Schizophrenia

NOTICE: This health information was not created by the University of Michigan Health System (UMHS) and may not necessarily reflect specific UMHS practices. For medical advice relating to your personal condition, please consult your doctor. Complete disclaimer

Schizophrenia

Need to Know

Schizophrenia
Hallucinations and delusions are two telltale signs of schizophrenia. According to research or other evidence, the following self-care steps may be helpful.
  • Go for the glycine

    With a healthcare professional’s supervision, help improve symptoms such as depression with daily use of this nutritional supplement; take 0.8 grams for every 2.2 pounds (1 kg) of body weight

  • Rest easy with melatonin

    Improve sleep quality and duration with this natural hormone; take 2 mg of a controlled-release preparation before bedtime

  • Try megadose vitamin therapy

    Work with a healthcare professional knowledgeable in nutritional treatment of schizophrenia to find out whether large amounts of vitamin B3, B6, or C improves symptoms

  • Find a fix for low folic acid levels

    Visit your doctor to determine if your blood is low in folic acid, and if 10 to 20 mg a day of this vitamin might help improve symptoms

About

About This Condition

Schizophrenia is a common and serious mental disorder characterized by loss of contact with reality.

The behaviors, described below, must be present for six months or longer to establish a diagnosis. Approximately 1% of the world’s population is affected by this condition. Schizophrenia is more common among lower socioeconomic classes in urban areas, perhaps because its disabling effects lead to unemployment and poverty. In the United States, 25% of all hospital beds are occupied by people with schizophrenia.

Symptoms

Symptoms and signs of schizophrenia include loss of contact with reality (psychosis), auditory and visual hallucinations (false perceptions), delusions (false beliefs), abnormal thinking, restricted range of emotions, diminished motivation, and disturbed work and social functioning. People with schizophrenia may also engage in speech that does not make sense, exhibit silly or childlike facial expressions, and experience poor memory or confusion.

Holistic Options

Magnetic stimulation to the skull and underlying motor cortex (the part of the brain that controls movement) significantly reduced auditory hallucinations in a group of people with schizophrenia in a small, controlled trial.1 The procedure was performed by psychiatrists using sophisticated electromagnetic medical equipment, not a simple magnet.

Eating Right

The right diet is the key to managing many diseases and to improving general quality of life. For this condition, scientific research has found benefit in the following healthy eating tips.

Recommendation Why Get started
Try a gluten-free, dairy-free diet Work with a nutritionist to follow a gluten-free, dairy-free diet that may help improve responses to medication.

Try a gluten-free, dairy-free diet

For many years there has been speculation that certain dietary proteins may contribute to the symptoms of schizophrenia.2 , 3 , 4 Gluten, a protein from wheat and some other grains, and to a lesser extent casein, a dairy protein, have been the targets of research on food sensitivities as contributors to schizophrenia.5 People with schizophrenia have been shown to be more likely to have immune reactions to these proteins, than the general population.6 A preliminary trial of a gluten-free/dairy-free diet found that patients with schizophrenia improved on the diet and had shorter hospital stays than those eating normal diets.7 The results of double-blind trials, however, have been inconsistent. The gluten-free/dairy-free diet improved responses to medications in one controlled trial.8 These improvements were lost and symptoms of schizophrenia were aggravated when gluten was re-introduced in a “blinded” fashion. Another clinical trial found similar positive responses in only 8% of patients.9 Other controlled trials have found no improvement when gluten and dairy were removed from the diet.10 , 11 In one clinical trial, blinded reintroduction of gluten appeared to cause improvement of symptoms.12 These results suggest that some, but not all, people with schizophrenia may benefit from a gluten-free/dairy-free diet.

Supplements

What Are "Star" Ratings?

a7_3star   Reliable and relatively consistent scientific data showing a substantial health benefit.

a7_2star   Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.

a7_1star   For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support.

Our proprietary “Star-Rating” system was developed to help you easily understand the amount of scientific support behind each supplement in relation to a specific health condition. While there is no way to predict whether a vitamin, mineral, or herb will successfully treat or prevent associated health conditions, our unique ratings tell you how well these supplements are understood by the medical community, and whether studies have found them to be effective for other people.

