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Roger S. McIntyre
Deborah A. Mancini
Janaki Srinivasan
Sonia McCann McCann
Jakub Z. Konarski
Sidney H. Kennedy


Bipolar disorder, risperidone, olanzapine, adjunct therapy, cohort study



To describe the antidepressant effectiveness of olanzapine and risperidone and compare their tolerability when employed adjunctively in bipolar I/II disorder.



In an observational study, twenty-one ambulatory subjects with DSM-IV defined bipolar I/II disorder, in any phase of the illness, openly received adjunctive risperidone or olanzapine. The primary efficacy

parameters were the Hamilton Depression Rating Scale (HDRS-17) and the Maier and Philips Severity Subscale. Secondary efficacy parameters included the Young Mania Rating Scale (YMRS) along with the Clinical Global Impressions Scale (CGI). Response was defined as a significant change from baseline to endpoint in the total mean HDRS-17 score. The primary tolerability parameters were the Abnormal Involuntary Movement Scale (AIMS) along with changes in weight and body mass index (BMI-kg/m2). Patients were evaluated prospectively with repeated monthly assessments for up to 6 months.



Eleven patients openly received risperidone; 10  received olanzapine adjunctive to  either lithium or divalproex. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups

(p=0.001), with the mean HDRS-17 total scores falling from 17(SD=3.2) to 5(SD=1.5) by 6 months in the risperidone-treated  group  and  from  18  (SD=1.9)  to  7  (SD=2.0)  in  the  olanzapine-treated  group. Differences between the risperidone-treated group and the olanzapine-treated group were not significant at  6  months  (p=0.754). The  mean  doses  of  study  medication were  2.88  (SD=1.6) mg/day  for  the risperidone-treated group and 12.69 (SD=2.3) mg/day for the olanzapine-treated group. Both risperidone

and olanzapine were generally well tolerated. No patients developed tardive dyskinesia. Significant

weight gain was experienced by patients in both groups [mean weight gain at endpoint was 5.9 kg in risperidone (p=0.023) and 11.3 kg in olanzapine (p=0.001)]. There was a significant difference in weight gain between the risperidone-treated group and the olanzapine-treated group (p=0.001).



These pilot data, from the first prospective comparison study of risperidone and olanzapine in bipolar disorder, suggest that adjunctive administration of either agent may reduce depressive symptom severity. No subjects receiving risperidone or olanzapine developed tardive dyskinesia. Both compounds imparted substantial weight gain with significantly more weight gain accrual with olanzapine. As this was an observational  study,  the  antidepressant  effect  and  tolerability  profile  of  these  compounds  requires

validation via double-blind placebo controlled investigations.

Abstract 299 | PDF Downloads 51


1. Angst J: Major depression in 1998: are we providing optimal therapy? J Clin Psychiatry
1999; 60(Suppl 6):5-9.
2. Angst J, Sellaro R: Historical perspectives and natural history of bipolar disorder. Biol Psychiatry 2000; 48(6):445-57.
3. Tohen M, Jacobs TG, Feldman PD: Onset of action of antipsychotics in the treatment of mania. Bipolar Disord 2000; 2(3 Pt 2):261-8.
4. Murray CJ, Lopez AD: Evidence-based health policy--lessons from the Global Burden of Disease Study. Science 1996; 274(5288):740-
5. Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, Bryant-Comstock L: The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics 2001; 19(5):483-95.
6. Sachs GS: Bipolar mood disorder: practical strategies for acute and maintenance phase treatment. J Clin Psychopharmacol 1996; 16(2
Suppl 1):32S-47S.
7. Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs TG, David SR, Toma V: Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 1999; 156(5):702-9.
8. Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM: The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994; 31(4):281-94.
9. Keller MB, Baker LA: Bipolar disorder: epidemiology, course, diagnosis, and treatment. Bull Menninger Clin 1991;
10. Gitlin MJ, Swendsen J, Heller TL, Hammen C: Relapse and impairment in bipolar disorder. Am J Psychiatry 1995; 152(11):1635-40.
11. Isometsa ET, Henriksson MM, Aro HM,
Lonnqvist JK: Suicide in bipolar disorder in
Finland. Am J Psychiatry 1994; 151(7):1020-
12. Ghaemi SN: On defining 'mood stabilizer'.
Bipolar Disord 2001; 3(3):154-8.
13. Sanger TM, Grundy SL, Gibson PJ, Namjoshi MA, Greaney MG, Tohen MF: Long-term olanzapine therapy in the treatment of bipolar
I disorder: an open-label continuation phase
study. J Clin Psychiatry 2001; 62(4):273-81.
14. Vieta E, Herraiz M, Fernandez A, Gasto C, Benabarre A, Colom F, Martinez-Aran A, Reinares M: Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. Group for the Study of Risperidone in Affective Disorders (GSRAD). J Clin Psychiatry 2001; 62(8):623-30.
15. Association AP: Diagnostic and statistical manual of mental disorders. Washington, D.C.: American Psychiatric Association, 1994.
16. Hamilton M: A rating scale for depression. J
Neurol Neurosurg. Psychiatry 1960; 23:56-62.
17. Munetz MR, Benjamin S: How to examine patients using the Abnormal Involuntary Movement Scale. Hosp Community Psychiatry 1988; 39(11):1172-7.
18. Young RC, Biggs JT, Ziegler VE, Meyer DA: A rating scale for mania: reliability, validity, and sensitivity. Br J of Psychiatry 1978;
19. Guy W: CGI: Clinical Global Impression.
Rockville, Maryland:ECDEU Assessment Manual for Psychopharmacology., National Institute of Mental Health, 1976.
20. Frank E, Prien RF, Jarrett RB, Keller MB,
Kupfer DJ, Lavori PW, Rush AJ, Weissman MM: Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry
1991; 48(9):851-5.
21. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY: A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158(1):131-4.
22. Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW, Beasley C, Jr., Tollefson GD: Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997; 17(5):407-18.
23. 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; 158(5):765-74.
24. Ghaemi SN, Cherry EL, Katzow JA, Goodwin FK: Does olanzapine have antidepressant properties? A retrospective preliminary study. Bipolar Disord 2000; 2(3 Pt 1):196-9.
25. Ostroff RB, Nelson JC: Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999; 60(4):256-9.
26. Dwight MM, Keck PE, Jr., Stanton SP, Strakowski SM, McElroy SL: Antidepressant

