Review Article Drugs 12: 362-373 (1976) © ADIS Press 1976

Antianxiety Drugs: Clinical Pharmacology and Therapeutic Use M. Lader Institute of Psychiatry, University of London, London

Summary

It is difficult to choose among the many drugs advocated for treating anxiety symptoms. The barbiturates were the most commonly used antianxiety agents until recently but are being superseded by the benzodiazepines. The latter are more effective than the barbiturates as shown in comparative clinical trials, they are safer in overdosage (deliberate or accidental), and they are somewhat less likely to induce dependence. The barbiturates have the additional drawback of interfering with the action of other drugs by inducing liver microsomal (oxidising) drug metabolising enzymes. The major tranquillisers (neuroieptics or antipsychotics) are often of value in low dosage in patients with a previous history of dependence on alcohol, the barbiturates or the benzodiazepines. Tricyclic antidepressants are the treatment of choice in anxious and depressed patients and monoamine oxidase inhibitors may be helpful in phobic patients. The {3-adrenoreceptor blocking agents such as propranolol often ameliorate somatic symptoms such as palpitations and tremor. In the treatment of anxious patients it is important to remove causes for the anxiety and to limit any course of drug treatment to a finite period. Both dosage level and dosage interval should be flexible. Benzodiazepines remain the drug treatment of choice.

The older term for this group of drugs is 'sedative', meaning anxiety-allaying, but this now implies the unwelcome production of feelings of slowness, heaviness and drowsiness, particularly associated with the barbiturates. The term 'minor tranquilliser', often applied to newer compounds of this type, is inappropriate as these drugs are neither minor in their actions nor extent of usage nor related to the major tranquillisers (neuroleptics or antipsychotics) in their pharmacology or clinical indications. 'Anxiolytic' or 'antianxiety' are the commonest labels in current use. The distinction between these drugs and hypnotics is a practical and not a pharmacological one. In high

dosage at night, antianxiety drugs induce sleep and in lower doses during the day most hypnotics are calming in action. Many drugs have been used to treat anxiety and associated symptoms, the oldest being alcohol. The widespread usage of alcohol both in past eras and at present is being echoed by the extensive prescription of antianxiety drugs. In 1973 more than 46 million prescriptions for psychotherapeutic drugs were prescribed by retail pharmacists in England and Wales and the number is increasing each year. Sedative barbiturates accounted for 8.3 million and the benzodiazepines for 13.6 million of this total. These drugs are prescribed for a

Antianxiety Drugs

variety of somatic and mental disorders as well as for anxiety and insomnia. It is more likely that doctors are increasingly ready to prescribe these drugs rather than that the incidence of mental disease is rising. New compounds are being introduced all the time so that it is now difficult to give firm relative indications for all these drugs, many of which differ in only minor respects. A number of nonspecific factors also affect treatment response, often appreciably, and include the placebo response, the doctor's attitude towards drugs, other treatments given at the same time, and the patient's expectations from drugs. Nevertheless, some consensus regarding their relative effectiveness has emerged. Each group of drugs will be discussed in turn with emphasis on relative effectiveness and toxicity, particularly the relative advantages of the benzodiazepines over the barbiturates, and the place of /3-adrenoreceptor blocking agents in the therapy of anxiety.

1. Barbiturates

Barbitone and phenobarbitone were introduced early this century and followed by many similar compounds. Over 2,000 were syntheSised and about 50 marketed, many still being available. They were until recently the most widely prescribed antianxiety and hypnotic drugs but have been supplanted by the benzodiazepines. Despite long usage, the mode of action of barbiturates is not clearly understood. 1.1 Pharmacokinetics and Drug Interactions Barbiturates are well absorbed from the gut, except for barbitone, are metabolised by the microsomal Oxidising enzymes in the liver to less lipid-soluble derivatives which are then excreted by the kidneys. Even low therapeutic doses of a barbiturate are sufficient to stimulate the activity

