Human EEG response to beta-endorphin

83

Psychiafry Research, 1, 83-88 (1979) @ Elsevier/North-Holland Biomedical Press

Human

EEG Response

to Beta-Endorphin

Adolf Pfefferbaum, Philip A. Berger, Glen R. Elliott, Jared Bert S. Kopell, Jack D. Barchas, and Choh Hao Li Received

R. Tinklenberg,

April 15, 1979; revised version received June 3, 1979; accepted June 7, 1979.

Abstract. Beta-endorphin, morphine, and saline were given intravenously to a single schizophrenic subject on separate occasions in a double-blind design. EEG

spectral analyses performed on data collected before and after drug injection demonstrated that Pendorphin and morphine produced similar increases in alpha power within 5 to 15 minutes after injection. This effect could be distinguished from two placebo (saline) injections. These data suggest that intravenous p-endorphin can produce changes in the central nervous system in humans. Key words. Beta-endorphin,

morphine, EEG, spectral analysis, schizophrenia.

The discovery of endogenous peptides with opiatelike action in the human brain has led to a variety of suggestions about their possible physiological role. They have been implicated in the modulation or regulation of mechanisms controlling pain, temperature, respiration, motor activity, endocrine functions, and mood; they also have been suggested to play a role in some forms of human psychopathology, especially depression and schizophrenia (for reviews of this area, see Berger, 1978; Watson et al., 1979). These speculations have led to the administration of /3-endorphin to humans in attempts to (1) induce analgesia, (2) prevent opiate withdrawal symptoms, and (3) treat the symptoms of depression and schizophrenia. Intravenous administration of P-endorphin as an analgesic has produced disappointingly equivocal results (Catlin et al., 1977; Foley et al., 1978; Hosobuchi and Li, 1979). These studies used peripheral doses of 5 to 20 mg, which may have been too low to achieve sufficient brain concentrations. In support of this interpretation, intraventricular administration of /3-endorphin has been reported to produce significant analgesia (Foley et al., 1978; Hosobuchi and Li, 1979). It is also unclear whether intravenous /3-endorphin can block the symptoms of opiate withdrawal. Catlin et al. (1977) reported equivocal results in two patients, while Su et al. (1978) successfully prevented opiate withdrawal symptoms with as little as 4 to 8 mg of intravenous /3-endorphin. Two groups have described the effects of P-endorphin on the symptoms of human psychopathology. In a single-blind study with 15 patients, Kline and Lehmann (1979) compared 10 mg of intravenous /3-endorphin to morphine, sodium amytal, and saline controls. They reported that P-endorphin pioduced a significant reduction in Adolf Pfefferbaum, M.D.. Philip A. Berger, M.D., Glen K. Elliott, M.D., Jared R. Tinklenberg,

M.D., Bert S. Kopell, Ph.D., and Jack D. Barchas, M.D., are all members of the Veterans Administration Medical Center, Palo Alto, and the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA. Choh Hao Li, Ph.D., is Director of the Hormone Research Laboratory, University of California, San Francisco, CA. (Reprint requests to Dr. Pfefferbaum at Psychiatry Service116A3, VA Medical Center, Palo Alto, CA 94304.)

