Efficacy of Gemfibrozil as an Adjunct to Sertraline in Major Depressive Disorder, A Double-Blind, Randomized, and Placebo-Controlled Clinical Trial
-
Atefeh Zandifar
,
Rahim Badrfam
,
Ahmad Shamabadi
,
Shakiba Jalilevand
,
Shayan Pourmirbabaei
,
Farbod Torkamand
,
Erfan Sahebolzamani
,
Shahin Akhondzadeh
Abstract
Objective: Major depressive disorder (MDD) is predicted to be the first cause of burden of disease. The antidepressant activity of gemfibrozil has been recently considered. This study was designed to evaluate the effectiveness of gemfibrozil as a sertraline adjunct in treating patients with MDD.
Method: A total of 46 patients with MDD based on the DSM-V criteria with a minimum score of 22 on the 17-item Hamilton Rating Scale for Depression (HAM-D) were randomized to receive either 300 mg daily gemfibrozil or placebo in addition to 100 mg sertraline for 8 weeks in a randomized, double-blind placebo-controlled trial. Patients were evaluated for response to treatment using the HAM-D score at baseline and weeks 2, 4, and 8.
Results: Forty-five patients completed the study and took part in all follow-up visits. Repeated measure ANOVA with a Greenhouse-Geisser correction showed a significant difference for time×treatment interaction on within-subjects HAM-D scores [p–value= 0.026]. A significant difference was seen in time [p–value < 0.001]. The test of between-subject effects also showed a significant effect of treatment on HAM-D scores at weeks 2, 4, and 8 [p–value = 0.07]. Using Kaplan-Meier estimate curves, time to remission periods were significantly different between the 2 trial arms [Log-Rank p–value = 0.003].
Conclusion: Gemfibrozil is an effective adjunctive treatment in MDD and can be used to reduce depression symptoms.
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2. Richards CS, O'Hara MW. The Oxford handbook of depression and comorbidity: Oxford University Press; 2014.
3. Bachmann S. Epidemiology of Suicide and the Psychiatric Perspective. Int J Environ Res Public Health. 2018;15(7):1425.
4. Organization WH. The global burden of disease: 2004 update: World Health Organization; 2008.
5. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540-60.
6. Kennedy SH, Lam RW, Cohen NL, Ravindran AV. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry. 2001;46 Suppl 1:38s-58s.
7. Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164(5):350-9.
8. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:5-9.
9. Kornstein SG, Schneider RK. Clinical features of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:18-25.
10. Fava M. Augmentation and combination strategies for complicated depression. J Clin Psychiatry. 2009;70(11):e40.
11. Templeton IE, Chen Y, Mao J, Lin J, Yu H, Peters S, et al. Quantitative Prediction of Drug-Drug Interactions Involving Inhibitory Metabolites in Drug Development: How Can Physiologically Based Pharmacokinetic Modeling Help? CPT Pharmacometrics Syst Pharmacol. 2016;5(10):505-15.
12. Todd PA, Ward A. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs. 1988;36(3):314-39.
13. Roy A, Pahan K. Gemfibrozil, stretching arms beyond lipid lowering. Immunopharmacol Immunotoxicol. 2009;31(3):339-51.
14. Ni YF, Wang H, Gu QY, Wang FY, Wang YJ, Wang JL, et al. Gemfibrozil has antidepressant effects in mice: Involvement of the hippocampal brain-derived neurotrophic factor system. J Psychopharmacol. 2018;32(4):469-81.
15. Glueck CJ, Tieger M, Kunkel R, Tracy T, Speirs J, Streicher P, et al. Improvement in symptoms of depression and in an index of life stressors accompany treatment of severe hypertriglyceridemia. Biol Psychiatry. 1993;34(4):240-52.
16. Hamilton M. The Hamilton rating scale for depression. Assessment of depression: Springer; 1986. p. 143-52.
17. Alamdarsaravi M, Ghajar A, Noorbala AA, Arbabi M, Emami A, Shahei F, et al. Efficacy and safety of celecoxib monotherapy for mild to moderate depression in patients with colorectal cancer: A randomized double-blind, placebo controlled trial. Psychiatry Res. 2017;255:59-65.
18. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL, Kashani AR, Farzanehgan ZM. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. J Clin Pharm Ther. 2000;25(5):347-53.
19. Chiriţă AL, Gheorman V, Bondari D, Rogoveanu I. Current understanding of the neurobiology of major depressive disorder. Rom J Morphol Embryol. 2015;56(2 Suppl):651-8.
20. Perez-Caballero L, Torres-Sanchez S, Romero-López-Alberca C, González-Saiz F, Mico JA, Berrocoso E. Monoaminergic system and depression. Cell Tissue Res. 2019;377(1):107-13.
21. Henter ID, de Sousa RT, Zarate CA, Jr. Glutamatergic Modulators in Depression. Harv Rev Psychiatry. 2018;26(6):307-19.
22. Phillips C. Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection. Neural Plast. 2017;2017:7260130.
23. Björkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72-9.
24. Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig. 2010;7(4):231-5.
25. Yu H, Chen ZY. The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol Sin. 2011;32(1):3-11.
26. Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005;33(2):262-70.
27. Wen X, Wang JS, Backman JT, Kivistö KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos. 2001;29(11):1359-61.
28. Jiang B, Huang C, Zhu Q, Tong LJ, Zhang W. WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway. Psychopharmacology (Berl). 2015;232(9):1629-42.
