While replicating the association betweenexpressed emotion and relapse in schizophrenia atfive Sydney hospitals [1,2], we observed an intenseinterest in orthomolecular treatments among patientsand their relatives. Despite their awareness thatorthomolecular medicine was considered unorthodoxby conventional psychiatry, eight patients (9.5%) hadalready had a course of orthomolecular treatmenteither alone or in addition to antipsychotic medica-tions. Reports in the popular press keep orthomolec-

ular ideas current and make them the major alterna-tive medical approach for schizophrenia. In 1997,Jorm et al. [3] reported the astonishing finding fromthe Australian Bureau of Statistics that as a treatmentfor schizophrenia, 57% of respondents indicated vit-amins, minerals, tonics and herbs, 45% indicatedspecial diets, and only 23% indicated antipsychoticsas helpful.

The term orthomolecular medicine was originatedin 1968 by Nobel laureate Linus Pauling [4]. Hedefined orthomolecular medicine as:

The achievement and preservation of good healthand the prevention and treatment of disease by reg-ulating the concentration of molecules that are nor-mally present in the human body. Importantorthomolecular substances are the vitamins, especi-ally vitamin C.

Orthomolecular medicine is highly eclectic anddraws together diverse practitioners who place them-

Ordinary article OA 527 EN

Megavitamin and dietary treatment inschizophrenia: a randomised, controlled trial

Kevin Vaughan, Nathaniel McConaghy

O b j e c t i v e : The aim of this study was to assess the efficacy of adjunctive megavita-min and dietary treatment in schizophrenia.M e t h o d : Arandom allocation double-blind, controlled comparison of dietary supple-ment and megavitamin treatment, and an alternative procedure was given for5 months to 19 outpatients with a diagnosis of schizophrenia. In addition to usualfollow-up, the experimental group received amounts of megavitamins based on theirindividual serum vitamin levels plus dietary restriction based on Radioallergosorbent(RAST) tests. The control group received 25 mg vitamin C and were prescribed sub-stances considered allergenic from the RAST t e s t .R e s u l t s : Five months of treatment showed marked differences in serum levels of vit-amins but no consistent self-reported symptomatic or behavioural diff e r e n c e sbetween groups.C o n c l u s i o n s : This study does not provide evidence supporting a positive relation-ship between regulation of levels of serum vitamins and clinical outcome in schizo-phrenia over 5 m o n t h s .Key words: megavitamin, schizophrenia, treatment trial.

Australian and New Zealand Journal of Psychiatry 1999; 33:84–88

Kevin Vaughan, Staff Specialist and Clinical Lecturer(Correspondence)

Palmerston Centre, Hornsby Hospital, Hornsby, New South Wales2077, Australia

Nathaniel McConaghy, Visiting Professor

Department of Psychiatry, University of New South Wales, Sydney,Australia

Received 22 July 1998; revised 23 October 1998; accepted 27 October1998.

85K. VAUGHAN, N. MCCONAGHY

selves outside the mainstream of modern medicine.Emphasis on diet and vitamins is central to theseapproaches which have been considered useful formany conditions in addition to schizophrenia, mostnotably: the common cold; cancer; drug addiction;wound repair; atherosclerosis; and hyperactivity inchildren.

Orthodox nutritionists [5] have been critical of thelack of evidence supporting these approaches.Nevertheless, they remain popular with psychiatricpatients and their relatives despite a critical positionstatement by the American Psychiatric Association in1973 concerning niacin (vitamin B3) therapy [6] anda critical position statement by the Royal Australianand New Zeland College of Psychiatrists who sug-gested that controlled clinical trials of orthomolecu-lar therapy be carried out [7].

