Drugs 11: 209-220 (1976) © ADIS Press 1976
Psychotherapeutic Drugs: How to Minimise Complications of Therapy G.D. Burrows Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Melbourne
The introduction of new psychotherapeutic drugs over the last two decades has dramatically changed psychiatric practice. Although the aetiology of many psychiatric disorders is still unclear, the biochemical basis of an increasing number, such as the affective illnesses of depression and mania, are more advanced. Consequently, there is a growing emphasis on biological psychiatry. That the number of hospital beds occupied by psychiatric patients has declined is in large part due to the availability of these drugs. Community management has been more easily attained. Such drugs, however, have not yet supplied the solutions to many other psychiatric problems. Further developments and research are necessary. 1. Nomenclature of Psychotherapeutic Drugs
There are many (and often confusing) classifications of psychotherapeutic agents. Recent systems of nomenclature have been based on the clinical uses of these various drugs. For practical clinical purposes psychotherapeutic drugs are classified generally into four categories: antipsychotic
(major tranquillisers). antimanic, antianxiety (minor tranquillisers) and antidepressant. Such a classification has defects as under certain circumstances each drug type may be used for other purposes. Indications for the use of these categories of drug are summarised in table I.
2. General Considerations
In attempting to minimise side-effects, a reliable guide in selecting a drug is the patient's previous response. A full drug history must include detailed information on daily dosage, clinical efficacy, side-effects, patient acceptance and the individual's reliability in taking medication as prescribed. Other factors include issues such as toxicity, the need for additional medication, age of the patient and the relative potency of the drugs. The clinical state of the patient may affect his sensitivity to a drug. As the illness changes, so may the response to medication. Regular review of dosage is needed. Drug combinations should be avoided wherever possible.
210
Psychotherapeutic Drugs
Table I. Diagnostic categories vs drugs Antipsychotic drugs Schizophrenia Delirium Chronic brain syndrome (over-activity and delusions) Severe panic reactions Severe paranoid reactions Anxiety (small doses) Agitation (small doses)
2 Antimanic drugs Mania Lithium carbonate (Lithicarb) 1200-1800rng/day Haloperidol and chlorpromazine (as above)
3 Antianxiety drugs Transient anxiety reactions Transient grief reactions Moderate panic reactions
4 Antidepressant drugs Primary depressive illness Reactive - situational depression Anxiety states (depressive mechanisms) Personality disorders (depressive mechanisms) 'Masked depression' (neurotic; psychophysiologic)
atric patients to take overdoses of their prescribed drugs. The general considerations in the use of psychotherapeutic drugs and how to minimise side-effects are summarised in table II.
3. Antipsychotic Drugs
Many of the following statements on the use of antipsychotic drugs also apply to antidepressant and antianxiety drugs, although generally, prescribing practices with these drugs have not been studied as adequately as with the antipsychotic drugs. The phenothiazine derivatives are the longest known and most prescribed. The butyrophenone (e.g. haloperidol) and the thioxanthene (e.g. thiothixene) derivatives were later developments and others such as the diphenylbutylpiperidines (e.g.
Table II. General considerations in the use of psychotherapeutic drugs: How to minimise side-effects Accurate diagnosis
Psychotherapeutic drugs are generally more effective in the treatment of 'psychotic disorders' than in 'neurotic illness'. The gravity of an illness for which a drug has shown efficacy must be balanced against its possible dangers and undesirable side-effects. In general, psychotherapeutic drugs are effective, complications are few, they may be used with relative ease and their effects are usually reversible. When long-term administration of these drugs is required after a period of time, reluctance to continue with medication may be in direct relationship to the unpleasantness of side-effects. Hence it is essential to minimise the less serious but unpleasant phenomena as well as to guard against toxic effects. Special care should be taken in the elderly, the brain damaged, the patient with abnormal 'sensitivity' or with drug combinations. A further hazard is the propensity of many psychi-
2
Selection of appropriate drug: details required: a) Age of patient b) Clinical state of patient c) Additional medication required d) Patient's previous response e) Clinical efficacy of drug f) Side-effects of drug g) Toxicity of drug h) Patient acceptance j) Individual's reliability in taking medication
3
Special care with children; elderly; brain damaged; and patients with abnormal sensitivity
4
Regular review of dosage effective dose
5
Avoid drug combinations and polypharmacy
6
Regular review of need for medication
7
Know the hazards of long-term therapy
maintenance at lowest
211
Psychotherapeutic Drugs
pimozide), dibenzoxazepines (e.g. loxapine) and indolics (e.g. molindone) more recent still. All antipsychotic drugs share two basic actions: the amelioration of schizophrenia and the production of extrapyramidal syndromes. Many attempts to relate the potency of drugs in producing extrapyramidal effects to ultimate therapeutic outcome have not been rewarding (Hollister et aI., 1972, 1974). A healthy scepticism should be maintained towards claims that one phenothiazine is more effective than another. Large scale studies have failed to identify patient sub-groups or target symptoms that respond differentially to these drugs. The usual rule is to master one of each of the three types of phenothiazines, one thioxanthene and a butyrophenone (table III). Failure to respond to one drug does not necessarily mean the individual patient will fail to respond to others. 3.1 Side-Effects of Antipsychotic Drugs Most side-effects are an extension of known pharmacological actions (table IV). Because of differences in potency of individual compounds, the patient who develops side-effects at low doses of one compound may tolerate quite high doses of another. Allergic or toxic manifestations may however, occur. The cholestatic jaundice initially seen with chlorpromazine, is now rare and thought to be due originally to impurities. Agranulocytosis is due to the direct toxic effect of phenothiazines on myeloid elements in bone marrow. Both jaundice and agranulocytosis occur within the first few weeks of therapy and are manifested by fever. Daily temperature recording may detect these complications. In view of the danger of pigmentary retinopathy the dosage of thioridazine should not exceed 800mg daily. The extrapyramidal reactions include akinesia, dyskinesia, akathisia, tasoonesia, oculogyric crises, blepharospasm and Parkinsonism.
Table III. Doses of psychotherapeutic drugs Generic name
Average adult dosage range (mg/day)
Antipsychotic drugs Phenothiazines - aliphatics Chlorpromazine Promazine Phenothiazines - piperidines Thioridazine Phenothiazines - piperazines Pericyazine Trifluoperazine Prochlorperazine Perphenazine F Iuphenaz ine Butyrophenones Haloperidol Thioxanthenes Chlorprothixene Thiothixene 2 Antianxiety drugs Meprobamate Chlordiazepoxide Diazepam Oxazepam Lorazepam Clorazepate 3
100 to 200 150 to 800 75 to 800 10 to 60 10 to 60 30 to 150 12 to 64 5 to 50 6to 30 75 to 600 10 to 60
200 10 6 30 2 15
to 1200 to 100 to 40 to 120 to 15 to 60
Tricyclic antidepressant drugs Imipramine DeSipramine Trimipramine Amitriptyline Nortriptyline Protriptyline Dibenzepin Chlormipramine Opipramol Doxepin
75 to 75 to 75 to 75 to 75 to 15 to 120 to 75 to 50 to 75 to
300 300 300 300 300 60 400 100 300 300
4 Monoamine oxidase inhibitor antidepressants Hydrazine derivatives lsocarboxazid Phenelzine Non-hydrazine derivatives Tranylcypromine
30 to 90 45 to 90
10 to 30
Psychotherapeutic Drugs
3.2 Polypharmacy with Antipsychotic Drugs Unfortunately, patients often receive multiple antipsychotic drug regimens. There is no conclusive evidence that psychotherapeutic drug combinations are any more effective than properly selected single drugs. Many surveys show that adverse drug reactions are related to the number of drugs the patient is receiving (Ayd, 1975). Errors in taking medication also increase with the number of drugs prescribed. Patients suffering from schizophrenia are frequently unreliable in following drug prescriptions and polypharmacy adds to their problems. It is also difficult when taking many drugs to adjust drug dosage when toxicity occurs. In treating acutely disturbed patients, dosage should be increased until maximum clinical improvement or unacceptable side-effects occur. Under-dosage should be avoided as low doses may prolong the course of treatment and risk exacerbations of the illness. With less disturbed patients, dosage increments are more gradual, with 3 to 4 days between changes. A short-acting parenteral preparation is the most reliable form for adjusting dosage. It is more rapid in action and about 3 to 4 times more potent than oral medication. It is useful for short-term control of acute symptomatology. It is not desirable for prolonged periods because of irritation at the injection site, expense and inconvenience. Sustained release drugs are of questionable value because of their expense and erratic absorption.
