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SSRIs Do Not Cause Affective Blunting in Healthy Elderly Volunteers
SSRIs Do Not Cause Affective Blunting in Healthy Elderly Volunteers Patricia M. Furlan, Ph.D., Michael J. Kallan, M.S. Thomas Ten Have, Ph.D., Irwin Lucki, Ph.D. Ira Katz, M.D., Ph.D.
Objective: This study was undertaken to evaluate the effects of selective serotonin reuptake inhibitors (SSRIs) on affective experience in healthy older adults. Methods: After 1 week of observation, normal elderly volunteers (age range: 65–84 years) were given placebo, paroxetine (10 mg–40 mg/day), or sertraline (50 mg–150 mg/day) for 3 weeks in a double-blind study. Paroxetine- and sertraline-treated subjects were analyzed together as the SSRI group (N⳱30). Volunteers were assessed weekly and recorded mood and events in a daily diary each evening. All data were analyzed with mixed-effects random-regression models. Results: There were significant relationships between daily affect and events reported in the daily diary for the sample as a whole, with no differences between groups in mean slopes of positive or negative affect across the length of the study. There were no differences between groups in affective variability. However, the SSRI group, but not the placebo group, demonstrated a significant drug-dependent decrease in negative affect related to negative events. There were no other observed group differences on any other measure. Conclusion: Interpreting the results conservatively, they demonstrate that SSRIs are not associated with affective toxicity in elderly persons. (Am J Geriatr Psychiatry 2004; 12:323–330)
T
here has been discussion in both the scientific and lay literature of the possibility that selective serotonin reuptake inhibitors (SSRIs) may be associated with diverse alterations in emotion and personality function, including increased suicidality, impulsiveness, affective blunting, and assertiveness.1–9 Indeed, the impact of these agents on emotional behaviors distinct from depression is supported by their therapeutic use as a treatment for pathologic crying10,11
and violent outbursts.12 These effects may reflect a blunting of affective response that may be clinically desirable in these contexts. However, in patients treated for depression, affective blunting could represent an adverse effect; that is, a form of affective toxicity, as has been suggested in some case reports.13,14 These reports of affective side effects may reflect rare events brought on by the interaction of personal history, a psychiatric illness, and idiosyn-
Received June 30, 2003; revised October 3, 2003; accepted November 18, 2003. From the Department of Psychiatry, University of Pennsylvania, Philadelphia, PA (PMF,IL,IK); MIRECC, Philadelphia Veterans Administration Medical Center, Philadelphia, PA (PMF,IK), and the Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA (MJK,TTH). Send correspondence to Ira Katz, M.D., Ph.D., University of Pennsylvania School of Medicine, Department of Psychiatry, 3535 Market Street, Room 3001, Philadelphia, PA 19104. e-mail: [email protected] 䉷 2004 American Association for Geriatric Psychiatry
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SSRIs and Affective Blunting cratic responses to the drugs. Alternatively, they may be sentinel reports, indicating that there may be underappreciated and underreported side effects of SSRIs that impair overall functioning despite the responses of the identified psychiatric symptoms to treatment. In addition to standard psychiatric rating scales, another approach to evaluating the effects of medications on affective processes is through self-reports generated in daily diaries. A daily sampling technique that elicits a diary of daily events along with positive and negative affect ratings has demonstrated contingency between affective experience and events in both healthy and depressed populations.15 Diaries can provide information about mean levels of affect, trends over time, and variability. Also, they can provide measures of sensitivity to the occurrence of daily “hassles” and “uplifts” that may have a significant impact on emotional states.16 To understand the effect of SSRIs on affect, it may be important to assess mood in the context of daily events. This study was designed to assess the effect of SSRIs on the affective variability of older adults, with a particular interest in identifying affective toxicity that might be manifested as affective blunting. Currently, no published placebo-controlled studies have reported on the effect of SSRIs on personality function or on affective responding in older adults. Although most information about the effects of SSRIs on affective function is derived from the treatment of depression, this approach captures little about the normal ecology of affective variability. Furthermore, in patients treated for depression, it may be difficult to distinguish between putative affective side effects and residual symptoms of their illness. Therefore, testing for the effects of SSRIs on affective functioning requires administration of these medications to normal volunteers. In the current study, healthy elderly volunteers were given SSRIs or placebo for 3 weeks in a double-blind, randomized, placebo-controlled study to assess the effects of these medications on measures of affective functioning and personality. The cognitive effects of medication exposure in this population have been reported previously.17 The hypotheses to be tested in this study were that SSRIs would lead to an alteration of affective variability and an altered response to daily events, relative to placebo.
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MATERIALS AND METHODS Volunteers Study volunteers were 54 healthy adults over the age of 64 years, who responded to a newspaper advertisement. Volunteers received a screening examination consisting of a physical exam, a semistructured psychiatric interview, and a screen of cognitive capacity. Exclusion criteria consisted of hospitalizations for any reason or significant changes in medication within the past month, previous use of the study medications, less than 8 years of education, Mini-Mental State Exam (MMSE) score below 24, Center for Epidemiological Studies–Depression (CES–D) score over 12, significant clinical laboratory abnormalities, disease of the central nervous system, alcohol or substance abuse within the past 5 years, history of mental retardation, psychotic disorder, major depression, or bipolar disorder, active liver or kidney disease evidenced from a review of systems or screening laboratory evaluations, insulin-dependent diabetes, taking medication capable of causing cognitive or affective toxicity, taking concomitant medications with significant interaction with study medications, and performance outside the range of normal on practice tasks conducted during the baseline evaluation. After providing a complete description of the study to the subjects, we obtained written informed consent before any study procedures were performed. Protocols were approved by the Institutional Review Board of the University of Pennsylvania. Volunteers were reimbursed for participation in the study. Behavior Test Battery Volunteers completed the Lawton Positive Affect and Negative Affect rating scales at the end of each day for the duration of the study.16 The scale consists of five positive affect terms and five negative affect terms for rating affective states on a 5-point scale. The positive affect scale (range: 5–25) includes “energetic,” “warmth toward others,” “interested,” “happy,” and “content,” and the negative affect scale (range: 5–25) includes “annoyed,” “irritated,” “depressed,” “worried,” and “sad/blue.” Subjects also recorded significant positive and negative daily events that were outside of their usual routine. The
