Why do we use zinc in the treatment of Schizophrenia and Mood Disorders?

Zinc is involved in over 200 enzymatic reactions, one of the most important of which is neurotransmitter production.

The basic principle reactions involving zinc and B6 are for protein manufacture at the RNA/DNA level, that is at the transcription and translation level. Most major brain neurotransmitters (catecholamines, serotonin, etc.) are proteins and without them intercellular communication comes to a halt.

As described in my two part Review on Schizophrenia and my Review on Mood and Behaviour Disorders we see zinc and B6 deficiency as an extremely important psychiatric treatment interventions.

Metalallothionein is a zinc-dependent enzyme that helps the body to rid the heavy metals. Copper and cadmium and other metals are in physiological opposition with zinc.

Below are some abstracts on: zinc deficiency in psychiatric conditions; the importance of B6 and zinc in psychiatric prescribing; and zinc-dependent metallothionein aspects in psychiatry

1) Stanley PC, Wakwe VC. Toxic trace metals in the mentally ill patients. Niger Postgrad Med J. 2002 Dec. 9(4): 199-204. Department of Mental Health, Jos University Teaching Hospital.

Serum Cadmium and lead were measured in 61 in- and out-patients of the Mental Health Unit of a University Teaching Hospital. Diagnosis using the ICD-10 Criteria divided the patients into 21 Depressives, 20 Manic-depressive and 20 Schizophrenics. Twenty “healthy” individuals matched for age and sex were used as controls. The measurements of cadmium and lead were done on admission and at 3 and 7 weeks after the relevant treatment had been given. Serum zinc was also measured because of the interaction between zinc and these toxic metals. Measurement was with the Atomic Absorption Spectrophotometer. Results showed that cadmium was raised in depressives (p < 0.02) and reduced in mania patients (p < 0.01). Lead was increased in depressives (p < 0.01) and schizophrenics (p < 0.05) but not in mania patients. Serum zinc was reduced in all mental patients. Serum levels of the toxic metals of the mental patients tended to move towards the values of the control group with treatment.

2) Pfeiffer CC, Braverman ER. Zinc, the brain and behavior. Biol Psychiatry. 1982 Apr. 17(4): 513-32.

The total content of zinc in the adult human body averages almost 2 g. This is approximately half the total iron content and 10 to 15 times the total body copper. In the brain, zinc is with iron, the most concentrated metal. The highest levels of zinc are found in the hippocampus in synaptic vesicles, boutons, and mossy fibers. Zinc is also found in large concentrations in the choroid layer of the retina which is an extension of the brain. Zinc plays an important role in axonal and synaptic transmission and is necessary for nucleic acid metabolism and brain tubulin growth and phosphorylation. Lack of zinc has been implicated in impaired DNA, RNA, and protein synthesis during brain development. For these reasons, deficiency of zinc during pregnancy and lactation has been shown to be related to many congenital abnormalities of the nervous system in offspring. Furthermore, in children insufficient levels of zinc have been associated with lowered learning ability, apathy, lethargy, and mental retardation. Hyperactive children may be deficient in zinc and vitamin B-6 and have an excess of lead and copper. Alcoholism, schizophrenia, Wilson’s disease, and Pick’s disease are brain disorders dynamically related to zinc levels. Zinc has been employed with success to treat Wilson’s disease, achrodermatitis enteropathica, and specific types of schizophrenia.

3) Johnson S. Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson’s disease? Med Hypotheses. 2001 May. 56(5): 641-5.

Zinc has several crucial functions in brain development and maintenance: it 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. For example, 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. Unfortunately, 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. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD).Increased Cu levels may also be found in people with Wilson’s disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. 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, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson’s disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases.

4) Ebadi M, Iversen PL, Hao R, Cerutis DR, Rojas P, Happe HK, Murrin LC, Pfeiffer RF: Expression and regulation of brain metallothionein. Neurochem Int, 1995(Jul); 27(1): 1-22.

Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These “vesicular” pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down’s syndrome, epilepsy, Friedreich’s ataxia, Guillaine-Barré syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson’s disease, Pick’s disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.