Serotonin-Based Pharmacotherapy for Acute Neuroleptic-Induced Akathisia

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 efficacy 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.

Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:11:17, subject to the Cambridge Core terms of use. PHARMACOTHERAPY FOR ACUTE AKATHISIA

11 Ta b l e 11Tab 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-HT5-HT 5-HT5-HT 5-HT5-HT 5-HT5-HT 5-HT5-HT 2a/2c2a/2c 1a1a 2a2a 2c2c 33 66 tagonist in the treatment of acute NIA. ClozapineClozapine 145 9.613 108 4 Poyurovsky et aletal 1998), in a prelimin- RisperidoneRisperidone 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 antihistaminergic and anticholinergic activity. by the same team Poyurovsky et aletal,, 5-HT22 antagonists Its anti-akathitic properties were explored 1999), wherein patients who met the The results of clinical trials with seroto- by WeissbyWeiss et aletal 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 et aletal 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 and 5-and5- 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 with ritanserin 5±20 mg/day) and noted a action to its anti-akathitic effect cannot patients in the mianserin group 26.6%) reduction of more than 50% in the be disregarded, it seems unlikely that the but in none of the placebo group. More- Hillside Akathisia Scale score in six of them robust improvement in the akathisia was over, the beneficial effect of mianserin and a reduction close to 50% in two others. due solely to a non-specific sedative effect. was accompanied by a corresponding re- Only two of the 10 patients did not re- These encouraging preliminary results have duction in neuroleptic-induced dysphoria spond. The effect of ritanserin was rapid recently been replicated in a double-blindblinddouble- and psychotic symptoms, indicating an and cliniandclinicallycally significant, and no signifi- comparison study of cyproheptadine nn18, association between these clinical phenom- cant side-cantside-effectseffects were noted. The same 16 mg/day) and propranolol nn12,12,8080 mg/ ena and akathisia. By contrast, mianserin group of investigators Miller et aletal, 1992),1992) day) in patients with acute NIA Fischel had no effect on concurrent symptoms of subsequently reported a beneficial effect of et aletal, 2001). Both drugs demonstrated neuroleptic-induced parkinsonism in these ritanserin 10 mg twice daily) in three significant anti-NIA activity 46% v.v. 42%42% NIA patients. Furthermore, the response patients with NIA who had a proven resis- decrease in the BAS score, respectively) rate for mianserin 40%) and the mean rate tance to anticholinergics, benzodiazepines within 4 days of treatment. In contrast to of reduction in akathisia scores 52.2%) and beta-blockers. A large-scale placebo- findings in NIA, the benefit of cypro- reported by our group Poyurovsky et aletal,, controlled study is still necessary to heptadine in the treatment of neuroleptic- 1999) were similar to those for the substantiate these important preliminary induced parkinsonism is far from conclusive. currently used anti-NIA compounds, pro- findings.findings. pranolol and benzatropine Adler et aletal,, Data on the efficacy of ritanserin in 1989). Our studies Poyurovsky et aletal,, other movement disorders, such as Mianserin 1998, 1999) confirmed the tolerability neuroleptic-induced parkinsonism, are less Mianserin is a tetracyclic antidepressant and safety of low-dose mianserin; mild,

consistent.consistent. with marked 5-HT2a2a and 5-HTand5-HT2c2c antagonism transient sedation and clinically irrelevant

Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:11:17, subject to the Cambridge Core terms of use. POYUROVSKY & WEIZMAN 5/11 in placebo group 5/11 in placebo group v. disappearance of NIA were efficacious 40 and 42% decrease in BAS, respectively) worse 2/10 improved v. disappearance of NIA were efficacious 40 and 42% decrease in BAS, respectively) worse 2/10 improved Improved 14/15 of mianserin group improved 8/10 improved Improvement in all three BAS sub-scales 3/3 improved Both cyproheptadine and propanolol 2/10 improved, 6/10 unchanged, 2/10 Resistant NIA, 3/3 improved 3/10 dropouts, 5/10 unchanged, Improved 14/15 of mianserin group improved Results 15/17 improved; 6/17 complete Both cyproheptadine and propanolol Improvement in all three BAS sub-scales 3/3 improved 2/10 improved, 6/10 unchanged, 2/10 Resistant NIA, 3/3 improved 8/10 improved 3/10 dropouts, 5/10 unchanged, HRSDHRSD HRSDHRSD Outcome measures BAS, SAS BAS, SAS, BPRS, mLAS, BAS, BPRS, SAS BAS, SAS Outcome measures Results HAS, BPRS, HRSD, AIMS 15/17 improved; 6/17 complete BAS, SAS HAS, CGI HAS, CGI BAS, SAS, mLAS, BPRS, 0 2 0 6 6 5 5 2 BAS, SAS, mLAS, BPRS, 15 ^ 15 BAS, SAS 15 BAS, SAS, BPRS, mLAS, 15 BAS, SAS 16 BAS, BPRS, SAS 16 HAS, BPRS, HRSD, AIMS 20 HAS, CGI 5^20 HAS, CGI Dose Dose 10^15 10^30 BAS, SAS mg/day) mg/day) Rating Scale for Depression; SAS, Simpson and Angus Scale for extrapyramidal side-effects; 5 4 4 4 3 4 41 51 41 41 410^30 32 35 42 14 14 TreatmentTreatment Not reported Not reported 10^15 duration days) duration days) 14 3 33 5 paeo5placebo 15 placebo15 12 propanolol nn 15 mianserin 18 cyproheptadine 12 propanolol 16 17 10 10 10 Mirtazapine Cyproheptadine Serotonergic Buspirone agent Ritanserin Mirtazapine 1 Mianserin 15 mianserin Cyproheptadine 18 cyproheptadine Mianserin 16 Cyproheptadine 17 Buspirone 10 Buspirone 3 Ritanserin 3 Ritanserin 10 Serotonergic agent Granisetron 10 placebo placebo Mianserin v.v. propanololpropanolol v. v. Double blind trial Open trial obebidtrial Double-blind Open trial Case reports Case reports Open trial Study design Double blind trial Open trialMianserin Double-blind trial Open trialCyproheptadine Open trialBuspirone Case reports Case reports Open trialRitanserin Study design Open trialGranisetron , 1998,1998 , 1999 , 1999 , 1989,1989 et aletal et aletal 2001) 2001) , 1992,1992 , 1990,1990 , 1995 , 1995 et aletal Reports on the efficacy of NIA) akathisia agents in serotonergic patients with neuroleptic-induced Reports on the efficacy of serotonergic agents in patients with neuroleptic-induced akathisia NIA) et aletal et aletal et aletal et aletal antagonists antagonists antagonistantagonist partialagonists partialagonists 2a 33 2a 11 ouosy&Poyurovsky Weizman 2001) FischelFischel Poyurovsky Poyurovsky Poyurovsky & Weizman, 1997 Weiss D'Mello MillerMiller MillerMiller Poyurovsky & Weizman, 1999 ouosy&Wimn01 aerprCs report &Poyurovsky Weizman 2001) Case reportCase Poyurovsky Poyurovsky Poyurovsky & Weizman, 1997 Open trial Weiss D'Mello Poyurovsky & Weizman, 1999 Open trial 5-HT5-HT 5-HT5-HT 5-HT5-HT mLAS, modified Leeds Anxiety Scale. Ta b l e 2 Reference Scale;HAS, Akathisia Hillside Clinical Global CGI, BAS, Impression; Barnes Scale; Akathisia BPRS, BriefRating Scale; Psychiatric Rating Hamilton Scale HRSD, for SAS, Depression; Simpson and Angus Scale side-effects; for extrapyramidal mLAS, modified Leeds Anxiety Scale. Reference A,Hlsd ktii Scale;HAS, Akathisia Hillside Clinical Global CGI, BAS, Impression; Barnes Scale; Akathisia BPRS, BriefRating Scale; Psychiatric Hamilton HRSD, Ta b l e 2

Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:11:17, subject to the Cambridge Core terms of use. PHARMACOTHERAPY FOR ACUTE AKATHISIA

orthostatic hypotension were the only side- at the 5-HT1a1a receptor. Thus, it is possible SUMMARYAND CLINICAL effects. In a recent case report, mirtazapine, that it is their predominantly antagonistic IMPLICATIONS a tetracyclic antidepressant structurally and activity rather than their agonistic activity

pharmacologically similar to mianserin, an at the presynaptic 5-HT1a1a receptor that Overall, the results of the systematic

agent with 5-HT2a/2c2a/2c and 5-HTand5-HT33 antagon-antagon- contributes to their anti-akathitic effect. evaluation of serotonin-active agents with istic properties, was also found to possess Further research is needed in this area. predominant affinity for different subtypes anti-akathisia activity Poyurovsky & of 5-HT receptors indicate that within the