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of these enzymes, both with respect to its own metabolism and to that of other drugs. This stimulating effect, 'enzyme induction', is associated with increased liver weight and increased production of microsomal protein. Among the drugs whose metabolism is known to be accelerated by the barbiturates are the coumarin anticoagulants, phenytoin, griseofulvin, chlorpromazine and amitriptyline. The best-documented interaction is with the coumarin drugs involving the follOWing typical sequence. A patient is admitted to hospital with a myocardial infarction, a stroke or a venous thrombosis and is treated with a coumarin anticoagulant together with a barbiturate to alleviate anxiety and help sleep. The latter drug induces liver enzymes which increases the rate of hydroxylation of the coumarin drug thereby reducing its effect. Accordingly, the dose required to prolong prothrombin time appropriately has to be increased. When the barbiturate is withdrawn, often when the patient returns to his familiar home surroundings, the microsomal enzyme activity returns to normal over the course of a week or two and the coumarin drug is metabolised more slowly. An unexpected, unwanted and frequently dangerous excessive lengthening of prothrombin time ensues. Interactions among psychotherapeutic drugs have not been systematically studied but there is evidence that concomitant administration of a barbiturate lowers the plasma concentrations of anti psychotics like chlorpromazine (Loga et al., 1975) and tricyclic antidepressants such as nortriptyline (Gram and Over¢J, 1972). It is sound prescribing practice not to combine barbiturates and other psychotherapeutic drugs. 1.2 Effect on eNS Barbiturates are depressants of the central nervous system, especially of the neocortex and ascending reticular activating pathways. At the

Antianxiety Drugs

biochemical level, the barbiturate drugs probably act by diminishing the formation of high energy phosphate which is essential for normal brain function. In man, the initial action may be excitatory following release of inhibitory influences on the cortex. Depressant effects supervene later and at higher dose levels. The more complex the human psychological function, the more likely it is to be impaired by barbiturates. Tasks requiring intricate dextrous manipulations such as handwriting are also markedly affected.

1.3 Preparation of Choice Among barbiturates given by mouth, amylobarbitone sodium has been extensively used in the United Kingdom and other European countries for the treatment of anxious patients. In addition, it is claimed to have a mild but often useful euphoriant action in a divided daily dose of 150 to 300mg. In the United States, phenobarbitone is the standard drug but is more depressant and sometimes less acceptable to patients.

1.4 Precautions Barbiturates should not be given routinely to elderly patients who may become confused, and are contraindicated in patients with myxoedema, myasthenia gravis, or acute porphyria. liver function has to be grossly impaired before the metabolism of barbiturates becomes retarded.

1.5 Unwanted Effects The gap between the dose of a barbiturate drug sufficient to relieve anxiety and that producing other evidence of central nervous depression is

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small. Consequently, it is difficult to attain a satisfactory antianxiety effect without some impairment of alertness and mental performance. Thus, as the dosage latitude is narrow, tiredness, drowsiness and objectively assessed impairment of psychological functioning are common, the patient oscillating between inadequate symptom control and sleepiness. Hypersensitivity reactions sometimes occur, usually skin reactions, but blood dyscrasias have been recorded in rare instances.

1.5.1 Overdosage Accidental or deliberate overdosage is a serious problem and suicide attempts frequently involve the ingestion of barbiturates, either on their own or in synergistic combination with other depressants such as alcohol or other psychotherapeutic drugs such as the tricyclic antidepressants. In most Western countries, suicidal attempts have increased greatly in recent years to reach almost epidemic proportions but the rate of increase appears to have slowed down or stopped over the past 2 years. The number of individuals taking an overdose of barbiturates has actually dropped, quite closely paralleling the recent decrease in the usage of barbiturates.

1.5.2 Tolerance Tolerance to barbiturates readily occurs and psychological dependence is common. Physical dependence may be induced with doses as low as 500mg/day. Doses of 600 to 800mg/day often produce persistent mild intoxication with impaired mental functioning, emotional lability, dysarthria, ataxia, and nystagmus. If barbiturates are discontinued abruptly in patients on high dosage, grand mal convulsions and delirium may supervene. With less abrupt withdrawal, anxiety, tremor, muscle twitching, dizziness, nausea and vomiting, insomnia, weight loss, and orthostatic hypotension may still ensue. The non-medical use of barbiturates is undoubtedly a major problem, although its full extent can only be suspected.

