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The apolipoprotein E ε4 allele and antidepressant efficacy in cognitively intact elderly depressed patients
ORIGINAL ARTICLES The Apolipoprotein E ε4 Allele and Antidepressant Efficacy in Cognitively Intact Elderly Depressed Patients Greer M. Murphy, Jr., Charlotte Kremer, Heidi Rodrigues, Alan F. Schatzberg, and the Mirtazapine versus Paroxetine Study Group Background: Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE ε4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that ε4 carriers would show impaired antidepressant response. Methods: The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15– 45 mg (n ⫽ 124) or paroxetine 20 – 40 mg (n ⫽ 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping. Results: Patients carrying the ε4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the ε4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age. Conclusions: The APOE ε4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications. Biol Psychiatry 2003;54:665– 673 © 2003 Society of Biological Psychiatry Key Words: Pharmacogenetics, antidepressant, apolipoprotein E, major depression, aging
From the Neuroscience Research Laboratories, Department of Psychiatry and Behavioral Sciences (GMM, AFS), Stanford University School of Medicine, Stanford, California; and Organon Pharmaceuticals Inc. (CK, HR), West Orange, New Jersey. Address reprint requests to Alan F. Schatzberg, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 300, Stanford CA 94305-5548. Received October 17, 2002; revised January 17, 2003; accepted January 24, 2003.
© 2003 Society of Biological Psychiatry
Introduction
T
here is wide variation in the response of patients with major depression to antidepressant pharmacotherapy. Some of this variation may be due to genetic differences among patients. The expanding field of pharmacogenetics seeks to identify DNA markers for differential medication response and to use these markers to individualize patient treatment so as to maximize efficacy and minimize side effects (Roses 2000). The apolipoprotein E (APOE) ε4 allele is an established genetic risk factor for Alzheimer’s disease (AD; Farrer et al 1997). In nondemented elderly, the APOE ε4 allele is associated with mild impairment in certain aspects of cognition (Bondi et al 1995; Caselli et al 2001; O’Hara et al 1998; Small et al 1999). These findings suggest impairment of brain function in ε4 carriers even in the absence of frank dementia. ApoE also affects recovery after physical trauma and stress in both animals and humans (Friedman et al 1999; Gordon et al 1996; Han and Chung 2000; Horsburgh et al 1999, 2000; Jordan et al 1997; Laskowitz et al 1997; Sheng et al 1998, 1999). There is no consistent evidence that the APOE ε4 allele is a risk factor for major depression (Mauricio et al 2000); however, because major depression is characterized by many signs and symptoms of stress including abnormalities of the hypothalamic-pituitary-adrenal axis (Brown et al 1999), we hypothesized that nondemented carriers of the APOE ε4 allele would respond poorly to antidepressant medications because of an impaired capacity for recovery. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that increases the availability of serotonin at synapses (Dechant and Clissold 1991). It has been shown to be efficacious in the treatment of major depression including depression in geriatric patients (Mulsant et al 1999; Walters et al 1999). Mirtazapine is a noradrenergic and specific serotonergic agent that induces the release of norepinephrine as well as serotonin in the brain (de Boer 1996; Stahl 1998). Mirtazapine has also been shown to be efficacious in the treatment of major depression, and several studies, including two with geriatric patients, have indicated that mirtazapine shows a faster onset of action 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00174-4
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than SSRI (Benkert et al 2000; Leinonen et al 1999; Schatzberg et al 2002; Wheatley et al 1998). We performed a multicenter, 8-week, double-blind pharmacogenetic comparison with a 16-week extension of paroxetine and mirtazapine in nondemented patients 65 years of age and older with major depression; APOE genotypes were determined for all patients. Clinical outcomes were quantified including improvement in mood, medication compliance, severity of adverse events, and discontinuations due to adverse events.
Methods and Materials
investigators with scores falling within a predetermined range participated in the study.
Treatment Protocol Initial treatment was with 15 mg of mirtazapine (one active capsule and one placebo capsule) or 20 mg of paroxetine (two 10-mg capsules) given each evening. After 2 weeks, doses were increased to 30 mg of mirtazapine or paroxetine once daily. At week 4 and 6 clinic visits, dose increases to 45 mg of mirtazapine or 40 mg of paroxetine were allowed if the patient had not been assigned CGI change scores of 1 or 2, indicating “much improved” or “very much improved.”
Clinical Trial Design and Patients
Extension Phase
The study design was an 8-week, double-blind, randomized trial with a 16-week extension comparing mirtazapine and paroxetine; it was conducted at 18 outpatient clinics in the United States. All aspects of the study received institutional review board approval at Stanford and at each participating site, and all patients provided written informed consent. Patients were 65 years of age or older and had been medically stable for at least 3 months. At screening, all met DSM-IV criteria for major depression (single or recurrent), had Mini-Mental State Examination (MMSE; Folstein et al 1975) scores above the 25th percentile for their age (Crum et al 1993), and had Hamilton Depression Rating Scale (17-item version, HDRS-17; Hamilton 1967) scores of at least 18. Patients were excluded for clinically significant laboratory abnormalities, drug or alcohol abuse, psychosis, recent suicide attempt, and psychiatric conditions other than major depression. Treatment with antidepressant medications within 7 days of commencing the study, and treatment with mirtazapine or paroxetine during the current depressive episode were grounds for exclusion. Patients taking medications approved for the treatment of cognitive disorders were excluded.
Patients who showed a CGI-change score of much or very much improved or a reduction of at least 50% on the HDRS-17 (or both) at the end of the 8-week acute phase were invited to continue for a 16-week extension phase under continued doubleblind conditions. Assessments were performed at weeks 12, 16, 20, and 24 weeks.
Genetic Analysis Genomic DNA was extracted from ethylenediamine tetraacetate– treated whole blood by using the Puregene DNA extraction kit (Gentra Systems, Minneapolis, MN). The APOE genotypes were determined as previously described (Murphy et al 1997). Electrophoretic gel images were assessed independently for APOE genotype by two observers blinded to clinical data, and if there was disagreement, the assay was repeated until the result was unequivocal. Greater than 95% of APOE genotyping assays gave unequivocal results on the first attempt. The remaining samples were resolved on a second attempt.
Plasma Drug Concentrations Outcome Measures Mood was rated using the HDRS-17, the Geriatric Depression Scale (GDS) (Yesavage et al 1983), and the Clinical Global Impression Scale (CGI) (Guy 1976) after 1, 2, 3, 4, 6, and 8 weeks of treatment in the acute phase. The severity of adverse events was rated by clinicians as mild (1), moderate (2), or severe (3). These scores were summed and standardized for drug exposure time and average daily dosage to create an adverse event index. Indices were calculated for adverse events judged by clinicians as related to the study drug and for all adverse events. Actual medication taken was determined by counting the number of prescribed capsules remaining at each clinic visit. Dosing compliance was determined by total number of medication doses taken divided by total number of capsules given across the entire study. Final daily dose was the dose each patient achieved during the acute phase after any dosing adjustments. Cognition was assessed at baseline and at week 8 using the MMSE. A meeting was held for physicians and staff from the different sites before the onset of the study for assessment training and standardization of assessment techniques. Mood ratings by investigators were evaluated using a videotaped patient interview, and only those
Samples for plasma drug concentrations were obtained after 4 weeks. Mirtazapine concentrations were analyzed by using a liquid chromatographic assay with fluorescence detection after extraction of plasma using n-hexane. Paroxetine was assayed using an ultraviolet high-performance liquid chromatography method. All plasma drug measurements were performed in accordance with Good Laboratory Practice standards. Sample collection times varied from patient to patient according to clinic appointment time, therefore time since the prior evening dose also differed.
