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Mechanism of synergistic action on behavior, oxidative stress and inflammation following co-treatment with ketamine and different antidepressant classes

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Abstract

Background

Major depressive disorder (MDD) affects many people in the world. However, around 40% of patients do not respond to any pharmacological drugs. An alternative is to use a combination of different pharmacological groups or the combination of a classical antidepressant with a substance that can potentiate its effect. Thus, this study aimed to investigate the synergistic interactions between different antidepressants, including fluoxetine, quetiapine and lamotrigine in combination with ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist.

Methods

Wistar rats were acutely treated with fluoxetine (1.25 mg/kg), quetiapine (5 mg/kg), and lamotrigine (5.0 mg/kg) alone or in combination with ketamine (5.0 mg/kg), and then subjected to behavioral tests. In addition, oxidative damage and antioxidant capacity were assessed in the rat brain, and pro-inflammatory cytokines levels were evaluated in the serum.

Results

It was observed a synergistic effect of ketamine in combination with fluoxetine on the immobility time in the forced swimming test, indicating an antidepressant effect. Other antidepressant did not show effects when administrated alone or joint to ketamine. The combination of ketamine with other antidepressants, particularly quetiapine, in some brain regions induced an increase in damage to lipids and proteins. However, the combination of ketamine with fluoxetine increased the antioxidant activity of superoxide dismutase, and decreased oxidative damage, thus suggesting a neuroprotective effect of the combination of these drugs. The combination of ketamine with fluoxetine or lamotrigine reduced pro-inflammatory cytokines levels.

Conclusion

In conclusion, ketamine induced antioxidant or pro-antioxidant effects dependent of antidepressant classes or brain area.

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Authors and Affiliations

  1. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil

    Gislaine Z. Réus, Beatriz I. Matias, Amanda L. Maciel, Helena M. Abelaira, Zuleide M. Ignácio, Airam B. de Moura, Danyela Matos & João Quevedo

  2. Laboratory of Clinical and Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, SC, Brazil

    Lucineia G. Danielski & Fabricia Petronilho

  3. Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  4. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  5. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil

    André F. Carvalho

  6. Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

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  1. Gislaine Z. Réus
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  2. Beatriz I. Matias
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  3. Amanda L. Maciel
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  4. Helena M. Abelaira
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  5. Zuleide M. Ignácio
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  6. Airam B. de Moura
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  11. João Quevedo
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Correspondence to Gislaine Z. Réus.

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Réus, G.Z., Matias, B.I., Maciel, A.L. et al. Mechanism of synergistic action on behavior, oxidative stress and inflammation following co-treatment with ketamine and different antidepressant classes. Pharmacol. Rep 69, 1094–1102 (2017). https://doi.org/10.1016/j.pharep.2017.04.021

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  • DOI: https://doi.org/10.1016/j.pharep.2017.04.021

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