Manganese in the treatment of Drug induced Dyskinesias




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Can Med Assoc J. 1977 Oct 22;117(8):859.

Tardive dyskinesia treated with manganese.

Hoffer A.



Prog Neuropsychopharmacol Biol Psychiatry. 2010 May 30;34(4):692-6. Epub 2010 Mar 25.

Association of the manganese superoxide dismutase gene Ala-9Val polymorphism with clinical phenotypes and tardive dyskinesia in schizophrenic patients.

Liu H, Wang C, Chen PH, Zhang BS, Zheng YL, Zhang CX, Meng HQ, Wang Y, Chen da C, Xiu MH, Kosten TR, Zhang XY.

Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, China.


OBJECTIVE: Several recent studies that have investigated the genetic association between the manganese superoxide dismutase (MnSOD) gene Ala-9Val single-nucleotide polymorphism (SNP) and tardive dyskinesia (TD) have produced conflicting results. This study was to investigate whether this SNP was associated with clinical phenotypes and antipsychotic-induced tardive dyskinesia (TD) in schizophrenia in a genetically homogeneous Han Chinese inpatient population.

METHODS: Genotyping was performed for the MnSOD gene Ala-9Val SNP in Chinese schizophrenia patients with (n=176) and without TD (n=346). The severity of TD was assessed using the abnormal involuntary movement scale (AIMS), and psychopathology using the Positive and Negative Syndrome Scale (PANSS).

RESULTS: The frequencies of genotypes and alleles did not differ significantly between schizophrenic patients with and without TD (both p>0.05). Also, there was no significant difference in the AIMS total score between the Val/Val and Ala allele carrier groups (p>0.05). However, the PANSS negative symptom subscore was significantly higher in patients with Val/Val genotype (21.8+/-7.3) than those with Ala alleles (20.1+/-7.7) (t=2.32, p=0.03).

CONCLUSION: While the MnSOD gene Ala-9Val polymorphism did not play a major role in the susceptibility to TD in schizophrenic patients, it might be associated with negative symptoms of schizophrenia.


Psychiatry Res. 2008 Dec 15;161(3):336-8. Epub 2008 Oct 31.

Additive effect between quinine oxidoreductase gene (NQO1: Pro187Ser) and manganese superoxide dismutase gene (MnSOD: Ala-9Val) polymorphisms on tardive dyskinesia in patients with schizophrenia.

Pae CU.

Department of Psychiatry, Kangnam St Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seocho-Gu, Seoul, Republic of Korea.


This study investigated whether there was an interaction between the NQO1 Pro187Ser and MnSOD Ala-9Val gene polymorphisms in the development of tardive dyskinesia (TD). The combined genotypes of T/T in NQO1 Pro187Ser and Val/Val in MnSOD Ala-9Val polymorphisms were found to be independently associated with a significantly higher risk of TD. However, further adequately powered studies will be needed to confirm these preliminary findings.


Prog Neuropsychopharmacol Biol Psychiatry. 2008 Dec 12;32(8):1844-7. Epub 2008 Aug 28.

Manganese superoxide dismutase gene Ala-9Val polymorphism might be related to the severity of abnormal involuntary movements in Korean schizophrenic patients.

Kang SG, Choi JE, An H, Park YM, Lee HJ, Han C, Kim YK, Kim SH, Cho SN, Joe SH, Jung IK, Kim L, Lee MS.

Department of Psychiatry, Korea University College of Medicine, Seoul, South Korea.


OBJECTIVE: This study examined whether the manganese superoxide dismutase (MnSOD) gene Ala-9Val single-nucleotide polymorphism (SNP) is associated with neuroleptic-induced tardive dyskinesia (TD) and the severity of the abnormal involuntary movements in Korean schizophrenic patients.

METHOD: We investigated whether the MnSOD gene Ala-9Val SNP is associated with TD in Korean schizophrenic patients with (n=83) and without (n=126) TD who were matched for exposure to antipsychotics and other relevant variables.

RESULTS: Logistic regression analysis revealed that being older (p=0.026) was a risk factor for TD, but that there was no significant association between MnSOD gene and TD. Abnormal involuntary movements were more severe in carriers of the Ala allele than in noncarriers (p=0.044).

CONCLUSION: These findings do not support that the MnSOD gene Ala-9Val SNP is associated with TD in Korean schizophrenic patients. However, this polymorphism might be related to the severity of abnormal involuntary movements in this population.


Psychiatr Pol. 2006 Sep-Oct;40(5):937-48.

[Manganese superoxide dismutase gene (MnSOD) polimorphism in schizophrenics with tardive dyskinesia from central Poland].

[Article in Polish]

Gałecki P, Pietras T, Szemraj J.

Klinika Psychiatrii Dorosłych, Uniwersytet Medyczny w Lodzi.


