Crocus sativus L. versus Citalopram in the Treatment of Major Depressive Disorder with Anxious Distress: A Double-Blind, Controlled Clinical Trial

Abstract

Introduction: Saffron (Crocus sativus L.) has demonstrated antidepressant effects in clinical studies and extensive anxiolytic effects in experimental animal models.

Methods: 66 patients with major depressive disorder accompanied by anxious distress were randomly assigned to receive either saffron (30 mg/day) or citalopram (40 mg/day) for 6 weeks. Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) were used to assess treatment effect during the trial.

Results: 60 participants finished the study. Patients who received either saffron or citalopram showed significant improvement in scores of the Hamilton Rating Scale for Depression (P-value<0.001 in both groups) and Hamilton Rating Scale for Anxiety (P-value<0.001 in both groups). Comparison of score changes between the 2 trial arms showed no significant difference (P-value=0.984). Frequency of side effects was not significantly different between the 2 groups.

Discussion: The present study indicates saffron as a potential efficacious and tolerable treatment for major depressive disorder with anxious distress.

Key words

anxious distress - citalopram Crocus sativus - major depressive disorder

^* The first three authors contributed equally in this study.

• References

• 1 Kessler RC, Berglund P, Demler O. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593-602
• 2 Lamers F, van Oppen P, Comijs HC. et al. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry 2011; 72: 341-348
• 3 Ameringen MV. Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis. In: Post TW, Stein MB, Hermann R. editors. uptodate Waltham, MA: uptodate 2016
• 4 Rush AJ, Trivedi MH, Wisniewski SR. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry 2006; 163: 1905-1917
• 5 Farabaugh A, Alpert J, Wisniewski SR. et al. Cognitive therapy for anxious depression in STAR* D: what have we learned?. J Affect Disord 2012; 142: 213-218
• 6 Fava M, Rush AJ, Alpert JE. et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR* D report. Am J Psychiatry 2008; 165: 342-351
• 7 Lépine J-P, Gastpar M, Mendlewicz J. et al. Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol 1997; 12: 19-29
• 8 Tylee A, Gastpar M, Lépine JP. et al. Identification of depressed patient types in the community and their treatment needs: findings from the DEPRES II (Depression Research in European Society II) Survey. Int Clin Psychopharmacol 1999; 14: 153-166
• 9 American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 5^th ed. Arlington: American Psychiatric Publishing; 2013
• 10 Nutt DJ, Ballenger JC, Sheehan D. et al. Generalized anxiety disorder: comorbidity, comparative biology and treatment. Int J Neuropsychopharmacol 2002; 5: 315-325
• 11 Paré D, Quirk GJ, Ledoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol 2004; 92: 1-9
• 12 Pandey A, Tripathi S, Bajpeyi K. PHARMACY AND LIFE SCIENCES. 2013;
• 13 Nutt D. Treatment of depression and concomitant anxiety. Eur Neuropsychopharmacol 2000; 10: S433-S437
• 14 Kasper S. Pharmacological treatment of mixed anxiety and depression. Eur Neuropsychopharmacol 1994; 4: 170-171
• 15 Quante A. Acute pharmacotherapy for anxiety symptoms in patients with depression. Fortschritte der Neurologie-Psychiatrie 2015; 83: 142-148
• 16 Wunderlich U, Bronisch T, Wittchen HU. Comorbidity patterns in adolescents and young adults with suicide attempts. Eur Arch Psychiatry Clin Neurosci 1998; 248: 87-95
• 17 Treatments CNfMaA. MIXED ANXIETY & DEPRESSION http://www.canmat.org/cme-anxiety-mixed-anxiety-&-depression.php Canadian Network for Mood and Anxiety Treatments; [cited 2016]; Available from: http://www.canmat.org/cme-anxiety-mixed-anxiety-&-depression.php
• 18 Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 2001; 3: 22
• 19 Goldstein BJ, Goodnick PJ. Selective serotonin reuptake inhibitors in the treatment of affective disorders – III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol 1998; 12 4 suppl S55-S87
• 20 Spigset O. Adverse reactions of selective serotonin reuptake inhibitors. Drug Safety 1999; 20: 277-287
• 21 Dewan MJ, Anand VS. Evaluating the tolerability of the newer antidepressants. J Nerv Ment Dis 1999; 187: 96-101
• 22 Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant agomelatine for anxiety symptoms in major depression. Hum Psychopharmacol 2013; 28: 151-159
• 23 Kamalipour M, Jamshidi A, Akhondzadeh S. Antidepressant effect of Crocus sativus: An evidence based review. Journal of Medicinal Plants 2010; 1: 35-38
• 24 Baldwin DS, Polkinghorn C. Evidence-based pharmacotherapy of generalized anxiety disorder. Int J Neuropsychopharmacol 2005; 8: 293-302
• 25 Papakostas GI. Tolerability of modern antidepressants. J Clin Psychiatry 2008; 69 Suppl E1 1478-1413
• 26 Schweitzer I, Maguire K, Ng C. Sexual side-effects of contemporary antidepressants: review. Aust N Z J Psychiatry 2009; 43: 795-808
• 27 Kasper S, Volz HP, Dienel A. et al. Efficacy of Silexan in mixed anxiety-depression – A randomized, placebo-controlled trial. Eur Neuropsychopharmacol 2016; 26: 331-340
• 28 Kessler RC, Soukup J, Davis RB. et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry 2001; 158: 289-294
• 29 Elkins G, Rajab MH, Marcus J. Complementary and alternative medicine use by psychiatric inpatients. Psychol Rep 2005; 96: 163-166
