Psychoactive drugs: Effective use of low doses

ROGER BOUTIN, M.D.

Psychoactive drugs: Effective use of low doses ABSTRACT: The author reviews the literature on the effectiveness

of low doses of psychoactive drugs. In addition to being effective in many cases, low doses may arouse less patient resistance, leave the patient better able to participate in his treatment, and involve physician and patient in a beneficial reappraisal of treatment goals-from attempted cure using high drug doses, to helping the patient live with his problems, using low doses. A physician who gives double the required dose of penicillin may be a good doctor, but the one who gives twice the required dose of digitalis certainly is not. With psychoactive drugs we often must give a high dose and hope for the best; but as techniques improve and studies accumulate, the evidence increases that "more" is not necessarily "better." Careful titration is often indicated and low doses may prove effective, sometimes even more effective than higher ones. Giving the least amount of medication that is effective is not only "elegant," it also results in more involved, more compliant patients. In addition, it

seems reasonable to assume that low doses should help reduce sideeffects and long-term toxicity, although controlled studies to that effect are lacking. Present-day ethical and medicolegal trends, reinforced by the rising voice of consumerism, add pressure in the same direction. Even ifsmall doses may be better in some cases, can they be effective? It is hard enough to prove that standard doses are effective. For example, when the average difference between relapse rates in patients on full maintenance antipsychotic therapy and those on placebo is 40%,1 we are left with a

Dr. Boutin is assistant director of the inpatient unil at Ollawa General Hospital and associate professor of psychiatry at the University of Ollawa Faculty of Medicine. Reprint requests to him at 43 Bruyere, Ollawa, Ontario, Canada KIN 5C8. JUNE 1979 • VOL 20 • NO 6

substantial number of patients for whom the advantage is not so obvious. It could even be argued that they are taking medication needlessly. The problems of showing that very little medication is better than none at all, or better than a lot of it, seem insurmountable. Nevertheless, some supporting evidence seems to exist. For example, Gardos and Cole) talk about "the elusive and illusory minimal effective dose" and point out-with justification-that such a dose would not only have to be established for each individual, but also would vary with changes in the individual and in the environment. Attempts to find this dose are further complicated by a variable delay in clinical response to starting, stopping, or adjusting the dosage of a drug. Yet, in the same chapter these authors summarize studies which indicate that in certain settings, at least, over 90% of patients can do without medication two days a week, a reduction of 29%. Aside from studies of this type (spurred by concern about tardive dyskinesia), the literature on the effectiveness of low 403

Psychoactive drugs: Low doses

doses of drugs is meager, but not without some interest. Many years ago, Sarwer-Foner and Ogle2.3 pointed out that some patients responded poorly and in paradoxical fashion to intermediate doses of psychoactive medications. These psychotic or prepsychotic patients felt physically constrained by the "chemical straitjacket"; their anxiety remained high and was compounded by a panic resulting from their feeling of helplessness and inner agitation under the near-paralysis imposed by the medication. One way out of this, sometimes the only one, is to give massive doses very quickly, in order to assuage the inner turmoil. Another solution, however, is to be more conservative, using small doses of medication which will be effective less quickly, but without being so threatening to the patient. Specific drug studies The following studies have reported interesting results with low doses of specific drugs. • In 1968, Bucci4 advocated the use of smaller doses of fluphenazine HCL, which he found particularly effective for chronic paranoid schizophrenic patients. • In France, Lambert and associatesS and Schnetzler and Naveau6 proposed the use of small doses of fluphenazine, thioridazine, and thioproperazine as effective for long-term maintenance of psychotic patients. • Denber7 found that doses of 75 mg of doxepin per day were just as effective as doses of 300 mg, and with fewer side-effects. • Okasha and associates8 found the following doses of psychoactive drugs were more effective than placebo in preventing migraine, when taken three times a day: 10 mg of 404

