Eur Arch Psychialry Clin Neurosci (2006)

ORIGINAL PAPER

Jose de Leon

DOl 10.1007/s00406-006-0705-z

The effect of atypical versus typical antipsychotics on tardivedyskinesiaAnaturalistic study

Recrived: 3t May 20061 ACupted: 18 October 20061 Published onli~ 5 Decembrr 2006

• Abstract Objective The aim was testing whetheratypical antipsychotics (versus typicals) were associ­ated with less risk of tardive dyskinesia (TO) in 516severely mentally ill patients. Methods The sampleincluded 11% (57/516) with no exposure before currenttreatment wilh atypicals; 9% (48/516) with prior andcurrent treatment with atypicals but no exposure totypicals; 18% (94/516) with lifetime exposure to typi­cals for <5 years (plus atypicals); and 62% (317/516)with lifetime exposure to typicals for ~5 years (plusatypicals). The Abnormal Involuntary Movement Scale(AlMS) was used to assess dyskinetic movements.Following Schooler and Kane's criteria TO was con­sidered present when mild movements were present inat least two body areas or moderate movements werepresent in at least one body area. Results TO preva­lences were 5% (3/57) in previously naive patients, 19%(9/48) after exposure only to atypicals, 19% (18/94)after typical exposure of <5 years, and 42% (132/317)after typical exposure of;;::5 years. There was no sig~

nificant effect comparing those taking only atypicals tothose exposed to typicals for <5 years (OR = 1.0, CI0.42-2.5). Conclusion This study is limited by thenaturalistic design, the relatively small samples in thefirst two groups, the lack of information on the dura­tion of the atypicals and their relatively recent intro­duction to the market (ziprasidone and aripiprazolewere introduced to the market in the middle of the

J. de Leon, MD (0)MenIal Health Research Center at EMtern State HospitalUniversity of Kentucky627 West Fourth St.Lexington, KY 40508, USATel.; +1·8591246-7487Fax: +1·859n46-7019E-Mail; jdeleonthky.edu

J. de LeonDepartment of Psychiatry and Institute of NeurosciencesUniversity of GranadaGranada, Spain

study). This study raises the question that new TDstudies need to establish whether decades of treatmentwith atypical antipsychotics make a difference.

• Key words tardive dyskinesia' atypical antipsy­choties . typical antipsychotics . case-control study

Introduction

The review of the atypical antipsychotic trials whichhave used typical antipsychotics as a comparisonsuggests that atypical antipsychotics tend to be asso­ciated with less reversible extrapyramidal symptoms[5] and with less propensity to cause tardive dyski­nesia (TO) [I], particularly in elderly subjects 16]. Alongitudinal study in 240 outpatients also showed lessTO with atypicals than with typical antipsychotics [3}.However, a recent large naturalistic study in more than20,000 geriatric patients suggested that in the clinicalenvironment, and in older patients who have morerisk of developing TD, it might not be possible to see adifference between the effects of typicals and atypicalsin the development of TO [4}. In summary, the liter­ature appears to suggest that when the more controlledstudies are considered, atypicals may be less prone tocause TO. One has to acknowledge that some of thesestudies may have short-term follow-ups and be fundedby pharmaceutical companies. On the other hand, it isnot clear that naturalistic studies, looking at effec­tiveness in the real world, may be able to find TOdifferences between typical and atypical antipsychot­ics in the midst of the noisy clinical environment.

