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AJP-724; No. of Pages 2 Asian Journal of Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Letter to the Editor Quetiapine induced restless legs syndrome: A series of four cases Restless legs syndrome (RLS) is a distressing sensorimotor disorder which is characterised by uncomfortable sensations in the legs (paresthesias) which occurs mainly in the evening and gets relieved with mobility (Ferini-Strambi, 2007; Gamaldo and Earley, 2006). Very few cases of quetiapine induced RLS have been reported in the literature (Urbano and Ware, 2008; Pinninti et al., 2005; Rittmannsberger and Werl, 2013). This article presents a case series of four patients with RLS apparently induced by quetiapine. 1. Case reports Patient 1 is a 40 years old white woman with a diagnosis of schizo-affective disorder and is known to psychiatric services for many years. Earlier she had received the diagnosis of bipolar affective disorder. She received many anti-psychotics and antidepressants in the past. In March 2014, she was on aripiprazole, amitriptyline, omeprazole and Ramipril when her aripiprazole was substituted with increasing dose of quetiapine. Couple of months later, she reported symptoms of RLS in the form of periodic leg movements mainly in the evening with multiple interruptions of sleep and worsening of symptoms during inactivity. Her quetiapine was gradually discontinued and the symptoms of RLS abated. Patient 2 is a white woman, aged 43 year, diagnosed with bipolar affective disorder and known to psychiatric service for a long time. She had been treated with Escitalopram, Dothieapin, Fluoxetine, Lofepramine and Lithium Carbonate in the past. In September 2014, she was taking citalopram 20 mg/day and quetiapine 300 mg a day when few weeks later she described a feeling of twitching in her legs at night time which was soon followed by symptoms of RLS as mentioned above in patient 1. Her citalopram was stopped but the symptoms of RLS continued until her quetiapine was discontinued. Patient 3 is a 39 years old white woman who received multiple psychotropic medications over the period of 7 years for the management of recurrent depressive disorder. In November 2014, quetiapine was gradually added to build up the dose of 250 mg a day to her Fluoxetine. A couple of months later, she reported symptoms of RLS similar to those stated above. Symptoms of RLS disappeared after discontinuation of quetiapine but her mental state deteriorated and she insisted to go back on quetiapine. Patient 4 is a 38 years old white woman, with a diagnosis of recurrent depressive disorder for which she received multiple antidepressants and anti-psychotics for a long time in the past. She developed RLS twice about 12 and 1½ years ago with mirtazapine. Four months ago quetiapine was added to her existing treatment of sertraline 200 mg mane and propranolol 120 mg daily. She
developed RLS when she reached the dose of quetiapine 300 mg daily. She responded well with Ropinirole, a dopamine agonist and she continued with quetiapine as she found immense improvement in her mental state with quetiapine. All these cases had unremarkable haematological and biochemical investigations including ferritin levels and kidney functions. 2. Discussion All the cases reported here fulfilled the diagnostic criteria of RLS (Allen et al., 2003). Their symptoms of RLS differed from akathisia. Unlike akathisia, these patients experienced worsening of symptoms during inactivity and at night (presences of circadian component) and relief by the movement of their limbs. On the contrary, akathisia is generally characterised by a general feeling of inner restlessness and it occurs mainly during daytime (FeriniStrambi, 2007; Ekbom and Ulfberg, 2009). The common features in all these cases are that they all were female patients with affective presentations who developed RLS when they were receiving moderate dose of quetiapine (200– 300 mg) with anti-depressant which disappeared with the discontinuation of quetiapine. These findings are quite in line with the findings of seven cases of quetiapine induced RLS reported by Rittmannsberger and Werl (2013). Patient 4 developed RLS with mirtazapine which is consistent with the findings of other studies (Prospero-Garcia et al., 2006; Kim et al., 2008). Later, this patient developed RLS with quetiapine, which responded well with ropinirole, a dopaminergic agent and these observations are similar to the findings in other studies (Urbano and Ware, 2008; Rittmannsberger and Werl, 2013). The relatively close temporal relationship between commencement of quetiapine and appearance of RLS and its disappearance with discontinuation of quetiapine indicates a causative relationship between the two. The mechanism by which RLS is produced by quetiapine remains unclear. It is speculated that it could be due to dopaminergic hypoactivity (Ekbom and Ulfberg, 2009). However, quetiapine has poor affinity for D2 receptors (Seeman and Tallerico, 1999), has a moderate and transient occupancy of D2 receptors (58–64%), has little risk of causing extrapyramidal symptoms and akathisia (Kumar and Sachdev, 2009). On the other hand, quetiapine has high affinity for H1 receptors which may be responsible for causing RLS as is caused by anti-histaminic agents (Ondo, 2005). The other factor contributing towards the RLS may be the concomitant use of quetiapine and anti-depressant and their interaction. Restless legs syndrome has been reported with various anti-depressants including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and mirtazapine (Ondo, 2005; Prospero-Garcia et al., 2006; Kim et al., 2008; Chopra et al., 2011).
