Simvastatin as an adjuvant therapy to fluoxetine in patients with moderate to severe major depression: A double-blind placebo-controlled trial
Abstract
Statins have been shown to decrease depressive symptoms in certain groups of patients, an effect that is mostly attributed to their anti-inflammatory and neurotransmitter modulatory potentials. We aimed to investigate the antidepressant effects of simvastatin as an adjuvant therapy in patients with moderate to severe depression. In this double-blind placebo-controlled clinical trial, 48 patients were randomly allocated to receive simvastatin or placebo as an adjunct to fluoxetine for six weeks. Patients were evaluated with the Hamilton Depression Rating Scale (HDRS) at baseline and weeks 2, 4 and 6. Probable clinical and laboratory adverse events were also monitored and compared between the two groups. Simvastatin-treated patients experienced significantly more reductions in HDRS scores compared to the placebo group by the end of the trial ( p=0.02). Early improvement and response rates were significantly greater in the simvastatin group than the placebo group ( p=0.02 and p=0.01, respectively) but remission rate was not significantly different between the two groups ( p=0.36). No serious adverse event was reported during this trial. In conclusion, simvastatin seems to be a safe and effective adjuvant therapy for patients suffering from major depressive disorder. However, more confirmatory studies are warranted.
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In a 6-week RCT of participants meeting criteria for major depressive disorder (n = 48), the fluoxetine plus simvastatin group showed significantly lower depressive symptoms, whereas differences in remission rates did not achieve statistical significance.
“at study completion, the latter showed significantly lower depressive symptoms, whereas differences in remission rates did not achieve statistical significance.”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [174]
Cites
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., Rush, A. J., Walters, E. E., & Wang, P. S. (2003) · JAMA · doi:10.1001/jama.289.23.3095 · Cited by 7,988 · see citing works
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881 · see citing works
Frank, E. (1991) · Archives of General Psychiatry · doi:10.1001/archpsyc.1991.01810330075011 · Cited by 1,959 · cited 1× · see citing works
“Early improvement (⩾20% reduction in HDRS score by the end of the second week), response rate (⩾50% decrease in the HDRS score), and remission rate (HDRS score ⩽7) were also compared between the two groups (Frank et al., 1991; Szegedi et al., 2009).”
ResultNew insights into BDNF function in depression and anxiety
Martinowich, K., Manji, H., & Lu, B. (2007) · Nature Neuroscience · doi:10.1038/nn1971 · Cited by 1,221 · see citing works
Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach
McIntyre, R. S., Filteau, M.-J., Martin, L., Patry, S., Carvalho, A., Cha, D. S., Barakat, M., & Miguelez, M. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.10.043 · Cited by 421 · see citing works
Akhondzadeh, S., Jafari, S., Raisi, F., Nasehi, A. A., Ghoreishi, A., Salehi, B., Mohebbi-Rasa, S., Raznahan, M., & Kamalipour, A. (2009) · Depression and Anxiety · doi:10.1002/da.20589 · Cited by 397 · see citing works
Self-citationAbbasi, S.-H., Hosseini, F., Modabbernia, A., Ashrafi, M., & Akhondzadeh, S. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.03.033 · Cited by 344 · see citing works
Self-citationSzegedi, A., Jansen, W. T., van Willigenburg, A. P. P., van der Meulen, E., Stassen, H. H., & Thase, M. E. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.07m03780 · Cited by 341 · see citing works
Decreased plasma BDNF level in depressive patients
Lee, B.-H., Kim, H., Park, S., & Kim, Y. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.11.005 · Cited by 327 · see citing works
Zunszain, P. A., Hepgul, N., & Pariante, C. M. (2012) · Current topics in behavioral neurosciences · doi:10.1007/7854_2012_211 · Cited by 317 · see citing works
Effects of lovastatin on cognitive function and psychological well-being
Muldoon, M. F., Barger, S. D., Ryan, C. M., Flory, J. D., Lehoczky, J. P., Matthews, K. A., & Manuck, S. B. (2000) · The American Journal of Medicine · doi:10.1016/s0002-9343(00)00353-3 · Cited by 290 · see citing works
