Assessing Rates and Predictors of Tachyphylaxis During The

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ORIGINAL RESEARCH Key Words: loss of antidepressant response, psychopharmacology, major depressive disorder, serotonin norepinephrine reuptake inhibitor, Rothschild Scale for Antidepressant Tachyphylaxis Assessing Rates and Predictors of Tachyphylaxis During the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study By Anthony J. Rothschild, Boadie W. Dunlop, David L. Dunner, Edward S. Friedman, Alan Gelenberg, Peter Holland, James H. Kocsis, Susan G. Kornstein, Richard Shelton, Madhukar H. Trivedi, John M. Zajecka, Corey Goldstein, Michael E. Thase, Ron Pedersen, Martin B. Keller

ABSTRACT ~ Background: Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment. Methods: Data were collected from a multiphase, double- blind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) score 7 in patients with prior satisfactory therapeutic response. A Kaplan–Meier

Dr. Rothschild, MD, University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, MA. Dr. Dunlop, MD, Emory University School of Medicine, Atlanta, GA. Dr. Dunner, MD, Center for Anxiety and Depression, Mercer Island, WA. Dr. Friedman, MD, University of Pittsburgh School of Medicine, Pittsburgh, PA. Dr. Gelenberg, MD, University of Arizona, Tucson, AZ. Dr. Holland, MD, Florida Atlantic University, Boca Raton, FL. Dr. Kocsis, MD, Weill Cornell Medical College, New York, NY. Dr. Kornstein, MD, Virginia Commonwealth University, Richmond, VA. Dr. Shelton, MD, Vanderbilt University, Nashville, TN. Dr. Trivedi, MD, University of Texas Southwestern Medical School, Dallas, TX. Drs. Zajecka, MD, Goldstein, MD, Rush University Medical Center, Chicago, IL. Dr. Thase, MD, University of Pennsylvania, Philadelphia, PA. Dr. Pedersen, MD, Wyeth Research, Collegeville, PA. Dr. Keller, MD, Brown University, Providence, RI. To whom correspondence should be addressed: Anthony J. Rothschild, MD, University of Massachusetts Medical School, 361 Plantation Street, Worcester, MA 01605. Phone: (508) 856-1027; Email: [email protected]

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estimate of the cumulative probability of not experiencing tachyphylaxis, and a 2-sided Fisher exact test was used to assess the relationship between tachyphylaxis and recurrence. Results: The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n 129], fluoxetine [n 79], placebo [n 129]), whereas 128 patients (venlafaxine ER [n 43], fluoxetine [n 45], placebo [n 40]) were treated during maintenance phase B. No difference in the probability of experiencing tachyphylaxis were observed between the active treatment groups during either maintenance phase; however, a significant difference between venlafaxine ER and placebo was observed at the completion of maintenance phase A. A significant relationship between tachyphylaxis and recurrence was observed. Limitations: Despite demonstrating psychometric validity and reliability, the current definition of tachyphylaxis has not been widely studied. Conclusions: Although no significant differences were observed in the probability of tachyphylaxis among patients receiving active treatment, the relationship between tachyphylaxis and recurrence suggests that tachyphylaxis may be a prodrome of recurrence. Psychopharmacology Bulletin. 2009;42(3):5–20. 6 NTRODUCTION Rothschild, Dunlop, I Dunner, et al. Antidepressant tachyphylaxis has traditionally been broadly defined as the appearance of depressive symptoms following a full recovery from a major depressive episode despite continued treatment with a previously effective antidepressant.1,2 However, it has been suggested that the phenomenon of tachyphylaxis is distinct from that of an initial or recurrent major depressive episode.3 In the current study a unique con- ceptualization of tachyphylaxis was used, which primarily characterized tachyphylaxis as symptoms of apathy or decreased motivation (com- monly known as “the blahs”), fatigue, dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction.4 Defining tachyphylaxis as a clinical phenomenon that is distinct from a full recurrence has significant clinical utility. It may serve as an early marker for an impending recurrence, indicating the need for a change in clinical intervention to prevent a worsening of the patient’s status, and may ulti- mately serve as a phenotype for studies seeking to identify genetic markers for recurrence. Other names for this phenomenon include acquired drug tolerance, antidepressant tolerance, antidepressant “poop- out,” and breakthrough depression.1,3 Regardless of the label applied and its perceived causes, tachyphylaxis is a clinically significant phenomenon that deleteriously impacts the care of depressed patients. The lack of a standard definition of tachyphylaxis makes it chal- lenging to determine an accurate prevalence for this phenomenon.1 However, a number of studies that equate tachyphylaxis with a loss of antidepressant response have been conducted. An observational