The aim of these analyses is to test whether atypicalantipsychotics are associated with lower TO preva- !:lence when compared with typical antipsychotics in a <"lz"previously published naturalistic cross-sectionalstudy of 516 severely mentally ill patients [2). 51

Table 1 Prevalen(es and <ategorical odd! ratio! (OR) according to antipsychotic intake

Patirots • % ddju5ted for GlIegorial OR eategori(al 011 adjust(oofounders "''''''-

Naive S (3/S1) 54.2 (01.1-16.3)' 4.3 ((I 1.H7.4)d

Only taken atypkals 19 (9/48) 18Sh

1.0 (0 0.42_lS)b 1.2 ((I 0.46-2.8)"Typkals for <5 years 19 (18194) 21.41

3.0" (O 1.1-5.3)' 239 (a 13-411'Typkals for ~ years 42 (1321317)38.9 38.9

• Wald 41. df _ 1, P= 0.04. It (~res patients who IIave only taken atypicals YS. !hosf' who nave l1f'Yef been treated on anlips)'(hotio (naive) before thisatypKal trialb Wald 0.003, df = 1, P= 0.95. It rompar~ patients who have also taken IypiGlIs for <5 years Yef5US those who have only taken atypiQls'Wald 14.9. df = 1, P < 0.001. II rompar~ patients who ha'l'e taken typKals for 25 years Yef5US those who have taken typicals for <5 years• Wald 41. df = 1, P= 0.04. II rornpare patients who have only taken atypicals Yef5US those who have never been treated on anlipsydlotio (naive) befono thisatypical trial• Wald 0.089. df = 1, P = 0.16. IIc~ patients who haW' also taken typials fOI" <S years vmus those who haW' only taken atypkalsI Wald 8.1, df = 1, P = 0.005.11 cornpar~ patients who have taken typicals for 2'5 years versus those who haW' taken typicals for <S)'tJrS, The deuuse of the OR from 3.0 to 2.3 ptobab/y refIeas the (Oflfounding effects of variab1e'5 on TO. As a maltef of fact, only Idling the variable '9l' > 45 years,by melt, ausa:! the OR to decre.ase from 3.0 10 2.6• The adjusted prevalence WitS (omputed by P = mt(1 + m) x 100 = 185. where m = 43 x (0.DS/{1 - O.DS)) = 0.226. This computation asstrneS Nt the S""prevalence wrresponding to the naive group was not substantially affected by (OflfouOOen. The (ornputation is based on the definition of odds (= plO - pI, wherep is the ~usted previlen(e for the group of patients who are taken only atypicals Iivided by 100), so thaI the adjusted OR is~I to 43 = (p/(1 - pIli (0.051(l - 0.05)). SoMng this ~tion for p, we obtain the fornwla usa:!I The adjusted prevalence WitS (omputed by P = mt(1 + m)( 100. where m = 1.2 x (0.1851(1 - 0.185)j The adjusted prevaleoce was computed by P = mI(l + m) x 100. where m = 2J x (0.2141(1 - 0114))

Methods

The sample of 516 inpatients and ourpatienlS from tentra1 Ken­tlKky facilities has been described before and wu coUected in theconten of a pharmacogenetic sludy 121. The mean (SO) was 42.4(12.8) years of age, 26.6 (11.4) years of age at the onset of psychi­atric medication, 15.8 (11.6) years of dunuion on psychiatricmedications, 11.3 (11.3) years of duration on typical antipsychotics.and 383 (391) chlorpromazine equivalenls as th~ daily antipsy­chotic dose. The most frequent antipsychotics were risperidone.65% (3341516); olan~apine, 11'1f1 (851516); typicals, 14% (701516),and quetiapine. 13% (691516). All have taken at least one atypicalantipsychotic at some point in their life. The sample induded 46%(238/516) females, 32% (1531516) age 45 years or more, 79% (4091516) who had ever taken typical antipsychotics, 61% (317/516) whohad taken typical antipsychotic.s for five or more years, and 11%(57/516) who had never taken anlipsychotics before. Diagnoseswere dinical OSM-IV diagnoses made by the treating physician.The most frequent were schizophrenic disorders, 49% (schizo­phrenia 29%,1501516, and schi~oaffective disorders, 20%,105(516),and mood disorders, 29% (bipolar disorders 18%, 931516, andmajor depressive disorders, 11%, 581516).

