- Email: [email protected]
A Pilot Study of Standardized Treatment in Geriatric Bipolar Disorder
BRIEF REPORTS A Pilot Study of Standardized Treatment in Geriatric Bipolar Disorder Ariel G. Gildengers, M.D. Benoit H. Mulsant, M.D. Amy E. Begley, M.A. Mary McShea, M.S. Jacqueline A. Stack, M.S.N. Mark D. Miller, M.D. Andrea Fagiolini, M.D. David J. Kupfer, M.D. Robert C. Young, M.D. Charles F. Reynolds III, M.D.
tained in younger patients with bipolar disorder or retrospective case series in older adults.2 We report on a prospective, open-label study of a group of elderly outpatients with bipolar disorder (N⳱31), treated according to standardized treatment pathways. The purpose of the study was to collect data on the feasibility of recruiting, eliciting informed consent, assessing, treating, and following patients age 60 and older with bipolar disorder. Given the methodological difficulties defining treatment response in patients with high-variability illness characteristics and unstable response,3 we present response as a percentage of euthymic days or “days well,” during the period of observation.
METHODS Subjects
Objective: The authors sought to determine the feasibility of treating elderly adults with bipolar disorder under standardized-treatment conditions. Methods: Thirty-one patients age 60 and older with bipolar disorder were treated in standardized pathways. Mood state was checked at each study visit with the Hamilton Rating Scale for Depression–17 item (Ham-D–17) and the Young Mania Rating Scale (YMRS). Results: Defining “well days” as both Ham-D and YMRS scores of ⱕ10, the mean percentage of well days was 72.5 (range: 0%–100%) over study participation. Conclusions: Treating older adults with bipolar disorder under standardized treatment is feasible and is associated with low symptom levels. However, most older adults with bipolar disorder do not experience sustained recovery. (Am J Geriatr Psychiatry 2005; 13:319– 323)
B
ipolar disorder represents 5% to 12% of geriatric psychiatry inpatient admissions.1 In the absence of any controlled studies, the treatment of geriatric bipolar disorder must be extrapolated from data ob-
Patients age 60 years and older with bipolar disorder who presented as inpatients to Western Psychiatric Institute and Clinic or as outpatients at the Intervention Research Center for Late-Life Mood Disorders (IRC/LLMD) were invited to participate in this pilot study. Diagnosis of bipolar disorder was confirmed through the Structured Clinical Interview for the DSM-IV (SCID)4 and reviewed at diagnostic consensus case conferences attended by at least three faculty geriatric psychiatrists from the IRC/LLMD. Measures Trained research staff performed ratings with the Hamilton Rating Scale for Depression–17-item (HamD–17) and the Young Mania Rating Scale (YMRS) during acute, continuation, and maintenance treatment, as described below. Lithium and valproic acid levels (trough) were checked at each clinic visit. Interrater reliability was established, with a criterion of no more than 2 points variance for established raters in the IRC/LLMD. Medication side effects were measured with the UKU Side Effect Rating Scale.5 The UKU Side Effect Rating Scale included 48 items that
Received October 17, 2004; revised November 15, 2004; accepted November 19, 2004. From the Intervention Research Center for Late-Life Mood Disorders, Dept. of Psychiatry, the Bipolar Disorder Center for Pennsylvanians, University of Pittsburgh School of Medicine (AGG, BHM,AEB,MM,JAS,MDM,AF,DJK,CFR), and the Department of Psychiatry at the Weill College of Medicine, Cornell University (RCY). Send correspondence and reprint requests to Dr. Mulsant, 3811 O’Hara St., Pittsburgh, PA 15213. e-mail address: [email protected] 䉷 2005 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 13:4, April 2005
319
Standardized Treatment of Bipolar Disorder were grouped into four categories: Psychic, Neurological, Autonomic, and Other. Each item was scored on a 4-point scale (0: none or doubtful; 1: present to a mild degree; 2: present to a moderate degree; and 3: present to a severe degree). Procedures We obtained written informed consent, approved by the Institutional Review Board at the University of Pittsburgh, after the study had been fully explained. Treatment was organized into acute, continuation, and maintenance phases. Subjects with clinically significant mood symptoms began in the acute phase and were seen at least weekly by a master’slevel clinician and a study psychiatrist. Acute treatment