Statistical Analysis To test for departure from Hardy–Weinberg equilibrium we used GENEPOP version 3.3 and the algorithm of Louis and Dempster (Louis and Dempster 1987). All other statistical analyses were performed using the SAS software package (SAS Institute, Cary, NC). Data at each time point were derived from only those subjects evaluated at that time point. We did not use a last observation carried forward approach. For clinical measures of depression (HDRS-17, GDS, and CGI), analyses of covariance were performed with baseline values as the covariate, and APOE
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Table 1. Baseline Measures and Acute Phase Dosing, Adverse Events, and Plasma Drug Concentrations, Stratified by Medication and APOE Genotype (Means with Standard Errors)
Number of patients (N ⫽ 246) Age (years) Gender Body Weight (kg) MMSE HDRS-17 CGI GDS Discontinuations due to Adverse Events Adverse Event Index (study drug) Final Daily Dose Dosing Compliance Index Day 28 Plasma Drug Concentration (ng/mL)
Paroxetine ε4 Carrier
Paroxetine ε4 Noncarrier
Mirtazapine ε4 Carrier
Mirtazapine ε4 Noncarrier
30 73.2 (.99) 12 M, 18 F 75.05 (2.74) 28.47 (.28) 22.3 (.059) 4.23 (.11) 19.16 (.96) 5 59.09 (6.29) 30.04 (1.63) 98.11 (1.73) 88.82 (9.22) n ⫽ 25
92 71.89 (.52) 45 M, 47 F 78.88 (1.81) 28.73 (.12) 22.45 (.38) 4.11 (.07) 19.8 (.57) 27 53.08 (3.35) 29.57 (1.02) 97.76 (.77) 69.31 (6.29) n ⫽ 70
31 71.13 (.85) 15 M, 16 F 75.65 (3.09) 28.55 (.25) 21.19 (.59) 4.26 (.13) 18.27 (1.05) 6 51.49 (6.22) 31.28 (2.17) 97.75 (.66) 32.6 (4.11) n ⫽ 25
93 72.1 (.62) 48 M, 45 F 76.91 (1.53) 28.73 (.12) 22.61 (.40) 4.22 (.06) 19.04 (.59) 13 44.42 (3.14) 31.14 (1.14) 96.96 (.82) 43.15 (2.24) n ⫽ 71
APOE, apolipoprotein E; CGI, Clinical Global Impression Scale; F, female; GDS, Geriatric Depression Scale; HDRS-17, Hamilton Depression Rating Scale (17-item version); M, male; MMSE, Mini-Mental State Exam.
genotype (ε4 allele carrier vs. noncarrier) and medication (mirtazapine, paroxetine) as the predictors. The genotypes ε2/ε4, ε3/ε4, and ε4/ε4 were classified as carriers, whereas the genotypes ε2/ε2, ε2/ε3, and ε3/ε3 were classified as noncarriers. For responder and remitter analyses of clinical measures of depression, we used Cochran–Mantel–Haenszel (CMH) statistics. We defined HDRS-17 and GDS 50% responders as those patients showing a 50% or greater reduction in their baseline scores at a subsequent assessment; we defined HDRS-17 remitters as those patients having a HDRS-17 score of 7 or less at a postbaseline visit. We also used CMH analyses to compare ε4 carriers and noncarriers in the two treatment groups for discontinuations due to adverse events. For comparison of medication and genotype groups on baseline demographic measures, medication dosing, medication compliance, severity of adverse events, and week 4 plasma drug concentrations, two-way analyses of variance were used. The effects of the APOE ε4 allele on cognitive impairment can depend on ethnic background (Farrer et al 1997). Hence, we reanalyzed our data with only Caucasian patients to reduce the likelihood that results were due to population stratification. There were not enough non-Caucasian patients in the study cohort (20 out of 246) to analyze data for these patients separately. Separate analyses were also performed for patients who had entered the extension phase. In analyses involving extension phase patients, data from both the acute as well as the extension phases were included.
Results Acute Phase Of the 255 patients randomized into the study, 246 received study medication, provided blood for genetic analysis, and had at least one postbaseline assessment of efficacy, adverse events, or compliance. APOE allele frequencies among the 246 patients were ε2 ⫽ .08, ε3 ⫽ .78, and ε4 ⫽ .14. These values are typical for nondemented elderly patients (Farrer et al 1997). Observed
genotype frequencies showed no significant departure from Hardy–Weinberg equilibrium. Of the total sample, 122 patients were treated with paroxetine and 124 with mirtazapine. Among the mirtazapine-treated patients, 31 (25.0%) carried an ε4 allele, whereas among the paroxetine-treated patients, 30 (24.6%) were ε4 carriers. Demographic and clinical characteristics of the patients are presented in Table 1. The mean ages, numbers of men and women, mean baseline body weights, MMSE scores, final daily dosages, dosing compliance, and daily medication taken were not significantly different among ε4 carriers and noncarriers for paroxetine- and mirtazapinetreated patients. There were no significant differences between ε4 carriers and noncarriers in the proportion of patients who discontinued because of adverse events for either mirtazapine or paroxetine, and no significant differences in indices of adverse event severity. Week 4 plasma drug concentrations were available on 96 mirtazapinetreated patients and 95 paroxetine-treated patients and showed that mean plasma drug concentrations were higher for paroxetine ε4 carriers than for noncarriers (p ⫽ .012). An overall comparison of the efficacy and side effects of paroxetine and mirtazapine in this cohort has been presented (Schatzberg et al 2002). In the present analysis, after stratifying by APOE genotype, there were no differences in baseline HDRS-17, CGI, and GDS scores for ε4 carriers and noncarriers in the paroxetine and the mirtazapine treatment groups. Across both treatment groups, there were no significant differences in mean HDRS-17 and CGI scores between ε4 carriers and ε4 noncarriers at weeks 1 and 2; however, at week 2, analysis of covariance showed there was an interaction between treatment and APOE genotype effects on HDRS-17 (p ⫽ .036; Figure 1) and CGI (p ⫽ .029) scores, with mirtazapine patients
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Figure 1. Mean Hamilton Depression Rating Scale (17-item version; HDRS-17) scores with standard errors by week for patients treated with mirtazapine in the acute phase of the study.
carrying an ε4 allele showing significantly lower scores, indicating greater improvement in mood, than those without an ε4 allele. Conversely, paroxetine-treated patients with an ε4 allele showed higher scores (less improvement) on the HDRS-17 (Figure 2), and the CGI than did those without an ε4 allele. For the GDS, after 2 weeks of treatment scores were lower (improved) among ε4 carriers than among non-ε4 carriers across both treatment groups (p ⫽ .025). This difference was due to lower GDS scores among mirtazapine-treated patients with an ε4 allele (p ⫽ .021; Figure 3), whereas there was no significant difference in GDS scores between paroxetine-treated patients with and without an ε4 allele at week 2 (Figure 4). At weeks 3 and 4 as well, GDS scores for mirtazapine-treated ε4 carriers were lower than those for noncarriers (p ⫽ .042, p ⫽ .026; Figure 3). At week 2, there were more HDRS-17 50% responders among mirtazapine-treated patients with an ε4 allele (48%) than among those without an ε4 allele (27.1%; p ⫽
Figure 2. Mean Hamilton Depression Rating Scale (17-item version; HDRS-17) scores by week for patients treated with paroxetine in the acute phase of the study.
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Figure 3. Mean Geriatric Depression Scale (GDS) scores for patients by week treated with mirtazapine in the acute phase of the study.
.049; Figure 5). In contrast, at week 2 none of the paroxetine-treated patients with an ε4 allele showed a 50% decrease in HDRS-17 score over baseline; all paroxetinetreated patients meeting this criterion were among those without an ε4 allele (p ⫽ .016; Figure 5). At week 1, there were more HDRS-17 remitters among mirtazapine-treated ε4 carriers (10.1%) than among noncarriers (1.1%; p ⫽ .018; Figure 6), whereas no difference was seen between paroxetine ε4 carriers and noncarriers. Similarly, at week 2 there were more HDRS-17 remitters among ε4 carriers in the mirtazapine-treated group (28%) than among those without an ε4 allele (7.1%; p ⫽ .005; Figure 6). Among paroxetine-treated patients, none of those with an ε4 allele met this criterion for improvement. Mirtazapine-treated patients with an ε4 allele were more likely to show a 50% reduction in GDS score at week 2 than were those without an ε4 allele (p ⫽ .046), whereas among paroxetine-treated
Figure 4. Mean Geriatric Depression Scale (GDS) scores for patients by week treated with paroxetine in the acute phase of the study.
