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 Table of Contents  
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 102-104

Role of serotonin receptor antagonist cyproheptadine in treatment-resistant akathisia

1 Department of Psychiatry, Aarupadai Veedu Medical College and Hospital, Guwahati, India
2 Department of Physiology, AIIMS, Guwahati, India

Date of Submission02-Sep-2020
Date of Decision24-Nov-2020
Date of Acceptance03-Feb-2021
Date of Web Publication15-Apr-2021

Correspondence Address:
Dr. Vishnupriya Veeraraghavan
Department of Psychiatry, Aarupadai Veedu Medical College and Hospital, Puducherry
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aip.aip_97_20

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Akathisia is a term used for motor restlessness along with subjective feelings of tension and discomfort. It requires both subjective and objective aspects, and these behaviors are attributed to the inner feelings of tension. It is due to antipsychotic drug exposure. Treatment involves lowering the dosage of the antipsychotic medications, adding propranolol, benzodiazepines like diazepam or clonazepam, clonidine, or mirtazapine. Here, we present a case of akathisia which we found novel as the patient did not respond to the forementioned conventional methods and developed adverse effects but responded only to cyproheptadine syrup.

Keywords: Adrenergic antagonists, movement disorders, psychomotor agitation

How to cite this article:
Veeraraghavan V, Srinivasan K. Role of serotonin receptor antagonist cyproheptadine in treatment-resistant akathisia. Ann Indian Psychiatry 2022;6:102-4

How to cite this URL:
Veeraraghavan V, Srinivasan K. Role of serotonin receptor antagonist cyproheptadine in treatment-resistant akathisia. Ann Indian Psychiatry [serial online] 2022 [cited 2023 Mar 30];6:102-4. Available from: https://www.anip.co.in/text.asp?2022/6/1/102/313756

  Introduction Top

Akathisia is a term used for motor restlessness along with subjective feelings of tension and discomfort. It requires both subjective and objective aspects, and these behaviors are attributed to inner feelings of tension.[1] Akathisia meaning “Never to sit down” is a drug-induced movement disorder which develops within first 4 weeks of starting or increasing the dose of antipsychotic medications or after decreasing the dose of antiparkinsonian drugs.[2] The incidence of antipsychotic-induced akathisia is 20%–45%.[3] It is also reported with selective serotonin reuptake inhibitors where it is mediated by the serotonin agonism of the dopamine system. These symptoms should not be a part of any other psychiatric illness, neurological or a general medical condition. Cholinergic, adrenergic, serotonergic, and dopamine pathways are implicated in the etiology of akathisia.[4] This condition is often misdiagnosed with persistent anxiety or agitation or manic excitement. The two traditional methods involved in the treatment are the change in antipsychotic regimen and addition of an anti-akathisia agent.[5] Pharmacological regimens mainly focus on the role of beta adrenergic blockers like propranolol in the treatment of akathisia. Newer research focuses on the role of 5HT 2A receptor mediators like mirtazapine and cyproheptadine.[4] This activity is thought to counteract antipsychotic-induced dopamine D2 receptor blockade with subsequent enhancement in dopamine neurotransmission.[4] Lack of response to conventional methods is common, but developing adverse effects with most of the first-line drugs are quite unusual. We find this case interesting as she failed to respond to conventional methods of treatment but responded only to cyproheptadine syrup.

  Case Report Top

A 45-year-old married female, presented to the outpatient department with complaints of inability to stay still, rocking to and fro movements, subjective and objective restlessness for the past 1½ months. She told like she had the powers of goddess Durga. She had agitation, aggression, increased speech, and sleep disturbance for the past 2 months. Past history suggestive of multiple similar episodes of agitation, aggression, tall claims, and sleep disturbances was present. However, she always sought magicoreligious healing for the same. Since the current episode did not resolve with the spiritual methods, she consulted a psychiatrist who started her on tablet haloperidol 10 mg, tablet trihexyphenidyl 4 mg, and tablet divalproex sodium 500 mg. She started to experience restlessness within 15 days of treatment, so they discontinued the treatment and consulted our outpatient department. She was admitted in the psychiatric ward. Baseline investigations such as complete blood count, renal function test, liver function test, serum electrolytes, and electrocardiogram done were normal. Her glycemic control was good which was evident from her glycosylated hemoglobin levels. Neuroimaging such as computerized tomography and magnetic resonance imaging brain was normal. Following psychological scales were administered

  1. Barnes Akathisia Rating Scale (BARS) – Subjective and objective restlessness amounted to a score of 9

  2. Her Global Clinical Assessment of Akathisia score was 5

  3. Young Mania Rating Scale (YMRS) Score 30

A diagnosis of bipolar affective disorder–current episode mania with psychotic features was made. Haloperidol was stopped. Tablet divalproex sodium dose was increased up to 750 mg, tablet olanzapine 10 mg was added in view of her grandiose ideas, and tablet trihexiphenidyl dose was increased to 4 mg.