Weizman, 2001). 5-HT system, the 5-HT2a2a receptors rather

than the other subtypes e.g. 5-HT1a1a andand

5-HT5-HT33) are involved in the pharmacotherapy of acute NIA. In at least some patients with 5-HT5-HT33 ANTAGONISTS acute NIA, 5-HT post-synaptic antagon- 5-HT5-HT1a1a PARTIAL AGONISTS 2a2a Granisetron ism ritanserin, cyproheptadine, mianserin) BuspironeBuspirone Since mianserin, mirtazapine and some rather than a presynaptic 5-HT1a1a modu-modu- Despite the encouraging results reported for novel atypical antipsychotics also possess latory effect buspirone) or post-synaptic

5-HT5-HT2a2a antagonists, these agents fail to 5-HT5-HT33 antagonistic properties Richelson, 5-HT5-HT33 antagonism granisetron) might be

yield a response in a substantial proportion 1996), it is possible that 5-HT33 blockadeblockade required to produce a rapid and efficient of NIA patients. Furthermore, some studies may play a role in the anti-akathitic effect. anti-NIA effect. of atypical novel antipsychotics have found However, this was disproved in a study of Currently, the treatment of acute NIA

that despite their high 5-HT2a2a receptor occu- 10 patients with acute NIA treated with involves two major strategies: the modifi-

pancy rate 4490%), they can still induce the 5-HTthe5-HT33 receptor antagonist granisetron cation of the antipsychotic drug regimen EPS and akathisia. This suggests that the 2mg/day for 4 days) Poyurovsky & and/or the addition of anti-akathisia agents.

protective action of 5-HT2a2a blockers against Weizman, 1999). Three of the patients dis- Today, the traditional approach of a reduc-

akathisia due to D22 blockade may not be continued the drug because of lack of re- tion in neuroleptic dosage and a switch to a universal, and other pathophysiological sponse, and the remainder showed no low-potency conventional neuroleptic e.g. mechanisms may be involved Kapur & significant change in BAS score during the thioridazine) is followed, as necessary, by Remington, 1996). Extensive evidence trial. The symptoms of NIA remained un- a switch to a novel atypical antipsychotic

indicates that 5-HT1a1a receptor antagonists changed or worsened in five patients e.g. risperidone, olanzapine, quetiapine,

have effects similar to 5-HT2a2a receptorreceptor 71.4%) and showed insignificant improve- ziprasidone), and finally, initiation of cloza-

antagonists in a variety of systems Meltzer, ment in two. It seems that 5-HT33 antago-antago- pine see Fig. 1). When the decision is made 1999).1999). nists are of limited value in the treatment to initiate an anti-akathisia compound, the Buspirone, an azaperone, acting as a of acute NIA. beta-adrenergic blocking agent propranolol

partial agonist of 5-HT1a1a somatodendritic and terminal autoreceptors, appears to in- hibit the firing of 5-HT neurons located in the median and dorsal raphe nuclei. The inhibitory effect of buspirone on 5-HT neuro- transmission might disinhibit dopamine release and counteract the dopamine blockade induced by neuroleptics D'Mello et aletal,, 1989). However, in a more recent open- label short-term clinical trial, buspirone 15±30 mg/day for 4 days) exerted a mod- erate therapeutic effect in only two out of 10 NIA patients Poyurovsky & Weizman, 1997). Furthermore, seven of the eight buspirone non-responders who were subsequently switched to mianserin 15 mg/ day) showed an improvement; in five of them, the NIA completely disappeared. The open nature of this study, the small sample size and the short duration of treatment precluded definitive conclusions. Furthermore, new evidence of cross-talk of

the 5-HTthe5-HT1a1a receptor with the 5-HT1a1a withwith

the 5-HTthe5-HT2a2a receptors Meltzer, 1999), makes buspirone's lack of anti-akathitic effect even more surprising. Along the same lines, beta-beta-lines, blockers, which are well-documented anti- akathisia agents, exhibit antagonistic activity Fig. 11Fig. Therapeutic options for acute neuroleptic-induced akathisia.

Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:11:17, subject to the Cambridge Core terms of use. POYUROVSKY & WEIZMAN

40±120 mg/day) or a 5-HT antagonistantagonist 2a2a MICHAELMICHAELPOYUROVSKY,TiratCarmelMentalHealthCenterandFacultyofMedicine,IsraelInstituteof POYUROVSKY,Tirat Carmel Mental Health Center and Faculty of Medicine, Israel Institute of mianserin, 15±30 mg/day, cyproheptadine Technology 1Technion), Haifa, Israel; ABRAHAM WEIZMAN, Felsenstein Medical Research Center and Geha 8±16 mg/day, or ritanserin 5±20 mg/day) Psychiatric Hospital, PetahTiqva, and Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel are the first choices. In cases of NIA associated with neuroleptic-induced parkinson- CorrespCorrespondence:ondence: A.Weizman,Research Unit,Geha Psychiatric Hospital,PO Box102,PetahTiqva 49100, ism, priority may be given to anticholinergic Israel.Tel: +972 3 9258290;9258290;Fax: Fax: +972 3 9241041; e-mail: weizmana@@post.tau.ac.il agents biperiden 4±12mg/day, benzatro- 1First received12received 12 April 2000, finalrevision1Novemberfinal revision 1November 2000, accepted 22 January 2001) pine 1.5±8 mg/day or trihexyphenidyl 2± 10 mg/day), although their efficacy is still controversial. A benzodiazepine lorazepam 2mg/day, clonazepam 0.5 mg/day, new line of thought, some researchers sug- Lane, R. M. )1998) SSRI-induced extrapyramidal or diazepam 5±15 mg/day) may need to be gest that antipsychotic agents with `loose' side-effects and akathisia: implications for treatment. Journal of Psychopharmacology,, 12,192^214. added to propranolol or an anticholinergic binding of the dopamine D22 receptor e.g. compound to provide additional anxiolytic clozapine and quetiapine) may exhibit a Leysen, J. E., Gommeren,W. & Shotte, A. )1996) Serotonin receptor subtypes: possible roles and or sedative effects, especially in patients lesser propensity to provoke EPS and applications in antipsychotic drug action. In Serotonin in with subjective distress. It seems that the akathisia Seeman & Tallerico, 1998). A AntipsychoticTreatment. Mechanisms and Clinical Practice addition of a benzodiazepine to the avail- promising direction is the development of 1eds J.M.Kane,J. M.Kane,H.-J. H.-J.Moller Moller & F.Awouters),F. Awouters), pp. 51^75. New York: Marcel Dekker. able 5-HTable5-HT2a2a antagonists should be avoided new EPS-sparing antipsychotic agents owing to the sedative effects of both com- possessing this specific pharmacodynamic Meltzer,H.Y.)1999)Meltzer, H. Y. )1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology,, 2121 pounds. If all these agents are ineffective, property.property. 1suppl. 2),106S^115S.2), 106S ^115S. amantadine or clonidine can be tried. The Miller,G. H., Fleischhacker,W.W., Ehrman, H., et aletal suggested guidelines are summarised in ACKNOWLEDGEMENTS )19 9 0) Treatment of neuroleptic-induced akathisia with

