Pharmacological Reviews, Vol 17, 101-141, Copyright © 1965 by the American Society for Pharmacology and Experimental Therapeutics

CLINICAL PHARMACOLOGY OF IMIPRAMINE AND RELATED ANTIDEPRESSANT COMPOUNDS

¹ Harvard Medical School and Massachusetts Mental Health Center, Boston, Massachuetts, and National Institute of Mental Health, Bethesda, Maryland

Our review of the studies of clinical efficacy of the tricyclic compounds in the treatment of depression supports the general view that imipramine and amitriptyline are more effective than placebo, and that amitriptyline may even be a little more effective than imipramine. The controlled data show a reasonable consistency. Moreover, this review confirms an impression that the authors have gained from other studies that clinical ratings of general iniprovemnent and of symnpomatic changes are a good deal more useful for detection of drug-placebo differences than has often been assumed.

These heterogeneous reports give few clear criteria, however, of what kinds of depressed patients with what kinds of symptoms are particularly responsive to these drugs. An equally important unanswered question concerns the kinds of depressed patients who respond well to placebo or nonpharniacologic therapies. Imprecision or lack of general agreement on meaningful subgroups among depressions certainly hinders the interpretation of pooled data. For a condition as variable as depression, the sizes of patient samples so far studied appear woefully small. To make progress in this area, larger studies with clearly defined patient groups will be needed. More attention also will have to be given to nondrug factors, including those attendant to the administration of placebo, that influence the therapeutic outcome in depression. There is some evidence that depressed patients are affected by the attitudes of their doctors toward these drugs (285) and some evidence that the patient's expectations influence his responses to placebo (157).

Another particularly fruitful area for further research is that of followup and maintenance therapy. There is already suggestive evidence that imipramnine has unusual virtues as a maintenance therapy and that patients receiving even a short period of drug treatmnent show better adjustment a year later than do patients treated with control (158, 177, 339).

These agents are reasonably safe if used with care. There is no good evidence that imipramine is significantly more dangerous than ECT. It is probably less dangerous than iproniazid if it is properly used, that is, if the dosage is watched, and its side effects are properly managed either by reduction in dosage or other corrective medication.

Ideally, to understand the mode of clinical action of any therapeutic agent requires knowledge in four areas : 1) objective criteria to identify patients with a specific clinical feature, i.e., anemia, jaundice, depression, anxiety, etc. (this requires knowledge of the range and limits of the phemiomnena within the normal population) ; 2) knowledge of etiology on the basis of which groups of patients with a given clinical manifestation can be significantly classified in meaningful groups; 3) understanding both the pathogenesis (i.e., the sequences of events leading to formation of symptoms) and the pathologic physiology and psychopathology of the disease states; and 4) knowledge of the actions of a drug which clarifies how the treatment interrupts the pathogenetic sequence that results in symptom formation or alters the pathologic physiology characteristic of the disease state. This ideal is seldom realized even in the fields of medicine other than psychiatry. In studying the pharmacotherapy of depression, we are hampered by lack of knowledge in all areas. The range of depressive emotional mnanifestations in the normal population or secondary to life stresses amid medical illness—is undoubtedly wide. Quantitative criteria for determining pathologic depressive reactions are limited. Within the group of depressions, few etiologic principles have been substantiated and little agreement exists on subgroups. Consequently, differential drug responses are not clearly understood. Most significantly for understanding modes of drug actions, we have little knowledge of the altered psychophysiology of depression. it is encouraging that some promising leads are being developed (83, 281).

Nevertheless, the advent of effective psychopharmacologic treatments of depression has provided considerable impetus to basic laboratory research and clinical investigations and a number of new techniques have yielded interesting findings. Among the various hypotheses, most attemition has been focused on the relationship of imipramine's actions to effects on central adrenergic mechanisms, probably in hypothalamic and other diencephalic regions. In this respect there appears to be some convergence of data in a number of areas: potentiation of the peripheral actions of norepinephrine, alteration of the uptake and storage of amines, clinical effects on urinary excretion of catecholamine metabolites, and behavioral stimulation. These findings are compatible with the hypothesis that depression is associated with a relative deficiency of catecholamines in selected subcortical regions of the brain and that some depressed patients, like animals receiving reserpine, may have released intracellularly deaminated endogenous norepinephrine to excess, so that less of this amine is available for release in active form. These results, moreover, suggest that a possible common mode of action of monoamine oxidase inhibitors and the imipramine class of antidepressant drugs may be to increase the active catecholamines, particularly norepinephrine, available for functional extracellular release (188, 277). Attractive as these hypotheses may be, it is important to recognize their limitations. There is noclear evidence of alterations of amine metabolism in depressed patients. The role of cholinergic mechanisms remains unclear as does the possible relationship to indoleanmine metabolism (1, 2, 56, 333). Conceptually, considerably more sophistication on regional brain drug effects seems to be evolving, and many widely accepted clinical concepts are undergoing reappraisal and empirical validation. Interesting research on these and related hypotheses are underway and the prospects are that many of these issues will be partially clarified within the next five years.

Note:

The authors wish to express their thanks to the many persons who assisted them in preparing this review: To Dr. Richard Shader and Miss Joanne Dwinnell, who helped review many literature sources, and to Mrs. R. Edidin, Mrs. S. Bradlee, Mrs. P. H. Ambrose and Miss Diane Zucker, who helped prepare the manuscript and reference list. Appreciation is due to Dr. Eric Kandel, Dr. Dale G. Friend, Dr. Milton Greenblatt, Dr. Max Fink, Dr. R. Liberman and Dr. Norman Weiner, many of whose ideas and suggestions are included in this paper. Particular acknowledgment is due to Dr. Joseph J. Schildkraut, Laboratory of Clinical Science, NIMH, Bethesda, whose unpublished review of the pharmacology of imipramine relative to catecholamine metabolism was available to us for consultation.

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