Perhaps surprisingly, there has been an active earlyliterature with trials reporting encouraging results withniacin. Most notably, Hoffer [8] reported a significante ffect in a double-blind trial with 30 schizophrenicpatients, and a second double-blind trial [9] replicatedan effect with niacin in 171 patients. This study indi-cated that patients benefited most who were outpa-tients and already in remission. Length of time onniacin was important, but even those who were onniacin for short periods (less then 1 month) showedimprovement. Findings of Denson [10] andWhittenborn [11] were also positive. However, anumber of well-constructed controlled studiesreported negative results with niacin [12–16]. Hoff e r’sstudies were criticised on methodological grounds andin turn Hoffer criticised the negative studies for usingmostly chronic hospitalised patients which he hadalready reported were the least likely to respond.

Since Hoffer’s studies with niacin, orthomolecularapproaches became more diversified. Herjanic [17]reported encouraging results from adding 3 g ascor-bic acid daily. Anath et al. [18] reported improvedefficacy by adding pyradoxine. Reading [19,20], oneof the foremost exponents of orthomolecular psychi-atry in Australia, reported that of 402 patients treatedby him in 8 years, 90% had improved with a combi-nation of orthomolecular approaches which includedmeasurement of serum vitamins and the correction ofdeficiencies using large amounts of vitamins. It washypothesised that these deficiencies were related tovarious food allergies, and diets excluding thesefoods were also prescribed. This technique offered areplicable procedure that could bring orthomolecularpractices and therapies into conformity with ortho-dox methods of diagnosis and treatment.

Method

Selection

At the end of the expressed emotion study, a circu-lar explaining the vitamin study was sent to 56patients that were still living with their families.Twenty-nine patients indicated interest. Beforeadmission to the study, seven dropped out leaving 22patients who volunteered for the study.

Treatment and control groups

All patients had already satisfied diagnostic criteriafor schizophrenia according to the Present StateExamination [21] as previously reported [1,2]. A tentry to the study, random allocation was achieved bysealing patient’s ID numbers in opaque envelopes,which were later distributed either to a megavitamin ora control group by an independent research worker.

At the start of the study, all patients were in partialremission and receiving phenothiazines. Three werealso receiving antidepressants. A l t o g e t h e r, sevenwere partially employed. There were no differencesbetween the two groups with respect to sex; therewere seven males in both groups. The mean age was32.1 in the vitamin group and 29.9 in the controlgroup. The mean number of previous admissions was2.8 in the vitamin group and 3.1 in the control group.The number of years since first admission was 7.4 inthe vitamin group and 7.2 in the control group.

Outcome measures

Any patients readmitted to psychiatric units receiveda Present State Examination [21] to confirm psychoticrelapse. In a 6-month trial, however, the relapse rateusing this measure was expected to be so low as tolack sensitivity. To augment this, a self-report ques-tionnaire (the Brief Symptom Inventory (BSI) [22], a53-item check list) was used as a more generalmeasure of distress and discomfort. The questionnairewas administered on six occasions: at entry to the trialand at the end of each month for 5 m o n t h s .

In addition, a Behaviour Disturbance Inventory(BDI), a 45-item problem checklist, was completed bya key family member on six occasions: at entry, and atthe end of each subsequent month for 5 m o n t h s .Initially designed for parental report of problems inchildren [23], the content was altered to include prob-lems usually reported by parents of their offspring withschizophrenia [24]. When two parents were living with

86 MEGAVITAMIN TRIALIN SCHIZOPHRENIA

the patient, each parent individually completed thequestionnaire and the mean score was calculated.

Orthomolecular and control treatment

The results from the serum vitamin levels and thefood allergy test were both sent to an establishedorthomolecular psychiatrist who assessed each bloodand food allergy result. He then wrote out individualdietary advice and a megavitamin prescription foreach individual patient on the basis of their serumvitamin levels and the radioallergosorbent test(RAST) [25].