29. Jiang B, Wang YJ, Wang H, Song L, Huang C, Zhu Q, et al. Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway. Br J Pharmacol. 2017;174(2):177-94.
30. Rodriguez BSQ, Correa R. Gemfibrozil. StatPearls [Internet]. 2020.
31. Magarian GJ, Lucas LM, Colley C. Gemfibrozil-induced myopathy. Arch Intern Med. 1991;151(9):1873-4.
32. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-7.
33. Kashani L, Omidvar T, Farazmand B, Modabbernia A, Ramzanzadeh F, Tehraninejad ES, et al. Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology. 2013;38(6):767-76.
2. Richards CS, O'Hara MW. The Oxford handbook of depression and comorbidity: Oxford University Press; 2014.
3. Bachmann S. Epidemiology of Suicide and the Psychiatric Perspective. Int J Environ Res Public Health. 2018;15(7):1425.
4. Organization WH. The global burden of disease: 2004 update: World Health Organization; 2008.
5. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540-60.
6. Kennedy SH, Lam RW, Cohen NL, Ravindran AV. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry. 2001;46 Suppl 1:38s-58s.
7. Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164(5):350-9.
8. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:5-9.
9. Kornstein SG, Schneider RK. Clinical features of treatment-resistant depression. J Clin Psychiatry. 2001;62 Suppl 16:18-25.
10. Fava M. Augmentation and combination strategies for complicated depression. J Clin Psychiatry. 2009;70(11):e40.
11. Templeton IE, Chen Y, Mao J, Lin J, Yu H, Peters S, et al. Quantitative Prediction of Drug-Drug Interactions Involving Inhibitory Metabolites in Drug Development: How Can Physiologically Based Pharmacokinetic Modeling Help? CPT Pharmacometrics Syst Pharmacol. 2016;5(10):505-15.
12. Todd PA, Ward A. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs. 1988;36(3):314-39.
13. Roy A, Pahan K. Gemfibrozil, stretching arms beyond lipid lowering. Immunopharmacol Immunotoxicol. 2009;31(3):339-51.
14. Ni YF, Wang H, Gu QY, Wang FY, Wang YJ, Wang JL, et al. Gemfibrozil has antidepressant effects in mice: Involvement of the hippocampal brain-derived neurotrophic factor system. J Psychopharmacol. 2018;32(4):469-81.
15. Glueck CJ, Tieger M, Kunkel R, Tracy T, Speirs J, Streicher P, et al. Improvement in symptoms of depression and in an index of life stressors accompany treatment of severe hypertriglyceridemia. Biol Psychiatry. 1993;34(4):240-52.
16. Hamilton M. The Hamilton rating scale for depression. Assessment of depression: Springer; 1986. p. 143-52.
17. Alamdarsaravi M, Ghajar A, Noorbala AA, Arbabi M, Emami A, Shahei F, et al. Efficacy and safety of celecoxib monotherapy for mild to moderate depression in patients with colorectal cancer: A randomized double-blind, placebo controlled trial. Psychiatry Res. 2017;255:59-65.
18. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL, Kashani AR, Farzanehgan ZM. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. J Clin Pharm Ther. 2000;25(5):347-53.
19. Chiriţă AL, Gheorman V, Bondari D, Rogoveanu I. Current understanding of the neurobiology of major depressive disorder. Rom J Morphol Embryol. 2015;56(2 Suppl):651-8.
20. Perez-Caballero L, Torres-Sanchez S, Romero-López-Alberca C, González-Saiz F, Mico JA, Berrocoso E. Monoaminergic system and depression. Cell Tissue Res. 2019;377(1):107-13.
21. Henter ID, de Sousa RT, Zarate CA, Jr. Glutamatergic Modulators in Depression. Harv Rev Psychiatry. 2018;26(6):307-19.
22. Phillips C. Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection. Neural Plast. 2017;2017:7260130.
23. Björkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72-9.
24. Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig. 2010;7(4):231-5.
25. Yu H, Chen ZY. The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol Sin. 2011;32(1):3-11.
26. Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005;33(2):262-70.
27. Wen X, Wang JS, Backman JT, Kivistö KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos. 2001;29(11):1359-61.
28. Jiang B, Huang C, Zhu Q, Tong LJ, Zhang W. WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway. Psychopharmacology (Berl). 2015;232(9):1629-42.
29. Jiang B, Wang YJ, Wang H, Song L, Huang C, Zhu Q, et al. Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway. Br J Pharmacol. 2017;174(2):177-94.
30. Rodriguez BSQ, Correa R. Gemfibrozil. StatPearls [Internet]. 2020.
31. Magarian GJ, Lucas LM, Colley C. Gemfibrozil-induced myopathy. Arch Intern Med. 1991;151(9):1873-4.
32. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-7.
33. Kashani L, Omidvar T, Farazmand B, Modabbernia A, Ramzanzadeh F, Tehraninejad ES, et al. Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology. 2013;38(6):767-76.
| Files | ||
| Issue | Vol 16 No 1 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijps.v16i1.5379 | |
| Keywords | ||
| Adjunctive Treatment Depression Gemfibrozil Major Depressive Disorder Randomized Controlled Trial | ||
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How to Cite
1.
Zandifar A, Badrfam R, Shamabadi A, Jalilevand S, Pourmirbabaei S, Torkamand F, Sahebolzamani E, Akhondzadeh S. Efficacy of Gemfibrozil as an Adjunct to Sertraline in Major Depressive Disorder, A Double-Blind, Randomized, and Placebo-Controlled Clinical Trial. Iran J Psychiatry. 2021;16(1):52-59.