3.3 Dosage of Antipsychotic Drugs After the acute symptomatology subsides, dosage should be stabilised at the lowest levels for retaining therapeutic gains. Too low a dose may precipitate a relapse while too high a dose may establish a pattern of over-medication that may unnecessarily continue for many years. Patients whose clinical condition has stabilised may have
212
Table IV. Side-effects of antipsychotic drugs
Side-effect
Action/notes
Serious side-effects (rare)
a) Agranulocytosis
b) Progressive jaundice
c) Extrapyramidal crisis (profuse perspiration, dyspnoea, fever, tachycardia, cyanosis, convulsions)
2 Common side-effects a) Autonomic nervous system Blurred vision Flushing, pallor Dry mouth
Hyperhydrosis 7 Narrow angle glaucoma aggravated Paralytic ileus Constipation Nasal congestion Postural hypotension Inhibition of ejaculation
Cease medication. Isolate from sources of infection Antibiotics. Hospitalisation Cease medication. Change to another phenothiazine (as cross sensitivity is rare) Bedrest and diet Routine WBC and liver function tests may help. Advise patients to report sore throats, fever, severe itching, increased bruising or bleeding tendency Cease medication
Reassurance, usually diminishes in few weeks Rinse mouth frequently Suck an object or sweet Neostigmine 7 .5-15mg orally Decrease dose if possible cholinergic drugs Tonometry Consultation with eye specialist Local cholinergic drug Cease medication Hospitalisation Exercise, fluids, mild laxative Nasal decongestant drops Advise to get up slowly Try a less antiadrenergic drug
213
Psychotherapeutic Drugs
Table I V. (continued)
Side-effect b) Cardiovascular effects Peripheral oedema Thrombosis Bradycardia Tachycardia Hypotensive crisis c) Endocrine effects Abnormal lactation, menstruation and sex drive Weight gain Oedema d) CNS effects Parkinsonism Dyskinesia Dystonia Occulogyric crisis Convulsions
Action/notes
Weight benefit vs severity Cease medication Decrease dose if possible
Reassurance. Substitute another group of drugs
Diet Reassurance or diuretic if necessary
Antiparkinsonian drug (e.g. benztropine mesylate 1-Smg) Cease drug, or change to another drug Cease drug or lower dosage
their dosage reduced by 25% every 2 or 3 months if no signs of relapse occur. Many patients suffering from schizophrenia need to continue maintenance medication for many years or 'indefmitely'. 3.4 Long-Term Hazards of Antipsychotic Drugs The hazards of long-term medication should always be considered. These include tardive dyskinesia, a late appearing extrapyramidal syndrome characterised mainly by bucco-faciomandibular and bucco-lingual movements. There are stereotyped involuntary movements of the tongue, jaw and lips. They may be accompanied by choreiform movements of the limbs or trunk. Tardive dyskinesia is resistant to treatment and may persist for years. Recently, some success has
been obtained in amelioration of tardive dyskinesia with the drug deanol which acts by increasing cholinergic transmission. Most cases of tardive dyskinesia reported have received moderate to high doses of antipsychotic drugs for extended periods. For this reason caution should be given to the use of only minimum medication for long treatment periods. Long-term therapy may lead to skin pigmentation and opaque deposits in the comea, lens and retina. Electrocardiographic abnormalities and sudden death, even in young apparently healthy adults, have been reported with these drugs. Toxic cardiomyopathy or asphyxia during convulsive seizures have been given as a reason for these ECG changes. Long-term medication may also contribute to institutionalism by reducing drive and initiative in chronic patients. The clinician may come to rely on those drugs and exclude necessary psychosocial and rehabilitative therapies. Some researchers advocate that for the majority of patients on stabilised maintenance doses, withdrawal of antipsychotic drugs for a day or so weekly is feasible and beneficial (Prien and Caffey, 1974). The practice of prescribing these compounds in multiple doses is questionable. Drug treatment for long-term periods should be based on daily or twice daily administration. Drugs with sedativehypnotic activity should be prescribed mainly in the evening, whilst drugs with stimulating properties, in the morning. The advantages of only once or twice daily schedules include time saving in administration by staff, less expense, and with outpatients, more convenience and less chance of medication error. 3.5 Use of Antiparkinsonian Drugs Antiparkinsonian drugs should not be used routinely for prophylaxis and should be administered only to control emergent extrapyramidal symptoms. After 3 months, usage of these drugs
214
Psychotherapeutic Drugs
should be reviewed. Only a minority of patients on antipsychotic medication require antiparkinsonian drugs for a prolonged period. Antiparkinsonian drugs are potent anticholinergics with their own side-effects of lethargy, dizziness, blurred vision, gastro-intestinal disturbance and may even present as a confusional state or schizophrenic-like illness. 3.6 Long-Acting Antipsychotic Preparations The newer longer-acting parenteral antipsychotic drugs have permitted greater control of long-term medication. Their disadvantages include the patient's objection to an injection, the need for a regular 4- to 6-weekly attendance at a clinic and the high incidence of extrapyramidal symptoms. They are capable of causing minor autonomic side-effects, including frequent hypotensive episodes and sporadic dermatological disorders. Disturbances of menstruation including amenorrhoea have been reported (Ayd, 1975). Recent studies (Chien and Cole, 1973) confirm that antiparkinsonian drugs given initially with these longacting compounds do not provide a prophylaxis for extrapyramidal reactions. Antiparkinsonian drugs should only be prescribed to treat emergent extrapyramidal symptoms. All these drugs may produce an affective reaction with early morning waking and retardation, self-reproachfulness and depressed mood. It most often occurs in the first week after injection and diminishes as the extrapyramidal reaction wanes. Extensive clinical experience involving over a hundred different drugs indicates that there is little reason to fear adverse interactions with the long-acting fluphenazine esters. Serious adverse reactions to depot fluphenazines are less frequent than found with the more potent oral neuroleptics (Ayd, 1975). This safety is in part attributable to the fact that the injectable dose is only a fraction of the oral dose of the same drug.
