THE UNINTENDED (AND COSTLY) EFFECTS DUE TO THE INTRODUCTION OF AN UNRESTRICTED REIMBURSEMENT POLICY FOR ATYPICAL ANTIPSYCHOTIC MEDICATIONS IN A CANADIAN PUBLIC PRESCRIPTION DRUG PROGRAM: 1996/97 TO 2005/06
Main Article Content
Keywords
Drug utilization, provincial drug formulary, drug policy, drug access
Abstract
Background
Due to the increasing costs of pharmaceuticals, drug benefit programs often implement various policies that limit availability of drugs. These policies can have unforeseen consequences.
Objectives
To examine the utilization and expenditures for antipsychotic medications in a provincial government community-based drug program over a 10-year period when atypical antipsychotics were introduced and multiple reimbursement policy changes with respect to these agents were employed.
Methods
Retrospective analysis of the Newfoundland and Labrador Prescription Drug Program (NLPDP) claims database from 1996/97 to 2005/06. Antipsychotic medication utilization and expenditure were measured and effects of changes in reimbursement policies examined. Excess expenditure was measured by subtracting the actual from modelled expenditure under different policies.
Results
Between 1996/97 and 2005/06, the number of prescriptions for antipsychotic medications increased by 75% and expenditures by more than 720% to $7.2 million (peaking at $7.9 million in 2003/04), with atypical agents making up 96% of the total. Expenditure for antipsychotic medications grew by an annual average rate of 26.3%. At the same time, the number of people enrolled in the drug program declined by an annual average rate of 1.13%. The total excess amount of money spent was $266,195 per 1,000 beneficiaries during unlimited access to atypical agents.
Conclusion
There has been a substantial, unintentional, increase in the prescribing of atypical antipsychotics each year in Newfoundland and Labrador over the 10 years, likely due to off-label use following the unrestricted and partial restrictive access policies for these medications. Perhaps restricted access for recognized usage should be enforced.
References
1. Canadian Institute for Health Information. Drug Expenditure in Canada 1985 to 2006. Ottawa: CIHI 2007.
2. Ess SM, Schneeweiss S, Szucs TD. European healthcare policies for controlling drug expenditure. PharmacoEconomics 2003;21(2):89- 103.
3. Gulliford M, Figueroa-Munoz J, Morgan M, et al. What does 'access to health care' mean? J Health Serv Res Policy 2002 Jul;7(3):186-8.
4. Bourgault C, Elstein E, Le LJ, Suissa S. Reference-based pricing of prescription drugs: exploring the equivalence of angiotensinconverting-enzyme inhibitors. CMAJ 1999 Aug 10;161(3):255-60.
5. Thomas M, Mann J. Increased thrombotic vascular events after change of statin. Lancet 1998 Dec 5;352(9143):1830-1.
6. Soumerai SB, McLaughlin TJ, Ross-Degnan D, Casteris CS, Bollini P. Effects of a limit on Medicaid drug-reimbursement benefits on the use of psychotropic agents and acute mental health services by patients with schizophrenia. N Engl J Med 1994 Sep 8;331(10):650-5.
7. Harrington C, Gregorian R, Gemmen E, et al. Access and utilization of new antidepressant and antipsychotic medications. The Lewin Group; 2000 Jan.
8. Jacobs P, Bachynsky J. Public Policies Related to Drug Formularies in Canada: Economic Issues. Edmonton: IHE; 2000.
9. Beasley CM, Dellva MA, Tamura RN, et al. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999 Jan;174:23-30.
10. Schillevoort I, de BA, Herings RM, Roos RA, Jansen PA, Leufkens HG. Risk of extrapyramidal syndromes with haloperidol, risperidone, or olanzapine. Ann Pharmacother 2001 Dec;35(12):1517-22.
11. O'Reilly D, Craig D, Phillips L, Goeree R, Tarride JE, Parfrey P. Costs of new atypical antipsychotic agents for schizophrenia: Does unrestricted access reduce hospital utilization? Healthcare Policy 2007;3(1):58-79.
12. Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatmentresistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998 Apr;155(4):499-504.
13. Breier AF, Malhotra AK, Su TP, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999 Feb;156(2):294-8.
14. Azorin JM, Spiegel R, Remington G, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001 Aug;158(8):1305-13.
15. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997 Oct;17(5):407-18.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001 May;158(5):765-74.
17. Ho BC, Miller D, Nopoulos P, Andreasen NC. A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia. J Clin Psychiatry 1999 Oct;60(10):658-63.
18. Mullen J, Jibson MD, Sweitzer D. A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 2001 Nov;23(11):1839-54.
19. Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002 Feb;159(2):255-62.
20. Santamaria B, Perez M, Montero D, Madurga M, de Abajo FJ. Use of antipsychotic agents in Spain through 1985-2000. Eur Psychiatry 2002 Dec;17(8):471-6.
21. Mond J, Morice R, Owen C, Korten A. Use of antipsychotic medications in Australia between July 1995 and December 2001. Aust N Z J Psychiatry 2003 Feb;37(1): 55-61.
22. Ashcroft DM, Frischer M, Lockett J, Chapman SR. Variations in prescribing atypical antipsychotic drugs in primary care: crosssectional study. Pharmacoepidemiol Drug Saf 2002 Jun;11(4):285-9.
23. Geddes J. Generating evidence to inform policy and practice: the example of the second generation "atypical" antipsychotics. Schizophr Bull 2003;29(1):105-14.
24. Glick ID, Murray SR, Vasudevan P, Marder SR, Hu RJ. Treatment with atypical antipsychotics: new indications and new populations. J Psychiatr Res 2001 May;35(3): 187-91.
25. Lieberman J. Primary Care Companion. J Clin Psychiatry 2003;5(Supplement 3):3-8.
26. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ 2005;330(7496):874.
27. Zhong KX, Tariot PN, Mintzer J, Minkwitz MC, Devine NA. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebocontrolled study. Current Alzheimer Research 2007;4(1):81-93.
28. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999 Sep 22;53(5):946- 55.
29. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 1999 Feb;60(2):107-15.
30. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003 Feb;64(2):134-43.
31. Chan WC, Lam LC, Choy CN, Leung VP, Li SW, Chiu HF. A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001;16(12):115
32. Fontaine CS, Hynan LS, Koch K, Martin-Cook K, Svetlik D, Weiner MF. A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities. J Clin Psychiatry 2003;64(6):726-30.
33. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a doubleblind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):4
34. Gareri P, Cotroneo A, Lacava R, et al. Comparison of the efficacy of new and conventional antipsychotic drugs in the treatment of behavioral and psychological
symptoms of dementia (BPSD). Archives of Gerontology & Geriatrics - Supplement 2004;(9):207-15
35. Deberdt WG, Dysken MW, Rappaport SA, et al. Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia. Am J Geriatr Psychiatry 2005;13(8):722-30.
36. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355(15):1525-38.
37. Verhey FR, Verkaaik M, Lousberg R, Olanzapine-Haloperidol in Dementia Study group. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dement Geriatr Cogn Disord 2006;21(1):1-8.
38. Therapeutic Products Directorate HC. Risperidone. Notices of compliance [database online].Ottawa: 2007.
39. Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clinical Neuropharmacology 1998;21(3):176-80.
40. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Amer J Psychiat 2002;159(7):1146-54.
41. Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. International Clinical Psychopharmacology 1999;14(6):339- 43.
42. Shi L, Namjoshi MA, Zhang F, et al. Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status. Int Clin Psychopharmacol 2002;17(5):227-37.
43. Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. A 12-week, double-blind comparison of olanzapine vs. haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003;60(12):1218-26.
44. Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 2002;159(6):1011-7.
45. Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry 2002;63(12):1148-55.
46. Revicki DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM, Depakote Comparator Study Group. Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes. J Clin Psychiatry 2003;64(3):288-94.
47. Meehan K, Zhang F, David S, et al. A doubleblind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol 2001;21(4):389- 97.
48. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiat 2005;66(1):111-21.
49. McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. European Neuropsychopharmacology 2005;15(5):573-85.
50. Smulevich AB, Khanna S, Eerdekens M, Karcher K, Kramer M, Grossman F. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. European Neuropsychopharmacology 2005;15(1):75-84.
51. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003;160(7):1263-71.
52. Therapeutic Products Directorate HC. Quetiapine. Notices of compliance [database online].Ottawa: 2007.
53. Therapeutic Products Directorate HC. Olanzapine. Notices of compliance [database online].Ottawa: 2007.
54. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347(5):314-21.
55. Nagaraj R, Singhi P, Malhi P. Risperidone in children with autism: randomized, placebocontrolled, double-blind study. Journal of Child Neurology 2006;21(6):450-5.
56. Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004;114(5):e634-e641.
57. Troost PW, Lahuis BE, Steenhuis MP, et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Academy of Child & Adolescent Psychiat 2005;44(11):1137-44.
58. Luby J, Mrakotsky C, Stalets MM, et al. Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy. Journal of Child & Adolescent Psychopharmacology 2006;16(5):575-87.
59. Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Academy of Child & Adolescent Psychiat 2001;40(8):887-94.
60. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.
61. Calabrese JR, Keck PE, Jr., MacFadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60.
62. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebocontrolled study (the BOLDER II study). J Clin Psychopharmacol 2006;26(6):600-9.
63. Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depression & Anxiety 2006;23(6):364-72.
64. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.
65. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006;31(11):2505- 13.
66. Doree JP, Des RJ, Lew V, et al. Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Current Medical Research & Opinion 2007; 23(2):333-41.
67. Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002;17(3):115-9.
68. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 2004;65(4):565-8.
69. Denys D, de GF, van Megen HJ, Westenberg HG. A double-blind, randomized, placebocontrolled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004;65(8):1040-8.
70. Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Eur Neuropsychopharmacol 2005;15(1):69-74.
71. Fineberg NA, Sivakumaran T, Roberts A, Gale T. Adding quetiapine to SRI in treatmentresistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol 2005;20(4):223-6.
72. Hollander E, Baldini RN, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2003;6(4):397-401.
73. Li X, May RS, Tolbert LC, Jackson WT, Flournoy JM, Baxter LR. Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study. J Clin Psychiatry 2005;66(6):736-43.
74. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebocontrolled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
75. Carey PD, Vythilingum B, Seedat S, Muller JE, van AM, Stein DJ. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebocontrolled study [ISRCTN83050762]. BMC Psychiatry 2005;5(1):5.
76. Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry 2004;55(5):553-5.
77. Schneeweiss S, Soumerai SB, Glynn RJ, Maclure M, Dormuth C, Walker AM. Impact of reference-based pricing for angiotensinconverting enzyme inhibitors on drug utilization. CMAJ 2002 Mar 19;166(6):737-45.
78. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005 Sep 22;353(12):1209-23.
79. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006 Apr;163(4):600-10.
80. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006 Oct;63(10):1079-87.
2. Ess SM, Schneeweiss S, Szucs TD. European healthcare policies for controlling drug expenditure. PharmacoEconomics 2003;21(2):89- 103.
3. Gulliford M, Figueroa-Munoz J, Morgan M, et al. What does 'access to health care' mean? J Health Serv Res Policy 2002 Jul;7(3):186-8.
4. Bourgault C, Elstein E, Le LJ, Suissa S. Reference-based pricing of prescription drugs: exploring the equivalence of angiotensinconverting-enzyme inhibitors. CMAJ 1999 Aug 10;161(3):255-60.
5. Thomas M, Mann J. Increased thrombotic vascular events after change of statin. Lancet 1998 Dec 5;352(9143):1830-1.
6. Soumerai SB, McLaughlin TJ, Ross-Degnan D, Casteris CS, Bollini P. Effects of a limit on Medicaid drug-reimbursement benefits on the use of psychotropic agents and acute mental health services by patients with schizophrenia. N Engl J Med 1994 Sep 8;331(10):650-5.
