The British Journal of Psychiatry (1972) 120: 673-677. doi: 10.1192/bjp.120.559.673
© 1972 The Royal College of Psychiatrists
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On the Slowness of Action of Tricyclic Antidepressant Drugs

IAN OSWALD M.A., M.D., D.Sc., D.P.M.1, VLASTA BREZINOVA M.D., Ph.D.2, and D. L. F. DUNLEAVY M.B., B.Ch., D.P.M.2

1 Reader in Psychiatry, Department of Psychiatry, University of Edinburgh, Edinburgh, EH10 5HF, Scotland
2 Research Psychiatrist, Department of Psychiatry, University of Edinburgh, Edinburgh, EH10 5HF, Scotland

Tricyclic drugs almost immediately affect the brain but relief from depression takes several weeks. Theories of the drug's action ignore this and rest upon acute experiments. The results of the 1965 Medical Research Council trial of imipramine are reassessed and in the imipramine-placebo difference it is noted that improvement began after two weeks. Rate of rise of plasma and tissue concentrations cannot explain the clinical time-course.

Imipramine 75 mg. daily made 12 non-depressed volunteers rate themselves as depressed in the first week, but not in the third. This action, plus a steadily mounting `therapeutic' mechanism, could partly explain the lag to clinical improvement from depression.

In human and rat brains there are effects of tricyclic drugs that (1) change gradually with weeks and others that (2) remain constant with weeks. The former imply synthesis of modified long-life, protein-containing components of neurones. Arnong neuronal amine mechanisms are some known to have life-spans of about a month, and in man experimental evidence indicates that some tricyclic drugs cause synthesis of modified cerebral components having a life-span of the same duration. The therapeutic effects of tricyclic drugs could therefore proceed through mechanisms of this kind.

Submitted on June 14, 1971




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