Alec Coppen

AMITRIPTYLINE PLASMA-CONCENTRATION AND CLINICAL EFFECT: A World Health Organisation Collaborative Study

54 patients in five centres participated in a study of the relationship between steady-state plasma-levels of amitriptyline (AT) and its active metabolite nortriptyline (NT) and therapeutic response. The participants were inpatients who, after a 7-12 day period of assessment, were rated greater than or equal to 16 on the Hamilton rating scale for depression. They were given 75 mg of amitriptyline for 3 days and then 150 mg daily for an active-treatment period of 6 weeks. Clinical ratings and plasma-samples were obtained at baseline then at 2, 4, and 6 weeks after starting therapy. Contrary to the findings of three previous trials, no important correlations were found between steady-state plasma-levels and therapeutic outcome or corrected side-effects. Corrected side-effects correlated negatively with therapeutic outcome. There seems little advantage in routine monitoring of AT and NT, since variations in plasma-levels do not account for the considerable variation in therapeutic outcome.

Prophylactic lithium in affective disorders. Controlled trial.

Abstract The prophylactic effect of lithium was studied in a group of sixty-five patients with recurrent affective disorders in four centres. Patients were randomly allocated to lithium or identical-looking placebo tablets for periods of up to 112 weeks. In addition, patients received any further medication or treatment which the psychiatrist in charge of the case thought was necessary. Patients receiving lithium had very significantly less affective illness than patients receiving placebo tablets, whether this was measured by time spent as an inpatient or by the duration of outpatient episodes. The amount of antidepressant or of antimanic medication prescribed was also significantly less in the lithium group. No patient on lithium was given electroconvulsive therapy (E.C.T.), whereas 43% of the placebo group received one or more courses of E.C.T. A global rating was made independently by two assessors who did not know whether the patient was in the lithium or in the placebo group. These assessors, the psychiatrist in charge of the case and a psychiatric social worker, showed a very high concordance in their ratings. 86% of patients on lithium were rated as showing little or no affective disorders (global rating 1 and 2) during the trial, as compared to only 8% of the placebo group. Only 11% of the lithium group was rated as unchanged or worse than during the 2 years previous to the trial, as compared with 75% of the placebo group. Lithium seemed to be as effective in patients with unipolar recurrent depressive illness as in patients with both mania and depression.

NORADRENALINE, 5-HYDROXYTRYPTAMINE, AND 5-HYDROXYINDOLEACETIC ACID IN HINDBRAINS OF SUICIDAL PATIENTS

Abstract 5-hydroxytryptamine (5-H.T.), noradrenaline (N.A.), and 5-hydroxyindoleacetic acid (5-H,I.A.A.) were measured in the hindbrains of twenty-three depressed and non-depressed suicides, and in twenty-eight controls who had died from other causes. 5-H.T. and N.A. levels were not significantly different, but 5-H.I.A.A. was significantly lower in the hindbrains of the suicides.

Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial

BACKGROUND A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants. The present investigation was designed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine. METHODS 127 patients were randomly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. RESULTS Patients receiving folate showed a significant increase in plasma folate. This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93. 9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). LIMITATIONS AND CONCLUSIONS Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants. Folic acid should be given in doses sufficient to decrease plasma homocysteine. Men require a higher dose of folic acid to achieve this than women, but more work is required to ascertain the optimum dose of folic acid.

TRYPTOPHAN IN THE TREATMENT OF DEPRESSION

Abstract The antidepressive effect of tryptophan, with and without the addition of a monoamine-oxidase inhibitor, has been compared with electroconvulsive therapy (E.C.T.) in three groups of patients with severe depression. The results suggest that tryptophan was as effective as E.C.T. in treating depressive illness. The patients given tryptophan and a monoamine-oxidase inhibitor tended to show a greater improvement than those treated by tryptophan alone. The addition of potassium and carbohydrate may also enhance the antidepressive activity of tryptophan and a monoamine-oxidase inhibitor.

PLASMA CONCENTRATION OF AMITRIPTYLINE AND CLINICAL RESPONSE

Abstract Plasma amitriptyline and nortriptyline concentrations were measured in fifteen depressive patients who were treated with 150 mg. amitriptyline daily for 6 weeks. There was a considerable variation in plasma levels of both amitriptyline and its metabolite nortriptyline in individual patients. There was no correlation after 4 weeks between plasma levels and the side-effects reported by the patient, but there was a highly significant positive correlation between plasma levels of both compounds and clinical improvement. Patients who had plasma concentrations of amitriptyline and nortriptyline below 120 ng. per ml. showed a poor clinical response.

