- Email: [email protected]
The use of concomitant medications in psychiatric inpatients treated with either olanzapine or other antipsychotic agents
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437 – 440
Article
The use of concomitant medications in psychiatric inpatients treated with either olanzapine or other antipsychotic agents A naturalistic study at a state psychiatric hospital Haranath Parepallya,b,c, Sudeep Chakravortya, Joseph Levinea,b,c, Jaspreet S. Brara,b, Amit M. Patelc, James W. Bairdb,c, Lokaranjit Chalasania,b,c, Joyce A. Delaneya,b,c, Rebecca Atzerta,b,c, K.N. Roy Chengappaa,b,c,* a
Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA University of Pittsburgh Medical Center, Pittsburgh, PA, USA c Special Studies Center, Mayview State Hospital, Pittsburgh, PA, USA b
Abstract Concomitant medications are frequently used in the treatment of resistant psychiatric conditions to augment the primary psychotropic agent or to ameliorate side effects. The present study evaluated the prescription of concomitant psychiatric medications for psychiatric inpatients that were prescribed either olanzapine at its first commercial availability or another first-line antipsychotic agent. Sixty-nine newly admitted patients (mainly with schizophrenia) who were prescribed either olanzapine (n = 35) or another first-line antipsychotic agent (n = 34) were assessed (for the prescription of other concomitant psychotropic drugs) before (2 – 4 weeks prior to study) and following 8 weeks of treatment (unless discharged sooner). The results indicate that significantly fewer olanzapine-treated subjects were prescribed anticholinergic agents as compared to those prescribed other first-line antipsychotic agents, and a similar trend was noted in the prescription of mood stabilizers as well. Olanzapine-treated subjects used less as needed (PRN) antipsychotic medication compared to pre-olanzapine treatment period. Olanzapine-treated subjects used more anxiolytic agents compared to the control group in the early stages of treatment, probably due to the greater baseline severity of illness. These data suggest that olanzapine use is associated with less use of anticholinergic and moodstabilizing agents as compared to older antipsychotic agents. These results also suggest that there is less need for PRN antipsychotic medication following olanzapine treatment. More severely ill subjects may require more anxiolytics during olanzapine initiation. The need for less anticholinergic and mood-stabilizing agent use with olanzapine could lead to greater adherence to long-term treatment and perhaps decreased cost (i.e. use of blood and organ system monitoring with mood stabilizers). At the end of treatment, olanzapine-treated subjects had statistically significantly lesser concomitant medicine usage compared to control subjects. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Concomitant medication; Olanzapine; Polypharmacy; Schizophrenia; Schizoaffective
1. Introduction The use of concomitant medications along with antipsychotic agents is frequently noted in clinical practice. These additional medications may control cognitive and affective psychopathology, anxiety symptoms, aggressive behavior,
Abbreviations: CGI, Clinical global improvement; CPZ, Chlorpromazine; EPS, Extrapyramidal side effects; PANSS, Positive and negative syndrome scale; PRN, As needed * Corresponding author. Special Studies Center, Mayview State Hospital, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel.: +1-412-624-2634; fax: +1-412-624-3429. E-mail address: [email protected] (K.N.R. Chengappa).