continued until remission. Remission was defined as Ham-D–17 and YMRS scores of ⱕ10, for at least 4 consecutive weeks. Subjects meeting criteria for remission entered the continuation phase for 12 weeks and had study visits and mood ratings every 2 weeks. Subjects scoring ⱕ10 on the Ham-D–17 and YMRS for 12 weeks of continuation therapy entered the maintenance phase for 1 year, with study visit and mood ratings done every 4 weeks. Subjects who developed acute mood episodes during continuation or maintenance phases were offered re-stabilization treatment and could continue in the study for up to 2 years. Pharmacotherapy followed protocols modeled after the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP–BD).6 The goals of the pharmacotherapy intervention were to maximize the appropriate use of lithium or valproate (either singly or in combination), to achieve remission of acute mood episodes, maintain euthymia, and minimize adjunctive antipsychotic or antidepressant medication, except as judged clinically necessary by the study psychiatrist. Daily doses of lithium carbonate were typically in the range of 300 mg/day–900 mg/ day, titrated to a plasma level of 0.5 mEq/L–1.0 mEq/ L; valproate doses were in the range of 500 mg/day– 1,500 mg/day, titrated to a plasma level of 40 mcg/ ml–100 mcg/ml. Although manualized psychotherapy was not offered as part of the intervention, treatment occurred in a supportive medication clinic that emphasized education about bipolar mood disorder, treatment adherence, partnering with families and other caregivers, and attention to good sleep prac-
320
tices. Although no strict definition of adherence was used in the study protocol, participants who were grossly noncompliant with study procedures (that is, repeatedly not taking medications as prescribed, not having detectable levels of mood-stabilizers, or not presenting to scheduled study visits) were terminated from the study and referred to treatment elsewhere. Statistical Analyses “Days well” was defined with cut-off score of either ⱕ10 or ⱕ7 on both the Ham-D–17 and YMRS. A straight line connected each successive assessment, and the numbers of days that fell below the cut-off scores were counted.
RESULTS Thirty-one individuals consented to study participation. The mean age of the participants was 71.9 years (standard deviation [SD]: 9.7; range: 60–95). Seventeen of the subjects (55%) were female, 28 (90%) were Caucasian, 2 (7%) were African American, and 1 was Asian (3%). The median period of follow-up was 398 days (range: 20–735). Twenty-three subjects had Bipolar I and eight subjects had Bipolar II disorder. The median age at onset was 30 years (range: 16–76); seven subjects (23%) developed bipolar disorder after the age of 50. On entering the study, 11 subjects were in an acute episode (manic: N⳱3, hypomanic: N⳱2, depressed: N⳱5, or mixed: N⳱1); 20 subjects were euthymic. Mean modal doses and serum levels of lithium and valproate were as follows: lithium (N⳱17) doses: 657 mg/day (SD: 376; median: 600; range: 150–1,500); serum levels: 0.67 mEq/L (SD: 0.24; median: 0.7; range: 0.23–1.0); valproate: (N⳱11) doses: 806 mg/day (SD: 341; median: 750; range: 250–1,500); serum levels: 66.1 mcg/ml (SD: 14.8; median: 64; range: 45.5–89.3). Eight subjects were treated with olanzapine; mean dose: 10 mg/day (SD: 9.1; median: 8.75; range: 2.5– 30). Four were treated with risperidone at doses of 0.5 mg to 1 mg per day. Three subjects received combined treatment with lithium and olanzapine. In one subject, lithium and valproate were combined with olanzapine. In seven subjects, both a mood stabilizer and an atypical antipsychotic were combined with
Am J Geriatr Psychiatry 13:4, April 2005
Gildengers et al.
YMRS
FIGURE 1.
Mean Young Mania Rating Scale (YMRS) Scores and Hamilton Rating Scale for Depression–17-Item (Ham-D–17) Scores in Elderly Patients With Bipolar Disorder Over 76 Weeks of Treatment
10
Ham-D–17
0
10
20
N= 19 15 14 16 13 11 9 8 8 6 5 9 6 5 7 3 2 2 3 15 16 15 13 9 5 13 11 11 11 7 7 11 7 5 7 7 4 2 16 19 15 15 13 8 7 10 6 4 6 3 7 6 7 5 4 5 4 31 19 15 15 11 9 10 8 10 9 8 9 5 6 6 5 6 4 3 0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
Week Note: YMRS: Young Mania Rating Scale; Ham-D–17: Hamilton Rating Scale for Depression. YMRS scores range from 0 to 20, and Ham-D–17 scores range from 0 to 20 (more severe), with 0 representing absence of manic or depressive symptoms. Dotted lines correspond to scores of 7 and 10. The number of subjects in each observation is listed above the week.
