BRITISH JOURNAL OF PSYCHIATRY )2001), 179, 4^8 EDITORIAL compounds with a marked dopamine D Serotonin-based pharmacotherapy for acute 22 receptor antagonism. neuroleptic-induced akathisia: a new approach to an old problem Benzodiazepines and amantadine MICHAEL POYUROVSKY and ABRAHAM WEIZMAN The benzodiazepines e.g. clonazepam, lorazepam, diazepam) constitute a third group of agents with some therapeutic effi- cacy in NIA, presumably owing to their non-specific sedating and tranquillising AKATHISIA AS A CLINICAL switching to a low-potency antipsychotic properties. Amantadine, a dopamine reup- CHALLENGE agent.agent. take inhibitor, was also suggested as an optimal treatment for NIA Fleischhacker Neuroleptic-induced akathisia NIA) is et aletal, 1990).,1990). characterised by a subjective sense of inner Anticholinergics restlessness and objective fidgety move- Extrapyramidal syndromes, including ments. It is a major extrapyramidal side- akathisia, are attributed to the dopamine/ effect of conventional antipsychotic agents. acetylcholine imbalance produced by the AKATHISIA AND THE Despite its high incidence 20±45%), the neuroleptic blockage of the D22 receptorsreceptors SEROTONERGIC SYSTEM underlying mechanisms have not yet been in the nigrostriatal system. This assumption adequately explained. Diagnosis may be is based on the inverse relationship between The high rate of non-response to the con- difficult owing to the existence of various the affinity of conventional neuroleptic ventional anti-akathisic agents led clini- forms of NIA, namely acute, chronic, agents for muscarinic receptors and their cians to search in new directions. It was withdrawal and tardive, along with diur- propensity for causing EPS. However, suggested that 5-HT22 receptor antagonism, nal variations in its expression and its although anticholinergic agents have proven by counteracting dopamine D22 blockadeblockade common association with other extra- efficacious in the treatment of neuroleptic- may prevent the onset or mitigate the severity pyramidal syndromes EPS). The complex induced Parkinsonism and acute dystonia, of neuroleptic-induced EPS Meltzer et aletal,, interplay of the subjective and observable they produced equivocal results in NIA 1999). Dopamine neurons in the ventral components of NIA may account for the Fleischhacker et aletal, 1990). Furthermore, tegmental area and substantia nigra ± brain reported difficulties in differentiating the use of anticholinergic agents is limited regions apparently involved in the patho- NIA from psychotic excitement, agitated by their side-effects e.g. cognitive impair- physiology of EPS and NIA ± receive depression and anxiety. ment, blurred vision, constipation, urinary inhibitory 5-HT input from midbrain raphe The early detection and adequate retention). The tendency of patients with nuclei. Some researchers have hypothesised treatment of NIA are important because akathisia associated with Parkinsonian that a reduction in brain 5-HT function of its negative clinical consequences and symptoms to respond to anticholinergic 5-HT5-HT2a2a antagonists, 5-HT1a1a agonists, raphe serious adverse effects. Akathisia is agents has led to the suggestion of a specific lesions) may increase the basal activity of thought to be a risk factor for the devel- Parkinsonian-related subtype of akathisia dopaminergic neurons and thereby alleviate opment of tardive dyskinesia; it may be Barnes & McPhillips, 1999). EPS induced by D22 receptor antagonists for predictive of more severe psychopathol- a review, see Kapur & Remington, 1996). ogy; and it seems to herald a poor re- An indication of a link between EPS Lane, sponse to treatment. Moreover, it may Adrenergic agents: beta-blockers 1998) and the serotonergic system was be a contributing factor in the suicidal and clonidine provided by studies showing that selective and violent behaviour of patients with Later studies have demonstrated the anti- serotonin reuptake inhibitors SSRIs), which schizophrenia. Finally, the mental distress NIA efficacy of lipophilic beta-adrenergic apparently increase 5-HT neurotransmis- that often accompanies akathisia makes blockers. Propranolol remains one of the sion, have a propensity to induce EPS and it one of the most common reasons for most efficacious and well-tolerated thera- an `akathisia-like syndrome' Lane, 1998). non-adherence with antipsychotic drug peutic agents for NIA, and its beneficial Moreover, the novel atypical antipsychotic treatment.treatment. effect has been extended to other centrally agents, which display low propensity to acting non-selective beta-adrenergic recep- induce EPS and NIA, share at least one tor antagonists Adler et aletal, 1989).,1989). pharmacological property that distinguishes Clonidine, a