doxepin; 10 mg of amitriptyline; and 2 mg of diazepam. • Ayd9 and Rogerson and Butler lO suggested 0.5-mg doses of haloperidol for anxiety. The use of low doses of phenothiazines for anxiety is not new, of course. • Bocci and associates " found small doses of lorazepam to be as effective as larger doses. • Bojanovsky and associates,'2 using diazepam (although over brief periods) found interesting differences between small doses (2.5 mg on days I and 2; 5 mg on day 3) and large doses (10, 10, and 20 mg). Low doses were more effective in improving sleep and appetite in their neurotic patients, while high doses were more effective against anxiety, at the cost of producing more side-effects. • Curry,'3 studying plasma levels of chlorpromazine, found some patients who responded with marked improvement to a reduction in dosage of about one third, as their blood levels returned to a lower concentration (25 to 300 ng/ml seemed an effective level while 600 to 800 ng/ml gave adverse results). • Kishimoto and associates,'4 on the other hand, reported that both the highest and lowest dose levels of trifluperidol were more effective than the medium ones in treating schizophrenia, while the small doses were most useful in autism. • Davis and associates lS and Bunneyl6 suggested an optimal therapeutic level for butaperazine. • Bunneyl6 and Asberg 17 suggested a "therapeutic window" effect or an "inverted U-shaped dose responsecurve" as a result of blood level studies of amitriptyline and nortriptyline (with an optimal plasma concentration of the latter in the vicinity of 50 to 150 ng/ml). • Of particular interest for our

purpose is the report by Goldstein and associates,'8 who were deliberately trying to find a dose that would be ineffective, or at least close to it, since they could not use true placebos. They used fluphenazine enanthate to make sure the medication would be absorbed by the patient and had planned 1.5 ml (37.5 mg) as the effective dose and 0.5 ml (12.5 mg) as the placebo-like dose. Side-effects and other considerations brought them to use I ml (25 mg) as the effective dose and 0.25 ml (6.25 mg) as the "ineffective" dose. Half the patients in each group were then treated with only medication and the other half with medication and crisis-oriented family psychotherapy. Not unexpectedly, when drugs were used alone, the high doses brought better results than the low doses. The low-dose group with family therapy, however, did best of all the four subgroups, showing the fewest treatment failures and the lowest level of residual symptomatology. There were even indications that the higher dose of medication meant less improvement with social therapy. Clinical implications Better treatment, therefore, may often mean lower, more carefully adjusted dosage, as more factors and more complex interactions are taken into account. Although the result may sometimes be higher doses, it should often be low doses used more effectively. We shall try to illustrate some of the considerations involved. The simple awareness of the fact that lesser doses may be effective will encourage their use. Doses may tend to be relatively high in treatment of acute cases, but even there an occasional hyper-absorbing paPSYCHOSOMATICS

tient or one with a toxic reaction will benefit from the alertness of a therapist who considers a lesser dose. In maintenance therapy, progressively lower doses can be achieved with a little extra effort and with careful monitoring. As blood level determinations of various agents become more easily available, they will be recognized for their practical use and not only for their research interest. The combination of clinical and biochemical monitoring with a more sophisticated general approach should allow us to do a good job with less and less medication. Some patience will be required, since we must take into account a time lag of many weeks and months for some drug effects, at the same time that we make allowance for current and future stresses and changes patients may have to face. Nonspecific factors must also be considered. For example, years ago prochlorperazine became generally "ineffective" in certain long-term treatment wards as the residents changed, while chlorpromazine just as magically began to work well until the residents changed again and the process was reversed. A medication that "agrees" with both patient and physician is likely to be effective in much smaller doses; and the extra effort to find it may be well spent. 19 DiMascio,2° Silverman,21 Van Putten and May,22 and others have drawn our attention to nonspecific factors or, more precisely, patientspecific rather than drug-specific factors. Some of these may also dictate the use of low doses for reasons such as those cited previously by Sarwer-Foner and Ogle.2.3 Many schizophrenic patients, particularly the paranoid ones, do better with lower doses of drugs simply JUNE 1979 • VOL 20 • NO 6