7. Harrington C, Gregorian R, Gemmen E, et al. Access and utilization of new antidepressant and antipsychotic medications. The Lewin Group; 2000 Jan.
8. Jacobs P, Bachynsky J. Public Policies Related to Drug Formularies in Canada: Economic Issues. Edmonton: IHE; 2000.
9. Beasley CM, Dellva MA, Tamura RN, et al. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999 Jan;174:23-30.
10. Schillevoort I, de BA, Herings RM, Roos RA, Jansen PA, Leufkens HG. Risk of extrapyramidal syndromes with haloperidol, risperidone, or olanzapine. Ann Pharmacother 2001 Dec;35(12):1517-22.
11. O'Reilly D, Craig D, Phillips L, Goeree R, Tarride JE, Parfrey P. Costs of new atypical antipsychotic agents for schizophrenia: Does unrestricted access reduce hospital utilization? Healthcare Policy 2007;3(1):58-79.
12. Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatmentresistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998 Apr;155(4):499-504.
13. Breier AF, Malhotra AK, Su TP, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999 Feb;156(2):294-8.
14. Azorin JM, Spiegel R, Remington G, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001 Aug;158(8):1305-13.
15. Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997 Oct;17(5):407-18.
16. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001 May;158(5):765-74.
17. Ho BC, Miller D, Nopoulos P, Andreasen NC. A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia. J Clin Psychiatry 1999 Oct;60(10):658-63.
18. Mullen J, Jibson MD, Sweitzer D. A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 2001 Nov;23(11):1839-54.
19. Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002 Feb;159(2):255-62.
20. Santamaria B, Perez M, Montero D, Madurga M, de Abajo FJ. Use of antipsychotic agents in Spain through 1985-2000. Eur Psychiatry 2002 Dec;17(8):471-6.
21. Mond J, Morice R, Owen C, Korten A. Use of antipsychotic medications in Australia between July 1995 and December 2001. Aust N Z J Psychiatry 2003 Feb;37(1): 55-61.
22. Ashcroft DM, Frischer M, Lockett J, Chapman SR. Variations in prescribing atypical antipsychotic drugs in primary care: crosssectional study. Pharmacoepidemiol Drug Saf 2002 Jun;11(4):285-9.
23. Geddes J. Generating evidence to inform policy and practice: the example of the second generation "atypical" antipsychotics. Schizophr Bull 2003;29(1):105-14.
24. Glick ID, Murray SR, Vasudevan P, Marder SR, Hu RJ. Treatment with atypical antipsychotics: new indications and new populations. J Psychiatr Res 2001 May;35(3): 187-91.
25. Lieberman J. Primary Care Companion. J Clin Psychiatry 2003;5(Supplement 3):3-8.
26. Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ 2005;330(7496):874.
27. Zhong KX, Tariot PN, Mintzer J, Minkwitz MC, Devine NA. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebocontrolled study. Current Alzheimer Research 2007;4(1):81-93.
28. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999 Sep 22;53(5):946- 55.
29. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry 1999 Feb;60(2):107-15.
30. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003 Feb;64(2):134-43.
31. Chan WC, Lam LC, Choy CN, Leung VP, Li SW, Chiu HF. A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001;16(12):115
32. Fontaine CS, Hynan LS, Koch K, Martin-Cook K, Svetlik D, Weiner MF. A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities. J Clin Psychiatry 2003;64(6):726-30.
33. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a doubleblind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):4
34. Gareri P, Cotroneo A, Lacava R, et al. Comparison of the efficacy of new and conventional antipsychotic drugs in the treatment of behavioral and psychological
symptoms of dementia (BPSD). Archives of Gerontology & Geriatrics - Supplement 2004;(9):207-15
35. Deberdt WG, Dysken MW, Rappaport SA, et al. Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia. Am J Geriatr Psychiatry 2005;13(8):722-30.
36. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355(15):1525-38.
37. Verhey FR, Verkaaik M, Lousberg R, Olanzapine-Haloperidol in Dementia Study group. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dement Geriatr Cogn Disord 2006;21(1):1-8.
