Reported findings of differences in essential plasma unsaturated fatty acid membrane composition in patients with schizophrenia led to the consideration of prescribing omega-3 fatty acids, which was bolstered by a dramatic case report.21,22 Controlled studies have resulted in encouraging but somewhat mixed findings, unlike the more robust findings for omega-3 in depression. Two essential omega-3 fatty acids were compared in a 3-month, double-blind pilot study that found that augmentation with eicosapentaenoic acid (EPA) was superior to docosahexaenoic acid(Drug information on docosahexaenoic acid) (DHA) or placebo in significantly reducing Positive and Negative Syndrome Scale (PANSS) scores23; a second study using EPA suggested that supplementation with omega-3 for extended periods can benefit some patients even without antipsychotics.23
In a 16-week, double-blind study of 40 patients with schizophrenia that augmented antipsychotic treatment with either 3 g/d of ethyl-EPA (e-EPA) or placebo, Emsley and colleagues24 found superiority for the e-EPA condition in reducing PANSS scores (mean decrease in PANSS score of 12.6 on e-EPA vs 3.1 on placebo; P = .03). Using the PANSS and other scales, an open-label augmentation study of 33 patients with schizophrenia reported an advantage in omega-3 augmentation—in this case using EPA, DHA, and vitamins C and E.25
On the other hand, a 16-week trial in 87 patients that compared 3 g/d of e-EPA with placebo found no difference in positive, negative, mood, or cognitive symptoms of schizophrenia.26 Noting that both the active and placebo groups had improvements in their PANSS ratings, these investigators evaluated the placebo response in 37 study participants and found that the 9.5% improvement in the PANSS total score usually occurred by the end of the first 2 weeks of participation, which argues for the value of a placebo run-in phase for future studies.27
Revisiting the initial findings of plasma membrane abnormalities, a 24-hour dietary recall in 146 community-dwelling patients with schizophrenia found little difference in dietary fatty acid and antioxidant intake from controls.28 However, a more elaborate evaluation of 72 subjects with schizophrenia found that the previously reported membrane lipid abnormalities could be explained by the fact that many of the subjects were smokers and had a significantly different omega-3 dietary intake from that of the controls.29 A recent review of the few randomized controlled trials concluded that while there was some evidence for clinical improvement and decreased need for neuroleptics in patients with schizophrenia who have EPA or e-EPA added to their treatment regimen, larger studies are still needed to establish a clear benefit.30NMDA glutamate receptor and glycine(Drug information on glycine), d-serine, and d-alanine
Sitting between mainstream and alternative therapies are amino acid treatments, derived from the recognition that phencyclidine (PCP) psychosis was a better model for schizophrenia than the previous model of amphetamine psychosis. Among other observations, those with PCP intoxication presented with negative as well as positive symptoms. The mechanism of PCP's action was eventually elucidated; it specifically blocked the ion channel in NMDA (N-methyl-d-aspartate) glutamate receptors in the brain. An allosteric modulatory site on this complex receptor has been referred to as the "glycine" site, and its endogenous ligands plausibly may be the amino acids glycine, d-serine, and d-alanine (the latter 2 unusual d-forms present in the brain because of a racemizing enzyme).31
Some lines of evidence suggest that the NMDA glycine site may be the locus of a primary lesion in persons with schizophrenia. Furthermore, Hashimoto and associates32,33 have found reduced serum d-serine levels and reduced cerebrospinal fluid d-serine/ serine ratios in patients with schizophrenia; other studies suggest that identified genes linked to schizophrenia may be acting at this site.34
A meta-analysis of short-term clinical trials found that treatment augmented with the agonists glycine and d-serine moderately reduced negative symptoms, while partial agonist d-cycloserine was less efficacious.35 These agents do not appear helpful for patients treated with clozapine(Drug information on clozapine), although glycine and d-serine may be effective for those being treated with olanzapine(Drug information on olanzapine) or risperidone(Drug information on risperidone).36,37 A more recent study supports the efficacy of d-alanine.38 Glycine is available to the public as a dietary supplement.