EFFICACY AND SAFETY OF RISPERIDONE
ORAL SOLUTION IN AGITATION ASSOCIATED
WITH DEM ENTIA IN THE ELDERLY
Jerson Laks
1, Eliasz Engelhardt
1, Valeska M arinho
1, M arcia Rozent hal
1,
Fernando de Cast ro e Souza
1, Josué Bacalt chuk
2, Albert o St oppe Jr.
3,
R.C.R. Ferreira
3, Cassio Bot t ino
3, M ônica Scalco
3ABSTRACT - Background: Behavioral and psychological symptoms in dementia (BPSD) contribute to caregiver burden and institutionalization of elderly. Neuroleptics are prescribed to control agitation. Side effects of typical neuroleptics are harmful, making atypical neuroleptics an indication. Objectives: To evaluate efficacy and tolerability of risperidone oral solution (ROS) given once daily to demented elderly outpatients w ith BPSD (agitation). Method: Patients (n= 26), 76.35± 8.63 years, Diagnostic and Statistical M anual of M ental Disorders 4th ed. (DSM -IV) criteria for dementia. RSO w as given, starting dose of 0.25 mg and increments of 0.25 mg every w eek. M ini-M ent al St at e Examinat ion (M M SE) assessed cognit ive st at us, Behavioral and Emot ional Activities M anifested in Dementia (BEAM -D) and Clinical Global Impression (CGI) measured BPSD, Extrapiramidal Symptom Rating Scale (ESRS) evaluated extrapyramidal symptoms. Cardiovascular side effects w ere evaluated clinically. Results: There w as a 26% reduction in agitation and no cardiovascular side effects in the range from 1.0 to 1.25 mg. Side effects w ere more prevalent above 2.5 mg. Conclusion: Risperidone oral solution improved agitation w ith good tolerability from 0.5 to 1.25 mg. A single dose w ith increments of 0.25 mg may be more acceptable to patients and caregivers.
KEY WORDS: risperidone, dementia, BPSD, elderly.
Eficácia e segurança de risperidona solução oral na agitação associada a demência em idosos
RESUM O - Fundamentos: Sintomas psicológicos e do comportamento nas demências (BPSD) contribuem para a sobrecarga dos cuidadores e institucionalização dos idosos. Neurolépticos são prescritos para agitação. Ef eit os colat erais dos t ípicos são prejudiciais, sendo os at ípicos indicáveis. Objet ivo: Avaliar ef icácia e tolerabilidade da risperidona solução oral (RSO), dose única diária, em idosos demenciados ambulatoriais com BPSD (agitação). Método: Pacientes (n= 26), 76,35± 8,63 anos, critérios do M anual Diagnóstico e Estatístico de Transtornos M entais 4.ed. (DSM -IV) para demência. RSO administrada, com dose inicial de 0,25 mg e incrementos de 0,25 mg toda semana. Foram utilizados mini-mental (M EEM ) para estado cognitivo, behavioral and emotional activities manifested in dementia (BEAM -D) e clinical and global impression (CGI) para BPSD, extrapyramidal symptom rating scale (ESRS) para sintomas extrapiramidais. Efeitos colaterais cardiovasculares f oram avaliados clinicam ent e. Result ados: Houve redução de 26% na agit ação, sem ef eit os colat erais cardiovasculares, numa faixa de 1,0 a 1,25 mg. Efeitos colaterais foram mais prevalentes acima de 2,5 mg.
Conclusão: Risperidona melhorou agitação com boa tolerabilidade entre 0,5 e 1,25 mg. Dose única diária e aumentos de 0,25 mg podem ser mais aceitáveis para pacientes e cuidadores.
PALAVRAS-CHAVE: risperidona, demência, BPSD, idosos.
1Psychogeriat ric Unit /Inst it ut e of Psychiat ry of Federal Universit y of Rio de Janeiro (UFRJ), Rio de Janeiro RJ, Brazil; 2Federal Universit y of
São Paulo (UNIFESP/EPM ), São Paulo SP, Brazil; 3Prot er/Inst it ut e of Psychiat ry Universit y of São Paulo Hospit al (HC-USP) São Paulo SP,
Brazil. Support ed by Janssen-Cilag.
Received 18 December 2000, received in final form 3 August 2001. Accept ed 7 August 2001. Dr. Jerson Laks - Av. Nossa Senhora Copacabana 749/1101 – 20250-000 Rio de Janeiro RJ - Brasil.