because they provoke less aversion and therefore ensure better compliance. Certain neurotic patients, such as rigid obsessive-compulsive individuals, will often respond better to low doses of drugs because they do not feel obnubilated or altered by the medication, do not feel controlled by it, or do not see the lighter form of treatment as self-indulgence or abdication. It is probably for such reasons that many of them seem to react well to very small doses of amitriptyline with or without perphenazine and/or equally small doses of benzodiazepines, usually prescribed to be taken as needed. Having to decide when to take the drug gives the patients more of a feeling of being in control. Modifying goals Goals of treatment may have to be modified in these cases as well as in others. While some illnesses can be approached with the idea of the simple chemical eradication of a symptom, others may impose on both therapist and the patient a rethinking of what their objectives are. The hard-pressed physician is tempted to think in terms ofa quick answer: target symptom, drug, cure. Patients also like that idea and accept less readily the need to learn to live with some problems or to be satisfied with partial relief. Yet, what do you do with the not uncommon problem of the housewife who complains of depression and lack of energy but who, unknowingly, uses this as a silent protest against her husband and, even more, as a way to make sure that her rebellion will never come into the open? If you could restore her energy and exchange her depression for healthy aggressiveness, you would end up with a patient in

panic at the emergence of rage and other unacceptable feelings and impulses. For such a patient and for her physician, a reappraisal of goals seems the only solution. Instead of heroic efforts at "curing" her depression and massive doses of medication, she may do much better with lower doses of medication aimed at simply helping her to live with the problem until she is ready for a more drastic solution. Settling for less may not be easy for the patient to accept and may threaten the omnipotent image of the therapist, but it can benefit both in the long run. Studies of the interaction of psychopharmacology with other treatments do more to suggest complex interrelations than to demonstrate their nature. Reports such as the one by Goldstein and associates '8 indicate that potentiation can occur in psychopharmacologic treatment even if we do not always know exactly how other treatment modalities interact with it. It would seem logical, in any case, not only to make use of other resources at hand but also to seek to understand the forces at play in each patient and to reinforce them, where possible, with medication, instead of attempting a radical change. Less medication should be required to help a person do what comes more naturally than would be needed to push that person in another direction that, while possibly more desirable in theory, is contrary to that person's nature. The examples of paranoid or rigid patients mentioned above can serve here also. A drug treatment that could make the rigid compulsive into a flexible, happy-go-lucky person may appeal to us (possibly less so to the patient), but it would have to be pow405

Psychoactive drugs: Low doses

erful indeed. What is more possible (and more acceptable to the patient) is for him or her to become, for example, obsessively involved in the ritual of pill-taking. The effect of making the patient an active participant in the treatment, a "self-healer," seems in itself a reasonable one, aside from the fact that it may accomplish more with less medication. The effective drugs we have at our disposal open the field to creative uses (such as the use of antidepressants against migraineS or against phobic anxiet y23). Some methods of treatment would seem like attempting to make our depressed housewife into a freeswinging interlocutor. Other methods would attempt to modify such factors as anxiety, depression, or anger in a more subtle way,

more than a lot, used less carefully. Regarding psychoactive drugs, we are still far from the sophistication we can claim in using digitoxin, for instance. And research in evaluating subtle effects of drugs or complex interactions with other factors remains extremely difficult.

One source of hope lies in the availability of precise microtechniques. Another possibility may arise from the broader use of computers in collating data from diverse and much more numerous sources. With this kind of help, we can hope to offset the problem of dealing with subtle effects in a population that would, almost by definition, be far from homogeneous. In the meantime, the empirical practice of our art can go on in this direction and wait-and hope-for theory to catch up. Psychiatry and medicine have been radically changed by the advent of psychoactive drugs, and are still being changed. Our increasing ability to make full and effective use of low doses of psychoactive drugs may well mark an important step in that evolution. 0

blind trial for the clinical management of psychogenic headache. Br J Psychiatry 122:181, 1973. 9. Ayd FJ Jr: Comparative trial of low dose haloperidol and fluphenazine in office patients. Dis Nerv Syst 33:192-195,1972. 10. Rogerson R, Butler JK: Assessment of low dosage haloperidol in anxiety states. Br J Psychiatry 119:169-170, 1971. 11. Bocci U, Inga EF, Luzi T: Use of an anxiolytic agent (Iorazepam) in low doses in the treatment of anxiety states. Minerva Med 68:2517-2522,1977. 12. Bojanovsky J, Hanysova A, Bouchal M, et al: Comparison of the therapeutic effect of lower and higher doses of diazepam with a placebo during short-term administration in neuroses. Act Nerv Super (Praha) 9(4):370, 1967. 13. Curry SH: Chlorpromazine: Concentrations in plasma, excretion in urine and duration of effect. Proc R Soc Med 64:285-289, 1971. 14. Kishimoto A, Inagaki T, Motoike M: Dose level and effects of trifluperidol in clinical use for schizophrenia. Clin Psychiatry (Tokyo) 16(6):568-587,1974. 15. Davis JM, Erickson S, Dekirmenjian H: Plasma levels of antipsychotic drugs and clinical response, in Lipton MA, DiMascio A, Killam KF (eds): Psychopharmacology: A Generation of Progress. New York, Raven Press, 1978, pp 905-915. 16. Bunney WE Jr: Drug Therapy and Psychobiological Research Advances in the Psychoses in the Past Decade. Am J Psychiatry 35 (suppl):8-13, 1978. 17. ASberg M: Individualization of treatment with

