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Schizophrenia: a genetic disorder of the synapse?

BMJ 2005; 330 doi: (Published 20 January 2005) Cite this as: BMJ 2005;330:158

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Does zinc deficiency in early foetal life cause schizophrenia?

Dr John Howard says I have misunderstood his theory that
DHEAndrostenedione deficiency in early foetal development is involved in
causing schizophrenia. In my previous response I referred to Hamadi et
al’s finding that even mild zinc deficiency caused significant decrease in
testicular androgens including androstenedione. Severe zinc deficiency
caused the greatest decrease.1,2

Zinc is the commonest deficiency before conception, during foetal
development, in children and in adults of all ages. Zinc deficiency in
early foetal life reduces the production of foetal steroid hormones but
also, in animals and humans in my experience of dyslexic individuals,
causes a reduced ability to cope with stress and a predisposition for zinc
deficiency throughout life.

If I am not wrong, as Dr Nehrlich kindly writes, it is because I have
had the advantage of measuring mineral levels in my patients for 35 years,
including hundreds of preconception couples, who usually have histories of
unexplained infertility and recurrent miscarriages. In London, clinicians
are especially fortunate in being able to employ the tests available at Dr John McLaren Howard’s sweat mineral test measures
zinc and other essential minerals to an accuracy of parts per billion.
Functional tests for B vitamins show that vitamin B 6, pyridoxine, is most
commonly deficient. Red blood cell essential fatty acid profiles find that
delta-desaturase enzyme blocks commonly cause deficiencies in EFA
pathways. Enzyme blocks result from zinc, magnesium, vitamin C,
pyridoxine, niacin, folate and magnesium deficiencies, and excessively
high or low copper levels, and alcohol consumption. The late professor
David Horrobin wrote, “Attempts at treatment (of schizophrenia) without
attention to nutritional status are doomed to failure or, at the very best
suboptimal performance”.3

Ananda Prasad has difficulty understanding why zinc repletion has not
become a key therapeutic tool in establishment medicine and has been
ignored for 40 years. A major stumbling block has been the diagnosis of
copper stores deficiency. Women taking hormones usually have abnormally
high levels of copper in their sweat, hair and serum but copper stores
become depleted. A red functional blood cell superoxide dismutase test is
the best indicator of depleted copper stores, but may also be due to
manganese deficiency. Zinc needs to be repleted with enough copper to
maintain copper stores but not enough to block EFA pathways by excess
copper intake. Ideally such tests should be part of routine medical
assessments and not relegated, as supplementation with minerals and
vitamins was described on the BBC news this morning, to alternative or
complimentary medicine.

1 Grant ECG Schizophrenics need zinc and not DHEA or testosterone
supplements., 1 Feb 2005

2 Hamdi SA, Nassif OI, Ardawi MS. Effect of marginal or severe
dietary zinc deficiency on testicular development and functions of the
rat. Arch Androl. 1997; 38(3):243-53.

3 Horrobin DF. A possible biochemical basis for alcoholism and for
schizoid reactions during alcohol withdrawal. In Biological Aspects of
Schizophrenia and Addiction. Ed G Hemmings. 1982 John Wiley & Sons
Ltd. Chichester

4 Grant ECCG. Preventing schizophrenia, 11 Nov 2004

“Preventing schizophrenia” seems to need repeating.

Editor – I remain puzzled why it is so easy to find published
evidence of the importance of the effects of essential nutrient
deficiencies or excesses in toxic metals in nearly all mental and systemic
illnesses and why such evidence is being still being ignored by
Are zinc (Zn) supplements too cheap compared with drugs? Is the problem
lack of generally available laboratories carrying out the most relevant

Nechifor et al consider plasma Cu(2+)/erythrocyte Mg(2+) and plasma
Cu(2+)/Zn(2+) ratio two important biological markers of the acute paranoid
schizophrenia. 2 There is no good reason for these tests not being

