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
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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
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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
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