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Figure 5. Percent of patients showing a 50% reduction in Hamilton Depression Rating Scale (17-item version; HDRS-17) scores in comparison with baseline (HDRS-17 responders) in the acute phase stratified by medication and apolipoprotein E genotype.
patients there was no difference in the number of responders between APOE genotype groups. A similar effect was seen at week 4: more mirtazapine-treated patients with an ε4 allele showed a 50% reduction in GDS score than did noncarriers (p ⫽ .007), but among paroxetine-treated patients there was no significant effect of APOE genotype. There was no significant difference in the number of ethnic minority patients in the mirtazapine and paroxetine groups (7 of 124 for mirtazapine: 1 Asian, 4 African American, 2 other minority; 13 of 122 for paroxetine: 2 Asian, 6 African American, 5 other minority). Likewise, for mirtazapine-treated patients, there was no significant difference in number of ethnic minorities among ε4 carriers (0 of 31) and noncarriers (6 of 93); however, for paroxetine-treated patients, there were more ethnic minor-
Figure 6. Percent of patients showing Hamilton Depression Rating Scale (17-item version; HDRS-17) score of 7 or less (HDRS-17 remitters) in the acute phase stratified by medication and apolipoprotein E genotype.
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ities among patients with the ε4 allele (7 of 23) than among noncarriers (6 of 86; p ⫽ .016). Among Caucasian patients, there were no differences in mean age, number of men and women, final daily dosage achieved, dosing compliance, baseline body weight, or plasma drug concentrations between ε4 carriers and non-ε4 carriers for either mirtazapine or paroxetine. There were no significant differences between Caucasian ε4 carriers and noncarriers in the number of patients who discontinued because of adverse events for either mirtazapine or paroxetine. The same interaction between APOE genotype and medication on treatment outcome was observed among Caucasian patients as in the full sample. At baseline, there were no differences between ε4 carriers and noncarriers for any of the mood scales. At week 2, mean scores for the HDRS-17 were lower for mirtazapine than for paroxetine (p ⫽ .002). There was an interaction between APOE genotype and medication for HDRS-17 scores (p ⫽ .04). Mirtazapine patients with an ε4 allele showed greater improvement than those without an ε4 allele, whereas among paroxetine-treated patients, HDRS scores for ε4 carriers showed less improvement than did those of noncarriers. Week 2 GDS scores were lower for ε4 carriers than for noncarriers treated with mirtazapine (p ⫽ .031), but APOE genotype had no effect on GDS scores among paroxetine-treated patients. Among mirtazapine-treated Caucasian patients, week 2 CGI scores showed more improvement for ε4 carriers than for noncarriers (p ⫽ .042), but for paroxetine-treated patients there were no differences between ε4 carriers and noncarriers. Among Caucasian patients, interactions between medication and APOE genotype at week 2 were also observed in 50% reduction in HDRS-17 (p ⫽ .036), HDRS-17 remission (p ⫽ .007), and 50% reduction in GDS (p ⫽ .042). For each measure the percentage of ε4 carriers responding to medication treatment was greater for mirtazapine than for paroxetine. Similarly, at week 4 there were more patients showing a 50% reduction in GDS score (41.7%) among mirtazapine-treated ε4 carriers than among noncarriers (16.9%; p ⫽ .012), whereas for paroxetine-treated patients there was no significant effect of the ε4 genotype on the number of patients showing a 50% reduction in the GDS. We obtained MMSE scores on all patients at week 8. Analysis of covariance showed there was no significant difference between ε4 carriers and noncarriers in MMSE score at week 8, adjusting for HDRS-17 score. Likewise, there was no interaction effect between medication and APOE genotype in determining week 8 MMSE. The scores at week 8 were mitazapine ε4 carrier 28.5 ⫾ .2 mirtazapine noncarrier 28.8 ⫾ .1, paroxetine ε4 carrier 28.0 ⫾ .5, paroxetine noncarrier 28.7 ⫾ 0.1.
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24 for either medication in an analysis of covariance adjusting for HRDS-17 scores. There were no significant differences in the numbers of ethnic minorities among ε4 carriers and noncarriers for either medication group in the extension phase. A separate analysis for Caucasian patients (n ⫽ 60 for mirtazapine and n ⫽ 47 for paroxetine) gave results similar to those obtained for the full extension phase cohort, with mirtazapine-treated ε4 carriers showing significantly greater improvement on the HDRS-17 and the GDS. There were no significant effects of the ε4 allele on response to paroxetine among Caucasian patients entering the extension phase. Figure 7. Mean Geriatric Depression Scale (GDS) scores by week for patients treated with mirtazapine who entered the extension phase. The p values are for test of mean difference between ε4 carriers and noncarriers. Also, at weeks 2, 3, 6, 8, and 12, there were significant drug-by-genotype interaction effects.
Extension Phase Of the original cohort, 62 mirtazapine-treated patients (15 with ε4) and 54 paroxetine-treated patients (15 with εf4) entered the extension phase. The same effect of the ε4 allele on treatment outcome was seen in the extension phase cohort. There were genotype by drug interactions at weeks 2, 3, 4, 6, 8, and 12 (p ⬍ .05 for all). These interactions were due to significantly lower GDS scores among mirtazapine-treated ε4 carriers in the acute phase (simple main effect p values shown in Figure 7). Similar results were obtained for HDRS-17 and CGI scores. In contrast, there were no differences between ε4 carriers and noncarriers among paroxetine-treated patients for the GDS (Figure 8) or for other clinical measures during the extension phase. There were no significant differences between ε4 carriers and noncarriers in MMSE scores at week 8 or at week
Figure 8. Mean Geriatric Depression Scale (GDS) scores by week for patients treated with paroxetine who entered the extension phase. There were no significant differences in mean scores between paroxetine-treated ε4 carriers and noncarriers.
Discussion These results demonstrate that depressed nondemented elderly patients carrying the APOE ε4 allele show a rapid remission of symptoms when treated with mirtazapine. In contrast, paroxetine-treated ε4 carriers showed a slower antidepressant onset than noncarriers. These findings were consistent across the HDRS-17, GDS, and CGI rating scales. Our original hypothesis of impaired antidepressant efficacy among ε4 carriers was not confirmed. Individuals with the ε4 allele have a poor outcome following intracerebral hemorrhage (Alberts et al 1995), display greater cognitive decline following cardiac surgery (Newman et al 1995), are more vulnerable to brain injury associated with boxing (Jordan et al 1997), and are at increased risk following head injury (Nicoll et al 1995; Sorbi et al 1995). Thus, we expected that ε4 carriers would show a slower recovery from depression than would noncarriers. Surprisingly, ε4 carriers showed a more rapid onset of action in the mirtazapine sample. There are many potential confounding factors in a pharmacogenetic study such as this; however, we found no significant differences between ε4 carriers and noncarriers in the numbers of men and women, mean age, baseline body weight, baseline depression, or cognition for either drug treatment group. Because there were more ethnic minorities in the ε4 group among paroxetine-treated patients, we analyzed the data including only Caucasians; reanalysis of data from Caucasian patients alone yielded results similar to those for the full sample. Studies with additional ethnic minority patients will be required to determine if the effect seen in Caucasians occurs in other populations. Varying levels of medication compliance and individual differences in pharmacokinetics can confound pharmacogenetic results. Plasma drug levels obtained at week 4 showed significantly higher levels for acute phase paroxetine ε4 carriers than for noncarriers; however, plasma samples were obtained at each patient’s regular clinic visit,