suicidality and parkinsonian side effects. Such a strategy may have some beneficial effects as it may enable more optimal control of symptoms, especially in subjects where only partial response is achieved with antipsychotic monotherapy (Wolkowitz, 1993; Siris, 1993). However, such polypharmacy is also associated with an increased risk for side effects, drug interactions and decreased compliance (Siris, 1993) and also increased cost of treatment overall. Williams et al. (1999) evaluated the use of antipsychotic and concomitant medication patterns in an outpatients with schizophrenia reporting that nearly 90% of these patients received concomitant medications. This suggests that the use of concomitant medications is more common rather than the exception in the treatment of patients with schizophre-
0278-5846/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 7 9 - 2
438
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
nia. Galletly and Tsourtos (1997) reported an association between the use of high doses of neuroleptic treatment and the use of lithium, carbamazepine or benzodiazepines as adjunctive treatment in patients with schizophrenia. Such data may suggest that the treating physician tends to augment or add concomitant medications in patients who respond only partially or still have residual symptoms following the use of high doses of antipsychotic agents. Interestingly, these authors also reported that the use of antiparkinsonian drugs was not related to the chlorpromazine (CPZ) equivalent dose. Such data are generally unavailable from efficacy-driven, acute-controlled trials. Hence, we and the hospital administrators were interested in this issue. The study was conducted soon after the commercial availability of olanzapine in a state hospital setting. The following study evaluated the use of concomitant medications in olanzapine-treated subjects compared to a group who received other first-line antipsychotic agents.
2. Methods 2.1. Patient population and data assessments The present study assessed the use of concomitant medications among newly admitted inpatients to a state hospital suffering from schizophrenia, schizoaffective disorder or bipolar illness. Patients were grouped according to the antipsychotic treatment prescribed, which was olanzapine (n = 35) or another antipsychotic agent (n = 34). These included haloperidol (n = 11), loxapine (n = 1), thioridazine (n = 3), perphenazine (n = 3), trifluperanzine (n = 2), thiothixene (n = 4), fluphenazine (n = 6) and risperidone (n = 4). Treatment was initiated in nearly all cases by a treating psychiatrist — not associated with the study — on clinical grounds, i.e. doctor and patient choice. Each patient receiving olanzapine was matched to a comparator patient based upon length of illness, length of hospital stay and diagnostic group (either bipolar disorder or schizoaffective –bipolar type taken together or schizophrenia and schizoaffectivedepressed type taken together). Patients treated with clozapine were not included, as this drug is not a first-line antipsychotic agent in this hospital. The concomitant psychotropic medication data as well as as needed (PRN) medication data were gathered for two periods. The first was prior to olanzapine treatment (range of 2– 4 weeks in all subjects) and during olanzapine treatment for up to 8 weeks unless discharged or discontinued sooner. The mean duration of hospitalization prior to olanzapine treatment was 68 days (66 days for the comparator group). The mean duration of hospital stay following olanzapine treatment was 90 days (84 days for the comparator group). The study was carried out between January 1997 and July 1997. The medical charts were reviewed. The data were extracted, coded for research identity and were supplied blinded to treatment assignment by a volunteer staff member independent of the
investigative staff. The study was approved by the Office of Mental Health and Substance Abuse Services of the Commonwealth of Pennsylvania and by the University of Pittsburgh as exempt from requiring informed consent. 2.2. Data analysis Baseline demographic and clinical data were evaluated by Pearson’s c2 Test or Fisher’s Exact Test for categorical data, and independent sample t test was used for continuous data. Dichotomous responses were used to record the use of any given class of concomitant medications before and during the study in both the olanzapine and control groups. Within-group comparisons of the concordance (or discordance) for the number of subjects using adjunct medications before and during the study medication periods were examined using a McNemar modification of a c2 test. Betweengroup comparisons were tested using the Pearson’s c2 Test. The Wilcoxon Sign Test was used to test for differences within each of the study groups (before vs. during treatment) in the number of patients with increased vs. decreased use of PRN medications. All analyses were tested for statistical significance at a two-tailed a level of .05.
3. Results Table 1 describes the characteristics of the two study groups. Mean ± S.D. daily dose of olanzapine group was 15.2 ± 5 mg, and for the control group, it was 937 ± 648 CPZ equivalent dose. The olanzapine group had higher clinical global improvement (CGI) severity scores at baseline compared to the control group. Tables 2 and 3 present the number of subjects using or not using concomitant medications before and during treatment with either olanzapine or other antipsychotic agents. In the olanzapine-treated group, there was a significant deTable 1 Demographic characteristics of the study groups Variable Age in years (mean ± S.D.) Gender Males Females DSM-IV diagnosis Schizophrenia Schizoaffective Bipolar disorder Age of onset in years (mean ± S.D.) Length of illness in years (mean ± S.D.) No. Previous Hospitalization (Mean ± S. D.) Baseline CGI (mean ± S.D.)
