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Obsessive—Compulsive Disorder as a 5-HT Subsystem-Related Behavioural Disorder

Published online by Cambridge University Press:  06 August 2018

D. L. Murphy ,
J. Zohar ,
C. Benkelfat ,
M. T. Pato ,
T. A. Pigott  and
T. R. Insel
D. L. Murphy*
Affiliation:
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
J. Zohar
Affiliation:
Beer-Sheva Mental Health Centre, Beer-Sheva, Israel
C. Benkelfat
Affiliation:
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
M. T. Pato
Affiliation:
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
T. A. Pigott
Affiliation:
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
T. R. Insel
Affiliation:
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland
*
∗Correspondence
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Extract

Involvement of the brain serotonin (5-HT) neurotransmitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semi-selective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m-CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 155 , Issue S8: SEROTONIN IN BEHAVIOURAL DISORDERS , December 1989 , pp. 15 - 24
Copyright
Copyright © Royal College of Psychiatrists, 1989 

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References

Aloi, J. A., Insel, T. R., Mueller, E. A., et al (1984) Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys. Life Sciences, 34, 1325–1331.Google ScholarPubMed
Ananth, J., Pecknold, J. C., van den Steen, N., et al (1981) Double-blind comparative study of clomipramine and amitriptyline in obsessive neurosis. Progress in Neuro-psychopharmacology and Biological Psychiatry, 5, 257–262.Google Scholar
Baxter, L. R., Phelps, M. E., Mazziotta, J. C., et al (1987) Local cerebral glucose metabolic rates in obsessive—compulsive disorder: a comparison with rates in unipolar depression and in normal controls. Archives of General Psychiatry, 44, 211–218.Google Scholar
Benkelfat, C., Murphy, D. L., Zohar, J., et al (1989) Clomipramine in obsessive-compulsive disorder: further evidence for a serotonergic mechanism of action. Archives of General Psychiatry, 46, 23–28.Google Scholar
Blier, P. & De Montigny, C. (1985) Short-term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence in the rat CNS. European Journal of Pharmacology, 113, 69–79.Google Scholar
Caccia, S., Ballabio, M., Samanin, R., et al (1981) (–)-m-Chlorophenyl-piperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. Journal of Pharmacy and Pharmacology, 33, 477–478.Google ScholarPubMed
Charney, D. S., Goodman, W. K., Price, L. H., et al (1988) Serotonin function in obsessive–compulsive disorder: a comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Archives of General Psychiatry, 45, 177–185.Google Scholar
Eisenberg, J. & Asnis, G. (1985) Lithium as an adjunct treatment in obsessive–compulsive disorder. American Journal of Psychiatry, 142, 663.Google Scholar
Engelman, K., Lovenberg, W. & Sjoerdsma, A. (1967) Inhibition of serotonin synthesis by para-chlorophenylalanine in patients with the carcinoid syndrome. New England Journal of Medicine, 211, 1103–1108.Google Scholar
Fernández Córdoba, E. & López-Ibor Aliño, J. (1967) Clomipramine in resistant psychiatric disorders and other treatments. Actos Luso-Españolas de Neurologia, Psiquiatria y Ciencias Afines, 26, 119–147.Google Scholar
Fernstrom, J. D. & Wurtman, R. J. (1974) Nutrition and the brain. Scientific American, 230, 84–91.Google Scholar
Flament, M. F., Rapoport, J. L., Berg, C. J., et al (1985) Clomipramine treatment of childhood obsessive—compulsive disorder: a double-blind controlled study. Archives of General Psychiatry, 42, 977–983.Google Scholar
Flament, M. F., Rapoport, J. L., Murphy, D. L., et al (1987) Biochemical changes during clomipramine treatment of childhood obsessive—compulsive disorder. Archives of General Psychiatry, 44, 219–225.Google Scholar
Frazer, A. & Brunswick, D. J. (1989) Antidepressant drugs. In Basic Pharmacology and Medicine 3rd edn (eds DiPalma, J. R. & DiGregor, G. J.). New York: McGraw-Hill.Google Scholar
Frazer, A., Offord, S. J. & Lucki, I. (1989) Regulation of serotonin receptors and responsiveness in the brain. In The Serotonin Receptors (ed., Sanders-Bush, E.). Clifton: Humana Press Inc.Google Scholar
