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Letters   |    
Escitalopram and Ischemic Stroke: Causal or Chance Association?
Ashish Aggarwal, M.D.; Ramish Kumar, M.D.; Ravi Sharma, M.D.; Dinesh Dutt Sharma, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2011;23:E38-E39.

To the Editor: Selective serotonin reuptake inhibitors (SSRIs) are now widely used for the treatment of depression as well as anxiety disorders. Among various SSRIs, escitalopram is the latest, and a highly selective serotonin reuptake inhibitor. It has been reported to have faster onset of action, with benign side-effect profile. Recently, there have been reports of increased chances of bleeding associated with escitalopram and other SSRIs.1,2 this is even translated to an increased risk of hemorrhagic stroke with its use.3 however, to the best of our knowledge, there is only one report of deep vein thrombosis (DVT) associated with escitalopram4 and few reports of stroke with SSRIs.58 The authors would like to present a case of ischemic stroke that might be probably associated with escitalopram in a young man without any major risk factors for stroke.

A 39-year-old married man presented to the psychiatry ouTPatient department with complaints of tiredness, sadness of mood, difficulty concentrating, and disturbed biological functions for the last 5 months. There was no significant past or family history. General physical examination and systemic examination, including neurological examination was within normal limits. Mental status examination revealed depressed affect, with ideas of hopelessness and worthlessness. A diagnosis of depressive episode, moderate, was made according to ICD-10. His routine investigations, including thyroid-function tests, were normal. He was started on escitalopram 10 mg per day along with clonazepam 1 mg per day. Gradually, his clonazepam was stopped, and escitalopram was increased to 20 mg per day after a period of 1 month. The patient reported improvement in depressive symptoms. He was maintaining improvement on this treatment. After 6 months of escitalopram therapy, the patient presented to the emergency department with complaints of deviation of mouth to right side, drooling of saliva from the mouth, and difficulty in speaking. Neurological examination revealed left 7th supranuclear palsy with no other abnormality. CT scan of the head revealed hypodensity involving both gray and white matter of the right temporo-parietal (TP) region, with a CT value of 19-20HU, suggestive of right TP infarct. He was further evaluated for the risk factors of stroke. He was a nonsmoker, normotensive, non-diabetic man with no previous history of any cardiac illness or migraine. There was no history of using any medication other than escitalopram. There was no family history of any cardiac illness. Serum tests for total blood count, renal and hepatic functions, sedimentation rate, HIV, lipid profile, anti-nuclear antibodies, serum vitamin b12 levels, antidsDNA, and coagulation profile were all found to be in the normal range. ECG and Chest X-ray were also normal. Echocardiography done revealed mitral valve prolapse (MVP). Magnetic resonance angiography was also done and was normal. The patient improved gradually over the next 15 days and was then started on amitriptyline for mild depressive symptoms. He has been maintaining improvement on this for the last 6 months of follow-up.

A possibility of a escitalopram treatment-related cerebrovascular adverse drug reaction (CV-ADR) was considered. The Naranjo Adverse Reaction Probability Scale, as well as the Edwards criteria to determine the causality of the stroke suggested a possible causal relationship.9,10 The temporal relation of initiation of escitalopram treatment and the appearance of stroke in the absence of any other major risk factors drew our attention to a possible association between escitalopram and stroke. Also, previous reports of SSRI treatment-associated CV-ADRs, as previously mentioned, reports on the WHO monitoring system,11 and the pharmacologic action of serotonin on coagulation and the vascular system supported our assumption. However, a chance association cannot be ruled out. In our patient, MVP can be a putative risk factor, although the reports about its link with ischemic stroke are controversial.12 Recent reports have suggested that depressive symptoms may increase risk of stroke through increased platelet activity due to sympatho-adrenal hyperactivity. Depression increases risk of hypercoagulability through increased platelet aggregation. However, at the time of the stroke, our patient was in remission from his depressive symptoms.13 To the best of our knowledge, despite many cases of increased bleeding tendency caused by SSRIs, including escitalopram, there has been only one report of thrombosis associated with escitalopram. The DVT in the case reported developed very acutely within a few days of escitalopram therapy, and the patient was also bedridden for some time before the DVT.4 A previous report of causality assessment between stroke and paroxetine use reported inconsistent findings. Carotid and cardiac thromboembolism was present in the cases reported. Also other factors were responsible, such as drug interactions, Epstein-Barr infection, and higher doses of paroxetine prescribed.7 Regarding pathogenesis, there is a possibility that SSRIs can induce platelet adhesion and thrombosis through activation of 5-HT2 receptors in platelets.14 Another possible mechanism could be the vasospastic effect of SSRIs (based on evidence that serotonin induces vasoconstriction of larger cerebral arteries and vasodilation of small vessels).15 Also, serotonin syndrome might be a factor responsible, as has been previously reported.6 Although the association between antidepressants and stroke has also been investigated, the results are not conclusive, and further exploration is required.1618 Large-scale studies are required to examine the link between CV-ADRs related to SSRI and other antidepressants and also to understand the possible pathogenetic mechanisms. Also, one must consider the already-increased risk for CVA due to the underlying depression and possible spurious association between the two conditions.

