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1 Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276-Ba, which has been shown to have antidepressant activity. 2 In five normal volunteers tested before and during treatment with Ciba 34276-Ba, no abnormalities of resting or post-exercise electrocardiographs occurred. A three-fold reduction in tyramine-responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276-Ba whilst on long-term treatment with bethanidine showed loss of blood pressure control. 3 The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276-Ba.

Intravenous infusions of phenylephrine, noradrenaline, adrenaline, and isoprenaline were given to healthy human volunteers after five to seven days on phenelzine, tranylcypromine, or imipramine, and cardiovascular responses were compared with those observed under control conditions. With monoamine oxidase inhibitors there was a 2-2(1/2) fold potentiation of the pressor effect of phenylephrine, but no clinically significant potentiation of cardiovascular effects of noradrenaline, adrenaline, or isoprenaline. With imipramine there was potentiation of the pressor effects of phenylephrine (2-3 fold), noradrenaline (4-8 fold), and adrenaline (2-4 fold); there were dysrhythmias during adrenaline infusions, but no noticeable or consistent changes in response to isoprenaline.Noradrenaline and adrenaline in amounts contained in local anaesthetics used in dentistry are not likely to be significantly potentiated in otherwise healthy patients receiving monoamine oxidase inhibitors. Hazardous potentiation of their cardiovascular effects might occur in patients receiving tricyclic antidepressants.Our observations do not indicate that the hazards associated with isoprenaline inhalation by bronchial asthmatics would be increased by coincident therapy with a monoamine oxidase inhibitor or tricyclic antidepressant.

It is surprising that, so far as we can ascertain, no trial has been reported in which the efficacy of a modern "anti depressive " drug has been compared with that of a combina tion of drugs (dexamphetamine and amylobarbitone) widely used in the treatment of depressive illness before the newer drugs were introduced five or six years ago. Proprietary mixtures of dexamphetamine and amylobarbitone are still advertised as of value in depression, and the lack of any comparative trial is perhaps more surprising when it is remembered that the basic cost to the National Health Service of a week's treatment with the ingredients of such mixtures (dexamphetamine sulphate 5 mg. and amylobarbitone sodium 50 mg. t.i.d.) is 5d., while that of the currently most popular antidepressant (imipramine hydrochloride (" tofranil ") 50 mg. t.i.d.) is about 11s. 6d. In this paper we report a controlled comparative trial of imipramine and a proprietary mixture of dexamphetamine and amylobarbitone ("drinamyl"), in the treatment of depressive illness.

AN ANALYSIS OF THE CASE HISTORIES OF NINE PATIENTS WHO DEVELOPED EPILEPTIC FITS SHORTLY AFTER STARTING TRICYCLIC ANTIDEPRESSANT DRUGS SHOWED THAT ALL OF THEM HAD ONE OR MORE OF THE FOLLOWING FACTORS: previous or family history of epilepsy, pre-existing brain damage, cerebral arteriosclerosis, alcoholism, withdrawal of barbiturates, and history of previous electric convulsive therapy. Before prescribing antidepressant drugs these factors should be sought for in the history, and if any are present prophylactic anticonvulsant medication is indicated. From a limited experience we do not think that chlordiazepoxide is adequate to counteract the convulsant effect of antidepressant drugs.

Electric convulsion therapy (E.C.T.) was used in the treatment of 13 women inpatients suffering from depressive symptoms. Twelve of the patients showed a significant increase in urinary excretion of 3′, 5′ cyclic adenosine monophosphate (cAMP) on the day of treatment, whereas four controls who received all or part of the preliminary treatment but no electric shock showed a reduction. The results of this study are consistent with the hypothesis that the antidepressant action of E.C.T. is mediated through an increased production of cAMP in brain tissue.

THERE is indirect evidence of a relationship between serious disorders of mood, such as mania and depression, and amines, particularly noradrenaline1,2. This is based in part on the observation that two classes of drugs which deplete the brain of noradrenaline (reserpine and alpha-methyl-DOPA), acting through different mechanisms, can cause depression in some patients. The imipramine class of drugs and the monoamine oxidase inhibitors have been shown in controlled studies to benefit many clinical depressions. The monoamine oxidase inhibitors have been found to block an important breakdown pathway of noradrenaline1, while the imipramine type drugs block the re.uptake of noradrenaline into the adrenergic tissues1. It has been suggested that both classes of drugs increase “functional” noradrenaline at the receptor sites, and that this effect is related to their antidepressant actions.