Fuller, R. W., Mason, N. R. & Molloy, B. B. (1980) Structural relationships in the inhibition of [3H]serotonin binding to rat brain membranes in vitro by 1-phenyl-piperazines. Biochemical Pharmacology, 29, 833–835.Google ScholarPubMed
Fuller, R. W., Snoddy, H. D., Mason, N. R., et al (1981) Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology, 20, 155–162.Google ScholarPubMed
Fuxe, K., Ögren, S.-O., Agnati, L. F., et al (1983) Chronic antidepressant treatment and central 5-HT synapses. Neuropharmacology, 22, 389–400.Google Scholar
Goodman, W. K., Price, L. H., Rasmussen, S. A., et al (1989) Efficacy of fluvoxamine in obsessive—compulsive disorder: a double-blind comparison with placebo. Archives of General Psychiatry, 46, 36–44.Google Scholar
Gorman, J. M., Liebowitz, M. R., Fyer, A. J., et al (1985) Lactate infusions in obsessive—compulsive disorder. American Journal of Psychiatry, 142, 864–866.Google ScholarPubMed
Heym, J. & Koe, B. K. (1988) Pharmacology of sertraline: a review. Journal of Clinical Psychiatry, 49:8 (Suppl.), 40–45.Google Scholar
Hollander, E., Fay, M., Cohen, B., et al (1988) Serotonergic and noradrenergic sensitivity in obsessive—compulsive disorder: behavioral findings. American Journal of Psychiatry, 145, 1015–1017.Google Scholar
Hyttel, J. & Larsen, J.-J. (1985) Serotonin-selective antidepressants. Acta Pharmacologica et Toxicologia, 56 (Suppl. 1), 146–153.Google Scholar
Insel, T. R. & Murphy, D. L. (1981) The psychopharmacological treatment of obsessive-compulsive disorder: a review. Journal of Clinical Psychopharmacology, 1, 304–311.CrossRefGoogle ScholarPubMed
Insel, T. R., Murphy, D. L., Cohen, R. M., et al (1983) Obsessive-compulsive disorder: a double-blind trial of clomipramine and clorgyline. Archives of General Psychiatry, 40, 605–612.CrossRefGoogle ScholarPubMed
Insel, T. R., Mueller, E. A. III, Gillin, J. C., et al (1984) Biological markers in obsessive—compulsive and affective disorders. Journal of Psychiatric Research, 18, 407–423.CrossRefGoogle ScholarPubMed
Insel, T. R., Mueller, E. A. III, Alterman, I., et al (1985) Obsessive—compulsive disorder and serotonin: is there a connection? Biological Psychiatry, 20, 1174–1188.Google Scholar
Invernizzi, R., Cotecchia, S., De Blasi, A., et al (1981) Effects of m-chlorophenylpiperazine on receptor binding and brain metabolism of monoamines in rats. Neurochemistry International, 3, 239–244.Google Scholar
Jimerson, D. C. & Berrettini, W. (1985) Cerebrospinal fluid amine metabolite studies in depression: research update. In Pathochemical Markers in Major Psychoses (eds Beckmann, H. & Riederer, P.). Berlin: Springer Verlag.Google Scholar
Kahn, R. S., Asnis, G. M., Wetzler, S., et al (1988a) Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder. Psychopharmacology, 96, 360–364.Google Scholar
Kahn, R. S., Wetzler, S., van Praag, H. M., et al (1988b) Behavioral indications for serotonin receptor hypersensitivity in panic disorder. Psychiatry Research, 25, 101–104.Google Scholar
Karno, M., Golding, J. M., Sorenson, S. B., et al (1988) The epidemiology of obsessive—compulsive disorder in five US communities. Archives of General Psychiatry, 45, 1094–1099.Google Scholar
Leonard, H., Swedo, S., Rapoport, J. L., et al (1988) Treatment of childhood obsessive—compulsive disorder with clomipramine and desmethylimipramine: a double-blind crossover comparison. Psychopharmacology Bulletin, 24, 93–95.Google ScholarPubMed
Liebowitz, M. R., Fyer, A. J., Gorman, J. M., et al (1988) Tricyclic therapy of the DSM-III anxiety disorders: a review with implications for further research. Journal of Psychiatric Research, 22, 7–31.Google Scholar
Lingjærde, O. (1984) Blood platelets as a model system for studying the biochemistry of depression. In Frontiers in Biochemical and Pharmacological Research in Depression: Advances in Biochemical Psychopharmacology (eds Usdin, E., Åsberg, M., Bertilsson, L., et al), Vol. 39. New York: Raven Press.Google Scholar
Linnoila, M., Virkkunen, M., Scheinin, M., et al (1983) Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sciences, 33, 2609–2614.Google Scholar