Experimental group subjects were each given theindividual medications as prescribed monthly. At theend of each month, the medications were delivered tothe patients’homes and the completed questionnaireswere collected. Each patient received on average 18tablets per day. The mean dosages of vitamin were:vitamin A, 6000 iu, SD = 5 1 6 3 iu; vitamin B,1 3 4 5 mg, SD = 5 1 mg; vitamin B, 3520 m g ,S D = 7 5 mg; vitamin B, 6223 mg, SD = 7 5 m g ;vitamin B12, 25 mg; vitamin C, 2822 m g ,S D = 9 0 9 mg; vitamin E, 204 mg, SD = 1 5 0 m g ;folic acid, 5.2 mg.

Control group subjects were given tablets identicalin character and quantity to the mean number givento the vitamin group. Tablets were all inert except forone, which was vitamin C 25 mg. The daily dose ofthis vitamin recommended by World HealthOrganization is 30 mg. This small dose of vitamin Cwas added to conform to the requirements of thePrince of Wales Ethics Committee. A dietitian wasmade available to consult with patients or familymembers by phone.

Dietary advice was based on the results of theRAST [25], which in orthomolecular medicine, isone of the most commonly used in vitro tests tomeasure levels of antibodies of IgE and otherimmunoglobulin classes in the serum to 18 commonfoods. Patients in the experimental group were givendietary sheets instructing them to avoid substancesthat tested positive. Most common foods were eggs,gluten, sugar, corn, beef and bread. The control dietwas essentially a dietary challenge: patients weregiven sheets instructing them to eat foods testingpositive, at least three times per week.

Results

After assessment but prior to commencement ofthe study, one patient allocated to the vitamin group

and two patients allocated to the control group with-drew. One further patient withdrew from the controlgroup in the first month of treatment. Results, there-fore, are presented on 10 patients who receivedvitamin and dietary treatment and eight patients inthe comparison group.

The serum vitamin levels at pre-treatment and atthe end of the 5-month treatment period for the twogroups of patients indicated a high level of compli-ance (Table 1). In the treatment group levels ofVitamin A, B1, B6, B12 and folate significantlyincreased. Vitamin C increased non-significantlywith only Vitamin E showing a decrease. In markedcontrast, the levels in the control group remainedremarkably stable except for B6 which inexplicablyfell dramatically.

During the first month of treatment, one controlpatient suffered a major psychotic relapse confirmedby Present State Examination and was hospitalisedfor 3 months. For the purposes of this study he wasassessed as having deteriorated at each subsequentassessment interval (see Tables 2 and 3). Apart fromthis patient 97% of all BSI and BDI were completedsatisfactorily.

There was a large amount of variation in theoutcome scores and a small sample size, therefore itwas thought that group comparisons would be lessinformative then comparisons based on classifyingpatients as ‘deteriorated’ or ‘improved’. An effectsize (ES) of one standard deviation (SD) or less ofsymptomatic change was treated as indicating nochange, falls greater then one SD indicated improve-ment, and increases greater then one SD indicateddeterioration. The use of an effect size (standard dif-

Table 1. Mean vitamin serum levels at startand at end of trial

Treatment group (n=10) Control group (n=7)Vitamin Start End Start End

A 568 879* 540 528B1 58.4 87.4** 59.5 54.7B3 66.8 68.8 65.2 66.7B6 57.4 86.7** 50.3 18.1**C 0.81 1.03 0.87 0.45E 8.7 8.2 9.5 6.1B12 296.7 1366** 290 264.2Folate 8.1 46.2** 7.0 7.3

t test: *p < 0.05; **p < 0.001.

87K. VAUGHAN, N. MCCONAGHY

ference score) of 1.0 is recognised as correspondingto clinically useful change (if a group has improvedby 1.0 ES then 85% of patients are above the pre-treatment mean).

Alteration in mental states as assessed by self-report and disturbed behaviour as assessed by familymembers are reported in Table 2 and Table 3 in termsof numbers showing improvement, no change, ordeterioration. At each time point, there was no rela-tionship between treatment group and outcome cate-gory using Chi-squared analysis. Pearson’scoefficient between the BSI and the BDI at the fivetime points was r = 0.71 (p < 0.0001).