The relationship between plasma concentration of nortriptyline and therapeutic effect after two weeks' treatment with the drug was investigated in 29 psychiatric inpatients. Endogenous depression was diagnosed in all patients. Amelioration of depressive symptoms was estimated as reduction in score on a rating scale, based on a psychiatric interview. Amelioration was not correlated to the patient's sex or age. There was a curved relationship between plasma level of nortriptyline and therapeutic effect. Amelioration was most pronounced in the intermediate plasma level range (50-139 ng nortriptyline/ml plasma) and was slight both at lower and at higher plasma levels. This type of relationship may be due to the dual action of tricyclic antidepressants which has been found in animal experiments. On larger dosages a phenothiazine-like blockade of the monoaminergic receptor is added to the blockade of monoamine reuptake thought to be related to the antidepressant action of the drugs.THIS STUDY THUS SUGGESTS TWO POSSIBLE REASONS FOR A THERAPEUTIC FAILURE WITH NORTRIPTYLINE: a too low or a too high plasma level. The large individual variation in the pharmacokinetics of the tricyclic antidepressants makes prediction of plasma level from dosage in a given individual virtually impossible without knowledge of rate of elimination and apparent volume of distribution. Hence monitoring plasma levels may be a way to increase the efficacy of treatment with these drugs.

The widespread prescription of antidepressant and tranquilizing drugs has resulted, perhaps inevitably in an increasing incidence of these drugs in specimens from Coroner's autopsy cases. Particularly prominent are the tricyclic compounds imipramine and amitriptyline. Examples of toxicological investigations involving these and some other structurally related drugs, nortriptyline, dothiepin and dibenzepin form the basis of this paper.

Effects upon behavior in animals are qualitatively similar to those seen with other p0tent amine-oxidase inhibitors. They include a pressor effect and central nervous system excitation. At the same time there is a marked rise in the norepinephrine and serotonin content of the brain. In animals, pretreatment with the drug produces a reversal of the sedative effects of reserpine. Since iproniazid had already proved to have very valuable antidepressant properties in man, Catron was given a clinical trial and a number of favorable reports have been made.'" It also has been found useful in the treatment of angina pectoris,' rheumatoid arthritis' and hypertension.It This paper reports upon 73 patients treated with Catron* (JB-516). The majority of them manifested depressive symptoms, three had schizophrenia without depression and nine were classified as anxiety or tension states without depressive symptoms. Treatment of this latter group was prompted by the feeling of well being and relaxation described by some of the ,earlier group of depressed patients while taking the drug. Methampbetamine (De80xyepbedrlne) Ampbetamine (Benzedrine)

IN previous papers we have directed attention to the enhancement of imipramine mortality in mice by hyper-thyroidism and its diminution by propylthiouracil pre-treatment1,2. One of the major metabolites of imipramine is its demethylated product, desmethylimipramine (DMI)3, and this compound is said to be responsible for the antidepressant effect of the drug4,5. DMI is more potent than imipramine in antagonizing reserpine sedation in rats4 and in potentiating the reaction of cat nictitating membrane to norepinephrine6. For these reasons it seemed of interest to ascertain the effect of thyroid status on DMI mortality according to the previous technique.

I would like to open my paper by first of all complimenting the many conscientious and enthusiastic clinicians who are regularly publishing the results of comparative studies of antidepressant and tranquilizing drugs. I extend to these people my heartiest congratulations knowing somewhat of the trials and difficulties involved. In 1959 I ambitiously embarked on a comparative study of the then known antidepressant agents. My conclusions were that, in all honesty, it was practicallyimpossible to be absolutely certain of the relative efficacy of these drugs on a comparative basis without involving a slide rule, arithmetical formulre, biostatisticians and various other pseudoscientific devices which are presently being used perhaps to compensate for the lack of clinical acuity. My problem, however, was not solved, and as 1961 continues, with additional antidepressant agents further complicating the project, I feel that I must regretfully turn more and more to scientific formulre for absolute results and rely less on the clinical impressions and observations that are essentially the only yardsticks of the clinical investigator. Some of the difficulties involved in the treatment of a depression arise from much confusion concerning the term itself. This is a word which has been given much emphasis in recent years;l it is descriptive of a fairly normal emotion; of a syndrome; and, certainly a specific disease. The primary symptoms of depression, however, are well known: they include melancholia, sadness, despair, dejection, a dearth of psychic energy, lack of mental