activity and mania associated with risperidone treatment of schizoaffective disorder. Lancet
1994; 344(8921):554-5.
27. Hillert A, Maier W, Wetzel H, Benkert O: Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome--a functional approach. Pharmacopsychiatry 1992; 25(5):213-7.
28. Keck PE, Jr., Wilson DR, Strakowski SM, McElroy SL, Kizer DL, Balistreri TM, Holtman HM, DePriest M: Clinical predictors
of acute risperidone response in schizophrenia,
schizoaffective disorder, and psychotic mood disorders. J Clin Psychiatry 1995; 56(10):466-
29. Rothschild AJ, Bates KS, Boehringer KL, Syed A: Olanzapine response in psychotic depression. J Clin Psychiatry 1999; 60(2):116-
30. Thase ME: Depression, sleep, and antidepressants. J Clin Psychiatry 1998;
59(Suppl 4):55-65.
31. Arvanitis LA, Miller BG: Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a
comparison with haloperidol and placebo. The
Seroquel Trial 13 Study Group. Biol
Psychiatry 1997; 42(4):233-46.
32. Zarate E, Sa Rego MM, White PF, Duffy L, Shearer VE, Griffin JD, Whitten CW: Comparison of adenosine and remifentanil
infusions as adjuvants to desflurane anesthesia.
Anesthesiology 1999; 90(4):956-63.
33. Meltzer HY: Dimensions of outcome with clozapine. Br J Psychiatry Suppl 1992(17):46-
34. Siris SG: Depression in schizophrenia: perspective in the era of "Atypical" antipsychotic agents. Am J Psychiatry 2000;
35. Tollefson GD, Andersen SW: Should we consider mood disturbance in schizophrenia as an important determinant of quality of life? J Clin Psychiatry 1999; 60(Suppl 5):23-9; discussion 30.
36. Ghaemi SN: New treatments for bipolar disorder: the role of atypical neuroleptic agents. J Clin Psychiatry 2000; 61(Suppl
37. Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L: Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol 1980; 13(4):156-67.
38. Remington G, Chong SA: Conventional versus novel antipsychotics: changing concepts and clinical implications. J Psychiatry Neurosci 1999; 24(5):431-41.
39. Kapur S, Remington G: Atypical antipsychotics. Bmj 2000; 321(7273):1360-1.
40. den Boer JA, Westenberg HG, De Leeuw AS, van Vliet IM: Biological dissection of anxiety
disorders: the clinical role of selective serotonin reuptake inhibitors with particular
reference to fluvoxamine. Int Clin
Psychopharmacol 1995; 9 Suppl 4:47-52.
41. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S: Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol 2001; 21(4):425-31.
42. Li XM, Perry KW, Wong DT, Bymaster FP: Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology (Berl) 1998;
43. Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP: Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 2000; 23(3):250-
44. Allison DB, Mentore JL, Heo M, Chandler LP, appelleri JC, Infante MC, Weiden PJ: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156(11):1686-96.
45. Meyer JM: Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;
46. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC: Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry 2000; 157(6):975-81.

47. McIntyre R, McCann S, Kennedy S: Antipsychotic metabolic effects: weight gain, diabetes and hypertriglyceridemia. Canadian Journal of Psychiatry 2001; 46:273-281
48. Conley RR: Risperidone side effects. J Clin
Psychiatry 2000; 61(Suppl 8):20-3; discussion
49. Guille C, Sachs GS, Ghaemi SN: A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry 2000;