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Cilostazol as an adjunctive treatment in major depressive disorder: a pilot randomized, double-blind, and placebo-controlled clinical trial

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Abstract

Background

Cilostazol, a phosphodiesterase-3 inhibitor, has been reported to improve depressive-like behavior in experimental studies of depression. We investigated the safety and efficacy of cilostazol combination therapy with sertraline in treating patients with major depressive disorder (MDD) in a 6-week, parallel, randomized controlled trial.

Method

Among patients referred to the outpatient clinic of a tertiary hospital, those with a diagnosis of MDD with moderate to severe severity (a score of >19 on the Hamilton depression rating scale (HAM-D)) were enrolled. A total of 54 MDD patients aged 18–65 years were randomly assigned to either the cilostazol (100 mg daily) or the placebo group. Both groups received sertraline 100 mg per day similarly. Changes in HAM-D at weeks 2, 4, and 6 were the primary outcome. Participants and outcome assessors were blinded.

Results

At week 6, patients in the cilostazol group had significantly lower HAM-D score (p value= 0.015). General linear model repeated-measure analysis showed significant effect for treatment in improving MDD severity (p value <0.001). The remission rate at the study endpoint and number of responders at week 4 were significantly higher in the cilostazol group (p value= 0.047, p value= 0.032, respectively). The cilostazol group demonstrated a significantly shorter time to response. No significant difference was observed in treatment response at the study endpoint, and there were no serious adverse effects.

Conclusion

Our study supports safety and efficacy of cilostazol in treating MDD patients.

Trial registration

This trial was registered at the Iranian registry of clinical trials (IRCT: www.irct.ir; registration number: IRCT20090117001556N130)

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Abbreviations

AD:

Alzheimer’s disease

BDNF:

Brain-derived neurotrophic factor

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

CREB:

CAMP-response element-binding protein

CVD:

Cardiovascular disease

DSM-5:

Diagnostic and Statistical Manual of Mental Disorders, 5th Edition

ECT:

Electroconvulsive therapy

GLM:

General linear model

HAM-D:

Hamilton rating scale for depression

IGF-1:

Insulin-like growth factor-I

MD:

Mean difference

MDD:

Major depressive disorder

Nrf2:

Nuclear factor-erythroid 2-related factor-2

PDE:

Phosphodiesterase

TrkB:

Tropomyosin receptor kinase B

References

  • Abdallah MS, Ramadan AN, Omara‐Reda H, Mansour NO, Elsokary MA, Elsawah HK, Zaki SA, Abo Mansour HE, Mosalam EM (2021) Double‐blind, randomized, placebo‐controlled pilot study of the phosphodiesterase‐3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder. CNS Neurosci Ther

  • Abuelezz SA, Hendawy N (2018) Insights into the potential antidepressant mechanisms of cilostazol in chronically restraint rats: impact on the Nrf2 pathway. Behav Pharmacol 29:28–40

    Article  CAS  Google Scholar 

  • Agrawal R, Bhargava M, Santani D, Agrawal V, Ahmad I, Mishra A (2014) Antidepressant activity of cilostazol: an experimental study.

  • Akhondzadeh S, Ghayyoumi R, Rezaei F, Salehi B, Modabbernia AH, Maroufi A, Esfandiari GR, Naderi M, Ghebleh F, Tabrizi M, Rezazadeh SA (2011) Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. Psychopharmacology 213:809–815

    Article  CAS  Google Scholar 

  • American Psychiatric Association A (1980) Diagnostic and statistical manual of mental disorders. American Psychiatric Association Washington, DC

  • Amiri S, Mohammadi MR, Mohammadi M, Nouroozinejad GH, Kahbazi M, Akhondzadeh S (2008) Modafinil as a treatment for Attention-Deficit/Hyperactivity Disorder in children and adolescents: a double blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry 32:145–149

    Article  CAS  Google Scholar 

  • Association WM (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194

    Article  Google Scholar 

  • Bobon D, Breulet M, Gerard-Vandenhove MA, Guiot-Goffioul F, Plomteux G, Sastre-y-Hernández M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H Is Phosphodiesterase inhibition a new mechanism of antidepressant action?

  • Brunoni AR, Fraguas R Jr, Fregni F (2009) Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability. Ther Clin Risk Manag 5:897

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell E, Edwards T (2006) Zaprinast consolidates long-term memory when administered to neonate chicks trained using a weakly reinforced single trial passive avoidance task. Behav Brain Res 169:181–185

    Article  CAS  Google Scholar 

  • Delhaye S, Bardoni B (2021) Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Molecular Psychiatry: 1-13.