Research on neurochemistry and neuropharmacology of the affective disorders rests upon prior evidence of the therapeutic efficacy of antidepressant drugs; this paper reviews the evidence for clinical efficacy with particular attention to the role of differential response and the search for meaningful subtypes among the larger group of depressions. Three classes of drugs are generally considered to have specific antidepressant actions clinically: the amphetamines and other psychomotor stimulants, the monoamine oxidase (MAO) inhibitors, and the tricyclic derivatives related to imipramine. Although there remain unresolved issues as to the limits of their therapeutic efficacy and the range of their possible toxicity, controlled clinical trials and therapeutic experience indicate that significant antidepressant effects occur in moderate proportions of depressed patients. Moreover, therapeutic and research experience with these drugs indirectly supports the view that clinical depressions are composed of heterogeneous groups and considerable research efforts are now underway to identify the characteristics of depressed patients who respond differentially to one or another compound in the expectation that these differential responses can contribute to developing newer models of etiology and of nosology. The clinical investigations using antidepressant drugs have two main goals: first, clinical efficacy studies attempting to determine the overall utility of drugs and the relationship between specific drugs and patient subtypes, and second, clinical pharmacologic research attempting to test hypotheses about the neuropharmacology of affective disorders. In this, amine precursors, such as dopa and tryptophan and enzyme inhibitors, such as alphamethyl-dopa and alpha-methyl-tyrosine, have emerged as important investigational tools. Although clinical investigations with these compounds have demonstrated only limited therapeutic efficacy, through carefully designed investigation the attempt is made to indirectly test hypotheses about the role of various amines in the pathogenesis and etiology of depression.

RECENT studies have demonstrated that imipramine (Tofrānil),* an antidepressant agent, is effective in controlling enuresis in children.1-9These accounts have appeared mainly in the psychiatric literature. The aim of this paper is to acquaint the pediatrician with the nature of the drug and its use in the control of enuresis and to report our results with imipramine in a small group of enuretic children. Imipramine, a dibenzazepine derivative, is not a monoamine oxidase inhibitor. Its antidepressant effect has been attributed to activation of adrenergic mechanisms in the reticular formation of the brain stem.10Chemically, it is similar in structure to the phenothiazines and has the following structural formula: Since imipramine is widely used in the treatment of depression, its side effects have been amply documented. Though the drug is well tolerated

It is evident from the literature that there is a relation between thyroid hormones and the toxicity of drugs and other chemical substances. The administration of thyroxine or desiccated thyroid to various animal species is reported to increase suscep tibility to the toxic effects of the following compounds: alloxan (Houssay and Sara, 1945), endotoxin (Kroneberg and Potzsch, 1952), cocaine, o-dinitrophenol, and dinitro-o-cresol (Glaubach and Pick, 1931, 1934), morphine (Hunt and Seidell, 1910), adrenaline (Kroneberg and Hilter, 1951), ephedrine (Halpern, Drudi-Baracco, and Bessirard, 1964), amphetamine (Moore, 1965), a non-hydrazide monoamine oxidase inhibitor (Carrier and Buday, 1961), and imipramine (Prange and Lipton, 1962). There is less evidence concerning the toxicity of drugs in the hypothyroid state; a search of the literature showed references to only two substances. The toxicity of imipramine was reported to be lower in mice in which thyroid function had been reduced by treatment with propylthiouracil (Prange, Lipton, and Love, 1963), though this was not confirmed by later studies (Prange, Lipton, and Love, 1964), and the toxicity of alloxan was reduced in thyroidectomized rats (Houssay and Sara, 1945). The purpose of this paper is to report on the toxicity of several widely used antidepressant and tranquillizer drugs in mice made hyperthyroid by the addition of desiccated thyroid to the diet, and to draw attention to possible hazards in their use in the hyperthyroid state in man.

DESPITE the plethora of published material concerning side effects of psychopharmacologic agents, only passing attention has been given to dryness of the mouth. This common, often distressing, but frequently unheeded complaint is well-known to occur with antidepressant and phenothiazine treatment.1It has recently been shown to be associated with oral moniliasis in patients treated with chlorpromazine.2-4In a large-scale investigation of 3,000 psychiatric patients who had recently received phenothiazines or antidepressants (imipramine hydrochloride) [Tofranil] and amitriptyline [Elavil], or both, 48% of the patients had oral cultures positive for monilia and 29.5% had actual clinical lesions.5Quantitative measurement has shown that salivary flow decreases with chlorpromazine administration. This finding has been reported, with a warning to the dental profession to watch for subsequent complications.6 The case to be reported in this paper describes