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investigation of participants in the National Institute of Mental Health Collaborative Depression Study found rates of tachyphylaxis, defined as a loss of antidepressant response, of 25%.1 Rates of recurrence in clinical trials assessing maintenance pharmacotherapy have been found to vary considerably, ranging from 9% to 45%.5-8 There is some evidence that the likelihood of tachyphylaxis varies across antidepressant class. Specifically, it has been observed that patients receiving maintenance treatment with selective serotonin reuptake inhibitors (SSRIs) are at an increased risk for tachyphylaxis, defined as a recurrence of depression.9 In a retrospective, naturalistic analysis of patients with major depressive disorder (MDD), those receiving antidepressants that modulate serotonin and norepinephrine neuro- transmission (i.e., venlafaxine or tricyclic antidepressants) had significantly lower rates (3.7%) of tachyphylaxis than those being treated with SSRIs (14.1%; p 0.01).2 The mechanism(s) underlying tachyphylaxis remain unclear. Theories include pharmacodynamic sensitization, pharmacokinetic tolerance, changes in disease severity, loss of placebo response, and the oppositional 7 tolerance model, which suggests that continued antidepressant treat- Rothschild, Dunlop, ment triggers neurological processes that counteract the mechanisms of Dunner, et al. an initially positive treatment response.3,10–12 Serotonin receptor desensitization, which may be moderated by the noradrenergic effect of the dual-acting antidepressants, has been hypothesized to be the primary factor responsible for the observation of an increased risk for the return of depressive symptoms during long-term SSRI treatment.2 In the current analysis, tachyphylaxis was evaluated using the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT),4 which consists of 7 symptoms (i.e., energy level, motivation/interest, cognitive function, weight gain, sleep disturbances, sexual functioning, and affect) that characterize antidepressant “poop-out”.4 Data were collected during the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study, a multiphase, double-blind, randomized clinical trial designed to assess the efficacy of long-term venlafaxine extended release (ER) maintenance treatment.13–15 The objectives of the current analysis were to explore the differences between venlafaxine ER, fluoxetine, and placebo in the frequency and time to onset of antidepressant tachyphylaxis; to identify patient characteristics that are associated with the development of tachyphylaxis; and to assess the relationship between recurrence and tachyphylaxis. Our hypothesis was that rates of tachyphylaxis would be lower in subjects receiving venlafaxine ER compared with fluoxetine, resulting from the serotonin receptor desensitization associated with fluoxetine being moderated by the noradrenergic effect of the dual-acting antidepressant.2,10 In addition, we

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suggest a novel definition of antidepressant tachyphylaxis that is distinct from previous definitions that equate recurrence and tachyphylaxis.

MATERIALS AND METHODS

The PREVENT Study Design In the PREVENT study, patients were initially randomized to receive double-blind venlafaxine ER (75 to 300 mg/d) or fluoxetine (20 to 60 mg/d) treatment during a 10-week acute phase and a 6-month continuation phase. Patients achieving and sustaining a positive response during these 2 phases were then enrolled into the first of 2 consecutive 1- year maintenance phases. Venlafaxine ER patients were rerandomized to either continue receiving venlafaxine ER or were switched to placebo (placebo A), whereas the fluoxetine group continued receiving fluoxetine. At the end of the first maintenance phase (A), those who maintained a positive response were then enrolled into the second maintenance phase (B). At the start of maintenance phase B, venlafaxine ER patients with a 8 sustained positive response were rerandomized to venlafaxine ER or Rothschild, Dunlop, Dunner, et al. placebo (placebo B), and those receiving fluoxetine or placebo in maintenance phase A continued to do so. Recurrence was defined as a 17-item 16 Hamilton Rating Scale for Depression (HAM-D17) 12 and a HAM- D17 reduction from acute-phase baseline that was less than 50% at 2 consecutive visits or at the last valid visit prior to patient discontinuation. All treatments were administered in a double-blind manner throughout all study phases. After completely describing the study to each subject, written informed consent was obtained. Detailed descriptions of the study design and procedures, as well as the outcomes from the primary analyses, have been published elsewhere.13–15

Outcomes The primary outcome for this secondary analysis was tachyphylaxis, defined as an RSAT 7. The RSAT consists of 7 items (6 self-rated items and 1 clinician-rated item [affect]) and has demonstrated validity and reliability in assessing antidepressant tachyphylaxis distinctly from the severity of overall depressive symptoms, as assessed by the 4 HAM-D17. The RSAT was administered at baseline, at each visit during month 1 through month 12, and at the end point of both maintenance phases.

