TRANQUILLIZING AND THYMOLEPTIC DRUGS IN OUTPATIENT AND GENERAL PRACTICE BY r R. E. HEMPHILL, M.A., M.D., D.P.M. Lecturer in Mental Health, University of Bristol, Consultant Psychiatrist, Glenside-Barrow and United Bristol Hospitals AND J. E. BARBER, M.B., CH.B., D.(OBST.)R.C.O.G. * Clinical Research Assistant, Barrow Hospital. An account of these drugs was published in this Journal in 1962 (Hemphill, 1962). The present paper is a revision of the earlier survey, and includes a review of the newer drugs and recent developments. For clarity, sections of the original paper have been quoted completely or in part. The numerous preparations are divided for convenience into tranquillizers, anti- depressants and an intermediate group. This classification is clinical, and does not necessarily imply that the drugs in one group have a similar chemical structure or pharmacological action. The effect of these drugs in the human is complex, and is not necessarily the same in the sick as in the mentally well. Anxious persons and those with autonomic instability are particularly sensitive to some, and may develop side effects at a low dosage, in contrast to the usual tolerance of schizophrenics and other psychotics. Since tranquillizers and thymoleptics influence mood and emotion, it is to be expected that they will have an effect on other functions which involve the autonomic nervous system. Control of blood pressure, of intestinal and bladder muscle, and secretion of saliva and alimentary juices, for example, may be interfered with. Hypotension and dry mouth are common side effects, and therapeutic doses of some of the drugs can cause retention of urine and ileus. They should be used with greater care than the older sedatives, and should not be prescribed without a clear reason for the choice of drug and dose. The patient should be warned that prescribed instructions must be followed, that side effects may occur, and that certain foodstuffs, alcohol and other drugs may be forbidden while the tablets are being taken. Relief of symptoms such as agitation, anxiety and insomnia, as well as treatment of the underlying disorder, is particularly important in psychiatry, for this is what the patient will expect. He may be unable to apply himself to the problems of his illness as long as he is disturbed by symptoms, and as long as they are not controlled and are severe he is liable to turn to self-medication. To prescribe tranquillizers as placebos, as is sometimes done, is not justified, and if reassurance only is required, some harmless preparation like Glycero- phosphates or a mild sedative should be given. The doctor may mistake side effects such as giddiness, hypotension, sleepiness, dulling of initiative, Parkinsonian stiffness or slowing, and involuntary movements of the lips for symptoms of the illness, and increase the dose. This is a serious error, for these may be due to overdosage or idiosyncracy. If they persist when the dose is reduced the patient should be investigated in a psychiatric hospital. It should be noted that continuing or increasing loss of initiative and mental slowing are more likely to *Working under Research Grant from William R. Warner & Co. 6y 68 R. E. HEMPHILL and J. E. BARBER be due to overdosage than a worsening of the psychotic illness. The main principle of treatment should be to arrive at a dose which controls the illness but as far as possible does not produce mental inertia, unpleasant side effects, addiction or dependency, or extrapyramidal symptoms. It is wise from time to time to enquire if the patient is taking any other preparations such as an old prescription, or purchasing "tablets. We have seen many cases where the patient takes other tablets as well as what is pre- scribed, or even helps himself to a relative's prescription if it has been well spoken of in the family. "I have been taking some of mother's tablets" is a not uncommon remark. The dangers of cheese and other foodstuff, alcohol and amphetamine or dexedrine preparations will be mentioned later, but cannot be stressed too often. TRANQUILLIZERS Tranquillizers reduce mental agitation and turmoil, have a calming effect on restless- of ness, and in normal doses should not produce sleepiness like barbiturates. Some them inhibit the production of hallucinations and psychotic thought material from the unconscious, and in this way free the patient from the ensuing disturbances and dis- tractions. This group, of which the large majority, like Chlorpromazine, are pheno- thiazine derivatives, are indicated in the treatment of schizophrenia. Some tranquillizers slow down hyperactivity of thought in mania. Others, Librium and Valium for example, have a relaxing and calming effect, but little influence on abnormal thought processes and hallucinations. Stelazine seems to stimulate thought as well as to tranquillize. There is an intermediate group whose clinical indications are less clearly defined and whose use is more empirical than the other tranquillizers and thymoleptics. Thus drugs of the tranquillizer and intermediate