Duijvestijn  YC;  Kalmeijer  MD;  Passier  AL  et al:  Neonatal intraventricular haemorrhage associated with maternal use of paroxetine.  Br J Clin Pharmacol 2003; 56:581–582
[PubMed]
[CrossRef]
 
Lake  MB;  Birmaher  B;  Wassick  S  et al:  Bleeding and selective serotonin reuptake inhibitors in childhood and adolescence.  J Child Adolesc Psychopharmacol 2000; 10:35–38
[PubMed]
[CrossRef]
 
Bak  S;  Tsiropoulos  I;  Kjaersgaard  JO  et al:  Selective serotonin reuptake inhibitors and the risk of stroke: a population-based, case–control study.  Stroke 2002; 33:1465–1473
[PubMed]
[CrossRef]
 
Kurne  A;  Ertugrul  A;  Anil Yağcioğlu  AE  et al:  Venous thromboembolism and escitalopram.  Gen Hosp Psychiatry 2004; 26:481–483
[PubMed]
[CrossRef]
 
Conde López  VJ;  Ballesteros Alcalde  MC;  Blanco Garrote  JA  et al:  Cerebral infarction in an adolescent girl following an overdose of paroxetine and caffedrine combined with theodrenaline.  [Spanish] Actas Luso Esp Neurol Psiquiatr Cienc Afines 1998; 26:333–338
 
Molaie  M:  Serotonin syndrome presenting with migraine-like stroke.  Headache 1997; 37:519–521
[PubMed]
[CrossRef]
 
Ramasubbu  R:  SSRI treatment-associated stroke: causality assessment in two cases.  Ann Pharmacother 2004; 38(7,8):1197–1201
[PubMed]
 
Singhal  AB;  Caviness  VS;  Begleiter  AF  et al:  Cerebral vasoconstriction and stroke after use of serotonergic drugs.  Neurology 2002; 58:130–133
[PubMed]
 
Naranjo  CA;  Busto  U;  Sellers  EM  et al:  A method for estimating the probability of adverse drug reactions.  Clin Pharmacol Ther 1981; 30:239–245
[PubMed]
[CrossRef]
 
Edwards  IR;  Jason Aronson  JK:  Adverse drug reactions: definitions, diagnosis, and management.  Lancet 2000; 356:1255–1259
[PubMed]
[CrossRef]
 
Edwards  IR;  Olsson  S:  World Health Organization programme: global monitoring, in  Pharmacovigilance . Edited by Mann  R;  Andrews  A.  Chichester, England,  Wiley, 2002, pp 169–182
 
Gilon  D;  Buonanno  FS;  Joffe  MM  et al:  Lack of evidence of an association between mitral-valve prolapse and stroke in young patients.  N Engl J Med 1999; 341:8–13
[PubMed]
[CrossRef]
 
Musselman Evans  DL;  Nemeroff  CB:  The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.  Arch Gen Psychiatry 1998; 55:580–592
[PubMed]
[CrossRef]
 
Cerrito  F;  Lazzano  MP;  Gaudio  E  et al:  5HT2-receptors and serotonin release: their role in human platelet aggregation.  Life Sci 1993; 53:209–215
[PubMed]
[CrossRef]
 
Bonvento  G;  Mackenzie  ET;  Edvinsson  L:  Serotonergic innervation of the cerebral vasculature: relevance to migraine and ischemia.  Brain Res Rev 1991; 16:257–263
[PubMed]
[CrossRef]
 
Ramasubbu  R:  Cerebrovascular effects of selective serotonin reuptake inhibitors: a systematic review.  J Clin Psychiatry 2004b; 65:1642–1653
[CrossRef]
 
Kharofa  J;  Sekar  P;  Haverbusch  M  et al:  Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke.  Stroke 2007; 38:3049–3051
[PubMed]
[CrossRef]
 