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Furlan et al. events were rated by judges as positive (Ⳮ1 to Ⳮ3), negative (–1 to –3), or neutral (0) in valence depending on the investigators’ judgment as to whether the events would be viewed positively or negatively in usual conditions by reasonable persons. Examples of negative events or “hassles” include difficulties with transportation, minor accidents, or interpersonal conflicts. Examples of positive events or uplifts include outings or visits from family or friends. Two judges independently assigned valences and attained an exact agreement of 94%. To assess affect using more traditional methods, the Positive and Negative Affect Scale (PANAS)18 and the Profile of Mood States (POMS) were administered. The POMS includes the subscales of Anger, Confusion, Depression, Fatigue, Tension, and Vigor.19 To test for changes in personality structure, the Revised NEO Personality Inventory (NEO-PI-R) was administered; it assesses five traits: neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness.20 Testing Procedures The initial evaluation of volunteers, instruction on test procedure, and practice occurred during their first visit to the Geriatric Behavioral Psychopharmacology Laboratory of the University of Pennsylvania. The battery included a cognitive assessment, the results of which have been published previously.17 The study test sessions were conducted at Days 7 (baseline), 14, 21, and 28. Although volunteers were seen at various times of the day, individual volunteers reported to the laboratory at the same time for each test session. Daily diary entries were recorded by the volunteer each evening at home and collected at the end of each of the 4 test weeks (Baseline Week (Days 1– 7), Week 1 (Days 8–14), Week 2 (Days 15–21), and Week 3 (Days 22–28). The PANAS and NEO were administered at Days 7 and 28, and the POMS was administered at Days 7, 14, 21, and 28. Drugs and placebo were administered for 21 days in morning doses. Paroxetine doses doubled each week from the initial dosing of 10 mg/day to a final dose of 40 mg/day. Sertraline doses began at 50 mg/day for Days 8–14, were increased to 100 mg/day for Days 15–21, and to 150 mg/day for Days 22–28. Volunteers were randomized by use of a computergenerated random-number table, such that for each
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block of six volunteers, two were assigned to each of the three treatment groups. In order to maintain the double blind, all medication was administered in identical-appearing capsules. Statistical Analysis This study was designed to assess the behavioral effects of subchronic administration of SSRIs in nondepressed volunteers in order to study the effect of this class of drugs on affect, independent of the presence of depression and its change with treatment. In a previous article on cognitive effects associated with SSRIs,17 we compared the effects of sertraline and paroxetine. In this study investigating the affective changes associated with SSRIs, we collapsed the two SSRIs into one group on the basis of the demonstrated ability of both medicines to effectively treat depression. All volunteers were included in the tolerability analyses according to an intention-to-treat design (N⳱54). In contrast, only volunteers who completed the 3-week drug treatment were included in the analysis of drug effects (N⳱49). The analysis of daily affect and events from the diary entries consisted of the testing and estimation of the following hypothesized contrasts: 1) differences in mean, slope, and variability of positive and negative affect within each treatment group across the length of the study; and 2) the assessment of regression effect of positive or negative events on positive and negative affect across time for the entire sample and within and between each treatment group. For all of the analyses for the above hypotheses, with affect (positive or negative) as the outcome and both time (Baseline, Week 1, Week 2, Week 3) and event (positive or negative), and in some models, treatment (placebo or SSRI) as the grouping factors, hierarchical linear models were used with random intercepts and slopes for time, main effects for the grouping factors, and their respective two-way and three-way interactions. Number of positive and negative diary events, PANAS, POMS, and NEO data were also analyzed using hierarchical linear models. For PANAS and NEO, the Time factor consisted of only two levels (Baseline, and Week 3). These models were fitted with Proc Mixed in SAS V8 (SAS Institute, Inc., Cary, NC). Post-hoc pairwise comparisons among treatment groups and across time were performed along with Bonferroni adjustments. Tolera-
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SSRIs and Affective Blunting bility, as measured by early termination secondary to adverse events, was analyzed with Pearson chisquare analysis. All statistical analyses were conducted with two-tailed alpha levels of 0.05. In these analyses, variability of positive and negative affect was calculated as the square-root of the square of the residuals from the regression of plots of Affect ⳯ Time divided by the number of observations.
RESULTS A total of 49 volunteers completed the study protocol (placebo: N⳱19; SSRI: N⳱30). Demographics of Completer volunteers are presented in Table 1. One volunteer randomized to the Placebo condition reported the adverse event of vomiting, leading to early termination. Four volunteers randomized to the SSRI condition reported the following adverse events leading to early termination: burning in stomach; drowsiness; nervousness, diarrhea, and rectal bleeding; and vertigo (a recurrence of a prior condition). No volunteers terminated secondary to confusion or depression. The dropout rate was not significantly different between treatment groups (v2[1]⳱0.69; p⳱0.41). Daily Diary Affective Change Independent of Events As shown in Table 2, the result of the mixed-model random regression indicated no significant group differences in the baseline mean or slope of positive or negative affect. The SSRI group demonstrated significantly greater positive affective variability than the placebo group during the Baseline Week, but this difference was not significant during the treatment phase (Weeks 1–3) of the study. There was no statistically TABLE 1.
significant difference in the variability of negative affect between groups at any time during the study. Understanding the significance of the findings of Table 2 requires an estimate of the magnitude of effects that can be ruled out by the observed data. From a clinical perspective, this is most important for the effect of the medications on positive affect. Here, the mean difference between pre-drug and post-drug variability was 0.02 (95% confidence interval [CI]: –0.25 to 0.31) for placebo and 0.18 (95% CI: –0.12 to 0.47). From the upper limit of this confidence interval, we can exclude a drug-related decrease in positive affect variability greater than 0.47, or approximately 25% or more of the pre-drug mean, with p ⬍0.025. Similarly, for negative affect, we find a decrease in variability after placebo administration of approximately 0.31 (95% CI: –0.08 to 0.69), or approximately 22% of the pre-drug mean, and a decrease after SSRI administration of 0.75 (95% CI: 0.16 to 1.34), or 37% of the pre-drug mean. Here, based on the lower limit for the confidence interval, the magnitude of the effect that can be excluded with p⬍0.025 is approximately 55% of the pre-placebo variability; that is, a decrement approximately 25% greater than the mean difference in variability after placebo administration. Event Reporting The results of the mixed-model random regression analyses indicated that, for the number of positive events, there was no significant main effect of Group (F[1, 47]⳱0.18; p⳱0.67), a significant effect of Week (F[3, 144]⳱3.91; p⳱0.01), and a nonsignificant Group ⳯ Week interaction (F[3, 141]⳱2.49; p⳱0.06). Similar results were observed for negative events: no significant main effect of Group (F[1, 47]⳱0.15; p⳱0.70), a significant main effect for Week (F[3, 144]⳱3.81; p⳱0.012), and no significant Group ⳯ Week interaction (F[3, 141]⳱0.10; p⳱0.96). Both groups reported fewer positive and negative events as the study progressed. Average event valences were low
Sample demographics
Age, years Education, years Gender, male Race, Caucasian CES–D
Placebo (Nⴔ19)
SSRI (Nⴔ30)
Statistic[df]
p
70.3Ⳳ4.9 15.1Ⳳ2.5 68% 77% 3.5Ⳳ2.7
73.3Ⳳ5.8 15.2Ⳳ3.1 53% 73% 4.3Ⳳ3.3
t[47]⳱1.71 t[47]⳱0.14 v2[1]⳱1.10 v2[1]⳱0.20 t[47]⳱0.87
0.09 0.89 0.30 0.66 0.39
Note: Values are mean Ⳳ standard deviation, unless otherwise indicated. SSRI: selective serotonin reuptake inhibitors; CES–D: Center for Epidemiological Studies–Depression scale.
