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.

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.

Suicide mortality in patients on lithium maintenance therapy.

Mood disorders are frequently recurrent and it has been shown that maintenance treatment can reduce long-term morbidity in this condition. It has also been shown that mood disorders carry an increased risk of suicide and that a significant proportion of individuals who commit suicide suffer from a mood disorder. This paper reports the results of a long term follow-up of a cohort of patients attending a specialist mood disorder clinic over a period of 18 years. Sixty-seven suffered from unipolar depression and 36 had bipolar or schizo-affective disorders In order to qualify for entry to the cohort the unipolar patients had to have had at least three episodes of depression and those with bipolar disorders had to have had at least three episodes - with at least one manic episode and one depressive episode. All patients were treated with lithium. The initial treatment refusal rate and drop our rates were low. The mortality from suicide in this group was compared with that reported in five recent studies - all of which involved patients who had not been given maintenance therapy. The standardised mortality ratio (SMR) for all causes for the whole group was 0.93. There were two suicides. In one case the patient had continued treatment with lithium until death and in the other the patient had discontinued treatment 12 months before death. The overall suicide rate was 1.3 per 1000 patient years. Amongst similar groups of patients who had not been given maintenance therapy suicide rates of about 5.5 per 1000 patient years have been reported. It is concluded that maintenance treatment of mood disorders reduces the suicide rate in this vulnerable group of patients.

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)

Does lithium reduce the mortality of recurrent mood disorders?

Numerous follow-up studies have shown that patients with mood disorders who do not receive prophylactic medication are at increased risk of death, particularly from suicide. After 11 years follow-up we compared the mortality of 103 patients attending a lithium clinic with that expected on the basis of age/sex/year-specific rates for England and Wales. Only 10 patients died during the study, although the expected number of deaths was 18.31 (P = 0.052, two-tailed) and no deaths from suicide were observed. After correcting for the prevalence of mood disorder in the general population, the relative risk was 0.60 (95% CI 0.29-1.12) which suggests that lithium reverses the excess mortality associated with recurrent mood disorders, including that from suicide.

Serum and red blood cell folate in depression.

Serum folate concentrations were estimated in patients with major depressive disorders, lithium-treated patients, detoxified alcoholic patients and normal controls. Red blood cell (RBC) folate concentrations were also estimated in subgroups of patients with major depressive disorder and normal controls. Results showed significantly lower serum and RBC folate concentrations in patients with major depressive disorder than in normal controls. Lower serum folate concentrations were associated with greater severity of depression. There was no association between serum and RBC folate concentrations and endogenicity of depression or the presence of weight loss.

Depression and tetrahydrobiopterin: the folate connection.

Total biopterin, neopterin and creatinine were measured in spot urine samples from affective disorder patients on lithium therapy and control subjects. Folic acid was also measured in plasma in a sample of the patients. The mean neopterin: biopterin ratio was significantly higher in the 76 patients (3.2 +/- 0.5) than in the 61 controls (1.8 +/- 0.1). In female patients biopterin levels were significantly lower than in controls. In the control groups there was a significant correlation between the molar concentration of neopterin and biopterin. No such correlation was found in the patients. These data indicate that tetrahydrobiopterin (BH4) biosynthesis is reduced in this group. A significant positive correlation was found between plasma folate and urinary biopterin. It is suggested that folate deficiency may impair the synthesis of BH4, a cofactor essential for the synthesis of 5-HT and other monoamines that are involved in the pathogenesis of affective disorders.

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.

Lithium therapy: from clinical trials to practical management.

Controlled trials have shown that lithium significantly reduces the morbidity of recurrent affective disorders. We describe here the ongoing affective morbidity in unipolar, bipolar and schizoaffective illness treated primarily by low dosage, once daily lithium, supplemented as necessary by antidepressant or neuroleptic medication. Seventy-eight percent of unipolar patients and 73% of bipolar and schizoaffective patients had no or only slight morbidity during the study year. The treatment was equally effective for both older (age greater than 70 years) and younger patients. Unipolar patients rated as endogenous on the Newcastle Scale had significantly lower morbidity than the nonendogenous patients. Subjective side effects were minimal. These patients, whose untreated morbidity is known to be high, derive considerable benefit from regular supervision in an affective disorder clinic.

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.

Seasonal variations in the dexamethasone suppression test.

One hundred and fifty-six patients from Epsom (U.K.) and Brussels, all suffering from major depressive disorder, were tested on the dexamethasone suppression test. Post-dexamethasone cortisol concentration in the plasma was found to be much lower in the winter months (November to February) than in the rest of the year.