For over a decade, our team has combed through thousands of research articles published in reputable journals. To help you make educated decisions, and to better understand controversial or confusing supplements, our medical experts have digested the science into these three easy-to-follow ratings. We hope this provides you with a helpful resource to make informed decisions towards your health and well-being.


Supplement Amount Why
Folic Acid
(Folic Acid Deficiency)
 If deficient: 10 to 20 mg a day under medical supervision 3 stars   People with schizophrenia may have a tendency to be deficient in folic acid and they may see improvements when given supplements.


3 stars  Folic Acid

If deficient: 10 to 20 mg a day under medical supervision

People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population13 and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.14 In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.15 The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.16 , 17 In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.18

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.19 All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.


Supplement Amount Why
Glycine
 0.8 grams for every 2.2 lbs (1 kg) of body weight under medical supervision 3 stars   Supplementing with glycine appears to help improve depression and mental symptoms and may reduce symptoms in people unresponsive to drug therapy.


3 stars  Glycine

0.8 grams for every 2.2 lbs (1 kg) of body weight under medical supervision

There have been several reports of glycine reducing the symptoms of people with schizophrenia who were unresponsive to drug therapy.20 Large amounts of glycine (0.8 gram per 2.2 pounds of body weight per day) have been shown to reduce negative symptoms of schizophrenia and improve psychiatric rating scores in one preliminary trial;21 however, these results have not been repeated in later trials using similar (very high) amounts.22 , 23 Earlier double-blind trials found significant improvements in depression and mental symptoms in people with schizophrenia who took glycine for six weeks.24 , 25 Most trials demonstrated a moderate improvement in schizophrenia symptoms in those taking glycine supplements.26 Long-term supplementation with high amounts of glycine may be toxic to nerve tissue, however. Some preliminary successes have been reported using smaller amounts of glycine, such as 10 grams per day.27 Long-term studies on the safety of glycine therapy are needed.

Supplement Amount Why
Fish Oil
 2,000 to 3,000 mg daily of EPA 2 stars   Omega-6 and omega-3 fatty acids appear to be deficient or improperly used in people with schizophrenia. Supplementing with fish oil may correct an imbalance and improve symptoms.


2 stars  Fish Oil

2,000 to 3,000 mg daily of EPA

There are two different classes of essential fatty acids: omega-6 fatty acids and omega-3 fatty acids. There is considerable evidence these fatty acids are deficient, or are not used properly, in people with schizophrenia.28 , 29 , 30 , 31 , 32 , 33 Some investigators suggest this altered fatty acid metabolism may be involved in the increased need for niacin seen in some schizophrenic patients.34 A case has been reported in which a man with schizophrenia had dramatic and sustained improvement while being supplemented with 2 grams daily of omega-3 fatty acids.35 In a preliminary trial, schizophrenic patients receiving omega-3 fatty acids showed improvement in symptoms, as well as a reduction in adverse effects from their anti-psychotic medications.36 Another study found that people with schizophrenia had lower blood levels of both omega-3 and omega-6 fatty acids, compared with non-schizophrenic people, even though both groups were consuming similar amounts of these fatty acids.37 In a separate preliminary study, higher intake of omega-3 fatty acids was associated with less severe disease, and supplementation with 10 grams of concentrated fish oil, a source of omega-3 fatty acids, led to significant improvement in symptoms over a six-week period.38 In addition, a double-blind trial found that supplementing with 1.2 g per day of omega-3 fatty acids from fish oil prevented the development of psychosis in adolescents and young adults who were at very high risk of developing a psychotic disorder.39

In a double-blind trial that included 87 patients with chronic schizophrenia or a related illness (schizoaffective disorder), supplementation with 3 grams per day of eicosapentaenoic acid (one of the omega-3 fatty acids found in fish oil) was ineffective.40 The patients in this negative study were older and had been ill for longer, compared with patients in earlier studies who improved with omega-3 fatty acid supplementation.