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Furlan et al. and did not differ significantly between groups (see Table 3). Affect Change Contingent on Events As shown in Table 4, the mixed-model random regression analysis of the relationship between events and affect among all subjects across the study indicated that positive events were associated with significant increases in positive affect and significant decreases in negative affect, and negative events were associated with significant decreases in positive affect and significant increases in negative affect. In an effort to address the potential confound introduced by recording affect and events on the same day, we also analyzed the relationship between the previous days’ events and current affect among all subjects. The result of this analysis indicated a similarly significant pattern of contingency as in the “same-day” analysis, except for the effect of positive events on positive affect. However, when the analyses were extended to encompass the relationship of daily TABLE 2.
affect with events recorded 2 days previously, there was no significant contingency. The attenuation of these effects after lags of 1 and 2 days is expectable, and these observations support the validity of the observed associations between events and affects.
Effect of SSRIs on Contingency of Affect on Events Mixed-model random regression models tested for the contingency of positive and negative affect on the presence or absence of positive and negative events in the drug and placebo conditions across the length of the study. All of the significant effects for the “same-day” analysis of all subjects (Table 4) were again significant for both the drug and placebo groups at p ⬍0.001 except for the relationship between positive affect and negative events, where the contingency in the placebo group was not significant (F[1, 510]⳱1.78; p⳱0.18). Specific effects of the medications were examined by testing for Event ⳯ Week and Event ⳯ Week ⳯ Drug interactions (Table 5). For positive affect, there were no significant Event ⳯
Comparison of placebo and SSRI mean positive and negative affect, slope, and variability
Positive Affect Baseline mean (SD) Slope (SEM) Variability Baseline (SEM) Weeks 1–3 (SEM) Negative Affect Baseline mean (SD) Slope (SEM) Variability Baseline (SEM) Weeks 1–3 (SEM)
Placebo (Nⴔ19)
SSRI (Nⴔ30)
18.89 (2.60) ⳮ0.011 (0.019)
18.20 (2.68) ⳮ0.030 (0.020)
0.89 0.71
1.40 (0.197) 1.39 (0.204)
2.06 (0.158) 1.89 (0.163)
ⳮ2.59 ⳮ1.94
0.013 0.06
6.37 (1.74) ⳮ0.018 (0.014)
6.47 (2.08) ⳮ0.032 (0.028)
ⳮ0.17 ⳮ0.44
0.86 0.67
1.41 (0.344) 1.11 (0.225)
2.05 (0.270) 1.29 (0.180)
ⳮ1.46 ⳮ0.65
0.15 0.52
t[47]
p 0.38 0.47
Note: SSRI: selective serotonin reuptake inhibitors; SD: standard deviation; SEM: standard error of the mean.
TABLE 3.
Mean number of events and mean event valence by treatment group Positive Events Placebo (Nⴔ19) SSRI (Nⴔ30)
Number Baseline Week 1 Week 2 Week 3 Valence Baseline Week 1 Week 2 Week 3
Negative Events Placebo (Nⴔ19) SSRI (Nⴔ30)
4.11 (4.81) 3.53 (4.57) 4.00 (4.97) 4.16 (4.96)
6.00 (5.71) 4.37 (4.69) 4.17 (5.14) 3.53 (4.46)
1.53 (1.17) 1.16 (1.12) 0.84 (1.50) 0.84 (1.46)
1.33 (1.65) 1.13 (1.66) 0.83 (1.26) 0.63 (0.96)
1.01 (0.03) 1.00 (0.00) 1.02 (0.07) 1.02 (0.04)
1.02 (0.07) 1.09 (0.24) 1.05 (0.23) 1.08 (0.26)
ⳮ1.00 (0.00) ⳮ1.12 (0.39) ⳮ1.00 (0.00) ⳮ1.19 (0.38)
ⳮ1.24 (0.44) ⳮ1.07 (0.18) ⳮ1.00 (0.00) ⳮ1.15 (0.34)
Note: Values are mean (standard deviation).
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SSRIs and Affective Blunting TABLE 4.
Contingency of affect on daily events among all subjects (Nⴔ49) Positive Affect
Same-day events Positive Negative 1-day-previous events Positive Negative 2-days-previous events Positive Negative
Negative Affect
Effect (SEM)
F[df]
p
Effect (SEM)
F[df]
p
1.36 (0.14) ⳮ1.16 (0.18)
95.47[1, 1340] 40.95[1, 1317]
⬍0.001 ⬍0.001
ⳮ0.68 (0.14) 2.01 (0.17)
23.50[1, 1351] 139.12[1, 1321]
⬍0.001 ⬍0.001
0.09 (0.14) ⳮ0.59 (0.18)
0.42[1, 1332] 10.47[1, 1316]
0.52 0.001
ⳮ0.30 (0.14) 0.49 (0.17)
4.79[1, 1342] 7.94[1, 1320]
0.029 0.005
0.16 (0.14) ⳮ0.21 (0.19)
1.29[1, 1333] 1.27[1, 1315]
0.26 0.26
ⳮ0.13 (0.14) 0.23 (0.18)
0.86[1, 1344] 1.77[1, 1319]
0.35 0.18
Note: Effect is the difference in affect on days when an event was reported minus days when the event was not reported. The F-test was for the null hypothesis that the effect size ⳱ 0. SEM: standard error of the mean.
Week interactions within either treatment group; nor were there significant Event ⳯ Week ⳯ Drug interactions. For negative affect, there were no significant negative affect–positive event interactions within either treatment group, nor were there significant Event ⳯ Week ⳯ Drug interactions. However, as shown in Table 5, there was a significant Week ⳯ Negative Affect–Negative Event interaction in the SSRI group, in contrast to the nonsignificant analogous interaction effect in the placebo group. The results of the mixed-model random regression analyses of the linear relationship between negative events and negative affect for the SSRI group across time indicated a decrease in the contingency of negative affect on negative events such that, at Week 3, the mean effect of negative events on negative affect was no longer significantly different from 0 as assessed by
TABLE 5.
