Vitamin Therapy in Schizophrenia

Isr J Psychiatry Relat Sci Vol 45 No. 1 (2008) 3–10 Vitamin Therapy in Schizophrenia Leonard John Hoffer, MD, PhD, Professor of Medicine McGill University, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada. Abstract: Schizophrenia is a devastating and poorly understood disease for which the only accepted therapy is non- specific antipsychotic and anti-seizure medication. This article summarizes the evidence that certain vitamin deficiencies likely worsen the symptoms of schizophrenia, and the evidence that large doses of certain vitamins could improve the core metabolic abnormalities that predispose some people to develop it; it recounts the history of a controversial vitamin-based therapy for schizophrenia called orthomolecular psychiatry; and it concludes by advocating a process for discovering promising new schizophrenia therapies that involves small, carefully conducted clinical trials of nutrient combinations in appropriately selected patients. It is dismaying that well into the 21st century schizo- it has been reported that patients with a history of phrenia remains a highly prevalent, devastating and poor pre-morbid psychological adjustment and poorly understood disease for which the only ac- more neuropsychological and neurological abnor- cepted therapy is non-specific antipsychotic and malities have a worse prognosis (1). anti-seizure medication. Fresh approaches, even un- People in the early stage of schizophrenia gener- conventional ones, should be welcomed for study by ally respond better to antipsychotic drug therapy the psychiatric community if they are biologically than those who have had the disease for many years, plausible and non-toxic. This article summarizes the and early intervention is currently believed to pre- evidence that certain vitamin deficiencies can vent the disease from progressing to a treatment-re- worsen the symptoms of schizophrenia, and the evi- sistant stage (2). These drugs control psychosis with dence that large doses of certain vitamins could im- varying degrees of success, but their toxicity and prove the core metabolic abnormalities that often disabling side effects reduce medication adher- predispose some people to develop it; it recounts the ence and contribute to the high relapse rate typical of history of a controversial vitamin-based therapy for schizophrenia (3). Some people with well-diagnosed schizophrenia called orthomolecular psychiatry; schizophrenia have spontaneous remissions and no and it concludes by advocating a process for discov- longer require antipsychotic drugs; the explanation ering promising new schizophrenia therapies that for these favorable outcomes is unknown (4). involves small, carefully conducted clinical trials of nutrient combinations in appropriately selected pa- Psychiatrists attempting to discover an etiology- tients. based therapy for schizophrenia may take two general approaches. The first is subgroup analysis of Schizophrenia is a chronic disorder of brain func- large randomized clinical trials. Unfortunately, sub- tion that affects perception, cognition, motivation and behavior. Its predisposition, precipitating causes group analysis is difficult and notoriously unreliable, and pathophysiology are very poorly understood, andthevalidityofeventheoverallanalysisoflarge but, as in all chronic diseases, likely to be strongly in- randomized clinical trials is questionable when their fluenced by psychological factors. Lacking biological eligibility criteria exclude much of the patient popu- insight, psychiatrists diagnose schizophrenia purely lation, only a small fraction of eligible patients par- from its clinical presentation, a practice that is ticipate, and a large fraction of participants withdraw known be highly unsatisfactory but may be of some from the study prematurely (3). The second ap- value in identifying patients whose symptoms are proach is for the interested and open-minded psy- predominantly “positive” or “negative.” For example, chiatrist to gather clinical and biological information Address for Correspondence: L. J. Hoffer, MD, PhD, Lady Davis Institute for Medical Research, 3755 Cote Ste Catherine, Montreal, Quebec, Canada H3T 1E2. E-mail: [email protected] 4 VITAMIN THERAPY IN SCHIZOPHRENIA on the lookout for promising leads, as described later which variations in the concentration of a vitamin or in this article. other naturally-occurring molecule that serves a metabolic regulatory role could improve brain function,suchasbychanginganenzyme’scatalyticactiv- Vitamin Deficiencies and Vitamin ity through a shift in the equilibrium between co- Therapy in Schizophrenia enzyme and apo-enzyme. It is currently popular to regard schizophrenia as a Anexamplepertinenttomyownresearchmaybe “multiple-hit” neurodevelopmental