The Abnormal lnvoluntary Movement Scale (AIMS) was usedto assess dyskinetic movements. The highest single score amongthe seven body areas was considered the global severity soore.Three quarters of the ratings were conducted by the author andone quarter independently by two experienced research nurses.Inter-rater reliabilities of the three raters have been described [21.FoUowing &haoler and Kane's criteria [10l TO was consideredpresent when mild movements were present in at least two bodyareas or moderate movements were present in at least one bodyarea. Once patients were considered as having TO, they wereclassified as severe if they had severe movement in at least onebody area.

For these analyses, Ihe antipsychotic exposure was categoricallydistributed at four levels (no exposure before current treatmenl withatypicals, 11% (571516); prior and current treatment with atypicalsbut no exposure to typicals, 9'Ml (481516); lifetime exposure to typ­icals for <5 years (plus llypicals). I~ (941516); and lifetimeaposure to typicals for ~ years (plus ltypicals), 62% (317/516).

The prevalence of TO was compared using cross-tabulations andcategorical odds ratios (DRs) using the rq>eated contrast methodfrom the Statistical Package for the Social Sciences (SPSS), whichcompares each calegory of the predictor variable (antipsychoticaposure) to the category thai precedes it. Logistic regression wasused 10 control for significant confounding variables (gender. age>45 years, current antipsychotic and anticholinergic Ireatmenl anda polymorphic variation in the giutathione-S-transferase MI; 121affecting the categorical variable measuring atypical exposure.

Results

The prevalence of TO was 5% in previously naivepatients, 19% in those exposed only to atypicals, 19%in those with typical exposure of <5 years, and 42% inthose exposed to typicals for ~5 years (Table 1).

The categorical DRs suggest that there was a sig­nificant effect in those previously na·"ve versus withthose only taking atypicals (OR =4.2). There was nosignificant effect in those only taking atypicals versusthose with a relatively short treatment with typicals(OR = 1.0). There was a significant effect in thosetaking typicals for <5 years versus those taking typi­cals for 2:5 years (OR = 3.0) (Table 1). The categoricalORs, adjusted for significant confounding variables.were similar (Table I).

When the TO cases were classified according toantipsychotic exposure, most were associated withlong-term typical exposure. The TO cases included2% (31162) of those previously naive, 5% (91162) ofthose with only atypical exposure, 11% (181162) ofthose with typical exposure of <5 years; and most,82% (132/162), of those associated with typicalexposure for ~5 years.

When severe TD was examined in 162 patients withTD, the patients only on atypicals did not appear tohave a better profile. The prevalence of severe TO was0% (0/3) in those previously naive, 56% (5/9) in thosewith only atypical exposure, 28% (5118) in those withtypical exposure for <5 years. and 30% (391132) inthose with typical exposure for 2:5 years.

Discussion

The study was not designed to test this hypothesis (itwas a pharmacogenetic study; [2]. total duration ofatypical exposure was not quantified and the designwas limited since the presence of TO was evaluatedonly as a cross-sectional assessment at a specificmoment in time (patients were not followed 3 monthslater to verify whether dyskinetic movements werestill present). The criterion of inclusion in the originalpharmacogenetic study may have introduced somebiases. Only patients with past or current risperidonetreatment who were willing to sign a written informedconsent in a study that included a blood collectionwere included in the sample. Obviously the need tosign a consent form and be willing to cooperate with ablood collection may have biased the sample some­what, but the first bias (willingness to sign a consentform) is unavoidable in current times. However. afterexcluding consenting biases. the sample probably wellrepresents Central Kentucky's severely mentally illpatients taking antipsychotics at the time of the study.since risperidone was the most frequently used anti­psychotic. In fact, it was unusual to find antipsy­chotic-prescribed patients who have never takenrisperidone.

The sample sizes of the first two groups (naYve andonly on atypicals) were relatively small. around 50patients. The sample size in the third group (typicalsfor <5 years) was moderate (almost 100); only thepatients on typicals 2:5 years comprise a large samplesize (>300 subjects).