Effect of SSRIs on contingency of affective response to daily events Event ⴒ Week
Positive Affect Positive event Placebo SSRI Negative event Placebo SSRI Negative Affect Positive event Placebo SSRI Negative event Placebo SSRI
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Event ⴒ Week ⴒ Drug
F[df]
p
F[df]
p
1.54[3, 505] 0.81[3, 796]
0.20 0.49
0.80[3, 1302]
0.50
1.13[3, 506] 0.13[3, 798]
0.34 0.94
0.45[3, 1303]
0.72
0.77[3, 506] 0.63[3, 797]
0.51 0.60
0.80[3, 1303]
0.49
0.57[3, 507] 3.25[3, 798]
0.64 0.021
1.84[3, 1304]
0.14
t-tests (Baseline Week mean effect ⳱ 3.25 (standard error of the mean [SEM]: 0.43); t[798]⳱7.64; p ⬍0.001; Week 1 mean effect ⳱ 2.35 (0.46); t[799]⳱5.15; p ⬍0.001; Week 2 mean effect ⳱ 2.65 (0.50); t[799]⳱5.24; p ⬍0.001; Week 3 mean effect ⳱ 0.99; t[798]⳱1.69; p⳱0.09). A post-hoc test for the magnitude of the linear decrease in the contingency of negative affect on negative events across time indicated that this decrease was significant (F[1]⳱8.35; p⳱0.004). Other Scales The results of the mixed-model random regression analyses indicated no significant behavioral effects of SSRIs on affect as measured by PANAS and POMS or on personality as measured by the NEO. There were no main effects of Group or any Group ⳯ Week interactions for any measure. There was a main effect of Week for PANAS positive affect (F[1, 47]⳱9.29; p⳱0.003) but not for PANAS negative affect. Both groups demonstrated higher PANAS positive affect scores at Baseline (placebo mean⳱39.3, [5.9]; SSRI mean⳱39.6 [6.0]) than at Day 21 (placebo mean⳱38.1 [7.4]; SSRI mean⳱36.0 [8.5]). The analysis of POMS Vigor scores indicated no significant effect of Group, a significant effect of Week (F[3, 141]⳱4.08; p⳱0.008), and no significant Group ⳯ Week interaction. Both groups demonstrated higher Vigor scores at Baseline (placebo mean⳱21.2 [6.3]; SSRI mean⳱20.6 [6.1]) than at Day 21 (placebo mean⳱20.9 [6.8]; SSRI mean⳱17.3 [6.9]). There were no significant main effects of Group or Week or any Group ⳯ Week interactions for the Anger, Confusion, Depression, Fatigue, or Tension scales of the POMS. There were no significant main effects of Group or Week or any Group ⳯ Week interactions for any scale of the NEO. Nonsignificant results are not presented.
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Furlan et al. DISCUSSION The main finding of this study was that healthy elderly volunteers treated with SSRIs demonstrated no significant alterations in personality or affect. These healthy volunteers did not demonstrate increased emotional lability, alterations in daily mood, or diminution in affective variability. Moreover, limits on the magnitude of any affective blunting due to the medications can be calculated on the basis of the confidence intervals for measures of affective variability pre- and post-drug. For positive affect, the upper limit for the confidence intervals allows the exclusion of effects greater than approximately 25% (p ⬍0.025). Effects smaller than this are unlikely to be clinically or ecologically significant. For negative affect, the upper limits of the confidence intervals for drug-related difference in variability were 49% of the pre-drug means for placebo and 55% for the SSRIs; the upper limit of the confidence interval was approximately 25% greater than the mean change in variability on placebo. These findings are more difficult to interpret, and estimates of the effect sizes on negative affect that can be excluded must be viewed with caution for several reasons. First, there are questions about how to interpret the placebo effects. Second, the skewed nature of the data raises questions about the validity of the assumptions underlying these calculations. Third, as suggested by the findings reported here, understanding the effects of the medication on negative affect is best accomplished using models that include the impact of daily events. Thus, our observations can be interpreted from two perspectives. First, they fail to confirm the hypothesis that medications are associated with significant decrements in affective variability. Second, and more powerfully, they allow us to exclude effects of a magnitude that are likely to be clinically significant, at least for positive affect. One other observation is of heuristic interest. The data analyses demonstrated a decreased negative affective response to negative events over time in subjects receiving SSRIs, but not in those receiving placebo. However, there were no observed changes in the responsiveness of positive affect to daily events. This raises questions about whether SSRIs may selectively alter the experience or expression of negative affect tied to negative events.
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Although there were no drug-related changes in affects, slopes, or variability, the effects observed when affect was examined in relationship to diary events suggests that an in-depth examination of affect may not be reliable without taking into account everyday events. It remains important to emphasize that although the decrease in sensitivity to negative events was significant in the SSRI but not the placebo group, there was no significant three-way interaction. However, the decrease was significantly linear, suggesting a dose-dependent role of SSRIs in the observed affective alteration. As shown in Table 3, most events reported in the daily diary were “uplifts” and “hassles,” events with the lowest possible intensity, which have been associated with depression.21–24 This examination of affect raises questions about the ability of SSRIs to modulate the emotional effects of everyday events. It suggests the hypothesis that SSRIs can improve “hassle tolerance,” and suggests methods that may be used for formal tests of this hypothesis. The effects on the negative affective response to negative events associated with serotonin enhancement in healthy volunteers may be pertinent to the efficacy of SSRIs in diverse clinical populations. Given that SSRIs are prescribed for individuals with various disorders of depression and anxiety, this medication’s impact on the ecology of affect may have broader significance for clinical treatment. In order to try to address the confound of recording both events and affect at the end of the day, the analysis of the relationship of the previous 2 days’ events on daily affect was performed. The diminishing relationship between current affect and events that occurred 1 and 2 days before suggests the contingency, rather than mere correlation, of affect on events, replicating and extending the usefulness of the daily diary, as developed by Lawton.16 The observation that both groups recorded fewer diary events and demonstrated decreases in POMS Vigor scores and PANAS Positive Affect as the study progressed was not predicted. The results of post-hoc multiple-regression analyses indicated that the decrease in event reporting was not associated with any psychological measure such as increased fatigue, decreased vigor, or changes in affect. “Instrument fatigue” or decreased motivation secondary to the demands of a 28-day study requiring daily reporting may account for the observed changes.
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CONCLUSION The results of this study did not reveal any significant adverse alterations in affective functioning or personality associated with the administration of SSRIs, as compared with placebo, in this sample of healthy elderly volunteers. The findings do not demonstrate affective blunting, and they allow exclusion of significant decreases in affective variability as side effects. It remains to be confirmed whether the contingency between affect and events is changed by SSRIs and whether this effect occurs in depressed patients treated with SSRIs, whether contingency changes persist with chronic treatment, and whether they return to baseline upon SSRI discontinuation. It is also unknown whether SSRI administration would alter
the affective response to more severe negative events in this healthy population, possibly conferring a “protective barrier” from depression in the event of loss or tragedy. The authors acknowledge the assistance of Tina D’Angelo, Suzanne DiFillipo, Alecia Johnston, Trisha Stump, and Ken Rockwell, Ph.D., in the completion of this study. This study was supported by National Institutes of Mental Health grants R01 MH583249, P30 MH66270, T32 MH19931; and by an Office of Academic Affiliations, VA Special MIRECC Fellowship Program in Advanced Psychiatry and Psychology. This work was also supported by an unrestricted grant from Pfizer, Inc.