Chen  Y;  Guo  JJ;  Li  H  et al:  Risk of cerebrovascular events associated with antidepressant use in patients with depression: a population-based, nested, case–control study.  Ann Pharmacother 2008; 42:177–184
[PubMed]
[CrossRef]
 
References Container
+

References

Duijvestijn  YC;  Kalmeijer  MD;  Passier  AL  et al:  Neonatal intraventricular haemorrhage associated with maternal use of paroxetine.  Br J Clin Pharmacol 2003; 56:581–582
[PubMed]
[CrossRef]
 
Lake  MB;  Birmaher  B;  Wassick  S  et al:  Bleeding and selective serotonin reuptake inhibitors in childhood and adolescence.  J Child Adolesc Psychopharmacol 2000; 10:35–38
[PubMed]
[CrossRef]
 
Bak  S;  Tsiropoulos  I;  Kjaersgaard  JO  et al:  Selective serotonin reuptake inhibitors and the risk of stroke: a population-based, case–control study.  Stroke 2002; 33:1465–1473
[PubMed]
[CrossRef]
 
Kurne  A;  Ertugrul  A;  Anil Yağcioğlu  AE  et al:  Venous thromboembolism and escitalopram.  Gen Hosp Psychiatry 2004; 26:481–483
[PubMed]
[CrossRef]
 
Conde López  VJ;  Ballesteros Alcalde  MC;  Blanco Garrote  JA  et al:  Cerebral infarction in an adolescent girl following an overdose of paroxetine and caffedrine combined with theodrenaline.  [Spanish] Actas Luso Esp Neurol Psiquiatr Cienc Afines 1998; 26:333–338
 
Molaie  M:  Serotonin syndrome presenting with migraine-like stroke.  Headache 1997; 37:519–521
[PubMed]
[CrossRef]
 
Ramasubbu  R:  SSRI treatment-associated stroke: causality assessment in two cases.  Ann Pharmacother 2004; 38(7,8):1197–1201
[PubMed]
 
Singhal  AB;  Caviness  VS;  Begleiter  AF  et al:  Cerebral vasoconstriction and stroke after use of serotonergic drugs.  Neurology 2002; 58:130–133
[PubMed]
 
Naranjo  CA;  Busto  U;  Sellers  EM  et al:  A method for estimating the probability of adverse drug reactions.  Clin Pharmacol Ther 1981; 30:239–245
[PubMed]
[CrossRef]
 
Edwards  IR;  Jason Aronson  JK:  Adverse drug reactions: definitions, diagnosis, and management.  Lancet 2000; 356:1255–1259
[PubMed]
[CrossRef]
 
Edwards  IR;  Olsson  S:  World Health Organization programme: global monitoring, in  Pharmacovigilance . Edited by Mann  R;  Andrews  A.  Chichester, England,  Wiley, 2002, pp 169–182
 
Gilon  D;  Buonanno  FS;  Joffe  MM  et al:  Lack of evidence of an association between mitral-valve prolapse and stroke in young patients.  N Engl J Med 1999; 341:8–13
[PubMed]
[CrossRef]
 
Musselman Evans  DL;  Nemeroff  CB:  The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.  Arch Gen Psychiatry 1998; 55:580–592
[PubMed]
[CrossRef]
 
Cerrito  F;  Lazzano  MP;  Gaudio  E  et al:  5HT2-receptors and serotonin release: their role in human platelet aggregation.  Life Sci 1993; 53:209–215
[PubMed]
[CrossRef]
 
Bonvento  G;  Mackenzie  ET;  Edvinsson  L:  Serotonergic innervation of the cerebral vasculature: relevance to migraine and ischemia.  Brain Res Rev 1991; 16:257–263
[PubMed]
[CrossRef]
 
Ramasubbu  R:  Cerebrovascular effects of selective serotonin reuptake inhibitors: a systematic review.  J Clin Psychiatry 2004b; 65:1642–1653
[CrossRef]
 
Kharofa  J;  Sekar  P;  Haverbusch  M  et al:  Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke.  Stroke 2007; 38:3049–3051
[PubMed]
[CrossRef]
 
Chen  Y;  Guo  JJ;  Li  H  et al:  Risk of cerebrovascular events associated with antidepressant use in patients with depression: a population-based, nested, case–control study.  Ann Pharmacother 2008; 42:177–184
[PubMed]
[CrossRef]
 
References Container
+
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