Statistical Analysis A Kaplan–Meier estimate of the cumulative probability of not experiencing tachyphylaxis, and a chi-square test was used for analyzing

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rates of tachyphylaxis. To identify an association between baseline characteristic data and the occurrence of tachyphylaxis, a chi-square test was used for categorical variables and a t-test was used for continuous variables. A Cox proportional hazard regression model was used to identify an association between RSAT score and recurrence. To further investigate the associations between tachyphylaxis and subsequent recurrence, 2-sided Fisher exact test was employed in subgroup analyses, which excluded patients who had recurrence prior to or concurrent with tachyphylaxis.

RESULTS

Baseline Demographic Characteristics Data from 337 patients in maintenance A and 128 patients in maintenance B were analyzed. The baseline demographic characteristics for the 3 treatment groups in both maintenance phases are presented in Table 1. No significant differences were observed between treatment groups on any baseline characteristics. Baseline RSAT scores, ranging 9 from 3.6 to 4.6, were generally consistent across treatment groups and Rothschild, Dunlop, Dunner, et al. phases of treatment. Incidence of Tachyphylaxis No significant differences in the rates of tachyphylaxis were observed between the active treatment groups during either maintenance phase, but, compared to those receiving venlafaxine ER, a significantly greater number patients who were treated with placebo met tachyphylaxis criteria during the first year of maintenance treatment. The rates of tachyphylaxis for maintenance phase A were venlafaxine ER, 61%; fluoxetine, 66% (p NS; venlafaxine ER vs fluoxetine); and placebo A, 73% (p 0.05; venlafaxine ER vs placebo). Maintenance phase B tachyphylaxis rates were: venlafaxine ER, 63%; fluoxetine, 53% (p NS; venlafaxine ER vs fluoxetine); and placebo B, 60% (p NS; venlafaxine ER vs placebo). Kaplan–Meier estimates of the cumulative probability of not experiencing tachyphylaxis at month 12 of maintenance phase A were venlafaxine ER, 36%; fluoxetine, 24% (p NS; venlafaxine ER vs fluoxetine); and placebo, 14% (p 0.01; venlafaxine ER vs placebo; Figure 1). The cumulative probabilities of not experiencing tachyphylaxis at the end of maintenance phase B were venlafaxine ER, 31%; fluoxetine, 38% (p NS; venlafaxine ER vs fluoxetine); and placebo, 34% (p NS; venlafaxine ER vs placebo; Figure 2). During maintenance phases A and B, approximately 45% of the patients who met tachyphylaxis criteria did so over consecutive visits, whereas the remaining patients only transiently experienced an RSAT 7.

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10 Rothschild, Dunlop, 129) n