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14. Oleshansky MA Labbate LA: Inability to cry during SRI treatment. J Clin Psychiatry 1996; 57:593 15. Lawton MP, DeVoe MR, Parmelee P: Relationship of events and affect in the daily life of an elderly population. Psychol Aging 1995; 10:469–477 16. Zautra AJ, Affleck G, Tennen H: Assessing life events among older adults, in Annual Review of Gerontology and Geriatrics. Edited by Lawton MP, Teresi J. New York, Springer, 1994, pp 324–352 17. Furlan PM, Kallan MJ, Ten Have T, et al: Cognitive and psychomotor effects of paroxetine and sertraline on healthy elderly volunteers. Am J Geriatr Psychiatry 2001; 9:429–438 18. Watson D, Clark LA, Tellegen A: Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988; 54:1063–1070 19. McNair DM, Loor M, Droppleman LF: Profile Of Mood States. San Diego, CA, Educational and Industrial Testing Service, 1971 20. Costa PT Jr, McCrae RR: Revised NEO Personality Inventory (NEOPI-R) and NEO Five-Factor Inventory (NEO-FFI). Odessa, FL, Psychological Assessment Resources, Inc., 1991 21. Kraaij V, Arensman E, Spinhoven P: Negative life events and depression in elderly persons: a meta-analysis. J Gerontol B Psychol Sci Soc Sci. 2002; 57:87–94 22. Klein DN, Lewinsohn PM, Seeley JR: Psychosocial characteristics of adolescents with a past history of dysthymic disorder, adolescents with past histories of major depressive and non-affective disorders, and never-mentally-ill controls. J Affect Disord 1997; 42:127–135 23. Willner P, Wilkes M, Orwin A: Attributional style and perceived stress in endogenous and reactive depression. J Affect Disord 1990; 18:281–287 24. Holahan CK, Holahan CJ, Belk SS: Adjustment in aging: the roles of life stress, hassles, and self-efficacy. Health Psychol 1984; 3:315–328
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Objective: This study was undertaken to evaluate the effects of selective serotonin reuptake inhibitors (SSRIs) on affective experience in healthy older adults. Methods: After 1 week of observation, normal elderly volunteers (age range: 65–84 years) were given placebo, paroxetine (10 mg–40 mg/day), or sertraline (50 mg–150 mg/day) for 3 weeks in a double-blind study. Paroxetine- and sertraline-treated subjects were analyzed together as the SSRI group (N⳱30). Volunteers were assessed weekly and recorded mood and events in a daily diary each evening. All data were analyzed with mixed-effects random-regression models. Results: There were significant relationships between daily affect and events reported in the daily diary for the sample as a whole, with no differences between groups in mean slopes of positive or negative affect across the length of the study. There were no differences between groups in affective variability. However, the SSRI group, but not the placebo group, demonstrated a significant drug-dependent decrease in negative affect related to negative events. There were no other observed group differences on any other measure. Conclusion: Interpreting the results conservatively, they demonstrate that SSRIs are not associated with affective toxicity in elderly persons. (Am J Geriatr Psychiatry 2004; 12:323–330)
T
here has been discussion in both the scientific and lay literature of the possibility that selective serotonin reuptake inhibitors (SSRIs) may be associated with diverse alterations in emotion and personality function, including increased suicidality, impulsiveness, affective blunting, and assertiveness.1–9 Indeed, the impact of these agents on emotional behaviors distinct from depression is supported by their therapeutic use as a treatment for pathologic crying10,11
and violent outbursts.12 These effects may reflect a blunting of affective response that may be clinically desirable in these contexts. However, in patients treated for depression, affective blunting could represent an adverse effect; that is, a form of affective toxicity, as has been suggested in some case reports.13,14 These reports of affective side effects may reflect rare events brought on by the interaction of personal history, a psychiatric illness, and idiosyn-
Received June 30, 2003; revised October 3, 2003; accepted November 18, 2003. From the Department of Psychiatry, University of Pennsylvania, Philadelphia, PA (PMF,IL,IK); MIRECC, Philadelphia Veterans Administration Medical Center, Philadelphia, PA (PMF,IK), and the Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA (MJK,TTH). Send correspondence to Ira Katz, M.D., Ph.D., University of Pennsylvania School of Medicine, Department of Psychiatry, 3535 Market Street, Room 3001, Philadelphia, PA 19104. e-mail: [email protected] 䉷 2004 American Association for Geriatric Psychiatry
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SSRIs and Affective Blunting cratic responses to the drugs. Alternatively, they may be sentinel reports, indicating that there may be underappreciated and underreported side effects of SSRIs that impair overall functioning despite the responses of the identified psychiatric symptoms to treatment. In addition to standard psychiatric rating scales, another approach to evaluating the effects of medications on affective processes is through self-reports generated in daily diaries. A daily sampling technique that elicits a diary of daily events along with positive and negative affect ratings has demonstrated contingency between affective experience and events in both healthy and depressed populations.15 Diaries can provide information about mean levels of affect, trends over time, and variability. Also, they can provide measures of sensitivity to the occurrence of daily “hassles” and “uplifts” that may have a significant impact on emotional states.16 To understand the effect of SSRIs on affect, it may be important to assess mood in the context of daily events. This study was designed to assess the effect of SSRIs on the affective variability of older adults, with a particular interest in identifying affective toxicity that might be manifested as affective blunting. Currently, no published placebo-controlled studies have reported on the effect of SSRIs on personality function or on affective responding in older adults. Although most information about the effects of SSRIs on affective function is derived from the treatment of depression, this approach captures little about the normal ecology of affective variability. Furthermore, in patients treated for depression, it may be difficult to distinguish between putative affective side effects and residual symptoms of their illness. Therefore, testing for the effects of SSRIs on affective functioning requires administration of these medications to normal volunteers. In the current study, healthy elderly volunteers were given SSRIs or placebo for 3 weeks in a double-blind, randomized, placebo-controlled study to assess the effects of these medications on measures of affective functioning and personality. The cognitive effects of medication exposure in this population have been reported previously.17 The hypotheses to be tested in this study were that SSRIs would lead to an alteration of affective variability and an altered response to daily events, relative to placebo.