A checklist of side-effects completed at the end ofthe study indicated few side effects with no differ-ence between groups. One woman in the vitamingroup previously diagnosed with a hiatus hernia suf-fered an acute episode of vomiting over a period of3 days. She was admitted to an acute medical wardfor parenteral replacement of fluids. After discharge,she completed the study without further symptoms.

Discussion

The megavitamin treatment administered over5 months succeeded in increasing subjects’ serumlevels of vitamin A, B1, B6, B12 and folate signifi-cantly. Vitamin C levels increased non-significantlywith only vitamin E showing a decrease. In markedcontrast, the levels in the control group remainedstable except for B6, which inexplicably fell dramat-ically. No physical symptoms were noted with thevitamin changes in both groups. Apart from thechanges in B6, there was no generalised fall in levelsof vitamins in the control group that could indicate amalabsorbtion syndrome.

Levels of symptoms were measured at monthlyintervals to identify onset and degree of any improve-ment. Comparisons of levels of self-reported symp-tomatology or behavioural disturbance at no pointwithin the 5 months showed a consistent trend. Aslight trend for some members if the vitamin group toshow more improvement on the BSI is offset by atendency for others to also show more deterioration.This greater deviance in outcome is mirrored to alesser extent in the relatives’ report using the BDI.All trends, however, are weak and do not approachstatistical significance.

Only one patient, the control patient who relapsedin the first week had sufficient deterioration to lead toadmission. Psychotic relapse in this patient was con-firmed using the PSE. The omission of an outcomemeasure such as the Brief Psychiatric Rating Scale[26] to measure outcome in the other patients is aweakness in this study. The BSI is designed not formeasuring the levels of core schizophrenic sympto-matology but to measure features in the mental statesuch as anxiety depression and interpersonal sensi-tivity. Typically correlation of the BPI and the BPRSaverages 0.5 [27]. The BDI is more accepted as avalid measure of schizophrenic symptomatology. Inthis study, it correlated 0.71 with the BSI.

In studies with a small sample size, as in thepresent study, comparison of an effective therapywith a placebo can result in a trend for the therapy to

Table 2. Five-month alteration in symptomsassessed by Brief Symptom Inventory

Month Improved Unchanged Deteriorated

Vitamin group (n=10)1 1 7 22 3 3 43 2 6 24 3 4 35 3 4 3

Control group (n=8)1 0 7 12 1 6 13 1 5 24 1 5 25 2 5 1

Table 3. Five-month alteration in disturbed behaviour assessed by Behaviour Disturbance

Inventory

Month Improved Unchanged Deteriorated

Vitamin group (n=10)1 0 8 22 2 5 33 3 4 34 3 5 25 3 3 4

Control group (n=8)1 0 7 12 0 7 13 2 4 24 2 5 15 1 6 1

88 MEGAVITAMIN TRIALIN SCHIZOPHRENIA

be effective which does not reach statistical signifi-cance. Conclusion that the therapy is ineffective iserroneous: a type 2, beta or false negative error [28].When a non-significant trend is noted, with smallsubject numbers, a replication of that study is indi-cated. However, there is no trend in the present studyfor the experimental group to have a better outcomethan the control group.

Orthomolecular treatment using a combination ofdietary and megavitamin treatment is the most com-monly used alternative treatment for schizophrenia.We could find no evidence supporting its efficacy inthe first 5 months of treatment.

The widespread divergence in views betweenmembers of the public and psychiatrists on the rela-tive effectiveness of treatments for schizophreniadescribed by Jorm [3] is something that we in psy-chiatry are confronted with on a daily basis. In thisera of evidence-based medicine, results from thisstudy could be used by psychiatrists to informpatients and their relatives allowing them to play amore effective role in managing the patients’ mentalhealth.

Acknowledgement

We are grateful to Dr Duson Hadlipablovic for sta-tistical advice.

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