Dunner, et al. ( PLACEBO 79) n Rothschild Scale for Antidepressant Tachyphylaxis;Rothschild Scale for Antidepressant SD ( FLUOXETINE HARACTERISTICS C MAINTENANCE PHASE A EMOGRAPHIC 129) AXINE ER D extended release; RSAT n ( 4.4 (4.0) 4.6 (3.5) 4.6 (4.1) 4.6 (3.0) 3.6 (3.6) 3.9 (3.8) VENLAF a ASELINE AND B body mass index; ER HASE P MaleFemaleWhiteBlackAsian 40 (31%)Hispanic 89 (69%)Other(years), mean (SD) 28 (35%) 51 (65%) 105 (81%) 10 (8%) 42 (33%) 87 (67%) 6.3 (6.3) 5 (4%) 4 (3%) 70 (89%) 5 (4%) 17 (40%) 26 (60%) 7.9 (6.8) 2 (3%) 114 (88%) 4 (5%) 1 (1%) 20 (44%) 25 (56%) 2 (3%) 7.1 (5.9) 35 (81%) 3 (2%) 12 (30%) 28 (70%) 10 (8%) 2 (2%) 7.0 (7.0) 38 (84%) 0 (0%) 1 (2%) 4 (9%) 1 (2%) 32 (80%) 7.5 (7.6) 2 (5%) 3 (7%) 3 (7%) 0 (0%) 5.6 (4.8) 1 (2%) 5 (13%) 1 (3%) 2 (5%) 0 (0%) AINTENANCE TABLE 1 TABLE Assessed at end of continuation phase. M Gender, n (%) Age (years), mean (SD) (lb),Weight mean (SD)Height (in), mean (SD)BMI, mean (SD)Ethnicity, 42.0 (10.4) n (%) 178.8 (46.3) 66.8 (3.7) 185.9 (50.0) 43.0 (11.7) 28.1 (6.4)Duration episode of current 66.9 (3.8) 185.9 (49.7) 42.6 (13.3) Score,Total mean (SD) RSAT 176.5 (51.6) 29.1 (7.1) 44.8 (11.3) 66.1 (3.5)Abbreviations: BMI a 190.9 (43.5) 46.1 (12.7) 66.9 (4.2) 29.9 (7.6) 175.5 (40.4) 42.8 (9.9) 67.7 (3.1) 27.5 (6.9) 67.2 (3.4) 29.2 (6.3) 27.3 (6.4)

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FIGURE 1

KAPLAN–MEIER ESTIMATES OF THE CUMULATIVE PROBABILITY OF NOT EXPERIENCING TACHYPHYLAXIS,MAINTENANCE PHASE A

11 Rothschild, Dunlop, Dunner, et al.

FIGURE 2

KAPLAN–MEIER ESTIMATES OF THE CUMULATIVE PROBABILITY OF NOT EXPERIENCING TACHYPHYLAXIS,MAINTENANCE PHASE B

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Association Between Demographic Characteristics and Tachyphylaxis When analyzing baseline demographic data by tachyphylaxis status, tachyphylaxis was associated with older age in both maintenance phases (Table 2). In maintenance phase A, the mean age of patients experiencing tachyphylaxis was significantly higher (44 years) than those who did not (39 years; p 0.001). The results from the maintenance phase B population were similar (tachyphylaxis, 47 years; no tachyphylaxis, 41 years [p 0.01]). During the first phase of maintenance treatment, the mean body mass index (BMI) of patients who experienced tachyphylaxis was significantly higher (29.7) than those who did not (27.6; p 0.01). Additionally, the duration of the current episode of depression was significantly shorter for patients who met the criteria for tachyphylaxis (5.6 years) compared with those who did not (8.4 years; p 0.05) during phase B.

Tachyphylaxis as a Risk Factor for Recurrence A significant risk for experiencing a recurrence and tachyphylaxis (vs a recurrence and no tachyphylaxis) was observed in both maintenance 12 phase A (OR [95% CI]: 16.35 [5.81 to 45.97]; p 0.001) and mainte- Rothschild, Dunlop, nance phase B (OR [95% CI]: 25.47 [3.32 to 195.50]; p 0.001), Dunner, et al. regardless of the timing of either event. It is worth noting that during maintenance phases A and B only a minority of assessed patients (26% [88/337] and 20% [25/126]) experienced a recurrence. Of these patients, 36% (32/88) and 76% (19/25) had an RSAT 7 prior to recurrence during phases A and B, whereas 59% (52/88) and 20% (5/25) of patients met criteria for tachyphylaxis and recurrence at the same visit. Further analyses, which excluded patients who experienced a recurrence prior to or concurrent with tachyphylaxis, showed that patients treated with fluoxetine and placebo who met criteria for tachyphylaxis were at a significant risk for experiencing a subsequent recurrence during both maintenance phases (p 0.01; Table 3). Specifically, later recurrences were significantly more common in patients who had experienced tachyphylaxis than in those who did not, suggesting that tachyphylaxis may be a risk factor for subsequent recurrence. Venlafaxine ER patients who met tachyphylaxis criteria were not found to be at a significantly greater risk for recurrence, but when analyzing the overall population (i.e., venlafaxine ER, fluoxetine, and placebo) a similar association was found. A Cox proportional hazard regression model showed that total RSAT score was associated with an increased risk for recurrence (Maintenance phase A: hazard ratio [HR]: 1.117; 2 24.51; p 0.001; Maintenance phase B: HR: 1.135; 2 5.39; p 0.05), which suggests that a one-point increase in total RSAT score at the prior visit was associated with a 12% to 14% increase in the risk of recurrence at the current visit.