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MATERIALS AND METHODS Volunteers Study volunteers were 54 healthy adults over the age of 64 years, who responded to a newspaper advertisement. Volunteers received a screening examination consisting of a physical exam, a semistructured psychiatric interview, and a screen of cognitive capacity. Exclusion criteria consisted of hospitalizations for any reason or significant changes in medication within the past month, previous use of the study medications, less than 8 years of education, Mini-Mental State Exam (MMSE) score below 24, Center for Epidemiological Studies–Depression (CES–D) score over 12, significant clinical laboratory abnormalities, disease of the central nervous system, alcohol or substance abuse within the past 5 years, history of mental retardation, psychotic disorder, major depression, or bipolar disorder, active liver or kidney disease evidenced from a review of systems or screening laboratory evaluations, insulin-dependent diabetes, taking medication capable of causing cognitive or affective toxicity, taking concomitant medications with significant interaction with study medications, and performance outside the range of normal on practice tasks conducted during the baseline evaluation. After providing a complete description of the study to the subjects, we obtained written informed consent before any study procedures were performed. Protocols were approved by the Institutional Review Board of the University of Pennsylvania. Volunteers were reimbursed for participation in the study. Behavior Test Battery Volunteers completed the Lawton Positive Affect and Negative Affect rating scales at the end of each day for the duration of the study.16 The scale consists of five positive affect terms and five negative affect terms for rating affective states on a 5-point scale. The positive affect scale (range: 5–25) includes “energetic,” “warmth toward others,” “interested,” “happy,” and “content,” and the negative affect scale (range: 5–25) includes “annoyed,” “irritated,” “depressed,” “worried,” and “sad/blue.” Subjects also recorded significant positive and negative daily events that were outside of their usual routine. The
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Furlan et al. events were rated by judges as positive (Ⳮ1 to Ⳮ3), negative (–1 to –3), or neutral (0) in valence depending on the investigators’ judgment as to whether the events would be viewed positively or negatively in usual conditions by reasonable persons. Examples of negative events or “hassles” include difficulties with transportation, minor accidents, or interpersonal conflicts. Examples of positive events or uplifts include outings or visits from family or friends. Two judges independently assigned valences and attained an exact agreement of 94%. To assess affect using more traditional methods, the Positive and Negative Affect Scale (PANAS)18 and the Profile of Mood States (POMS) were administered. The POMS includes the subscales of Anger, Confusion, Depression, Fatigue, Tension, and Vigor.19 To test for changes in personality structure, the Revised NEO Personality Inventory (NEO-PI-R) was administered; it assesses five traits: neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness.20 Testing Procedures The initial evaluation of volunteers, instruction on test procedure, and practice occurred during their first visit to the Geriatric Behavioral Psychopharmacology Laboratory of the University of Pennsylvania. The battery included a cognitive assessment, the results of which have been published previously.17 The study test sessions were conducted at Days 7 (baseline), 14, 21, and 28. Although volunteers were seen at various times of the day, individual volunteers reported to the laboratory at the same time for each test session. Daily diary entries were recorded by the volunteer each evening at home and collected at the end of each of the 4 test weeks (Baseline Week (Days 1– 7), Week 1 (Days 8–14), Week 2 (Days 15–21), and Week 3 (Days 22–28). The PANAS and NEO were administered at Days 7 and 28, and the POMS was administered at Days 7, 14, 21, and 28. Drugs and placebo were administered for 21 days in morning doses. Paroxetine doses doubled each week from the initial dosing of 10 mg/day to a final dose of 40 mg/day. Sertraline doses began at 50 mg/day for Days 8–14, were increased to 100 mg/day for Days 15–21, and to 150 mg/day for Days 22–28. Volunteers were randomized by use of a computergenerated random-number table, such that for each
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block of six volunteers, two were assigned to each of the three treatment groups. In order to maintain the double blind, all medication was administered in identical-appearing capsules. Statistical Analysis This study was designed to assess the behavioral effects of subchronic administration of SSRIs in nondepressed volunteers in order to study the effect of this class of drugs on affect, independent of the presence of depression and its change with treatment. In a previous article on cognitive effects associated with SSRIs,17 we compared the effects of sertraline and paroxetine. In this study investigating the affective changes associated with SSRIs, we collapsed the two SSRIs into one group on the basis of the demonstrated ability of both medicines to effectively treat depression. All volunteers were included in the tolerability analyses according to an intention-to-treat design (N⳱54). In contrast, only volunteers who completed the 3-week drug treatment were included in the analysis of drug effects (N⳱49). The analysis of daily affect and events from the diary entries consisted of the testing and estimation of the following hypothesized contrasts: 1) differences in mean, slope, and variability of positive and negative affect within each treatment group across the length of the study; and 2) the assessment of regression effect of positive or negative events on positive and negative affect across time for the entire sample and within and between each treatment group. For all of the analyses for the above hypotheses, with affect (positive or negative) as the outcome and both time (Baseline, Week 1, Week 2, Week 3) and event (positive or negative), and in some models, treatment (placebo or SSRI) as the grouping factors, hierarchical linear models were used with random intercepts and slopes for time, main effects for the grouping factors, and their respective two-way and three-way interactions. Number of positive and negative diary events, PANAS, POMS, and NEO data were also analyzed using hierarchical linear models. For PANAS and NEO, the Time factor consisted of only two levels (Baseline, and Week 3). These models were fitted with Proc Mixed in SAS V8 (SAS Institute, Inc., Cary, NC). Post-hoc pairwise comparisons among treatment groups and across time were performed along with Bonferroni adjustments. Tolera-
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SSRIs and Affective Blunting bility, as measured by early termination secondary to adverse events, was analyzed with Pearson chisquare analysis. All statistical analyses were conducted with two-tailed alpha levels of 0.05. In these analyses, variability of positive and negative affect was calculated as the square-root of the square of the residuals from the regression of plots of Affect ⳯ Time divided by the number of observations.
RESULTS A total of 49 volunteers completed the study protocol (placebo: N⳱19; SSRI: N⳱30). Demographics of Completer volunteers are presented in Table 1. One volunteer randomized to the Placebo condition reported the adverse event of vomiting, leading to early termination. Four volunteers randomized to the SSRI condition reported the following adverse events leading to early termination: burning in stomach; drowsiness; nervousness, diarrhea, and rectal bleeding; and vertigo (a recurrence of a prior condition). No volunteers terminated secondary to confusion or depression. The dropout rate was not significantly different between treatment groups (v2[1]⳱0.69; p⳱0.41). Daily Diary Affective Change Independent of Events As shown in Table 2, the result of the mixed-model random regression indicated no significant group differences in the baseline mean or slope of positive or negative affect. The SSRI group demonstrated significantly greater positive affective variability than the placebo group during the Baseline Week, but this difference was not significant during the treatment phase (Weeks 1–3) of the study. There was no statistically TABLE 1.
significant difference in the variability of negative affect between groups at any time during the study. Understanding the significance of the findings of Table 2 requires an estimate of the magnitude of effects that can be ruled out by the observed data. From a clinical perspective, this is most important for the effect of the medications on positive affect. Here, the mean difference between pre-drug and post-drug variability was 0.02 (95% confidence interval [CI]: –0.25 to 0.31) for placebo and 0.18 (95% CI: –0.12 to 0.47). From the upper limit of this confidence interval, we can exclude a drug-related decrease in positive affect variability greater than 0.47, or approximately 25% or more of the pre-drug mean, with p ⬍0.025. Similarly, for negative affect, we find a decrease in variability after placebo administration of approximately 0.31 (95% CI: –0.08 to 0.69), or approximately 22% of the pre-drug mean, and a decrease after SSRI administration of 0.75 (95% CI: 0.16 to 1.34), or 37% of the pre-drug mean. Here, based on the lower limit for the confidence interval, the magnitude of the effect that can be excluded with p⬍0.025 is approximately 55% of the pre-placebo variability; that is, a decrement approximately 25% greater than the mean difference in variability after placebo administration. Event Reporting The results of the mixed-model random regression analyses indicated that, for the number of positive events, there was no significant main effect of Group (F[1, 47]⳱0.18; p⳱0.67), a significant effect of Week (F[3, 144]⳱3.91; p⳱0.01), and a nonsignificant Group ⳯ Week interaction (F[3, 141]⳱2.49; p⳱0.06). Similar results were observed for negative events: no significant main effect of Group (F[1, 47]⳱0.15; p⳱0.70), a significant main effect for Week (F[3, 144]⳱3.81; p⳱0.012), and no significant Group ⳯ Week interaction (F[3, 141]⳱0.10; p⳱0.96). Both groups reported fewer positive and negative events as the study progressed. Average event valences were low
Sample demographics
Age, years Education, years Gender, male Race, Caucasian CES–D
Placebo (Nⴔ19)
SSRI (Nⴔ30)
Statistic[df]
p
70.3Ⳳ4.9 15.1Ⳳ2.5 68% 77% 3.5Ⳳ2.7
73.3Ⳳ5.8 15.2Ⳳ3.1 53% 73% 4.3Ⳳ3.3
t[47]⳱1.71 t[47]⳱0.14 v2[1]⳱1.10 v2[1]⳱0.20 t[47]⳱0.87
0.09 0.89 0.30 0.66 0.39
Note: Values are mean Ⳳ standard deviation, unless otherwise indicated. SSRI: selective serotonin reuptake inhibitors; CES–D: Center for Epidemiological Studies–Depression scale.