antidepressant treatment. In 24 participants, antidepressant medication was initiated or continued. Over the period of study participation, 12 subjects were treated for episodes of mania or hypomania; 16 subjects were treated for episodes of depression; and 4 subjects were treated for mixed episodes. Twentynine subjects had at least one observation in which they were symptomatically recovered, with both Ham-D–17 and YMRS score of ⱕ7. Only three subjects (10%) were assessed as recovered throughout study participation. Defining “days well” as both Ham-D–17 and YMRS scores ⱕ10, the participants experienced, as a group, a mean percentage of 72.5% days well (SD: 24.3; median: 79.5%; range: 0%–100%). Defining days well as both Ham-D–17 and YMRS scores ⱕ7, the mean percentage of days well de-
Am J Geriatr Psychiatry 13:4, April 2005
creased to 44.7% (SD: 31.8; median: 49.7; range: 0%– 100%). Figure 1 depicts the response to treatment over the first 76 weeks of observation. Table 1 displays the range of medications prescribed, broken down by category and specific agent. Sequentially or concurrently, participants took a mean of 2.4 mood stabilizers (SD: 1.6; median: 2; range: 1–8), a mean of 1.6 antidepressants (SD: 0.9; median: 1; range: 1–4), and a mean of 1.3 sedative-hypnotics (SD: 0.5; median: 1; range: 1–3). The mean level of side effects the participants experienced on the Total UKU Side Effect Rating Scale was 9.3 (SD: 3.3; median: 9.0; range: 2.5– 14.9). Eight subjects either withdrew consent, terminated from participation, or died during the course of the study. Four participants withdrew their consent. Par-
321
Standardized Treatment of Bipolar Disorder TABLE 1.
Psychotropic Agents Used in Standardized Treatment of Elderly Patients With Bipolar Disorder Over 76 Weeks
Mood Stabilizer
N
%
Antidepressant
N
%
Sedative-Hypnotic
N
%
lithium olanzapine valproic acid lamotrigine risperidone gabapentin quetiapine oxcarbazepine topiramate carbamazepine
19 16 13 6 6 4 3 2 2 1
61.3% 51.6% 41.9% 19.4% 19.4% 12.9% 9.7% 6.5% 6.5% 3.2%
bupropion citalopram venlafaxine mirtazapine paroxetine trazodone escitalopram amitriptyline sertraline tranylcypromine clomipramine fluoxetine imipramine
9 7 7 6 4 4 3 2 2 2 1 1 1
29.0% 22.6% 22.6% 19.4% 12.9% 12.9% 9.7% 6.5% 6.5% 6.5% 3.2% 3.2% 3.2%
lorazepam clonazepam zolpidem alprazolam temazepam oxazepam buspirone hydroxyzine
12 3 3 2 2 1 1 1
38.7% 9.7% 9.7% 6.5% 6.5% 3.2% 3.2% 3.2%
Note: Every agent that was prescribed for at least 1 day is included. The percentage represents the number of participants out of the 31 who were treated.
ticipants withdrew consent for the following reasons: family members’ disapproval of research, dissatisfaction with the study investigators’ recommendation to stop using alcohol, problems with transportation, and inconvenience of study requirements (frequency of visits and blood draws). Two participants were terminated because of treatment noncompliance. Two participants died from natural causes: one from cardiac arrest, the other from respiratory failure.