disorder; cited. For unknown reasons, plasma homocysteine equally plausible is the older hypothesis of a toxic concentrations are markedly increased in most peo- psychosis triggered by an abnormal endogenous me- ple with end-stage renal disease. We and others re- tabolite. Organic brain disorders indistinguishable cently showed that parenteral vitamin B12 therapy from schizophrenia may be induced by certain drugs greatly increases the serum cobalamin concentra- and by neurological, metabolic, inflammatory and tions of hemodialysis patients and can virtually elim- infectious diseases (1). Such disorders account for inate their hyperhomocysteinemia. It is known from approximately 5% of cases initially diagnosed as cell-culture studies that in very high concentrations first-episode schizophrenia by expert psychiatrists cobalamin greatly increases the activity of the (5). Wilson’s disease, unrecognized adult cobalamin-dependent, homocysteine-metabolizing phenylketonuria (6), pellagra and celiac disease (7) enzyme, methionine synthase. Accordingly, we have can induce brain disorders indistinguishable from suggested that the hyperhomocysteinemia of renal schizophrenia. A patient with celiac disease and clas- failure is largely due to uremic inhibition of sic schizophrenia with typical SPECT scan abnor- methionine synthase which can be overcome in vivo malities had complete resolution of both diseases by therapeutically increasing the tissue concentra- after being placed on a gluten-free diet (8). Although tion of its coenzyme (10). known metabolic disorders and neurologic injury Vitamin therapy could benefit people with only rarely cause clinical schizophrenia, their very schizophrenia by preventing or reversing the symp- existence is good reason to search for the abnormal toms of vitamin deficiency disease, or by normaliz- molecules, enzyme activities, and markers of brain ing disordered brain metabolism when administered injury that may eventually reveal its cause or causes. in doses greater than required to prevent deficiency. In 1968 the renowned chemist Linus Pauling Since the diet of people with mental illness is often published an article in Science entitled Ortho- extremely poor, it is quite likely some of them suffer molecular Psychiatry in which he described a bio- from vitamin deficiencies which could worsen their chemical model for investigating nutritional already disturbed brain function. Simple correction therapies for mental diseases (9). Pauling defined of unrecognized nutrient deficiencies could explain orthomolecular psychiatric therapy as the treatment the improvements reported in mentally ill patients of mental diseases by providing the optimum molec- and prison inmates administered standard vitamin ular environment for the brain, especially the opti- supplements (11, 12). mum concentration of substances normally present Modern advances in molecular biology generally in the body. Examples of orthomolecular therapy in- support the concept of orthomolecular psychiatry as clude dietary phenylalanine restriction in proposed 40 years ago (9). As many as one-third of phenylketonuria, high-dose pyridoxine therapy in pathologic gene mutations are now considered to pyridoxine-responsive variants of homocystinuria, cause clinical disease by decreasing the affinity of an and the treatment of the psychosis caused by pella- enzyme for its coenzyme or substrate, reducing the gra with niacin. The notion that the brain is affected enzyme’s catalytic activity (13). Many single-nucleo- by its molecular environment is hardly controversial; tide polymorphisms could also reduce catalytic ac- what made Pauling’s article novel was that it laid out tivity by decreasing coenzyme-apoenzyme binding, a conceptual framework for generating hypotheses including the binding of nicotinamide adenine about the pathogenesis and treatment of mental dis- dinucleotide (NAD) and nicotinamide adenine eases. He identified a number of mechanisms by dinucleotide-phosphate (NADP), the cofactors syn- LEONARD JOHN HOFFER 5 thesized from dietary niacin and niacinamide (13). fect in folic acid metabolism has been shown to cause In such situations the impairment could, in princi- a schizophrenic syndrome (27). The addition of 15 ple, be at least partly remedied by raising mg/day of methylfolate to standard psychiatric ther- intracellular cofactor concentrations with high-dose apy improved the clinical and social recovery of pa- vitamin therapy. Evidence has steadily accumulated tients with acute schizophrenia (28, 29). that cellular NAD, the concentrations of which can be modified by niacin or niacinamide administra- tion, plays critical roles in metabolic regulation and Ascorbic Acid repair (14). In

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