Platelet 5-hydroxytryptamine accumulation in depressive illness

The uptake of 5-hydroxytryptamine (5-HT) by blood platelets from controls, depressed patients and recovered depressed patients has been determined using short incubation times and low substrate concentrations. The affinity of serotonin for the platelet membrane appears to be normal in acutely depressed and recovered depressed patients. The capacity of transport of 5-HT through the platelet membrane is impaired in these depressive patients and this impairment is independent of the psychiatric status of the patients and is discussed in the light of the electrolyte and enzyme disturbances that are associated with depressive illness.

Mineral Metabolism in Melancholia

comparisons between the treatments are unbiased and independent of any general trend in scores, which applies to all treatment groups during the trial. From the clinicians viewpoint the results are bound to be regarded as somewhat less satisfactory. It is obvious that, taken as a whole, the anticipated clinical course of multiple sclerosis is not one of clinical improvement, and from this point of view the standard of measurement we have employed in these trials has failed us. In seeking the reasons for these anomalous results the short duration of the gammaglobulin trial imposed on us by the limited availability of the substance should be noted. The tonic effect of any new form of treatment in a chronic disease is notorious, and six months might well not be long enough for such a non-specific psychological effect to be dissipated by subsequent disappointment. The clinical examinations in the two trials were carried out by two different observers, but the observer was the same throughout each trial, and it is improbable that the mean improvement observed in treated and control patients in each trial was due to an overall simultaneous change in the standard of scoring of both observers. Again, a placebo effect seems to be the likeliest explanation: in a chronic and fluctuating disease, where the subjective component of the patients disablement represents a variable moiety of the total incapacity, the detailed interest and attention shown and the rituals attendant on taking part in such a trial often have a striking effect on the patients attitude towards his disability. Such a patient not infrequently carried out activities previously thought to be quite beyond his capacity. We believe that such factors probably account for the results described above. Most of our previous trials have covered longer periods of time, when the inexorable progression of the organic process inevitably comes to outweigh the subjective effects of early optimism. In one such trial (Miller et al., 1961a) re-examination after six months did fail to reveal any significant deterioration in both control and treated cases, though we have not previously encountered the slight clinical improvement observed here. It should also be mentioned that the doctors and nurses engaged in treating and examining the patients in the present study were an entirely different group from those concerned in previous trials and may well have exuded more optimism. The therapeutic effect of suggestive measures in chronic disease is the basis of a great deal of unorthodox treatment in these disorders, and it is unfortunate that our observations could be used to furnish ammunition for the view that at the present time-possibly with the solitary exception of corticotrophin in acute episodes of the disease (Miller et al., 1961b)-treatment with inert substances accompanied by suggestion has at least as much to offer as any of the more rational lines of therapy which we have tried during the past few years. Summary Two separate controlled therapeutic trials are reported. The first, employing 57 patients, was designed to measure the effects of dosage with chloroquine (250 mg. daily) and also with soluble calcium aspirin (54 g. (3.5 g.) daily) on the clinical course of multiple sclerosis over a period of 14 months. The second, employing 21 female patients, was designed to measure the effect of 500 mg. of gammaglobulin, given intramuscularly at fortnightly intervals, on the course of the disease during a six-months period. Disability was scored numerically and clinical examinations were carried out by an observer unaware of the patients treatment group. In the dosages and over the respective periods involved none of these three substances could be shown to influence the clinical course of the disease. The only patients who showed assessable deterioration during these two observations were those on chloroquine, who deteriorated by 13.3 points over a 14-months period.

Indoleamines and affective disorders

Abstract The role of the indoleamines in the affective disorders is reviewed. There is increasing evidence of abnormal indoleamine metabolism in depression and mania. In depression the urinary excretion of tryptamine and the cerebrospinal fluid concentration of 5-hydroxy-indoleacetic acid is considerably reduced. Brain levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid are lower in the brains of suicides than in those of subjects who died by other means. In mania, C.S.F. levels of 5-HIAA were also found be to low. In neither mania nor depression did the lumbar C.S.F. 5-HIAA levels change after clinical recovery. These changes in indoleamine metabolism may play a role in the aetiology of depression, since tryptophan, the amino acid precursor of the indoleamines, administered with or without a monoamine-oxidase inhibitor has a therapeutic action in depressed patients.

Zimelidine: a therapeutic and pharmacokinetic study in depression.

Zimelidine, a bicyclic compound with a strong effect on the neuronal reuptake of 5-hydroxytryptamine and with weak anticholinergic actions, was evaluated for its antidepressant efficacy in a double-blind comparative trial with amitriptyline. In doses of 200 mg a day it was found to be as effective as 150 mg amitriptyline, but with significantly less subjective side-effects. The plasma concentration of zimelidine and its metabolite, norzimelidine, showed no significant correlation with therapeutic outcome.