38. Therapeutic Products Directorate HC. Risperidone. Notices of compliance [database online].Ottawa: 2007.
39. Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clinical Neuropharmacology 1998;21(3):176-80.
40. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Amer J Psychiat 2002;159(7):1146-54.
41. Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. International Clinical Psychopharmacology 1999;14(6):339- 43.
42. Shi L, Namjoshi MA, Zhang F, et al. Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status. Int Clin Psychopharmacol 2002;17(5):227-37.
43. Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. A 12-week, double-blind comparison of olanzapine vs. haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003;60(12):1218-26.
44. Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 2002;159(6):1011-7.
45. Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry 2002;63(12):1148-55.
46. Revicki DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM, Depakote Comparator Study Group. Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes. J Clin Psychiatry 2003;64(3):288-94.
47. Meehan K, Zhang F, David S, et al. A doubleblind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol 2001;21(4):389- 97.
48. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiat 2005;66(1):111-21.
49. McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. European Neuropsychopharmacology 2005;15(5):573-85.
50. Smulevich AB, Khanna S, Eerdekens M, Karcher K, Kramer M, Grossman F. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. European Neuropsychopharmacology 2005;15(1):75-84.
51. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003;160(7):1263-71.
52. Therapeutic Products Directorate HC. Quetiapine. Notices of compliance [database online].Ottawa: 2007.
53. Therapeutic Products Directorate HC. Olanzapine. Notices of compliance [database online].Ottawa: 2007.
54. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347(5):314-21.
55. Nagaraj R, Singhi P, Malhi P. Risperidone in children with autism: randomized, placebocontrolled, double-blind study. Journal of Child Neurology 2006;21(6):450-5.
56. Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004;114(5):e634-e641.
57. Troost PW, Lahuis BE, Steenhuis MP, et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Academy of Child & Adolescent Psychiat 2005;44(11):1137-44.
58. Luby J, Mrakotsky C, Stalets MM, et al. Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy. Journal of Child & Adolescent Psychopharmacology 2006;16(5):575-87.
59. Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Academy of Child & Adolescent Psychiat 2001;40(8):887-94.
60. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079-88.
61. Calabrese JR, Keck PE, Jr., MacFadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60.
62. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebocontrolled study (the BOLDER II study). J Clin Psychopharmacol 2006;26(6):600-9.
63. Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depression & Anxiety 2006;23(6):364-72.
64. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.
65. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006;31(11):2505- 13.
66. Doree JP, Des RJ, Lew V, et al. Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Current Medical Research & Opinion 2007; 23(2):333-41.
67. Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002;17(3):115-9.
68. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 2004;65(4):565-8.
69. Denys D, de GF, van Megen HJ, Westenberg HG. A double-blind, randomized, placebocontrolled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004;65(8):1040-8.
70. Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Eur Neuropsychopharmacol 2005;15(1):69-74.
71. Fineberg NA, Sivakumaran T, Roberts A, Gale T. Adding quetiapine to SRI in treatmentresistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol 2005;20(4):223-6.
72. Hollander E, Baldini RN, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2003;6(4):397-401.
73. Li X, May RS, Tolbert LC, Jackson WT, Flournoy JM, Baxter LR. Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study. J Clin Psychiatry 2005;66(6):736-43.
74. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebocontrolled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2000;57(8):794-801.
75. Carey PD, Vythilingum B, Seedat S, Muller JE, van AM, Stein DJ. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebocontrolled study [ISRCTN83050762]. BMC Psychiatry 2005;5(1):5.
76. Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry 2004;55(5):553-5.
77. Schneeweiss S, Soumerai SB, Glynn RJ, Maclure M, Dormuth C, Walker AM. Impact of reference-based pricing for angiotensinconverting enzyme inhibitors on drug utilization. CMAJ 2002 Mar 19;166(6):737-45.
78. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005 Sep 22;353(12):1209-23.
79. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006 Apr;163(4):600-10.
80. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006 Oct;63(10):1079-87.