4. Antimanic Drugs
Mania may be effectively managed with drugs such as chlorpromazine, haloperidol and lithium. Acute mania is controlled more quickly with chlorpromazine. Lithium carbonate is effective as a maintenance therapy in patients who have relatively frequent exacerbations. Lithium serum levels must be measured weekly initially until control is obtained and then regularly at 1 to 3 month intervals. Precision in dosage is extremely important as serious tOxicity occurs just above the therapeutic range of 0.8 to l.2mEq/litre. lithium clinics offer the best form of management (Jarrett et al., 1973). A full physical examination including careful examination of the thyroid is mandatory before commencement of lithium therapy. A total and differential leucocyte count, haemoglobin, liver, thyroid and renal function test should be included. Common side-effects of lithium therapy include nausea, vomiting, diarrhoea, abdominal pain, muscle weakness, polydypsia, polyuria and a fine tremor. If the tremor is severe a /3-adrenoreceptor blocking drug or a benzodiazepine drug such as diazepam may be helpful. The gastro-intestinal symptoms are related to peak serum lithium levels and usually disappear after a few weeks of therapy. All symptoms may be diminished by taking the lithium in divided doses during the day. Lithium intoxication occurs at levels close to or above 2.0mEq/litre. These include drowsiness, slurred speech, muscle twitching, coarse tremors and may lead to coma, convulsions and death. The presence of renal and cardiovascular disease may increase the risk of toxicity by decreasing renal clearance of lithium or by alteration of plasma electrolytes. The ability to excrete lithium decreases with age. The elderly patient should initially receive lithium in low doses. Diffuse thyroid enlargement occurs following long-term therapy. Some patients become hypothyroid or develop myxoedema. If lithium is with·
Psychotherapeutic Drugs
drawn the thyroid function returns to normal. The addition of thyroxine usually makes withdrawal of lithium unnecessary. Thyroid function tests should be repeated at 6 to 12 month intervals. The polyuria and polydipsia of the nephrogenic diabetes insipidus syndrome due to lithium is effectively managed with a thiazide diuretic. The leucocytosis sometimes found is reversible and innocuous. Other side-effects of lithium include leg ulcers, headache, transient hyperglycemia, generalised pruritus with or without rash, swelling of ankles or wrists and a metallic taste. Regular monitoring of serum lithium is essential to minimise toxic side-effects. The more common milder side-effects may have to be tolerated by the patient, who previous to lithium therapy suffered from frequent exacerbations of an affective illness. 5. Antianxiety Drugs
There are many difficulties in evaluating the efficacy of antianxiety drugs. This group of drugs is of limited value in psychotic disorders, but is considered useful in many neurotic illnesses. The benzodiazepines like diazepam, oxazepam, chlordiazepoxide are the most popular drugs prescribed today. Meprobamate, small doses of antipsychotics, tricyclic antidepressants and antihistamine drugs may be useful in selected patients with anxiety. The barbiturates have been prescribed less over recent years because of the problems of dependency, the complications of withdrawal and the dangers of suicidal overdosage. The prolonged use of meprobamate has similar problems of dependency and withdrawal symptoms. Toxic effects are not common, but thrombocytopenia, leukopenia, aplastic anaemia and agranulocytosis have been reported for meprobamate. The benzodiazepines are the best drugs to use as they have been shown to be effective in the treatment of anxiety. They do not readily produce physical dependence and are less dangerous on
215
overdosage. These drugs are relatively less toxic than many other antianxiety agents. Most of these drugs have plasma half-lives of 10 to 30 hours so that once or twice daily medication is desirable. The major portion of dosage at night helps the insomnia of the anxious patient while some mild sedation is carried ove~ for the daytime effects required. 5.1 Side-Effects and Interactions of Benzodiazepines Ataxia, drowsiness, confusion, dysarthria, headache, lethargy, giddiness, inco-ordination, so mnambulance are frequent central nervous system effects of the benzodiazepine group of drugs. They are minimised if the initial dose is low and if it is gradually increased over 3 to 4 days. Doses and dosage should be tailored to the individual patient's needs, as there is a wide range of individual responsiveness to the benzodiazepines. A number of paradoxical reactions have been reported. These indicate acute excited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, convulsions, sleep disturbances and stimulation. These reactions are usually managed satisfactorily by cessation of the medication. The benzodiazepine drugs may be involved in a number of clinically important interactions with other drugs. Thus, the dose of a stable anticonvulsant regimen may require adjustment when diazepam is added. There is also mutual potentiation of alcohol, central nervous system depressants, sedatives, hypnotics, antipsychotic drugs and mutual potentiation of sedation with the tricyclic antidepressants. Patients should be advised to be careful on taking these drugs when operating dangerous machinery or when driving motor vehicles. The benzodiazepines may be transferred in significant quantities via the milk of the breast feedingmother.
216
Psychotherapeutic Drugs
5.2 Selection of a Benzodiazepine There is no convincing evidence that anyone of the benzodiazepines is therapeutically more effective than another, but clinical experience shows that individual patients sometimes prefer one particular drug to another.
the types of antidepressants available. The ideal antidepressant is not yet available. In broad terms there are four groups of antidepressant drug: (1) the psychomotor stimulants; (2) the monoamine oxidase inhibitors (MAOI); (3) tricyclic antidepressant compounds; and (4) a relatively recent drug used for the treatment of depression, lithium carbonate.
5.3 Multiple Therapy Few experts recommend any drug as the sole therapy for the management of anxiety. The medical practitioner who has good interaction with the patient who wants to get well, can include drugs with which he feels at ease as adjunctive therapy. It is vital to remember, and a help to the patient, to realise that no drug in itself will solve all the problems with cause anxiety.
6. Antidepressant Drugs
Depression may be the most common psychiatric disorder which clinicians treat. It is one of the few that may be lethal. The clinical manifestations of depression may take the form of several syndromes, possibly differing in their aetiology. So-called 'endogenous depressions' are the most severe and probably have a genetic biochemical basis. These depressions, fortunately respond to tricyclic antidepressant drugs, particularly in the middle-aged and elderly. Some types of depressive illness may either require no specific drug treatment or may be better managed with other drugs, such as antianxiety drugs or small doses of phenothiazines. Concurrent psychotherapy in all cases is essential. In very severe depression electroconvulsive therapy is still the optimum treatment. Although a limited number of drugs are termed 'antidepressant', the wise doctor would treat his patient best by not limiting himself to only one of
6.1 Tricyclic Antidepressants It is generally believed that tricyclic antidepressants are effective in about 75% of cases of depressive illness. There are no clear-cut differences between the members of the tricyclic antidepressant group as regards potency, speed of action and consistency of effect. There is little evidence that these drugs have any difference in their onset of action. Early improvement may be noted not infrequently at the end of the first week, but may become evident after 3 to 6 weeks. Amitriptyline, trimipramine, nortriptyline and doxepin have sedative effects which are useful in agitated depression. Imipramine and desipramine have a less comparable sedative component. There is good evidence that responses to therapy are, in part, genetically deterinined, and evidence of response in previous depressive illness, or in relatives, may help in the choice between the tricyclics and the monoamine oxidase inhibitors. The most useful therapeutic dosage is 150mg of the tricyclic drug per day. In some outpatients, it may be advisable to begin with a lower dose but to rapidly increase to the maximum dose within a week or fwo at the most, as the patient's tolerance will permit. If adequate use of a tricyclic has failed to relieve the depression, it is unlikely that another of the same group will prove effective. Change to a monoamine oxidase inhibitor may be tried; more commonly ECT will need serious consideration. If the depression is severe and social conditions unfavourable, and where suicide is a possibility, early specialist referral is indicated.
Psychotherapeutic Drugs
217
6.1.1 Side-Effects and Toxic Reactions of Tricyclic Antidepressants The spectrum of actions of the tricyclic antidepressants include an effect of noradrenaline by blocking uptake and blocking a-adrenoreceptors. They have a guanethidine-like action at the higher dosage levels. They also have an effect on 5hydroxytryptamine, histamine and acetylcholine. Many of the side-effects of the tricyclic antidepressants are extensions of their pharmacodynamic actions. The most common symptoms are dryness of the mouth, sweating, faintness, giddiness, and a fine tremor of the hand. The dry mouth or blurred vision produced by the peripheral anticholinergiC actions of tricyclics may be managed simply by sucking a sweet or chewing gum for a dry mouth, or using a magnifying lens for blurred vision. Patients should be told about the possible sideeffects at the onset of prescribing tricyclic drugs and should in fact expect them to occur, and not to become too concerned. This may be one reason why patients treated by psychiatrists appear to tolerate much higher doses of the drug than many general practitioners report that their patients do. Atropine-like symptoms are often of minor importance but they may be sufficiently marked to require withdrawal of the drug. Other effects include difficulty in initiating micturition, delayed ejaculation and impotence, and constipation. Paralytic ileus may develop and requires hospitalisation. Acute brain syndromes or toxic delirium will occur in the occasional patient, particularly when very high dosages are used. Agranulocytosis and obstructive jaundice have been reported but are certainly rare.
Il"eventing their uptake. Non-specific T-wave changes are seen in many patients. Doses of the tricyclics in excess of Ig are seriously toxic, with fatalities in adults fairly common after ingestion of 2g or more. There are conflicting reports on the differences between the various tricyclics and their supposedly more toxic or less toxic effects. A decreasing level of consciousness leading to coma is common. This may be initially preceded by agitation or delirium. Cardio-respiratory depression with hypotension is frequent and pupils are dilated and sluggish. Hyperthermia may occur. Myoclonic seizures, twitches, increased tendon reflexes, and plantar extensor responses may occur. There are a number of disturbances of cardiac rhythm and conduction. These include ventricular flutter, tachycardia, artial fibrillation or tachycardia, and varying degrees of atrio-ventricular or intra-ventricular block. These cardiac problems are uniquely difficult to manage. Many treatments have been advocated, including anticholinesterases, especially physostigmine; sodium bicarbonate; sodium lactate and mannitol. There is little evidence that the tricyclics are dialysable, as they are highly bound to plasma proteins. Some authorities advocate forced diuresis. Activated charcoal may be helpful as an absorbent. f3-Adrenoreceptor blocking drugs may be helpful in managing cardiac arrhythmias of tricyclic overdoses. Use of procainamide and quinidine, which have a similar action to tricyclic drugs in prolonging distal intracardiac conduction, should be avoided. This important area has recently been reviewed (Vohra and Burrows, 1974), as there is an increase in the number of tricyclic overdoses.