tricyclic compounds. Med Clin North Am 58(5):1083. Philadelphia, WB Saunders Co, 1974. 18. Goldstein MJ, Rodnick EH, Evans JR, et al: Long-acting phenothiazine and social therapy in the community treatment of acute schizophrenia, in Greenblatt M (ed): Drugs in Combination with Other Therapies. New York, Grune & Stratton, 1975, pp 35-48. 19. Davis JM, Cole JO: Antipsychotic drugs, in Freedman AM, Kaplan HI, Saddock BI (eds): Comprehensive Textbook 01 Psychiatry. Baltimore, Williams & Wilkins, 1975, pp 19201933. 20. DiMascio A: Personality and variability of response to psychotropic drugs: Relationship to "paradoxical effects," in Rickels K (ed): Non-Specific Factors in Drug Therapy, Springfield, III, Charles C Thomas, 1968, pp 40-49. 21. Silverman A, quoted in Psychiatric News 12:22-23, sept 2,1977. 22. Van Putten T, May PRA: Subjective response as a predictor of outcome in pharmacotherapy. Arch Behav Psychiatry 35:477-480, 1978. 23. Committee on Research: Pharmacotherapy and Psychotherapy: Paradoxes, Problems and P;ogress. New York, Group for the Advancement of Psychiatry, 1975. 24. Goldman D: Clinical contrasts in psychopharmacology: Difference between drugs and groups of drugs, possible theoretical implications, in Rinkel M (ed): Biological Treatment 01 Mental Illness. New York, IC Page and Co, 1966, pp 523-535

opening the way to further evolution in a more gradual and eventually more effective, if roundabout, fashion. 24 Thus, in the treatment of major or minor psychiatric difficulties, it may be true that a little, judiciously applied, may benefit

The hard-pressed physician is tempted to think in terms ofa quick answer: target symptom, drug, cure.

REFERENCES 1. Gardos G, Cole JO: Maintenance antipsychotic therapy: For whom and how long?, in Lipton MA, DiMascio A, Killam KF (eds): Psychopharmacology: A Generation of Progress. New York, Raven Press, 1978, pp 11691178. 2. Sarwer-Foner GJ, Ogle W: Psychosis and enhanced anxiety produced by reserpine and chlorpromazine. Can Med Assoc J 74:526, 1956. 3. Sarwer-Foner GJ: Recognition and management of drug-induced extrapyramidal reactions and "paradoxical" behavioural reactions in psychiatry. Can Med Assoc J 83:312318,1960. 4. Bucci L: Fluphenazine hydrochloride in small doses. Psychosomatics 9(6):344-345, 1968. 5. Lambert PA, Midenet MG, Bouchardy M: Probh~mes poses par I'utilisation de faibles doses de neuroleptiques (Thioproperazine) dans les etats psychotiques, in CompteRendu, Congres de Psychiatrie el Neurologie de Langue Francaise. Paris, Masson et Cie, Editeurs, 1965, pp 721-725. 6. Schnetzler JP, Naveau C: Traitements d'entretien par 1'0enanthate de flupMnazine, associe a la Thioridazine et aux thymo-analeptiques. Utilisation des faibles doses, in Annales medico-psycho/ogiques, t. 1, 12ge annee, no 5: 800-805, Paris. 7. Denber HC: High vs low dose doxepin in depressed patients: A controlled study, in Mendels J (ed): Sinequan (doxepin HCI). Amsterdam, Excerpta Medica, 1975, pp 5964. 8. Okasha A, Ghaleb MH, Sadek A: A double

JUNE 1979 • VOL 20 • NO 6

I

«

1