x4 target symptoms (e.g., hallucinations, delusions, compulsions, unusual behavior, agoraphobia, anxiety, and panic attacks) in patients with a variety of diagnoses, including schizophrenia, schizoaffective schizophrenia, agoraphobia, anxiety neurosis, and obsessive-compulsive neurosis. Angst et al. (1979), giving /3-endorphin to a relatively homogeneous group of depressed females, reported that three of their six subjects switched from depression to hypomania on either the day of the infusion or the day after. These preliminary studies have demonstrated that P-endorphin can be given safely to humans and suggest that it potentially may have some role in the treatment of psychopathology. The greater efficacy of intraventricular, compared to intravenous, administration of the compound also raises the question of whether P-endorphin crosses the blood-brain barrier. The concomitant use of EEG analysis before and after psychoactive drug administration can provide information about central nervous system (CNS) activity in addition to that obtained by clinical observations (Fink, 1974; Itil et al., 1972; Pfefferbaum et al., 1979). In their study of the effects of P-endorphin on depression, Angst et al. (1979) used EEG spectral analysis techniques to demonstrate changes in CNS activity following drug administration; however, they could not conclude that these changes were specifically due to P-endorphin since no placebo control was employed. Because of the increasing interest in the potential role of endorphins in psychiatric disorders and the question of brain access by the intravenously administered compound, the following single case report is presented. As part of a double-blind investigation of the effects of P-endorphin (Berger et al., in preparation), we had the opportunity to examine the effects of /3-endorphin, morphine, and saline on the EEG of a single schizophrenic patient who was able to cooperate with the data acquisition procedures. The data presented suggest a direct effect of /?-endorphin on the human CNS but should be regarded with the same caution reserved for all single case reports. We present a single case report because of the scarcity of /3-endorphin, the significant restraints on its administration to nonschizophrenics, and the difficulty of finding drugfree, symptomatic schizophrenic patients who can cooperate sufficiently to permit good EEG recordings.

Methods The subject, a 27-year-old white male, was diagnosed independently as schizophrenic, chronic paranoid type by two psychiatry residents (Spitzer et al., 1977). He was drugfree for at least 2 weeks before the protocol began and remained drug-free until its conclusion. The subject gave written informed consent to enter the study. The EEG protocol used a double-blind design with EEG testing before and after drug administration. The data were collected on four separate occasions, each separated by 1 week. The subject received iv injections of 1 ml of saline (inert placebo) on 2 of the days, ! 0 mg morphine (active control) on 1 day, and 20 mg P-endorphin on 1 day. He had an ir. . dwelling, heparin-lock, intravenous needle in place before coming to the EEC laboratory at 8:30 am each testing day. After the EEG and ECG electrodes were applied, the subject was moved to a sound-attenuated EEG recording booth. The injections were given at 10 am on each testing day. Attempts were made to keep the subject’s attention and state of arousal constant throughout the experimental run. When

85 the experimenters were not in the booth, the subject was asked to alternate between periods of sitting with his eyes closed and periods of reading a magazine. The EEG was recorded during the eyes-closed periods. EEG was recorded in 2- to 5-minute discrete epochs. At least two observations were made both before and after the injection. The time of the observations varied slightly from day to day, reflecting exigencies of blood drawings, clinical observations, and technical limitations of EEG recording. On all 4 days, early (5 to 15 minutes postinjection) and late (15 to 60 minutes postinjection) EEG data were collected. EEG was recorded from central (Cz) and parietal (Pz) electrode sites with disc electrodes referenced to linked ear electrodes. EOG was recorded from disc electrodes placed above and below the right eye. ECG was monitored with electrodes attached to the arms. The EEG was amplified 10K and EOG 2K, with the amplifiers set at a nominal bandpass of .03 to 100 Hz (3 dB points of 6 dB/octave rolloff rate). The EEG was monitored on paper and simultaneously re-corded on FM tape for later spectral analysis. The EEG data were entered into a PDP-1 1/ 40 computer. Data with large eye movements and blink artifacts were omitted from the analysis by a technician who was blind to the protocol design. This procedure resulted in 1.5 to 2.5 minutes of artifact-free data for each observation. The data then were subjected to a fast Fourier analysis, which resulted in a power spectrum with .5 Hz resolution for theO-32 Hz components. The power spectra were transformed from absolute power values to the percentage contributions to the total power of each frequency component because this measure is more stable than absolute power measurements in the normal resting EEG (Matousek, 1973). Results Spectral analysis plots were made for each observation for each of the treatment days. Visually identifiable changes were seen in the alpha frequency range (8 to 12 Hz). The percent of the total EEG power present in the alpha range (8 to 12 Hz) for each observation is presented in graphic form in figure 1. Preinjection observations on all 4 days were reasonably stable. Shortly after the morphine injection, there was a sharp increase in the amount of alpha, which persisted for at least 50 minutes. An even faster rise in alpha power followed administration of /3-endorphin, but it was of shorter duration, lasting less than 30 minutes. Neither placebo treatment produced an acute rise in alpha, but there was a later increase (25 to 40 minutes postinjection) that was less pronounced than the earlier increases produced by morphine and P-endorphin. Figure 2 presents superimposed spectral analysis plots of pre- and postinjection EEG for each drug treatment. Attention is directed to the increase in alpha power after morphine and /3-endorphin. For each drug treatment, a predrug observation immediately before injection and a postdrug observation 5 to 15 minutes after injection were analyzed as follows: Each 1.5 to 2.5 minute observation period was divided into 4-second epochs, producing from 20 to 65 separate measures for each pre- and postdrug condition. Spectral analysis was performed on each epoch, and the alpha activity from each of these epochs was subjected to a two-way analysis of variance. A drug effect was demonstrated by a significant drug X time interaction Cp < .OOl).