• 30 Williamson EM. Synergy and other interactions in phytomedicines. Phytomedicine 2001; 8: 401-409
• 31 Spinella M. The psychopharmacology of herbal medicine: Plant drugs that alter mind, brain and behavior. Cambridge: MIT Press; 2001
• 32 Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res 2007; 21: 703-716
• 33 Sarris J, Panossian A, Schweitzer I. et al. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol 2011; 21: 841-860
• 34 Rios J, Recio M, Giner R. et al. An update review of saffron and its active constituents. Phytother Res 1996; 10: 189-193
• 35 Akowuah GA, Htar TT. Therapeutic properties of saffron and its chemical constituents. J Nat Prod 2014; 7: 05-13
• 36 Ravindran AV, Lam RW, Filteau MJ. et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults: Section 5. Complementary and alternative medicine treatments. J Affect Disord 2009; 117: S54-S64
• 37 Wang Y, Han T, Zhu Y. et al. Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med 2010; 64: 24-30
• 38 Pitsikas N, Boultadakis A, Georgiadou G. et al. Effects of the active constituents of Crocus sativus L., crocins, in an animal model of anxiety. Phytomedicine 2008; 15: 1135-1139
• 39 Ahmad AS, Ansari MA, Ahmad M. et al. Neuroprotection by crocetin in a hemi-parkinsonian rat model. Pharmacol Biochem Behav 2005; 81: 805-813
• 40 Pitsikas N, Zisopoulou S, Tarantilis PA. et al. Effects of the active constituents of Crocus sativus L., crocins on recognition and spatial rats’ memory. Behav Brain Res 2007; 183: 141-146
• 41 Pitsikas N, Sakellaridis N, Crocus sativus L. extracts antagonize memory impairments in different behavioural tasks in the rat. Behav Brain Res 2006; 173: 112-115
• 42 Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res 2009; 23: 768-774
• 43 Hosseinzadeh H, Sadeghnia H. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007; 14: 256-262
• 44 Agha-Hosseini M, Kashani L, Aleyaseen A. et al. Crocus sativus L.(saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG 2008; 115: 515-519
• 45 Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA. et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res 2005; 19: 148-151
• 46 Moshiri E, Basti AA, Noorbala AA. et al. Crocus sativus L.(petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine 2006; 13: 607-611
• 47 Basti AA, Moshiri E, Noorbala AA. et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 439-442
• 48 Noorbala A, Akhondzadeh S, Tahmacebi-Pour N. et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol 2005; 97: 281-284
• 49 Akhondzadeh S, Fallah-Pour H, Afkham K. et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med 2004; 4: 1
• 50 Lechtenberg M, Schepmann D, Niehues M. et al. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma1 (sigma-1) receptors. Planta Med 2008; 74: 764
• 51 Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: pharmacology and clinical uses. Wien Med Wochenschr 2007; 157: 315-319
• 52 Modabbernia A, Sohrabi H, Nasehi AA. et al. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology 2012; 223: 381-388
• 53 Akhondzadeh S, Jafari S, Raisi F. et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 2009; 26: 607-611
• 54 Shahmansouri N, Farokhnia M, Abbasi SH. et al. 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 2014; 155: 216-222
• 55 Gougol A, Zareh-Mohammadi N, Raheb S. et al. Simvastatin as an adjuvant therapy to fluoxetine in patients with moderate to severe major depression: A double-blind placebo-controlled trial. J Psychopharmacol 2015; 29: 575-581
• 56 Abbasi SH, Mohammadinejad P. Shahmansouri et al. Simvastatin versus atorvastatin for improving mild to moderate depression in post-coronary artery bypass graft patients: a double-blind, placebo-controlled, randomized trial. J Affect Disord 2015; 183: 149-155
• 57 Jafarinia M, Afarideh M, Tafakhori A. et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord 2016; DOI: 10.1016/j.jad.2016.05.076.
• 58 Howes MJR, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 2003; 17: 1-18
• 59 Shamsa A, Hosseinzadeh H, Molaei M. et al. Evaluation of Crocus sativus L.(saffron) on male erectile dysfunction: a pilot study. Phytomedicine 2009; 16: 690-693
• 60 Berger F, Hensel A, Nieber K. Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices. Neuroscience 2011; 180: 238-247
• 61 Hausenblas HA, Saha D, Dubyak PJ. et al. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med 2013; 11: 377-383
• 62 Georgiadou G, Tarantilis P, Pitsikas N. Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of obsessive – compulsive disorder. Neurosci Lett 2012; 528: 27-30
• 63 Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol 2014; 29: 517-527
• 64 Akhondzadeh S, Sabet MS, Harirchian MH. et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology 2010; 207: 637-643
• 65 Farokhnia M, Shafiee Sabet M, Iranpour N. et al. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer’s disease: a double-blind randomized clinical trial. Hum Psychopharmacol 2014; 29: 351-359
• 66 Modaghegh MH, Shahabian M, Esmaeili HA. et al. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008; 15: 1032-1037
• 67 Ulbricht C, Conquer J, Costa D. et al. An evidence-based systematic review of saffron (Crocus sativus) by the natural standard research collaboration. J Diet Suppl 2011; 8: 58-114
• 68 Kamalipour M, Akhondzadeh S. Cardiovascular effects of saffron: an evidence-based review. J Tehran Heart Center 2011; 6: 59-61