6.1.2 Toxic Doses of Tricyclic Antidepressants Cardiac abnormalities and cardiovascular complications, including postural hypotension, disturbances of cardiac rhythm and conduction, are frequent complications of overdoses of tricyclic antidepressants. It is thought that these drugs deplete the myocardium of catecholamines by
6.1.3 Use of Tricyclic Antidepressants in Patients with Heart Disease The tricyclic drugs prolong intracardiac conduction. It is possible that the reported increase in sudden deaths in cardiac patients receiving therapeutic doses of these drugs could be related to this drug-induced prolongation of distal conduction
Psychotherapeutic Drugs
time. There is enough evidence to make psychiatrists cautious in treating depressed patients with heart disease with tricyclic antidepressant drugs. For the moderately depressed patient with persistent symptoms, the benefits of antidepressant response should not be withheld, since the risks are small. A cardiological assessment should be made, starting with a clinical history and followed by a physical examination and an ECG. Patients with heart failure and/or angina may be made worse because of the increase in heart rate produced by tricyclic drugs. Certainly, cardiac failure should be treated before tricyclic drugs are used. If the ECG is abnormal and shows evidence of bundle branch block, special consideration should be given before starting tricyclic drugs since they can, though rarely, lead to a complete heart block and cardiac syncope. In these patients, the use of doxepin may be preferable (Vohra et aI., 1975). Dosage should be increased gradually and the patients seen at regular intervals. There is an association between high plasma nortriptyline levels and impairment of distal conduction (Burrows et aI., 1975). The same may apply with amitriptyline and imipramine. Measurement of plasma levels of tricyclic drugs may be helpful, as nortriptyline levels above 20Ong/ml are associated with cardiac disturbances. Because of the wide variation in plasma levels produced by the same oral dose of tricyclic drugs in different individuals, plasma levels equivalent to 200ng/ml nortriptyline may be reached, even with oral doses as low as 100mg/day. In this respect, phenothiazines should be used with caution in association with tricyclic drugs, since they can increase the plasma levels of the tricyclic drug (Gram et aI., 1972).
6.2 Monoamine Oxidase Inhibitor (MAOI) Drugs Although the monoamine oxidase inhibitor group of drugs have been used in psychiatry for
218
about 20 years there is still continuing dispute over their use (Tyler, 1973). This is in large part due to concern for their potential dangers of hypertensive crises and hyperthermia. Tyraminecontaining foods, particularly matured cheeses, Chianti and Alicante-type red wines, yeast and beef extracts are a problem. Interactions with sympathomimetic amines, tricyclic antidepressant drugs, and pethidine can also prove dangerous. A II patients should be warned carefully about dietary and drug restrictions with MAOI's and should carry a printed card giving details of these. Continual clinical use has established that the MAOI's do have a limited but important place in certain neurotic conditions, but their use should be rep stricted to specialist prescribing.
6.3 MAOI and Tricyclic Interactions with Other Drugs There are a number of clinical problems due to the concomitant prescribing of antidepressants with other drugs. An important one is the interaction of the monoamine oxidase inhibitors with amine drugs (e.g. anorexiants, nasal decongestants and common cold remedies) and tyramine-rich foods (see above). The clinical picture is one of acute adrenergic crisis, due to an increased amount of circulating noradrenaline. Central nervous system signs include headache, stiff neck, nausea and vomiting, subarachnoid haemorrhage, hyperpyrexia and convulsions which may be fatal. Cardiovascular effects include tachycardia, marked hypertension and sometimes acute pulmonary oedema. The treatment of this reaction is phentolamine Smg intravenously, or chlorpromazine intramuscularly. Pharmacologists have shown that sometimes one drug affects the absorption, distribution, metabolism or excretion of another drug. These pharmacokinetic interactions have become of potential importance over recent years as patients
219
Psychotherapeutic Drugs
are often prescribed more than one drug at the same time. In a small number of patients studied, a number of drugs have been shown to alter plasma levels of tricyclic antidepressants (table V). The clinical importance of these findings is not yet clear.
6.4 Management Therapy
of Antidepressant
Drug
Patients receiving treatment with antidepressants should be seen weekly initially, until the sustained clinical improvement occurs. They should be advised of side-effects which are expected if therapy is to be adequate. They should also be told of the dangers of driving motor vehicles and of concurrent alcohol consumption. If sleep is disturbed, a benzodiazepine such as nitrazepam, should be given as these drugs do not alter the plasma levels of tricyclics, in contrast to the barbituates, which lower levels. Tricyclics should be continued for a further 3 months once symptoms have eased. If symptoms recur the antidepressant should be started at the original dosage.
7. Problems of Psychotherapeutic Drugs in the Elderly The elderly patient should be treated cautiously because of a diminished ability to eliminate psychotherapeutic drugs. When prescribing a drug, its pharmacological action and pharmacokinetic properties should be known. Drug dosage should be correlated with patient response - aiming for the lowest effective dose. Only the minimum number of drugs to treat the primary cause, and not just symptoms, should be prescribed. A drug with side-effects worse than the illness should not be given, while no drug should be used for a longer period than necessary (Hall, 1973).
Table V. Effect of other drugs on 'steady-state' plasma nortriptyline levels
Lowers
No effect
Raises
Barbiturates
Diazepam, nitrazepam
Haloperidol Alcohol
Oral contraceptives
Oxazepam, lorazepam
Methylphenidate
Methaqualone
Chloral hydrate
Chlordiazepoxide
Fenfluramine
Lithium carbonate
Methaqualone +diphenhydramine
L-Tri-iodothyronine
Chloram· phenicol'
Glutethimide
Short-term Norethisterone Thioridazine
Perphen· azine' Aspirin'
Variable
Single dose studies
The extrapyramidal symptoms of the antipsychotic phenothiazine drugs can be particularly worrying and are resistant to therapy in the elderly patient. Phenothiazines may also interfere with blood pressure in normotensives producing hypotension and perhaps falls, fractures and confusion. In hypertenSive patients, chlorpromazine (like tricyclic antidepressants) may interfere with blood pressure control in those receiving adrenergic neurone blocking drugs such as guanethidine. The elderly patient should have a starting dose of about one half of that used for young adults and dosage increases should be gradual. In the elderly, lithium toxicity may occur easily, and particular care with sodium depleting diuretics must always be remembered. The benzodiazepines in elderly patients often increase any confusion present and lead to an increase in anxiety, while barbiturates frequently lead to dependence.
Psychotherapeutic Drugs
Tricyclic antidepressants have an increased risk of troublesome atropine-like side-effects with drugs such as the antihistamines and antiparkinsonian agents in the older patient. The tricyclic compounds should be used cautiously in the elderly patient with cardiovascular disease. Regular electrocardiographic monitoring is advisable for the treatment of the older depressed patient.
References Ayd, F.J.: The depot fluphenazines: A reappraisal after 10 years clinical experience. American Journal of Psychiatry 132: 491-500 (1975). Burrows, G.D.; Scoggins, B.A.; Turecek, L.R. and Davies, B.: Plasma nortriptyline and clinical response. Clinical Pharmacology and Therapeutics 16: 639 (1974). Chien, C. and Cole, J.~.: Depot phenothiazine treatment in acute psychosis: A sequential comparative clinical study. American Journal of Psychiatry 130: 13 (1973). Hollister, L.E.: The clinical use of psychotherapeutic drugs. Current Therapeutics/New Ethicals: Part I antidepressants, October 1972; part II antianxiety drugs
220
and special problems in the use of psychotherapeutic drugs, November 1972; part 1lI antipsychotic drugs, September 1973; part IV antimanic drugs, December 1973. Hollister, L.E.; Overall, I.E.; Kimbell, I. and Pokorny, A.: Specific indications for different classes of phenothiazines. Archives of General Psychiatry 30: 94 (1974). Jarrett, D.B.; Burrows, G.D. and Davies, B.: Lithium as a prophylactic agent in recurring affective disorders. Medical Journal of Australia 1: 325 (1973). Prien, R.F. and Caffey, E.M.: Guidelines for antipsychotic drug use. V.A. Central Neuropsychiatric Research Laboratory Research Report 95 (1974). Tyler, P.: Current status of monoamine oxidase inhibitors in psychiatry. British Journal of Hospital Medicine 6: 795 (1973). Vohra, 1. and Burrows, G.D.: Cardiovascular complications of tricyclic antidepressant overdosage. Drugs 8: 432 (1974). Vohra, J.; Hunt, D.; Burrows, G.D. and Sloman, G.: Intracardiac conduction defects following overdose of tricyclic antidepressant drugs. European Journal of Cardiology 2: 453 (1975).
Author's address: Dr Gralulm Burrows. Department of Psychiatry. Royal Melbourne Hospital, Victoria 3050 (Australia).