86 Figure 1. Effects of beta-endorphin,

morphine,

and placeboon

alpha activity

181716-

w

15-

o-o

Morphine

0--0

P-endorphin

u 14

,

-60

I

-50

I

-40

I

-30

I

-20

I

-10 Time

0

I

10

I

20

I

30

Placebo I

40

I

50

I

60

(min)

The EEG was recorded from the vertex (Cz) for the two placebo, the morphine, and the /?-endorphin injections. Alpha activity (8 to 12 Hz) is expressed as a percent of the total EEG power spectrum. Subanalyses revealed that both the morphine and the /3-endorphin treatments produced significant drug X time interactions when compared to the two placebo treatments @ < .OOl for both). Conversely, neither the P-endorphin-to-morphine nor the placebo-to-placebo comparisons produced a significant drug X time interaction. The drug X time effect was due to an increase in alpha activity that occurred after morphine and p-endorphin but not after placebo treatment. Discussion Both morphine and P-endorphin produced an acute increase in the amount of alpha activity, as demonstrated with fast Fourier analysis of the EEG. This finding is consistent with the reports of Wikler (1954) and Fink et al. (197 1) that morphine produces an increase in alpha activity. In our study, the alpha increase occurred within 15 minutes of morphine injection and persisted for at least 50 minutes; the similar increase seen with p-endorphin began at 5 minutes postinjection but did not persist so long. Thus, the two drugs produced similar increases in alpha activity, but the action of P-endorphin was much briefer. The two placebo injections also produced increases in alpha activity, which occurred later than the increases produced by morphine and pendorphin. Angst et al. (1979) reported an increase in alpha activity at 30 minutes after an injection of /3-endorphin. They cautioned, however, that this could be a placebo effect, in part attributable to the relaxation of the patient after the injection experience. Our data support this interpretation, in that the placebo injections in our study produced an increase in alpha at about 30 minutes postinjection. The data presented here suggest that intravenously administered p-endorphin and morphine have similar CNS effects in a human subject. Although the EEG changes might be secondary to peripheral actions of the drugs, it is equally likely that they reflect direct CNS activity. Possible involvement of central opioid peptide receptors is supported further by the recent demonstration that methionine-enkephalin,

