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Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs

  • Michael J. Peluso (a1), Shôn W. Lewis (a2), Thomas R. E. Barnes (a3) and Peter B. Jones (a4)



Second-generation antipsychotics have been thought to cause fewer extrapyramidal side-effects (EPS) than first-generation antipsychotics, but recent pragmatic trials have indicated equivalence.


To determine whether second-generation antipsychotics had better outcomes in terms of EPS than first-generation drugs.


We conducted an intention-to-treat, secondary analysis of data from an earlier randomised controlled trial (n = 227). A clinically significant difference was defined as double or half the symptoms in groups prescribed first- v. second-generation antipsychotics, represented by odds ratios greater than 2.0 (indicating advantage for first-generation drugs) or less than 0.5 (indicating advantage for the newer drugs). We also examined EPS in terms of symptoms emergent at 12 weeks and 52 weeks, and symptoms that had resolved at these time points.


At baseline those randomised to the first-generation antipsychotic group (n = 118) had similar EPS to the second-generation group (n = 109). Indications of resolved Parkinsonism (OR = 0.5) and akathisia (OR = 0.4) and increased tardive dyskinesia (OR = 2.2) in the second-generation drug group at 12 weeks were not statistically significant and the effects were not present by 52 weeks. Patients in the second-generation group were dramatically (30-fold) less likely to be prescribed adjunctive anticholinergic medication, despite equivalence in terms of EPS.


The expected improvement in EPS profiles for participants randomised to second-generation drugs was not found; the prognosis over 1 year of those in the first-generation arm was no worse in these terms. The place of careful prescription of first-generation drugs in contemporary practice remains to be defined, potentially improving clinical effectiveness and avoiding life-shortening metabolic disturbances in some patients currently treated with the narrow range of second-generation antipsychotics used in routine practice. This has educational implications because a generation of psychiatrists now has little or no experience with first-generation antipsychotic prescription.

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Corresponding author

Mr Michael J. Peluso, Harkness Hill, ESH 219, 367 Cedar Street, New Haven, CT 06510, USA. Email:


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The Cost Utility of the Latest Antipsychotics in Schizophrenia Studies (CUtLASS) 1 and 2 were commissioned by the National Health Service Health Technology Assessment Programme.

Declaration of interest

In the past 3 years S.W.L. has received advisory board fees from Janssen-Cilag and speaker fees from AstraZeneca; T.R.E.B. has acted as a speaker at an event sponsored by Lilly; P.B.J. declares membership of a scientific advisory board for Roche, and has received research support from GlaxoSmithKline and a speaker fee from Lilly.



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Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs

  • Michael J. Peluso (a1), Shôn W. Lewis (a2), Thomas R. E. Barnes (a3) and Peter B. Jones (a4)


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Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs

  • Michael J. Peluso (a1), Shôn W. Lewis (a2), Thomas R. E. Barnes (a3) and Peter B. Jones (a4)
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"Second Generation Antipsychotics" and Developing Countries- Sri Lankan Experience

K.A.L.A. Kuruppuarachchi, Professor of Psychiatry
21 July 2012

The article on Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs (Peluso et al. 2012) has been read with concern.

First generation antipsychotics had been routinely prescribed all over the world a few decades ago whereas they have been continued to be used in the developing countries such as Sri Lanka until recently.

As we normally follow the prescribing guidelines such as NICE, FDA, Maudsley Guidelines we are also naturally bound to adhere to the contemporary practice in the west. Even though the original brands of second generation antipsychotics produced in the developed countries are more expensive there are cheap affordable brands coming mainly from India available in countries such as Sri Lanka. Hence clinicians are tempted to prescribe more and more second generation antipsychotics. Even in countries such as Sri Lanka many trainees are not very familiar with usingfirst generation anti-psychotics as the clinicians tend to prescribe second generation anti-psychotics for a variety of clinical conditions.

Globally it seems that there is a rising tendency of prescribing moreand more second generation antipsychotics for other clinical conditions such as anxiety disorders, mood disorders and child psychiatric problems. The increasing tendency of psychotropic usage amongst the very young has also been highlighted and the need for guidelines has been discussed( Gleason et al. 2007). Also the increasing trend in second generation antipsychotic prescription for anxiety disorders has been shown( Comer etal. 2011).

Clinicians note that a considerable number of patients who received first generation antipsychotics such as Haloperidol, Trifluoperazine needed anticholinergics most of the time in order to counteract the extrapyramidal side effects. If we do studies including a bulk of patientswho received high potency first generation antipsychotics such as Haloperidol compared with the second generation antipsychotics the outcome( Extrapyramidal Side Effect Profile) might be different.

Even though there is an increasing trend in prescribing second generation antipsychotics even in our part of the world it is also interesting to note that some clinicians in countries like Sri Lanka still prefer to prescribe conventional anti psychotics such as Haloperidol, Trifluoperazine, Chlorpromazine for special group of patients like the pregnant and lactating mothers as they seem to be more familiar with their side effect profile and comfortable of using them.

It is clear that we are going to prescribe more and more psychotropicmedication for a variety of psychiatric ailments. The benefits of proper prescribing of psychotropic medication in psychiatry have been addressed (Harrison et al. 2011).