Non-cognitive behavioral disorders are prominent feat ures of dement ia1 and oft en lead t o nursing ho-me placeho-ment , besides t he pat ient ’s dist ress, care-givers’ burden and serious medical complicat ions2-4. Such disorders have been report ed as behavioral and psychological sympt oms of dement ia (BPSD), being present in up t o 90% of dement ed pat ient s st ud-ied1,5,6. The majorit y of st udies published on t he
sub-ject deal w it h case series and/or severely inst it ut ion-alized dement ed pat ient s.
agitation, a broad assembly of syndromes that range from delusions and anxiet y manifest at ions t o w an-dering and so on8,9. Nine double-blind, placebo con-t rolled con-t rials evaluacon-t ed con-t he use of con-t ypical neurolepcon-t ics in dement ia. Alt hough haloperidol and t hioridazine have been show n t o be superior t o placebo in t reat -ing psychot ic sympt oms in dement ia, a considerable degree of ext rapyramidal sympt oms have also been described8. Hence, t he efficacy of neurolept ics in reducing psychot ic sympt oms in dement ia does not alw ays t ranslat e int o improvement s in daily act ivi-t ies and funcivi-t ional capaciivi-t y8.
At ypical neurolept ics have been considered at least as effect ive as t ypical ones in cont rolling agit a-t ion in demena-t ia w ia-t h a-t he advana-t age of reduced side effects and a more favorable EPS profile. Risperidone, a D2/HT2 blocker, is t he most st udied at ypical ant ip-sychot ic in BPSD10-13. An open st udy found risperido-ne to be safe and effective in treating behavioral sym-pt oms in 109 dement ed nursing home resident s and several anecdot al report s have also been published reconfirming these findings12. To date, only tw o w ell-designed randomized, double-blind, placebo-con-t rolled splacebo-con-t udies w iplacebo-con-t h risperidone for behavioral dis-t urbances in demendis-t ia have been published2,14. All pat ient s included in t he above ment ioned st udies w ere inst it ut ionalized w it h severe dement ia. Despit e opt imal t reat ment of neuropsychiat ric syndromes and t he role of at ypical neurolept ics among nursing home resident s being a leading issue in t he research agenda concerning elderly people15, t here dat a do not allow direct extrapolation to outpatient samples. Furt her dat a are required t o ascert ain efficacy, dose range and side effect profile in t his populat ion. This know ledge could prevent unnecessary inst it ut ional-izat ion, lessen caregiver burden and help rat ionalize family and public expendit ures.
The present st udy is t he first Brazilian evaluat ion of risperidone in dement ia, as w ell as t he first t rial administ ering a daily dose of risperidone oral solu-t ion solu-t o an ousolu-t pasolu-t iensolu-t sample w isolu-t h agisolu-t asolu-t ion in de-ment ia. Our object ive in t his st udy is t o assess t he efficacy and safet y of risperidone oral solut ion in BPSD in a sample of agit at ed elderly out pat ient s w it h dement ia.
M ETHOD
Tw ent ysix elderly pat ient s aged 60 years or more, fit -t ing DSM -IV16 crit eria for dement ia w it h agit at ion and/or psychosis, w ere t reat ed w it h increasingly higher doses of risperidone oral solut ion. All pat ient s received an init ial dose of 0.25 mg/day follow ed by increases of 0.25 mg, up t o a maximum of 3.0 mg once daily, according t o t heir
needs. Lorazepan 2 mg w as t he only medicat ion allow ed for insomnia during the first month of treatment. Biperiden 1mg t o 2mg w as alloved t hroughout t he st udy t o t reat ext rapyramidal sympt oms (EPS).
Pat ient s w ere seen w eekly during t he first mont h and at regular int ervals for t he proceeding four mont hs t o a t ot al of 9 visit s. Tw o universit y psychogeriat ric unit s in Rio de Janeiro and São Paulo – Brazil, t ook part in t he t rial, bot h approved by t he local et hics commit t ee. All pat ient s and t heir next of kin signed t he informed consent t o t he st udy.
Efficacy w as assessed by means of t he Behavioral and Emot ional Act ivit ies M anifest ed in Dement ia (BEAM -D)17 and Clinical Global Impression (CGI) scales18 , w hereas for cognit ive st at us M ini-M ent al St at e Examinat ion (M M SE)19 w ereemployed. The Extrapyramidal Symptom Rating Scale (ESRS)20 w as used t o assess ext rapyram idal sym pt om s (EPS). Cardiovascular effect s w here assessed by vit al signs at every visit s and elect rocadiography (ECG) at baseline ans last visit .
