Periodiko 3 int

Special Article
Psychiatric Sector, Psychiatric Department, HIPPOCRATIO General Hospital, Thessaloniki, Greece Atypical antipsychotic agents have been recently used in the clinical practice for the treatment of delirium and the existing
data have been shown atypicals to be effective and safe. Conversely, information regarding the efficacy and safety comes
mainly from open trials in small non-representative samples; randomized controlled trials are extremely few. The existing
literature lacks the required scientific evidence, however a lot of data provide the rationale for prospective large-scale
double-blind studies.
Delirium is an acute confusional state characterized by the symptoms of delirium; treatment was associated with an fluctuating levels of consciousness and impairment in extremely low prevalence of EPS; lorazepam alone was attention, cognition, perception, and behavior. There is ineffective and associated with treatment-limiting adverse evidence that the disturbance is caused by the direct effects. Results of several open studies suggest that combined physiological consequences of general medical conditions1.
treatment (haloperidol plus lorazepam) is more efficacious; Conditions commonly associated with delirium are CNS benzodiazepines maybe particular useful for antipsychotic side disorders, metabolic disorders, cardiopulmonary disorders, effects (anticholineric, EPS) or when there is a need to raise systemic illness, postoperative state, medications and toxins…2 The prevalence of delirium have been reported between 10%- 30% in the hospitalized medically ill to more than 80% of Recently several papers have been published reporting the use of the atypical antipsychotic agents risperidone, olanzapine, The duration of symptoms range from less than one week to quetiapine, and ziprasidone. Atypicals have been used in more than two months. Typically the symptoms of delirium clinical practice for the treatment of delirium as they are are resolved within 10-12 days. The majority of the patients principally associated with a lower risk of EPS. Second recover fully. Delirium may progress to stupor, coma, seizures generation antipsychotics have been also used in delirium or death particularly if untreated. Full recovery is less likely in resistant to haloperidol treatment (Vidalis et al, unpublished the elderly. Delirium, particularly in the elderly, is associated with significant morbidity and an increased mortality rate; To our knowledge, the first report on the use of atypicals in however delirium remains an underrecognized, delirium was a retrospective study of 103 elderly patients with underdiagnosed and undertreated mental disorder2.
dementia or delirium. Robertsson et al (1996)7 treated the patients with remoxipride and reported that when The management of delirium involves two key aspects: First psychomotor hyperactivity was the dominant problem a good the treatment of the underlying pathological condition and effect was rated in 81% of the patients, while side effects were second the symptomatic and supportive therapy.
few and mild. Remoxipride has been world-wide withdrawn Antipsychotics have been the medication of choice2.
Haloperidol is most frequently used because it has no active metabolites, few or no anticholinergic side effects, minimal Sipahimalani & Masand8 and Sipahimalani et al (1997)9 cardiovascular side effects and a relatively small likelihood of reported at least some improvement in 8 out of 11 delirious causing sedation2. However haloperidol is frequently patients in which they had administered risperidone. Dosages associated with extrapyramidal side effects (EPS) –including were started at 0.5mg bid, and were gradually increased every laryngeal dystonia and dysphagia5; intravenous administration 3-4 days (range: 1-4mg/d). One patient showed signs of EPS is maybe associated with less EPS; elderly and patients with and one experienced dizziness. Azuma et al (1998)10 reported comorbid conditions not-rarely observed in the medical a case of delirium developed during the treatment for setting (Parkinson disease, Lewy-body dementia, basal ganglia parkinson’s disease in an 69y old patient; restlessness and strokes, AIDS…) are more sensitive to EPS; Neuroleptic excitement were resolved after administration of risperidone malignant syndrome and increased vulnerability to QT 1mg/d. Ravona-Springer et al (1998)11 reported three elderly prolongation are also problematic side effects of the patients treated with risperidone; Lerner et al (2000)12 also reported the treatment of three delirious patients; Nishimura The use of haloperidol is primarily based in accumulated clinical wisdom; research is limited. Breitbart et al (1996)6 in a neuropsychiatric lupus erythematosus treated with risperidone; randomized controlled trial (RCT) with delirious AIDS patients concluded that low-dose neuroleptics (haloperidol or chlorpromazine) resulted in a significant improvement in the Horikawa et al (2003)15 conducted a preliminary open clinical study on risperidone in 10 patients with delirium, at a dose of enough to interrupt treatment. Age >70y was a powerful 1.7mg/d on average; one patient responded at a dose of predictor of poorer response to olanzapine treatment. 0.5mg/d. The treatment was effective in eight patients, Skrobik et al (2004)5 in a RCT compared safety and efficacy however sleepiness (in three patients) and mild drug-induced of olanzapine to haloperidol in a critical care setting. Clinical parkinsonism (in one patient) were observed. Liu et al improvement was similar, whereas the use of haloperidol was (2004)16 retrospectively analyzed 41 delirious patients who associated with low scores on EPS testing. The authors received risperidone treatment and 36 patients who received concluded that olanzapine is maybe of particular interest in haloperidol. Risperidone (mean dose 1.2±0.8 mg, range 0.5- patients in whom haloperidol is contradicted.
