Rheumatol Int (2007) 27:599–601 DOI 10.1007/s00296-006-0254-9 C AS E RE PO RT Citalopram-induced Raynaud’s phenomenon A. M. Peiró · C. Margarit · M. Torra Received: 21 September 2006 / Accepted: 6 October 2006 / Published online: 14 November 2006  Springer-Verlag 2006 Introduction Case report Selective serotonin reuptake inhibitors (SSRIs) are being proposed for inhibiting vasoconstriction in Raynaud’s phenomenon-patients (RP) [1–3]. Recently, Herrick revised vascular, neural and intravascular abnormalities which may have a pathophysiological role in RP. It is well known that endothelial cells and platelets activation -mediate by circulating factors as tromboxane A2 and serotonin (5-HT)- control vascular tone and governs several functions involving the vessel wall and the interstitial zone. Repeated attacks of vasospasm may cause ischaemic reperfusion injury to the endothelium, resulting in a vicious and self propagating cycle of cause [2]. But the mechanism of SSRIs real clinical beneWt is not completely understood because serotonin has the ability to also stimulate vasodilatation in healthy vascular bed [4]. Here we report the Wrst case of RP associated with citalopram administration. A 43-year-old white female presented with bilateral and symmetric subcianotic erythematic in her hands. Surgical calcanean dystrophy in 1995 had left our patient suVering from neuropathic pain, controlled for over a year with topiramate (100 mg t.i.d), gabapentine (300 mg t.i.d), clonazepam (0.5 mg o.d.) and tramadol (100 mg b.i.d). The patient presented with a general anxiety syndrome, depressive mood and insomnia, due to personal problems, and was administered clorazepate (10 mg t.i.d.), citalopram (25 mg o.d.) and zopiclona (7.5 mg o.d.). The subcianotic episode appeared 7 days after her psychiatrist prescription. She had never suVered before from arthritis episodes or RP. Nor were there any known drug allergies. There was no clinical or laboratory evidence of disorders damaging the endothelium. Laboratory investigations were normal and tests for antinuclear antibody (ANA), rheumatoid factor and C-reactive protein (PCR) were negative. Pulse, neurological and rheumatologic examination and gammagraphy showed no abnormalities. Further examination revealed subcianotic erythematic episodes associated with cold temperatures. A diagnosis of RP was established. As the anxiety syndrome persisted, clorazepate and zopiclona were replaced by olanzapine (5 mg o.d.) and lormetazepam (20 mg o.d.). Gabapentine was in decreasing doses. All without clinical improvement. We suspected a citalopram adverse eVect. Laboratory levels were in a normal range for citalopram and its metabolites desmethylcitalopram (DCIT) and didesmethylcitalopram (DDCIT). Raynaud symptoms remitted for over a month post citalopram discontinuation and did no report any RP symptoms thereafter. Given that the symptoms started A. M. Peiró (&) Clinical Pharmacology Unit, Hospital General de Alicante, c/Pintor Baeza s/n, 03010 Alicante, Spain e-mail: peiro_ana@gva.es C. Margarit Department of Anaesthesiology and Reanimation, Pain Unit, Hospital General Universitario de Alicante, Pintor Baeza s/n, 03008 Alicante, Spain M. Torra Biochemistry and Genetic Molecular Service, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain 123 600 Rheumatol Int (2007) 27:599–601 shortly after citalopram therapy was initiated and were relieved after it was discontinued, citalopram was thought to be the cause. Discussion Derive from clinical observations, SSRIs are being proposed as new potential targets for treatment of RP. Actually, no peripheral vascular disorders are established as SSRIs adverse event. Although drugs as citalopram (10 mg b.i.d.) has been associated to report cases as an extensive papule and purpuric erythematic with keratinocytes necrosis and dermal leucocytoclastic vasculitis [5]. Thus, Xuoxetine (20 mg o.d.) [6, 7], paroxetine (20 mg o.d.) [8] and escitalopram (10 mg o.d.) [3] clearly reduced in some reports RP attacks (Table 1). Also, Buecking et al. [3] stand out serotonin ability to modulate