DISCUSSION This prospective study confirms the feasibility of treating older adults with bipolar disorder by use of lithium or valproate under protocolized conditions. The results are congruent with and complement our previous naturalistic study of elderly inpatients with bipolar disorder,7 showing that treatment offers significant clinical improvement. Participants were assessed as being well for more than two-thirds of the time they participated in the study; this finding underscores the idea that standardized treatment can be beneficial and tolerable. Nevertheless, only 10% of participants experienced sustained symptomatic recovery, despite the use of standardized treatment. This low level of sustained recovery is in contrast to the treatment of unipolar depression in elderly adults at our research center, where fewer than half of patients receiving maintenance antidepressant pharmacotherapy experienced a recurrence of a major depressive episode over 3 years of follow-up.8 On the other hand, the level of recovery is consistent with
322
findings on the long-term natural history of bipolar disorder in mixed-age adults.9,10 Judd and colleagues reported that patients with Bipolar I disorder were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up.10 Also, Judd and colleagues reported that patients with Bipolar II disorder were symptomatically ill 53.9% of weeks throughout a mean of 13.4 years of follow-up.9 Given that sustained recovery appears to be the exception in patients with bipolar disorder across the lifespan, further research is needed to improve maintenance treatment of bipolar disorder, especially in late life, where controlled studies have been absent. The authors thank the staff of Intervention Research Center for Late-Life Mood Disorders for their care of the patients in the study reported. This work was supported in part by Public Health Service grants MH19986, MH52247, MH01684, MH01613, MH067028; and by the Commonwealth of Pennsylvania Department of Health grant ME-02385. Dr. Mulsant has been involved with the speaker’s bureau for AstraZeneca, Forest, Pfizer/Esai, GlaxoSmithKline, and Janssen; and has received grants/research support from NIH, Janssen, AstraZeneca, Corcept, and Forest. Dr. Miller has been involved with the speaker’s bureau for Forest Labs, GlaxoSmithKline, and Wyeth-Ayerst. Dr. Fagiolini has been involved with the speaker’s bureau for Pfizer and Bristol-Myers-Squibb. Dr. Kupfer has served on the advisory boards of Pfizer, Eli Lilly and Company, Forest Laboratories, and Hoffman LaRoche; and has served as a consultant to Servier Amerique. Dr. Reynolds has received research support from Forest, GlaxoSmithKline, and Pfizer. The other authors have no competing interest to disclose.
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References 1. Van Gerpen MW, Johnson JE, Winstead DK: Mania in the geriatric patient population: a review of the literature. (comments). Am J Geriatr Psychiatry 1999; 7:188–202 2. Young RC, Gyulai L, Mulsant BH, et al: Pharmacotherapy of bipolar disorder in old age. Am J Geriatr Psychiatry 2004; 12:342–357 3. Post RM, L’Herrou T, Luckenbaugh DA, et al: Statistical approaches to trial durations in episodic affective illness. Psychiatry Res 1998; 78:71–87 4. First MB, Spitzer RL, Gibbon M, et al: Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition. New York, Biometrics Research, New York State Psychiatric Institute, 2002 5. Lingjaerde O, Ahlfors UG, Bech P, et al: The UKU Side Effect Rating Scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand (suppl) 1987; 334:1–100 6. Sachs GS, Thase ME, Otto MW, et al: Rationale, design, and
Am J Geriatr Psychiatry 13:4, April 2005
methods of the Systematic Treatment-Enhancement Program for Bipolar Disorder (STEP-BD). Biol Psychiatry 2003; 53:1028– 1042 7. Wylie ME, Mulsant BH, Pollock BG, et al: Age at onset in geriatric bipolar disorder: effects on clinical presentation and treatment outcomes in an inpatient sample. Am J Geriatr Psychiatry 1999; 7:77– 83 8. Reynolds CF III, Frank E, Perel JM, et al: Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years (comments). JAMA 1999; 281:39–45 9. Judd LL, Akiskal HS, Schettler PJ, et al: A prospective investigation of the natural history of the long-term weekly symptomatic status of Bipolar II disorder. Arch Gen Psychiatry 2003; 60:261–269 10. Judd LL, Akiskal HS, Schettler PJ, et al: The long-term natural history of the weekly symptomatic status of Bipolar I disorder. Arch Gen Psychiatry 2002; 59:530–537
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tained in younger patients with bipolar disorder or retrospective case series in older adults.2 We report on a prospective, open-label study of a group of elderly outpatients with bipolar disorder (N⳱31), treated according to standardized treatment pathways. The purpose of the study was to collect data on the feasibility of recruiting, eliciting informed consent, assessing, treating, and following patients age 60 and older with bipolar disorder. Given the methodological difficulties defining treatment response in patients with high-variability illness characteristics and unstable response,3 we present response as a percentage of euthymic days or “days well,” during the period of observation.