4.0 mg) and haloperidol were both effective for treating hyperactive symptoms of delirium; the psychiatrists tended to Schwartz & Massand (2000)25 retrospectively reviewed charts recommend haloperidol for patients with severely hyperactive of 22 patients with delirium; eleven had been treated with symptoms and risperidone for older patients and patients with quetiapine (average dose 211.4mg/d) and 11 with haloperidol moderate hyperactive symptoms; the patients on haloperidol (3.4mg/d). Authors reported that quetiapine was as effective needed much more anticholinergics. A 6-day clinical trial on as haloperidol but was better tolerated with a lower incidence risperidone was carried out in 10 medically-ill patients with of EPS. Torres et al (2001)26 and Al-Samarrai et al (2003)27 delirium by Mitral et al (2004)17. They administered an initial presented quetiapine for treatment of delirium in case reports. dose of 0.5 mg bid, with additional doses on day 1, until Kim et al (2003)28, administered quetiapine (mean dose Delirium Rating Scale (DRS) score was <13; dosage was then 94±23mg/d) to 12 elderly hospitalized delirium patients (mean decreased by 50% (mean maintenance dose: 0.75mg/d). Their age 74±7y). They reported that treatment was effective and conclusion was that risperidone can improve cognitive and safe in older patients with delirium. The DRS scores as well as behavioral symptoms of delirium. Two patients discontinued the scores of the Mini-Mental State Examination and Clock because of sedation or hypotension. Parellada et al (2004)18 Drawing test continued to improve throughout the 3-month conducted a prospective, multicenter, observational 7-day study period. Sasaki et al (2003)29 conducted an open-label study in 67 patients with delirium. Response to the treatment flexible-dose study in 12 patients with delirium. The mean was defined as a reduction in DRS score to <13 within 72 dose of quetiapine was 45±31mg/d. All patients achieved hours. Risperidone (mean dose 2.6±1.7mg at day 3) was remission of delirium several days after and no EPS were effective in 90.6% of the patients; two patients (3.1%) quetiapine in a pilot trial, in 22 patients; authors concluded Hans & Kim (2004)19 performed a double-blind comparative that quetiapine could be a useful alternative agent to classical study; twenty-eight patients with delirium were randomly assigned to receive haloperidol or risperidone over a period of 7 days. The RCT showed no difference in the efficacy between Leso & Schwartz (2002)31 in a case-report found ziprasidone (100mg/d, po) to be effective in an AIDS patient with cryptococaal meningitis and electrolyte abnormalities for Sipahimalani & Masand (1998)20 reported an open study in whom risperidone was stopped due to EPS. Young & Lujan which 11 delirious patients were treated with olanzapine (2004)32 presented the use of intravenous ziprasidone to treat (8.23.4mg/d, range 5-15mg/d) and 11 delirious control ICU-related delirium refractory to haloperidol treatment.
patients were treated with haloperidol (5.1±3.5mg/d, range 1.5-10mg/d). Five of the olanzapine patients showed Tune et al (2001)33 reported the preliminary results of a significant improvement on DRS and none of the patients had prospective investigation for the management of acute side effects, whereas six of the control subjects showed delirium in elderly patients with dementia. Twenty-seven improvement on the DRS but five had EPS or excessive patients received atypicals (risperidone, olanzapine or sedation. Peak response time was similar in both groups.