Dat a w here represent ed as mean and st andard-devia-t ions. Analysis of variance andard-devia-t echnique w as applied andard-devia-t o evalu-at e devalu-at a varievalu-at ion over t ime. Pearson’s correlevalu-at ion coefficient w as calculat ed t o measure t he correlat ion grade bet -w een M M SE and BEAM -D Target Behaviours Scores. M c-Nemar’s t est w as applied t o compare t he proport ion of pat ient s w it h EPS at baseline and at final visit . The signifi-cance level w as est ablished at 0.05 and st at ist ical analysis w as performed using t he SPSS® st at ist ical package.
RESULTS
26 pat ient s (10 male and 16 female), w it h mean age of 76.35± 8.63 years, w ere enrolled on the study. Alzheimer’s dement ia (AD) w as present in 17 t ient s, vascular dement ia (VD) in 5, AD-VD in 6 pa-tients. Tw o patients had received typical neuroleptics prior t o t he w ash out period, and 11 pat ient s w ere t aking ot her medicat ions such as digoxin, insulin, and ant ihypert ensives.
Cognit ive impairment w as moderat e or severe according t o M M SE (M ean of 10.04 and st andard-deviat ion of 7.09, range = 0 – 25).
Tables 1 and 2 show t he mean profile variat ion of BEAM -D Target Behaviors and BEAM -D Inferred St at e by dose. Comparison bet w een BEAM -D per-cent age scores am ong doses revealed signif icant result s for bot h Target Behaviors and Inferred St at es scores (p= 0.05 and p< 0.001 respect ively). For In-ferred St at es scores, mult iple comparisons among scores over a dose up t o 1.25 mg indicat ed t hat t he effect ive daily dose fell in t he range 1.00 mg t o 1.25 mg. The difference among doses for Target Beha-viours ranged bet w een 0.25 mg and 0.50 mg.
Table 3. Pat ient s’ dist ribut ion, according t o EPS measured by t he ESRS at baseline and last visit .
Baseline Last visit N %
No EPS EPS 5 25.0
No EPS no EPS 8 40.0
EPS EPS 6 30.0
EPS no EPS 1 5.0
Tot al 20 100
Table 1. Descript ive measures of percent age variat ion BEAM -D Target Behaviors scores (compared w it h visit 1), for each dose.
Dose M ean % SD % M inimum % M aximum % N
0.25 -5.70 24.44 -70.00 62.85 25
0.50 -11.62 19.54 -62.50 28.37 24
0.75 -13.49 18.00 -38.09 18.66 21
1.00 -19.40 16.63 -60.00 0.00 22
1.25 -13.96 15.33 -43.99 9.53 15
1.50 -21.05 19.10 -55.99 11.12 16
1.75 -27.78 17.58 -55.99 0.00 8
2.00 -30.63 11.66 -52.00 -13.63 10
2.25 -40.00 1
Table 2. Descript ive measures of percent age variat ion of BEAM -D Inferred St at es scores (compared w it h visit 1), for each dose.
Dose M ean % SD % M inimum % M aximum % N
0.25 -5.90 14.14 -44.34 30.00 25
0.50 -9.93 18.75 -38.90 42.29 24
0.75 -15.20 18.55 -50.01 27.27 21
1.00 -19.20 17.84 -47.63 14.28 22
1.25 -23.47 17.23 -41.19 15.38 15
1.50 -26.29 17.47 -50.01 19.24 16
1.75 -35.40 13.27 -50.01 -10.00 8
2.00 -29.69 24.76 -55.01 20.51 10
Table 3 show s t he descript ive m easures of ESRS scores for each visit in t hose pat ient s w it h posit ive scores. There w as no significant change in t he pro-port ion of pat ient s w ho present ed EPS t hroughout t he st udy, since only five pat ient s w it h no previous sympt oms present ed t hem, all w it h mild int ensit y at
endpoint . Eight pat ient s w ho had not present ed EPS at baseline also had no sym pt om s at endpoint , w hereas six w ho had show n EPS at baseline remained unchanged and one pat ient improved by endpoint (p= 0.2188) (Table 4). No cardiovascular or clinical side effect s w ere observed w it h dose increase dur-ing t he four mont hs of t he t rial (Table 5).
Nine pat ient s dropped out of t he st udy (34.6%): 2 due t o insufficient response, 4 ow ing t o side ef-fect s and 3 for loss of follow up and consent w it h-draw al. All but one pat ient w ho had dropped out w ere considered severe/marked in CGI for agit at ion. All dropout s due t o side effect s had EPS.