METHODS Subjects
Objective: The authors sought to determine the feasibility of treating elderly adults with bipolar disorder under standardized-treatment conditions. Methods: Thirty-one patients age 60 and older with bipolar disorder were treated in standardized pathways. Mood state was checked at each study visit with the Hamilton Rating Scale for Depression–17 item (Ham-D–17) and the Young Mania Rating Scale (YMRS). Results: Defining “well days” as both Ham-D and YMRS scores of ⱕ10, the mean percentage of well days was 72.5 (range: 0%–100%) over study participation. Conclusions: Treating older adults with bipolar disorder under standardized treatment is feasible and is associated with low symptom levels. However, most older adults with bipolar disorder do not experience sustained recovery. (Am J Geriatr Psychiatry 2005; 13:319– 323)
B
ipolar disorder represents 5% to 12% of geriatric psychiatry inpatient admissions.1 In the absence of any controlled studies, the treatment of geriatric bipolar disorder must be extrapolated from data ob-
Patients age 60 years and older with bipolar disorder who presented as inpatients to Western Psychiatric Institute and Clinic or as outpatients at the Intervention Research Center for Late-Life Mood Disorders (IRC/LLMD) were invited to participate in this pilot study. Diagnosis of bipolar disorder was confirmed through the Structured Clinical Interview for the DSM-IV (SCID)4 and reviewed at diagnostic consensus case conferences attended by at least three faculty geriatric psychiatrists from the IRC/LLMD. Measures Trained research staff performed ratings with the Hamilton Rating Scale for Depression–17-item (HamD–17) and the Young Mania Rating Scale (YMRS) during acute, continuation, and maintenance treatment, as described below. Lithium and valproic acid levels (trough) were checked at each clinic visit. Interrater reliability was established, with a criterion of no more than 2 points variance for established raters in the IRC/LLMD. Medication side effects were measured with the UKU Side Effect Rating Scale.5 The UKU Side Effect Rating Scale included 48 items that
Received October 17, 2004; revised November 15, 2004; accepted November 19, 2004. From the Intervention Research Center for Late-Life Mood Disorders, Dept. of Psychiatry, the Bipolar Disorder Center for Pennsylvanians, University of Pittsburgh School of Medicine (AGG, BHM,AEB,MM,JAS,MDM,AF,DJK,CFR), and the Department of Psychiatry at the Weill College of Medicine, Cornell University (RCY). Send correspondence and reprint requests to Dr. Mulsant, 3811 O’Hara St., Pittsburgh, PA 15213. e-mail address: [email protected] 䉷 2005 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 13:4, April 2005
319
Standardized Treatment of Bipolar Disorder were grouped into four categories: Psychic, Neurological, Autonomic, and Other. Each item was scored on a 4-point scale (0: none or doubtful; 1: present to a mild degree; 2: present to a moderate degree; and 3: present to a severe degree). Procedures We obtained written informed consent, approved by the Institutional Review Board at the University of Pittsburgh, after the study had been fully explained. Treatment was organized into acute, continuation, and maintenance phases. Subjects with clinically significant mood symptoms began in the acute phase and were seen at least weekly by a master’slevel clinician and a study psychiatrist. Acute treatment continued until remission. Remission was defined as Ham-D–17 and YMRS scores of ⱕ10, for at least 4 consecutive weeks. Subjects meeting criteria for remission entered the continuation phase for 12 weeks and had study visits and mood ratings every 2 weeks. Subjects scoring ⱕ10 on the Ham-D–17 and YMRS for 12 weeks of continuation therapy entered the maintenance phase for 1 year, with study visit and mood ratings done every 4 weeks. Subjects who developed acute mood episodes during continuation or maintenance phases were offered re-stabilization treatment and could continue in the study for up to 2 years. Pharmacotherapy followed protocols modeled after the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP–BD).6 The goals of the pharmacotherapy intervention were to maximize the appropriate use of lithium or valproate (either singly or in combination), to achieve remission of acute mood episodes, maintain euthymia, and minimize adjunctive antipsychotic or antidepressant medication, except as judged clinically necessary by the study psychiatrist. Daily doses of lithium carbonate were typically in the range of 300 mg/day–900 mg/ day, titrated to a plasma level of 0.5 mEq/L–1.0 mEq/ L; valproate doses were in the range of 500 mg/day– 1,500 mg/day, titrated to a plasma level of 40 mcg/ ml–100 mcg/ml. Although manualized psychotherapy was not offered as part of the intervention, treatment occurred in a supportive medication clinic that emphasized education about bipolar mood disorder, treatment adherence, partnering with families and other caregivers, and attention to good sleep prac-
320
tices. Although no strict definition of adherence was used in the study protocol, participants who were grossly noncompliant with study procedures (that is, repeatedly not taking medications as prescribed, not having detectable levels of mood-stabilizers, or not presenting to scheduled study visits) were terminated from the study and referred to treatment elsewhere. Statistical Analyses “Days well” was defined with cut-off score of either ⱕ10 or ⱕ7 on both the Ham-D–17 and YMRS. A straight line connected each successive assessment, and the numbers of days that fell below the cut-off scores were counted.