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and hence the time since the prior day’s dose varied. There were no significant differences between ε4 carriers and noncarriers in dosing compliance across the entire study or in final daily dose. At week 4, capsule counts showed a trend toward paroxetine ε4 carriers having taken more medication in the prior week than had noncarriers, which may have accounted for the higher plasma level. Nevertheless, there were no significant differences in the acute phase among ε4 carriers and noncarriers in the severity of side effects due to the study medication for either treatment group, nor in the proportion of patients discontinuing due to adverse events, suggesting that medications were tolerated equally well by ε4 carriers and noncarriers. Although the extension phase cohort was smaller, results showed that the differential effect of the ε4 allele on mirtazapine response was sustained, with significant differences detected through week 12. Sustained response makes it unlikely that the strong early difference in antidepressant response between ε4 carriers and noncarriers was due to a difference in degree of sedation induced by mirtazapine (Stahl et al 2001) or due to a placebo effect. There was no significant difference between ε4 carriers and noncarriers in baseline or week 8 MMSE, no significant effect of treatment on MMSE score for either medication, and no significant MMSE interaction effect between genotype and treatment. We expected that antidepressant treatment would improve MMSE score in noncarriers but not in ε4 carriers; however, it is possible that because of the high mean baseline MMSE scores for both genotype groups, this instrument lacked sufficient sensitivity to detect small improvements in cognition. In any case, based on MMSE results, we found no evidence that the improvement in mood was associated with an improvement in cognition. The neurobiological basis for the differential effect of the ε4 allele on response to mirtazapine and paroxetine cannot be determined from these results. Monoaminergic neurons thought to be important in modulating mood (Leonard 2000) degenerate with aging in mice lacking ApoE expression. Noradrenergic neurons appear to be particularly vulnerable to APOE knockout (Chapman and Michaelson 1998; Puolivali et al 2000). Noradrenergic presynaptic terminals and norepinephrine levels are reduced in the hippocampus and to a lesser extent in other brain regions. After chemical injury to the locus ceruleus, mice lacking APOE show impaired recovery compared with wild type animals (Puolivali et al 2000). Serotonergic projection neurons also degenerate in APOE knockout mice. Transgenic expression of human E3 or E4 isoforms results in restoration of noradrenergic and serotonergic deficits in APOE knockout mice (Chapman et al 2000); however, APOE knockout mice expressing human E4 are more vulnerable to physiologic stress than those expressing human E3, suggesting
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that the capacity of noradrenergic neurons in human ε4 carriers to recover when challenged could be impaired (Horsburgh et al 2000; Sheng et al 1998). Paroxetine is an SSRI that increases the availability of serotonin at synapses between neurons arising in the brain-stem raphe nuclei and their target neurons in a number of brain regions (Dechant and Clissold 1991). Mirtazapine induces the release of norepinephrine as well as serotonin in the brain through antagonism of ␣-2adrenergic receptors on noradrenergic and serotonergic neurons (de Boer 1996; de Boer et al 1996). Norepinephrine release at synapses with serotonergic neurons also augments serotonin release. Thus, whereas paroxetine has a primarily serotonergic mode of action, mirtazapine has both serotonergic and noradrenergic actions. It is conceivable that in elderly depressed patients, the E4 isoform affects brain-stem noradrenergic and serotonergic neurons so that the dual-action agent mirtazapine results in a rapid response, but the single action agent paroxetine has a slower response. Interestingly, when paroxetine dose was increased to 30 mg at week 2, there was a marked increase in the number of ε4 carriers showing a 50% reduction in HDRS-17 over baseline values (Figure 5). Animal data suggest that when paroxetine concentrations increase, this agent may inhibit the norepinephrine reuptake transporter, resulting in increased synaptic norepinephrine levels (Owens et al 2000). Hence, after week 2, a noradrenergic effect of paroxetine could have accounted for the increase in the number of responders among ε4 carriers (Figure 5). There is no convincing evidence that the APOE ε4 allele is a risk factor for major depression in humans. We previously showed in a 5-year longitudinal study of nondemented elderly that the ε4 allele does not predispose to depression (Mauricio et al 2000). Cross-sectional studies have had similar results (Class et al 1997; Forsell et al 1997; Schmand et al 1998). It may be that the interaction between APOE genotype and mood becomes apparent only in the setting of antidepressant treatment, as demonstrated in this study. Alternatively, the rapid response to mirtazapine among ε4 carriers may reflect reduced hypothalamic-pituitaryadrenal (HPA) axis activity after treatment with this medication. Many studies have reported increased HPA activity in depressed patients, and Peskind et al (2001) found that Alzheimer’s disease patients carrying the ε4 allele have significantly elevated cerebrospinal fluid cortisol levels compared with noncarriers. Mirtazapine significantly reduces cortisol levels soon after initiation of treatment (Schule et al 2002), which may have been particularly beneficial to patients carrying the ε4 allele. In our study we did not measure cortisol levels, but future studies should include assessment of both APOE genotype and HPA axis activity.
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Statistical hypothesis testing with multiple outcome measures increases the risk for type I error. Therefore, these results will require replication. Another explanation for these findings is that the effect on antidepressant treatment outcome is due to a polymorphism in another gene in linkage disequilibrium with APOE. Population stratification of the self-identified Caucasian sample cannot be ruled out. Hence, it is conceivable, although unlikely, that ε4 carriers and noncarriers were drawn from different Caucasian subpopulations that have differing responses to antidepressant medications. There are no well-documented differences among Caucasian groups in antidepressant response. In summary, these results suggest that the APOE ε4 allele may be a pharmacogenetic marker for rapid onset of mirtazapine action in nondemented elderly with major depression. In contrast, ε4 carriers treated with paroxetine showed a slower onset of action than noncarriers. These differences among genotype groups in medication response could not be attributed to baseline patient characteristics, and the result was the same regardless of whether ethnic minorities were included in the analysis. It is surprising that despite evidence that the ε4 allele impairs recovery from trauma and stress, ε4 carriers showed a superior antidepressant response during initial treatment, at least for mirtazapine. These findings should be tested using data from other antidepressant clinical trials for which DNA samples were collected. It will be interesting to determine if results obtained with mirtazapine and paroxetine apply to other antidepressants.
Supported by funding from Organon Pharmaceuticals, Inc., the Nancy Pritzker Network for the Study of Depression, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center. Mirtazapine versus Paroxetine Study Group: M. Bari, Chula Vista, CA; B. Baumel, Miami Beach, FL; L. Blake, Chicago, IL; C. DeBattista, Stanford, CA; S. Cheren, Natick, MA; L. Eisner, Ft. Lauderdale, FL; W. Falk, Charlestown, MA; S. Hand, Scottsdale, AZ; H. Hassman, Berlin, NJ; L. Kirby, Peoria, AZ; E. Kramer and G. Greenwald, Glen Oaks, NY; C. Nelson, Hartford, CT; P. Ripley, South Yarmouth, MA; L. Rone, Evanston, IL; R. Riesenberg, Atlanta, GA; A. Strauss, Boynton Beach, FL; K. Weiss, Conshohocken, PA. Nina Pascoe, Jeremy Claassen, Clara Poon, and Feifei Zhao provided technical assistance. William Cheuk assisted with data management and with illustrations. Christopher Pan provided assistance with statistical analysis.
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Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278 –296. Han SH, Chung SY (2000): Marked hippocampal neuronal damage without motor deficits after mild concussive-like brain injury in apolipoprotein E-deficient mice. Ann N Y Acad Sci 903:357–365. Horsburgh K, Kelly S, McCulloch J, Higgins GA, Roses AD, Nicoll JA (1999): Increased neuronal damage in apolipoprotein E-deficient mice following global ischaemia. Neuroreport 10:837–841. Horsburgh K, McCulloch J, Nilsen M, Roses AD, Nicoll JA (2000): Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia. Eur J Neurosci 12:4309 –4317. Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S (1997): Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278:136 – 140. Laskowitz DT, Sheng H, Bart RD, Joyner KA, Roses AD, Warner DS (1997): Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab 17:753–758. Leinonen E, Skarstein J, Behnke K, Agren H, Helsdingen JT (1999): Efficacy and tolerability of mirtazapine versus citalopram: A double-blind, randomized study in patients with major depressive disorder. Nordic Antidepressant Study Group. Int Clin Psychopharmacol 14:329 –337. Leonard BE (2000): Evidence for a biochemical lesion in depression. J Clin Psychiatry 61:12–7. Louis EJ, Dempster ER (1987): An exact test for Hardy– Weinberg and multiple alleles. Biometrics 43:805–811. Mauricio M, O’Hara R, Yesavage JA, Friedman L, Kraemer HC, Van De Water M, Murphy GM Jr (2000): A longitudinal study of apolipoprotein-E genotype and depressive symptoms in community-dwelling older adults. Am J Geriatr Psychiatry 8:196 –200. Mulsant BH, Pollock BG, Nebes RD, Miller MD, Little JT, Stack J, et al (1999): A double-blind randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome. J Clin Psychiatry 60:16 –20. Murphy GM Jr, Taylor J, Kraemer HC, Yesavage J, Tinklenberg JR (1997): No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer’s disease. Am J Psychiatry 154:603–608. Newman MF, Croughwell ND, Blumenthal JA, Lowry E, White WD, Spillane W, et al (1995): Predictors of cognitive decline after cardiac operation. Ann Thorac Surg 59:1326 –30. Nicoll JA, Roberts GW, Graham DI (1995): Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med 1:135–137. O’Hara R, Yesavage JA, Kraemer HC, Mauricio M, Friedman LF, Murphy GM Jr (1998): The APOE epsilon4 allele is associated with decline on delayed recall performance in community-dwelling older adults. J Am Geriatr Soc 46:1493– 1498. Owens MJ, Knight DL, Nemeroff CB (2000): Paroxetine binding to the rat norepinephrine transporter in vivo. Biol Psychiatry 47:842–845.
