibitors, sleep and mood. Electroenceph clin Neurophysiol 29:47–56 Wyatt RJ, Fram DH, Buchbinder R, Snyder F (1971a): Treat- Dement W (1960): The effects of dream deprivation. Science ment of intractable narcolepsy with a monoamine oxi- 131:1705–1707 dase inhibitor. New Engl J Med 285:987–991 Dunleavy DLF, Oswald I (1973): Phenelzine, mood response, Wyatt RJ, Fram DH, Kupfer DJ, Snyder F (1971b): Total and sleep. Arch Gen Psychiatry 28:353–356 prolonged drug-induced REM sleep suppression in Endo T, Roth C, Landolt HP, Werth E, Aeschbach D, Acher- anxious-depressed patients. Arch Gen Psychiatry mann P, Borbély AA (1998): Selective REM sleep depri- 24:145–155