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2. Propanetiio/s Meprobamate is a substituted propanediol compound with some muscle relaxant actions. It is the major member of this group and was formerly vigorously promoted as an anxiolytic distinct from the barbiturates. However, the drug is about midway between the barbiturates and benzodiazepines in many of its actions. It is more specific than the barbiturates but less than the benzodiazepines and it tends to produce sedation at dose levels close to those necessary for the relief of anxiety. The usual dosage of meprobamate is 600 to 1,600mgJ day. It is now largely superseded by the benzodiazepines. Drowsiness and anaphylactoid reactions such as rashes, purpura, oedema, and fever are . the commonest unwanted effects. The drug is dangerous in overdosage. Although less likely to produce dependence than the barbiturates, tolerance, psychological and physical dependence are all real dangers. The meprobamate withdrawal syndrome resembles that of the barbiturates. Meprobamate or one of its congeners such as tybamate is sometimes useful in anxious patients with muscular tension as a major symptom.

3. Benzodiazepines Chlordiazepoxide was synthesized in 1947 and was found to tame aggressive animals. Administered to chronic schizophrenic patients it alleviated their anxiety. Extensive evaluation in anxious patients culminated in the drug's introduction to clinical practice in 1960. Other benzodiazepines such as diazepam, medazepam and oxazepam, lorazepam and clorazepate have since been marketed as anxiolytics. Nitrazepam and flurazepam in smaller doses than their hypnotic dose are also effective anxiolytic agents and many of the day-time antianxiety drugs such as oxazepam and lorazepam are effective hypnotics when given as a large single dose at night.

3.1 Pharmacology Medazepam, diazepam, oxazepam, lorazepam and clorazepate are closely related both chemically and pharmacologically. These compounds are metabolised in the liver but oxidising enzymes are induced much less than with the barbiturates and probably to a clinically insignificant extent. In animals, the benzodiazepines depress activity in the limbic system and reticular formation, leaving the cortex relatively unaffected when compared with the effects of barbiturates. Despite these differential actions in animals the spectrum of psychotherapeutic effects of the benzodiazepines in normal individuals resembles that of the barbiturates, with psychomotor impairment and drowsiness in higher doses. 3.2 Preparation of Choice None of the currently available benzodiazepines holds appreciable advantages over the others. This is hardly surprising in view of the metabolic pathways of the benzodiazepines (see fig. 1). Thus, medazepam is metabolised to diazepam, desmethyldiazepam (nor diazepam) and oxazepam and finally conjugated and excreted. Chlordiazepoxide is also partly metabolised to desmethyldiazepam. Desmethydiazepam is the most important metabolite as it has the longest half-life in the body (over 36 hours). Consequently, after several days' treatment with medazepam or diazepam, desmethyldiazepam concentrations exceed those of the parent compounds. For these pharmacokinetic reasons, desmethyldazepam would be the most logical compound to administer for persisting control of chronic anxiety. Alternatively, in the acid conditions of the stomach and on absorption, clorazepate dipotassium is changed into desmethyldiazepam. For episodic anxiety and preoperative sedation, oxazepam and lorazepam, with their shorter half-life and inactive metabolites, are more appropriate.

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3.3 Unwanted Effects

Benzoctamine is a compound similar in many respects to the benzodiazepines.

Drowsiness or tiredness is common with higher doses but can be avoided by careful adjustment of dosage. Dizziness, ataxia, confusion, disorientation, headache, and a paradoxical phase of stimulation are less common. As with the barbiturates, potentiation of alcohol readily occurs. Excessive weight gain and hypersensitivity phenomena such as rashes have been reported. Physical dependence can be induced by all the benzodiazepines and withdrawal after administration in high dosage may result in fits. The dangers of abuse are less than with the barbiturates. The benzodiazepines are apparently safe in overdosage. No fully authenticated cases of death due to overdosage, intentional or accidental, with these drugs alone, have been reported in adults.

