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Identifying the specific clinical actions of amitriptyline: interrelationships of behaviour, affect and plasma levels in depression

  • Martin M. Katz (a1), Stephen H. Koslow (a1), James W. Maas (a1), Alan Frazer (a1), James Kocsis (a1), Steven Secunda (a1), Charles L. Bowden (a1) and Regina C. Casper (a1)...


Despite increasing knowledge of the neurochemical bases of the action of the tricyclic drugs, little is known about the sequence of psychological effects which precede recovery in drug-responsive patients. This research was aimed at identifying the specific behavioural effects associated with the therapeutic action of amitriptyline in depression. The design involved measurement (post-hoc) of weekly changes in a severely depressed placebo-resistant group who recovered with drug treatment, compared with a group of similar patients treated for the equivalent four weeks, who showed minimal to no clinical response. The research strategy, in accordance with a dose–response paradigm, was to determine which of the early changes in emotion and behaviour found in treatment responders were systematically associated with plasma concentrations of amitriptyline or its major metabolite. Amitriptyline was found to act within seven days on the components of anxiety and on hostility in the responders, and on sleep disorder in all patients. After 12 to 14 days of treatment these effects increased, with improvements in other significant components distinguishing the responders from the non-responders. At the 12th to 14th treatment days when a steady state concentration of drug in plasma was approached, reductions in anxiety and hostility and in certain somatic components correlated significantly with plasma concentrations of amitriptyline. Implications of the findings for clarifying the specificity of clinical actions of the tricyclic drugs, and for understanding the psychobiological dynamics underlying rapid drug-induced recovery in depression, were explored.


Corresponding author

1 Address for correspondence: Dr Martin M. Katz, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210 street, Bronx, NY 10467, USA.