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Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD, Raskind MA (2001): Increased CSF cortisol in AD is a function of APOE genotype. Neurology 56:1094 –1098. Puolivali J, Pradier L, Riekkinen P Jr (2000): Impaired recovery of noradrenaline levels in apolipoprotein E-deficient mice after N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine lesion. Neuroscience 95:353–358. Roses AD (2000): Pharmacogenetics and the practice of medicine. Nature 405:857–865. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr, The Mirtazapine vs. Paroxetine Study Group (2002): Doubleblind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 10:541–550. Schmand B, Hooijer C, Jonker C, Lindeboom J, Havekes LM (1998): Apolipoprotein E phenotype is not related to late-life depression in a population-based sample. Soc Psychiatry Psychiatr Epidemiol 33:21–26. Schule C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G (2002): The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects. Psychopharmacology (Berl) 163:95–101. Sheng H, Laskowitz DT, Bennett E, Schmechel DE, Bart RD, Saunders AM, et al (1998): Apolipoprotein E isoformspecific differences in outcome from focal ischemia in transgenic mice. J Cereb Blood Flow Metab 18:361–366. Sheng H, Laskowitz DT, Mackensen GB, Kudo M, Pearlstein RD, Warner DS (1999): Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke 30:1118 –1124. Small GW, Chen ST, Komo S, Ercoli L, Bookheimer S, Miller K, et al (1999): Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4 allele. Am J Psychiatry 156:1035–1038. Sorbi S, Nacmias B, Piacentini S, Repice A, Latorraca S, Forleo P, Amaducci L (1995): ApoE as a prognostic factor for post-traumatic coma. Nat Med 1:852. Stahl SM (1998): Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 59:5–14. Stahl SM, Nierenberg AA, Gorman JM (2001): Evidence of early onset of antidepressant effect in randomized controlled trials. J Clin Psychiatry 62:17–23; discussion: 37– 40. Walters G, Reynolds CF 3rd, Mulsant BH, Pollock BG (1999): Continuation and maintenance pharmacotherapy in geriatric depression: An open-trial comparison of paroxetine and nortriptyline in patients older than 70 years. J Clin Psychiatry 60:21–25. Wheatley DP, van Moffaert M, Timmerman L, Kremer CM (1998): Mirtazapine: Efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. Mirtazapine–Fluoxetine Study Group. J Clin Psychiatry 59:306 –312. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO (1983): Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiat Res 17:37–49.
From the Neuroscience Research Laboratories, Department of Psychiatry and Behavioral Sciences (GMM, AFS), Stanford University School of Medicine, Stanford, California; and Organon Pharmaceuticals Inc. (CK, HR), West Orange, New Jersey. Address reprint requests to Alan F. Schatzberg, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 300, Stanford CA 94305-5548. Received October 17, 2002; revised January 17, 2003; accepted January 24, 2003.
© 2003 Society of Biological Psychiatry
Introduction
T
here is wide variation in the response of patients with major depression to antidepressant pharmacotherapy. Some of this variation may be due to genetic differences among patients. The expanding field of pharmacogenetics seeks to identify DNA markers for differential medication response and to use these markers to individualize patient treatment so as to maximize efficacy and minimize side effects (Roses 2000). The apolipoprotein E (APOE) ε4 allele is an established genetic risk factor for Alzheimer’s disease (AD; Farrer et al 1997). In nondemented elderly, the APOE ε4 allele is associated with mild impairment in certain aspects of cognition (Bondi et al 1995; Caselli et al 2001; O’Hara et al 1998; Small et al 1999). These findings suggest impairment of brain function in ε4 carriers even in the absence of frank dementia. ApoE also affects recovery after physical trauma and stress in both animals and humans (Friedman et al 1999; Gordon et al 1996; Han and Chung 2000; Horsburgh et al 1999, 2000; Jordan et al 1997; Laskowitz et al 1997; Sheng et al 1998, 1999). There is no consistent evidence that the APOE ε4 allele is a risk factor for major depression (Mauricio et al 2000); however, because major depression is characterized by many signs and symptoms of stress including abnormalities of the hypothalamic-pituitary-adrenal axis (Brown et al 1999), we hypothesized that nondemented carriers of the APOE ε4 allele would respond poorly to antidepressant medications because of an impaired capacity for recovery. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that increases the availability of serotonin at synapses (Dechant and Clissold 1991). It has been shown to be efficacious in the treatment of major depression including depression in geriatric patients (Mulsant et al 1999; Walters et al 1999). Mirtazapine is a noradrenergic and specific serotonergic agent that induces the release of norepinephrine as well as serotonin in the brain (de Boer 1996; Stahl 1998). Mirtazapine has also been shown to be efficacious in the treatment of major depression, and several studies, including two with geriatric patients, have indicated that mirtazapine shows a faster onset of action 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00174-4
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than SSRI (Benkert et al 2000; Leinonen et al 1999; Schatzberg et al 2002; Wheatley et al 1998). We performed a multicenter, 8-week, double-blind pharmacogenetic comparison with a 16-week extension of paroxetine and mirtazapine in nondemented patients 65 years of age and older with major depression; APOE genotypes were determined for all patients. Clinical outcomes were quantified including improvement in mood, medication compliance, severity of adverse events, and discontinuations due to adverse events.
Methods and Materials
investigators with scores falling within a predetermined range participated in the study.
Treatment Protocol Initial treatment was with 15 mg of mirtazapine (one active capsule and one placebo capsule) or 20 mg of paroxetine (two 10-mg capsules) given each evening. After 2 weeks, doses were increased to 30 mg of mirtazapine or paroxetine once daily. At week 4 and 6 clinic visits, dose increases to 45 mg of mirtazapine or 40 mg of paroxetine were allowed if the patient had not been assigned CGI change scores of 1 or 2, indicating “much improved” or “very much improved.”
Clinical Trial Design and Patients
Extension Phase
The study design was an 8-week, double-blind, randomized trial with a 16-week extension comparing mirtazapine and paroxetine; it was conducted at 18 outpatient clinics in the United States. All aspects of the study received institutional review board approval at Stanford and at each participating site, and all patients provided written informed consent. Patients were 65 years of age or older and had been medically stable for at least 3 months. At screening, all met DSM-IV criteria for major depression (single or recurrent), had Mini-Mental State Examination (MMSE; Folstein et al 1975) scores above the 25th percentile for their age (Crum et al 1993), and had Hamilton Depression Rating Scale (17-item version, HDRS-17; Hamilton 1967) scores of at least 18. Patients were excluded for clinically significant laboratory abnormalities, drug or alcohol abuse, psychosis, recent suicide attempt, and psychiatric conditions other than major depression. Treatment with antidepressant medications within 7 days of commencing the study, and treatment with mirtazapine or paroxetine during the current depressive episode were grounds for exclusion. Patients taking medications approved for the treatment of cognitive disorders were excluded.
Patients who showed a CGI-change score of much or very much improved or a reduction of at least 50% on the HDRS-17 (or both) at the end of the 8-week acute phase were invited to continue for a 16-week extension phase under continued doubleblind conditions. Assessments were performed at weeks 12, 16, 20, and 24 weeks.
Genetic Analysis Genomic DNA was extracted from ethylenediamine tetraacetate– treated whole blood by using the Puregene DNA extraction kit (Gentra Systems, Minneapolis, MN). The APOE genotypes were determined as previously described (Murphy et al 1997). Electrophoretic gel images were assessed independently for APOE genotype by two observers blinded to clinical data, and if there was disagreement, the assay was repeated until the result was unequivocal. Greater than 95% of APOE genotyping assays gave unequivocal results on the first attempt. The remaining samples were resolved on a second attempt.