Psychotherapeutic Drugs: How to Minimise Complications of Therapy G.D. Burrows Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Melbourne
The introduction of new psychotherapeutic drugs over the last two decades has dramatically changed psychiatric practice. Although the aetiology of many psychiatric disorders is still unclear, the biochemical basis of an increasing number, such as the affective illnesses of depression and mania, are more advanced. Consequently, there is a growing emphasis on biological psychiatry. That the number of hospital beds occupied by psychiatric patients has declined is in large part due to the availability of these drugs. Community management has been more easily attained. Such drugs, however, have not yet supplied the solutions to many other psychiatric problems. Further developments and research are necessary. 1. Nomenclature of Psychotherapeutic Drugs
There are many (and often confusing) classifications of psychotherapeutic agents. Recent systems of nomenclature have been based on the clinical uses of these various drugs. For practical clinical purposes psychotherapeutic drugs are classified generally into four categories: antipsychotic
(major tranquillisers). antimanic, antianxiety (minor tranquillisers) and antidepressant. Such a classification has defects as under certain circumstances each drug type may be used for other purposes. Indications for the use of these categories of drug are summarised in table I.
2. General Considerations
In attempting to minimise side-effects, a reliable guide in selecting a drug is the patient's previous response. A full drug history must include detailed information on daily dosage, clinical efficacy, side-effects, patient acceptance and the individual's reliability in taking medication as prescribed. Other factors include issues such as toxicity, the need for additional medication, age of the patient and the relative potency of the drugs. The clinical state of the patient may affect his sensitivity to a drug. As the illness changes, so may the response to medication. Regular review of dosage is needed. Drug combinations should be avoided wherever possible.
210
Psychotherapeutic Drugs
Table I. Diagnostic categories vs drugs Antipsychotic drugs Schizophrenia Delirium Chronic brain syndrome (over-activity and delusions) Severe panic reactions Severe paranoid reactions Anxiety (small doses) Agitation (small doses)
2 Antimanic drugs Mania Lithium carbonate (Lithicarb) 1200-1800rng/day Haloperidol and chlorpromazine (as above)
3 Antianxiety drugs Transient anxiety reactions Transient grief reactions Moderate panic reactions
4 Antidepressant drugs Primary depressive illness Reactive - situational depression Anxiety states (depressive mechanisms) Personality disorders (depressive mechanisms) 'Masked depression' (neurotic; psychophysiologic)
atric patients to take overdoses of their prescribed drugs. The general considerations in the use of psychotherapeutic drugs and how to minimise side-effects are summarised in table II.
3. Antipsychotic Drugs
Many of the following statements on the use of antipsychotic drugs also apply to antidepressant and antianxiety drugs, although generally, prescribing practices with these drugs have not been studied as adequately as with the antipsychotic drugs. The phenothiazine derivatives are the longest known and most prescribed. The butyrophenone (e.g. haloperidol) and the thioxanthene (e.g. thiothixene) derivatives were later developments and others such as the diphenylbutylpiperidines (e.g.
Table II. General considerations in the use of psychotherapeutic drugs: How to minimise side-effects Accurate diagnosis
Psychotherapeutic drugs are generally more effective in the treatment of 'psychotic disorders' than in 'neurotic illness'. The gravity of an illness for which a drug has shown efficacy must be balanced against its possible dangers and undesirable side-effects. In general, psychotherapeutic drugs are effective, complications are few, they may be used with relative ease and their effects are usually reversible. When long-term administration of these drugs is required after a period of time, reluctance to continue with medication may be in direct relationship to the unpleasantness of side-effects. Hence it is essential to minimise the less serious but unpleasant phenomena as well as to guard against toxic effects. Special care should be taken in the elderly, the brain damaged, the patient with abnormal 'sensitivity' or with drug combinations. A further hazard is the propensity of many psychi-
2
Selection of appropriate drug: details required: a) Age of patient b) Clinical state of patient c) Additional medication required d) Patient's previous response e) Clinical efficacy of drug f) Side-effects of drug g) Toxicity of drug h) Patient acceptance j) Individual's reliability in taking medication
3
Special care with children; elderly; brain damaged; and patients with abnormal sensitivity
4
Regular review of dosage effective dose
5
Avoid drug combinations and polypharmacy
6
Regular review of need for medication
7
Know the hazards of long-term therapy
maintenance at lowest
211
Psychotherapeutic Drugs
pimozide), dibenzoxazepines (e.g. loxapine) and indolics (e.g. molindone) more recent still. All antipsychotic drugs share two basic actions: the amelioration of schizophrenia and the production of extrapyramidal syndromes. Many attempts to relate the potency of drugs in producing extrapyramidal effects to ultimate therapeutic outcome have not been rewarding (Hollister et aI., 1972, 1974). A healthy scepticism should be maintained towards claims that one phenothiazine is more effective than another. Large scale studies have failed to identify patient sub-groups or target symptoms that respond differentially to these drugs. The usual rule is to master one of each of the three types of phenothiazines, one thioxanthene and a butyrophenone (table III). Failure to respond to one drug does not necessarily mean the individual patient will fail to respond to others. 3.1 Side-Effects of Antipsychotic Drugs Most side-effects are an extension of known pharmacological actions (table IV). Because of differences in potency of individual compounds, the patient who develops side-effects at low doses of one compound may tolerate quite high doses of another. Allergic or toxic manifestations may however, occur. The cholestatic jaundice initially seen with chlorpromazine, is now rare and thought to be due originally to impurities. Agranulocytosis is due to the direct toxic effect of phenothiazines on myeloid elements in bone marrow. Both jaundice and agranulocytosis occur within the first few weeks of therapy and are manifested by fever. Daily temperature recording may detect these complications. In view of the danger of pigmentary retinopathy the dosage of thioridazine should not exceed 800mg daily. The extrapyramidal reactions include akinesia, dyskinesia, akathisia, tasoonesia, oculogyric crises, blepharospasm and Parkinsonism.
Table III. Doses of psychotherapeutic drugs Generic name
Average adult dosage range (mg/day)
Antipsychotic drugs Phenothiazines - aliphatics Chlorpromazine Promazine Phenothiazines - piperidines Thioridazine Phenothiazines - piperazines Pericyazine Trifluoperazine Prochlorperazine Perphenazine F Iuphenaz ine Butyrophenones Haloperidol Thioxanthenes Chlorprothixene Thiothixene 2 Antianxiety drugs Meprobamate Chlordiazepoxide Diazepam Oxazepam Lorazepam Clorazepate 3
100 to 200 150 to 800 75 to 800 10 to 60 10 to 60 30 to 150 12 to 64 5 to 50 6to 30 75 to 600 10 to 60
200 10 6 30 2 15
to 1200 to 100 to 40 to 120 to 15 to 60
Tricyclic antidepressant drugs Imipramine DeSipramine Trimipramine Amitriptyline Nortriptyline Protriptyline Dibenzepin Chlormipramine Opipramol Doxepin
75 to 75 to 75 to 75 to 75 to 15 to 120 to 75 to 50 to 75 to
300 300 300 300 300 60 400 100 300 300
4 Monoamine oxidase inhibitor antidepressants Hydrazine derivatives lsocarboxazid Phenelzine Non-hydrazine derivatives Tranylcypromine
30 to 90 45 to 90
10 to 30
Psychotherapeutic Drugs
3.2 Polypharmacy with Antipsychotic Drugs Unfortunately, patients often receive multiple antipsychotic drug regimens. There is no conclusive evidence that psychotherapeutic drug combinations are any more effective than properly selected single drugs. Many surveys show that adverse drug reactions are related to the number of drugs the patient is receiving (Ayd, 1975). Errors in taking medication also increase with the number of drugs prescribed. Patients suffering from schizophrenia are frequently unreliable in following drug prescriptions and polypharmacy adds to their problems. It is also difficult when taking many drugs to adjust drug dosage when toxicity occurs. In treating acutely disturbed patients, dosage should be increased until maximum clinical improvement or unacceptable side-effects occur. Under-dosage should be avoided as low doses may prolong the course of treatment and risk exacerbations of the illness. With less disturbed patients, dosage increments are more gradual, with 3 to 4 days between changes. A short-acting parenteral preparation is the most reliable form for adjusting dosage. It is more rapid in action and about 3 to 4 times more potent than oral medication. It is useful for short-term control of acute symptomatology. It is not desirable for prolonged periods because of irritation at the injection site, expense and inconvenience. Sustained release drugs are of questionable value because of their expense and erratic absorption.