Olanzapine group (n = 35)
Control group (n = 34)
42 ± 9
42 ± 9
19 16
16 18
21 12 (three bipolar types) 2 23 ± 7
22 11 (three bipolar types) 1 23 ± 8
18 ± 9
18 ± 10
14 ± 16
10 ± 6
4.8 ± 0.7
3.9 ± 1.0
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
crease in the numbers of patients using anti-parkinsonian medications during olanzapine treatment as compared to the pretreatment period (Table 2). No such difference was found for the control group. One subject in the comparator group was receiving b-blockers for akathisia. The issue of using two antipsychotics was considered but was not applicable to this study, as olanzapine-treated subjects did not have a second antipsychotic agent after the cross-taper and titration, which occurred in 1– 2 weeks. Also, none of the subjects in the control group required a second antipsychotic agent. No other within-group comparison was statistically significant for any other concomitant medication class (i.e. mood stabilizers, antidepressants and anxiolytic agents). Between-group comparison demonstrated a statistically significant decrease in the number of subjects using anticholinergic drugs and a statistically significant increase in the number of subjects using anxiolytic agents during olanzapine treatment as compared to the control group (especially in the first 2 –4 weeks of treatment). A trend towards decrease in the number of subjects using mood stabilizers during the olanzapine treatment as compared to the control treatment was also noted (Table 3). No other between-group statistically significant differences were noted (Table 3). No difference was found in either the olanzapine or comparator group for PRN anxiolytic use or for medications used to treat extrapyramidal side effects (EPS; data not shown separately). However, the use of PRN antipsychotic medications (mainly intramuscular haloperidol or droperidol) was increased in 1 and decreased in 7 of 33 patients in the olanzapine-treated group, demonstrating a statistically significant difference ( P = .023). An opposite trend was noted in the comparator group for PRN antipsychotic medication use: increase in 6 and decrease in 2 of 31 patients, though this was not statistically significant. Independent t tests were conducted to compare the change for number of patients taking different classes of PRN medications between the two study groups. No statistically significant difference was found for the use of anxiolytics, EPS or antipsychotic medications between the study groups.
Table 2 Use of concomitant medications prior to and during the study periods: within group comparisons for discordant pairsa Olanzapine group
Comparator group
Concomitant medication
Pre
During
Pre
During
Antidepressants Mood stabilizers Anxiolytics Anticholinergics
10 20 15 25
12 16 16 15
10 21 11 23
11 22 6 25
a
(29%) (59%) (43%) (74%)
(35%) (47%) (47%) (44%)b
(30%) (64%) (33%) (70%)
(34%) (69%) (19%) (81%)
Number of subjects in the olanzapine group was 35 and the control group was 33. Data for one to two subjects was missing for one or two of the concomitant drugs in either the olanzapine or the control group. b Not significant.
439
Table 3 Use of concomitant medications during the study period: between group comparisonsa
Antidepressants Mood stabilizers Anxiolytics Anticholinergics
Olanzapine group
Control group
c2 test
Level of significance ( P value)
12 16 16 15
11 (34%) 22 (69%) 6 (19%) 25 (81%)
0.06 3.18 5.56 9.14
NSb .06c .035d .003e
(35%) (47%) (47%) (44%)
a Number of subjects in the olanzapine group was 35 and the control group was 33. Data for one to two subjects was missing for one or two of the concomitant drugs in either the olanzapine or the control group. b Not significant. c Statistical trend for fewer olanzapine treated subjects to use mood stabilizers than controls. d Statistically significant increased use of anxiolytics in olanzapinetreated subjects. e Statistically fewer olanzapine-treated subjects use anticholinergic agents.