4. Antipsychotics The phenothiazines, such as chlorpromazine, trifluoperazine, fluphenazine, perphenazine and thioridazine; the butyrophenones, for example haloperidol, and thioxanthenes such as flupenthixol have all been advocated for use in patients with anxiety. The dosage suggested is usually quite low in comparison with that used in the treatment of disturbed patients. The antipsychotics are not as specific as the benzodiazepines and are sometimes not well tolerated by anxious patients. The unwanted effects of these drugs may upset anxious patients because somatic symptoms such as dry

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mouth, dizzmess and blurred vision are increased. Even more disconcerting are the extrapyramidal effects such as restlessness and mild akathisia. However, in the usual doses recommended for anxiety, only a small percentage of patients develop noticeable side-effects. More important are the delayed unwanted effects such as tardive dyskinesia and for this reason, these drugs should not be prescribed on a long-term basis. Their principal advantage is that dependence on them does not occur. Accordingly, the main indication for the antipsychotics is in the management of anxious patients previously dependent upon alcohol, barbiturates or benzodiazepines (Hollister et aI., 1971).

5. Other Treatments

5.1 Tricyclic Antidepressants Several tricyclic antidepressants such as amitriptyline, doxepin and dothiepin have useful anxiolytic properties. In patients with depressive as well as anxiety symptoms such drugs are the treatment of choice. However, there is little to recommend combinations of antidepressants and antianxiety or antipsychotic drugs. In most instances the dosage taken means that the drug combination is primarily sedative in nature. Indeed, in several instances the dosage of antidepressant is low and reliance on these combinations may result in patients not receiving effective antidepressant therapy. Also, relief from anxiety is often best achieved with a highly flexible dosage schedule which is impractical with these fixed combinations. Therefore the two constituents, if needed, should be prescribed separately. 5.2 Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors such as phenelzine have been· advocated for the treatment of

patients with phobic anxiety states (Tyrer, 1976). Some patients intractable to other forms of therapy may improve dramatically a few weeks after starting treatment. However, the unwanted effects of these durgs, in particular their interaction with dietary constituents rich in tyramine, mean that the practitioner must prescribe these compounds with caution. The antianxiety effects of these drugs appear to be independent of any antidepressant action. 5.3 Alcohol and Hypnotics Alcohol is probably the most widely used selfadministered anxiolytic agent, especially for social phobias. A wide variety of drugs primarily formulated as hypnotics - chloral, paraldehyde, glutethimide, methyprylone and methaqualone will have all been tried as daytime sedatives for some patients and may occasionally be effective. Chlormethiazole, related chemically to thiamine, has been used to treat withdrawal symptoms in alcoholics and has general sedative properties. 5.4 J3-Adrenoreceptor Blocking Drugs In view of the widespread autonomically mediated physiological changes in anxiety, it is not surprising that several autonomic system blocking agents have been tried in its treatment. In particular, over the past decade, j3-adrenoreceptor blocking agents have been evaluated. J3-Blockade reduced heart rate more in anxious patients than in normal controls (Turner et al., 1965). In a clinical trial involving patients with anxious symptoms, propranolol was more effective than placebo in relieving autonomic symptoms such as palpitations, sweating and diarrhoea but had little effect on psychological symptoms including worry, tension and fear (Granville-Grossman and Turner, 1966).

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In our first clinical trial (Tyrer and Lader, 1973), sotalol in flexible dosage up to 400mg/day (mean dose 12Smg/day) was compared with placebo using a cross-over design and double-blind procedure. Outpatients with a history of morbid anxiety of at least 6 months' duration were included unless suffering from cardiac disease or asthma. A restricted sequential design was used: after each patient had completed the 2 treatments, both therapist and subject independently made a preference, if any, for the more effective treat· ment. Ratings were also made by the psychiatrist using the Hamilton Rating Scale for Anxiety. The patients completed simple linear scales of bodily symptoms and subjective mood. The sequential trial was terminated when the 14th patient had completed treatment, when the line indicating patient preference had crossed the inner boundary of no significance. At this point the psychatrist's preference line was approaching the upper boundary of sotalol preference. In the Hamilton ratings sotalol was superior to placebo in counteracting cardiovascular, muscular and tension symptoms but less effective on general anxiety symptoms. The patients' self-ratings of bodily symptoms did not show significant drug effects. Thus, the patients were much less impressed with the efficacy of sotalol than was the psychiatrist conducting the trial. Although this trial was not encouraging, a second investigation was conducted of the effects of j3-adrenoreceptor blockade, in comparison with the central anxiolytic effects of diazepam in patients with chronic anxiety states (Tyrer and Lader, 1974). 12 patients were studied, 6 of whom had primarily somatic anxiety with most emphasis on bodily symptoms, the other 6 with psychological anxiety who dismissed their somatic symptoms as secondary features. Each patient received a week's treatment with flexible doses of propranolol (mean 120mg/day), diazepam (9.6mg/day) and placebo using a cross-over design and double-blind procedures. Similar ratings were made as in the previous trial and at the end of the