The duration of psychiatric treatment and of typ­ical exposure was determined by research nurses whoreviewed the charts and by asking the patients.Obviously, these were rough estimations but weredone without any knowledge that the author wasplanning to use them in these TO analyses. Moreover,three quarters of the ratings were conducted by theauthor 121 before looking at the current patientmedication and with no knowledge of the duration ofthe psychiatric treatment estimated independently bythe research nurses.

The time frame when this study was conducted(July 2000-March 2003) and the methods of recruit­ment also limit the possibility of generalizing the re­sults to all atypical antipsychotics. In the US market.risperidone was introduced 6 years before the study'sonset (in 1994); olanzapine 5 years before the study'sonset (in 1996); quetiapine 3 years before the study's

onset (in 1997); ziprasidone 1 year after the study'sonset (in 2001) and aripiprazole 2 years after thestudy's onset (in 2002). Thus, it is very likely thateffects (or decreased effects) of ziprasidone and ari­piprazole on the risk of TO are not well represented inthis study. In the well-controlled short-term studies ofthe pharmaceutical companies. which use double­blind designs, monotherapy and healthy subjects.ziprasidone and aripiprazole appear to have limitedcapacity to cause extrapyramidal side effects {8).However, in the author's clinical experience in thereal world, some specific subjects appear to developclear cases of extrapyramidal side effects even withthese two drugs and, in some cases. they can even besevere [7). Despite these limitations. this study can beconsidered a naturalistic study that tries to give a firstimpression of the relative importance of the atypicalantipsychotic's contribution to TO in the clinicalenvironment. Due to the tendency of patients to benon-compliant and the tendency of doctors to switchand combine atypical antipsychotics, it is not going tobe easy to distinguish the contribution of specificatypicals to the long-term risk of developing tardivedyskinesia in the real world.

The long-term exposure to typical antipsychotics(2:5 years) was a major predictor of TD but shorterexposure to typicals was not significantly differentfrom exposure only to atypicals (OR = 1.0. Cl 0.42­2.5). even after correcting for confounding variables(OR = 1.2. CI 0.46-2.8). Thus, this study failed toshow major significant benefits of only atypicalexposure versus exposure to atypicals and typicals for<5 years. These results are complementary to thelarge naturalistic study described by Lee et aI. [4]since they included different populations. Lee et aI.'sstudy was restricted to patients aged 66 or older witha diagnosis of dementia and excluded patients with aprior diagnosis of abnormal movement disorders.Thus, they probably excluded TD associated withlong-term treatment of antipsychotics in the contextof severe mental illnesses. As a matter of fact, anotherarticle from the same cohort explains that schizo­phrenia and depression were criteria of exclusion [9].The current study sample included patients with se­vere mental illnesses, particularly schizophrenic psy­choses and severe mood disorders. who tended to beyounger than Lee et a1.'s patients; only 4% (23/516) ofpatients were aged 66 years or older.

Future cross-sectional and prospective studiesneed to consider that. when comparing atypical ver­sus typical risk for TD, it is important to recognizethat longer treatment with typicals may contaminatethe results. The complexity of analyzing naturalisticdata is due to the fact that the long-term treatmentsare not randomized and any attempt to divide natu­ralistic groups results in uneven distributions. Thus.our four samples have different durations of any kindof psychiatric treatment. The median duration oftreatment was 1 year for the nai've group. 5 years for

those exposed only to atypicals, 6 years for those withtypical exposure of <5 years, and 21 years for thoseexposed to typicals for ;::-:5 years. Thus, long-term TDstudies (by necessity naturalistic) may never be ableto completely rule out the possibility that atypicalspose less risk of causing TD; one can only do that inwell-controlled experimental studies with enoughpower. However, naturalistic studies can provide anidea of whether long-term treatment with atypicalsand typicals is associated with clinically relevant dif­ferences in the risk of TD or not.

Any way, new studies need to establish whether ornot decades of treatment with typical versus decadesof treatment with atypical antipsychotics make a dif­ference in long-term TD prognosis in the clinicalenvironment.