selective aa-2adrenergic pre- them from typical neuroleptics ± a prepon- CURRENT TREATMENT synaptic agonist, can also improve NIA; derance of 5-HT2a2a receptor blockade over OF AKATHISIA however, its use is frequently complicated DD22 receptor antagonism. The affinity of by side-effects of sedation and hypotension. atypical antipsychotics to the various 5-HT The traditional recommended treatment The mechanism of the anti-NIA effect of receptor subtypes is shown in Table 1.) This approach to NIA consists of a reduction agents that reduce central noradrenergic property supports the use of agents with in the neuroleptic dosage, discontinuation transmission is still unclear, because marked 5-HT2a2a antagonistic effect in the of the culprit neuroleptic agent or akathisia is predominantly induced by treatment of NIA. 44 Downloaded from https://www.cambridge.org/core. 25 Sep 2021 at 12:06:33, subject to the Cambridge Core terms of use. PHARMACOTHERAPY FOR ACUTE AKATHISIA 11 TaTablbel e1 1 In vitro binding affinities Kii values in nM) of currently available atypical antipsychotics for 5-HT as well as antihistaminergic and aa-2antag- receptor subtypes onistic activity, without anticholinergic properties. So far, mianserin has been the most intensively investigated 5-HT an-an- 5-5-HHTT 5-5-HHTT 5-5-HHTT 5-5-HHTT 5-5-HHTT 2a/2c2a/2c 1a1a 2a2a 2c2c 33 66 tagonist in the treatment of acute NIA. ClozapineClozapine 145 9.613 108 4 Poyurovsky etetalal 1998), in a prelimin- RRiissppeerriidonedone 420 0.5248 4410 000425 ary open trial, treated 16 patients with Olanzapine 2720 2.5 7.184 2.5 acute NIA with low-dose mianserin 15 mg/day). A beneficial effect was de- Quetiapine 320 963800 4060 NA tected in 14 patients on the third day of Sertindole 280 0.391.9 3200 NA treatment, consisting primarily of the dis- 1. The lower the K ii values, the higher the affinity for the receptor. appearance of the subjective sense of inner KK inhibition constant. Modified from data based on Leysen et al,1996. ii restlessness, followed by a substantial decrease in the characteristic akathitic movements. The drug was well tolerated, and the only side-effect, mild sedation in RELEVANCE OF 5-HT Cyproheptadine five patients, was transient. These promis- RECEPTOR SUBTYPES TO ing preliminary results were confirmed in Cyproheptadine is a potent 5-HT2a2a andand PHARMACOTHERAPYOF NIA a double-blind placebo-controlled study 5-HT5-HT2c2c antagonist with additional anti- histaminergic and anticholinergic activity. by the same team Poyurovsky etetalal,, 5-HT22 antagonists Its anti-akathitic properties were explored 1999), wherein patients who met the The results of clinical trials with seroto- bybyWeissWeiss etetalal 1995) in an open clinical DSM±IV American Psychiatric Associa- nergic agents in the treatment of acute trial of 17 patients with acute NIA. The drug tion, 1994) criteria for acute NIA were ran- NIA are summarised in Table 2. Although was administered in a fixed oral dose of domly allocated to receive either low-dose there are no selective 5-HT antagonistsantagonists 2a2a 16 mg/day, in four divided doses for 4 days, mianserin 15 mg/day; nn15) or placebo available for clinical use, three compounds and the severity of akathisia was assessed nn15) once a day at 08.00 h) for 5 days. with pronounced 5-HT antagonistic activ- 2a2a with the Barnes Akathisia Scale BAS). The Treatment response was defined as a ity, ritanserin, cyproheptadine and mian- therapeutic effect of cyproheptadine was reduction of at least one point on the BAS serin, have been suggested as anti-akathisia pronounced and could be discerned already global sub-scale. Results indicated that 14 remedies.remedies. by Day 2of treatment. By Day 4, all 17 of the 15 patients treated with mianserin participants had improved to some degree, 93.3%) responded, compared with only five of the 11 patients 45.6%) given Ritanserin and 15 showed a more than50% reduction in the BAS score. In six patients, the NIA placebo who completed the trial. When a MillerMiller etetalal 1990) were among the first re- disappeared completely. The drug was well more rigorous response criterion was searchers to directly evaluate the putative tolerated, and side-effects of mild sedation, applied, namely, reduction of at least two anti-akathisia properties of ritanserin, an dry mouth and blurred vision occurred points on the BAS, the positive response agent with a pronounced 5-HT andand5-5- rate was 40% in the mianserin group and 2a2a only in those patients receiving concurrent HTHT antagonistic activity. In an open-label only 9.1% in the placebo group. Complete 2c2c anticholinergic medication. Although the study, they treated 10 patients with NIA contribution of cyproheptadine's sedative disappearance of the NIA occurred in four