third week patients ranked the 3 treatments in order of preference. Overall, the patients showed a clear preference for diazepam, in only one instance propranolol being preferred: further, propranolol was not conSistently preferred to placebo. However, propranolol was preferred to placebo in the somatic group although it seemed less preferred in the psychic group. The Hamilton ratings confirmed this pattern. Overall, diazepam yielded the lowest ratings; propranolol was almost as effective in the somatically anxious patients but significantly worse in the psychically anxious ones.

6. Barbiturates Versus Benzodiazepines In many countries much concern has been expressed about the widespread use of the barbiturates. As an interim measure it has been suggested that it would be advantageous for the barbiturates to be replaced by the benzodiazepines, the eventual aim being a major diminution in the usage of this class of drugs altogether. The disadvantages of the barbiturates vis-a-vis the benzodiazepines are 4-fold: 1) The barbiturates are generally considered to be less efficacious than the benzodiazepines in the treatment of anxious patients. This clinical impression is strongly reinforced by the results of numerous controlled clinical trials. In one such study (Lader et aI., 1974),20 outpatients suffering from chronic anxiety states completed a trial of anxiolytic drug therapy. Each patient received in sequence 5 treatments amylobarbitone sodium, chlordiazepoxide, diazepam, medazepam and a placebo - in flexible dosage in a fully balanced design using doubleblind procedures. They completed self-ratings over 3 days during each treatment period of2 to 4 weeks. These self-ratings were based on at least three 'prime symptoms' chosen by the patient himself and phrased in his own words, as well as 'loss of appetite' and 'insomnia'. It can be seen

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from figure 2 that there is a placebo effect on the mean rating of prime symptoms. This placebo effect is not ·marked and amylobarbitone has no additional effect to that of placebo. All three benzodiazepines, however, effect an appreciable decrease in score. Amylobarbitone has less effect than placebo on appetite and sleep and again the benzodiazepines have useful effects in stimulating appetite and improving sleep. The Hamilton rating scale for anxiety was completed by the rating psychiatrist at the end of each of the periods of treatment. In this instance, no placebo effects could be discerned but again the barbiturate was ineffective. However, all three benzodiazepines halved the psychopathology scores both for the mean of all scales and for the

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somatic and psychic symptoms separately. There were no differences among the benzodiazepines. 2) Although both groups of drugs are likely to produce dependence, this propensity is much less marked with the benzodiazepines. Abuse of barbiturates is widespread and ranges from the teenage addict injecting barbiturates to the middle-aged housewife relying on them indefmitely for sleep. 3) The barbiturates have been widely used in deliberate overdosage with suicidal intent. The figures for barbiturate overdose are now dropping but this entirely reflects the lessening use of these drugs. There is no doubt that with barbiturates the danger level for overdoses is uncomfortably close to the therapeutic dose, that is, the therapeutic index is low. All the evidence suggests that the