DISCUSSION
eld-erly out pat ient s aft er a four mont h period. A recent met a-analysis of randomized, double-blind cont rol-led t rials involving neurolept ics in behavioral disor-ders associat ed w it h dement ia show ed t herapeut ic effect t o be only 26% (neurolept ic minus placebo) and show ed no difference bet w een high and low pot ency profiles of t hese drugs9. Tw o furt her st ud-ies, t he first being a randomized, placebo cont rolled, double-blind design of risperidone for agit at ion in dement ia, have produced similar result s, albeit in severely dement ed inst it ut ionalized samples2,14. De Deyn found only 11% more pat ient s in t he rispe-ridone group and 8% in t he haloperidol group t o have improved, compared t o t he placebo cont rol group14,15.
Clinicians w ould prefer t reat ment dat a on spe-cific t arget behaviors and dist urbances such as de-lusions, aggression, anxiet y, and mood dist urbances given t hat t his is how t hey select drugs in clinical practice15. Symptoms of aggression, restlessness, de-lusions, hallucinat ions and inappropriat e sexual be-havior seem t o show a bet t er response t o medica-t ion w hereas w andering and umedica-t medica-t erances respond po-orly t o any kind of t reat ment21,22.
Pat ient s w it h cognit ive impairment are more pro-ne t o aggressive behavior and w andering t han t hose
w it h milder impairment , w ho show more verbal agi-t aagi-t ed behaviors. How ever, agi-t his is observed mainly in inst it ut ions23. A recent nine year prospect ive st udy on t he relat ionship bet w een cognit ion and BPSD in a communit y sample of dement ed pat ient s failed t o show such t endencies. BPSD sympt oms may appear in t he beginning of t he disease in it s int erim or final st ages and can last for a period or become chronic, t hus displaying no organizat ion according t o cogni-t ive scogni-t acogni-t us. This scogni-t udy does nocogni-t supporcogni-t cogni-t he view cogni-t hacogni-t behavioral and psychiat ric changes occur predomi-nant ly at any one st age of t he illness24.
M ost published dat a on agit at ion in t he elderly, especially in dement ia, does not specify w hich t ar-get sympt oms have been evaluat ed. This oft en leads t o unclear conclusions concerning t he efficacy of t he medicat ion st udied. BEAM -D is an effect ive t ool for psychopathological description of the symptoms and t heir int ensit y, alt hough t he present st udy could be crit icized for having used an inst rument not com-monly applied in similar t rials, t hus making it diffi-cult to compare our results w ith those found in other studies. This w as an outpatient sample of moderately and severely dement ed elderly. Taking t his int o con-siderat ion, it is int erest ing t o not e t hat t he progres-sion of cognitive decline does not necessarily correla-t e w icorrela-t h a w orsening of agicorrela-t acorrela-t ion w hen correla-t reacorrela-t mencorrela-t is implement ed. This may be import ant in prevent ing unnecessary inst it ut ionalizat ion of pat ient s w it h de-ment ia, given t hat bet t er cont rol of insomnia, ag-gressiveness and psychosis m ay reduce caregiver burden t o a more manageable level.
The likely durat ion of episodes of a given behav-ior is also relevant in t hat t he lengt h of t reat ment may be det ermined. Episodes of physical aggression last ed less t han 10 mont hs in 25% of AD pat ient s from a prospect ive st udy of a communit y sample24. Therefore, our t rial has covered a t ime period dur-ing w hich no remission w ould be expect ed in t he
Table 5. Dist ribut ion of pat ient s according t o ECG result s at first and last visit s.
First ECG Last ECG N %
Normal Normal 7 87.5
Abnormal 1 12.5
Tot al 8 100
Abnormal Normal 2 15.4
Abnormal 11 84.6
Tot al 13 100
Table 4. Descript ive measures of ESRS scores in each visit , for pat ient s w it h non-null scores.
M ean SD M inimum M aximum N# N&
Visit 1 6.25 4.87 2.78 13.89 8 26
Visit 5 4.37 2.18 2.78 8.33 7 22
Visit 7 4.72 3.71 2.78 13.89 10 21
Visit 8 6.75 4.49 2.78 13.89 7 19
Final Visit 8.84 5.80 2.78 16.67 11 20
absence of t reat ment for most of t he pat ient s st ud-ied. Nevert heless, opt imal durat ion of t reat ment has yet to be determined through appropriately designed cont rolled-st udies.
