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Treatment Resistance in Schizophrenia: The Role of Alternative Therapies: Page 3 of 3

Treatment Resistance in Schizophrenia: The Role of Alternative Therapies: Page 3 of 3

Early interest in homocysteine and folate metabolism

Methionine is an essential amino acid that is centrally involved in key methylation reactions in the body; when a methyl group is added to methionine it becomes a homocysteine. In the early 1960s, several reports noted that when persons with schizophrenia were challenged with a methionine load, some experienced worsened psychiatric symptoms, generating the transmethylation hypothesis for the cause of schizophrenia.39,40

In the 1960s and 1970s, interest was sparked by several case reports of patients who had psychotic disorders and genetic-based functional deficiencies of key enzymes in methylation pathways that involved methionine and homocysteine, including deficiencies in cystathionine synthase (associated with homocystinuria)41 and of 5,10-methylenetetrahydrofolate reductase (MTHFR).42 These patients were treated with high-dose folate, which decreased high homocysteine levels and significantly improved psychiatric symptoms. However, a screening of 949 consecutive psychiatric admissions (one third presenting with schizophrenia) failed to uncover a single case of aminoaciduria,43 and it became clear that such interesting case reports had little to do with the cause of most cases of schizophrenia.

In part inspired by findings that pregnant women exposed to famine conditions are more likely to give birth to offspring with neural tube defects (likely from folate deficiency) as well as offspring with schizophrenia, there has been continuing interest in folate, homocysteine, and the MTHFR gene in the possible pathogenesis of schizophrenia. Thus far, some suggestive findings have failed to be replicated; yet there appear to be unexplained disturbances in this metabolic pathway that are associated with the risk of a diagnosis of schizophrenia.44,45

Homocysteine and vitamin B redux

High homocysteine levels have been found to interfere with NMDA receptors in animal studies. Neeman and coauthors46 reported finding lower plasma glycine levels and higher homocysteine levels in patients with schizophrenia compared with controls, and glycine levels correlated with increased negative symptoms. Findings of higher homocysteine levels in patients with schizophrenia may often involve folate-deficient dietary choices, obesity, or cigarette smoking, but one study found that these variables explained relatively little of the high homocysteine levels.47 In any case, remediation of high homocysteine levels with vitamin supplements is fairly straightforward, accomplished by adding high-dose folate, vi- tamin B12, and sometimes pyridoxine.

Recently, 42 individuals with schizophrenia who had high homocysteine levels received 3 months of treatment with vitamins or placebo in a crossover study. Those receiving the vitamins were found to have significant improvements in clinical symptoms as measured by PANSS and neuropsychological test scores, compared with placebo.48


Oxidative stress/free radical damage has been proposed as mediating pathology in various neuropsychiatric disorders, including schizophrenia. Small initial trials failed to shed adequate light on the value of ascorbic acid (vitamin C) in the treatment of schizophrenia,49,50 although a recent 8-week study reported significant improvement in Brief Psychiatric Rating Scale scores for those receiving an adjunctive 500 mg/d dosage of vitamin C.51 In addition, one study25 with positive findings used adjunctive omega-3 with vitamins C and E. Additional studies are needed to evaluate this approach.

Another putative adjunctive antioxidant strategy in schizophrenia involves the addition of EGb, a standardized Ginkgo biloba extract. Although several studies have shown fairly consistent preliminary results,52-54 larger and more definitive studies are still needed.

Other modalities

Recent Cochrane Database Reviews addressing other modalities for the treatment of patients with schizophrenia have found insufficient evidence to recommend acupuncture,55 hypnosis,56 or art therapy.57 However, a review of adjunctive studies of Chinese herbal medicines found some suggestion of efficacy58 and a review of music therapy concluded that there was some evidence of benefit, if at least 20 sessions were provided.59

Many patients (80%) who have serious mental illnesses successfully use religious or spiritual beliefs and practices as coping strategies in their daily lives.60,61 We have organized a state hospital inpatient group designed to mobilize religious and spiritual resources to aid patients' coping and recovery62; it would be helpful to have more efforts exploring the potential value and drawbacks of patients' use of religion and spirituality.

Alternative approaches in other roles for schizophrenia

Vitamins may be useful as potential prophylaxis. The higher rates of schizophrenia in those born in winter or spring, and the reported association between prenatal exposure to the 1945 famine of the "Dutch Hunger Winter" and later development of schizophrenia in offspring may be rationalized by the hypothesis that schizophrenia is more prevalent in those who have had vitamin D deficiency during the first year of life. The results of a 1966 study of a Finnish-birth cohort lend support to this theory.63 However, as there were very few children not given the then-recommended vitamin D supplement, and since not receiving the supplement may have been associated with other plausible risk factors, this single study provides only weak support for this interesting idea.


The term "complementary medicine" may sound better than "alternative medicine" to most physicians. Whatever it is called, open-mindedness should not be an excuse for lowering the standards of evidence-based medicine in establishing definitive opinions. While waiting for better evidence to substantiate or disprove various complementary approaches, let us partner with patients and their families in deciding on rational treatment strategies, and share with each other the findings, case reports, or randomized controlled trials, whether their results are positive or negative.



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