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ANTIDEPRESSANT TACHYPHYLAXIS a 0.1509 0.3554 0.4574 0.8324 0.3169 0.0202 0.0001 0.0042 ALUE P V p p p 53) n ( ACHYPHYLAXIS NO T MAINTENANCE PHASE B 75) n ( -tests. 5.0 (3.2) 2.6 (3.4) t 28.4 (6.5) 27.5 (6.5) p 47.0 (11.3) 41.2 (10.8) ACHYPHYLAXIS T standard deviation. , n (%) a 13 0.6444 p 0.9344 5.6 (5.3) 8.4 (7.9) 0.2464 67.0 (3.5) 67.6 (3.7) p 0.0715 182.0 (43.9) 180.2 (48.6) p 0.4433 p 0.0001 0.0097 0.0006 ALUE Rothschild, Dunlop, TATUS P V Dunner, et al. S p p p 113) ACHYPHYLAXIS T n ( ACHYPHYLAXIS NO T ATA BY MAINTENANCE PHASE A D 224) Rothschild Scale for Antidepressant Tachyphylaxis;Rothschild Scale for Antidepressant SD n ( ACHYPHYLAXIS HARACTERISTIC T C ASELINE B body mass index; RSAT HASE P WhiteBlackAsianHispanicOtherepisode (years), mean (SD) 7.0 (6.5) 196 (88%) 9 (4%) 10 (5%) 4 (2%) 7.0 (5.8) 93 (82%) 5 (2%) 6 (5%) p 9 (8%) 3 (3%) 2 (2%) 63 (84%) 42 (79%) 5 (7%) 4 (5%) 3 (4%) 0 (0%) 4 (8%) 4 (8%) 0 (0%) 3 (6%) FemaleMale 70 (31%) 154 (69%) 40 (35%) 73 (65%) 26 (35%) 49 (65%) 23 (43%) 30 (57%) AINTENANCE TABLE 2 TABLE p values for categorical variables calculated tests and for continuous variables with Chi-square the p values calculated with Duration of current RSAT Total Score,Total mean (SD)RSAT 5.6 (4.2) 2.5 (2.4) BMI, mean (SD)Ethnicity, n (%) 29.7 (7.1) 27.6 (6.8) p Height (in), mean (SD) 66.4 (3.6) 66.9 (3.8) p Age (years), mean (SD) (lb),Weight mean (SD) 44.0 (11.9) 186.5 (47.8) 39.4 (11.1) 176.5 (49.2) p M Gender, n (%)Abbreviations: BMI a p

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ANTIDEPRESSANT TACHYPHYLAXIS a 0.1076 0.1299 0.2824 0.0026 0.0001 0.0094 0.0079 0.0001 ALUE P V p p p p p NO RECURRENCE (%) ACHYPHYLAXIS

14 TIENTS WITHOUT T

Rothschild, Dunlop, A Dunner, et al. P RECURRENCE (%) ,n(%) NO RECURRENCE (%) ECURRENCE R ACHYPHYLAXIS ATES OF R TIENTS WITH T A P TATUS ON S RECURRENCE (%) extended release. ACHYPHYLAXIS T TMENT GROUP TABLE 3 TABLE FFECT OF 2-sided Fisher exact test; analysis excludes prior with tachyphylaxis. patients who experienced to or concurrent a recurrence FluoxetinePlaceboOverallMaintenance Phase B ERVenlafaxine Fluoxetine 12/46 (26%)PlaceboOverall 11/64 (17%) 32/172 (19%) 3/27 (11%) 34/46 (74%) 7/23 (30%) 53/64 (83%) 140/172 (81%) 9/18 (50%) 24/27 (89%) 0/27 (0%) 19/68 (28%) 4/113 (4%) 2/35 (6%) 16/23 (70%) 0/16 (0%) 27/27 (100%) 9/18 (50%) 109/113 (97%) 49/68 (72%) 33/35 (94%) 0/21 (0%) 16/16 (100%) 1/16 (6%) 1/53 (2%) 21/21 (100%) p p 15/16 (94%) 52/53 (98%) E TREA Maintenance Phase A ERVenlafaxine 9/62 (15%) 53/62 (86%)Abbreviations: ER a 2/51 (4%) 49/51 (96%) p