http://dx.doi.org/10.1016/j.ajp.2015.05.045 1876-2018/ß 2015 Published by Elsevier B.V.
Please cite this article in press as: Vohra, A., Quetiapine induced restless legs syndrome: A series of four cases. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.05.045
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AJP-724; No. of Pages 2 2
Letter to the Editor / Asian Journal of Psychiatry xxx (2015) xxx–xxx
Based on these observations, it seems female patients with affective disorder are more at risk of developing quetiapine induced RLS due to various factors which if not recognised may promote the non-concordance with medication by the patients.
References Allen, R.P., Picchietti, D., Hening, W.A., et al., 2003. Restless legs syndrome; diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institute of Health. Sleep Med. 4, 101–119. Chopra, A., Pendergrass, D.S., Bostwick, J.M., 2011. Mirtazapine-induced worsening of restless legs syndrome (RLS) and ropinirole-induced psychosis: challenges in management of depression in RLS. Psychosomatics 52, 92–94. Ekbom, K., Ulfberg, J., 2009. Restless legs syndrome. J. Intern. Med. 266, 419–431. Ferini-Strambi, L., 2007. RLS-like symptoms: differential diagnosis by history and clinical assessment. Sleep Med. 8, 3–6. Gamaldo, C.E., Earley, C.J., 2006. Restless legs syndrome: a clinical update. Chest 130, 1596–1604. Kim, S.W., Shin, I.S., Kim, J.M., Opark, K.H., Youn, T., Yoon, J.S., 2008. Factors potentiating the risk of mirtazapine-associated restless legs syndrome. Hum. Psychopharmacol. 23, 615–620. Kumar, R., Sachdev, P., 2009. Akathisia and second-generation antipsychotic drugs. Curr. Opin. Psychiatry 22, 293–299. Ondo, W.G., 2005. Restless legs syndrome. Curr. Neurol. Neurosci. Rep. 5, 266–274.
Pinninti, N.R., Mago, R., Townsend, J., et al., 2005. Periodic restless legs syndrome associated with quetiapine use: a case report. J. Clin. Psychopharmacol. 25 (6), 617–618. Prospero-Garcia, K.A., Torres-Ruiz, A., Ramirez-Bermudes, J., Velazques-Moctezuma, J., Aran-Lechuga, Y., Teran-Perez, G., 2006. Fluoxetine–mirtazapine interaction may induce restless legs syndrome: report of 3 cases from a clinical trial. J. Clin. Psychiatry 67, 1820. Rittmannsberger, H., Werl, R., 2013. Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature. Int. J. Neuropsychopharmacol. 16 (6), 1427–1431. Seeman, P., Tallerico, T., 1999. Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy in early clinical relapse upon withdrawal of clozapine or quetiapine. Am. J. Psychiatry 156, 876–884. Urbano, M.R., Ware, J.C., 2008. Restless legs syndrome caused by quetiapine successfully treated with ropinirol in 2 patients with bipolar disorder. J. Clin. Psychopharmacol. 28, 704–705.