Another important area note worthy in prescribing psychotropic medication is the necessity to pay attention to "Ethno-Psychopharmacology". Efficacy and the side effect profile may be different amongst various ethnic groups. Pharmacogenetic variations between Asians and other ethnic groups have been highlighted (Pi and Zhu 2007). We need to be aware of the beneficial effects /advantages of "Second Generation Antipsychotics" such as their mood stabilizing properties, anxiolytic properties etc in addition to antipsychotic properties.

However it is worthwhile reducing the fears/uncertainties of prescribing "First Generation Antipsychotics" amongst the clinicians by educating them further and perhaps considering revising the existing prescribing guidelines as the general assumption is that there are more side effects(particularly extrapyramidal) with first generation antipsychotics which result in poor compliance etc. Perhaps we need to domore research work comparing more potent first generation antipsychotics which were widely prescribed such as Haoperdol, Trifluoperazine etc. withsecond generation antipsychotics.


Peluso MJ, Lewis SW, Barnes TRE, Jones PB. Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs. The British Journal of Psychiatry 2012; 200:387-392.

Gleason MM, Egger HL, Emslie GJ, Greenhill LL, Kowatch RA et al. Psychopharmacological Treatment for Very Young Children : Contexts and Guidelines. J. Am. Acad. Child Adolesc. Psychiatry 2007; 46(12):1532-1572.

Comer JS, Mojtabai R, Olfson M. National Trends in the Antipsychotic Treatment of Psychiatric Outpatients With Anxiety Disorders. American Journal of Psychiatry 2011; 168:1057-1065.

Harrison PJ, Baldwin DS, Barnes TRE, Burns T, Ebmeier KP et al. No psychiatry without psychopharmacology. The British Journal of Psychiatry 2011; 199:263-265.

Pi EH, Zhu W. New research advances in ethno-psychopharmacology: an Asian perspective. International Psychiatry 2007; 4(3):57-58.

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Conflict of interest: None declared

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Extrapyramidal motor side-effects and first generation antipsychotics: Are second generation agents still indicated?

Henk S Temmingh, FCPsych(SA), MMed(Psych), Consultant psychiatrist and lecturer, acute adult admissions unit
06 June 2012

Peluso et. al report on the differential effect of first generation antipsychotics (FGA's) versus second generation antipsychotics (SGA's) in ameliorating or exacerbating extrapyramidal side effects (EPS) in a secondary analysis of the CUtLASS-1 trial data(1). They report their findings as "essentially null" and mention that there is weak evidence forclinically significant differences in emergent or relieved EPS between FGA's and SGA's. These findings, although based on a secondary analysis, pose interesting and important challenges for the focus of future researchinto antipsychotics, but also raise some questions about the interpretation of negative study findings.

The majority of participants (49%) in the FGA group were prescribed sulpiride, a substituted benzamide that has been demonstrated in a meta-analysis to have a significantly lower propensity to cause EPS compared toother FGA's (2). It could be argued that it would not be unusual to find little differences in the two groups as the FGA group was biased toward sulpiride selection.

An a priori odds ratio of 2 and 0.5 was selected as clinically relevant, but no reason is given for this choice. The choice of this cut-off seems arbitrary. The authors conclude that their results are "essentially null" and that these two classes of drugs could be used with equivalence in EPS. Although equivalence is possible, failure to reject the null hypothesis does not imply that the null hypothesis is true or that treatments are equal (3). Failure to reject the null at this effect size means that the null would not be surprising at this particular value (4). However given a power of 78%, this implies a relatively high chance (22%) of a type II error. In some cases even a reduction of 20% in EPS occurrence can be clinically meaningful. The CUtLASS study would be underpowered even if a true effect existed at this effect size. Confidence limits around the EPS outcomes also appear to be wide at a number of time points. Although negative findings in superiority trials are important to report, it should be noted that some may argue that meaningful scientific evidence centres on replicated falsification.

In turn, the dichotomization of EPS outcome measures instead of usingchanges in continuous EPS scores over multiple time points in a longitudinal design and analysis strategy could potentially underestimate any treatment effect.

Nevertheless, these findings raise important points for the design ofsuperiority trials. Given the lack of superior efficacy in symptom relief of most SGA's, if the presence of EPS has become the sine qua non for treatment switches to SGA's, would this not highlight the importance of adequately powered trials where the primary outcome would be EPS? In addition in trials where EPS is only a secondary outcome, as is commonplace, that this outcome be adequately powered at well motivated, pre-agreed effect sizes? Although of global importance in the current economic climate, this would be particularly important for the developing world where funding authorities meticulously scrutinize the benefits of more expensive treatments.

Reference List

(1) Peluso MJ, Lewis SW, Barnes TR, Jones PB. Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs. Br J Psychiatry 2012 May;200:387-92.

(2) Soares BG, Fenton M, Chue P. Sulpiride for schizophrenia. Cochrane Database Syst Rev 2000;(2):CD001162.

(3) Nickerson RS. Null hypothesis significance testing: a review of an old and continuing controversy. Psychol Methods 2000 Jun;5(2):241-301.

(4) Aberson C. Interpreting null results: Improving presentation andconclusions with confidence intervals. Journal of Articles in Support of the Null Hypothesis 2002;1(3):36.

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Conflict of interest: None declared

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