Schizophrenia-like Psychoses of Epilepsy and Disturbances of Folate and Vitamin B₁₂Metabolism Induced by Anticonvulsant Drugs

Since it was first described by Mannheimer, Pakesch, Reimer and Vetter in 1952 megaloblastic anaemia has come to be recognized as an occasional complication of anticonvulsant drug therapy. More recently a disturbance in folic acid and vitamin B 12 metabolism has been observed in many non-anaemic drug-treated epileptic patients (Hawkins and Meynell, 1958; Klipstein, 1964; Malpas, Spray and Witts, 1966; Reynolds, Milner, Matthews and Chanarin, 1966a). Reynolds et al. (1966a) found megaloblastic haemopoiesis in 38 per cent. and subnormal serum folates in over 75 per cent. of a series of 54 out-patient epileptics. In addition, serum vitamin B 12 levels, though still within the normal range, were significantly lower in the megaloblastic group of patients than in controls. They suggested (1) that the anti-folate effects of phenobarbitone, phenytoin and primidone may be related to their therapeutic actions, and (2) that prolonged drug-induced disturbances of folate and vitamin B 12 metabolism may be responsible for certain side-effects, particularly mental symptoms. The latter possibility is supported by the increasing recognition of psychiatric illness due to vitamin B 12 deficiency in the absence of anaemia or subacute combined degeneration of the cord. (Langdon, 1905; McAlpine, 1929; Holmes, 1956; Smith, 1960; Edwin, Holten, Norum, Schrumpf and Skaug, 1965; Strachan and Henderson, 1965).