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LETTER TO EDITOR
Year : 2012  |  Volume : 34  |  Issue : 1  |  Page : 97-98  

The 'Holy Grail' and 'Poisoned Chalice' Effects of Antipsychotics on Oxidative Stress in Schizophrenia: Can 'Hormesis' Explain this Paradox?


Associate Professor and Wellcome Trust/DBT India Alliance Senior Fellow, The Metabolic Clinic in Psychiatry, Department of Psychiatry, Cognitive Neurobiology and Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India

Date of Web Publication15-May-2012

Correspondence Address:
Ganesan Venkatasubramanian
Associate Professor and Wellcome Trust/DBT India Alliance Senior Fellow, The Metabolic Clinic in Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka,
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7176.96172

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How to cite this article:
Venkatasubramanian G. The 'Holy Grail' and 'Poisoned Chalice' Effects of Antipsychotics on Oxidative Stress in Schizophrenia: Can 'Hormesis' Explain this Paradox?. Indian J Psychol Med 2012;34:97-8

How to cite this URL:
Venkatasubramanian G. The 'Holy Grail' and 'Poisoned Chalice' Effects of Antipsychotics on Oxidative Stress in Schizophrenia: Can 'Hormesis' Explain this Paradox?. Indian J Psychol Med [serial online] 2012 [cited 2019 Nov 14];34:97-8. Available from: http://www.ijpm.info/text.asp?2012/34/1/97/96172

Sir,

Oxidative stress-mediated pathogenesis has been proposed as an overarching model to understand schizophrenia. [1] This letter summarizes the 'holy grail' as well as 'poisoned chalice' effects of antipsychotics on oxidative stress in schizophrenia and hypothesizes the novel utility of 'hormesis' in understanding this curious paradox.

Antipsychotics have been demonstrated to influence oxidative stress in numerous studies ranging from animal models to patient population. [1] While this impact is unequivocal, the differential nature of the influence is puzzling. For instance, it has been shown that short-term antipsychotic treatment can reduce the oxidative stress in schizophrenia. [2] This supports the beneficial 'holy grail' effects of antipsychotics on oxidative stress. On the contrary, antipsychotics have also been shown to increase the 'oxidative stress' in schizophrenia. For instance, haloperidol and clozapine have been shown to induce oxidative stress. [3] Also, extrapyramidal side effects caused by antipsychotics are associated with increased oxidative stress. [4] Moreover, obesity and related metabolic derangements induced by newer antipsychotics are associated with excessive oxidative stress. [5] Intriguingly, the efficacy of antipsychotics has been shown to correlate with the propensity for both extrapyramidal [6] and metabolic [7] side effects. Thus, the long-term 'poisoned chalice' impact of these side effects might frequently co-occur with clinical improvement in psychosis.

I hypothesize that this curious paradox can be understood by the application of the principles of hormesis (defined as an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis [8] ). It is possible that the lower doses of oxidative stress induced by antipsychotics in various pathways (i.e., extrapyramidal as well as metabolic) might result in compensatory adaptive, neutralizing responses by biological systems that eventually ameliorate the psychosis. However, if the oxidative stress through these pathways increases beyond desirable limits, the side effects predominate. Rigorous application of this paradigm of hormesis in animal models as well as clinical research promises the potential to ascertain the minimum effective dose of antipsychotics, resulting in optimal clinical benefit with reduced burden of side effects.

 
   References Top

1.Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol 2009;19:220-30.  Back to cited text no. 1
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2.Chittiprol S, Venkatasubramanian G, Neelakantachar N, Babu SV, Reddy NA, Shetty KT, et al. Oxidative stress and neopterin abnormalities in schizophrenia: A longitudinal study. J Psychiatr Res 2010;44:310-3.  Back to cited text no. 2
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3.Martins MR, Petronilho FC, Gomes KM, Dal-Pizzol F, Streck EL, Quevedo J. Antipsychotic-induced oxidative stress in rat brain. Neurotox Res 2008;13:63-9.  Back to cited text no. 3
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4.O'Brien E, Dedova I, Duffy L, Cordwell S, Karl T, Matsumoto I. Effects of chronic risperidone treatment on the striatal protein profiles in rats. Brain Res 2006;1113:24-32.  Back to cited text no. 4
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5.Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sci 2009;84:705-12.  Back to cited text no. 5
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6.McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991;48:739-45.  Back to cited text no. 6
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7.Girgis RR, Javitch JA, Lieberman JA. Antipsychotic drug mechanisms: Links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 2008;13:918-29.  Back to cited text no. 7
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8.Calabrese EJ, Baldwin LA. Defining hormesis. Hum Exp Toxicol 2002;21:91-7.  Back to cited text no. 8
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1 Association between Antipsychotic-induced Metabolic Side-effects and Clinical Improvement: A Review on the Evidence for “Metabolic Threshold”
Eesha Sharma,Naren P. Rao,Ganesan Venkatasubramanian
Asian Journal of Psychiatry. 2013;
[Pubmed] | [DOI]



 

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