Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 43, Num. 4, 2011, pp. 460-462

Indian Journal of Pharmacology, Vol. 43, No. 4, July-August, 2011, pp. 460-462

Short Communication

Delayed-onset akathisia due to amisulpride

Murad Atmaca, Sevda Korkmaz

Department of Psychiatry, Faculty of Medicine, Firat University, Elazig, Turkey

Correspondence Address: Murad Atmaca Department of Psychiatry, Faculty of Medicine, Firat University, Elazig Turkey matmaca_p@yahoo.com

Date of Submission: 28-Sep-2010
Date of Decision: 09-Mar-2011
Date of Acceptance: 25-Apr-2011

Code Number: ph11121

DOI: 10.4103/0253-7613.83122

Abstract

Keywords: Akathisia, amisulpride, delayed

Introduction

Akathisia is an involuntary movement disorder characterized by a subjective feeling of restlessness and fidgety movements. First-generation antipsychotic agents had drug-induced akathisia due to its high incidence and particularly aversive nature. ^[1] Despite the fact that second-generation antipsychotics have a lower potential to cause extrapyramidal side-effects, including akathisia, their incidence is not negligible. A variety of akathisia subtypes have been described: acute, withdrawal, tardive and chronic. ^[2] Tardive akathisia is characterized by longer-term akathisia manifestations, and is occasionally confused with chronic akathisia. It may persist or may become worse when the antipsychotic treatment is discontinued or reduced. ^[3]

It seems that tardive akathisia may have pharmacological differences from acute akathisia. Unlike acute akathisia, neither chronic nor tardive akathisia has been reported with drugs not being neuroleptics, considering that these types of akathisias may be pure neuroleptic-related syndromes, and that this makes them potentially important syndromes to examine with regard to pathophysiology. ^[4] There appears to be dopamine receptor blockade in the mesocortical dopamine system in acute akathisia, while it has been noted that the delayed akathisia may have resulted from a pharmacodynamic effect through serotonin-dopamine and alfa-receptor interaction. ^[5] In the present study, we planned to evaluate the nature of delayed-onset akathisia in patients on amisulpride monotherapy.

Materials and Methods

Overall, 56 patients on amisulpride treatment for 2 months at a stabilized amisulpride dose for their schizophrenia, delusional or schizoaffective disorder were folowed-up. Of them, 18 patients with diagnostic and statistical manual of mental disorders-IV (DSM-IV) presented with acute or delayed-onset akathisia, and all of them also met the entry criteria. The inclusion criteria were: taking stabilized amisulpride dose for at least 2 months, having normal physical and neurological examination and normal routine laboratory tests and electrocardiography within the normal range. The exclusion criteria included the presence of a severe physical illness, the history of alcohol and substance abuse or dependence, a previous history of neurologic disease and the presence of any endocrinological state. The patients were evaluated at baseline and at the time when akathisia presented clinically, with respect to the positive and negative syndrome scale (PANSS) and Barnes Akathisia Scale (BAS). ^[6] To confirm the akathisia, a score of ≥2 on the global scale (range 0-5) of the BAS was required. Statistical analysis was performed using the statistical package for social sciences (SPSS/PC 10.0 version).

Results

All 56 patients completed the study. [Table - 1] shows the demographic and clinical data of the 18 patients who developed akathisia. Majority of the patients reported one or more adverse effects during the 2-month period apart from the akathisia, most of which were mild to moderate in intensity. The most frequently reported adverse effects were reduced energy (n = 6), tremor (n = 5) and nausea (n = 3). Overall, significant changes were noted in the PANSS and Clinical Global Impression-Severity (CGI-S) scores after the study period. The mean total PANSS scores were 69.4 ± 8.1 and 52.1 ± 7.2 at baseline and after 2 months, respectively (P < 0.01). The mean CGI-S scores were 3.64 ± 1.2 and 2.5 ± 0.9 at baseline and at 2 months, respectively (P < 0.05). Using the primary categorical criterion of akathisia (≥2 points of the BAS global scale), 12 (21.4%) of the 56 patients experienced delayed-onset akathisia, and six (10.7%) showed acute akathisia. The mean time of onset of acute or delayed-onset akathisia was 5.8 ± 2.1 and 39.4 ± 11.3 days, respectively. The mean BAS scores at baseline and after the period of 2 months were 1.3 ± 0.6 and 3.9 ± 2.4, respectively (P < 0.01). Eight patients (four with acute and four with tardive akathisia) responded to dose reduction and four responded to benzodiazepines and propranolol treatment while six did not respond to any treatment.

Discussion

To the best of our knowledge, this is the first study to assess the time course of the occurrence of amisulpride-induced akathisia. The present study revealed that amisulpride could lead to, especially, delayed-onset akathisia rather than acute akathisia. Because of its mechanism of action not having any affinity to 5-HT2 receptors, amisulpride, a benzamide derivative, has high and similar affinities for the dopamine D2 and D3 receptor subtypes and is devoid of any significant affinity to other receptor systems. ^[7] Therefore, its high D2 occupancy can account for the high rate of akathisia because of the fact that eight of the patients (four with acute and four with tardive akathisia) responded to dose reduction. However, a question arises: Why amisulpride induces delayed-onset akathisia? Despite the fact that no known active metabolites in rodents were determined, ^[8] Natesan et al. ^[9] reported slower brain penetration of the amisulpride, measured by its ability to displace [ ³ H] raclopride in the striatum when compared with haloperidol, risperidone and clozapine. Moreover, Natesan et al. ^[9] found that despite amisulpride′s effect of quick onset (1 h) and decline (6 h) of prolactin elevation, it showed a "delayed" pattern of D _2/3 receptor occupancy: 43, 60 and 88% after 1, 2 and 6 h (100 mg/kg), respectively, unlike the atypicals clozapine and risperidone, supporting its poor blood-brain barrier penetration. Therefore, we suggest that its delayed penetration into the brain may be a contributing factor for its delayed-onset akathisia effect. On the other hand, the severity and time difference for developing extrapyramidal side-effects, including akathisia, also depend on some pharmacological differences between drugs, such as the rate of dissociation from the D2 receptor, the degree of dopamine-2 (D2) and 5HT2A receptor antagonism and the antimuscarinic potential of the drug. ^[10] Therefore, when thinking on the mechanism of tardive akathisia, we should take into consideration not only the D2 receptor blocking effect but also the other receptor-binding profiles such as minimal muscarinic receptor or the 5-HT2 receptor affinity. Some limitations should be mentioned in the present study. First, we did not test amisulpride in comparison with the other antipsychotics. Second, the small sample may limit the interpretation and generalizability of our findings. Thus, although our results revealed that amisulpride could considerably lead to delayed-onset akathisia, studies comprising larger samples receiving different antipsychotics, and more comprehensive assessment, will help in ascertaining the role of amisulpride in delayed-onset akathisia.

References

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