Trihexyphenidyl dose was increased up to 6 mg, but her symptoms continued. Mirtazapine was not initiated in her in view of a possibility of worsening of the manic symptoms.[Figure 1] On the 4th week, due to the failure of the above-mentioned conventional methods, she was started on syrup cyproheptadine 5 ml which was equivalent to 2 mg, and gradually, the dose was increased up to 16 mg over 2 weeks. She started to improve within a week, her restlessness started to settle down, and there were no objective evidence of restlessness. BARS showed that her total subjective and objective restlessness scores were 2, and her global clinical assessment of akathisia score was 1. YMRS scores also dropped to 20. During follow-up, her mood symptoms settled down, and there were no movements, and cyproheptadine was gradually tapered and stopped.
Figure 1: Management flowchart

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  Discussion Top

Akathisia, a drug-induced movement disorder if left untreated, has high morbidity as it can lead to suicidal intention. Shear et al. reported completed suicides which occurred impulsively in schizophrenia patients with akathisia. Sculte have reported suicidal ideation attributed to akathisia.[5],[6] D2 receptor affinity of haloperidol is high, and its administration is found to have increased expression of fos protein in regions of high D2 expression such as striatum, prefrontal cortex, nucleus accumbeens, lateral septal nucleus, and dorsolateral striatum resulting in high incidence of akathisia.[7] Conventional treatment involves lowering the dosage of the antipsychotic medications, adding benzodiazepines like diazepam or clonazepam, clonidine, and mirtazapine.[2] In few patients, the first-line drugs such as anti-adrenergic drugs and anti-cholinergic medications have limitations based on tolerability and side effect profile. It suggests that there is a complex relationship between the neurotransmitter systems, including dopamine, acetylcholine, gamma-aminobutyric acid, norepinephrine, serotonin, and neuropeptides making the outcome more and more challenging.[4] Other modalities such as cyproheptadine a 5HT2a/c receptor antagonist have demonstrated significant efficacy and adequate tolerability in small, randomized, placebo controlled trials in patients with first-generation antipsychotic-induced akathisia based on the potential to counteract anti-psychotic-induced D2 receptor blockade.[8] In a double-blind study done in 30 schizophrenia patients with neuroleptic-induced akathisia, it was found that the reduction in severity of the akathisia was 46% in group that was given cyproheptadine, whereas it was only 42% in the group that was given proponolol.[9] In an open clinical trial, 16 mg cyproheptadine was administered to 17 neuroleptic-induced akathisia patients. 15 out of 17 participants showed marked improvement in 4 days.[10] It has also got better tolerability.[10] When conventional method fails and adverse effects prop in, treatment with alternative options such as cyproheptadine can be considered.

  Conclusion Top

There should be a personalized treatment plan for akathisia, incorporating details such as history, therapeutic response, and side effects profile. When the initial approach such as antipsychotic dose reduction, discontinuing polypharmacy, choosing of an antipsychotic agent with lower liability for akathisia and addition of an anti-adrenergic agent fails, next line measures like adding cyproheptadine can be considered.

Declaration of patient consent

The authors certify that they had obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images, and other clinical information to be reported in the journal. The patient understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Henderson M, Mellers JD. Movement disorders. In: Lishman's Organic Psychiatry. South London, UK: John Wiley and Sons, Ltd.; 2009. p. 745-816. Available from: https://. [Last accessed on 2020 Sep 15].  Back to cited text no. 1
Sethuram K, Gedzior J. Akathisia: Case presentation and review of newer treatment agents. Psychiatr Ann 2014;44:391-6.  Back to cited text no. 2
Poyurovsky M, Weizman A. Serotonin-based pharmacotherapy for acute neuroleptic-induced akathisia: A new approach to an old problem. Br J Psychiatry 2001;179:4-8.  Back to cited text no. 3
Salem H, Nagpal C, Pigott T, Teixeira AL. Revisiting antipsychotic-induced akathisia: Current issues and prospective challenges. Curr Neuropharmacol 2017;15:789-98.  Back to cited text no. 4
Shear MK, Frances A, Weiden P. Suicide associated with akathisia and depot fluphenazine treatment. J Clin Psychopharmacol 1983;3:235-6.  Back to cited text no. 5
Schulte JR. Homicide and suicide associated with akathisia haloperidol. Am J Forensic Psychiatry 1985;6:3-7.  Back to cited text no. 6
Kern DS, Lang AE. Acute akathisia. In: Friedman JH, editor. Medication-Induced Movement Disorders. Cambridge: Cambridge University Press; 2015. p. 3-19. Available from: https://. [Last accessed on 2020 Sep 15].  Back to cited text no. 7
Janicak PG, Beedle D. Medication-induced movement disorders. In: Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2009. p. 2996-3003.  Back to cited text no. 8
Fischel T, Hermesh H, Aizenberg D, Zemishlany Z, Munitz H, Benjamini Y, et al. Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: A comparative double-blind study. J Clin Psychopharmacol 2001;21:612-5.  Back to cited text no. 9
Weiss D, Aizenberg D, Hermesh H, Zemishlany Z, Munitz H, Radwan M, et al. Cyproheptadine treatment in neuroleptic-induced akathisia. Br J Psychiatry 1995;167:483-6.  Back to cited text no. 10


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