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DISCUSSION In this analysis from the PREVENT study, the probability of experiencing tachyphylaxis for patients receiving venlafaxine ER and fluoxetine were comparable during both maintenance phases, contradicting the hypothesis that SSRIs are associated with a greater risk for tachyphylaxis due to excessive serotonergic stimulation.2 Additionally, the observation of a significant difference between venlafaxine ER and placebo in the occurrence of tachyphylaxis suggests that tachyphylaxis may not be related to antidepressant treatment at all, as has been previously suggested.3 In fact, these results can be interpreted as suggesting that antidepressant treatment provides protection from the development of the symptoms assessed with the RSAT.The analysis that assessed the risk of recurrence in patients with tachyphylaxis found that a significant number of fluoxetine-treated patients who experienced tachyphylaxis also experienced a subsequent recurrence during maintenance treatment. These results suggest that the noradrenergic activity of the serotonin-norepinephrine reuptake inhibitor may provide some protection from tachyphylaxis becoming a full recurrence. This could explain the discrepancies between 15 the current results and the prior reports that equated tachyphylaxis and Rothschild, Dunlop, recurrence and demonstrated a difference in rates of tachyphylaxis Dunner, et al. between single- and dual-acting antidepressants. However, more impor- tantly, the observed significant relationship between tachyphylaxis and recurrence suggests that tachyphylaxis is a prodrome for recurrence. The rates of tachyphylaxis reported here are also higher than those that have been previously reported, which can primarily be explained by differences in the definitions of tachyphylaxis used. Previously published research equated tachyphylaxis with relapse or recurrence,1,2 whereas the current analysis used a unique, symptom-specific definition of tachyphylaxis that is distinct from a full recurrence of MDD. In this analysis, increased age and BMI and a shorter duration of current depressive episode were significantly associated with the occurrence of tachyphylaxis. The increased risk for tachyphylaxis seen in older patients stands in contrast to previously published results that found the subgroup of patients experiencing tachyphylaxis was significantly younger than the group that did not.1 Differences in the criteria used to define tachyphylaxis may account for the variation in these results, but the higher incidence of tachyphylaxis in older patients also may reflect the progression of underlying disease processes. Alternatively, the higher rate of tachyphylaxis found in older patients may reflect the loss of catecholamine signaling (particu- larly dopaminergic signaling) that develops with age.17 A previous analysis has shown that a BMI 25 is associated with poorer antidepressant treatment outcomes,18 supporting the current finding of a relationship between higher BMI and the occurrence of tachyphylaxis in maintenance phase A.

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The strengths of the current analysis lie in the length and prospective nature of the study. Patients were required to have a sustained positive treatment response for 8 months before being enrolled into the first maintenance phase. This aspect of the study design likely eliminated patients who experienced the loss of a placebo response, providing a clearer picture of the loss of a true drug response. A previously conducted review has suggested that the loss of response seen beyond acute-phase treatment may be the result of a loss of placebo response.19 Additionally, in contrast to previous retrospective analyses, tachyphylaxis was defined a priori and assessed prospectively in this study.

Limitations Although the criterion for tachyphylaxis (i.e., RSAT 7) was deter- mined a priori, this definition of tachyphylaxis has not been extensively studied. Comparisons with other studies are limited due to the lack of a consensus definition and standardized diagnostic criteria for tachyphylaxis.

CONCLUSION 16 Rothschild, Dunlop, These data represent the first attempt at prospectively assessing tachy- Dunner, et al. phylaxis during antidepressant maintenance treatment using a novel definition that, unlike previous definitions, makes a distinction between recurrence and tachyphylaxis. Future research should focus on more clearly describing the phenomenon of tachyphylaxis, developing consistent clinical criteria to identify tachyphylaxis, and prospectively assessing the effects of tachyphylaxis on long-term treatment outcomes. ✤

ACKNOWLEDGEMENTS The authors wish to thank Dennis Stancavish, MA and Jennifer B. Hutcheson, BA, of Advogent, for writing and editing assistance on this manuscript, and Dr. Saeeduddin Ahmed, MD, a former employee of Wyeth Research, Collegeville, Pennsylvania, who helped with the interpretation of these results.