The total number of concomitant psychotropic medicines of different classes, mood stabilizers, anti-parkinsonian, antidepressant, etc. between the olanzapine and comparator groups was evaluated at the end of the study period. Olanzapine-treated subjects had significantly fewer concomitant medicines (mean 2.3 ± 0.84) as compared to the control group (mean 2.9 ± 1.1, t = 2.37, df = 60, P=.021) at the end of the study period.
4. Discussion The present study is a naturalistic ‘‘real life’’ study comparing olanzapine with other first-line antipsychotic medications. Our results suggest that olanzapine may have an advantage over other antipsychotic medication (typical, first-generation antipsychotic agents) in the use of certain concomitant medications. However, our design was open, and comparisons with specific antipsychotic medications were not conducted. Fewer subjects in the olanzapine group received antiEPS medications. This is in agreement with previous studies that indicate olanzapine has fewer EPS compared with other traditional neuroleptics (Beasley et al., 1996). Since the use of anti-EPS medications is associated with anticholinergic effects including cognitive impairment and also carry the risk of abuse by some patients, such results are encouraging for the use of olanzapine. We have previously noted that an in vivo assay of anticholinergicity indicated olanzapine had one-fifth the anticholinergicity of clozapine (Chengappa et al., 2000). In the discussion section of that paper, we note that the use of standard anti-parkinsonian agents, such as benztropine, results in anticholinergic levels that are 10-fold higher than olanzapine (Chengappa et al., 2000). Therefore, the issue of anticholinergicity and olanzapine is more complex than suggested by the earlier in vitro data.
440
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
More subjects in the olanzapine group were taking anxiolytic medications. As subjects in this group were more severely ill at baseline, this may have led to more frequent use of anxiolytics at least during the early phase of olanzapine use. However, the use of anxiolytic agents may have potentiated the effects of olanzapine. There was a tendency towards less use of mood stabilizers in the olanzapine group compared with the comparator group. There are data indicating that olanzapine has antimanic effects (Tohen et al., 1999). Such reduced use of mood stabilizers, if clinically appropriate, may increase adherence to treatment by patients and reduce monitoring requirements (blood levels, liver functions, hematology, kidney and thyroid functions) and potential drug interactions. Overall, by the end of the study period, olanzapinetreated subjects were using less concomitant psychotropic medicines than the comparator group.
5. Conclusion This naturalistic study assessed the use of concomitant medications among newly admitted state hospital patients with either schizophrenia, schizoaffective or bipolar disorder prescribed either olanzapine or other antipsychotic agents. Data from this study suggest that olanzapine use was associated with less EPS or mood-stabilizing medications as concomitant therapy but increased use of anxiolytic agents in the initial phase of treatment. Overall, the reductions in the use of concomitant medications may result in increased patient adherence to long-term olanzapine treatment.
Acknowledgments The authors thank Tracy Anderson for help with data management, David Jones, CEO, Aziz Gopalani, MD, William Suvak and the Medical Records staff at Mayview State Hospital for technical help and Drs. Davis and Karp of the Office of Mental Health and Substance Abuse Services, Commonwealth of Pennsylvania for facilitating the study.
