The suggestion that folate deficiency might produce psychiatric disturbances was made more than 30 years ago (Herbert, 1962a). Since then the issue has been examined by three approaches: assessment of the incidence of psychiatric disturbances in patients presenting with a medical condition related to folate deficiency (e.g., megaloblastic anemia), assessment of the incidence of folate deficiency in patients presenting with a psychiatric condition (of any etiology), and evaluation of the efficacy of folate treatment in the resolution of psychiatric disorders. In general, the database linking folate to altered mental function is not large but appears sufficient to suggest the likelihood of a causative association. However, it is still unclear whether reduced folate intake is the cause or an effect of the mental disorders.
The most unambiguous observation suggesting this link is derived from studying patients with megaloblastic anemia. Shorvon and coworkers (1980) reported that among such patients having a clear folate deficiency (plasma folate 3.4 ± 1.4 [standard deviation] nmol/ L [1.5 ± 0.6 ng/mL]) in the absence of vitamin B12 deficiency, the prevalence of an affective (mood) disturbance was 56 percent. Other studies of nonpsychiatric patients are consistent with this observation, showing changes in mood and in mental function (Goodwin et al., 1983; Herbert, 1962a; Reynolds et al., 1973).
Most studies that attempt to link folate deficiency and mental disorder are in psychiatric patients. The studies involved measurements of serum, plasma, or erythrocyte folate concentrations in patients on long-term drug therapy, some of whom were drug free when examined. No patients with a psychiatric diagnosis appear to have been assessed at first admission before drug therapy was instituted. Coppen and Abou-Saleh (1982), for example, measured serum folate concentrations in unipolar and bipolar depressed patients: mean plasma folate concentrations were significantly lower than those in a group of control subjects (13 vs. 15 nmol/L [6 vs. 7 ng/mL]). They further observed that in the psychiatric subjects, morbidity was significantly higher in individuals with plasma folate concentrations below 9 nmol/L (4 ng/mL) than in those with values at or above 18 nmol/L (8 ng/mL). In subjects with depression, the prevalence of folate deficiency (plasma folate less than 5.7 nmol/L [2.5 ng/mL]) was found to be 15 to 17 percent, a value substantially higher than the 2 percent found in control subjects (Abou-Saleh and Coppen, 1989); erythrocyte folate was also measured and found to correlate highly with plasma folate concentrations.