López-Ibor, J. J. Jr. (1988) The involvement of serotonin in psychiatric disorders and behaviour. British Journal of Psychiatry, 153 (Suppl. 3), 26–39.Google Scholar
Maj, J. & Lewandowska, A. (1980) Central serotoninmimetic action of phenylpiperazines. Polish Journal of Pharmacology and Pharmacy, 32, 495–504.Google Scholar
Marks, I. M., Stern, R. S., Mawson, D., et al (1980) Clomipramine and exposure for obsessive—compulsive rituals: I. British Journal of Psychiatry, 136, 1–25.Google Scholar
Mavissakalian, M., Turner, S. M., Michelson, L. & Jacob, R. (1985) Tricyclic antidepressants in obsessive—compulsive disorder: antiobsessional or antidepressant agents? II. American Journal of Psychiatry, 142, 572–576.Google ScholarPubMed
Meltzer, H. Y., Witta, B., Tricou, B. J., et al (1982) Effect of serotonin precursors and serotonin agonists on plasma hormone levels. In Serotonin in Biological Psychiatry (eds Ho, B. T., Schoolar, J. C. & Usdin, E.). New York: Raven Press.Google Scholar
Mennini, T., Poggesi, E., Caccia, S., et al (1980) Adaptive changes in central serotonin receptors after long-term drug treatment in rats. In Neurotransmitters and Their Receptors (eds Littauer, U.Z., Dudai, Y., Silman, I., et al). New York: John Wiley & Sons, Ltd.Google Scholar
Mills, F. J. (1985) The endocrinology of stress. Aviation, Space, and Environmental Medicine, 56, 642–650.Google Scholar
Montgomery, S. A. (1980) Clomipramine in obsessional neurosis: A placebo-controlled trial. Pharmaceutical Medicine, I, 189–192.Google Scholar
Mueller, E. A., Murphy, D. L. & Sunderland, T. (1985a) Neuroendocrine effects of m-chlorophenylpiperazine, a serotonin agonist, in humans. Journal of Clinical Endocrinology and Metabolism, 61, 1179–1184.Google Scholar
Mueller, E. A., Murphy, D. L., Sunderland, T. et al (1985b) A new postsynaptic serotonin receptor agonist suitable for studies in humans. Psychopharmacology Bulletin, 21, 701–704.Google Scholar
Mueller, E. A., Murphy, D. L., Sunderland, T. (1986) Further studies of the putative serotonin agonist, m-chlorophenylpiperazine: evidence for a serotonin receptor mediated mechanism of action in humans. Psychopharmacology, 89, 388–391.Google Scholar
Murphy, D. L., Mueller, E. A., Hill, J. L., et al (1989) Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology, 98, 275–282.Google Scholar
Nordahl, T. E., Benkelfat, C., Semple, W., et al (1989) Cerebral glucose metabolic rates in obsessive—compulsive disorder. Neuropsychopharmacology, 3, 23–27.CrossRefGoogle Scholar
Ögren, S. O., Fuxe, K. & Agnati, L. (1985) The importance of brain serotonergic receptor mechanisms for the action of antidepressant drugs. Pharmacopsychiatry, 18, 209–213.CrossRefGoogle ScholarPubMed
Pato, M. T., Zohar-Kadouch, R., Zohar, J., et al (1988) Return of symptoms after discontinuation of clomipramine in patients with obsessive—compulsive disorder. American Journal of Psychiatry, 145, 1521–1525.Google Scholar
Paul, S. M., Rehavi, M., Rice, K. C., et al (1981) Does high affinity [3H] imipramine binding label serotonin reuptake sites in brain and platelet? Life Sciences, 28, 2753–2760.Google Scholar
Perse, T. L., Greist, J. H., Jefferson, J. W., et al (1987) Fluvoxamine treatment of obsessive—compulsive disorder. American Journal of Psychiatry, 144, 1543–1548.Google Scholar
Post, R. M. & Murphy, D. L. (1979) Research planning: studies of cerebrospinal fluid metabolites and blood cell enzymes. In Handbook of Biological Psychiatry (ed van Praag, H. M.). New York: Marcel Dekker.Google Scholar
Prasad, A. (1984) A double blind study of imipramine versus zimelidine in treatment of obsessive compulsive neurosis. Pharmacopsychiatry, 17, 61–62.CrossRefGoogle ScholarPubMed
Prasad, A. (1985) Efficacy of trazodone as an anti obsessional agent. Pharmacology, Biochemistry, and Behavior, 22, 347–348.Google Scholar
Price, L. H., Charney, D. S., Delgado, P. L., et al (1989) Lithium treatment and serotoninergic function: neuroendocrine and behavioral responses to intravenous tryptophan in affective disorder. Archives of General Psychiatry, 46, 13–19.Google Scholar
Rapoport, J., Elkins, R. & Mikkelsen, E. (1980) Clinical controlled trial of chlorimipramine in adolescents with obsessive—compulsive disorder. Psychopharmacology Bulletin, 16, 61–63.Google Scholar
