Is there any other antihistamine that can be used to treat akathisia now when cyproheptadine is off

Fråga: Is there any other antihistamine that can be used to treat akathisia now when cyproheptadine is off the market?

The questioner usally treats severe cases of neuroleptic-induced akathisia with cyproheptadine when nothing else is efficient, i.e. when propranolol or anticholinergic drugs do not work. Since 2009-12-31 cyproheptadine has been retrieved from the market. Is there any similar drug with the same or similar mechanism of action that can be used instead?

Sammanfattning: No antihistamine is approved for treating akathisia. The antihistamine diphenhydramine has been suggested to be effective in this context. However, the evidence for this treatment is rather weak and includes a small non-placebo controlled trial and a study showing that diphenhydramine is effective in preventing the development of akathisia. An alternative might be the use of low dose mirtazapine where there is some evidence in the literature of effect against akathisia.

Svar: Akathisia is a known adverse drug reaction to antipsychotic drugs and involves inner restlessness and persistent urge to keep moving (1,2).

The first measure in case of neuroleptic-induced akathisia is to reduce the dose of the neuroleptic drug (1,2). Pharmacological treatment involves propranolol (2,3), anti-parkinson drugs (1) and anti-cholinergic drugs (4). However, the evidence for this kind of treatment is weak (3,4).

Notably, no drugs in FASS is approved for the treatment of akathisia (5).

Cyproheptadine has a sedating mechanism of action and in a small comparative double-blind study (N=30), cyproheptadine (16 mg/day) was as effective as propranolol (80mg/day) to treat akathisia (6). This was also the case in an open, uncontrolled trial where cyproheptadine (16 mg/ day) was effective to treat akathisia in 17 neuroleptic-treated patients with akathisia (7).

Diphenhydramine is an anti-histamine that has anti-cholinergic and sedating mechanisms of action and might therefore, at least theoretically, be effective against akathisia. In a randomised placebo-controlled study (N=100) diphenhydramine was investigated for use in preventing prochlorperazine-induced akathisia. Patients recieveing diphenhydramine concomitantly with prochlorperazine (N=50) had a significantly reduced risk in developing akathisia than those receiving placebo (N=50) (8). In a comparative study (N=56) both midazolam 2 mg and diphenhydramine 20 mg was effective in treating akathisia. Midazolam could correct the symptoms of metoclopramide-induced akathisia faster but diphenhydramine was better tolerated (caused less sedation) (9). There was no placebo group in this trial.

Diphenhydramine is only available as oral solution in Sweden and is approved for the use in Allergic disorders.

There is also some evidence in the literature for the use of low dose mirtazapine (15 mg/day) to be effective in treating neuroleptic-induced akathisia (10). This includes a few case-reports (N=9 patients) (10), a small double-blind, placebo-controlled trial (N=26) (11) and a comparative double-blind, placebo- and propranolol-controlled trial (N=90) (12). In the latter patients with akathisia were randomised to either mirtazapine 15 mg/ day (N=30), placebo (N=30) or propranolol 80 mg/ day (N=30). Mirtazapine was as efficient as propranolol and better tolerated according to this study (12). SBU rapport Neuroleptika frågor och svar Vanna Beckman 1998 www. Lakemedelsverket.se 2009-03-19, Behandlingsrekommendationer: Använding av neuroleptika vid schizofreni och schizofreniliknande tillstånd, rekommendationer. Barnes TR, Soares-Weiser K, Bacaltchuk J. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia (Review). Cochrane Database Syst Rev 2004, Issue 4. CD001946. Rathbone J, Soares-Weiser K. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2006, Issue 4. CD003727. FASS 2009 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(6):612-615 Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37(2):125-131 Parlak I, Erdur B, Parlak M, Ergin A, Ayrik C, Tomruk O et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med 2007;14(8):715-721 Hieber R, Dellenbaugh T, Nelson LA. Role of mirtazapine in the treatment of antipsychotic-induced akathisia. Ann Pharmacother 2008;42(6):841-846 Poyurovsky M, Epshtein S, Fuchs C, Schneidman M, Weizman R, Weizman A. Efficacy of low-dose mirtazapine in neuroleptic-induced akathisia: a double-blind randomized placebo-controlled pilot study. J Clin Psychopharmacol 2003;23(3):305-308 Poyurovsky M, Pashinian A, Weizman R, Fuchs C, Weizman A. Low-dose mirtazapine: a new option in the treatment of antipsychotic-induced akathisia. A randomized, double-blind, placebo- and propranolol-controlled trial. Biol Psychiatry 2006;59(11):1071-1077