New pharmacological developments in antidepressants.

The new pharmacological developments in antidepressants are reviewed with particular reference to MAOIs. Combining an MAOI with amitriptyline reduces the risk of a tyramine-induced rise of blood pressure but does not eliminate the risk which is comparable to that of one of the new reversible MAO-A inhibitors (CGP 11305A).

Attempts to attenuate the 'cheese effect'. Combined drug therapy in depressive illness.

Although earlier results, employing intravenous tyramine challenge, had indicated that a tricyclic antidepressant plus monoamine oxidase inhibitor drug combination might be free from the 'cheese effect', the experiments reported here, involving oral tyramine challenge during the combined therapy, showed that relaxation of a tyramine-free diet during such a drug regimen might be unsafe. Preliminary observations indicated that combined (-)-deprenyl plus nonselective monoamine oxidase inhibitor therapy might lead to an unacceptable degree of orthostatic hypotension without reduction in tyramine sensitivity.

The present status of monoamine oxidase inhibitors.

The present status of monoamine oxidase inhibitors in the treatment of depression is reviewed. With adequate doses they are effective antidepressants, but dosages have in the past been too low. Provided proper dietary precautions are taken, the incidence of fatality from dietary interactions is very small and should not deter doctors from using these drugs, especially in those depressed patients who do not respond to tricyclic-type antidepressants. The present status of combining monoamine oxidase inhibitors with tricyclics is discussed, as are the newer specific inhibitors particularly clorgyline and deprenyl.

Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?

Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.

Is the failure of (-)deprenyl, a selective monoamine oxidase B inhibitor, to alleviate depression related to freedom from the cheese effect?

The selective monoamine oxidase (MAO) B inhibitor (-)deprenyl failed to produce any greater benefit than placebo in a limited double-blind trial conducted in depressive patients. Its relative freedom from the so-called cheese effect was confirmed, however, in drug-treated patients challenged IV with tyramine. There is evidence to suggest that this cheese effect, a facilitated tyramine-induced hypertensive response, is pharmacologically distinct from MAO inhibition proper. Thus, it is conceivable that its central counterpart, an enhanced noradrenaline release due to the access of traces of tyramine to the CNS, is a prerequisite for any therapeutic benefit obtainable with the MAO-inhibitory drugs in general.

Platelet uptake of 5-hydroxytryptamine and dopamine and its relationship to mood in normal subjects.

Platelet uptake of the amines 5-hydroxytryptamine (5-HT) and dopamine has been found to be lower in depressed than in normal subjects. In the latter the values were more scattered. To discover whether this scatter was due to mild depression or predisposition to depression, 50 normal subjects whose amine uptake had been studied were asked to complete a questionnaire on symptoms and history of depression. No significant correlation between decreased amine uptake and answers to the questionnaire was found, but a correlation of minor significance (r=0.33; P less than 0.025) was found between increased number of potentially depressing life events and increased 5-HT uptake, contrary to what might have been expected. The scatter of values for amine uptake does not appear to be related to mood, or to personal or family history of depression.

The effect of high dose oxprenolol on stress-induced physical and psychophysiological variables.

The effects of oral oxprenolol (480 mg) and lorazepam (2 mg) on skin conductance, reaction time, critical flicker frequency and self-rating visual analogue scales for anxiety, sedation and concentration were investigated in 6 healthy male volunteers. Oxprenolol exerted a central action similar to lorazepam as shown by a significant lowering of skin conductance and decrease in the number of spontaneous fluctuations during stress, impaired critical flicker frequency and decrease in alertness with reduced concentration.

Unwanted effects of long-term medication in schizophrenia and depression.

Medicine is an experimental science which proceeds by trial and error, and with pharmacotherapy doctors must continually review the drugs at their disposal for both effectiveness and adverse effects. These adverse effects must be assessed not only in relation to the therapeutic effect, but also, of course, in relation to the severity of the patient's illness and the likely prognosis in the absence of treatment. In this review I will select one or two side effects in each of the major group of drugs for consideration.

The effects of protriptyline and clomipramine in vitro on the uptake of 5-hydroxytryptamine and dopamine in human platelet-rich plasma.

The effects of protriptyline and clomipramine, at concentrations of 10(-7)M to 10(-4)M, were studied in vitro on the uptake of 5-hydroxytryptamine and dopamine uptake in human platelet-rich plasma. It was found that the tertiary amine, clomipramine, was a more potent inhibitor of 5-hydroxytryptamine uptake than the secondary amine, protriptyline. The activity of both compounds was competitive but it was thought unlikely that they acted through tryptamine receptor sites as methysergide 2.5 X 10(-8)M had very little effect on 5-hydroxytryptamine uptake. Neither tricyclic antidepressant had any marked effect on dopamine uptake.

Is there an increase in monoamine-oxidase activity in depressive illness?

In a group of depressed patients who had either been treated with or considered suitable for monoamine oxidase (M.A.O.) inhibitor therapy, a highly significant decrease in conjugated tyramine output was observed after an oral tyramine load compared with normal controls. However, there was no difference in conjugated isoprenaline output between the two groups after isoprenaline ingestion, even though this amine is almost solely metabolised by what is likely to be the same conjugation mechanism. Whilst some explanation in terms of altered gut motility is conceivable, it seems more likely that the apparent deficit in tyramine conjugation in depression represents an increase in functional M.A.O. activity. Consequently, this enzyme would metabolise a greater proportion of available amine, causing a proportionately large decrease in the smaller conjugate pool.

Sensitive method for the routine determination tricyclic antidepressants in plasma using a specific nitrogen detector.

The sensitivity of the alkali flame ionization detector to the tricyclic antidepressant drugs has been studied and limits of detection measured. A backflush system has been used to enable measurement in plasma extracts. A general method for the estimation of tricyclic plasma levels has been developed and exemplified by the measurement of imipramine at therapeutic levels.