Evidence-based management of akathisia

This comprehensive literature review cum treatment recommendation pertaining to neuroleptic-induced akathisia (by an international collaboration of pharmacists and psychiatrists first-authored by the University of Calgary’s Tamara Pringsheim and colleagues, Canadian Journal of Psychiatry 63(11):719-729, 2018) comprises both of the two principal themes of adverse effect management–prophylaxis and intervention. It begins by pointing out that akathisia was “largely overlooked until the 1980’s,” thirty years after its initial identification and characterization. They offer no speculation for the delay beyond complications posed by the dual “subjective-objective” presentation of akathisia, with its manifestations resembling the restlessness, discomfort, and dysphoria accompanying anxiety and its greater responsivity to anxiolytic agents than to anticholinergic compounds. Yet, its onset within hours to days after initiation of neuroleptic dosing; its greater severity after higher neuroleptic dosages or rapid dosage escalation, its association with typical extrapyramidal adverse effects, and emergence in some persons of serious complications (such as exhaustion and dehydration) doubtless conduced to its eventually correct attribution.

From an initial 5,053 “hits” (case reports, case series, and clinical trials) retrieved from Medline and CENTRAL databases, Cochrane reviews, and a Canadian pharmacovigilance registry, the authors extracted a small body of evidence detailing risk factors and describing responses to the congeries of agents with which persons with akathisia have been challenged, adding to it their own ratings of methodologic quality and proposing evidence-based treatment recommendations.

As with other evidence-based treatment recommendations, the authors’ begin with identifying risks requiring minimization: Use of first-generation neuroleptics, use of more than one first- or subsequent-generation neuroleptic, unnecessarily high neuroleptic dosage, rapid dosage escalation, use of haloperidol (more likely to induce akathisia than other first- or second-generation neuroleptics studied), use of risperidone (more akathitic in head-to-head comparisons with atypical neuroleptics olanzapine, quetiapine, ziprasidone, and clozapine).

The authors’ literature search turned up a paucity of within-class data on comparative propensities of individual drugs to induce akathisia, and that small sample is predictably variable with a propensity for type II error. Yet, the extensive use of some of the atypical neuroleptiics affords experienced clinicians a “personal N” that helps offset the authors’ small sample size, and lends credence to an impression of inconsistency of aripiprazole, in particular, described as both comparatively high (in one report wherein it exceeds that of risperidone) and “very low” ( reflected in large-N evidence base that gives rise to the highly regarded Maudsley Prescribing Guidelines in Psychiatry.). Scant evidence from comparisons among second-generation antipsychotics  preclude gravitas in the authors’ recommendations about the latter. This the authors implicitly concede in their diction: they go no further than to assert that some atypical neuroleptics are “perceived to be” more or less likely to induce akathisia.

Consistent with the risk factors identified by the authors is their recommendation to avoid prescribing two or more neuroleptics (associated with akathisia in 40 percent of patients taking more than one first-generation drug and in 34 percent of patients taking more than one second-generation drug, compared with 21 percent and 11 percent of patients receiving monotherapy with first- and second-generation drugs, respectively).

The authors’ recommendation to minimize exposure-related risk of akathisia is intended to protect persons who are not experiencing akathisia;  dose-reductive, such recommendations are appropriate for persons who have achieved stable control of psychotic symptoms. Yet, reduced risk and enhanced benefit are not mutually exclusive. The authors cite a controlled study in outpatients who had been switched from antipsychotic polytherapy to monotherapy; at outcome assessment six months later, more than two-thirds had resumed antipsychotic polytherapy. The one-third who had not were no more symptomatic than were patients in a control group who had remained on polytherapy throughout. (Not specified is whether the one-third who were “no worse” than the control group six months after discontinuing polytherapy and beginning monotherapy withal may have been more symptomatic than they had been at baseline while receiving polytherapy.) No flexible, reductive recommendations intended to improve efficacy are included among their suggestions for non-naive neuroleptic-treated  paitents. (One not uncommon clinical preference might have been continuation of polytherapy at a lower total daily chlorpromazine-equivalent dosage (allowing, for example, patients with sleep disturbances continuation of a nightly dose of a sedating neuroleptic (such as quetiapine) following a daytime dose of a non-sedating drug (such as aripiprazole)). Having pointed out that patients who have never been exposed to neuroleptics are more likely to develop akathisia than those who have, the authors may have been primed to avoid therapeutic exceptions of neuroleptic polytherapy in a context of managing akathisia. .

Then reviewing evidencce for interventive tactics for managing acute, relatively severe akathisia, the authors identified seven drug classes (some mitigating both subjective and ohjective symptoms of akathisia, some affording relief of only subjective symptoss, none of only objective symptoms, some ameliorating neigher, and some with intolerable adverse effects and/or unaccptable risks. The two classes affording improvement of subjective and objective symptoms and  coveying tolerable adverse effects and acceptable safety were beta adrenergic antagonists (propranolol and metoprolol, but not nadolol, which failed to separae from placebo,  and benzodiazepines (they discuss clonazepam, although each of several others have been reported.l lAnticholinergic agents (paricularly benztropine) have been reported more uniformly effective for subjective risks, but require dosages that exced those effective for dystojia and parkinsonism (e.g., 8 mg per day associated with central and peripheral adverse effect, and particularly prone to impair short-term memory. Only one (beta antagonists) spsecifically propranolol and metopralol were recommended as a first-resort for managing akathisia  Benzodiazepines were cosidered less desirable by the authors because of sedation and drug dependence.

The authors regarded the 5HT2a antagonist mirtazapine (approved for anxiety disorders and depression)  an evidence-based second choice, followed by at least partially effective drugs (by virtue of subjective improvement, acompanied or not by concerns about tolerance and/or safety)–a group that comprises anticholinergic agents at the high dosages associated with improvement  (benztropine, biperiden), benzodiazepines, trazodone, the H1 antihistamine cyproheptadine, vitamin B6 (its dose-related progressive sensory neuropathy notwithstanding).clonidine, gabapentin, and pregabalin.(Obiter:As the authors imply in their discussion of anticholinergic agents (partially effective for akathisia at high dosage,  intervention for managing akathisia should avoid coadinistration of drugs with pharmacodynamic effects similar to adverse effects of neuroleptics other than akathisia (such as mirtazapine or trazodone in patients receiving sedating neuroleptics such as olanzapine,  quetiapine, or clozapine.)









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