Keith Wood

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.

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.

Decreasing Lithium Dosage Reduces Morbidity and Side-Effects During Prophylaxis

In a prospective double-blind trial we examined the affective morbidity and side-effects of 72 patients who were randomly allocated either to continue with their usual dose of lithium or to receive either a 25% or 50% reduction in lithium dosage. Patients who underwent a dosage reduction with consequently lower plasma lithium levels (0.45-0.79 mmol/l) had significantly decreased affective morbidity. Thyroid stimulating hormone levels were also significantly decreased in this group. Total subjective side-effects score and tremor were also reduced. No change in affective morbidity was observed during the trial in patients whose dosage was not altered. These changes were observed in both unipolar and bipolar patients. It was concluded that a once a day dosage with a sustained release lithium preparation that maintained a 12-h plasma level of about 0.6 mmol/l is both more effective and produces less side effects than does conventional dosages.

Neuroendocrine studies in affective disorders

The plasma prolactin response to thyrotropin-releasing hormone, which is thought to be mediated by central 5-HT mechanisms, has been studied in patients with affective disorders. There was no difference between depressive patients (taken as a whole), bipolar patients undergoing a manic phase and controls in the prolactin response to thyrotropin-releasing hormone. When the depressive patients were divided on a genetic basis into familial pure and sporadic depressive disease it was found that the sporadic patients had an enhanced response. The results do not provide any strong evidence to suggest that central 5-HT mechanisms as measured by the prolactin response to thyrotropin-releasing hormone are abnormal in depressed patients or bipolar patients undergoing a manic phase. Patients after ECT had an increased prolactin response to thyrotropin-releasing hormone which may indicate increased sensitivity of central 5-HT receptors following this treatment.

Tryptophan and depressive illness.

Plasma free tryptophan is significantly decreased in monopolar, depressed patients. No evidence was found to suggest that poor nutritional history prior to hospital admission was responsible for these low levels. Factors known to influence tryptophan-albumin binding in plasma, e.g. concentration of plasma proteins, albumin and non-esterified fatty acids, did not account for the low levels of free tryptophan in depressed patients. A significant decrease in plasma free tryptophan levels was found in perimenopausal but not in pre- or post-menopausal female controls. This mirrors the decrease in circulating oestrogens. Although exogenously administered oestrogens do not have any therapeutic efficacy in relieving mild residual depressive symptoms of lithium treated patients, they increased the levels of plasma free tryptophan. Clofibrate also displaces tryptophan from plasma protein binding sites in both depressed patients and controls. Utilization of the increased levels of plasma free tryptophan is reduced in depressed patients. A situation therefore exists in depressed patients where the plasma free tryptophan is not only reduced but also leaves the plasma less readily than in control subjects.

Inhibition of 5-hydroxytryptamine reuptake by amitriptyline and zimelidine and its relationship to their therapeutic action

Amitriptyline and zimelidine significantly reduce the uptake of 5-HT into the blood platelets of depressive patients. The degree of inhibition is significantly correlated with the plasma drug level of amitriptyline. No significant relationship could be detected between the degree of inhibition of uptake and therapeutic outcome. The accepted mode of action of tricyclic antidepressant drugs and the deficiency hypotheses of affective disorders are discussed.

Lymphocyte beta-adrenergic receptor density of patients with recurrent affective illness

The binding characteristics of (-)3-[125I]iodocyanopindolol, a high specific activity antagonist for the lymphocyte beta-adrenoceptor, were determined in a group of euthymic lithium-treated patients and controls. There was a statistically significant reduction (less than 20%) in the density of beta-adrenoceptors in a group of 56 lithium-treated patients. Division of this group of patients into the unipolar and bipolar distinction indicated that the abnormality was based mainly in the bipolar group of patients. The unipolar patients with an endogenous form of the illness also showed this abnormality. Reduced beta-adrenoceptor density may be associated with endogenous affective illness. However, the results must be interpreted with caution since lymphocyte fractions prepared for beta-adrenoceptor assays can be contaminated with platelets and since platelets have been reported to have beta-receptors then a proportion of the total binding could be associated with platelet beta-adrenoceptors rather than with lymphocyte beta-adrenoceptors.

Peripheral Serotonergic Receptor Sensitivity in Depressive Illness

Platelet aggregation induced by 5-HT was used as a measure of the functional responsiveness of peripheral 5-HT receptors in controls and drug-free depressed patients. No significantly different aggregatory response (5-HT/ADP ratio) was noted between the controls and drug-free depressed patients. If the receptor mediating this response is a 5-HT2 receptor, there is no overwhelming evidence to suggest that the functional activity of this system is abnormal during a depressive illness. The results are discussed with reference to reported abnormalities of 5-HT2 receptors during a depressive illness and to their change during antidepressant treatment.

The effect of antidepressant drugs on plasma kynurenine in depressed patients

The concentration of kynurenine in plasma from depressed patients and control subjects has been measured using a sensitive and specific method. The levels of kynurenine in the plasma of depressed patients and controls are not significantly different and are not influenced by age or sex. The severity of affective disturbance was not related to plasma kynurenine levels in depressed patients. Clinical outcome could not be accurately predicted by measurement of plasma kynurenine levels. Amitriptyline did not significantly increase plasma kynurenine concentration in vivo, whereas lithium and mianserin did have a significant effect. These results are discussed with reference to known abnormalities of tryptophan metabolism in depressive illness and in particular to the 5-hydroxytryptamine uptake characteristics of blood platelets in depressive patients.

Prophylactic lithium treatment of patients with affective disorders is associated with decreased platelet [3H] dihydroergocryptine binding

Intact platelet [3H]dihydroergocryptine binding characteristics have been determined in female patients with a history of affective disorders who have been treated with prophylactic lithium. These results have been compared with results obtained from concurrent experiments in normal female controls and acutely-depressed, female drug-free patients. The platelet density of alpha 2-adrenoceptors in the lithium-treated patients is similar to that of the depressed patients as there are significantly fewer sites per platelet when compared to normal controls. It is concluded that lithium treatment with remission from affective illness is not associated with a change toward normal of alpha 2-adrenoceptor density and represents a trait in patients prone to affective disorder. The problem of comparison of results of platelet alpha 2-adrenoceptor density obtained from different laboratories is discussed with particular reference to the non-uniform choice of [3H]ligands used.