Bösel, J., Gandor, F., Harms, C., Synowitz, M., Harms, U., Djoufack, P. C., Megow, D., Dirnagl, U., Hörtnagl, H., Fink, K., et al. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02980.x · Cited by 210 · see citing works
Rendleman, R. L., & Walkup, J. T. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0435-8.00049-4 · Cited by 197 · see citing works
Karlović, D., Serretti, A., Vrkić, N., Martinac, M., & Marčinko, D. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2011.12.007 · Cited by 175 · see citing works
Stimpson, N. J., Agrawal, N., & Lewis, G. (2002) · The British Journal of Psychiatry · doi:10.1192/bjp.181.4.284 · Cited by 159 · see citing works
Sepanjnia, K., Modabbernia, A., Ashrafi, M., Modabbernia, M.-J., & Akhondzadeh, S. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.58 · Cited by 153 · see citing works
Self-citationSimvastatin Reduces the Association of NMDA Receptors to Lipid Rafts
Ponce, J., de la Ossa, N. P., Hurtado, O., Millán, M., Arenillas, J. F., Dávalos, A., & Gasull, T. (2008) · Stroke · doi:10.1161/strokeaha.107.498923 · Cited by 143 · see citing works
Shahmansouri, N., Farokhnia, M., Abbasi, S.-H., Kassaian, S. E., Tafti, A.-A. N., Gougol, A., Yekehtaz, H., Forghani, S., Mahmoodian, M., Saroukhani, S., et al. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.11.003 · Cited by 140 · see citing works
Self-citationAssociations Between Serum Lipids and Major Depressive Disorder
Dortland, A. K. B. V. R., Giltay, E. J., van Veen, T., PELT, J. V., Zitman, F. G., & Penninx, B. W. J. H. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04865blu · Cited by 127 · see citing works
The TNF-α System: Functional Aspects in Depression, Narcolepsy and Psychopharmacology
Berthold-Losleben, M., & Himmerich, H. (2008) · Current Neuropharmacology · doi:10.2174/157015908785777238 · Cited by 119 · see citing works
Tadić, A., Helmreich, I., Mergl, R., Hautzinger, M., Kohnen, R., Henkel, V., & Hegerl, U. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.04.014 · Cited by 113 · see citing works
Willey, J. Z., & Elkind, M. S. V. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.199 · Cited by 101 · see citing works
Pitavastatin prevents NMDA‐induced retinal ganglion cell death by suppressing leukocyte recruitment
Nakazawa, T., Takahashi, H., Nishijima, K., et al. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04274.x · Cited by 95 · see citing works
Stafford, L., & Berk, M. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05825blu · Cited by 93 · see citing works
Ludka, F. K., Zomkowski, A. D. E., Cunha, M. P., Dal-Cim, T., Zeni, A. L. B., Rodrigues, A. L. S., & Tasca, C. I. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.05.005 · Cited by 92 · see citing works
Oral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder
Khajavi, D., Farokhnia, M., Modabbernia, A., Ashrafi, M., Abbasi, S.-H., Tabrizi, M. H., & Akhondzadeh, S. (2012) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12m07706 · Cited by 86 · see citing works
Self-citationStewart, R. (2000) · Archives of Internal Medicine · doi:10.1001/archinte.160.20.3144 · Cited by 86 · see citing works
Ghanizadeh, A., & Hedayati, A. (2013) · Depression and Anxiety · doi:10.1002/da.22195 · Cited by 81 · see citing works
Cholesterol and suicide attempts: A prospective study of depressed inpatients
Fiedorowicz, J. G., & Coryell, W. H. (2007) · Psychiatry Research · doi:10.1016/j.psychres.2006.09.003 · Cited by 79 · see citing works
Targeting of NMDA receptors in the treatment of major depression
Dang, Y.-H., Ma, X.-C., Zhang, J.-C., Ren, Q., Wu, J., Gao, C.-G., & Hashimoto, K. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612819666140110120435 · Cited by 79 · see citing works
Relationship between Major Depression and High Serum Cholesterol in Japanese Men
Nakao, M., & Yano, E. (2004) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.204.273 · Cited by 76 · see citing works
Statins and biomarkers of inflammation
Devaraj, S., Rogers, J., & Jialal, I. (2007) · Current Atherosclerosis Reports · doi:10.1007/bf02693938 · Cited by 73 · see citing works
Tramontina, A. C., Wartchow, K. M., Rodrigues, L., Biasibetti, R., Quincozes‐Santos, A., Bobermin, L. D., Tramontina, F. F., & Gonçalves, C. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0680-z · Cited by 72 · see citing works