Fig. 1.Fig.1. the 5-HT5-HTthe 22 antagonist ritanserin. Psychopharmacology BulletinBulletin,, 2626, 373^376.,373^376. We wish to thank Professor Thomas R. E. Barnes for FUTURE DIRECTIONS his useful comments and Gloria Ginzach, Marian Miller,Miller,C. C. H., Hummer, M., Pycha R., et aletal )19 92) The Propp and Rena Kurs for their editorial and secre- effect of ritanserin on treatment-resistant neuroleptic- tarial assistance.We also thank the Sarah and Moshe induced akathisia: case reports. Progress in Neuro- The rapid increase in the number of identi- Psychopharmacology and Biological Psychiatry,, 1616,, Mayer Foundation for their support. fied 5-HT receptor subtypes has prompted 247^251.247^251. a new hypothesis regarding their involve- Poyurovsky, M. & Weizman, A. )1997) Serotonergic ment in the development of NIA and the REFERENCES agents in the treatment of acute neuroleptic-induced akathisia: open-label study of buspirone and mianserin. anti-NIA activity of putative anti-akathisia Adler, L. A., Angrist, B., Retter, S., et aletal )19 8 9) International Clinical Psychopharmacology,, 1212, 263^268. compounds. Recent studies have demon- Neuroleptic-induced akathisia: a review. && __ )1999))19 9 9) Lack of efficacy of the 5-HT receptor Psychopharmacology,, 9797,,1^11. 1 ^ 11. __ 33 strated a high affinity of some of the novel antagonist granisetron in the treatment of acute atypical antipsychotics, primarily cloza- American Psychiatric Association )1994) Diagnostic neuroleptic-induced akathisia. International Clinical and Statistical Manual of Mental Disorders 14th edn) Psychopharmacology,, 1414,,357^360. 357^360. pine, to the molecularly cloned 5-HT66 1DSM^IV).Washington, DC: APA. receptor. Because of the abundance of __ && __ )2001))2001) Low dose mirtazapine ameliorates acute Barnes, T. R. E. )1989) A rating scale for drug-induced neuroleptic-induced akathisia 1letter). American Journal 5-HT5-HT66 receptors in the striatum and limbic akathisia. British Journal of Psychiatry,, 154,672^676., 672^676. of Psychiatry,inpress., in press. system, it may be the ability of at least some of the atypical antipsychotics to interact __ & McPhillips, M. A. )1999) Critical analysis and __ , Fuchs, C. & Weizman, A. )1998) Low-doseLow-dose comparison of the side-effect and safety profiles of the mianserin in the treatment of acute neuroleptic-induced with the 5-HT66 receptor that contributes to new antipsychotics. British Journal of Psychiatry,, 174 akathisia.akathisia. Journal of Clinical Psychopharmacology,, 1818,, the lack of EPS Meltzer, 1999). The future 1suppl. 38), 34^43. 253^254. use of selective 5-HT receptor agents may 66 D'Mello, D. A., McNeil, J. A. & Harris,Harris,W. W. )1989) __ , Shardorodsky, M., Fuchs, C., et aletal )1999))1999) clarify the role of 5-HT66 in the pathophysiol- Buspirone suppression of neuroleptic-induced akathisia: Treatment of neuroleptic-induced akathisia with the 5- HT antagonist mianserin. Double-blind, placebo- ogy and pharmacotherapy of neuroleptic- multiple case reports 1letter). Journal of Clinical 22 Psychopharmacology,, 99,151^152. controlled study. British Journal of Psychiatry,, 174174,, induced EPS and akathisia. 238^242.238^242. Non-serotonergic receptor mechanisms Fischel,T., Hermesh, H., Alzenberg, D., et aletal )2001))2001) Cyproheptadine vs. propranolol for the treatment of Richelson, E. )1996) Preclinical pharmacology of also apparently play a critical role in the acute neuroleptic-induced akathisia: A comparative neuroleptics; focus on new generation compounds. development of EPS and NIA and may be double-blind study. Journal of Clinical Journal of Clinical Psychiatry,, 5757 1suppl. 11), 44^10. ^ 10. Psychopharmacology, in press.press.,in relevant in the search for new, potentially Seeman, P. & Tallerico,Tallerico,T. T. )1998) Antipsychotic drugs active anti-EPS compounds. A sub-threshold Fleischhacker,W.W., Roth, S. D. & Kane, J. M. )1990) which elicit little or no parkinsonism bind more loosely The pharmacologic treatment of neuroleptic-induced than dopamine to brain D receptors yet occupy high level level5575%) of DD75%)of receptor occupancy at 22 22 akathisia. Journal of Clinical Psychopharmacology,, 1010,, levels of these receptors. Molecular Psychiatry,, 33,, clinically relevant doses e.g. clozapine, low- 12^21. 123^134. doses of risperidone) may be the reason for Kapur, S. & Remington, G. )1996) Serotonin ^^Serotonin Weiss, D., Aizenberg, D., Hermesh, H., et aletal )19 95) freedom from EPS Kapur & Remington, dopamine interaction and its relevance to schizophrenia. Cyproheptadine treatment in neuroleptic-induced 1996). Furthermore, along an intriguing American Journal of Psychiatry,, 153,,466^476. 466^476. akathisia.akathisia. British Journal of Psychiatry,, 167167,483^486., 483^486.

Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 03:11:17, subject to the Cambridge Core terms of use.