The safet y profile of risperidone oral solut ion in our st udy w as good in respect of t he emergence of EPS sympt oms and cardiovascular side effect s. Since only five pat ient s w it hout previous EPS show ed mild EPS at endpoint, and eight presenting no such symp-t oms asymp-t baseline remained so asymp-t endpoinsymp-t , w e can regard risperidone as having a favorable profile con-cerning EPS. This dat a is also in agreement w it h t hat of ot her open label st udies, a recent ly published ret -rospective study in outpatients, as w ell as the double-blind risperidone t rial2,3,25. De Deyn et al.15 compared risperidone and haloperidol w it h 0.25 mg as a st art -ing dose, follow ed by 0.25 mg increment s every four days and found riperidone t o be as effect ive as ha-loperidol. Risperidone had a bet t er side effect pro-file t han haloperidol, compared w it h placebo.
Our t rial also used a once a day ingest ion sched-ule. This regimen w as safe, accept able t o caregivers and effect ive in cont rolling t he t arget sympt oms. That said, t he oral solut ion formulat ion may offer t he addit ional advant age of low ering t he dose re-quired t o cont rol agit at ion, w hile allow ing a 0.25 m g increm ent schedule, should low er st rengt h risperidone t ablet s not be available, t hus reducing EPS side effect s.
Dropout rat es are w it hin t he range observed in st udies of a similar nat ure. Kat z2 and DeDeyn15 had a 30% and 35.2% dropout rate, respectively, w hile me-t a-analyme-t ic sme-t udies show ed a 4% difference in drop-out s bet w een placebo and act ive drug9. Since most of our dropout s w ere because of side effect s com-bined w it h insufficient response, mainly in a series of more severely agit at ed pat ient s, t he present dat a are in line w it h t he current lit erat ure.
There are several limit at ions t o our st udy t hat should be t aken int o account w hen considering our dat a. We conduct ed an open label t rial including bot h AD and VD pat ient s. Even t hough t here w as a w ashout period for previous neurolept ics and ot her medicat ions w hich cont rolled agit at ion, it could be argued t hat side effect s and t he response profile of pat ient s may have differed from t hat expect ed if homogenized group of pat ient s w it h no previous medicat ion w ere t est ed w it h risperidone. M any pa-t ienpa-t s also had a series of concurrenpa-t diseases such as hypert ension and diabet es, albeit under cont rol at t he t ime of inclusion. How ever, excluding pat ient s
for t hese medical reasons w ould be t ant amount t o excluding t he “ real life” circumst ances t hat oft en int ervene in clinical decisions. Furt her st udies could be carried out w it h a more homogeneous sample of “ pure” AD or VD pat ient s. The use of BEAM -D could also be a focus of crit icism as it has not commonly been used in similar st udies, t hus making generali-zat ion more difficult . On t he ot her hand, BEAM -D has a complet e set of definit ions for each severit y st at e and described behaviour, making it a suit able t ool for defining and measuring int ensit y in a st rai-ght forw ard manner.
A considerable number of pat ient s show ed EPS at baseline. Biperiden 1mg t o 2 mg w as t he only ant iparkinsonian m edicat ion used t o lessen EPS, w hen needed. Of t he seven pat ient s w ho received t his drug, all present ed EPS at baseline. We also found it valuable t o learn w hat might be t he out -come of t hese pat ient s w it h risperidone, alt hough it can also be argued t hat t he effect of risperidone alone on EPS in this sample could not be ascertained.
CONCLUSION
Risperidone w as safe and effect ive in cont rolling agit at ion in dement ia w it h a minimum of side ef-fect s regarding cardiovascular and ext rapyramidal sympt oms. The dose t hat show ed a significant dif-ference in cont rolling t hese sympt oms varied from 1.00 mg t o 1.25 mg once daily, providing a reduc-t ion of 26% in agireduc-t areduc-t ion and relareduc-t ed sreduc-t areduc-t es in an out pat ient sample.
These result s are akin t o t hose of ot her open la-bel st udies w it h risperidone in dement ia, except t hat ours is t he first t o use an oral solut ion formulat ion. Since only t w o double-blind placebo cont rolled st udies w it h risperidone for BPSD in inst it ut ionalized dement ed elderly have been published so far, t here is st ill a need t o st udy communit y and out pat ient samples t o ascert ain t he best t reat ment schedule, w it h t he aim of maximizing efficacy w it h t he least side effect s possible.
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