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Åsberg, M., Bertilsson, L., Tuck, D., Cronholm, B. & Sjoqvist, F. (1972). Indoleamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline. Clinical Pharmacology and Therapeutics 14, 277286.
Biggs, J. T., Holland, S. W., Chang, S., Hipps, P. P. & Sherman, W. F. (1976). The electron beam ionization mass fragmentographic analysis of tricyclic antidepressants in human plasma. Journal of Pharmaceutical Science 65, 261268.
Bowden, C. L., Koslow, S. H., Hanin, I., Maas, J. W., Davis, J. M. & Robins, E. (1985). Effects of amitriptyline and imipramine on brain and amine neurotransmitter metabolites in cerebrospinal fluid. Clinical Pharmacology and Therapeutics 37, 316324.
Cole, J. O. & Davis, J. M. (1975). Antidepressant drugs. In Comprehensive Textbook of Psychiatry II (ed. Freedman, A. M., Kaplan, H. I. and Sadock, B. J.), pp.22902315. Williams & Wilkins: Baltimore.
DiMascio, A., Weissman, M. M., Prusoff, B. A., Neu, C., Zwilling, M. & Klerman, G. L. (1979). Differential symptom reduction by drugs and psychotherapy in acute depression. Archives of General Psychiatry 36, 14501456.
Edwards, A. L. (1962). Experimental Design in Psychological Research (Revised edition). Holt, Rinehart and Winston: New York.
Endicott, J. & Spitzer, R. (1978). A diagnostic interview: the schedule for affective disorders and schizophrenia. Archives of General Psychiatry 35, 837844.
Fava, G. A., Kellner, R., Lisansky, J., Park, S., Perini, G. I. & Zielezny, M. (1986). Hostility and recovery from melancholia. Journal of Nervous and Mental Disease 174, 414417.
Fingel, E. & Woodbury, D. M. (1975). General principles. In Pharmacological Basis of Therapeutics 5th Edition (ed. Goodman, L. S. and Gilman, A.), pp. 146. Macmillan: New York.
Frazer, A. & Conway, P. (1984). Pharmacological mechanisms of action of antidepressants. Psychiatric Clinics of North America 7, 575586.
Freud, S. (1959). Mourning and melancholia. In Collected Papers, V. 4.. Basic Books: New York.
Glassman, T., Kantor, S. J. & Shostak, M. (1975). Depression, delusions and drug response. American Journal of Psychiatry 132, 716719.
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Hollister, L. E., Overall, J. E., Johnson, M., Pennington, V., Katz, G. & Sheldon, J. (1964). Controlled comparison of amitriptyline, imipramine and placebo in hospitalized depressed patients. Journal of Nervous and Mental Disease 139, 370375.
Joyce, R. P. & Paykel, E. S. (1989). Predictors of drug response in depression. Archives of General Psychiatry 46, 8999.
Kahn, R. J., McNair, D. M., Lipman, R. S., Covi, L., Rickels, K., Downing, R., Fisher, S. & Frankenthaler, L. M. (1979). Imipramine and chlordiazepoxide in depression and anxiety disorders. II. Efficacy in anxious outpatients. Archives of General Psychiatry 43, 7985.
Katz, M. M., Secunda, S., Hirschfeld, R. M. S. & Koslow, S. H. (1979). NIMH Clinical Research Collaborative Program on the Psycho-biology of Depression. Archives of General Psychiatry 36, 765771.
Katz, M. M., Robins, E., Croughan, J., Secunda, A. & Swann, A. (1982). Behavioural measurement and drug response characteristics of unipolar and bipolar depression. Psychological Medicine 12, 2536.
Katz, M. M., Koslow, S. H., Berman, N., Secunda, S., Maas, J. W., Casper, R., Kocsis, J. & Stokes, P. (1984). Multivantaged approach to the measurement of behavioural and affect states for clinical and psychobiological research. Psychological Reports 55, 619671.
Katz, M. M., Koslow, S. H., Maas, J., Frazer, A., Bowden, C. L., Casper, R., Croughan, J., Kocsis, J. & Redmond, E. Jr., (1987). The timing, specificity and clinical prediction of tricyclic drug effects in depression. Psychological Medicine 17, 297309.
Klein, D. F., Zitrin, C. M. & Woerner, M. (1978). Antidepressants, anxiety panic and phobia. In Psychopharmacology: A Generation of Progress (ed. Lipton, M. A., DiMascio, A. and Killam, K. F.), pp. 14011410. Raven Press: New York.
Klerman, G. L. & Cole, J. O. (1965). Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacology Review 17, 101141.
Kocsis, J. H., Davis, J. M., Katz, M. M., Koslow, S. H., Stokes, P. E., Casper, R. & Redmond, D. E. (1985). Depressive behavior and hyperactive adrenocortical function. American Journal of Psychiatry 142, 12911298.
Kocsis, J., Hanin, I., Bowden, C. L. & Brunswick, D. (1986). Imipramine and amitriptyline plasma concentration and clinical response in major depression. British Journal of Psychiatry 148, 5257.