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benzodiazepines are entirely safe in overdose in adults, providing no other psychotherapeutic drug has been taken. 4) The barbiturates induce liver drug metabolising enzymes and produce the well-known interactions with other drugs. Benzodiazepines are much less important in this respect and interactions are of little clinical importance. For all these reasons the benzodiazepines are superior to the barbiturates. Apart from the use of phenobarbitone as an anticonvulsant and the thiobarbiturates as induction agents for anaesthesia, a growing body of opinion regards them as obsolete in their other roles as hypnotics and sedatives (Drug and Therapeutics Bulletin, 1976). Newly presenting patients should not be placed on barbiturates unless there is a very defInite reason for using them, such as failure to respond to all other appropriate compounds. Patients who are already on barbiturates and who seem unable to manage without some sedative or hypnotic agent should be switched over to the benzodiazepines. In one effective scheme substitution is begun gradually, Smg of diazepam for 100mg ofbarbiturate. The substitution can be made as slowly as one dose per week so that the changeover is spread over several weeks. Neither barbiturates nor benzodiazepines should be withdrawn abruptly. In many patients changed from barbiturates to benzodiazepines the latter drugs can be slowly withdrawn after a period of time.

7. Treatment of Anxiety Several aspects of treatment have already been mentioned and the following is a brief review. 7.1 Initial Treatment The fIrst step when a patient presents with anxiety is to try to establish the cause of the anxiety. Often there will have been a change in the

life-circumstances of the patient 'which has apparently precipitated anxiety symptoms. Treatment should then be directed towards modifying these factors so as to lessen the pressures on the patient. Discussion of the meaning of such factors with the patient also helps. In a patient experiencing anxiety symptoms for the fIrst time, reassurance is most important and an explanation of the physiological bases of the primary symptoms is helpful. If an underlying cause cannot be readily identifIed, resort must be to symptomatic relief with drugs. It is important to ascertain whether the patient has suffered from life-long 'personality' anxiety or whether the present episode has occurred in a previously calm individual. The former patients may need long-term treatment and psychological support; symptoms in the latter patients will probably subside of their own accord and the patients merely need tiding over a 'bad patch' . Benzodiazepines are the drug treatment of choice. However, there seems little to choose among the benzodiazepines, and the clinician should start treatment with the drug with which he has most experience, subject to the proviso regarding duration of action mentioned earlier. In may experience, patients often prefer one of these drugs to the others and claim to detect subtle differences in their psychotherapeutic actions. Despite the drugs' relatively long half-lives, some patients opt for sJll!lll divided doses: for example, diazepam 2mg 6 times a day rather than the traditional thrice-daily schedules or the logical once-nightly dose.

7.2 Pronounced Somatic Symptoms When a pronounced set of somatic symptoms is present, the j3-adrenoreceptor blocking agents have a useful place, but the most logical procedure is to combine centrally acting antianxiety drugs such as benzodiazepine and peripherally acting adrenoceptor blocking drugs. Firstly, the symptom

Antianxiety Drugs

profIle of the patient must be carefully evaluated. For patients who deny the psychological symptoms of anxiety and complain of its somatic manifestations, particularly palpitations, tachycardia and trembling, the combination should emphasise the ~blocker. For patients with predominantly psychological symptoms such as apprehension, irritability and restlessness, a combination may again be useful, with the bias towards the centrally acting drug.

7.3 Severe Panic and Anxiety Reactions In a severe attack of panic, amylobarbitone sodium (up to Soomg intravenously or intramuscularly) is effective: the patient usually sleeps for several hours and wakes up calmed. In patients with severe anxiety reactions to civil disasters such as earthquakes or following horrific wartime experiences, amylobarbitone (200 to Soomg intravenously at a rate below loomg per minute) may 'abreact' these patients, who often relive their experiences vividly, with strong emotional reactions. Diazepam is available for intravenous use and is a useful alternative to the barbiturates in the treatment of acute panic (10mg dose).

7.4 Duration of Treatment Too many drugs are being prescribed for the relief of anxiety and insomnia. Drug therapy is useful and important in the short-term relief of anxiety but should not be regarded as the only or even the major mainstay of treatment. Also important is psychotherapy and reassurance by the doctor. Many patients will then be found not to need drug treatment at all. Patients who have been dependent on this class of drugs should not be reintroduced to them except where there is

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Table I. Major drugs used in treating anxiety

Drug

Indications

Comments

Alcohol

Minor symptoms

Self-administered, time-hallowed

Barbiturates

Occasionally, severe panics

Obsolete - dangerous, addictive, relatively ineffective

Meprobamate

Occasionally, muscle tension

Obsolete. Disadvantages of barbiturates

Benzodiazepines

Treatment of choice

Some addictive properties but safe in overdose

Tricyclic antidepressants

Anxiety! depression

Many side-effects

MAOl's

Phobic anxiety

Dietary and drug interactions

Major tranquillisers (antipsychotics)

Previously dependent patients

Low dosage only

{J-blockers

Somatic symptoms

Combine with benzodiazepines

clear evidence of medical, social or occupational disability arising as a direct consequence of the anxiety symptoms. Table I summarises the indications for use of antianxiety drugs.