Plasma Drug Concentrations Outcome Measures Mood was rated using the HDRS-17, the Geriatric Depression Scale (GDS) (Yesavage et al 1983), and the Clinical Global Impression Scale (CGI) (Guy 1976) after 1, 2, 3, 4, 6, and 8 weeks of treatment in the acute phase. The severity of adverse events was rated by clinicians as mild (1), moderate (2), or severe (3). These scores were summed and standardized for drug exposure time and average daily dosage to create an adverse event index. Indices were calculated for adverse events judged by clinicians as related to the study drug and for all adverse events. Actual medication taken was determined by counting the number of prescribed capsules remaining at each clinic visit. Dosing compliance was determined by total number of medication doses taken divided by total number of capsules given across the entire study. Final daily dose was the dose each patient achieved during the acute phase after any dosing adjustments. Cognition was assessed at baseline and at week 8 using the MMSE. A meeting was held for physicians and staff from the different sites before the onset of the study for assessment training and standardization of assessment techniques. Mood ratings by investigators were evaluated using a videotaped patient interview, and only those
Samples for plasma drug concentrations were obtained after 4 weeks. Mirtazapine concentrations were analyzed by using a liquid chromatographic assay with fluorescence detection after extraction of plasma using n-hexane. Paroxetine was assayed using an ultraviolet high-performance liquid chromatography method. All plasma drug measurements were performed in accordance with Good Laboratory Practice standards. Sample collection times varied from patient to patient according to clinic appointment time, therefore time since the prior evening dose also differed.
Statistical Analysis To test for departure from Hardy–Weinberg equilibrium we used GENEPOP version 3.3 and the algorithm of Louis and Dempster (Louis and Dempster 1987). All other statistical analyses were performed using the SAS software package (SAS Institute, Cary, NC). Data at each time point were derived from only those subjects evaluated at that time point. We did not use a last observation carried forward approach. For clinical measures of depression (HDRS-17, GDS, and CGI), analyses of covariance were performed with baseline values as the covariate, and APOE
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Table 1. Baseline Measures and Acute Phase Dosing, Adverse Events, and Plasma Drug Concentrations, Stratified by Medication and APOE Genotype (Means with Standard Errors)
Number of patients (N ⫽ 246) Age (years) Gender Body Weight (kg) MMSE HDRS-17 CGI GDS Discontinuations due to Adverse Events Adverse Event Index (study drug) Final Daily Dose Dosing Compliance Index Day 28 Plasma Drug Concentration (ng/mL)
Paroxetine ε4 Carrier
Paroxetine ε4 Noncarrier
Mirtazapine ε4 Carrier
Mirtazapine ε4 Noncarrier
30 73.2 (.99) 12 M, 18 F 75.05 (2.74) 28.47 (.28) 22.3 (.059) 4.23 (.11) 19.16 (.96) 5 59.09 (6.29) 30.04 (1.63) 98.11 (1.73) 88.82 (9.22) n ⫽ 25
92 71.89 (.52) 45 M, 47 F 78.88 (1.81) 28.73 (.12) 22.45 (.38) 4.11 (.07) 19.8 (.57) 27 53.08 (3.35) 29.57 (1.02) 97.76 (.77) 69.31 (6.29) n ⫽ 70
31 71.13 (.85) 15 M, 16 F 75.65 (3.09) 28.55 (.25) 21.19 (.59) 4.26 (.13) 18.27 (1.05) 6 51.49 (6.22) 31.28 (2.17) 97.75 (.66) 32.6 (4.11) n ⫽ 25
93 72.1 (.62) 48 M, 45 F 76.91 (1.53) 28.73 (.12) 22.61 (.40) 4.22 (.06) 19.04 (.59) 13 44.42 (3.14) 31.14 (1.14) 96.96 (.82) 43.15 (2.24) n ⫽ 71
APOE, apolipoprotein E; CGI, Clinical Global Impression Scale; F, female; GDS, Geriatric Depression Scale; HDRS-17, Hamilton Depression Rating Scale (17-item version); M, male; MMSE, Mini-Mental State Exam.
genotype (ε4 allele carrier vs. noncarrier) and medication (mirtazapine, paroxetine) as the predictors. The genotypes ε2/ε4, ε3/ε4, and ε4/ε4 were classified as carriers, whereas the genotypes ε2/ε2, ε2/ε3, and ε3/ε3 were classified as noncarriers. For responder and remitter analyses of clinical measures of depression, we used Cochran–Mantel–Haenszel (CMH) statistics. We defined HDRS-17 and GDS 50% responders as those patients showing a 50% or greater reduction in their baseline scores at a subsequent assessment; we defined HDRS-17 remitters as those patients having a HDRS-17 score of 7 or less at a postbaseline visit. We also used CMH analyses to compare ε4 carriers and noncarriers in the two treatment groups for discontinuations due to adverse events. For comparison of medication and genotype groups on baseline demographic measures, medication dosing, medication compliance, severity of adverse events, and week 4 plasma drug concentrations, two-way analyses of variance were used. The effects of the APOE ε4 allele on cognitive impairment can depend on ethnic background (Farrer et al 1997). Hence, we reanalyzed our data with only Caucasian patients to reduce the likelihood that results were due to population stratification. There were not enough non-Caucasian patients in the study cohort (20 out of 246) to analyze data for these patients separately. Separate analyses were also performed for patients who had entered the extension phase. In analyses involving extension phase patients, data from both the acute as well as the extension phases were included.
Results Acute Phase Of the 255 patients randomized into the study, 246 received study medication, provided blood for genetic analysis, and had at least one postbaseline assessment of efficacy, adverse events, or compliance. APOE allele frequencies among the 246 patients were ε2 ⫽ .08, ε3 ⫽ .78, and ε4 ⫽ .14. These values are typical for nondemented elderly patients (Farrer et al 1997). Observed
genotype frequencies showed no significant departure from Hardy–Weinberg equilibrium. Of the total sample, 122 patients were treated with paroxetine and 124 with mirtazapine. Among the mirtazapine-treated patients, 31 (25.0%) carried an ε4 allele, whereas among the paroxetine-treated patients, 30 (24.6%) were ε4 carriers. Demographic and clinical characteristics of the patients are presented in Table 1. The mean ages, numbers of men and women, mean baseline body weights, MMSE scores, final daily dosages, dosing compliance, and daily medication taken were not significantly different among ε4 carriers and noncarriers for paroxetine- and mirtazapinetreated patients. There were no significant differences between ε4 carriers and noncarriers in the proportion of patients who discontinued because of adverse events for either mirtazapine or paroxetine, and no significant differences in indices of adverse event severity. Week 4 plasma drug concentrations were available on 96 mirtazapinetreated patients and 95 paroxetine-treated patients and showed that mean plasma drug concentrations were higher for paroxetine ε4 carriers than for noncarriers (p ⫽ .012). An overall comparison of the efficacy and side effects of paroxetine and mirtazapine in this cohort has been presented (Schatzberg et al 2002). In the present analysis, after stratifying by APOE genotype, there were no differences in baseline HDRS-17, CGI, and GDS scores for ε4 carriers and noncarriers in the paroxetine and the mirtazapine treatment groups. Across both treatment groups, there were no significant differences in mean HDRS-17 and CGI scores between ε4 carriers and ε4 noncarriers at weeks 1 and 2; however, at week 2, analysis of covariance showed there was an interaction between treatment and APOE genotype effects on HDRS-17 (p ⫽ .036; Figure 1) and CGI (p ⫽ .029) scores, with mirtazapine patients
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Figure 1. Mean Hamilton Depression Rating Scale (17-item version; HDRS-17) scores with standard errors by week for patients treated with mirtazapine in the acute phase of the study.
carrying an ε4 allele showing significantly lower scores, indicating greater improvement in mood, than those without an ε4 allele. Conversely, paroxetine-treated patients with an ε4 allele showed higher scores (less improvement) on the HDRS-17 (Figure 2), and the CGI than did those without an ε4 allele. For the GDS, after 2 weeks of treatment scores were lower (improved) among ε4 carriers than among non-ε4 carriers across both treatment groups (p ⫽ .025). This difference was due to lower GDS scores among mirtazapine-treated patients with an ε4 allele (p ⫽ .021; Figure 3), whereas there was no significant difference in GDS scores between paroxetine-treated patients with and without an ε4 allele at week 2 (Figure 4). At weeks 3 and 4 as well, GDS scores for mirtazapine-treated ε4 carriers were lower than those for noncarriers (p ⫽ .042, p ⫽ .026; Figure 3). At week 2, there were more HDRS-17 50% responders among mirtazapine-treated patients with an ε4 allele (48%) than among those without an ε4 allele (27.1%; p ⫽
Figure 2. Mean Hamilton Depression Rating Scale (17-item version; HDRS-17) scores by week for patients treated with paroxetine in the acute phase of the study.