References Beasley, C.M., Tollefson, G., Tran, P., Satterlee, W., Sanger, T., Hamilton, S., 1996. Olanzapine versus placebo and haloperidol: acute phase results of the north American double-blind olanzapine trial. Neuropsychopharmacology 14, 111 – 123. Chengappa, K.N.R., Pollock, B.G., Parepally, H., Levine, J., Kirshner, M.A., Brar, J.S., Zoretich, R.A., 2000. Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine. J. Clin. Psychopharmacol. 20, 311 – 316. Galletley, C.A., Tsourtos, G., 1997. Antipsychotic drug doses and adjunctive drugs in the outpatient treatment of schizophrenia. Ann. Clin. Psychiatry 9, 77 – 80. Siris, S.G., 1993. Adjunctive medication in the maintenance treatment of schizophrenia and its conceptual implications. Br. J. Psychiatry 163, 66 – 78. Tohen, M., Sanger, T.M., Mcelroy, S.L., Tollefson, G.D., Chengappa, K.N.R., Daniel, D.G., 1999. Olanzapine versus placebo in the treatment of acute mania. Am. J. Psychiatry 156, 702 – 709. Williams, C.L., Johnstone, B.M., Kesterson, J.G., Javor, K.A., Schmetzer, A.D., 1999. Evaluation of antipsychotic and concomitant medication use patterns in patients with schizophrenia. Med. Care 37, AS81 – AS86. Wolkowitz, O.M., 1993. Rational polypharmacy in schizophrenia. Ann. Clin. Psychiatry 5, 79 – 90.
Article
The use of concomitant medications in psychiatric inpatients treated with either olanzapine or other antipsychotic agents A naturalistic study at a state psychiatric hospital Haranath Parepallya,b,c, Sudeep Chakravortya, Joseph Levinea,b,c, Jaspreet S. Brara,b, Amit M. Patelc, James W. Bairdb,c, Lokaranjit Chalasania,b,c, Joyce A. Delaneya,b,c, Rebecca Atzerta,b,c, K.N. Roy Chengappaa,b,c,* a
Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA University of Pittsburgh Medical Center, Pittsburgh, PA, USA c Special Studies Center, Mayview State Hospital, Pittsburgh, PA, USA b
Abstract Concomitant medications are frequently used in the treatment of resistant psychiatric conditions to augment the primary psychotropic agent or to ameliorate side effects. The present study evaluated the prescription of concomitant psychiatric medications for psychiatric inpatients that were prescribed either olanzapine at its first commercial availability or another first-line antipsychotic agent. Sixty-nine newly admitted patients (mainly with schizophrenia) who were prescribed either olanzapine (n = 35) or another first-line antipsychotic agent (n = 34) were assessed (for the prescription of other concomitant psychotropic drugs) before (2 – 4 weeks prior to study) and following 8 weeks of treatment (unless discharged sooner). The results indicate that significantly fewer olanzapine-treated subjects were prescribed anticholinergic agents as compared to those prescribed other first-line antipsychotic agents, and a similar trend was noted in the prescription of mood stabilizers as well. Olanzapine-treated subjects used less as needed (PRN) antipsychotic medication compared to pre-olanzapine treatment period. Olanzapine-treated subjects used more anxiolytic agents compared to the control group in the early stages of treatment, probably due to the greater baseline severity of illness. These data suggest that olanzapine use is associated with less use of anticholinergic and moodstabilizing agents as compared to older antipsychotic agents. These results also suggest that there is less need for PRN antipsychotic medication following olanzapine treatment. More severely ill subjects may require more anxiolytics during olanzapine initiation. The need for less anticholinergic and mood-stabilizing agent use with olanzapine could lead to greater adherence to long-term treatment and perhaps decreased cost (i.e. use of blood and organ system monitoring with mood stabilizers). At the end of treatment, olanzapine-treated subjects had statistically significantly lesser concomitant medicine usage compared to control subjects. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Concomitant medication; Olanzapine; Polypharmacy; Schizophrenia; Schizoaffective
1. Introduction The use of concomitant medications along with antipsychotic agents is frequently noted in clinical practice. These additional medications may control cognitive and affective psychopathology, anxiety symptoms, aggressive behavior,
Abbreviations: CGI, Clinical global improvement; CPZ, Chlorpromazine; EPS, Extrapyramidal side effects; PANSS, Positive and negative syndrome scale; PRN, As needed * Corresponding author. Special Studies Center, Mayview State Hospital, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel.: +1-412-624-2634; fax: +1-412-624-3429. E-mail address: [email protected] (K.N.R. Chengappa).