Adarsh Vohra* Mountcroft, Albert Street, FY5 1PQ, United Kingdom *Tel.: +44 7507839843; fax: ++44 1253651892 E-mail address: [email protected] (A. Vohra). 7 April 2015 Accepted 31 May 2015
Please cite this article in press as: Vohra, A., Quetiapine induced restless legs syndrome: A series of four cases. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.05.045
AJP-724; No. of Pages 2 Asian Journal of Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Letter to the Editor Quetiapine induced restless legs syndrome: A series of four cases Restless legs syndrome (RLS) is a distressing sensorimotor disorder which is characterised by uncomfortable sensations in the legs (paresthesias) which occurs mainly in the evening and gets relieved with mobility (Ferini-Strambi, 2007; Gamaldo and Earley, 2006). Very few cases of quetiapine induced RLS have been reported in the literature (Urbano and Ware, 2008; Pinninti et al., 2005; Rittmannsberger and Werl, 2013). This article presents a case series of four patients with RLS apparently induced by quetiapine. 1. Case reports Patient 1 is a 40 years old white woman with a diagnosis of schizo-affective disorder and is known to psychiatric services for many years. Earlier she had received the diagnosis of bipolar affective disorder. She received many anti-psychotics and antidepressants in the past. In March 2014, she was on aripiprazole, amitriptyline, omeprazole and Ramipril when her aripiprazole was substituted with increasing dose of quetiapine. Couple of months later, she reported symptoms of RLS in the form of periodic leg movements mainly in the evening with multiple interruptions of sleep and worsening of symptoms during inactivity. Her quetiapine was gradually discontinued and the symptoms of RLS abated. Patient 2 is a white woman, aged 43 year, diagnosed with bipolar affective disorder and known to psychiatric service for a long time. She had been treated with Escitalopram, Dothieapin, Fluoxetine, Lofepramine and Lithium Carbonate in the past. In September 2014, she was taking citalopram 20 mg/day and quetiapine 300 mg a day when few weeks later she described a feeling of twitching in her legs at night time which was soon followed by symptoms of RLS as mentioned above in patient 1. Her citalopram was stopped but the symptoms of RLS continued until her quetiapine was discontinued. Patient 3 is a 39 years old white woman who received multiple psychotropic medications over the period of 7 years for the management of recurrent depressive disorder. In November 2014, quetiapine was gradually added to build up the dose of 250 mg a day to her Fluoxetine. A couple of months later, she reported symptoms of RLS similar to those stated above. Symptoms of RLS disappeared after discontinuation of quetiapine but her mental state deteriorated and she insisted to go back on quetiapine. Patient 4 is a 38 years old white woman, with a diagnosis of recurrent depressive disorder for which she received multiple antidepressants and anti-psychotics for a long time in the past. She developed RLS twice about 12 and 1½ years ago with mirtazapine. Four months ago quetiapine was added to her existing treatment of sertraline 200 mg mane and propranolol 120 mg daily. She
developed RLS when she reached the dose of quetiapine 300 mg daily. She responded well with Ropinirole, a dopamine agonist and she continued with quetiapine as she found immense improvement in her mental state with quetiapine. All these cases had unremarkable haematological and biochemical investigations including ferritin levels and kidney functions. 2. Discussion All the cases reported here fulfilled the diagnostic criteria of RLS (Allen et al., 2003). Their symptoms of RLS differed from akathisia. Unlike akathisia, these patients experienced worsening of symptoms during inactivity and at night (presences of circadian component) and relief by the movement of their limbs. On the contrary, akathisia is generally characterised by a general feeling of inner restlessness and it occurs mainly during daytime (FeriniStrambi, 2007; Ekbom and Ulfberg, 2009). The common features in all these cases are that they all were female patients with affective presentations who developed RLS when they were receiving moderate dose of quetiapine (200– 300 mg) with anti-depressant which disappeared with the discontinuation of quetiapine. These findings are quite in line with the findings of seven cases of quetiapine induced RLS reported by Rittmannsberger and Werl (2013). Patient 4 developed RLS with mirtazapine which is consistent with the findings of other studies (Prospero-Garcia et al., 2006; Kim et al., 2008). Later, this patient developed RLS with quetiapine, which responded well with ropinirole, a dopaminergic agent and these observations are similar to the findings in other studies (Urbano and Ware, 2008; Rittmannsberger and Werl, 2013). The relatively close temporal relationship between commencement of quetiapine and appearance of RLS and its disappearance with discontinuation of quetiapine indicates a causative relationship between the two. The mechanism by which RLS is produced by quetiapine remains unclear. It is speculated that it could be due to dopaminergic hypoactivity (Ekbom and Ulfberg, 2009). However, quetiapine has poor affinity for D2 receptors (Seeman and Tallerico, 1999), has a moderate and transient occupancy of D2 receptors (58–64%), has little risk of causing extrapyramidal symptoms and akathisia (Kumar and Sachdev, 2009). On the other hand, quetiapine has high affinity for H1 receptors which may be responsible for causing RLS as is caused by anti-histaminic agents (Ondo, 2005). The other factor contributing towards the RLS may be the concomitant use of quetiapine and anti-depressant and their interaction. Restless legs syndrome has been reported with various anti-depressants including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and mirtazapine (Ondo, 2005; Prospero-Garcia et al., 2006; Kim et al., 2008; Chopra et al., 2011).