quetiapine), 9 received a standing dose of haloperidol, 7 prn Passik & Cooper (1999)21 successfully managed by olanzapine haloperidol and 9 a combination of typical and atypical a complicated delirium, in which low doses of haloperidol antipsychotics. Atypical antipsychotics were obviously were ineffective; Khouzam et al (1999)22 reported three superior to therapy with prn haloperidol and to combination geriatric patients treated with olanzapine in the course of post- therapy. Patients receiving haloperidol or combination antipsychotics showed a significant deterioration in EPS. Kim et al (2001)23 conducted a trial of olanzapine in 20 patients with delirium (mean dose 5.9±1.5, max.dose 8.8±2.2 Novel antipsychotics are effective and well tolerated in mg/d). The scores of DRS were significantly improved and no common psychiatric disorders but they are not well studied in serious side effects were observed. Breitbart et al (2002)24 held medically-ill patients. Second generation antipsychotics are an open prospective clinical trial of olanzapine for the not without side effects. Somnolence or dizziness are treatment of delirium in a sample of 79 hospitalized cancer sometimes caused by atypicals use; quetiapine probably causes patients. Fifty-seven (76%) completely recovered from their more sedation. Risperidone and olanzapine are associated with delirium on olanzapine therapy. No patients experienced EPS; mild EPS, maybe dosage dependent. Olanzapine has mild however, 30% experienced sedation, which was not severe anticholinergic adverse effects. Olanzapine and quetiapine ATYPICAL ANTIPSYCHOTICS IN THE TREATMENT OF DELIRIUM have an adverse effect on glucose regulation. Ziprasidone is 5. Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, associated with QT prolongation; a case of torsades de pointes Grau C, Corbera K, Raymond S, Lund S, Jacobson P. A double- caused by a small dose of risperidone in a cancer patient has blind trial of haloperidol, chlorpromazine, and lorazepam in the been reported.35 Coadministration of benzodiazepines and treatment of delirium in hospitalized AIDS patients. Am J atypicals may be associated with an increased incidence of syncope and respiratory depression; parenteral 6. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs coadministration of olanzapine and benzodiazepine is haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004; 30:444-9. [Comment in: Intensive Care Med Recently (2003-4) safety warnings were issued by EMEA, as well as by the manufacturer of olanzapine (Eli Lilly) and the 7. Robertsson B, Karlsson I, Eriksson L, Olsson JO, Olofsson H, manufacturer of risperidone (Janssen); they refer to an Jacobsson NO, Arnell G. An atypical neuroleptic drug in the increased risk of cerebrovascular adverse events and mortality treatment of behavioural disturbances and psychotic symptoms in rate due to the use of olanzapine or risperidone in elderly elderly people. Dementia 1996; 7:142-6.
8. Sipahimalani A, Masand PS. Use of risperidone in delirium: case Bergeron & Strobik (2004)5 argue that besides the insufficient reports. Ann Clin Psychiatry 1997; 9:105-107.
data to confirm any difference in the risk of death between 9. Sipahimalani A, Sime R, Masand P. Treatment of delirium with antipsychotics, serious adverse events were found in long- risperidone. Int J Ger Psychopharmacol 1997; 1:24-26.
term therapy which limits the comparison to the short-term 10. Azuma M, Kirime E, Ohta J, Sugimoto M, Iida J, Hanada M. A drug treatment used in (ICU) delirium; anyway, identifying preexisting cardiovascular or cerebrovascular disease, case of delirium developed during treatment for Parkinson’s conditions which predispose to higher EPS risk, patients at disease successfully treated with risperidone. The Journal of the risk of hypotension and abnormal QT prolongation is essential Kyushu Neuropsychiatry Association 1998; 44(3,4):312-313.
prior to utilization of any antipsychotic. 11. Ravona-Springer R, Dolberg OT, Hirschmann S, Grunhaus L.
Delirium in elderly patients treated with risperidone: a report of The existing data have been shown that the newer atypical three cases. J Clin Psychopharmacol 1998; 18:171-2.
antipsychotics may have potential in the treatment of delirium 12. Lerner DM, Schuetz L, Holland S, Rubinow DR, Rosenstein DL.
and also have the added benefit of causing less dysphoria and Low-dose risperidone for the irritable medically ill patient.
akathisia37. On the other hand information regarding efficacy and risks comes mainly from case reports or open trials in 13. Nishimura K, Omori M, Horikawa N, Tanaka E, Furuya T, Harigai small non-representative samples; sometimes authors use M. Risperidone in the treatment of acute confusional state informal measures of delirium or delirium symptom severity; (delirium) due to neuropsychiatric lupus erythematosus: case lack of control group is another serious methodological report. Int J Psychiatry Med 2003; 33:299-303.
