Akathisia and Second-generation Antipsychotic Drugs

Rajeev Kumar; Perminder S. Sachdev


Curr Opin Psychiatry. 2009;22(3):293-299. 

In This Article

Abstract and Introduction


Purpose of Review: Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.
Recent Findings: Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.
Summary: Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.


Second-generation antipsychotics (SGAs), now the mainstay of antipsychotic treatment in most countries, have the shared feature that they produce fewer extrapyramidal side effects (EPSEs) than the conventional or first-generation antipsychotics (FGAs).[1] In fact, this relative lack of EPSEs is considered to be the defining feature of their 'atypicality'.[2] However, SGAs are not free of EPSEs and the whole range of EPSEs generally associated with FGAs has also been associated with the SGAs. In order to better understand the differential rates of EPSE production by the SGAs, a new classification has been suggested based on the dopamine D2 receptor binding affinity concept.[3] In this classification, clozapine and quetiapine are included in the low affinity group, olanzapine in the middle affinity group, and risperidone, ziprasidone, and aripiprazole in the high affinity group. Furthermore, it is suggested that olanzapine and risperidone at higher doses have high D2 occupancy, whereas quetiapine and clozapine do not.

We agree with a recent editorial[4] that the widespread and appropriate attention to metabolic effects with SGAs should not be a reason to ignore the problem of EPSEs, even though they may be mild or less frequent. In this update, we focus on akathisia (from Greek, literally 'not to sit'), one of the most common and disabling side effects of antipsychotics and some other drugs.[5,6] The various forms of akathisia have been well characterized in earlier studies, which include acute, chronic, withdrawal and tardive subtypes.[7,8] Because akathisia differs from Parkinsonian symptoms such as rigidity, bradykinesia, and tremor in its risk factors and treatment response, its pathogenetic mechanisms are also likely to be different, suggesting that drugs that do not produce significant EPSEs may yet cause akathisia. We examine the recent empirical evidence relating akathisia to SGAs and examine the risk factors, pathophysiology, and recent attempts at its treatment.


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