physiological mechanisms involved in temperature regulation in relation to decrease the sensitivity to cold in RP-patients. In contrast, other reports showed RP and digital infarction induced by SSRIs as our case (Table 2). Rudnick et al. [4] evidenced a Wxed RP in both hands of a depressive patient when Xuoxetine dose was raised from her regular 40–60 mg o.d.. Five days after reducing Xuoxetine dose RP disappeared. Hypercholesterolemia (341 mg/dl) was the only laboratory evidence of disorder damaging endothelium. Bell et al. [9] described the worsening of pre-existing RP, 12 weeks after she started with Xuvoxamine (increased to a daily dose of 250 mg o.d.). She developed a painful ulcer on the tip of the right index Wnger, requiring hospital admission. Bourgade et al. [10] described a RP appearance in a smoker depressive patient with history of beta-blocker-induced RP 3 years before. She was treated along 2 months with milnacipran (100 mg o.d.). RP progressively disappeared after 1 week milnacipran was discontinued. Variability in the response to SSRIs treatment has been evidenced too in other peripheral circulatory disorders as erythromelalgia. Rey et al. [11] observed two cases of RP symptoms relief with sertraline (50 mg o.d.) and Xuoxetine (when dose raise from 20 to 40 mg o.d.) but the occurrence of erythromelalgia as a consequence of vasodilatation related to serotonin depletion (Table 1). Erythromelalgia appearance in RP patients has been reported in association with other drugs inducing vasodilation such as nifedipine [12]. However, erythromelalgia has responded to serotonergic eVect of venlafaxine (37.5 mg b.i.d.) and sertraline (50 mg b.i.d.) in three refractory cases [13]. Also in a pilot study carried out with ten patients with primary erythromelalgia [14] was reported a marked improvement in pain and burning and a decrease in the warmth and erythema following a week of therapy with venlafaxine (Table 2). In both vascular acrosyndromes (RP and erythromelalgia) 5-HT was able to produce on microvasculature vasoconstriction or vasodilatation. Some authors aYrm that endothelium damage is necessary for vasoconstrictive eVects development during SSRIs treatment [8]. Platelets, when make contact with injured endothelium, are able to release substances that promote platelet adhesion and 5-HT which exerts a direct constrictor eVect. Furthermore, a destruction of endothelium could induce an EDRF deWciency. In this context, 5-HT local actions includes: feedback actions on platelets mediated by interaction with platelet 5-HT2 receptors, release of endothelium-derived relaxing factor (EDRF) mediated by 5-HT1 like-receptors and concentration of vascular smooth muscle mediated by 5-HT2A receptors [15]. Table 1 Characteristics of the patients with Raynaud’s phenomenon relief (with/without erythromelalgia concomitantly) associated to SSRIs treatment Case [Ref] Sex/age years Drug prescribed Clinical evolution Outcome 1 [3] F/31 Escitalopram 2 [7] F/31 Fluoxetine Relief of RP symptoms 30 min after the Wrst dose RP resolved by2 weeks 3 [8] F/58 Paroxetine She use SSRI when practice outdoor sports 8 days after Xuoxetine cessation, RP reappeared No recurrence 4 [11] F/68 Fluoxetine 5 [11] F/60 Sertraline No more digital ischemic episodes of CREST syndrome Relief of RP symptoms when dose raise. Erythromelalgia concomitantly Relief of RP symptoms by the 1 month. Erythromelalgia concomitantly SSRIs discontinuation Sertraline replaced by paroxetine with NI. SSRIs discontinuation F female, RP Raynaud’s phenomenon SSRIs Selective serotonin reuptake inhibitors, CREST acronym for calcinosis, RP, esophageal dysmotility, sclerodactyly and telangiectasia, NI no improvement 123 Rheumatol Int (2007) 27:599–601 601 Table 2 Characteristics of the patients with Raynaud’s phenomenon (or erythromelalgia relief) associated to SSRIs or SNRI treatment Case [Ref] Sex/age years Drug prescribed Clinical evolution Outcome 1[in this report] F/43 Citalopram Develop RP by the 7 day 2 [4] F/54 Fluoxetine 3 [9] F/25 Fluvoxamine 4 [10] F/35 Milnacipran* Develop RP 4 days after