Several clinical trials have examined the effects of supplementation with essential fatty acids in people with schizophrenia, with inconsistent results.41 , 42 , 43 , 44 While the results of trials using omega-3 fatty acids are promising, further double-blind trials are needed to establish whether fatty acid supplementation is an effective therapy for schizophrenia. Trials of omega-6 fatty acids (like GLA from borage oil) have yielded predominantly negative results.45

Supplement Amount Why
Folic Acid, Vitamin B6, and Vitamin B12
(High Homocysteine)
 Take folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) daily 2 stars   People with schizophrenia who have high homocysteine levels may improve symptoms by supplementing with folic acid, vitamin B6, and vitamin B12.

2 stars  Folic Acid, Vitamin B6, and Vitamin B12

Take folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) daily

People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population46 and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.47 In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.48 The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.49 , 50 In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.51

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.52 All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.


Supplement Amount Why
Ginkgo and Haloperidol
 360 mg daily of a standardized extract 2 stars   In one trial, schizophrenic patients who supplemented with ginkgo saw enhanced effectiveness of the antipsychotic drug haloperidol (Haldol) and reduced drug side effects.
L-Tryptophan
 1 to 8 grams per day (under a doctor's supervision) 2 stars   L-tryptophan supplementation has occasionally been helpful for specific schizophrenia symptoms, such as aggression and memory function.


2 stars  L-Tryptophan

1 to 8 grams per day (under a doctor's supervision)

Metabolism of the amino acid L-tryptophan may be abnormal in schizophrenia,53 and initially low blood levels of L-tryptophan rise when symptoms of schizophrenia improve but remain low in cases of poor recovery.54 L-tryptophan supplementation has occasionally been helpful for specific symptoms associated with schizophrenia. A small double-blind trial found that 4 to 8 grams per day of L-tryptophan reduced aggressive symptoms.55 Another double-blind trial found 1 gram per day of L-tryptophan improved memory function in schizophrenics.56 Schizoaffective disorder has features of both schizophrenia and mood disorders. A preliminary study reported that 8 grams per day of L-tryptophan improved mood symptoms in a group of patients with schizoaffective disorder, and a small, double-blind trial found that adding 9 grams per day of L-tryptophan to drug therapy was more effective for stabilizing mood in schizoaffective disorder than drug therapy plus a placebo.57 In contrast, other symptoms of schizophrenia have not responded to L-tryptophan in amounts from 1 to 20 grams per day, according to double-blind studies.58 , 59 In fact, a small preliminary study reported that schizophrenic patients on a low-tryptophan diet had improved scores on certain tests of brain function and also had small improvements in psychotic symptoms.60

Supplement Amount Why
Melatonin
(Schizophrenia and Sleep Disturbances)
 Take under medical supervision: 2 mg daily of a controlled-release preparation before bedtime 2 stars   Supplementing with melatonin appears to improve sleep quality and duration in people with schizophrenia.

2 stars  Melatonin

Take under medical supervision: 2 mg daily of a controlled-release preparation before bedtime

The results of one double-blind trial indicate that melatonin supplementation improves sleep quality in people with schizophrenia.61 In one study, all patients with a diagnosis of schizophrenia were found to have low melatonin output. Replacement of melatonin with 2 mg of a controlled-release supplement per day for three weeks improved sleep duration and quality compared to placebo. When patients receiving placebo were crossed over to the melatonin group, they too experienced improved sleep quality.

Supplement Amount Why
Vitamin B3
 Consult a qualified healthcare practitioner 2 stars   High amounts of vitamin B3 may create a more optimal biochemical environment and increase recovery rate and reduce hospitalization and suicide rates.