References Drug and Therapeutics Bulletin. Are barbiturates obsolete as hypnotics and sedatives? Drug and Therapeutics Bullein 14: 7-8 (1976). Gram, L.F. and Overc/, K.F.: Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic anti-

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depressants in man. British Medical Jomnal I: 463-465 (1972). Granville-Grossman, K.L. and Turner, P.: The effect of propranolol on anxiety. lancet 1: 788-790 (1966). Hollister, LE.; Overall, J.E.; Pokorny, A.D. and Shelton, J.: Acetophenazine and diazepam in anxious depressions. Archives of General Psychiatry 24: 273-278 (1971). lader, M.H.; Bond, A.J. and James, D.C.: Oinical comparison of anxiolytic drug therapy. Psychological Medicine 4: 381-387 (1974). Loga, S.; Curry, S. and lader, M.H. Interactions of orphenadrine and phenobarbitone with chlorpromazine: plasma concentrations and effects in man. British Jomnal of Oinical Pharmacology 2: 197-208 (1975). Overall, J.E.; Hollister, LE. and Pokorny, A.D. Alcohol history in drug treatment. Diseases of the Nervous System 34: 175-180 (1973). Turner, P.; Granville-Grossman, K.L. and Smart, J.V.: Effect of adrenergic receptor blockade on the tachycardia of thyrotoxicosis and anxiety state. lancet 2: 1316-1318 (1965). Tyrer, P.: Towards rational therapy with monoamine oxidase inhibitors. British Jomnal of Psychiatry 128: 354-360 (1976). Tyrer, P.J. and lader, M.H.: Effects of beta adrenergic blockade with sotalol in chronic anxiety. Oinical Pharmacology and Therapeutics 14: 418-426 (1973). Tyrer, P.J. and lader, M.H.: Response to propranolol and diazepam in somatic and psychic anxiety. British Medical Journal 2: 14-16 (1974).

Bibliography of Additional References Azima, H.; Arthurs, D. and Silver, A.: The effects of chlordiazepoxide (librium) in anxiety states. A multiblind study. Canadian Psychiatric Association Journal 7: 44-50 (1962). Daneman, E.A.: Double blind study with diazepam, chlordiazepoxide and placebo in the treatment of psychoneurotic anxiety. Journal of the Medical Association, Georgia 53: 55-58 (1964). Dickel, H.A.; Dixon, H.H.; Shanklin, J.G. and Dixon, H.H.: A clinical, double-blind comparison of Ubrium, meprobamate and phenobarbital. Psychosmatics 3: 129-133 (1962). Frankenhaeuser, M. and Jiirpe, G.: Psychophysiological changes during infusions of adrenaline in various doses. Psycho pharmacologia 4: 424-432 (1963). Garattini, S.; Mussini, E. and Randall, L.O.: The Benzodiazepines (Raven Press, New York 1973).