Rapoport, J. L. (1988) The neurobiology of obsessive—compulsive disorder. Journal of the American Medical Association, 260, 2880–2890.Google Scholar
Rasmussen, S. A. (1984) Lithium and tryptophan augmentation in clomipramine-resistant obsessive—compulsive disorder. American Journal of Psychiatry, 141, 1283–1285.Google Scholar
Rasmussen, S. A., Goodman, W. K., Woods, S. W., et al (1987) Effects of yohimbine in obsessive compulsive disorder. Psychopharmacology, 93, 308–313.Google Scholar
Rehavi, M., Skolnick, P. & Paul, S. M. (1984) High-affinity binding sites for tricyclic antidepressants in brain and platelets. In Brain Receptor Methodologies (eds Marangos, P. J., Campbell, I. C. & Cohen, R. M.). Orlando: Academic Press.Google Scholar
Saavedra, J. M. & Axelrod, J. (1974) Brain tryptamine and the effects of drugs. Advances in Biochemical Psychopharmacology, 10, 135–139.Google ScholarPubMed
Samanin, R., Mennini, T., Ferraris, A., et al (1979) m-Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 308, 159–163.Google Scholar
Samanin, R., Caccia, S., Bendotti, C., et al (1980) Further studies on the mechanism of serotonin-dependent anorexia in rats. Psychopharmacology, 68, 99–104.Google Scholar
Stern, R. S., Marks, I. M., Wright, J., et al (1980) Clomipramine: plasma levels, side effects and outcome in obsessive—compulsive neurosis. Postgraduate Medical Journal, 56 (Suppl. 1), 134–139.Google Scholar
Stern, T. A. & Jenike, M. A. (1983) Treatment of obsessive-compulsive disorder with lithium carbonate. Psychosomatics, 24, 671–673.Google Scholar
Thorén, P., Åsberg, M., Cronholm, B., et al (1980a) Clomipramine treatment of obsessive—compulsive disorder. I. A controlled clinical trial. Archives of General Psychiatry, 37, 1281–1285.Google Scholar
Thorén, P., Åsberg, M., Bertilsson, L., et al (1980b) Clomipramine treatment of obsessive—compulsive disorder. II. Biochemical aspects. Archives of General Psychiatry, 37, 1289–1294.CrossRefGoogle ScholarPubMed
van Praag, H. M. (1983) CSF 5-HIAA and suicide in non-depressed schizophrenics. Lancet, ii, 977–978.Google Scholar
Vetulani, J., Sansone, M., Bednarczyk, B., et al (1982) Different effects of 3-chlorophenylpiperazine on locomotor activity and acquisition of conditioned avoidance response in different strains of mice. Naunyn-Schmiedeberg's Archives of Pharmacology, 319, 271–274.Google Scholar
Virkkunen, M., Nuutila, A., Goodwin, F. K., et al (1987) Cerebrospinal fluid monoamine metabolite levels in male arsonists. Archives of General Psychiatry, 44, 241–247.Google Scholar
Volavka, J., Neziroglu, F. & Yaryura-Tobias, J. A. (1985) Clomipramine and imipramine in obsessive—compulsive disorder. Psychiatry Research, 14, 83–91.Google Scholar
Weizman, A., Carmi, M., Hemesh, H., et al (1986) High-affinity imipramine binding and serotonin uptake in platelets of eight adolescent and ten adult obsessive—compulsive patients. American Journal of Psychiatry, 143, 335–339.Google ScholarPubMed
Yaryura-Tobias, J. A. & Bhagavan, H. N. (1977) l-Trytophan in obsessive—compulsive disorders. American Journal of Psychiatry, 134, 1298–1299.Google Scholar
Zak, J. P., Miller, J. A. Jr., Sheehan, D. V., et al (1988) The potential role of serotonin reuptake inhibitors in the treatment of obsessive compulsive disorder. Journal of Clinical Psychiatry, 49 (8, Suppl.), 23–29.Google Scholar
Zohar, J. & Insel, T. R. (1987) Obsessive—compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. Biological Psychiatry, 22, 667–687.Google Scholar
Zohar, J., Mueller, E. A., Insel, T. R., et al (1987a) Serotonergic responsivity in obsessive—compulsive disorder: comparison of patients and healthy controls. Archives of General Psychiatry, 44, 946–951.Google Scholar
Zohar, J., Klein, E. M., Mueller, E. A., et al (1987b) 5HT, obsessive-compulsive disorder and anxiety. 140th Annual Meeting of the American Psychiatric Association, Chicago, IL, May 9–14, 1987. Abstract no. 950, p. 175.Google Scholar
Zohar, J., Insel, T. R., Zohar-Kadouch, R.C., et al (1988) Serotonergic responsivity in obsessive—compulsive disorder: effects of chronic clomipramine treatment. Archives of General Psychiatry, 45, 167–172.Google Scholar
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