groups may be given to control symptoms and/or to treat the underlying disorder. They are used to calm agitation, inhibit hallucinations and delusions, reduce hyperactivity in mania, secure relaxation, according to the diagnosis and according to the properties of the particular preparation used. ANTI-DEPRESSANTS Anti-depressants are used in the treatment of clinical depression, and not for the control of symptoms, nor to block hallucinations, nor to reduce manic activity, as are the tranquillizers. It has been found that up to 50 per. cent of cases of depression that otherwise would have required E.C.T. will improve within two weeks, and eventually recover when treated with anti-depressants alone. Although a few physicians hold Is that anti-depressants have no real value in the management of depression, this obviously untrue. The fact is that since they have been used in general practice, fewer cases of depression are referred for consultant treatment than five years ago. This has been the experience of psychiatrists in hospital and private practice wherever the drugs are widely used. Thymoleptics may be adjuvants to E.C.T. by reducing the number of electrical treatments required, and thereby the tendency to E.C.T. amnesia; and as maintenance therapy when E.C.T. has produced remission. Therapy with thymoleptics dates from the observation that Marsilid used in the treatment of tuberculosis often produced elevation of mood and relieved associated depression. It was thought that on theoretical grounds, inhibition of mono-amine- oxidase (an effect Marsilid had on the brain in laboratory conditions) might be physiological link in the process of the relief of depression. Some of the widely used thymoleptics belong to the group of mono-amine-oxidase (M.A.O.) inhibitors, although there is no proof that the theory is valid in the human. Marsilid is a powerfu1 TRANQUILLIZING AND THYMOLEPTIC DRUGS IN OUTPATIENT AND GENERAL PRACTICE 69 antidepressant, but most psychiatrists consider it too toxic for general use. M.A.O. inhibitors are possibly less effective in endogenous depression than other thymoleptics, and they are incompatible with some foodstuffs and drugs, but are believed to be useful in the treatment of neurotic forms of depression. The non-M.A.O. inhibitors, of which Imipramine and Amitriptyline are the most important, have some affinity with Amphetamine. As they are fairly quickly eliminated they may safely be followed by other anti-depressants. They should not be given less than two weeks after stopping an M.A.O. inhibitor because of the risk of cardiovascular disturbances due to summation of effect, as the latter are eliminated slowly. It should be stressed that only one anti-depressant preparation should be adminis- tered to a patient at any one time, and that the patient should be warned that it is dangerous to take any other tablets, and especially anti-depressants, which may have been left over from a previous course of treatment. Mixtures and Combinations Capsules and tablets containing mixtures of tranquillizers and anti-depressants in various strengths and combinations are marketed. Combinations of some have been advocated from time to time. In general, the use of mixtures is to be deprecated, as at the best the dose of one component is usually too small to be effective and a larger dose might be too dangerous. However, combinations containing Stelazine have their adherents, and Parstelin (Parnate + Stelazine) is undoubtedly more effective and more rapid in action than Parnate alone. The combination of Librium and Nardil is said to be more effective that Nardil alone where depression is accompanied by situational anxiety, but in our experience the addition of even a small dose of Librium to Tofranil can produce alarming postural hypotension. In general, however, with our present limited knowledge of the action and interaction of these drugs, most mixtures should be avoided. Reserpine Derivatives With the introduction of the more effective anti-psychotic drugs there is no longer a place for these in psychiatric treatment. Among their disadvantages there is the liability to produce severe depression which does not lift when the drug is discontinued, and is very resistant to any form of treatment. The trade and approved (pharmacological) names of the majority of preparations on the market, with comments on dosage, side effects and indications, are given in Table I. For convenience, the drugs that are commonly prescribed in the Bristol area head the lists. TABLE I Tranquillizers (P = Phenothiazines) Name Daily Dose Main Use Side Effects Cautions Largactil (M & B) 75-1200 mgm Psychotic Skin reactions Prolonged use can produce (Chlorpromazine) (single inj. agitation. (i) Photosensitivity dyskinesias, occasional P. 50-100 mgm) Schizophrenia. (ii) Allergy blood dyscrasias and (iii) Contact deep vein thrombosis. dermatitis Avoid in/with Parkinsonism (i) Hepatic dysfunction Hypotension (ii) Low leucocyte count Tachycardia (iii) Thiouracil drugs Polyuria (iv) Hypotensive drugs Liver damage.