The title of this review would be regarded by some psychiatrists as provocative; they would relegate the biochemical concomitants of depression and mania to a secondary position and deny that biochemical changes have any place in the aetiology of these conditions. However, in my view, the weight of evidence, although it is by no means conclusive, suggests that biochemical changes are most important in the aetiology of affective disorders. A biochemical aetiology implies that there are certain biochemical changes in the brain which need to be restored to normal before the patient's clinical condition will improve. This does not deny that psychological and environmental events may precipitate and maintain the biochemical events which in turn lead to the affective disorder. The study of these biochemical events is clearly at too early a stage for speculations about the interrelationship between environmental and endogenous elements to be fruitful; this study must wait until the biochemical aetiology is clearer than at present.

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.

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