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Furlan et al. and did not differ significantly between groups (see Table 3). Affect Change Contingent on Events As shown in Table 4, the mixed-model random regression analysis of the relationship between events and affect among all subjects across the study indicated that positive events were associated with significant increases in positive affect and significant decreases in negative affect, and negative events were associated with significant decreases in positive affect and significant increases in negative affect. In an effort to address the potential confound introduced by recording affect and events on the same day, we also analyzed the relationship between the previous days’ events and current affect among all subjects. The result of this analysis indicated a similarly significant pattern of contingency as in the “same-day” analysis, except for the effect of positive events on positive affect. However, when the analyses were extended to encompass the relationship of daily TABLE 2.
affect with events recorded 2 days previously, there was no significant contingency. The attenuation of these effects after lags of 1 and 2 days is expectable, and these observations support the validity of the observed associations between events and affects.
Effect of SSRIs on Contingency of Affect on Events Mixed-model random regression models tested for the contingency of positive and negative affect on the presence or absence of positive and negative events in the drug and placebo conditions across the length of the study. All of the significant effects for the “same-day” analysis of all subjects (Table 4) were again significant for both the drug and placebo groups at p ⬍0.001 except for the relationship between positive affect and negative events, where the contingency in the placebo group was not significant (F[1, 510]⳱1.78; p⳱0.18). Specific effects of the medications were examined by testing for Event ⳯ Week and Event ⳯ Week ⳯ Drug interactions (Table 5). For positive affect, there were no significant Event ⳯
Comparison of placebo and SSRI mean positive and negative affect, slope, and variability
Positive Affect Baseline mean (SD) Slope (SEM) Variability Baseline (SEM) Weeks 1–3 (SEM) Negative Affect Baseline mean (SD) Slope (SEM) Variability Baseline (SEM) Weeks 1–3 (SEM)
Placebo (Nⴔ19)
SSRI (Nⴔ30)
18.89 (2.60) ⳮ0.011 (0.019)
18.20 (2.68) ⳮ0.030 (0.020)
0.89 0.71
1.40 (0.197) 1.39 (0.204)
2.06 (0.158) 1.89 (0.163)
ⳮ2.59 ⳮ1.94
0.013 0.06
6.37 (1.74) ⳮ0.018 (0.014)
6.47 (2.08) ⳮ0.032 (0.028)
ⳮ0.17 ⳮ0.44
0.86 0.67
1.41 (0.344) 1.11 (0.225)
2.05 (0.270) 1.29 (0.180)
ⳮ1.46 ⳮ0.65
0.15 0.52
t[47]
p 0.38 0.47
Note: SSRI: selective serotonin reuptake inhibitors; SD: standard deviation; SEM: standard error of the mean.
TABLE 3.
Mean number of events and mean event valence by treatment group Positive Events Placebo (Nⴔ19) SSRI (Nⴔ30)
Number Baseline Week 1 Week 2 Week 3 Valence Baseline Week 1 Week 2 Week 3
Negative Events Placebo (Nⴔ19) SSRI (Nⴔ30)
4.11 (4.81) 3.53 (4.57) 4.00 (4.97) 4.16 (4.96)
6.00 (5.71) 4.37 (4.69) 4.17 (5.14) 3.53 (4.46)
1.53 (1.17) 1.16 (1.12) 0.84 (1.50) 0.84 (1.46)
1.33 (1.65) 1.13 (1.66) 0.83 (1.26) 0.63 (0.96)
1.01 (0.03) 1.00 (0.00) 1.02 (0.07) 1.02 (0.04)
1.02 (0.07) 1.09 (0.24) 1.05 (0.23) 1.08 (0.26)
ⳮ1.00 (0.00) ⳮ1.12 (0.39) ⳮ1.00 (0.00) ⳮ1.19 (0.38)
ⳮ1.24 (0.44) ⳮ1.07 (0.18) ⳮ1.00 (0.00) ⳮ1.15 (0.34)
Note: Values are mean (standard deviation).
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SSRIs and Affective Blunting TABLE 4.
Contingency of affect on daily events among all subjects (Nⴔ49) Positive Affect
Same-day events Positive Negative 1-day-previous events Positive Negative 2-days-previous events Positive Negative
Negative Affect
Effect (SEM)
F[df]
p
Effect (SEM)
F[df]
p
1.36 (0.14) ⳮ1.16 (0.18)
95.47[1, 1340] 40.95[1, 1317]
⬍0.001 ⬍0.001
ⳮ0.68 (0.14) 2.01 (0.17)
23.50[1, 1351] 139.12[1, 1321]
⬍0.001 ⬍0.001
0.09 (0.14) ⳮ0.59 (0.18)
0.42[1, 1332] 10.47[1, 1316]
0.52 0.001
ⳮ0.30 (0.14) 0.49 (0.17)
4.79[1, 1342] 7.94[1, 1320]
0.029 0.005
0.16 (0.14) ⳮ0.21 (0.19)
1.29[1, 1333] 1.27[1, 1315]
0.26 0.26
ⳮ0.13 (0.14) 0.23 (0.18)
0.86[1, 1344] 1.77[1, 1319]
0.35 0.18
Note: Effect is the difference in affect on days when an event was reported minus days when the event was not reported. The F-test was for the null hypothesis that the effect size ⳱ 0. SEM: standard error of the mean.
Week interactions within either treatment group; nor were there significant Event ⳯ Week ⳯ Drug interactions. For negative affect, there were no significant negative affect–positive event interactions within either treatment group, nor were there significant Event ⳯ Week ⳯ Drug interactions. However, as shown in Table 5, there was a significant Week ⳯ Negative Affect–Negative Event interaction in the SSRI group, in contrast to the nonsignificant analogous interaction effect in the placebo group. The results of the mixed-model random regression analyses of the linear relationship between negative events and negative affect for the SSRI group across time indicated a decrease in the contingency of negative affect on negative events such that, at Week 3, the mean effect of negative events on negative affect was no longer significantly different from 0 as assessed by
TABLE 5.
