Serotonin receptor sensitivity in major depression

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BRIEF REPORTS

Serotonin Receptor Sensitivity in Major Depression Ren6 S. Kahn, Scott Wetzler, Gregory M. Asnis, Denfitri Papolos, and Herman M. van Praag

Introduction Research on the role of serotonin (5-hydroxytryptamine, 5HT) in depression spans well over two decades. The most consistc~t finding is that the cerebrospinal fluid (CSF) concentration of the 5HT metabolite, 5-hydroxyindoleacetic acid (SHIAA) is lowered in about ,..10%of patients with major depression (MD) (review: Kalus et al. 1989). The fall of CSF 5HIAA levels suggests a decrease of 5HT metabolism in the CNS, which may be the result of, or lead to, increased 5HT receptor sensitivity. Studies examining 5HT receptor sensitivity, however, have provided conflirting results. One study reported increased 5HT receptor sensitivity in MD, using the 5HT precursor, 5-hy&'oxytryptophan (5HTP) as a 5HT challenger (Meltzer etal. 1984). However, Westenberg et al. (1982), using the same oral dose of 5HTP in combination with a decarboxylase inhibitor, found normal responses in depressed subjects..qty.!dies using tryptophan and fenfluramine as 5HT challenge agents found decreased (Heninger et al. 1984; Siever et al, 1984; Coctaro et al. 1989) or normal (Asnis et al. 1988) 5HT receptor sensitivity in depressed patients. The conflicting findings may be the result of the nonselectivity of these agents and their indirect stimuiation of 5HT receptors (van Praag et al. 1987). in contrast to the studies reviewed above, the

From the Department of Psychiatry, Albert Einstein CoY.egooi Meaicine, Montefiore Medical Center, New York, NY. Address reprint requests to Ren6 S.Kahn, M.D., Department of Psychiatry, Mount Sinai Medical Center, One Gustav L. Levy Place, Box 123(L New "fork, NY 10029-6574. R. . . . . . . Janu~-y 1990;revised lu¥ 1 a ~.^t. ip i i 7, man [ 77U,

© 1999 .qc~-_--ietyof Biological Psychiatry

present study used a direct 5HTI/5HT2 receptor agonist as a probe for 5HT receptors, i.e., mchlorophenylpiperazine (MCPP) (for reviews on MCPP see Kahn el al. 1990a, 1990b). Because the decreased CSF 5HIAA found in MD patient~ may be the result of, or lead to, increased postsynaptic 5HT receptor sensitivity, the present study tested whether 5HT receptors aa'e hypersensitive in MD. If hypersensitivity of 5HT receptors is suspected: then 5HT receptor stimulation should be low enough to avoid overstimulation of 5HT receptors, which may diminish the 6iscri_'minating effect of a response. (When hyposensitivity of 5HT receptors is suspected, 5HT receptor stimulation shotqd be large enough to detect a blamed . . . . . . . "- "-imental group). On the basi,~ of a 2ose-response study in normal subjects (Kahn et al. 1990~), an oral dose of 0.25 mg/kg was selected. Methods

Subjects Twenty normal co~at~ols (NC) (mean age 32.7 __. SD 12.6) including 9 men and 11 wonr,.en, and 23 MD patients (mean age 33.7 __. 10.5) including 8 men and 15 gamen (1 i outpatients, 12 inpatients) participated. NC met Rese~a-ch Diagnostic Criteria (RDC) (Endicott and Spitzer, 1978) for "never mentally ill." Five patie.nts met RDC for bipolar, depressed; the other patients met RDC for MD. All subjects were within 25% of their ideal body weight, had normal laboratory and physical exams, were free of drug and alcohol use for at least 2 weeks before the study, "0~5-322:3/90/$03.50

Prief Reports

BIOLPSYCHIATRY ~990;28:358-362

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and gave written informed consent prior to participation.

Procedure "l'--heprocedure was as described in Kahn et al. (!988). Briefly, subjects fasted from 11 PM on the night before the day of the procedure. At 9 AM. an intravenous catheter was inserted, and subjects leceived either 0.25 mg/kg MCPP or placebo orally in a randomized double-blind design at 10 AM (time "0" or "baseline"). Time between procedures was at least 2 days. Three inpatients and 1 control did not receive placebo challenges. Plasma prolactin, MCPP, and behavioral response variables ~ei~e raeasured at 30-min intervals between 9 AM end 1:30 PM. Behavioral response variables were measured using an abbreviated version of the Profile of Mood States (POMS) (McNair et al. 1980). In addition, various physical symptoms--i.e., palpitations, sweating, lightheadedness chest pressure, and nausea---were also rated. Prolactin and MCPP were assayed as described in Kahn et al. (!990a). To compare the effects of MCPP between