consideration. Scientific evidence is too limited to draw firm 14. Temple MJ. Use of atypical anti-psychotics in the management of conclusions, while a lot of data provide the rationale for post-traumatic confusional states in traumatic brain injury. J R In conclusion, atypicals may be a clinically efficacious and safe 15. Horikawa N, Yamazaki T, Miyamoto K, Kurosawa A, Oiso H, alternative in the treatment of delirium, especially when Matsumoto F, Nishimura K, Karasawa K, Takamatsu K. Treatment comorbid conditions raise concern about the side effects of the for delirium with risperidone: results of a prospective open trial haloperidol. However the few clinical trials, the weak research with 10 patients. Gen Hosp Psychiatry 2003; 25:289-292. methods and recent data regarding safety suggest that the 16. Liu CY, Juang YY, Liang HY, Lin NC, Yeh EK. Efficacy of literature lacks the required evidence-base; further double- risperidone in treating the hyperactive symptoms of delirium. Int blind, multicenter, large-scale studies to evaluate the safety Clin Psychopharmacol 2004; 19:165-8.
and efficacy of new atypical antipsychotics in the treatment of 17. Mittal D, Jimerson NA, Neely EP, Johnson WD, Kennedy RE, Torres RA, Nasrallah HA. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV). Washington, DC: 18. Parellada E, Baeza I, de Pablo J, Martinez G. Risperidone in the treatment of patients with delirium. J Clin Psychiatry 2004; American Psychiatric Association: Practice Guideline for the Treatment of Patients with Delirium. Am J Psychiatry 1999; 156 Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004; 3. Lipowski ZJ: Delirium (Acute confusional states). JAMA 1987; 20. Sipahimalani A, Masand PS. Olanzapine in the treatment of 4. Cacaeni A, Grassi L. Delirium: Acute Confusional States in delirium. Psychosomatics. 1998; 39:422-430.
Palliative Medicine. New York : Oxford University Press, 2003 21. Passik SD, Cooper M. Complicated delirium in a cancer patient successfully treated with olanzapine. J Pain Symptom Manage Leso L, Schwartz TL. Ziprasidone treatment of delirium.
22. Khouzam HR, Gazula K. Clinical experience with olanzapine in the 32. Young CC, Lujan E. Intravenous ziprasidone for the treatment of course of post-operative delirium associated with psychosis in delirium in the intensive care unit. Anesthesiology 2004; 101:794- geriatric patients: A report of three cases. Int J Psych Clin Pract 33. Tune L, Jewart D, Egeli S, Greene Y. Pharmacologic management 23. Kim KS, Pae CU, Chae JH, Bahk WM, Jun T. An open pilot trial of acute delirium: A naturalistic, prospective comparison of of olanzapine for delirium in the Korean population. Psychiatry atypical antipsychotics and haloperidol, using average length of stay and EPS rating as outcome measurements (poster). American 24. Breibart W, Tremblay A, Gibson C. An open trial of olanzapine Psychiatric Association Institute on Psychiatric Services; Orlando, for the treatment of delirium in hospitalized cancer patients.
34. Tune L. The role of antipsychotics in treating delirium. Curr 25. Schwartz TL, Masand PS. Treatment of Delirium With Quetiapine.
35. Tei Y, Morita T, Inoue S, Miyata H. Torsades de pointes caused 26. Torres R, Mittal D, Kennedy R. Use of quetiapine in delirium: case by a small dose of risperidone in a terminally ill cancer patient.
27. Al-Samarrai S, Dunn J, Newmark T, Gupta S. Quetiapine for European Agency for the Evaluation of Medicinal Products treatment-resistant delirium. Psychosomatics 2003;44:350-1.
(EMEA). Public statement on the safety of olanzapine.
28. Kim KY, Bader GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with quetiapine. J Geriatr Psychiatry Neurol 2003; 37. Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002; 167:1269- 29. Sasaki Y, Matsuyama T, Inoue S, Sunami T, Inoue T, Denda K, Koyama T. A prospective open-label, flexible-dose study of 38. Vaxevanis A, Vidalis A. Delirium and atypical antipsychotics: a quetiapine in the treatment of delirium. J Clin Psychiatry 2003; clinical perspective. Second World Congress on Quality in Clinical Practice; Chalkidiki, Greece; June 3-5, 2004.
30. Pae CU, Lee SJ, Lee CU, Lee C, Paik IH. A pilot trial of 39. Schwartz TL, Masand PS. The role of atypical antipsychotics in quetiapine for the treatment of patients with delirium. Hum the treatment of delirium. Psychosomatics 2002; 43:171-174


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