Lithium in unipolar depression and the prevention of suicide.

Unipolar depression is a severe recurrent illness with high lifetime morbidity and premature mortality due to suicide. Numerous double-blind, placebo-controlled trials have shown that lithium is very effective at reducing relapses when given as maintenance therapy. It is also very effective when given as maintenance therapy after electroconvulsive therapy. It can be given once a day at night, and controlled trials have shown a 12-hour plasma lithium level between 0.5 and 0.7 mmol/L the most effective, with very slight side effects. Long-term studies of lithium maintenance therapy show a suicide rate of 1.3 suicides per 1000 patient years. This is much lower than comparative studies in long-term follow-up of untreated depression, which show about 5.5 suicides per 1000 patient years. Although it is neither feasible nor ethical to carry out double-blind studies on suicide reduction, the massive evidence showing a reduction in morbidity on lithium treatment suggests that systematic long-term lithium treatment of unipolar depression could considerably lower the suicide rate.

Depression as a lethal disease: prevention strategies.

In 1971, my colleagues and I published the first prospective double-blind trial of the prophylactic effect of lithium in patients suffering from both unipolar and bipolar illness. In this trial we found that patients who received lithium experienced significantly less morbidity and required significantly less additional antidepressant and antimanic medication, as well as inpatient treatment and electroconvulsive therapy, compared with the patients who received placebo lithium. Subsequent to this trial we established a lithium clinic in which patients, both unipolar and bipolar, were given longterm lithium treatment. The patients attended regularly, usually four to eight times a year, and their clinical state and plasma lithium were regularly monitored and recorded. Patients were given lithium in a sustained-release form, once a day at night. In a careful random, double-blind trial, it was found that the optimum lithium dosage was that which gave a plasma level of 0.5-0.79 mmol/L 12 hours after the nightly dose. In 1982 all patients were switched to this lower dosage, and the recorded morbidity of the group showed a small but significant decline, thus confirming in practice the optimum dosage found in the double-blind trial. I report here the results of the follow-up of a group of 103 patients (67 unipolar, 30 bipolar, and 6 schizoaffective) from January 1977. The patients' mortality and, in particular, suicide rate has been carefully recorded. Compliance with the regimen had been high. At the end of December 1992, there had been 2 suicides in the group--one of the patients had discontinued taking lithium some months before the suicide.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin and its place in the pathogenesis of depression.

The authors review the literature in an attempt to evaluate the relationship between serotonin and depression. Animal studies show that the administration of tryptophan (the precursor of serotonin) increased serotonin synthesis and influenced behavior. Low plasma tryptophan levels have been found in patients with endogeneous depression. Postmortem studies have shown an association between lowered hindbrain serotonin levels and suicide among depressed persons. The decreased serotonin levels in blood platelets during depression mirrored the neuronal changes. Tricyclic antidepressants inhibited platelet serotonin uptake and reduced imipramine binding sites on the platelets. A positive correlation between depression rating scores and platelet aggregatory response has been reported. Serotonin stimulated release of prolactin and growth hormone, although the prolactin response was less marked in depression. A marker for depressive illness is still sought, but it is likely to be related in some way to serotonin.

Noradrenaline, depressive illness, and the action of amitriptyline.

The tyramine-dose/pressor response test was carried out on a series of patients suffering from primary depressive illness before and during treatment with amitriptyline. The severity of their depression was assessed during the study of the Hamilton Rating Scale (HRS). The decreased tyramine sensitivity induced by the drug, which is related to the inhibition of NA reuptake, correlated significantly with the plasma concentration of nortriptyline. However, contrary to the expectation of the noradrenaline hypothesis of depression, the decreased tyramine sensitivity, i.e., the degree of NA-reuptake blockade, did not show any correlation with clinical improvement following 6 weeks' treatment with amitriptyline.

Autonomic actions and interactions of mianserin hydrochloride (Org. GB 94) and amitriptyline in patients with depressive illness.

The clinical pharmacology of mianserin hydrochloride was studied in patients suffering from a primary depressive illness after steady-state plasma concentration of the drug had been achieved. The results were compared with those found with amitriptyline in both open and double-blind studies. The two drugs are equally effective in their antidepressive effect. Mianserin hydrochloride appears to be free of anticholinergic effects as assessed by the measurement of salivary volume, pupil diameter and the interactions with guanethidine and thymoxamine on the pupil. No peripheral adrenergic interaction as studied by the tyramine dose-pressor-response test were observed in patients treated with mianserin hydrochloride (20 mg three times daily).

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.

Antidepressant activity and pharmacological interactions of ciclazindol.

Ciclazindol, a new tetracyclic compound, appears to be a potentially important antidepressant of the same order as amitriptyline, but with significantly fewer subjective side effects. Although as a group the patients treated with ciclazindol lost weight, clinical improvement was observed to be significantly correlated with the weight gain in both groups. The peripheral adrenergic interactions were studied. In the dosage used (100 mg/day) ciclazindol was observed to be a peripheral Na-reuptake blocker with no significant effect on the postsynaptic alpha-receptors. Plasma concentrations of the drug were estimated and their relationship to the therapeutic outcome, side effects, and adrenergic interaction were studied. No significant change in resting BP or ECG was observed following 4--6 weeks' treatment with ciclazindol.

A clinical and pharmacodynamic evaluation of sulpiride.