2 stars  Vitamin B3

Consult a qualified healthcare practitioner

The term “orthomolecular psychiatry” was coined by Linus Pauling in 1968 to refer to the treatment of psychiatric illnesses with substances (such as vitamins) that are normally present in the body. In orthomolecular psychiatry, high amounts of vitamins are sometimes used, not to correct a deficiency per se, but to create a more optimal biochemical environment. The mainstay of the orthomolecular approach to schizophrenia is niacin or niacinamide (vitamin B3) in high amounts. In early double-blind trials, 3 grams of niacin daily resulted in a doubling of the recovery rate, a 50% reduction in hospitalization rates, and a dramatic reduction in suicide rates.62 In a preliminary trial, some schizophrenic patients continued a course of vitamins (4 to 10 grams of niacin or niacinamide, 4 grams of vitamin C, and 50 mg or more of vitamin B6) after being discharged from the hospital, while another group of patients discontinued the vitamins upon discharge. Both groups continued to take their psychiatric medications. Those who continued to take the vitamins had a 50% lower re-admission rate compared with those who did not.63 Several later double-blind trials, including trials undertaken by the Canadian Mental Health Association, have been unable to reproduce these positive results.64 , 65 Early supporters of niacin therapy contend that many of these trials were poorly designed.66 One clinical trial reported no greater improvement in a group of schizophrenic patients given 6 grams of niacin than in others given 3 mg of niacin; all patients were also being treated with psychiatric medications.67

There are potential side-effects of niacin therapy, including an uncomfortable flushing sensation, dermatitis (skin inflammation), heartburn, aggravation of peptic ulcers, increased blood sugar, increased panic and anxiety, and elevation of liver enzymes, which may indicate damage to liver cells. A positive side effect of niacin therapy is reduction of cholesterol levels. Some of these effects, such as flushing, gastric upset, and reduction of serum cholesterol, do not occur with the use of niacinamide.68 Because of the seriousness of some of these side effects, high amounts of niacin should not be used without the supervision of a healthcare practitioner.

Vitamin B6 has been used in combination with niacin in the orthomolecular approach to schizophrenia. Pioneers of orthomolecular medicine reported benefits from this combination. However, although two placebo-controlled trials found significant improvement when schizophrenic patients were given either 3 grams of niacin or 75 mg of pyridoxine along with their psychiatric medications, this improvement was lost when the two vitamins were combined.69 , 70 In a double-blind trial, schizophrenic patients were given either a vitamin program based on their individual laboratory tests or a placebo (25 mg of vitamin C) in addition to their psychiatric medications. The vitamin program included large amounts of various B vitamins, as well as vitamin C and vitamin E. After five months, the number of patients who improved was not different in the vitamin group compared with the placebo group.71

Clinical trials of the effects of vitamin B6 have yielded differing results. The results of supplementation with 100 mg daily in one schizophrenic patient included dramatic reduction in side effects from medication, as well as reduction in schizophrenic symptoms.72 In a preliminary trial, 60 mg per day of vitamin B6 resulted in symptomatic improvement in only 5% of schizophrenic patients after four weeks.73 Another preliminary trial, however, found that a higher amount of vitamin B6—50 mg three times daily given for eight to twelve weeks—in addition to psychiatric medications, did bring about significant improvements in schizophrenic patients. These patients experienced a better sense of well-being, increased motivation, and greater interest in their “personal habits and their environment.”74

Supplement Amount Why
Vitamin B6
 Consult a qualified healthcare practitioner 2 stars   Vitamin B6 has been used in combination with niacin in the treatment of schizophrenia with some reported benefits.