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General Practitioner Oinical Trials: Phenobarbitone compared with an inactive placebo in anxiety states. Practitioner 192: 147-151 (1964). Gjerris, F.: Poisoning with chlordiazepoxide (librium). Danish Medical Bulletin 13: 170-180 (1966). Grosz, H.J. and Farmer, B.B.: Blood lactate in the development of anxiety symptoms. A critical examination of Pitts and McOme's hypothesis and experimental study. Archives of General Psychiatry 21 : 611-619 (1969). Hare, H.P.: Comparison of diazepam, chlorpromazine and a placebo in psychiatric practice. Journal of New Drugs 3: 233-240 (1963), Hollister, L.E.: Methodological considerations in evaluating anti-anxiety drugs. Jomnal of Oinical Pharmacology 10: 12-18 (1970). Hollister, L.E. ; Stannard, A.N. and Drake, C.F .: Treatment of anxious patients with drugs. Diseases of the Nervous System 17: 289-293 (1956). Jenner, F.A.; Kerry, R.J. and Parkin, D. : A controlled trial of methaminodiazepoxide (chlordiazepoxide, 'Ubrium') in the treatment of anxiety in neurotic patients. Journal of Mental Science 107: 575-582 (1961). Jenner, F.A.; Kerry, R.J. and Parkin, D.: A controlled comparison of methaminodiazepoxide (chlordiazepoxide, 'librium') and amylobarbitone in the treatment of anxiety in neurotic patients. Jomnal of Mental Science 107: 583-589 (1961). Johnstone, E.E. and Claghorn, J.L.: Doxepin vs. chlordiazepoxide. A controlled comparison in neurotic outpatients. Current Therapeutic Research 10: 514-519 (1968). Kearney, T. and Bonime, H.C.: Problems of drug evaluation in out-patients. Diseases of the Nervous System 27: 604-606 (1966). Kelly, D.; Brown, C.C. and Shaffer, J.W.: A controlled physiological, clinical and psychological evaluation of chlordiazepoxide. British Journal of Psychiatry 115: 1387 -1392 (1969). lingjaerde, 0 .: Diazepam bei nervQser Angst und Spannung. Ein doppel blind Versuch mit Placebokontrolle und Anwendung von Sequenzanalyse. Psychopharmacologia 6: 159-162 (1964). Lorr, M.; McNair, D.M.; Weinstein, G.J.; Michaux, W.W. and Raskin, A.: Meprobamate and chlorpromazine in psychotherapy. Some effects on anxiety and hostility of outpatients. Archives of General Psychiatry 4: 381-389 (1961). McNair, D.M.: Antianxiety drugs a,nd human performance. Archives of General Psychiatry 29: 611-617 (1973).

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Masserman, J.H.: Drug effects on experimental neuroses in . animals; in Uhr and Miller (Eds.) Drugs and Behavior, p.250-254 (Wiley, New York 1960). Pitts, F.N. and McQure, J.N.: Lactate metabolism in anxiety neurosis. New England Journal of Medicine 277 : 1329-1336 (1967). Raymond, M.J.; Lucas, C.J.; Beesley, M.L. ; O'Connell, B.A. and Fraser Roberts, J.A.: A trial of five tranquillizing drugs in psychoneurosis. British Medical Journal 2: 63-66 (1957). Reynolds, E.; Joyce, C.R.B.; Swift, J.L.; Tooley, P.H. and Weatherall, M. : Psychological and clinical investigation of the treatment of anxious out-patients with three barbiturates and placebo. British Journal of Psychiatry 111 : 84-95 (1965). Rickels, K. and Snow, L.: Meprobamate and phenobarbital sodium in anxious neurotic psychiatric and medical clinic outpatients. A controlled study. Psychopharmacologia 5: 339-348 (1964). Smith, M.E. and Chassan, J.B.: Comparisons of diazepam, chlorpromazine and trifluoperazine in a double-blind

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clinical investigation. Journal of Neuropsychiatry 5: 593-600 (1964). Sternbach, L.H. ; Randall, L.O.; Banziger, R. and Lehr, H.: Structure-activity relationships in the 1-4 benzodiazepine series; in Burger (Ed.) Drugs Affecting the Central Nervous System, Vol. 2, p.237-264 (Dekker, New York 1968). Uhlenhuth, E.H.; Canter, A.; Neustadt, J.O. and Payson, H.E. : The symptomatic relief of anxiety with meprobamate, phenobarbital and placebo. American Journal of Psychiatry 115: 905-910(1959). Winstead, D.K.; Anderson, A.; Eilers, M.K.; Blackwell, B. and Zaremba, L : Diazepam on demand: Drug seeking behaviour in psychiatric inpatients. Archives of General Psychiatry 30: 349-351 (1974).

Author's address: Dr Malcolm Lader, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF (England).