Guest Editorial

Drugs 14: 161-162 (1977)© ADIS Press 1977

Individualised Dosage ofTricyclic Antidepressants

Leo E. Hollister

Stanford University School of Medicine and Veterans Administration Hospital. Palo Alto,California

Doses of tricyclic antidepressants have beenlargely determined empirically. The desired effect,amelioration of depression, is weighed against the un­desired effects, usually excessive sedation or the peri­pheral and central anticholinergic manifestations.Usual dosage patterns start with small doses followedby frequent increments until either the desired thera­peutic effect has been achieved or the presence of un­wanted effects makes further increases intolerable.

Undertreatment is probably the most commoncause of poor results with these drugs [I]. Of 51 pa­tients referred for hospitalisation in one study, pre­ceding treatment was thought proper in only 20 %;I9 patients had not been treated with any medicationand of 21 receiving tricyclic antidepressants, 13received less than 150mg/day [2]. In outpatient prac­tice, the proper usage of drugs leaves much to bedesired. Among a group of I 12 patients with depres­sion, 92 % received tricyclic antidepressants, but only25 % were given doses greater than 75mg/day [3].While it is always desirable to treat patients with theleast amount of drug required for a satisfactoryresult, to settle for less than an adequate result with­out having explored the full dosage range is poorpractice.

The minimum dose that should be sought in anypatient unresponsive to a lesser dose is 150mg/day.This dose of nortriptyline places all but a few patientsin the presumed therapeutic range of therapeuticplasma concentrations of the drug (usually thought tobe 50 to 150ng/mI) [4]. Less data are available forother tricyclics, that for amitriptyline suggest thateven this daily dose will be insufficient for almostone-half of patients [5]. A recent study of depressivestreated with imipramine (3.5mg/kg) for 28 daysfound combined imipramine/desipramine plasmaconcentrations at the steady-state ranging between 50and 1,050ng/ml. The clinical response to the drugwas linear, except in the case of delusional patients [6].Neither amitriptyline nor imipramine seem to showthe inverted U-shaped plasma level-response curvewhich has been described for nortriptyline. [4]. Withthe latter drug, the clinical response appears to be lessin those few patients with very low or very highplasma levels in comparison with those in the inter­mediate concentration range.

A reasonable practice for administering tricyclicantidepressants would be to start most otherwisehealthy patients on a daily dose of 75mg, probablygiven as a single dose about three hours prior to bed-

Dosage of Tricyclic Antidepressants

time. Additional 25mg daily dose increments shouldbe made frequently over the first several days to at­tain a dose of I 5Omg / day by the end of the first weekof treatment. This dose level should be maintained foranother week so that a steady-state can develop.Reassessment at the end of two weeks of treatmentmay reveal that this dose is adequate; if it is not, thedose should be further augmented by 25mg incre­ments to one that is effective or to a dose of300mg/day.

After four weeks of treatment, another reassess­ment might lead to reconsidering the diagnosis, thechoice of drug, or the need to increase the dose stillfurther. If a dose of 300mg/day has been well toler­ated, one may assume that the bioavailability of thedrug by oral administration is poor in that patient (itmay be as low as 25 %), and that increased doses areneeded. Is there much danger in raising doses beyond300mg/day? Apparently not; among 40 patientsreceiving doses in excess of 300mg/day (some up to700mg/day), no patients needed to have their treat­ment stopped because of side-effects and, for most,the high doses were crucial for maintenance of satis­factory improvement [7]. However, few clinicianswould feel compelled to raise doses higher than600mg/day, as seizures or cardiac toxicity becomemore likely complications.

A word of caution must be raised about the use oftricyclic antidepressants in patients at the extremes oflife. In the US, a ceiling dose of 2.5mg/kg has beenestablished for imipramine in children, due to at leastone fatality. The elderly are also likely to suffer ad­verse effects from high doses; in part this may be dueto decreased metabolism of the drug, decreased pro­tein binding, and increased receptor sensitivity,especially to the anticholinergic effects. Initial dosesof tricyclics should be smaller, perhaps not more than25mg daily, increments in dose less frequent, and theceiling dose smaller than would be the case for other­wise healthy patients. Even some of the latter,especiallyif they are small in size or poorly tolerant oflarger initial doses, may require a more conservativedosage schedule.

162

The important principle is that interpatient vari­ability in response to drugs is an established fact. Onesimply can not set up some standard dose, or followslavishly the recommendations of the package label.Whenever one exceeds the doses set on the packagelabels, one is well advised to tell the patient exactlywhy this step is being taken (that is, to get an in­formed consent) and to record these reasons and thepatient's assent in the records. Fear of legal actionshould not deter one from the assiduous attention todose that is required if depressed patients are to betreated effectively with tricyclic antidepressants.

References

I. Kline, N.A.: Antidepressant medications: A more effective useby general practitioners, family physicians. internists andothers. Journal of the American Medical Association 227:1158-1160 (1974).

2. Kotin, J.; Post. R.M. and Goodwin. F.K.: Drug treatment ofdepressed patients referred for hospitalization. American Jour­nal of PSYChiatry 130: 1139-1141 (1973).

3. Johnson. D.A.W.: A study of the use of antidepressantmedication in general practice. British Journal of Psychiatry125: 186-192 (1974).

4. Asberg, M.: Individualization of treatment with tricyclic com­pounds. Medical Clinics of North America 58: 1083-1091(1974).

5. Coppen, A. and Montgomery. S.: Effective dosage of tricyclicantidepressants. British Medical Journal I: 91 (1975).

6. Glassman. A.H.; Perel, J.M.; Shostak. M.; Kantor. S.J. andFleiss, J.L.: Clinical implications of imipramine plasma levelsfor depressive illness. Archives of General Psychiatry 34:197-204 (1977).

7. Schuckit, ~.A. and Feighner. J.P.: Safety of high-dose tricyc­lic antidepressant therapy. American Journal of Psychiatry128: 1456-1459 (1972).

Author's address: Prof. Leo E. Hollister. Veterans Administra­tion Hospital. 3801 Miranda Ave. Palo Alto. California 94304(USA).