groups, repeated measures multivariate analysis of variance (MANOVAs) were conducted and MD) and two repeated measures: Time (0, 30, 60, 90, 120, 150, 180, 210 rain) and Test (MCPP and placebo). When baseline values were different for the two groups, change from baseline (by subtracting baseline from the value at each subsequent time point) values were used. As depressed in- and outpatients did not differ significantly on baseline variables and responses to MCPP, the MD group was analyzed as a whole. Similarly, bipolar and nonbipolar depressed patients did not differ in their responses to MCPP. Cortisol responses on 17 of the depressed patiet~ts and 15 of the normal subjects were reported earlier (Kahn et al. 198,3).

Results MCPP levels changed significantly over :ime (F - 10.04, df = 6.35, p < 0.000!), but were not significantly different for NC and MD (Figure I).

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1990;28:358--362

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Figure 3. Physical symptom responses in patients with major depression (n = 23; square symbols) and normal controls (n = 20; round symbols) to 0.25 mg/kg MCPP (closed symbols) and placebo (open symbols), administered orally at time (0). Baseline prolactin was aot differeat for patients and controls. Although baseline prolactin levels were significantly higher in women than in men [men: 4.7 ± 2.9 and 4.2 ± 2.8 ng/ml; women: 9.6 __. 5.5 and 7.7 ± 4.0 ng/ml (F ---

8.59, df - 1,35, p < 0.01)], gender did not affect prolaetin release. MCPP significantly ¢levat~ prolacti~ l~vels as c o m F ~ l to placetm (Test x Time: F - - 6.38, df --- 7,26,p < 0.0001) in both groups, but its ef-

Brief Reports

feet on prolactin response was not different for the two groups (Figure 2). When analyzed separately for gender, fliese results did not change. POMS be~elive scores of anxiety, depression, hostility, fatigue, and physical symptoms were significantly higher, and POMS vigor scores were significantly lower in patients compared with controls. MCPP did not at'fec~, anxiety, depression, hostility, fatigue, or vigor e~sponses. Physical symptoms increased sJgnificantiy more ~n MCPP than on placebo in patients compared with controis (F = 6.81, df = 1,38, p < 0.02) [NC: MCPP versus placebo (ns); MD: MCPP versus placebo (F = 4.38, df = 7,13, p < 0.02)] (Figu~ 3).

Discussion This study reports normal prolactin and behavioral responses in patients with MD in response to challenge with a direct 5HT receptor agonist. As reported earlier, cortisol responses to 0.25 mg/kg MCPP were also normal in depressed patients (Kahn et ai. 1988). Thus, hormonal ~ad behavioral responses to 0.25 mg/kg MCPP suggest that 5HT receptor function is not increased in MD° The only difference found between patients and controls was that MCPP increased physical symptoms in patients but not in controls. The increased sensitivity suggests hypersensitivity to the somatic ei'fects of MCPP in MD. As physiological measures such as pulse rate and blood pressu~ were not consistently obtained, it is not possiMe to discriminate between increased aw~eness of physical symptoms or inc~ased psychophysio!ogica! sensitivity to MCPP in the MD group. Unis study, using a low oral dose of MCPP, was not designed to detect blunted hormonal responses in MD patients. Therefore, no statementJ can be made about possible st~bsensitNit~ of 5HT receptors as has been found using tryp~ophan (Heninger et al. 1984) and fenfluramine (Sieve~ et ~1. 1984; Coccaro et al. 1989) in such patients. The present study cont:'asts with the study by Meltzer et al. (1984) who found neuroendocrine evidence of inc teased 5HT receptor sensitivity in

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MD using 5HTP as a 5HT challenger, but confirms the observation by We~tenberg et al. (1982) who reported normal hormonal responses to 5HTP in depressed patients. In summary, this study does not find hormonal or behavioral evidence for increased 5HT receptor hypersensitivity in patients with major depres~ioh using the direct postsynaptic 5HT receptor agonist, MCPP.