suicidality and parkinsonian side effects. Such a strategy may have some beneficial effects as it may enable more optimal control of symptoms, especially in subjects where only partial response is achieved with antipsychotic monotherapy (Wolkowitz, 1993; Siris, 1993). However, such polypharmacy is also associated with an increased risk for side effects, drug interactions and decreased compliance (Siris, 1993) and also increased cost of treatment overall. Williams et al. (1999) evaluated the use of antipsychotic and concomitant medication patterns in an outpatients with schizophrenia reporting that nearly 90% of these patients received concomitant medications. This suggests that the use of concomitant medications is more common rather than the exception in the treatment of patients with schizophre-
0278-5846/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 7 9 - 2
438
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
nia. Galletly and Tsourtos (1997) reported an association between the use of high doses of neuroleptic treatment and the use of lithium, carbamazepine or benzodiazepines as adjunctive treatment in patients with schizophrenia. Such data may suggest that the treating physician tends to augment or add concomitant medications in patients who respond only partially or still have residual symptoms following the use of high doses of antipsychotic agents. Interestingly, these authors also reported that the use of antiparkinsonian drugs was not related to the chlorpromazine (CPZ) equivalent dose. Such data are generally unavailable from efficacy-driven, acute-controlled trials. Hence, we and the hospital administrators were interested in this issue. The study was conducted soon after the commercial availability of olanzapine in a state hospital setting. The following study evaluated the use of concomitant medications in olanzapine-treated subjects compared to a group who received other first-line antipsychotic agents.
2. Methods 2.1. Patient population and data assessments The present study assessed the use of concomitant medications among newly admitted inpatients to a state hospital suffering from schizophrenia, schizoaffective disorder or bipolar illness. Patients were grouped according to the antipsychotic treatment prescribed, which was olanzapine (n = 35) or another antipsychotic agent (n = 34). These included haloperidol (n = 11), loxapine (n = 1), thioridazine (n = 3), perphenazine (n = 3), trifluperanzine (n = 2), thiothixene (n = 4), fluphenazine (n = 6) and risperidone (n = 4). Treatment was initiated in nearly all cases by a treating psychiatrist — not associated with the study — on clinical grounds, i.e. doctor and patient choice. Each patient receiving olanzapine was matched to a comparator patient based upon length of illness, length of hospital stay and diagnostic group (either bipolar disorder or schizoaffective –bipolar type taken together or schizophrenia and schizoaffectivedepressed type taken together). Patients treated with clozapine were not included, as this drug is not a first-line antipsychotic agent in this hospital. The concomitant psychotropic medication data as well as as needed (PRN) medication data were gathered for two periods. The first was prior to olanzapine treatment (range of 2– 4 weeks in all subjects) and during olanzapine treatment for up to 8 weeks unless discharged or discontinued sooner. The mean duration of hospitalization prior to olanzapine treatment was 68 days (66 days for the comparator group). The mean duration of hospital stay following olanzapine treatment was 90 days (84 days for the comparator group). The study was carried out between January 1997 and July 1997. The medical charts were reviewed. The data were extracted, coded for research identity and were supplied blinded to treatment assignment by a volunteer staff member independent of the
investigative staff. The study was approved by the Office of Mental Health and Substance Abuse Services of the Commonwealth of Pennsylvania and by the University of Pittsburgh as exempt from requiring informed consent. 2.2. Data analysis Baseline demographic and clinical data were evaluated by Pearson’s c2 Test or Fisher’s Exact Test for categorical data, and independent sample t test was used for continuous data. Dichotomous responses were used to record the use of any given class of concomitant medications before and during the study in both the olanzapine and control groups. Within-group comparisons of the concordance (or discordance) for the number of subjects using adjunct medications before and during the study medication periods were examined using a McNemar modification of a c2 test. Betweengroup comparisons were tested using the Pearson’s c2 Test. The Wilcoxon Sign Test was used to test for differences within each of the study groups (before vs. during treatment) in the number of patients with increased vs. decreased use of PRN medications. All analyses were tested for statistical significance at a two-tailed a level of .05.