2 stars  Vitamin B6

Consult a qualified healthcare practitioner

The term “orthomolecular psychiatry” was coined by Linus Pauling in 1968 to refer to the treatment of psychiatric illnesses with substances (such as vitamins) that are normally present in the body. In orthomolecular psychiatry, high amounts of vitamins are sometimes used, not to correct a deficiency per se, but to create a more optimal biochemical environment. The mainstay of the orthomolecular approach to schizophrenia is niacin or niacinamide (vitamin B3) in high amounts. In early double-blind trials, 3 grams of niacin daily resulted in a doubling of the recovery rate, a 50% reduction in hospitalization rates, and a dramatic reduction in suicide rates.75 In a preliminary trial, some schizophrenic patients continued a course of vitamins (4 to 10 grams of niacin or niacinamide, 4 grams of vitamin C, and 50 mg or more of vitamin B6) after being discharged from the hospital, while another group of patients discontinued the vitamins upon discharge. Both groups continued to take their psychiatric medications. Those who continued to take the vitamins had a 50% lower re-admission rate compared with those who did not.76 Several later double-blind trials, including trials undertaken by the Canadian Mental Health Association, have been unable to reproduce these positive results.77 , 78 Early supporters of niacin therapy contend that many of these trials were poorly designed.79 One clinical trial reported no greater improvement in a group of schizophrenic patients given 6 grams of niacin than in others given 3 mg of niacin; all patients were also being treated with psychiatric medications.80

There are potential side-effects of niacin therapy, including an uncomfortable flushing sensation, dermatitis (skin inflammation), heartburn, aggravation of peptic ulcers, increased blood sugar, increased panic and anxiety, and elevation of liver enzymes, which may indicate damage to liver cells. A positive side effect of niacin therapy is reduction of cholesterol levels. Some of these effects, such as flushing, gastric upset, and reduction of serum cholesterol, do not occur with the use of niacinamide.81 Because of the seriousness of some of these side effects, high amounts of niacin should not be used without the supervision of a healthcare practitioner.

Vitamin B6 has been used in combination with niacin in the orthomolecular approach to schizophrenia. Pioneers of orthomolecular medicine reported benefits from this combination. However, although two placebo-controlled trials found significant improvement when schizophrenic patients were given either 3 grams of niacin or 75 mg of pyridoxine along with their psychiatric medications, this improvement was lost when the two vitamins were combined.82 , 83 In a double-blind trial, schizophrenic patients were given either a vitamin program based on their individual laboratory tests or a placebo (25 mg of vitamin C) in addition to their psychiatric medications. The vitamin program included large amounts of various B vitamins, as well as vitamin C and vitamin E. After five months, the number of patients who improved was not different in the vitamin group compared with the placebo group.84

Clinical trials of the effects of vitamin B6 have yielded differing results. The results of supplementation with 100 mg daily in one schizophrenic patient included dramatic reduction in side effects from medication, as well as reduction in schizophrenic symptoms.85 In a preliminary trial, 60 mg per day of vitamin B6 resulted in symptomatic improvement in only 5% of schizophrenic patients after four weeks.86 Another preliminary trial, however, found that a higher amount of vitamin B6—50 mg three times daily given for eight to twelve weeks—in addition to psychiatric medications, did bring about significant improvements in schizophrenic patients. These patients experienced a better sense of well-being, increased motivation, and greater interest in their “personal habits and their environment.”87

L-tryptophan is the amino acid precursor of serotonin, a neurotransmitter (chemical messenger in the brain). There is evidence that L-tryptophan levels in schizophrenic people are lower than in non-schizophrenics88 and the way the body uses L-tryptophan is altered in people with schizophrenia.89 , 90 In a preliminary trial, patients with schizophrenia were given 2–8 grams of L-tryptophan and 100 mg of vitamin B6 daily. This resulted in decreased agitation and less fear and anxiety, but these improvements were not as great as those achieved with psychiatric medications.91 It is not clear whether the benefits seen in this trial were due to vitamin B6, L-tryptophan, or a combination of the two. No other clinical trials using L-tryptophan have been published. L-tryptophan is currently available by prescription only.

Supplement Amount Why
Vitamin C
 Consult a qualified healthcare practitioner 2 stars   People with schizophrenia may require more vitamin C than the general population. In one trial, vitamin C reduced hallucinations, suspiciousness, and disorganized thoughts.