http://dx.doi.org/10.1016/j.ajp.2015.05.045 1876-2018/ß 2015 Published by Elsevier B.V.
Please cite this article in press as: Vohra, A., Quetiapine induced restless legs syndrome: A series of four cases. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.05.045
G Model
AJP-724; No. of Pages 2 2
Letter to the Editor / Asian Journal of Psychiatry xxx (2015) xxx–xxx
Based on these observations, it seems female patients with affective disorder are more at risk of developing quetiapine induced RLS due to various factors which if not recognised may promote the non-concordance with medication by the patients.
References Allen, R.P., Picchietti, D., Hening, W.A., et al., 2003. Restless legs syndrome; diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institute of Health. Sleep Med. 4, 101–119. Chopra, A., Pendergrass, D.S., Bostwick, J.M., 2011. Mirtazapine-induced worsening of restless legs syndrome (RLS) and ropinirole-induced psychosis: challenges in management of depression in RLS. Psychosomatics 52, 92–94. Ekbom, K., Ulfberg, J., 2009. Restless legs syndrome. J. Intern. Med. 266, 419–431. Ferini-Strambi, L., 2007. RLS-like symptoms: differential diagnosis by history and clinical assessment. Sleep Med. 8, 3–6. Gamaldo, C.E., Earley, C.J., 2006. Restless legs syndrome: a clinical update. Chest 130, 1596–1604. Kim, S.W., Shin, I.S., Kim, J.M., Opark, K.H., Youn, T., Yoon, J.S., 2008. Factors potentiating the risk of mirtazapine-associated restless legs syndrome. Hum. Psychopharmacol. 23, 615–620. Kumar, R., Sachdev, P., 2009. Akathisia and second-generation antipsychotic drugs. Curr. Opin. Psychiatry 22, 293–299. Ondo, W.G., 2005. Restless legs syndrome. Curr. Neurol. Neurosci. Rep. 5, 266–274.
Pinninti, N.R., Mago, R., Townsend, J., et al., 2005. Periodic restless legs syndrome associated with quetiapine use: a case report. J. Clin. Psychopharmacol. 25 (6), 617–618. Prospero-Garcia, K.A., Torres-Ruiz, A., Ramirez-Bermudes, J., Velazques-Moctezuma, J., Aran-Lechuga, Y., Teran-Perez, G., 2006. Fluoxetine–mirtazapine interaction may induce restless legs syndrome: report of 3 cases from a clinical trial. J. Clin. Psychiatry 67, 1820. Rittmannsberger, H., Werl, R., 2013. Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature. Int. J. Neuropsychopharmacol. 16 (6), 1427–1431. Seeman, P., Tallerico, T., 1999. Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy in early clinical relapse upon withdrawal of clozapine or quetiapine. Am. J. Psychiatry 156, 876–884. Urbano, M.R., Ware, J.C., 2008. Restless legs syndrome caused by quetiapine successfully treated with ropinirol in 2 patients with bipolar disorder. J. Clin. Psychopharmacol. 28, 704–705.
Adarsh Vohra* Mountcroft, Albert Street, FY5 1PQ, United Kingdom *Tel.: +44 7507839843; fax: ++44 1253651892 E-mail address: [email protected] (A. Vohra). 7 April 2015 Accepted 31 May 2015
Please cite this article in press as: Vohra, A., Quetiapine induced restless legs syndrome: A series of four cases. Asian J. Psychiatry (2015), http://dx.doi.org/10.1016/j.ajp.2015.05.045