In a double-blind study the therapeutic efficacy of sulpiride was compared to that of haloperidol--an established neuroleptic agent. A total of 30 female patients with a diagnosis of chronic schizophrenia were initially stabilised on the dosage of haloperidol which produced optimum therapeutic response when given once or twice daily. The patients were then randomly allocated to receive either sulpiride or haloperidol over a period of 12 weeks. Plasma drug concentrations and prolactin levels were determined. Clinical effects were evaluated by Brief Psychiatric Rating Scale (BPRS), Wing Rating Scale, and Extrapyramidal Symptoms Rating Scale (EPS). A standardised side-effects checklist was used. Treatment with sulpiride was associated with a significant rise in plasma prolactin level, but paradoxically these patients had significantly reduced extrapyramidal symptoms. No significant correlation was found between plasma sulpiride concentration and prolactin level or any of the clinical variables. The study confirms the antipsychotic activity of sulpiride.

Increased platelet monoamine oxidase activity in affective disorders.

Platelet monoamine oxidase activity was determined in 52 unipolar depressive patients, 26 patients with bipolar affective disorder and 48 controls using phenylethylamine as substrate. Unipolar depressive patients of either sex and bipolar depressive women showed significantly higher platelet MAO activity than controls. Women had higher activity than men. Neither age nor serum lithium level correlated with enzyme activity and there was no significant change in activity after the institution of lithium treatment.

Zimelidine: a therapeutic and pharmacokinetic study in depression.

Zimelidine, a bicyclic compound with a strong effect on the neuronal reuptake of 5-hydroxy-tryptamine 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.

Inhibition of 5-hydroxytryptamine reuptake by amitryptyline an 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.

Urinary 4-hydroxy-3-methoxyphenylglycol is not a predictor for clinical response to amitriptyline in depressive illness.

The urinary excretion of 4-hydroxy-3-methoxyphenylglycol was compared in a group of 23 depressive patients and 27 control subjects of similar age. There was no difference between patients and controls although female controls excreted less than males. After 6 weeks' treatment with 150 mg daily of amitriptyline there was no correlation between therapeutic response and pretreatment urinary excretion value.

The efficacy of low-dose lithium: clinical, psychological and biological correlates.

The relationships between lithium dosage, affective morbidity, side-effects, thyroid and renal function and biological markers for depression were examined in the context of a prospective double-blind lithium reduction study in patients receiving prophylactic lithium. Unipolar and bipolar patients on such treatment were randomly allocated to two groups over a period of one year, either continuing with their usual dosage of lithium or reducing their lithium dosage by up to 50%. Biological markers investigated included dexamethasone suppression test (DST) and 5-hydroxytryptamine (5-HT) transport into platelets (Vmax). Results showed no association between affective morbidity and lithium dosage/level. There was, however, an association between lower dosage/level of lithium and lower side-effects, including tremor and weight gain, lower TSH levels and lower 24 h urinary volume in these patients. Elderly patients, however, experienced significantly greater morbidity upon reduction of their lithium dosage. There was an association between increased Vmax of 5-HT transport and a reduction in morbidity. DST non-suppression was associated with lower mean weight for the whole year of the study.

The biology of folate in depression: implications for nutritional hypotheses of the psychoses.

Folate deficiency is a common occurrence in psychiatric disorders, whether organic or functional, particularly in depressive illness. We have shown that folate deficiency is a common association of depressive symptoms in a variety of settings including primary endogenous or non-endogenous depression, and in alcoholic, lithium-treated and anorexic patients. Possible pathogenetic mediating mechanisms for this association are methylation and hydroxylation and the implications for nutritional hypotheses of the psychoses are discussed. We suggest that folate deficiency, with or without deficiencies of other nutritional factors such as monoamine precursors, vitamins B6, B12 and C, may predispose to or aggravate psychiatric disturbances, particularly depression and a model for these interactions is proposed.

Antidepressant evaluation and the pharmacological actions of FG4963 in depressive patients.

FG4963 a phenylpiperidine derivative and potent 5-HT reuptake inhibitor at neuronal sites was investigated in a group of 10 depressive patients, and its effect was compared with that of amitryptyline in a group of 10 depressive patients treated with amitriptyline. FG4963 was found to be significantly inferior as an antidepressant compared to amitryptyline over a 6-week period. FG4963 did not appear to be anticholinergic as judged by its lack of effect on salivary flow. Its effect (in the dosage used) on the tyramine dose--pressor response and NA dose--pressor response tests were less than those of amitryptyline.

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.

Decreased tryptophan excretion by depressive patients.

The concentration and 24-h urinary excretion of tryptophan has been measured in urine samples from monopolar female depressed patients and female control subjects. Female depressed patients and the control subjects excrete similar amounts of tryptophan. Patients with endogenous features of depression excrete significantly less tryptophan in 24 h than do the patients with reactive features and the control subjects. The relationship between plasma tryptophan concentration and 24-h urine tryptophan excretion in control subjects has been investigated and the results discussed in the light of abnormalities of tryptophan metabolism in depressive illness.

Decreased cerebrospinal fluid concentration of free phenylacetic acid in depressive illness.

Cerebrospinal fluid free phenylacetic acid concentration in a series of depressive patients was significantly lower than values in control subjects. This acid derives from phenylethylamine and the findings may reflect a decrease in its brain formation. Such a deficit may be related to other recent observations of a decrease in urinary output of the major metabolites of the "trace amines", octopamine and tyramine: phenylethylamine is thought to be the precursor of these "trace amines".

Comparison of methods for the determination of total and free tryptophan in plasma.

A comparison is made between two fluorimetric techniques for the determination of total and free plasma tryptophan. Comparison is also made between methods for the separation of the unbound and bound fraction of plasma tryptophan using ultrafiltration, Centricones and small-scale equilibrium dialysis.

Tryptophan accumulation by blood platelets of depressed patients.

The accumulation of tryptophan by blood platelets has been investigated in depressive patients and controls using short incubation times and low substrate concentrations. The accumulation of tryptophan by the platelet is significantly greater in the acutely depressed patients than the control group. The results are discussed with reference to tryptophan transport in depression and also to the regulation of plasma levels of tryptophan.