2 stars  Vitamin C

Consult a qualified healthcare practitioner

Up to 6 grams daily of vitamin C has been reported to be beneficial for people with schizophrenia;92 , 93 in one case the addition of 400 IU daily of vitamin E enhanced this benefit.94 A small preliminary trial using 8 grams daily of vitamin C showed decreases in hallucinations, suspiciousness, and unusual and disorganized thoughts in 77% of schizophrenic patients.95 In all reported cases, patients were also being treated with sychiatric medications. Some early studies found no difference between blood and urine vitamin C levels in schizophrenics and non-schizophrenics, either before or after supplementation.96 , 97 , 98 However, later studies found that blood and urine levels of vitamin C were lower in schizophrenics than in non-schizophrenics before and after a single 1,000 mg “load” of vitamin C was taken. After four weeks of daily supplementation with 1,000 mg of vitamin C, blood levels became the same, but urinary levels remained lower in the schizophrenic group, leading the researchers to conclude that the amount of vitamin C required by people with schizophrenia may be greater than that of the general population.99 , 100

Supplement Amount Why
D-Serine
 Refer to label instructions 1 star   Supplementing with the amino acid D-serine may improve mental symptoms in people with schizophrenia who are also taking antipsychotic medications.
Vitamin B12
 Refer to label instructions 1 star   People with schizophrenia may have low vitamin B12 levels. Supplementing with the vitamin may correct an imbalance and improve symptoms.


1 star  Vitamin B12

Vitamin B12 deficiency can cause symptoms that are similar to those of schizophrenia and one case has been reported in which such symptoms cleared after supplementation with vitamin B12.101 Some studies have reported finding lower levels of vitamin B12 in people with schizophrenia than in the general population,102 but others have found no difference.103 No trials of vitamin B12 supplementation in schizophrenic patients have been published.

References

1. Hoffman RE, Boutros NN, Hu S, et al. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet 2000;355:1073–5.

2. Hall K. Allergy of the nervous system: a review. Ann Allergy 1976;36:49–64 [review].

3. Kety SS. Editorial: Dietary factors and schizophrenia. Ann Intern Med 1976;84:745 [editorial].

4. Ross-Smith P, Jenner FA. Diet (gluten) and schizophrenia. J Hum Nutr 1980;34:107–12 [review].

5. Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull 1988;14:489–94.

6. Reichelt KL, Landmark J. Specific IgA antibody increases in schizophrenia. Biol Psychiatry 1995;37:410–3.

7. Dohan FC, Grasberger JC. Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry 1973;130:685–8.

8. Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science 1976;191:401–2.

9. Vlissides DN, Venulet A, Jenner FA. A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry 1986;148:447–52.

10. Davis C. Dietary pathogenesis of schizophrenia: an investigation into the effects of gluten. Nurs Times 1978;74:2020–1.

11. Potkin SG, Weinberger D, Kleinman J, et al. Wheat gluten challenge in schizophrenic patients. Am J Psychiatry 1981;138:1208–11.

12. Storms LH, Clopton JM, Wright C. Effects of gluten on schizophrenics. Arch Gen Psychiatry 1982;39:323–7.

13. Herran A, Garcia-Unzueta MT, Amado JA, et al. Folate levels in psychiatric outpatients. Psychiatry Clin Neurosci 1999;53:531–3.

14. Carney MW, Sheffield BF. Associations of subnormal serum folate and vitamin B12 values and effects of replacement therapy. J Nerv Ment Dis 1970;150:404–12.

15. Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry 1991;159:271–2.

16. Freeman JM, Finkelstein JD, Mudd SH. Folate-responsive homocystinuria and “schizophrenia.” A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med 1975;292:491–6.

17. Folate-responsive homocystinuria and “schizophrenia.”Nutr Rev 1982;40:242–5.

18. Folate-responsive homocystinuria and “schizophrenia.”Nutr Rev 1982;40:242–5.

19. Levine J, Stahl Z, Sela BA, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry 2006;60:265–9.

20. Waziri R. Glycine therapy of schizophrenia: Some caveats. Biol Psychiatry 1996;39:155–6.

21. Heresco-Levy U, Javitt DC, Ermilov M, et al. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999;56:29–36.

22. Evins AE, Fitzgerald SM, Wine L, et al. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 2000;157:826–8.

23. Potkin SG, Jin Y, Bunney BG, et al. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry 1999;156:145–7.

24. Heresco-Levy U, Javitt DC, Ermilov M, et al. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 1996;169:610–7.

25. Javitt DC, Zylberman I, Zukin SR, et al. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 1994;151:1234–6.

26. Semba J. [Glycine therapy of schizophrenia; its rationale and a review of clinical trials]. Nihon Shinkei Seishin Yakurigaku Zasshi 1998;18:71–80 [review] [in Japanese].