3.3 Dosage of Antipsychotic Drugs After the acute symptomatology subsides, dosage should be stabilised at the lowest levels for retaining therapeutic gains. Too low a dose may precipitate a relapse while too high a dose may establish a pattern of over-medication that may unnecessarily continue for many years. Patients whose clinical condition has stabilised may have
212
Table IV. Side-effects of antipsychotic drugs
Side-effect
Action/notes
Serious side-effects (rare)
a) Agranulocytosis
b) Progressive jaundice
c) Extrapyramidal crisis (profuse perspiration, dyspnoea, fever, tachycardia, cyanosis, convulsions)
2 Common side-effects a) Autonomic nervous system Blurred vision Flushing, pallor Dry mouth
Hyperhydrosis 7 Narrow angle glaucoma aggravated Paralytic ileus Constipation Nasal congestion Postural hypotension Inhibition of ejaculation
Cease medication. Isolate from sources of infection Antibiotics. Hospitalisation Cease medication. Change to another phenothiazine (as cross sensitivity is rare) Bedrest and diet Routine WBC and liver function tests may help. Advise patients to report sore throats, fever, severe itching, increased bruising or bleeding tendency Cease medication
Reassurance, usually diminishes in few weeks Rinse mouth frequently Suck an object or sweet Neostigmine 7 .5-15mg orally Decrease dose if possible cholinergic drugs Tonometry Consultation with eye specialist Local cholinergic drug Cease medication Hospitalisation Exercise, fluids, mild laxative Nasal decongestant drops Advise to get up slowly Try a less antiadrenergic drug
213
Psychotherapeutic Drugs
Table I V. (continued)
Side-effect b) Cardiovascular effects Peripheral oedema Thrombosis Bradycardia Tachycardia Hypotensive crisis c) Endocrine effects Abnormal lactation, menstruation and sex drive Weight gain Oedema d) CNS effects Parkinsonism Dyskinesia Dystonia Occulogyric crisis Convulsions
Action/notes
Weight benefit vs severity Cease medication Decrease dose if possible
Reassurance. Substitute another group of drugs
Diet Reassurance or diuretic if necessary
Antiparkinsonian drug (e.g. benztropine mesylate 1-Smg) Cease drug, or change to another drug Cease drug or lower dosage
their dosage reduced by 25% every 2 or 3 months if no signs of relapse occur. Many patients suffering from schizophrenia need to continue maintenance medication for many years or 'indefmitely'. 3.4 Long-Term Hazards of Antipsychotic Drugs The hazards of long-term medication should always be considered. These include tardive dyskinesia, a late appearing extrapyramidal syndrome characterised mainly by bucco-faciomandibular and bucco-lingual movements. There are stereotyped involuntary movements of the tongue, jaw and lips. They may be accompanied by choreiform movements of the limbs or trunk. Tardive dyskinesia is resistant to treatment and may persist for years. Recently, some success has
been obtained in amelioration of tardive dyskinesia with the drug deanol which acts by increasing cholinergic transmission. Most cases of tardive dyskinesia reported have received moderate to high doses of antipsychotic drugs for extended periods. For this reason caution should be given to the use of only minimum medication for long treatment periods. Long-term therapy may lead to skin pigmentation and opaque deposits in the comea, lens and retina. Electrocardiographic abnormalities and sudden death, even in young apparently healthy adults, have been reported with these drugs. Toxic cardiomyopathy or asphyxia during convulsive seizures have been given as a reason for these ECG changes. Long-term medication may also contribute to institutionalism by reducing drive and initiative in chronic patients. The clinician may come to rely on those drugs and exclude necessary psychosocial and rehabilitative therapies. Some researchers advocate that for the majority of patients on stabilised maintenance doses, withdrawal of antipsychotic drugs for a day or so weekly is feasible and beneficial (Prien and Caffey, 1974). The practice of prescribing these compounds in multiple doses is questionable. Drug treatment for long-term periods should be based on daily or twice daily administration. Drugs with sedativehypnotic activity should be prescribed mainly in the evening, whilst drugs with stimulating properties, in the morning. The advantages of only once or twice daily schedules include time saving in administration by staff, less expense, and with outpatients, more convenience and less chance of medication error. 3.5 Use of Antiparkinsonian Drugs Antiparkinsonian drugs should not be used routinely for prophylaxis and should be administered only to control emergent extrapyramidal symptoms. After 3 months, usage of these drugs
214
Psychotherapeutic Drugs
should be reviewed. Only a minority of patients on antipsychotic medication require antiparkinsonian drugs for a prolonged period. Antiparkinsonian drugs are potent anticholinergics with their own side-effects of lethargy, dizziness, blurred vision, gastro-intestinal disturbance and may even present as a confusional state or schizophrenic-like illness. 3.6 Long-Acting Antipsychotic Preparations The newer longer-acting parenteral antipsychotic drugs have permitted greater control of long-term medication. Their disadvantages include the patient's objection to an injection, the need for a regular 4- to 6-weekly attendance at a clinic and the high incidence of extrapyramidal symptoms. They are capable of causing minor autonomic side-effects, including frequent hypotensive episodes and sporadic dermatological disorders. Disturbances of menstruation including amenorrhoea have been reported (Ayd, 1975). Recent studies (Chien and Cole, 1973) confirm that antiparkinsonian drugs given initially with these longacting compounds do not provide a prophylaxis for extrapyramidal reactions. Antiparkinsonian drugs should only be prescribed to treat emergent extrapyramidal symptoms. All these drugs may produce an affective reaction with early morning waking and retardation, self-reproachfulness and depressed mood. It most often occurs in the first week after injection and diminishes as the extrapyramidal reaction wanes. Extensive clinical experience involving over a hundred different drugs indicates that there is little reason to fear adverse interactions with the long-acting fluphenazine esters. Serious adverse reactions to depot fluphenazines are less frequent than found with the more potent oral neuroleptics (Ayd, 1975). This safety is in part attributable to the fact that the injectable dose is only a fraction of the oral dose of the same drug.
4. Antimanic Drugs
Mania may be effectively managed with drugs such as chlorpromazine, haloperidol and lithium. Acute mania is controlled more quickly with chlorpromazine. Lithium carbonate is effective as a maintenance therapy in patients who have relatively frequent exacerbations. Lithium serum levels must be measured weekly initially until control is obtained and then regularly at 1 to 3 month intervals. Precision in dosage is extremely important as serious tOxicity occurs just above the therapeutic range of 0.8 to l.2mEq/litre. lithium clinics offer the best form of management (Jarrett et al., 1973). A full physical examination including careful examination of the thyroid is mandatory before commencement of lithium therapy. A total and differential leucocyte count, haemoglobin, liver, thyroid and renal function test should be included. Common side-effects of lithium therapy include nausea, vomiting, diarrhoea, abdominal pain, muscle weakness, polydypsia, polyuria and a fine tremor. If the tremor is severe a /3-adrenoreceptor blocking drug or a benzodiazepine drug such as diazepam may be helpful. The gastro-intestinal symptoms are related to peak serum lithium levels and usually disappear after a few weeks of therapy. All symptoms may be diminished by taking the lithium in divided doses during the day. Lithium intoxication occurs at levels close to or above 2.0mEq/litre. These include drowsiness, slurred speech, muscle twitching, coarse tremors and may lead to coma, convulsions and death. The presence of renal and cardiovascular disease may increase the risk of toxicity by decreasing renal clearance of lithium or by alteration of plasma electrolytes. The ability to excrete lithium decreases with age. The elderly patient should initially receive lithium in low doses. Diffuse thyroid enlargement occurs following long-term therapy. Some patients become hypothyroid or develop myxoedema. If lithium is with·
Psychotherapeutic Drugs
drawn the thyroid function returns to normal. The addition of thyroxine usually makes withdrawal of lithium unnecessary. Thyroid function tests should be repeated at 6 to 12 month intervals. The polyuria and polydipsia of the nephrogenic diabetes insipidus syndrome due to lithium is effectively managed with a thiazide diuretic. The leucocytosis sometimes found is reversible and innocuous. Other side-effects of lithium include leg ulcers, headache, transient hyperglycemia, generalised pruritus with or without rash, swelling of ankles or wrists and a metallic taste. Regular monitoring of serum lithium is essential to minimise toxic side-effects. The more common milder side-effects may have to be tolerated by the patient, who previous to lithium therapy suffered from frequent exacerbations of an affective illness. 5. Antianxiety Drugs
There are many difficulties in evaluating the efficacy of antianxiety drugs. This group of drugs is of limited value in psychotic disorders, but is considered useful in many neurotic illnesses. The benzodiazepines like diazepam, oxazepam, chlordiazepoxide are the most popular drugs prescribed today. Meprobamate, small doses of antipsychotics, tricyclic antidepressants and antihistamine drugs may be useful in selected patients with anxiety. The barbiturates have been prescribed less over recent years because of the problems of dependency, the complications of withdrawal and the dangers of suicidal overdosage. The prolonged use of meprobamate has similar problems of dependency and withdrawal symptoms. Toxic effects are not common, but thrombocytopenia, leukopenia, aplastic anaemia and agranulocytosis have been reported for meprobamate. The benzodiazepines are the best drugs to use as they have been shown to be effective in the treatment of anxiety. They do not readily produce physical dependence and are less dangerous on
215
overdosage. These drugs are relatively less toxic than many other antianxiety agents. Most of these drugs have plasma half-lives of 10 to 30 hours so that once or twice daily medication is desirable. The major portion of dosage at night helps the insomnia of the anxious patient while some mild sedation is carried ove~ for the daytime effects required. 5.1 Side-Effects and Interactions of Benzodiazepines Ataxia, drowsiness, confusion, dysarthria, headache, lethargy, giddiness, inco-ordination, so mnambulance are frequent central nervous system effects of the benzodiazepine group of drugs. They are minimised if the initial dose is low and if it is gradually increased over 3 to 4 days. Doses and dosage should be tailored to the individual patient's needs, as there is a wide range of individual responsiveness to the benzodiazepines. A number of paradoxical reactions have been reported. These indicate acute excited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, convulsions, sleep disturbances and stimulation. These reactions are usually managed satisfactorily by cessation of the medication. The benzodiazepine drugs may be involved in a number of clinically important interactions with other drugs. Thus, the dose of a stable anticonvulsant regimen may require adjustment when diazepam is added. There is also mutual potentiation of alcohol, central nervous system depressants, sedatives, hypnotics, antipsychotic drugs and mutual potentiation of sedation with the tricyclic antidepressants. Patients should be advised to be careful on taking these drugs when operating dangerous machinery or when driving motor vehicles. The benzodiazepines may be transferred in significant quantities via the milk of the breast feedingmother.