3. Results Table 1 describes the characteristics of the two study groups. Mean ± S.D. daily dose of olanzapine group was 15.2 ± 5 mg, and for the control group, it was 937 ± 648 CPZ equivalent dose. The olanzapine group had higher clinical global improvement (CGI) severity scores at baseline compared to the control group. Tables 2 and 3 present the number of subjects using or not using concomitant medications before and during treatment with either olanzapine or other antipsychotic agents. In the olanzapine-treated group, there was a significant deTable 1 Demographic characteristics of the study groups Variable Age in years (mean ± S.D.) Gender Males Females DSM-IV diagnosis Schizophrenia Schizoaffective Bipolar disorder Age of onset in years (mean ± S.D.) Length of illness in years (mean ± S.D.) No. Previous Hospitalization (Mean ± S. D.) Baseline CGI (mean ± S.D.)
Olanzapine group (n = 35)
Control group (n = 34)
42 ± 9
42 ± 9
19 16
16 18
21 12 (three bipolar types) 2 23 ± 7
22 11 (three bipolar types) 1 23 ± 8
18 ± 9
18 ± 10
14 ± 16
10 ± 6
4.8 ± 0.7
3.9 ± 1.0
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
crease in the numbers of patients using anti-parkinsonian medications during olanzapine treatment as compared to the pretreatment period (Table 2). No such difference was found for the control group. One subject in the comparator group was receiving b-blockers for akathisia. The issue of using two antipsychotics was considered but was not applicable to this study, as olanzapine-treated subjects did not have a second antipsychotic agent after the cross-taper and titration, which occurred in 1– 2 weeks. Also, none of the subjects in the control group required a second antipsychotic agent. No other within-group comparison was statistically significant for any other concomitant medication class (i.e. mood stabilizers, antidepressants and anxiolytic agents). Between-group comparison demonstrated a statistically significant decrease in the number of subjects using anticholinergic drugs and a statistically significant increase in the number of subjects using anxiolytic agents during olanzapine treatment as compared to the control group (especially in the first 2 –4 weeks of treatment). A trend towards decrease in the number of subjects using mood stabilizers during the olanzapine treatment as compared to the control treatment was also noted (Table 3). No other between-group statistically significant differences were noted (Table 3). No difference was found in either the olanzapine or comparator group for PRN anxiolytic use or for medications used to treat extrapyramidal side effects (EPS; data not shown separately). However, the use of PRN antipsychotic medications (mainly intramuscular haloperidol or droperidol) was increased in 1 and decreased in 7 of 33 patients in the olanzapine-treated group, demonstrating a statistically significant difference ( P = .023). An opposite trend was noted in the comparator group for PRN antipsychotic medication use: increase in 6 and decrease in 2 of 31 patients, though this was not statistically significant. Independent t tests were conducted to compare the change for number of patients taking different classes of PRN medications between the two study groups. No statistically significant difference was found for the use of anxiolytics, EPS or antipsychotic medications between the study groups.
Table 2 Use of concomitant medications prior to and during the study periods: within group comparisons for discordant pairsa Olanzapine group
Comparator group
Concomitant medication
Pre
During
Pre
During
Antidepressants Mood stabilizers Anxiolytics Anticholinergics
10 20 15 25
12 16 16 15
10 21 11 23
11 22 6 25
a
(29%) (59%) (43%) (74%)
(35%) (47%) (47%) (44%)b
(30%) (64%) (33%) (70%)
(34%) (69%) (19%) (81%)
Number of subjects in the olanzapine group was 35 and the control group was 33. Data for one to two subjects was missing for one or two of the concomitant drugs in either the olanzapine or the control group. b Not significant.