References Asnis GM, Eisenberg J, van Praag HM, Lemuz CZ, HarkavyoFriedman JM, Miller AH (1988): The neuroendocrine response to fenfluramine in depressives and controls. Biol Psychiatry 24:1 | 7-120. Coccaro EF, Siever 13, Klar HM, et al (1989): Serotonergic studies in patients with affective and personality disorders: Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psy. chiatry 46:587-599. Heninger GR, Chamey DS, Sternberg DE (1984): Serotonergic function in depression: Prolactin response to intravenous tryptophan in depressed patienta and healthy subjects. Arch Gen Psychiatry 4l .~8e-~02. Kahn RS, Asnis GM, Wetzler S, van Praag HM (1988): Neuroendocrine evidence for serotonin receptor hypersensitivity in patients with panic disorder. Psychopharmacotegy 96:36~J-3'~¢. Kahn RS, Kalus O, Cahn W, Wetzler S, Asnis GM, van Praag HM (1990b): The eff~ts of serotonin antagonists of m-chlo,of,h~;ayipiperazine-mediated responses in normal subjects. Psychiatry Res (in press). Kahn RS, Wetzler S, Asnis GM, van Praag HM (1990a): The effects of m-chlorophenyipiperazine in normal subjects: A dose-response study. Psychopharomcology i00:239-344. Kalus O, Asnis GM, van Prang HM (1989): The role of se~otonin in depression. Psychiatr 348-353. McNair DM, Lorr M, Droppelman LF (1980): Manual for the Profile of Mood States. Educational a,ad IndiisUial Testing Service, San Diego, California, 1971. Meltzer HY, Umberl¢oman-Wiita ~, Rob,~rtson A, Trico BJ, Lowy M, Perline R (1984): Effect of 5-hydroxytryptophan on scram cortisoi ievels in major effec*.ive disorders. Arch Gen Psychiatry 41:366-374. Siever 13, Murphy DL, Slater S de ia Vega E~

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Lipper S (1984): Plasma pmlactin changes following fenfluramine in depressed patients compared to controls: An evaluation of central cerotonergic responsivity in depression. Life Sci 34:10291039. van Praag HM, Lemus CZ, Kahn RS (1987): Hormonal probes of central serotonergic activity: Do

they really exist? Biol Psychiatry 22:8698. Westenberg HGM, van Praag HM, de Jong JTVM, Thijssen ,IHH (1982): Postsyn~p*.ic serot~ncrgic activit.b, in depressive patients: Evaluation of the neuroendocrine strategy. Psychiatry Res 7:361371.

TRH/LHRH Stimulation Test and Alzheimer' s Disease M. Dhyanne Warner, Sophia Vinogradov, Cecilia A. Peabody, Leslie Wi&ow, Helen D. Davies, Jerome R. Minkoff, and Ca_:ol Hunter Winograd

Introduction Our previous data suggested that A!zheime,r patients may have lower s~rum prolactin (PRL) baseline levels and greater PRL responses to thyrotropin-releasing hormo~le (TRH) (Peabody et al. 1986). Thyrotropin-stimulating hormor~c (TSH) has also been reported to be abnormal in Aizheimer patients in response to TRH stimulation (Sunderland et al. 1985). To further elucidate these potential abnormalities we used a TPJI/lutcinizing hormone-releasing hormone (LHRH) sequential stimulation test to examine PRL, TSH, growth hormone (GH), and lutein-

From the Department of Psychiatry, University of Texas Medical School, Houston, TX (M.D.W., C.A.P.); The Departments of Psychiatry (S.V., L.W., H.D.D.~ end Medicine (C.H.W.), Stanf'~."~University Medic~ School, P~lo Alto. CA: and the Department of Medicine, Fermante Medical Group, Santa Rosa, CA (J.R.M.). Address reprint requests ~.o Cecilia Peabody, M.D., University of Texas Health Science Center Houston, 28t~0 South MacGregor Way, Houston, TX 77021. Received July 28, 1989, ~vised Octol~er 20, 1989.

Published 1990 by Elsev;ei Science Publishing Co., Ir~c.

iziag hormone tLH) responses. LHRH stimulation was added in order to explore this hypothalamic pituitary axis in Alzheimer's disease.

Methods Thirty-four men and women who were within 20% of normal body weight participated in the study. All subjects were in excellent general health and had a normal SMA20, cell blood count (CBC), chest x-ray, and electrocardiogram (ECG). The average Fdstein Mirfimental State Exam score (MIVlS) (Folstein et al. 1975) for the Alzhehner group wa~ 15.2 ± 6.9 ( + SD); the average for the control group was 28.9 + 0.9. Seventeen s~=~eets (12 men, 5 women) ~ad a di,ag~osis of primary degenerative dementia (/dzheimer's oisease) by DSMI!! c:'iteria, will: a rag:an global deterioration score (Reis'eerg et al. 1982) of 4.6 (ranTe 3.56.0). In addition, this group had normal B!2, folate, free T4, and TSH levels. Computed 0006-3223/90/$00.00