27. Rosse RB, Theut SK, Banay-Schwartz M, et al. Glycine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label, pilot study. Clin Neuropharmacol 1989;12:416–24.

28. Horrobin DF. The relationship between schizophrenia and essential fatty acid and eicosanoid metabolism. Prostaglandins Leukot Essent Fatty Acids 1992;46:71–7 [review].

29. Horrobin DF. Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot Essent Fatty Acids 1996;55:3–7 [review].

30. Warner R, Laugharne J, Peet M, et al. Retinal function as a marker for cell membrane omega-3 fatty acid depletion in schizophrenia: a pilot study. Biol Psychiatry 1999;45:1138–42.

31. Mahadik SP, Mukherjee S, Horrobin DF, et al. Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: comparison with bipolar patients and normal subjects. Psychiatry Res 1996;63:133–42.

32. Vaddadi KS, Gilleard CJ, Soosai E, et al. Schizophrenia, tardive dyskinesia and essential fatty acids. Schizophr Res 1996;20:287–94.

33. Peet M, Laugharne J, Rangarajan N, et al. Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients. J Psychiatr Res 1995;29:227–32.

34. Rudin DO. The major psychoses and neuroses as omega-3 essential fatty acid deficiency syndrome: substrate pellagra. Biol Psychiatry 1981;16:837–50.

35. Puri BK, Richardson AJ, Horrobin DF, et al. Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes. Int J Clin Pract 2000;54:57–63.

36. Peet M, Laugharne JD, Mellor J, Ramchand CN. Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins Leukot Essent Fatty Acids 1996;55:71–5.

37. Laugharne JD, Mellor JE, Peet M. Fatty acids and schizophrenia. Lipids 1996;31 Suppl:S163–5.

38. Laugharne JD, Mellor JE, Peet M. Fatty acids and schizophrenia. Lipids 1996;31 Suppl:S163–5.

39. Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2010;67:146–54.

40. Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001;158:2071–4.

41. Vaddadi KS, Courtney P, Gilleard CJ, et al. A double-blind trial of essential fatty acid supplementation in patients with tardive dyskinesia. Psychiatry Res 1989;27:313–23.

42. Mellor JE, Laugharne JDE, Peet M. Omega-3 fatty acid supplementation in schizophrenic patients. Hum Psychopharmacol 1996;11:39–46.

43. Shah S, Ramchand CN, Peet M. Eicosapentaenoic acid (EPA) as an adjunct to neuroleptic therapy in the treatment of schizophrenia. Presented at the 9th Schizophrenia Winter Workshop, Davos, Switzerland, February 7–13, 1998.

44. Mellor JE, Peet M. Double-blind, placebo-controlled, trial of omega-3 fatty acids as an adjunct to the treatment of schizophrenia. Presented at the 9th Schizophrenia Winter Workshop, Davos, Switzerland, February 7–13, 1998.

45. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000;47:8–21 [review].

46. Herran A, Garcia-Unzueta MT, Amado JA, et al. Folate levels in psychiatric outpatients. Psychiatry Clin Neurosci 1999;53:531–3.

47. Carney MW, Sheffield BF. Associations of subnormal serum folate and vitamin B12 values and effects of replacement therapy. J Nerv Ment Dis 1970;150:404–12.

48. Procter A. Enhancement of recovery from psychiatric illness by methylfolate. Br J Psychiatry 1991;159:271–2.

49. Freeman JM, Finkelstein JD, Mudd SH. Folate-responsive homocystinuria and “schizophrenia.” A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med 1975;292:491–6.

50. Folate-responsive homocystinuria and “schizophrenia.”Nutr Rev 1982;40:242–5.

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