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Figure 3. Mean Geriatric Depression Scale (GDS) scores for patients by week treated with mirtazapine in the acute phase of the study.
.049; Figure 5). In contrast, at week 2 none of the paroxetine-treated patients with an ε4 allele showed a 50% decrease in HDRS-17 score over baseline; all paroxetinetreated patients meeting this criterion were among those without an ε4 allele (p ⫽ .016; Figure 5). At week 1, there were more HDRS-17 remitters among mirtazapine-treated ε4 carriers (10.1%) than among noncarriers (1.1%; p ⫽ .018; Figure 6), whereas no difference was seen between paroxetine ε4 carriers and noncarriers. Similarly, at week 2 there were more HDRS-17 remitters among ε4 carriers in the mirtazapine-treated group (28%) than among those without an ε4 allele (7.1%; p ⫽ .005; Figure 6). Among paroxetine-treated patients, none of those with an ε4 allele met this criterion for improvement. Mirtazapine-treated patients with an ε4 allele were more likely to show a 50% reduction in GDS score at week 2 than were those without an ε4 allele (p ⫽ .046), whereas among paroxetine-treated
Figure 4. Mean Geriatric Depression Scale (GDS) scores for patients by week treated with paroxetine in the acute phase of the study.
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Figure 5. Percent of patients showing a 50% reduction in Hamilton Depression Rating Scale (17-item version; HDRS-17) scores in comparison with baseline (HDRS-17 responders) in the acute phase stratified by medication and apolipoprotein E genotype.
patients there was no difference in the number of responders between APOE genotype groups. A similar effect was seen at week 4: more mirtazapine-treated patients with an ε4 allele showed a 50% reduction in GDS score than did noncarriers (p ⫽ .007), but among paroxetine-treated patients there was no significant effect of APOE genotype. There was no significant difference in the number of ethnic minority patients in the mirtazapine and paroxetine groups (7 of 124 for mirtazapine: 1 Asian, 4 African American, 2 other minority; 13 of 122 for paroxetine: 2 Asian, 6 African American, 5 other minority). Likewise, for mirtazapine-treated patients, there was no significant difference in number of ethnic minorities among ε4 carriers (0 of 31) and noncarriers (6 of 93); however, for paroxetine-treated patients, there were more ethnic minor-
Figure 6. Percent of patients showing Hamilton Depression Rating Scale (17-item version; HDRS-17) score of 7 or less (HDRS-17 remitters) in the acute phase stratified by medication and apolipoprotein E genotype.
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ities among patients with the ε4 allele (7 of 23) than among noncarriers (6 of 86; p ⫽ .016). Among Caucasian patients, there were no differences in mean age, number of men and women, final daily dosage achieved, dosing compliance, baseline body weight, or plasma drug concentrations between ε4 carriers and non-ε4 carriers for either mirtazapine or paroxetine. There were no significant differences between Caucasian ε4 carriers and noncarriers in the number of patients who discontinued because of adverse events for either mirtazapine or paroxetine. The same interaction between APOE genotype and medication on treatment outcome was observed among Caucasian patients as in the full sample. At baseline, there were no differences between ε4 carriers and noncarriers for any of the mood scales. At week 2, mean scores for the HDRS-17 were lower for mirtazapine than for paroxetine (p ⫽ .002). There was an interaction between APOE genotype and medication for HDRS-17 scores (p ⫽ .04). Mirtazapine patients with an ε4 allele showed greater improvement than those without an ε4 allele, whereas among paroxetine-treated patients, HDRS scores for ε4 carriers showed less improvement than did those of noncarriers. Week 2 GDS scores were lower for ε4 carriers than for noncarriers treated with mirtazapine (p ⫽ .031), but APOE genotype had no effect on GDS scores among paroxetine-treated patients. Among mirtazapine-treated Caucasian patients, week 2 CGI scores showed more improvement for ε4 carriers than for noncarriers (p ⫽ .042), but for paroxetine-treated patients there were no differences between ε4 carriers and noncarriers. Among Caucasian patients, interactions between medication and APOE genotype at week 2 were also observed in 50% reduction in HDRS-17 (p ⫽ .036), HDRS-17 remission (p ⫽ .007), and 50% reduction in GDS (p ⫽ .042). For each measure the percentage of ε4 carriers responding to medication treatment was greater for mirtazapine than for paroxetine. Similarly, at week 4 there were more patients showing a 50% reduction in GDS score (41.7%) among mirtazapine-treated ε4 carriers than among noncarriers (16.9%; p ⫽ .012), whereas for paroxetine-treated patients there was no significant effect of the ε4 genotype on the number of patients showing a 50% reduction in the GDS. We obtained MMSE scores on all patients at week 8. Analysis of covariance showed there was no significant difference between ε4 carriers and noncarriers in MMSE score at week 8, adjusting for HDRS-17 score. Likewise, there was no interaction effect between medication and APOE genotype in determining week 8 MMSE. The scores at week 8 were mitazapine ε4 carrier 28.5 ⫾ .2 mirtazapine noncarrier 28.8 ⫾ .1, paroxetine ε4 carrier 28.0 ⫾ .5, paroxetine noncarrier 28.7 ⫾ 0.1.
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24 for either medication in an analysis of covariance adjusting for HRDS-17 scores. There were no significant differences in the numbers of ethnic minorities among ε4 carriers and noncarriers for either medication group in the extension phase. A separate analysis for Caucasian patients (n ⫽ 60 for mirtazapine and n ⫽ 47 for paroxetine) gave results similar to those obtained for the full extension phase cohort, with mirtazapine-treated ε4 carriers showing significantly greater improvement on the HDRS-17 and the GDS. There were no significant effects of the ε4 allele on response to paroxetine among Caucasian patients entering the extension phase. Figure 7. Mean Geriatric Depression Scale (GDS) scores by week for patients treated with mirtazapine who entered the extension phase. The p values are for test of mean difference between ε4 carriers and noncarriers. Also, at weeks 2, 3, 6, 8, and 12, there were significant drug-by-genotype interaction effects.
Extension Phase Of the original cohort, 62 mirtazapine-treated patients (15 with ε4) and 54 paroxetine-treated patients (15 with εf4) entered the extension phase. The same effect of the ε4 allele on treatment outcome was seen in the extension phase cohort. There were genotype by drug interactions at weeks 2, 3, 4, 6, 8, and 12 (p ⬍ .05 for all). These interactions were due to significantly lower GDS scores among mirtazapine-treated ε4 carriers in the acute phase (simple main effect p values shown in Figure 7). Similar results were obtained for HDRS-17 and CGI scores. In contrast, there were no differences between ε4 carriers and noncarriers among paroxetine-treated patients for the GDS (Figure 8) or for other clinical measures during the extension phase. There were no significant differences between ε4 carriers and noncarriers in MMSE scores at week 8 or at week
Figure 8. Mean Geriatric Depression Scale (GDS) scores by week for patients treated with paroxetine who entered the extension phase. There were no significant differences in mean scores between paroxetine-treated ε4 carriers and noncarriers.