ROLE OF FUNDING SOURCE Research supported by Wyeth Research.

CONFLICTS OF INTEREST Dr. Rothschild received grants or funding from the National Institute of Mental Health, Cyberonics, and Wyeth. He is a consultant for Pfizer, GlaxoSmithKline, Forest Laboratories, Eli Lilly & Company, and Takeda. Royalties include the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)TM, Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009.

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Dr. Dunlop has served as a consultant for Wyeth and Bristol–Myers Squibb and has served on the speaker’s bureau for Bristol–Myers Squibb. He has received research support from Novartis, Takeda, the National Institute of Mental Health, and Ono Pharmaceuticals. Dr. Dunner has received grants/research from Eli Lilly & Company, Pfizer, GlaxoSmithKline, Wyeth, Bristol–Myers Squibb, Forest Laboratories, Cyberonics, Janssen, and Novartis. He is a consultant for Eli Lilly & Company, Pfizer, GlaxoSmithKline, Wyeth, Bristol–Myers Squibb, Forest Laboratories, Roche Diagnostics, Cypress, Corcept, Janssen, Novartis, Shire, Somerset, Otsuka, Healthcare Technology Systems, Jazz Pharmaceuticals, and Wyeth. He is part of the speaker’s bureau for Eli Lilly & Company, Pfizer, GlaxoSmithKline, Wyeth, Bristol–Myers Squibb, and Organon. Dr. Friedman is a consultant for Pfizer. He has received grant/research support from Sanofi Aventis, AstraZeneca, Wyeth. He is part of the speaker’s bureau for AstraZeneca. Dr. Gelenberg is a consultant for Eli Lilly & Company, Pfizer, Best Practice, AstraZeneca, Wyeth, Cyberonics, Novartis, Forest Laboratories, 17 GlaxoSmithKline, ZARS Pharma, Jazz Pharmaceuticals, Lundbeck, Takeda, Rothschild, Dunlop, and eResearch Technology. He is part of the speaker’s bureau for Pfizer, Dunner, et al. GlaxoSmithKline, and Wyeth. He has received grants/research from Eli Lilly & Company and owns stock in Healthcare Technology Systems, Inc. Dr. Holland has received grants/research from Eli Lilly & Company, Cyberonics, Novartis, Forest Pharmaceuticals, and Pfizer. He is on the speaker’s bureau for Wyeth, Novartis, and Forest Laboratories. Dr. Kocsis has received grants/research from the National Institute of Mental Health, National Institute of Drug Abuse, Burroughs Wellcome Trust, Pritzker Consortium, AstraZeneca, Sanofi Aventis, Forest Laboratories, Novartis, and CNS Response. He is part of the speaker’s bureau for Pfizer, Wyeth, and AstraZeneca. Dr. Kornstein is a consultant and advisory board member for Wyeth Research. She has received grants/research support from the Department of Health and Human Services, the National Institute of Mental Health, Bristol–Myers Squibb Company, Lilly, Forest Pharmaceuticals, Wyeth, Novartis, Sepracor, Boehringer–Ingelheim, Sanofi–Aventis, Takeda, AstraZeneca, Pfizer, GlaxoSmithKline, Mitsubishi–Tokyo, Merck, Biovail, and Berlex. She has served on advisory boards or received honoraria from Wyeth, Pfizer, Biovail, Endo, Bristol–Myers Squibb, Forest Pharmaceuticals, Lilly, Neurocrine, Sepracor, Berlex, and Warner–Chilcott. She has received book royalties from Guilford Press. Dr. Shelton has received grants/research from Eli Lilly & Company, GlaxoSmithKline, Janssen, Pfizer, Sanofi Aventis, Wyeth–Ayerst,