RESULTS Thirty-one individuals consented to study participation. The mean age of the participants was 71.9 years (standard deviation [SD]: 9.7; range: 60–95). Seventeen of the subjects (55%) were female, 28 (90%) were Caucasian, 2 (7%) were African American, and 1 was Asian (3%). The median period of follow-up was 398 days (range: 20–735). Twenty-three subjects had Bipolar I and eight subjects had Bipolar II disorder. The median age at onset was 30 years (range: 16–76); seven subjects (23%) developed bipolar disorder after the age of 50. On entering the study, 11 subjects were in an acute episode (manic: N⳱3, hypomanic: N⳱2, depressed: N⳱5, or mixed: N⳱1); 20 subjects were euthymic. Mean modal doses and serum levels of lithium and valproate were as follows: lithium (N⳱17) doses: 657 mg/day (SD: 376; median: 600; range: 150–1,500); serum levels: 0.67 mEq/L (SD: 0.24; median: 0.7; range: 0.23–1.0); valproate: (N⳱11) doses: 806 mg/day (SD: 341; median: 750; range: 250–1,500); serum levels: 66.1 mcg/ml (SD: 14.8; median: 64; range: 45.5–89.3). Eight subjects were treated with olanzapine; mean dose: 10 mg/day (SD: 9.1; median: 8.75; range: 2.5– 30). Four were treated with risperidone at doses of 0.5 mg to 1 mg per day. Three subjects received combined treatment with lithium and olanzapine. In one subject, lithium and valproate were combined with olanzapine. In seven subjects, both a mood stabilizer and an atypical antipsychotic were combined with
Am J Geriatr Psychiatry 13:4, April 2005
Gildengers et al.
YMRS
FIGURE 1.
Mean Young Mania Rating Scale (YMRS) Scores and Hamilton Rating Scale for Depression–17-Item (Ham-D–17) Scores in Elderly Patients With Bipolar Disorder Over 76 Weeks of Treatment
10
Ham-D–17
0
10
20
N= 19 15 14 16 13 11 9 8 8 6 5 9 6 5 7 3 2 2 3 15 16 15 13 9 5 13 11 11 11 7 7 11 7 5 7 7 4 2 16 19 15 15 13 8 7 10 6 4 6 3 7 6 7 5 4 5 4 31 19 15 15 11 9 10 8 10 9 8 9 5 6 6 5 6 4 3 0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
Week Note: YMRS: Young Mania Rating Scale; Ham-D–17: Hamilton Rating Scale for Depression. YMRS scores range from 0 to 20, and Ham-D–17 scores range from 0 to 20 (more severe), with 0 representing absence of manic or depressive symptoms. Dotted lines correspond to scores of 7 and 10. The number of subjects in each observation is listed above the week.
antidepressant treatment. In 24 participants, antidepressant medication was initiated or continued. Over the period of study participation, 12 subjects were treated for episodes of mania or hypomania; 16 subjects were treated for episodes of depression; and 4 subjects were treated for mixed episodes. Twentynine subjects had at least one observation in which they were symptomatically recovered, with both Ham-D–17 and YMRS score of ⱕ7. Only three subjects (10%) were assessed as recovered throughout study participation. Defining “days well” as both Ham-D–17 and YMRS scores ⱕ10, the participants experienced, as a group, a mean percentage of 72.5% days well (SD: 24.3; median: 79.5%; range: 0%–100%). Defining days well as both Ham-D–17 and YMRS scores ⱕ7, the mean percentage of days well de-
Am J Geriatr Psychiatry 13:4, April 2005
creased to 44.7% (SD: 31.8; median: 49.7; range: 0%– 100%). Figure 1 depicts the response to treatment over the first 76 weeks of observation. Table 1 displays the range of medications prescribed, broken down by category and specific agent. Sequentially or concurrently, participants took a mean of 2.4 mood stabilizers (SD: 1.6; median: 2; range: 1–8), a mean of 1.6 antidepressants (SD: 0.9; median: 1; range: 1–4), and a mean of 1.3 sedative-hypnotics (SD: 0.5; median: 1; range: 1–3). The mean level of side effects the participants experienced on the Total UKU Side Effect Rating Scale was 9.3 (SD: 3.3; median: 9.0; range: 2.5– 14.9). Eight subjects either withdrew consent, terminated from participation, or died during the course of the study. Four participants withdrew their consent. Par-
321
Standardized Treatment of Bipolar Disorder TABLE 1.