439
Table 3 Use of concomitant medications during the study period: between group comparisonsa
Antidepressants Mood stabilizers Anxiolytics Anticholinergics
Olanzapine group
Control group
c2 test
Level of significance ( P value)
12 16 16 15
11 (34%) 22 (69%) 6 (19%) 25 (81%)
0.06 3.18 5.56 9.14
NSb .06c .035d .003e
(35%) (47%) (47%) (44%)
a Number of subjects in the olanzapine group was 35 and the control group was 33. Data for one to two subjects was missing for one or two of the concomitant drugs in either the olanzapine or the control group. b Not significant. c Statistical trend for fewer olanzapine treated subjects to use mood stabilizers than controls. d Statistically significant increased use of anxiolytics in olanzapinetreated subjects. e Statistically fewer olanzapine-treated subjects use anticholinergic agents.
The total number of concomitant psychotropic medicines of different classes, mood stabilizers, anti-parkinsonian, antidepressant, etc. between the olanzapine and comparator groups was evaluated at the end of the study period. Olanzapine-treated subjects had significantly fewer concomitant medicines (mean 2.3 ± 0.84) as compared to the control group (mean 2.9 ± 1.1, t = 2.37, df = 60, P=.021) at the end of the study period.
4. Discussion The present study is a naturalistic ‘‘real life’’ study comparing olanzapine with other first-line antipsychotic medications. Our results suggest that olanzapine may have an advantage over other antipsychotic medication (typical, first-generation antipsychotic agents) in the use of certain concomitant medications. However, our design was open, and comparisons with specific antipsychotic medications were not conducted. Fewer subjects in the olanzapine group received antiEPS medications. This is in agreement with previous studies that indicate olanzapine has fewer EPS compared with other traditional neuroleptics (Beasley et al., 1996). Since the use of anti-EPS medications is associated with anticholinergic effects including cognitive impairment and also carry the risk of abuse by some patients, such results are encouraging for the use of olanzapine. We have previously noted that an in vivo assay of anticholinergicity indicated olanzapine had one-fifth the anticholinergicity of clozapine (Chengappa et al., 2000). In the discussion section of that paper, we note that the use of standard anti-parkinsonian agents, such as benztropine, results in anticholinergic levels that are 10-fold higher than olanzapine (Chengappa et al., 2000). Therefore, the issue of anticholinergicity and olanzapine is more complex than suggested by the earlier in vitro data.
440
H. Parepally et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 437–440
More subjects in the olanzapine group were taking anxiolytic medications. As subjects in this group were more severely ill at baseline, this may have led to more frequent use of anxiolytics at least during the early phase of olanzapine use. However, the use of anxiolytic agents may have potentiated the effects of olanzapine. There was a tendency towards less use of mood stabilizers in the olanzapine group compared with the comparator group. There are data indicating that olanzapine has antimanic effects (Tohen et al., 1999). Such reduced use of mood stabilizers, if clinically appropriate, may increase adherence to treatment by patients and reduce monitoring requirements (blood levels, liver functions, hematology, kidney and thyroid functions) and potential drug interactions. Overall, by the end of the study period, olanzapinetreated subjects were using less concomitant psychotropic medicines than the comparator group.
5. Conclusion This naturalistic study assessed the use of concomitant medications among newly admitted state hospital patients with either schizophrenia, schizoaffective or bipolar disorder prescribed either olanzapine or other antipsychotic agents. Data from this study suggest that olanzapine use was associated with less EPS or mood-stabilizing medications as concomitant therapy but increased use of anxiolytic agents in the initial phase of treatment. Overall, the reductions in the use of concomitant medications may result in increased patient adherence to long-term olanzapine treatment.
Acknowledgments The authors thank Tracy Anderson for help with data management, David Jones, CEO, Aziz Gopalani, MD, William Suvak and the Medical Records staff at Mayview State Hospital for technical help and Drs. Davis and Karp of the Office of Mental Health and Substance Abuse Services, Commonwealth of Pennsylvania for facilitating the study.
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