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AstraZeneca, and Abbott. He is a consultant for Pfizer, Janssen, and Sierra Neuropharmaceuticals. He also is on the speaker’s bureau for Bristol–Myers Squibb, Eli Lilly & Company, Janssen, Pfizer, GlaxoSmithKline, Wyeth–Ayerst, and Abbott. Dr. Trivedi has received grants/research from the Agency for Healthcare Research and Quality, Corcept Therapeutics, Cyberonics, Merck, National Alliance for Research in Schizophrenia and Depression, the National Institute of Mental Health, National Institute of Drug Abuse, Novartis, Predix Pharmaceuticals, Pharmacia & Upjohn, Solvay, and Targacept. He is a consultant for Abbott, Abdi Brahim, Akzo, AstraZeneca, Bristol–Myers Squibb, Cephalon, Fabre–Kramer, Forest Laboratories, GlaxoSmithKline, Janssen, Johnson & Johnson, Eli Lilly & Company, Meade Johnson, Neuronetics, Parke–Davis, Pfizer, Sepracor, Vantage Point, and Wyeth. Dr. Zajecka has received grants/research from AstraZeneca, GlaxoSmithKline, McNeil, the National Institute of Mental Health, Bristol–Myers Squibb, Cephalon, CNS Response, Cyberonics, Eli Lilly & Company, Forest Laboratories, Novartis, PamLab, Pfizer, and 18 SanofiAventis. He is a consultant for Abbott, Eli Lilly & Company, Rothschild, Dunlop, Biovail, Bristol–Myers Squibb, Pfizer, Otsuka, Takeda, Wyeth–Ayerst, Dunner, et al. Novartis, and PamLab. He is part of the speaker’s bureau for Abbott, AstraZeneca, Bristol–Myers Squibb, Covidien, Cyberonics, Eli Lilly & Company, GlaxoSmithKline, PamLab, Pfizer, and Wyeth–Ayerst. Dr. Goldstein has received grants/research from Alza, AstraZeneca, Bristol–Myers Squibb, Cephalon, CNS Response, Cyberonics, Eli Lilly & Company, Forest Laboratories, McNeil, the National Institute of Mental Health, Novartis, PamLab, Pfizer, and Takeda. He is part of the speaker’s bureau for AstraZeneca, Eli Lilly & Company, Sepracor, and Wyeth. Dr. Thase is a consultant for AstraZeneca, Bristol–Myers Squibb Company, Cephalon, Cyberonics, Eli Lilly & Company, Forest Laboratories, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon International, Sepracor, Shire US, Supernus Pharmaceuticals, and Wyeth. He has received grants/research from Eli Lilly & Company and Sepracor. He also is part of the speaker’s bureau for AstraZeneca, Bristol–Myers Squibb Company, Cyberonics Eli Lilly & Company, GlaxoSmithKline, Sanofi Aventis, Schering Plough (formerly Organon), and Wyeth Pharmaceuticals. Dr. Thase has expert testimony with Jones Day (Wyeth Litigation), Phillips Lytle (GlaxoSmithKline Litigation), and Pepper Hamilton LLP (Eli Lilly & Company Litigation). He has equity holdings in MedAvante other income from American Psychiatric Publishing, Inc, Guilford Publications, Herald House, WW Norton & Company, Inc. Dr. Thase’s spouse is a Senior Medical Director at Advogent (formerly Cardinal Health). Dr. Pedersen is a Wyeth employee and stockholder.

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Dr. Keller is a consultant for Abbott, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest Laboratories, Janssen, JDS, Medtronic, Organon, Novartis, Pfizer, Roche, Solvay, and Wyeth. He has received grants/research from Pfizer and is part of the advisory board for Abbott, Bristol–Myers Squibb, CENEREX, Cyberonics, Cypress, Forest Laboratories, Janssen, Neuronetics, Novartis, Organon, and Pfizer.

CONTRIBUTORS Drs. Rothschild, Dunlop, Dunner, Friedman, Gelenberg, Holland, Kocsis, Kornstein, Shelton, Trivedi, Zajecka, Goldstein, Thase, and Keller, and Mr. Pedersen, contributed to the study design, analysis and interpretation of data, and the writing of the manuscript and decision to submit for publication.

DISCLOSURE The data in this manuscript have been previously presented at the American Psychiatric Association Annual Meeting, San Diego, CA, May 19–24, 2007; the New Clinical Drug Evaluation Unit Annual 19 Meeting, Boca Raton, FL, June 11–14, 2007; and the United States Rothschild, Dunlop, Dunner, et al. Psychiatric and Mental Health Congress, Orlando, FL, October 11–14, 2007.

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