87

Figure 2. Spectral and placebo

analyses of EEG activity

for beta-endorphin,

morphine,

~~~ ..: 8

zl

a

-

I

I

5

10

I

,

I

I

15

20

25

30

Frequency

(Hz)

Post Placebo 2 Pre Placebo 2 . . . . . . . . . . . . .

I

I

5 &

1

IO

I

15 Frequency

6-

I

I

I

20

25

30

(Hz)

g z w % H 6 : 8 6 a

4Post /i -endorphin Pre p-endorphin

___ .............

2-

-I

10

I

1

I

I

15

20

25

30

Frequency

(Hz)

Presented are plots of power spectra for vertex (Cz)-lead EEGs before and immediately after injection of the following: A. First placebo; B. Second placebo;C. Morphine; D. P-endorphin.

88 another naturally occurring endorphin, also increases alpha power (Krebs and Roubicek, 1979). This single case report illustrates the value of EEG assessment of psychoactive compounds and suggests that intravenous administration of P-endorphin may be appropriate for studying its CNS effects in human subjects. References Angst, J., Autenrieth, V., Brem, F., Koukkou, M., Meyer, H., Stassen, H.H., and Storek, U. Preliminary results of treatment with P-endorphin in depression. In: Usdin, E., Bunney, W.E., Jr., and Kline, N.S., eds. Endorphins in Mental Health Research. MacMillan Press, London (1979). Berger, P. A. Investigating the role of endogenous opioid peptides in psychiatric disorders. Neurosciences

Research

Program

Bulletin

16, 585 (1978).

Berger, P.A., Watson, S.J., Elliott, G.R., Kilkowsky, J., Akil, H., Barchas, J.D., and Li, C.H. B-endorphin and schizophrenia: A double-blind study (in preparation). Catlin, D.H., Hui, K.K., Loh, H.H., and Li, C.H. Pharmacological activity of P-endorphin in man. Communications in Psychopharmacology, 1, 493 (1977). Fink, M., Zaks, A., Volavka, J., and Roubicek, J. Opiates and antagonists. In: Clouet, D.H., ed. Narcotic Drugs: Biochemical Pharmacology, Plenum Press, New York (1971). Fink, M. EEG applications in psychopharmacology. In: Gordon, M., ed. Psychopharmacological Agents. Vol. III. Academic Press, Inc., New York (1974). Foley, K.M., Kaikov, R.F., Inturrisi, C.E., Posner, J.B., Li, C.H., and Houde, R.W. Intravenous and intraventricular administration of P-endorphin in man: Preliminary studies. Presented at the Second World Conference on Pain, Montreal, Canada, August 27 to September 2 (1978). Hosobuchi, Y., and Li, C.H. Demonstration of the analgesic activity of humanp-endorphin in six patients. In: Usdin, E., Bunney, W.E., Jr.,and Kline, N.S., eds. Endorphins in Mental Health Research. MacMillan Press, London (1979). Itil, T.M., Polvan, N., and Hsu, W. Clinical and EEG effects of BG-94, a “tetracyclic” antidepressant (EEG model in discovery of a new psychotropic drug). Current Therapeutic Research,

14, 395 (1972).

Kline, N.S., and Lehmann, H.E. b-endorphin therapy in psychiatric patients. In: Usdin, E., Bunney, W.E., Jr.. and Kline. N.S., eds. Endorphins in Mental Health Research. MacMillan

Press, London (I 979). Krebs, E., and Roubicek, J. EEG and clinical profile of a synthetic

analogue of methionineenkephalin-FK 33-824. Pharmakopsvchiatrie, 12, 86 (1979). Matousek, M. Frequency and correlation analysis. In: Remond, A., ed. Handbook of Electroencephalograph), and Clinical Neuroph,ssiologv. Part A, Vol. 5, Sec. II. Elsevier, Amsterdam (1973). Pfefferbaum. A., Davis, K.L., Coulter, CL., Mohs, R.C., Tinklenberg, J.R., and Kopell, B.S. EEC effects of physostigmine and choline chloride in humans. Ps~~chopharmacology 62,225 (1979).

Spitzer,

R.L., Endicott,

of Functional York (1977).

J., and Robins, E. Research Diagnostic Criteria (RDC)for a Group Biometrics Research, New York State Psychiatric Institute, New

Disorders.

Su, C.V., Li, C.H., and Lin, S.H. Effect of P-endorphin on the narcotics abstinence syndrome in man. Journal of the Formosan Medical Association, 77, I33 ( 1978). Watson, S.J., Akil, H., Berger, P.A., and Barchas, J.D. Some observations on the opiate peptides and schizophrenia. Archives of General Ps.vchiatry, 36, 35 (1979).

Wikler, A. Clinical and electroencephalographic normorphine and morphine in man. Journalof

studies on the effects of mescaline, Nervous

and Mental

Disease,

120,157

N-Allyl( 1954).

This work was supported by the Medical Research Service ofthe Veterans Administration. NIDA Research Grants DA 00854 and DA 01207, NIMH Specialized Research CenterGrant MH 30854. and NIMH Grant 30245.