Discussion These results demonstrate that depressed nondemented elderly patients carrying the APOE ε4 allele show a rapid remission of symptoms when treated with mirtazapine. In contrast, paroxetine-treated ε4 carriers showed a slower antidepressant onset than noncarriers. These findings were consistent across the HDRS-17, GDS, and CGI rating scales. Our original hypothesis of impaired antidepressant efficacy among ε4 carriers was not confirmed. Individuals with the ε4 allele have a poor outcome following intracerebral hemorrhage (Alberts et al 1995), display greater cognitive decline following cardiac surgery (Newman et al 1995), are more vulnerable to brain injury associated with boxing (Jordan et al 1997), and are at increased risk following head injury (Nicoll et al 1995; Sorbi et al 1995). Thus, we expected that ε4 carriers would show a slower recovery from depression than would noncarriers. Surprisingly, ε4 carriers showed a more rapid onset of action in the mirtazapine sample. There are many potential confounding factors in a pharmacogenetic study such as this; however, we found no significant differences between ε4 carriers and noncarriers in the numbers of men and women, mean age, baseline body weight, baseline depression, or cognition for either drug treatment group. Because there were more ethnic minorities in the ε4 group among paroxetine-treated patients, we analyzed the data including only Caucasians; reanalysis of data from Caucasian patients alone yielded results similar to those for the full sample. Studies with additional ethnic minority patients will be required to determine if the effect seen in Caucasians occurs in other populations. Varying levels of medication compliance and individual differences in pharmacokinetics can confound pharmacogenetic results. Plasma drug levels obtained at week 4 showed significantly higher levels for acute phase paroxetine ε4 carriers than for noncarriers; however, plasma samples were obtained at each patient’s regular clinic visit,
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and hence the time since the prior day’s dose varied. There were no significant differences between ε4 carriers and noncarriers in dosing compliance across the entire study or in final daily dose. At week 4, capsule counts showed a trend toward paroxetine ε4 carriers having taken more medication in the prior week than had noncarriers, which may have accounted for the higher plasma level. Nevertheless, there were no significant differences in the acute phase among ε4 carriers and noncarriers in the severity of side effects due to the study medication for either treatment group, nor in the proportion of patients discontinuing due to adverse events, suggesting that medications were tolerated equally well by ε4 carriers and noncarriers. Although the extension phase cohort was smaller, results showed that the differential effect of the ε4 allele on mirtazapine response was sustained, with significant differences detected through week 12. Sustained response makes it unlikely that the strong early difference in antidepressant response between ε4 carriers and noncarriers was due to a difference in degree of sedation induced by mirtazapine (Stahl et al 2001) or due to a placebo effect. There was no significant difference between ε4 carriers and noncarriers in baseline or week 8 MMSE, no significant effect of treatment on MMSE score for either medication, and no significant MMSE interaction effect between genotype and treatment. We expected that antidepressant treatment would improve MMSE score in noncarriers but not in ε4 carriers; however, it is possible that because of the high mean baseline MMSE scores for both genotype groups, this instrument lacked sufficient sensitivity to detect small improvements in cognition. In any case, based on MMSE results, we found no evidence that the improvement in mood was associated with an improvement in cognition. The neurobiological basis for the differential effect of the ε4 allele on response to mirtazapine and paroxetine cannot be determined from these results. Monoaminergic neurons thought to be important in modulating mood (Leonard 2000) degenerate with aging in mice lacking ApoE expression. Noradrenergic neurons appear to be particularly vulnerable to APOE knockout (Chapman and Michaelson 1998; Puolivali et al 2000). Noradrenergic presynaptic terminals and norepinephrine levels are reduced in the hippocampus and to a lesser extent in other brain regions. After chemical injury to the locus ceruleus, mice lacking APOE show impaired recovery compared with wild type animals (Puolivali et al 2000). Serotonergic projection neurons also degenerate in APOE knockout mice. Transgenic expression of human E3 or E4 isoforms results in restoration of noradrenergic and serotonergic deficits in APOE knockout mice (Chapman et al 2000); however, APOE knockout mice expressing human E4 are more vulnerable to physiologic stress than those expressing human E3, suggesting
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that the capacity of noradrenergic neurons in human ε4 carriers to recover when challenged could be impaired (Horsburgh et al 2000; Sheng et al 1998). Paroxetine is an SSRI that increases the availability of serotonin at synapses between neurons arising in the brain-stem raphe nuclei and their target neurons in a number of brain regions (Dechant and Clissold 1991). Mirtazapine induces the release of norepinephrine as well as serotonin in the brain through antagonism of ␣-2adrenergic receptors on noradrenergic and serotonergic neurons (de Boer 1996; de Boer et al 1996). Norepinephrine release at synapses with serotonergic neurons also augments serotonin release. Thus, whereas paroxetine has a primarily serotonergic mode of action, mirtazapine has both serotonergic and noradrenergic actions. It is conceivable that in elderly depressed patients, the E4 isoform affects brain-stem noradrenergic and serotonergic neurons so that the dual-action agent mirtazapine results in a rapid response, but the single action agent paroxetine has a slower response. Interestingly, when paroxetine dose was increased to 30 mg at week 2, there was a marked increase in the number of ε4 carriers showing a 50% reduction in HDRS-17 over baseline values (Figure 5). Animal data suggest that when paroxetine concentrations increase, this agent may inhibit the norepinephrine reuptake transporter, resulting in increased synaptic norepinephrine levels (Owens et al 2000). Hence, after week 2, a noradrenergic effect of paroxetine could have accounted for the increase in the number of responders among ε4 carriers (Figure 5). There is no convincing evidence that the APOE ε4 allele is a risk factor for major depression in humans. We previously showed in a 5-year longitudinal study of nondemented elderly that the ε4 allele does not predispose to depression (Mauricio et al 2000). Cross-sectional studies have had similar results (Class et al 1997; Forsell et al 1997; Schmand et al 1998). It may be that the interaction between APOE genotype and mood becomes apparent only in the setting of antidepressant treatment, as demonstrated in this study. Alternatively, the rapid response to mirtazapine among ε4 carriers may reflect reduced hypothalamic-pituitaryadrenal (HPA) axis activity after treatment with this medication. Many studies have reported increased HPA activity in depressed patients, and Peskind et al (2001) found that Alzheimer’s disease patients carrying the ε4 allele have significantly elevated cerebrospinal fluid cortisol levels compared with noncarriers. Mirtazapine significantly reduces cortisol levels soon after initiation of treatment (Schule et al 2002), which may have been particularly beneficial to patients carrying the ε4 allele. In our study we did not measure cortisol levels, but future studies should include assessment of both APOE genotype and HPA axis activity.
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Statistical hypothesis testing with multiple outcome measures increases the risk for type I error. Therefore, these results will require replication. Another explanation for these findings is that the effect on antidepressant treatment outcome is due to a polymorphism in another gene in linkage disequilibrium with APOE. Population stratification of the self-identified Caucasian sample cannot be ruled out. Hence, it is conceivable, although unlikely, that ε4 carriers and noncarriers were drawn from different Caucasian subpopulations that have differing responses to antidepressant medications. There are no well-documented differences among Caucasian groups in antidepressant response. In summary, these results suggest that the APOE ε4 allele may be a pharmacogenetic marker for rapid onset of mirtazapine action in nondemented elderly with major depression. In contrast, ε4 carriers treated with paroxetine showed a slower onset of action than noncarriers. These differences among genotype groups in medication response could not be attributed to baseline patient characteristics, and the result was the same regardless of whether ethnic minorities were included in the analysis. It is surprising that despite evidence that the ε4 allele impairs recovery from trauma and stress, ε4 carriers showed a superior antidepressant response during initial treatment, at least for mirtazapine. These findings should be tested using data from other antidepressant clinical trials for which DNA samples were collected. It will be interesting to determine if results obtained with mirtazapine and paroxetine apply to other antidepressants.
Supported by funding from Organon Pharmaceuticals, Inc., the Nancy Pritzker Network for the Study of Depression, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center. Mirtazapine versus Paroxetine Study Group: M. Bari, Chula Vista, CA; B. Baumel, Miami Beach, FL; L. Blake, Chicago, IL; C. DeBattista, Stanford, CA; S. Cheren, Natick, MA; L. Eisner, Ft. Lauderdale, FL; W. Falk, Charlestown, MA; S. Hand, Scottsdale, AZ; H. Hassman, Berlin, NJ; L. Kirby, Peoria, AZ; E. Kramer and G. Greenwald, Glen Oaks, NY; C. Nelson, Hartford, CT; P. Ripley, South Yarmouth, MA; L. Rone, Evanston, IL; R. Riesenberg, Atlanta, GA; A. Strauss, Boynton Beach, FL; K. Weiss, Conshohocken, PA. Nina Pascoe, Jeremy Claassen, Clara Poon, and Feifei Zhao provided technical assistance. William Cheuk assisted with data management and with illustrations. Christopher Pan provided assistance with statistical analysis.
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