In the 1970s we found that Charing Cross Hospital migraine patients,
many of whom also had mood disturbances, with the highest serum
copper/zinc (Cu/Zn) ratios also had the most reactions to foods and
chemicals.3 When I visited patients in the hospitals psychiatric wards,
who also had migraine, I could hardly see for cigarette smoke. The recent
legislation in Scotland to ban indoor smoking seems to acknowledge the
desperate need of some of the mentally ill to smoke by excluding mental
hospital wards from the ban.
Do psychiatrists still not see smoking as a cause of mental illness?
Increased cadmium (Cd) and lead and reduced Zn levels have been reported
in patients with mental illnesses, and criminals had lower mean plasma Zn
values but higher serum Cu values than non-criminal subjects. 4,5
Johnson’s excellent 2001 Hypothesis explains the importance of Zn for
brain development and maintenance.6 Zn binds to p53, preventing it from
binding to supercoiled DNA and ensuring that p53 cause the expression of
several paramount genes, such as the one that encodes for the type I
receptors to pituitary adenine cylase-activator peptide (PACAP), which
directs embryonic development of the brain cortex, adrenal glands, etc.;
it is required for the production of CuZnSOD and Zn-thionein, which are
essential to prevent oxidative damage; it is required for many proteins,
some of them with Zn fingers, many of them essential enzymes for growth
and homeostasis. As the synthesis of serotonin involves Zn enzymes and
since serotonin is necessary for melatonin synthesis, a Zn deficiency may
result in low levels of both hormones. Zn levels tend to be low when there
is excess Cu and Cd. Moreover, high estrogen levels tend to cause
increased absorption of Cu and Cd, and smoking and eating food
contaminated with Cd result in high levels of the latter. Also , ethanol
ingestion increases the elimination of Zn and Mg (which acts as a cofactor
for CuZnSOD).Therefore, the developing fetus of a pregnant women who is
low in Zn and high in Cu may experience major difficulties in the early
development of the brain, which may later manifest themselves as
schizophrenia, autism or epilepsy. Similarly, a person who gradually
accumulates Cu, (this can be detected by testing genetic SOD variants)
will tend to experience a gradual depletion of Zn, with a corresponding
increase in oxidative damage, eventually leading to Parkinson's disease.

Herron et al found serum copper levels were significantly higher in
schizophrenic patients (mean 117.4 microg/dl; S.D. 23.4) than in healthy
controls (105.6+/-27.9). Those patients on treatment with depot
neuroleptics had higher copper levels. 7

Chronic haloperidol treatment for both 45 and 90 days significantly
decreased manganese-superoxide dismutase (MnSOD), copper-zinc superoxide
dismutase (CuZnSOD) and catalase activity with parallel marked increase in
hydroxyalkenals, a marker of lipid peroxidation in rat brain.8

Brown reviewed the emerging evidence that schizophrenia may in some
cases be a neurodevelopmental disorder, resulting in part from the effects
of prenatal exposures and concluded that there is sufficient evidence to
warrant further studies of prenatal nutritional deficits as risk factors
for schizophrenia.9 Foresight, The Association for the Promotion for
Preconceptual Care, has been attempting to replete nutritional
deficiencies and lowering toxic metal levels in preconception couples
since the 1970s but no large scale financial back up has been forthcoming
for this fundamentally important work.10

The Schizophrenia Association of Great Britain is concerned that
practitioners often do not understand the illnesses they treat and
ridicule nutritional treatment for mental illnesses.11

1 Turner TH. Long term outcome of treating schizophrenia
Antipsychotics probably help—but we badly need more long term studies.BMJ
2004;329:1058-1059 (6 November), doi:10.1136/bmj.329.7474.1058

2 Nechifor M, Vaideanu C, Palamaru I, Borza C, Mindreci I. The
influence of some antipsychotics on erythrocyte magnesium and plasma
magnesium, calcium, copper and zinc in patients with paranoid
schizophrenia. J Am Coll Nutr. 2004 ;23:549S-551S.

3 Grant ECG. Allergies, smoking and the contraceptive pill. In
Biological Aspects of Schizophrenia and Addiction.1982.Ed Hemmings G, John
Wiley & Sons, Chichester pp 263-72

4 Stanley PC, Wakwe VC Toxic trace metals in the mentally ill
patients. Niger Postgrad Med J. 2002; 9:199-204.

5 Tokdemir M, Polat SA, Acik Y, et al. Blood zinc and copper
concentrations in criminal and noncriminal schizophrenic men. Arch Androl.

6 Johnson S Micronutrient accumulation and depletion in
schizophrenia, epilepsy, autism and Parkinson's disease? Med Hypotheses.
2001; 56: 641-5.

7 Herran A, Garcia-Unzueta MT, Fernandez-Gonzalez MD, et al. Higher
levels of serum copper in schizophrenic patients treated with depot
neuroleptics. Psychiatry Res. 2000 Apr 24; 94: 51-8.

8 Parikh V, Khan MM, Mahadik SP. Differential effects of
antipsychotics on expression of antioxidant enzymes and membrane lipid
peroxidation in rat brain. J Psychiatr Res. 2003; 37: 43-51.

9 Brown AS, Susser ES, Butler PD, et al. Neurobiological plausibility
of prenatal nutritional deprivation as a risk factor for schizophrenia.

10 Grant ECG. Nutritional supplements to prevent pregnancy
complications., 16 Jul 2004

11 Hemmings G. Summer 2004 Newsletter, The Schizophrenia Association
of Great Britain. 2004: 38; 2-12.

Competing interests:
None declared

Competing interests: No competing interests

03 February 2005
Ellen C G Grant
physician and medical gynaecologist
Kingston-upon-Thames, KT2 7JU, UK