Statins of Different Brain Penetrability Differentially Affect CSF PLTP Activity
Vuletic, S., Riekse, R. G., Marcovina, S. M., Peskind, E. R., Hazzard, W. R., & Albers, J. J. (2006) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000095679 · Cited by 66 · see citing works
Sonawalla, S. B., Papakostas, G. I., Petersen, T. J., Yeung, A. S., Smith, M. M., Sickinger, A. H., Gordon, J., Israel, J. A., Tedlow, J. R., Lamon-Fava, S., et al. (2002) · Psychosomatics · doi:10.1176/appi.psy.43.4.310 · Cited by 62 · see citing works
Statin Use and Risk of Depression in Patients With Coronary Heart Disease
Otte, C., Zhao, S., & Whooley, M. A. (2012) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.11m07038 · Cited by 61 · see citing works
Feng, L., Tan, C., Merchant, R. A., & Ng, T. P. (2008) · Drugs & Aging · doi:10.2165/00002512-200825090-00005 · Cited by 38 · see citing works
Long-term use of statins reduces the risk of hospitalization for dementia
Corrao, G., Ibrahim, B., Nicotra, F., Zambon, A., Merlino, L. G., Pasini, T. S., Catapano, A. L., & Mancia, G. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.07.009 · Cited by 37 · see citing works
Statins and their potential targets in multiple sclerosis therapy
Stüve, O., Prod’homme, T., Slavin, A., Youssef, S., Dunn, S. E., Steinman, L., & Zamvil, S. S. (2003) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.7.5.613 · Cited by 22 · see citing works
Domoki, F., Kis, B., Gáspár, T., Snipes, J. A., Bari, F., & Busija, D. W. (2009) · Neurochemistry International · doi:10.1016/j.neuint.2009.11.013 · Cited by 17 · see citing works
Validité du concept de dépression vasculaire : une revue de la littérature
THUILE, J., EVEN, C., & Guelfi, J. D. (2007) · L Encéphale · doi:10.1016/s0013-7006(07)91557-2 · Cited by 13 · see citing works
The effects of dietary cholesterol-lowering on psychological symptoms: A randomised controlled study
Weidner, G., Connor, S. L., Gerhard, G. T., et al. (2009) · Psychology Health & Medicine · doi:10.1080/13548500902730101 · Cited by 12 · see citing works
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Köhler‐Forsberg, O., N. Lydholm, C., Hjorthøj, C., Nordentoft, M., Mors, O., & Benros, M. E. (2019) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13016 · Cited by 432 · see citing works
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Bai, S., Guo, W., Feng, Y., Deng, H., Li, G., Nie, H., Guo, G., Yu, H., Ma, Y., Wang, J., et al. (2020) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-320912 · Cited by 235 · see citing works
Sun, J., Wang, F., Hong, G., Pang, M., Xu, H., Li, H., Tian, F., Fang, R., Yao, Y., & Liu, J. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.03.003 · Cited by 184 · see citing works
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Ghajar, A., Neishabouri, S., Velayati, N., Jahangard, L., Matinnia, N., Haghighi, M., Ghaleiha, A., Afarideh, M., Salimi, S., Meysamie, A., et al. (2017) · Pharmacopsychiatry · doi:10.1055/s-0042-116159 · Cited by 110 · see citing works
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- Authors
- Gougol, A., Zareh-Mohammadi, N., Raheb, S., Farokhnia, M., Salimi, S., Iranpour, N., Yekehtaz, H., & Akhondzadeh, S.
- Affiliations
- Roozbeh Hospital (IR)
- Baharloo Hospital (IR)
- Corresponding author
- Akhondzadeh, Shahin
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2015-03-31
- Volume
- 29
- Issue
- 5
- Pages
- 575-581
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W2153352631
- Cited by
- 77
- References
- 42
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 5 · 2021: 11 · 2020: 5 · 2019: 10 · 2018: 2 · 2017: 6 · 2016: 10 · 2015: 3
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tehran University of Medical Sciences and Health Services
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- simvastatin, fluoxetine, major depressive disorder, adjuvant therapy, antidepressant effects, statins, anti-inflammatory activity, antidepressant response, remission
- MeSH terms
- Adult, Major Depressive Disorder, Depressive Disorder, Major, Double-Blind Method, Drug Therapy, Combination, Female, Fluoxetine, Humans, Male, Middle Aged, Severity of Illness Index, Treatment Outcome, Simvastatin, Young Adult
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