Psychotropic Agents Used in Standardized Treatment of Elderly Patients With Bipolar Disorder Over 76 Weeks
Mood Stabilizer
N
%
Antidepressant
N
%
Sedative-Hypnotic
N
%
lithium olanzapine valproic acid lamotrigine risperidone gabapentin quetiapine oxcarbazepine topiramate carbamazepine
19 16 13 6 6 4 3 2 2 1
61.3% 51.6% 41.9% 19.4% 19.4% 12.9% 9.7% 6.5% 6.5% 3.2%
bupropion citalopram venlafaxine mirtazapine paroxetine trazodone escitalopram amitriptyline sertraline tranylcypromine clomipramine fluoxetine imipramine
9 7 7 6 4 4 3 2 2 2 1 1 1
29.0% 22.6% 22.6% 19.4% 12.9% 12.9% 9.7% 6.5% 6.5% 6.5% 3.2% 3.2% 3.2%
lorazepam clonazepam zolpidem alprazolam temazepam oxazepam buspirone hydroxyzine
12 3 3 2 2 1 1 1
38.7% 9.7% 9.7% 6.5% 6.5% 3.2% 3.2% 3.2%
Note: Every agent that was prescribed for at least 1 day is included. The percentage represents the number of participants out of the 31 who were treated.
ticipants withdrew consent for the following reasons: family members’ disapproval of research, dissatisfaction with the study investigators’ recommendation to stop using alcohol, problems with transportation, and inconvenience of study requirements (frequency of visits and blood draws). Two participants were terminated because of treatment noncompliance. Two participants died from natural causes: one from cardiac arrest, the other from respiratory failure.
DISCUSSION This prospective study confirms the feasibility of treating older adults with bipolar disorder by use of lithium or valproate under protocolized conditions. The results are congruent with and complement our previous naturalistic study of elderly inpatients with bipolar disorder,7 showing that treatment offers significant clinical improvement. Participants were assessed as being well for more than two-thirds of the time they participated in the study; this finding underscores the idea that standardized treatment can be beneficial and tolerable. Nevertheless, only 10% of participants experienced sustained symptomatic recovery, despite the use of standardized treatment. This low level of sustained recovery is in contrast to the treatment of unipolar depression in elderly adults at our research center, where fewer than half of patients receiving maintenance antidepressant pharmacotherapy experienced a recurrence of a major depressive episode over 3 years of follow-up.8 On the other hand, the level of recovery is consistent with
322
findings on the long-term natural history of bipolar disorder in mixed-age adults.9,10 Judd and colleagues reported that patients with Bipolar I disorder were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up.10 Also, Judd and colleagues reported that patients with Bipolar II disorder were symptomatically ill 53.9% of weeks throughout a mean of 13.4 years of follow-up.9 Given that sustained recovery appears to be the exception in patients with bipolar disorder across the lifespan, further research is needed to improve maintenance treatment of bipolar disorder, especially in late life, where controlled studies have been absent. The authors thank the staff of Intervention Research Center for Late-Life Mood Disorders for their care of the patients in the study reported. This work was supported in part by Public Health Service grants MH19986, MH52247, MH01684, MH01613, MH067028; and by the Commonwealth of Pennsylvania Department of Health grant ME-02385. Dr. Mulsant has been involved with the speaker’s bureau for AstraZeneca, Forest, Pfizer/Esai, GlaxoSmithKline, and Janssen; and has received grants/research support from NIH, Janssen, AstraZeneca, Corcept, and Forest. Dr. Miller has been involved with the speaker’s bureau for Forest Labs, GlaxoSmithKline, and Wyeth-Ayerst. Dr. Fagiolini has been involved with the speaker’s bureau for Pfizer and Bristol-Myers-Squibb. Dr. Kupfer has served on the advisory boards of Pfizer, Eli Lilly and Company, Forest Laboratories, and Hoffman LaRoche; and has served as a consultant to Servier Amerique. Dr. Reynolds has received research support from Forest, GlaxoSmithKline, and Pfizer. The other authors have no competing interest to disclose.
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Gildengers et al.
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