  • Ding L, Zhang C, Masood A, Li J, Sun J, Nadeem A, Zhang H-T, O’ Donnell JM, Xu Y, (2014) Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: involvement of antioxidant and anti-apoptotic mechanisms. Behav Brain Res 268:150–158

    Article  CAS  Google Scholar 

  • Duman CH, Schlesinger L, Terwilliger R, Russell DS, Newton SS, Duman RS (2009) Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behav Brain Res 198:366–371

    Article  CAS  Google Scholar 

  • El-Haggar SM, Eissa MA, Mostafa TM, El-Attar KS, Abdallah MS (2018) The phosphodiesterase inhibitor pentoxifylline as a novel adjunct to antidepressants in major depressive disorder patients: a proof-of-concept, randomized, double-blind, placebo-controlled trial. Psychother Psychosom 87:331–339

    Article  Google Scholar 

  • Farajollahi-Moghadam M, Sanjari-Moghaddam H, Ghazizadeh Hasemi M, Sanatian Z, Talaei A, Akhondzadeh S (2021) Efficacy and safety of pentoxifylline combination therapy in major depressive disorder: a randomized, double-blind, placebo-controlled clinical trial. Int Clin Psychopharmacol 36:140–146

    Article  Google Scholar 

  • Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, Vos T, Whiteford HA (2013) Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS med 10: e1001547

  • Gartlehner G, Wagner G, Matyas N, Titscher V, Greimel J, Lux L, Gaynes BN, Viswanathan M, Patel S, Lohr KN (2017) Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 7: e014912

  • Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M (2015) Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 49:206–215

    Article  CAS  Google Scholar 

  • Hebb AL, Robertson HA (2007) Role of phosphodiesterases in neurological and psychiatric disease. Curr Opin Pharmacol 7:86–92

    Article  CAS  Google Scholar 

  • Hishikawa N, Fukui Y, Sato K, Ohta Y, Yamashita T, Abe K (2017) Comprehensive effects of galantamine and cilostazol combination therapy on patients with Alzheimer’s disease with asymptomatic lacunar infarction. Geriatr Gerontol Int 17:1384–1391

    Article  Google Scholar 

  • Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950–966

    Article  CAS  Google Scholar 

  • Houslay MD, Schafer P, Zhang KY (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discovery Today 10:1503–1519

    Article  CAS  Google Scholar 

  • Itoh T, Tokumura M, Abe K (2004) Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol 498:135–142

    Article  CAS  Google Scholar 

  • Khajavi D, Farokhnia M, Modabbernia A, Ashrafi M, Abbasi SH, Tabrizi M, Akhondzadeh S (2012) Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 73:1428–1433

    Article  CAS  Google Scholar 

  • Kim YR, Kim HN, Hong KW, Shin HK, Choi BT (2016a) Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke. Psychopharmacology 233:1055–1066

    Article  CAS  Google Scholar 

  • Kim YR, Kim HN, Hong KW, Shin HK, Choi BT (2016b) Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke. Psychopharmacology 233:1055–1066

    Article  CAS  Google Scholar 

  • Maxwell C, Kanes S, Abel T, Siegel S (2004) Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications. Neuroscience 129:101–107

    Article  CAS  Google Scholar 

  • Menniti FS, Chappie TA, Humphrey JM, Schmidt CJ (2007) Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Current opinion in investigational drugs (London, England: 2000) 8: 54-59

  • Nandhakumar J, Raja AK, Tyagi MG (2010) Characterization of effects of phosphodiesterase (PDE) isozyme inhibitors in animal models of epilepsy. Life Sci Med Res 1–9

  • O’Donnell JM, Zhang H-T (2004) Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 25:158–163

    Article  CAS  Google Scholar 

  • Patel DS, Anand IS, Bhatt PA (2012a) Evaluation of antidepressant and anxiolytic activity of phosphodiesterase 3 inhibitor-cilostazol. Indian J Psychol Med 34:124–128

    Article  Google Scholar 

  • Patel DS, Anand IS, Bhatt PA (2012b) Evaluation of antidepressant and anxiolytic activity of phosphodiesterase 3 inhibitor - cilostazol. Indian J Psychol Med 34:124–128

    Article  Google Scholar 

  • Rezaei F, Mesgarpour B, Jeddian A, Zeionoddini A, Mohammadinejad P, Salardini E, Shahriari M, Zeinoddini A, Akhondzadeh S (2017) Cilostazol adjunctive therapy in treatment of negative symptoms in chronic schizophrenia: randomized, double-blind, placebo-controlled study. Hum Psychopharmacol 32:(4)

  • Sackeim HA (2001) The definition and meaning of treatment-resistant depression. J Clin Psychiatry 62:10–17

    CAS  PubMed  Google Scholar 

  • Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H, Iwamoto T (2013) Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer’s disease and cerebrovascular disease: a pilot study. Geriatr Gerontol Int 13:90–97