Koslow, S., Maas, J. W., Bowden, C., Davis, J., Hanin, I. & Javard, J. (1986). Letter to the editor: tricyclic anti-depressant washout effects on cerebrospinal fluix and urinary monoamine and metabolites. Archives of General Psychiatry 43, 10121013.
Lader, M., Lang, R. A. & Wilson, G. D. (1987). Patterns of Improvement in Depressed In-patients. Maudsley Monograph No. 30, Oxford University Press: Oxford.
LeDoux, J. E. (1987). Emotion. In Handbook of Physiology: The Nervous System, Vol. v, (ed. Geiger, S. R., Plum, F. and Mountcastle, V. B.), pp. 419461. American Physiological Society: Bethesda, Maryland.
Maas, J. W., Koslow, S., Davis, J., Katz, M. M., Mendels, J., Robins, E., Stokes, P. & Bowden, C. (1980). Biological component of the NIMH Clinical Research Branch Collaborative Program in the Psychobiology of Depression. I. Background theoretical considerations. Psychological Medicine 10, 759776.
Maas, J. W., Koslow, S. H., Katz, M. M., Bowden, C. L., Gibbons, R. L., Stokes, P. E., Robins, E. & Davis, J. M. (1984). Pretreatment neurotransmitter metabolite levels and response to tricyclic antidepressant drugs. American Journal of Psychiatry 141, 11591171.
Mason, J. W. (1968). A review of psychoendocrine research on the pituitary–adrenal cortical system. Psychosomatic Medicine 30 (09.–10. suppl.), 576607.
Medical Research Council (1965). Clinical trial of the treatment of depressive illness. British Medical Journal 6, 881886.
Nelson, J. C., Mazure, C., Quinlan, D. M. & Jatlow, P. I. (1984). Drug-responsive symptoms in melancholia. Archives of General Psychiatry 41, 663668.
Preskorn, S. H. & Mac, D. S. (1984). The implication of concentration/response studies of tricyclic antidepressants for psychiatric research and practice. Psychiatric Developments 3, 201222.
Quitkin, F. M., Rabkin, J. G., Ross, D. & Stewart, J. W. (1984). Identification of true drug response to anti-depressants: use of pattern analysis. Archives of General Psychiatry 41, 782786.
Redmond, D. Jr., Katz, M. M., Maas, J., Swann, A. & Casper, R. (1986). Cerebrospinal fluid biogenic amine metabolite relationships with behavioral measurements in unipolar and bipolar depressed, manic and healthy control subjects. Archives of General Psychiatry 43, 938947.
Schatzberg, A. F. & Cole, J. O. (1978). Benzodiasepines in depressive disorders. Archives of General Psychiatry 35, 13591365.
Secunda, S., Koslow, S., Redmond, D., Garner, D., Ramsey, T., Croughan, J., Kocsis, J., Hanin, I. & Lieberman, K. (1980). Biological component of the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression. I. Methodology and data analysis. Psychological Medicine 10, 777793.
Spitzer, R. L., Endicott, J. & Robins, E. (1978). Research diagnostic criteria: rationale and reliability. Archives of General Psychiatry 35, 773782.
Sulser, F., Vetulani, J. & Mobley, P. L. (1978). Commentary on mode of action of antidepressant drugs. Biochemical Pharmacology 27, 257261.
Task Force on the Use of Laboratory Tests in Psychiatry. (1985). Tricyclic Antidepressants – Blood Level Measurements and Clinical Outcome: An APA Task Force Report. American Journal of Psychiatry 142, 155162.
van Praag, H. M., Plutchik, R. & Conte, H. (1986). The serotonin-hypothesis of (auto) aggression. Critical appraisal of the evidence. In Psychobiological Suicide Behavior (ed. Mann, J. J. and Stanley, M.). Annals of the New York Academy of Science 487, 150167.
Weissman, M., Klerman, G. L. & Paykel, E. S. (1971). Clinical evaluations of hostility in depression. American Journal of Psychiatry 128, 4146.
Winer, B. J. (1971). Statistical Principles in Experimental Design (2nd edition). McGraw Hill: New York.
Wittenborn, J. R. (1966 a). The Clinical Psychopharmacology of Anxiety. Charles C. Thomas: Springfield, Illinois.
Wittenborn, J. R. (1966 b). The assessment of clinical change. In Pharmacotherapy of Depression (ed. Cole, J. O. & Wittenborn, J. R.), pp. 6790. Charles C. Thomas: Springfield, Illinois.

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Identifying the specific clinical actions of amitriptyline: interrelationships of behaviour, affect and plasma levels in depression

  • Martin M. Katz (a1), Stephen H. Koslow (a1), James W. Maas (a1), Alan Frazer (a1), James Kocsis (a1), Steven Secunda (a1), Charles L. Bowden (a1) and Regina C. Casper (a1)...


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