Effect of SSRIs on contingency of affective response to daily events Event ⴒ Week
Positive Affect Positive event Placebo SSRI Negative event Placebo SSRI Negative Affect Positive event Placebo SSRI Negative event Placebo SSRI
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Event ⴒ Week ⴒ Drug
F[df]
p
F[df]
p
1.54[3, 505] 0.81[3, 796]
0.20 0.49
0.80[3, 1302]
0.50
1.13[3, 506] 0.13[3, 798]
0.34 0.94
0.45[3, 1303]
0.72
0.77[3, 506] 0.63[3, 797]
0.51 0.60
0.80[3, 1303]
0.49
0.57[3, 507] 3.25[3, 798]
0.64 0.021
1.84[3, 1304]
0.14
t-tests (Baseline Week mean effect ⳱ 3.25 (standard error of the mean [SEM]: 0.43); t[798]⳱7.64; p ⬍0.001; Week 1 mean effect ⳱ 2.35 (0.46); t[799]⳱5.15; p ⬍0.001; Week 2 mean effect ⳱ 2.65 (0.50); t[799]⳱5.24; p ⬍0.001; Week 3 mean effect ⳱ 0.99; t[798]⳱1.69; p⳱0.09). A post-hoc test for the magnitude of the linear decrease in the contingency of negative affect on negative events across time indicated that this decrease was significant (F[1]⳱8.35; p⳱0.004). Other Scales The results of the mixed-model random regression analyses indicated no significant behavioral effects of SSRIs on affect as measured by PANAS and POMS or on personality as measured by the NEO. There were no main effects of Group or any Group ⳯ Week interactions for any measure. There was a main effect of Week for PANAS positive affect (F[1, 47]⳱9.29; p⳱0.003) but not for PANAS negative affect. Both groups demonstrated higher PANAS positive affect scores at Baseline (placebo mean⳱39.3, [5.9]; SSRI mean⳱39.6 [6.0]) than at Day 21 (placebo mean⳱38.1 [7.4]; SSRI mean⳱36.0 [8.5]). The analysis of POMS Vigor scores indicated no significant effect of Group, a significant effect of Week (F[3, 141]⳱4.08; p⳱0.008), and no significant Group ⳯ Week interaction. Both groups demonstrated higher Vigor scores at Baseline (placebo mean⳱21.2 [6.3]; SSRI mean⳱20.6 [6.1]) than at Day 21 (placebo mean⳱20.9 [6.8]; SSRI mean⳱17.3 [6.9]). There were no significant main effects of Group or Week or any Group ⳯ Week interactions for the Anger, Confusion, Depression, Fatigue, or Tension scales of the POMS. There were no significant main effects of Group or Week or any Group ⳯ Week interactions for any scale of the NEO. Nonsignificant results are not presented.
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Furlan et al. DISCUSSION The main finding of this study was that healthy elderly volunteers treated with SSRIs demonstrated no significant alterations in personality or affect. These healthy volunteers did not demonstrate increased emotional lability, alterations in daily mood, or diminution in affective variability. Moreover, limits on the magnitude of any affective blunting due to the medications can be calculated on the basis of the confidence intervals for measures of affective variability pre- and post-drug. For positive affect, the upper limit for the confidence intervals allows the exclusion of effects greater than approximately 25% (p ⬍0.025). Effects smaller than this are unlikely to be clinically or ecologically significant. For negative affect, the upper limits of the confidence intervals for drug-related difference in variability were 49% of the pre-drug means for placebo and 55% for the SSRIs; the upper limit of the confidence interval was approximately 25% greater than the mean change in variability on placebo. These findings are more difficult to interpret, and estimates of the effect sizes on negative affect that can be excluded must be viewed with caution for several reasons. First, there are questions about how to interpret the placebo effects. Second, the skewed nature of the data raises questions about the validity of the assumptions underlying these calculations. Third, as suggested by the findings reported here, understanding the effects of the medication on negative affect is best accomplished using models that include the impact of daily events. Thus, our observations can be interpreted from two perspectives. First, they fail to confirm the hypothesis that medications are associated with significant decrements in affective variability. Second, and more powerfully, they allow us to exclude effects of a magnitude that are likely to be clinically significant, at least for positive affect. One other observation is of heuristic interest. The data analyses demonstrated a decreased negative affective response to negative events over time in subjects receiving SSRIs, but not in those receiving placebo. However, there were no observed changes in the responsiveness of positive affect to daily events. This raises questions about whether SSRIs may selectively alter the experience or expression of negative affect tied to negative events.
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Although there were no drug-related changes in affects, slopes, or variability, the effects observed when affect was examined in relationship to diary events suggests that an in-depth examination of affect may not be reliable without taking into account everyday events. It remains important to emphasize that although the decrease in sensitivity to negative events was significant in the SSRI but not the placebo group, there was no significant three-way interaction. However, the decrease was significantly linear, suggesting a dose-dependent role of SSRIs in the observed affective alteration. As shown in Table 3, most events reported in the daily diary were “uplifts” and “hassles,” events with the lowest possible intensity, which have been associated with depression.21–24 This examination of affect raises questions about the ability of SSRIs to modulate the emotional effects of everyday events. It suggests the hypothesis that SSRIs can improve “hassle tolerance,” and suggests methods that may be used for formal tests of this hypothesis. The effects on the negative affective response to negative events associated with serotonin enhancement in healthy volunteers may be pertinent to the efficacy of SSRIs in diverse clinical populations. Given that SSRIs are prescribed for individuals with various disorders of depression and anxiety, this medication’s impact on the ecology of affect may have broader significance for clinical treatment. In order to try to address the confound of recording both events and affect at the end of the day, the analysis of the relationship of the previous 2 days’ events on daily affect was performed. The diminishing relationship between current affect and events that occurred 1 and 2 days before suggests the contingency, rather than mere correlation, of affect on events, replicating and extending the usefulness of the daily diary, as developed by Lawton.16 The observation that both groups recorded fewer diary events and demonstrated decreases in POMS Vigor scores and PANAS Positive Affect as the study progressed was not predicted. The results of post-hoc multiple-regression analyses indicated that the decrease in event reporting was not associated with any psychological measure such as increased fatigue, decreased vigor, or changes in affect. “Instrument fatigue” or decreased motivation secondary to the demands of a 28-day study requiring daily reporting may account for the observed changes.
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SSRIs and Affective Blunting
CONCLUSION The results of this study did not reveal any significant adverse alterations in affective functioning or personality associated with the administration of SSRIs, as compared with placebo, in this sample of healthy elderly volunteers. The findings do not demonstrate affective blunting, and they allow exclusion of significant decreases in affective variability as side effects. It remains to be confirmed whether the contingency between affect and events is changed by SSRIs and whether this effect occurs in depressed patients treated with SSRIs, whether contingency changes persist with chronic treatment, and whether they return to baseline upon SSRI discontinuation. It is also unknown whether SSRI administration would alter
the affective response to more severe negative events in this healthy population, possibly conferring a “protective barrier” from depression in the event of loss or tragedy. The authors acknowledge the assistance of Tina D’Angelo, Suzanne DiFillipo, Alecia Johnston, Trisha Stump, and Ken Rockwell, Ph.D., in the completion of this study. This study was supported by National Institutes of Mental Health grants R01 MH583249, P30 MH66270, T32 MH19931; and by an Office of Academic Affiliations, VA Special MIRECC Fellowship Program in Advanced Psychiatry and Psychology. This work was also supported by an unrestricted grant from Pfizer, Inc.
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