• Acknowledgements These analyses were conducted withoutexternal funding support. Francisco J. Diaz, Ph.D., (rom theDepartment o( Statistics, Universidad Nacional, Medellin, Colom­bia, helped to calculate the prevaleno:es adjusted for confoundersdescri?ed in Table I. The subject recruitment and genetic testing(or thiS sample was conducted for a pharmacogenetic study thaIwas supported by several sources: a re~archer·initiated grant fromthe Eli Lilly Reu;arch Foundation to Jose de Leon, M.D. (24% ofdiret"t costs), a NARSAD Independent Award to 10se de Leon, M.D.(ll% o( direct costs). internal funding (37% of direct coots), andfinally ~y Roche Molet"ular Systems, Inc., which provided (reI'genotyptng and laboratory supplies (equivalent to 28% of dire<:tcosts). Besides this support, in the past three year$ Dr. de Leon hasI) been on the advisory board o( Bristol-Myers Squibb and RocheMolecuJar S~tems, Inc.; 2) received researcher-initiated grants(rom Roche Molecular Systems, Inc. and Eli Lilly; and 3) lecturedsupported by Eli Ully (once). Bristol.Myers Squibb (once) and byRoche Moltcular Systems, Inc. (5 times). The author thanks Lor­rain~ Maw, M.A., {or editorial assistance. A shorter preliminaryversion o( this article was presented ;as an abstl'Kt at the 61stAnnual Meeting o( the Society of Biological Psychiatry. Toronto.Ontario, Canada, May 18-20, 2006.

References

I. Correll cu. Leucht S, Kane 1M (2004) Lower risk (or tardivedyskines~a uSl?'iated with second-generation antipsychotics: Asystematic revIew of I-year studieii. Am J Psychiatry 161:414­42S

2. de Leon I, SU$Ce MT, Pan RM, Fairchild M. Koch W, WedlundPI (2005) Polymorphic variations in GSTMI, GSTTI, PgP.CY~2[)6. <?"~3A5, .and dopamine D2 and 03 receptors andtherr association With tardive dyskinesia in $CVert mental ill­ness. J Clin Psychopbarmacol 25:443--456

3. Dolder CR,leste DV (2003) Incidence of tardive dyskinesia withtypical versus atypical antipsychotic.s in very high risk patients.Bioi Psychiatry 53:1142-1145

4. Lee PE, Sykora K, Gill S, Mamdani M, Marru C. Anderson GM,Shulman KI, Stukel T. Normand S-L, Rochon PA (2005) Anti­psychotic medications and drug·induced movement disordersother than parkinsonism: a population-based cohort study inolder adults. I Am Gerialr Soc 53:1374-1379

5. Leucht S, Pitschel-Walz G, Abraham 0, Kiuling W (1999)Efficacy and extrapyramidal side-effects of new antipsychotic.solanzapine, quetiapine, risperidone, and sertrindole comparedto conventional antipsychotics and placebo. A meta-analysis ofrandomiud controlled trails. Schizophr Res 35:51-68

6. Nasrallah HA (2006) Focus on lower risk of tardive dyskinesiawith atypical antipsychotics. Ann Clin Psychiatry 18:57-62

7. Markham-Abedi C, McNeely C, de Leon J (2006) Ziprasidone­induced catatonia symptoms (letter). I Neuropsychiatr ClinicalNeurosci (in press) .

8. Pierre 1M (2006) Extrapyramidal symptoms with atypical an­tipsychotics. Incidence, prevention and management. DrugSafety 28:191-208

9. Rochon PA, Stukel TA, Sykora K, Gill S, Garfinkel S, AndersonGM, Normand SL, Mamdani M. Lee: PE, U P, Bronskill Sf,Manu C. Gurwitz IH (2005) Atypical antipsychoric.s and par­kinsoni.sm. Arch Intern Med 165:1382-1838

10. Sch~er. NR, Kane JM (1982) Research diagooses for tardivedyskInesIa (leiter). Arch Gen Psychiatry 39:486-487