216
Psychotherapeutic Drugs
5.2 Selection of a Benzodiazepine There is no convincing evidence that anyone of the benzodiazepines is therapeutically more effective than another, but clinical experience shows that individual patients sometimes prefer one particular drug to another.
the types of antidepressants available. The ideal antidepressant is not yet available. In broad terms there are four groups of antidepressant drug: (1) the psychomotor stimulants; (2) the monoamine oxidase inhibitors (MAOI); (3) tricyclic antidepressant compounds; and (4) a relatively recent drug used for the treatment of depression, lithium carbonate.
5.3 Multiple Therapy Few experts recommend any drug as the sole therapy for the management of anxiety. The medical practitioner who has good interaction with the patient who wants to get well, can include drugs with which he feels at ease as adjunctive therapy. It is vital to remember, and a help to the patient, to realise that no drug in itself will solve all the problems with cause anxiety.
6. Antidepressant Drugs
Depression may be the most common psychiatric disorder which clinicians treat. It is one of the few that may be lethal. The clinical manifestations of depression may take the form of several syndromes, possibly differing in their aetiology. So-called 'endogenous depressions' are the most severe and probably have a genetic biochemical basis. These depressions, fortunately respond to tricyclic antidepressant drugs, particularly in the middle-aged and elderly. Some types of depressive illness may either require no specific drug treatment or may be better managed with other drugs, such as antianxiety drugs or small doses of phenothiazines. Concurrent psychotherapy in all cases is essential. In very severe depression electroconvulsive therapy is still the optimum treatment. Although a limited number of drugs are termed 'antidepressant', the wise doctor would treat his patient best by not limiting himself to only one of
6.1 Tricyclic Antidepressants It is generally believed that tricyclic antidepressants are effective in about 75% of cases of depressive illness. There are no clear-cut differences between the members of the tricyclic antidepressant group as regards potency, speed of action and consistency of effect. There is little evidence that these drugs have any difference in their onset of action. Early improvement may be noted not infrequently at the end of the first week, but may become evident after 3 to 6 weeks. Amitriptyline, trimipramine, nortriptyline and doxepin have sedative effects which are useful in agitated depression. Imipramine and desipramine have a less comparable sedative component. There is good evidence that responses to therapy are, in part, genetically deterinined, and evidence of response in previous depressive illness, or in relatives, may help in the choice between the tricyclics and the monoamine oxidase inhibitors. The most useful therapeutic dosage is 150mg of the tricyclic drug per day. In some outpatients, it may be advisable to begin with a lower dose but to rapidly increase to the maximum dose within a week or fwo at the most, as the patient's tolerance will permit. If adequate use of a tricyclic has failed to relieve the depression, it is unlikely that another of the same group will prove effective. Change to a monoamine oxidase inhibitor may be tried; more commonly ECT will need serious consideration. If the depression is severe and social conditions unfavourable, and where suicide is a possibility, early specialist referral is indicated.
Psychotherapeutic Drugs
217
6.1.1 Side-Effects and Toxic Reactions of Tricyclic Antidepressants The spectrum of actions of the tricyclic antidepressants include an effect of noradrenaline by blocking uptake and blocking a-adrenoreceptors. They have a guanethidine-like action at the higher dosage levels. They also have an effect on 5hydroxytryptamine, histamine and acetylcholine. Many of the side-effects of the tricyclic antidepressants are extensions of their pharmacodynamic actions. The most common symptoms are dryness of the mouth, sweating, faintness, giddiness, and a fine tremor of the hand. The dry mouth or blurred vision produced by the peripheral anticholinergiC actions of tricyclics may be managed simply by sucking a sweet or chewing gum for a dry mouth, or using a magnifying lens for blurred vision. Patients should be told about the possible sideeffects at the onset of prescribing tricyclic drugs and should in fact expect them to occur, and not to become too concerned. This may be one reason why patients treated by psychiatrists appear to tolerate much higher doses of the drug than many general practitioners report that their patients do. Atropine-like symptoms are often of minor importance but they may be sufficiently marked to require withdrawal of the drug. Other effects include difficulty in initiating micturition, delayed ejaculation and impotence, and constipation. Paralytic ileus may develop and requires hospitalisation. Acute brain syndromes or toxic delirium will occur in the occasional patient, particularly when very high dosages are used. Agranulocytosis and obstructive jaundice have been reported but are certainly rare.
Il"eventing their uptake. Non-specific T-wave changes are seen in many patients. Doses of the tricyclics in excess of Ig are seriously toxic, with fatalities in adults fairly common after ingestion of 2g or more. There are conflicting reports on the differences between the various tricyclics and their supposedly more toxic or less toxic effects. A decreasing level of consciousness leading to coma is common. This may be initially preceded by agitation or delirium. Cardio-respiratory depression with hypotension is frequent and pupils are dilated and sluggish. Hyperthermia may occur. Myoclonic seizures, twitches, increased tendon reflexes, and plantar extensor responses may occur. There are a number of disturbances of cardiac rhythm and conduction. These include ventricular flutter, tachycardia, artial fibrillation or tachycardia, and varying degrees of atrio-ventricular or intra-ventricular block. These cardiac problems are uniquely difficult to manage. Many treatments have been advocated, including anticholinesterases, especially physostigmine; sodium bicarbonate; sodium lactate and mannitol. There is little evidence that the tricyclics are dialysable, as they are highly bound to plasma proteins. Some authorities advocate forced diuresis. Activated charcoal may be helpful as an absorbent. f3-Adrenoreceptor blocking drugs may be helpful in managing cardiac arrhythmias of tricyclic overdoses. Use of procainamide and quinidine, which have a similar action to tricyclic drugs in prolonging distal intracardiac conduction, should be avoided. This important area has recently been reviewed (Vohra and Burrows, 1974), as there is an increase in the number of tricyclic overdoses.