Tardive dyskinesias (TD) are serious side effect symptoms appearing in the course of many years’ neuroleptic treatment. On average, TD appear in 20% patients who take neuroleptics chronically. The free radical hypothesis of tardive dyskinesias assumes that they come into existence due to cholinergic neuron damage in the extra-pyramidal system by reactive oxygen species (ROS). Manganese superoxide dismutase (MnSOD) plays a key role in protection against ROS.

AIM: The aim of this study was to evaluate functional gene polymorphism for MnSOD in schizophrenic patients with tardive dyskinesias presence.

METHOD: 122 paranoid schizophrenia patients were invited to paticipate in the study. TD symptoms were observed in 57 people. The evaluation was performed by applying the PANSS scale, while TD increase was evaluated with the AIMS scale.

RESULT: Statistical association in allele incidence frequency (p < 0.001) and in a genotype layout was observed between the control group and the schizophrenic group (p < 0.001), and also in a genotype layout between the TD group and the control group (p < 0.001). Allele layout also differentiated the control group and the TD symptoms group (p < 0.05). Relative risk for developing schizophrenia and TD development depends on the genotype in the gene for MnSOD.

CONCLUSION: In the Polish population there is a statistically substantial association between schizophrenia incidence and the Val-9Val genotype in a gene for MnSOD. Schizophrenic patients having a Val-9Val genotype in the gene for MnSOD have nearly a ten times higher risk for developing TD than schizophrenics not having this genotype. Risk for developing schizophrenia for people having the Val-9Val genotype in the gene for MnSOD is over three times higher than for people lacking this genotype.


Psychiatr Genet. 2003 Sep;13(3):187-92.

Interaction between polymorphisms of the dopamine D3 receptor and manganese superoxide dismutase genes in susceptibility to tardive dyskinesia.

Zhang ZJ, Zhang XB, Hou G, Yao H, Reynolds GP.

Department of Psychiatry, Nanjing Brain Hospital and Nanjing Medical University, Nanjing, People’s Republic of China.


OBJECTIVES: To investigate the influence of a functional polymorphism of the dopamine D3 receptor (DRD3), and assess its interaction with a Mn superoxide dismutase (MnSOD) polymorphism, in contributing to tardive dyskinesia in a chronic inpatient population with schizophrenia.

METHODS: Chinese Han patients with schizophrenia were assessed for abnormal involuntary movements, and subgroups of 42 patients with persistent tardive dyskinesia and 59 consistently without dyskinesias were assessed for the DRD3 ser9gly and the MnSOD ala-9val polymorphisms.

RESULTS: A higher, but not significant, frequency of DRD3 ser/gly heterozygotes was observed in the tardive dyskinesia group (0.52 versus 0.33, chi2=5, degrees of freedom=2, P=0.08). However, assessment of the combined influence of the two polymorphisms demonstrated a significant effect (chi2=8.09, degrees of freedom=3, P=0.04), whereby the combination of the MnSOD -9val and DRD3 9ser alleles was associated with tardive dyskinesia.

CONCLUSIONS: These results indicate a possible synergistic effect of genetic factors influencing mitochondrial free radical scavenging and dopamine receptor function on the susceptibility to tardive dyskinesia.


Neuropsychopharmacology. 2000 Aug;23(2):170-7.

Manganese superoxide dismutase gene polymorphism and schizophrenia: relation to tardive dyskinesia.

Hori H, Ohmori O, Shinkai T, Kojima H, Okano C, Suzuki T, Nakamura J.

Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.


There has been increasing evidence that deranged superoxide dismutase (SOD) activities might be a risk factor for schizophrenia and/or tardive dyskinesia (TD). In the present study, we investigated the genetic association between a functional polymorphism (Ala-9Val) in the human manganese (Mn) SOD gene and schizophrenia or TD (192 schizophrenics: 39 with TD and 153 without TD; 141 controls). No significant differences in the allelic or genotypic distribution between schizophrenics and controls were observed. However, we did find a significant difference in genotypic distribution between schizophrenics with and those without TD (p =. 03). Moreover, decreased -9Ala (mutant) allele was found among patients with TD (p =.02; odds ratio = 0.29; 95% confidence interval = 0.10-0.83). In conjunction with previous findings of increased free radicals and decreased SOD activities in TD subjects, these results suggest that the -9Ala (high activity) MnSOD allele may play a role in protecting against susceptibility to TD in schizophrenics.


Psychopharmacol Bull. 1995;31(1):159-65.

Free radical involvement in neuropsychiatric illnesses.

Lohr JB, Browning JA.

University of California, San Diego, USA.


Free radicals are highly reactive chemical species with an unpaired electron, and their formation is catalyzed by transition metals like iron, copper, and manganese. There have been numerous studies linking free radical damage with neuropsychiatric illnesses, including several psychiatric and motor disorders, raising the possibility that antioxidant strategies might serve a neuroprotective role for some conditions. The illnesses studied include tardive dyskinesia, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Although oxidative mechanisms may play a role in these conditions, further studies are necessary to define their involvement, and to determine the extent to which antioxidants may partially alleviate or prevent some of these conditions.


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