    Article  Google Scholar 

  • Shahmansouri N, Farokhnia M, Abbasi SH, Kassaian SE, Noorbala Tafti AA, Gougol A, Yekehtaz H, Forghani S, Mahmoodian M, Saroukhani S, Arjmandi-Beglar A, Akhondzadeh S (2014) A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord 155:216–222

    Article  CAS  Google Scholar 

  • Shirayama Y, Konishi T, Hashimoto K (2011) Effects of add-on cilostazol on cognition in patients with schizophrenia: an open-label pilot trial. J Clin Psychopharmacol 31:659–661

    Article  Google Scholar 

  • Smit A, Schene A, Peeters F, Spijker J (2016) Tailored pharmacotherapy. Consultations about medication in a care programme for depression. Tijdschr Psychiatr 58:881–885

    CAS  PubMed  Google Scholar 

  • Taguchi A, Takata Y, Ihara M, Kasahara Y, Tsuji M, Nishino M, Stern D, Okada M (2013) Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis. Psychogeriatrics 13:164–169

    Article  Google Scholar 

  • Takahashi K, Oshima A, Inoue K, Takeyoshi H, Fukuda M, Mikuni M (2008) Novel augmentation therapy with cilostazol for the geriatric major depressive disorder patient with deep white matter hyperintensities on T2-weighted brain MRI: a case report. Pharmacopsychiatry 41:37–39

    Article  CAS  Google Scholar 

  • Uchiyama S, Demaerschalk BM, Goto S, Shinohara Y, Gotoh F, Stone WM, Money SR, Kwon SU (2009) Stroke prevention by cilostazol in patients with atherothrombosis: meta-analysis of placebo-controlled randomized trials. J Stroke Cerebrovasc Dis 18:482–490

    Article  Google Scholar 

  • Wang Z-Z, Yang W-X, Zhang Y, Zhao N, Zhang Y-Z, Liu Y-Q, Xu Y, Wilson SP, O’Donnell JM, Zhang H-T (2015) Phosphodiesterase-4D knock-down in the prefrontal cortex alleviates chronic unpredictable stress-induced depressive-like behaviors and memory deficits in mice. Sci Rep 5:1–15

    Google Scholar 

  • Yasrebi S-O, Momtazmeaneh S, Moghaddam HS, Shahmansouri N, Mehrpooya M, Arbabi M, Ghazizadeh-Hashemi F, Akhondzadeh S (2021) Pentoxifylline for treatment of major depression after percutaneous coronary intervention or coronary artery bypass grafting: a randomized, double-blind, placebo-controlled trial. J Psychosom Res 150:110635

  • Yoneyama M, Tanaka M, Hasebe S, Yamaguchi T, Shiba T, Ogita K (2015) Beneficial effect of cilostazol-mediated neuronal repair following trimethyltin-induced neuronal loss in the dentate gyrus. J Neurosci Res 93:56–66

    Article  CAS  Google Scholar 

  • Zeinoddini A, Sorayani M, Hassanzadeh E, Arbabi M, Farokhnia M, Salimi S, Ghaleiha A, Akhondzadeh S (2015) Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial. Depress Anxiety 32:167–173

    Article  CAS  Google Scholar 

  • Zhang H-T, Huang Y, Jin SC, Frith SA, Suvarna N, Conti M, James M (2002) Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27:587–595

    CAS  PubMed  Google Scholar 

  • Zhao J, Harada N, Kurihara H, Nakagata N, Okajima K (2010) Cilostazol improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus. Neuropharmacology 58:774–783

    Article  CAS  Google Scholar 

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Acknowledgements

This study was the postgraduate thesis of Dr. Aida Khadivi toward the Iranian Board of Psychiatry under the supervision of Prof. Shahin Akhondzadeh.

Funding

This study was supported by a grant from Tehran University of Medical Sciences (TUMS) to Prof. Shahin Akhondzadeh (Grant number: 45985).

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Authors and Affiliations

  1. Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran, 13337, Iran

    Aida Khadivi, Parnian Shobeiri, Sara Momtazmaneh, Farhaneh-Sadat Samsami & Shahin Akhondzadeh

  2. Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mohammadreza Shalbafan & Elham Shirazi

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  1. Aida Khadivi
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  2. Parnian Shobeiri
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Correspondence to Shahin Akhondzadeh.

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Aida Khadivi, Parnian Shobeiri, Sara Momtazmaneh, and Farhaneh-Sadat Samsami contributed equally to this work.

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Khadivi, A., Shobeiri, P., Momtazmaneh, S. et al. Cilostazol as an adjunctive treatment in major depressive disorder: a pilot randomized, double-blind, and placebo-controlled clinical trial. Psychopharmacology 239, 551–559 (2022). https://doi.org/10.1007/s00213-021-06041-0

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