6.1.2 Toxic Doses of Tricyclic Antidepressants Cardiac abnormalities and cardiovascular complications, including postural hypotension, disturbances of cardiac rhythm and conduction, are frequent complications of overdoses of tricyclic antidepressants. It is thought that these drugs deplete the myocardium of catecholamines by
6.1.3 Use of Tricyclic Antidepressants in Patients with Heart Disease The tricyclic drugs prolong intracardiac conduction. It is possible that the reported increase in sudden deaths in cardiac patients receiving therapeutic doses of these drugs could be related to this drug-induced prolongation of distal conduction
Psychotherapeutic Drugs
time. There is enough evidence to make psychiatrists cautious in treating depressed patients with heart disease with tricyclic antidepressant drugs. For the moderately depressed patient with persistent symptoms, the benefits of antidepressant response should not be withheld, since the risks are small. A cardiological assessment should be made, starting with a clinical history and followed by a physical examination and an ECG. Patients with heart failure and/or angina may be made worse because of the increase in heart rate produced by tricyclic drugs. Certainly, cardiac failure should be treated before tricyclic drugs are used. If the ECG is abnormal and shows evidence of bundle branch block, special consideration should be given before starting tricyclic drugs since they can, though rarely, lead to a complete heart block and cardiac syncope. In these patients, the use of doxepin may be preferable (Vohra et aI., 1975). Dosage should be increased gradually and the patients seen at regular intervals. There is an association between high plasma nortriptyline levels and impairment of distal conduction (Burrows et aI., 1975). The same may apply with amitriptyline and imipramine. Measurement of plasma levels of tricyclic drugs may be helpful, as nortriptyline levels above 20Ong/ml are associated with cardiac disturbances. Because of the wide variation in plasma levels produced by the same oral dose of tricyclic drugs in different individuals, plasma levels equivalent to 200ng/ml nortriptyline may be reached, even with oral doses as low as 100mg/day. In this respect, phenothiazines should be used with caution in association with tricyclic drugs, since they can increase the plasma levels of the tricyclic drug (Gram et aI., 1972).
6.2 Monoamine Oxidase Inhibitor (MAOI) Drugs Although the monoamine oxidase inhibitor group of drugs have been used in psychiatry for
218
about 20 years there is still continuing dispute over their use (Tyler, 1973). This is in large part due to concern for their potential dangers of hypertensive crises and hyperthermia. Tyraminecontaining foods, particularly matured cheeses, Chianti and Alicante-type red wines, yeast and beef extracts are a problem. Interactions with sympathomimetic amines, tricyclic antidepressant drugs, and pethidine can also prove dangerous. A II patients should be warned carefully about dietary and drug restrictions with MAOI's and should carry a printed card giving details of these. Continual clinical use has established that the MAOI's do have a limited but important place in certain neurotic conditions, but their use should be rep stricted to specialist prescribing.
6.3 MAOI and Tricyclic Interactions with Other Drugs There are a number of clinical problems due to the concomitant prescribing of antidepressants with other drugs. An important one is the interaction of the monoamine oxidase inhibitors with amine drugs (e.g. anorexiants, nasal decongestants and common cold remedies) and tyramine-rich foods (see above). The clinical picture is one of acute adrenergic crisis, due to an increased amount of circulating noradrenaline. Central nervous system signs include headache, stiff neck, nausea and vomiting, subarachnoid haemorrhage, hyperpyrexia and convulsions which may be fatal. Cardiovascular effects include tachycardia, marked hypertension and sometimes acute pulmonary oedema. The treatment of this reaction is phentolamine Smg intravenously, or chlorpromazine intramuscularly. Pharmacologists have shown that sometimes one drug affects the absorption, distribution, metabolism or excretion of another drug. These pharmacokinetic interactions have become of potential importance over recent years as patients
219
Psychotherapeutic Drugs
are often prescribed more than one drug at the same time. In a small number of patients studied, a number of drugs have been shown to alter plasma levels of tricyclic antidepressants (table V). The clinical importance of these findings is not yet clear.
6.4 Management Therapy
of Antidepressant
Drug
Patients receiving treatment with antidepressants should be seen weekly initially, until the sustained clinical improvement occurs. They should be advised of side-effects which are expected if therapy is to be adequate. They should also be told of the dangers of driving motor vehicles and of concurrent alcohol consumption. If sleep is disturbed, a benzodiazepine such as nitrazepam, should be given as these drugs do not alter the plasma levels of tricyclics, in contrast to the barbituates, which lower levels. Tricyclics should be continued for a further 3 months once symptoms have eased. If symptoms recur the antidepressant should be started at the original dosage.
7. Problems of Psychotherapeutic Drugs in the Elderly The elderly patient should be treated cautiously because of a diminished ability to eliminate psychotherapeutic drugs. When prescribing a drug, its pharmacological action and pharmacokinetic properties should be known. Drug dosage should be correlated with patient response - aiming for the lowest effective dose. Only the minimum number of drugs to treat the primary cause, and not just symptoms, should be prescribed. A drug with side-effects worse than the illness should not be given, while no drug should be used for a longer period than necessary (Hall, 1973).
Table V. Effect of other drugs on 'steady-state' plasma nortriptyline levels
Lowers
No effect
Raises
Barbiturates
Diazepam, nitrazepam
Haloperidol Alcohol
Oral contraceptives
Oxazepam, lorazepam
Methylphenidate
Methaqualone
Chloral hydrate
Chlordiazepoxide
Fenfluramine
Lithium carbonate
Methaqualone +diphenhydramine
L-Tri-iodothyronine
Chloram· phenicol'
Glutethimide
Short-term Norethisterone Thioridazine
Perphen· azine' Aspirin'
Variable
Single dose studies
The extrapyramidal symptoms of the antipsychotic phenothiazine drugs can be particularly worrying and are resistant to therapy in the elderly patient. Phenothiazines may also interfere with blood pressure in normotensives producing hypotension and perhaps falls, fractures and confusion. In hypertenSive patients, chlorpromazine (like tricyclic antidepressants) may interfere with blood pressure control in those receiving adrenergic neurone blocking drugs such as guanethidine. The elderly patient should have a starting dose of about one half of that used for young adults and dosage increases should be gradual. In the elderly, lithium toxicity may occur easily, and particular care with sodium depleting diuretics must always be remembered. The benzodiazepines in elderly patients often increase any confusion present and lead to an increase in anxiety, while barbiturates frequently lead to dependence.
Psychotherapeutic Drugs
Tricyclic antidepressants have an increased risk of troublesome atropine-like side-effects with drugs such as the antihistamines and antiparkinsonian agents in the older patient. The tricyclic compounds should be used cautiously in the elderly patient with cardiovascular disease. Regular electrocardiographic monitoring is advisable for the treatment of the older depressed patient.
References Ayd, F.J.: The depot fluphenazines: A reappraisal after 10 years clinical experience. American Journal of Psychiatry 132: 491-500 (1975). Burrows, G.D.; Scoggins, B.A.; Turecek, L.R. and Davies, B.: Plasma nortriptyline and clinical response. Clinical Pharmacology and Therapeutics 16: 639 (1974). Chien, C. and Cole, J.~.: Depot phenothiazine treatment in acute psychosis: A sequential comparative clinical study. American Journal of Psychiatry 130: 13 (1973). Hollister, L.E.: The clinical use of psychotherapeutic drugs. Current Therapeutics/New Ethicals: Part I antidepressants, October 1972; part II antianxiety drugs
220
and special problems in the use of psychotherapeutic drugs, November 1972; part 1lI antipsychotic drugs, September 1973; part IV antimanic drugs, December 1973. Hollister, L.E.; Overall, I.E.; Kimbell, I. and Pokorny, A.: Specific indications for different classes of phenothiazines. Archives of General Psychiatry 30: 94 (1974). Jarrett, D.B.; Burrows, G.D. and Davies, B.: Lithium as a prophylactic agent in recurring affective disorders. Medical Journal of Australia 1: 325 (1973). Prien, R.F. and Caffey, E.M.: Guidelines for antipsychotic drug use. V.A. Central Neuropsychiatric Research Laboratory Research Report 95 (1974). Tyler, P.: Current status of monoamine oxidase inhibitors in psychiatry. British Journal of Hospital Medicine 6: 795 (1973). Vohra, 1. and Burrows, G.D.: Cardiovascular complications of tricyclic antidepressant overdosage. Drugs 8: 432 (1974). Vohra, J.; Hunt, D.; Burrows, G.D. and Sloman, G.: Intracardiac conduction defects following overdose of tricyclic antidepressant drugs. European Journal of Cardiology 2: 453 (1975).
Author's address: Dr Gralulm Burrows. Department of Psychiatry. Royal Melbourne Hospital, Victoria 3050 (Australia).