dose raise Worsening in attack frequency and severity of RP by the 3 month with a painful digital ulcer. Develop RP by the 2 month With SSRI discontinuation, RP disappeared at 1 month SSRI dosage was reduced 5 [13] F/52 Sertraline 6 [13] F/63 Venlafaxina* 7 [13] F/68 Venlafaxina* Relief of erythromelalgia symptoms by the 3 day Rapid relief of erythromelalgia symptoms Relief of erythromelalgia symptoms by the 3 day With SSRI discontinuation, symptoms gradually improved With SNRI discontinuation, RP disappeared at 1 week Erythromelalgia disappeared at 6 months No more major attacks in 14 months No previously improvement with other drugs or a lumbar sympathetic block F female, RP Raynaud’s phenomenon, SSRIs Selective serotonin reuptake inhibitors *SNRI serotonin and norepinephrine reuptake inhibitor Although the exact mechanism of vasoconstrictive eVect of SSRIs in healthy vascular bed, as in our case, remains unknown, blocking serotonin reuptake, could increase of free plasma serotonin and may have a higher inXuence than intraplatelet serotonin depletion. It could produce in stasis conditions a local serotonin accumulation, exacerbating a vasoconstriction and thereby, worsening RP [8, 9] and improving erythromelalgia [13] (Table 2). Genetic diVerences in metabolism or signalling serotonin pathways could contribute to some of that variability in the response [2, 6]. Raynaud’s phenomenon is a relatively common problem, which may be diYcult to treat in a minority of patients. Progress in understanding RP microvascular defects is required to assess eYcacy and security of SSRIs as a new advance. Meanwhile, it is necessary to envisage a drug-related etiology in patients treated with SSRIs who develop RP. Acknowledgments translation. We thank J. A. McLure for correct English References 1. Kahaleh B, Matucci-Cerinic M (1995) Raynaud’s phenomenon and scleroderma. Dysregulated neuroendothelial control of vascular tone. Arthritis Rheum 38:1–4 2. Herrick AL (2005) Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxford) 44:587–596 3. Buecking A, Rougemont E, Fabio Zullino D (2005) Treatment of Raynaud’s phenomenon with escitalopram. Int J Neuropsychopharmacol 8:307–308 4. Rudnick A, Modai I, Zelikovski A (1997) Fluoxetine-induced Raynaud’s phenomenon. Biol Psychiatry 41:1218–1221 5. Richard MA, Fiszenson F, Jreissati M, Jean Pastor MJ, Grob JJ (2001) Cutaneous adverse eVects during selective serotonin reuptake inhibitors therapy: 2 cases. Ann Dermatol Venereol 128:759–761 6. Coleiro B, Marshall SE, Denton CP et al (2001) Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor Xuoxetine. Rheumatology 40:1038–1043 7. Bolte MA, Avery D (1993) Case of Xuoxetine-induced remission of Raynaud’s phenomenon—a case report. Angiology 44:161–163 8. Garcia-Porrua C, Margarinos CC, Gonzalez-Gay MA (2004) Raynaud’s phenomenon and serotonin reuptake inhibitors. J Rheumatol 31:2090 9. Bell C, Coupland N, Creamer P (1996) Digital infarction in a patient with Raynaud’s phenomenon associated with treatment with a speciWc serotonin reuptake inhibitor. A case report. Angiology 47:901–903 10. Bourgade B, Jonville-Bera AP, Le Gare C, Ferquel D, Autret-Leca E (1999) Raynaud’s syndrome in a patient treated with milnacipran. Ann Pharmacother 33:1009–1010 11. Rey E, Cretel R, Pastor M-J, Durand J-M (2003) Serotonin reuptake inhibitors, Raynaud’s phenomenon and erythromelalgia. Rheumatology 42:601–602 12. Sunahara JF, Gora-Harper ML, Nash KS (1996) Possible erythromelalgia-like syndrome associated with nifedipine in a patient with Raynaud’s phenomenon. Ann Pharmacother 30:484–486 13. RudikoV D, JaVe IA (1997) Erythromelalgia: response to serotonin reuptake inhibitors. J Am Acad Dermatol 37:281–283 14. Moiin A, Yashar SS, Sanchez JE, Yashar B (2002) Treatment of erythromelalgia with a serotonin/noradrenaline reuptake inhibitor. Br J Dermatol 146:336–337 15. Sanders-Bush E, Mayer SE (2001) 5-Hysroxytryptamine (serotonin): receptor agonist and antagonist. In: Hardman JG, Limbird LE, eds. Goodman&Gilman’s. The pharmacological basis of therapeutics. 10th edn. McGraw Hill, New York 123