Abstract
Background
For patients with major depressive disorder (MDD) experiencing side effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).
Aims
We aimed to compare the switch between the TCA nortriptyline and the SSRI escitalopram.
Methods
Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa due to side effects or non-response. Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery-Aasberg Depression Rating scale (MADRS). We performed adjusted mixed effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% confidence intervals (95%-CI).
Results
Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (N=36; β=-0.38, 95%-CI=-0.51 to -0.25, p<0.001) and from nortriptyline to escitalopram (N=72; β=-0.34, 95%-CI=-0.41 to -0.26, p<0.001). Both switching options resulted in significant improvement among individuals who switched due to non-response or side effects, respectively. The results were supported by analyses on other rating scales and symptom dimensions.
Conclusions
These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.
Trial registration
EudraCT No.2004-001723-38, (http://eudract.emea.europa.eu) and ISRCTN No.03693000, (http://www.controlled-trials.com).
Keywords: depression, non-responders, side effects, antidepressants, switching, nortriptyline, escitalopram
Introduction
Among patients with major depressive disorder (MDD), guidelines recommend starting antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI) or mirtazapine 1. Although tricyclic antidepressants (TCA) represent the most efficient group of antidepressants 2,3, safety concerns usually reserve initial treatment with a TCA for patients suffering from a severe depression. However, despite state-of-the-art treatment, approximately 50% will not respond sufficiently to their first-line antidepressant 4. In order to achieve response, several approaches are relevant. This includes dose increase 5, augmentation 6 or switching to another antidepressant 7, with the latter including switching within the same class 8 or to a different class of antidepressants 7. Despite switching between antidepressants represents a frequent and important clinical approach, rather little research has been performed on this important aspect of clinical decision-making. Recent meta-analyses found that several studies have investigated switching, but only 8 randomized trials have compared the effect of switching antidepressant medication versus continuation 9,10. Interestingly, the results showed no difference between switching and continuation 10. Indeed, one randomized trial (N=189) found that continuation showed significantly better effects as compared to switching 11. In addition, the recent VAST-D trial included 1,522 US veteran patients with MDD and non-response to at least 1 antidepressant course 12. Augmentation with aripiprazole showed significant better remission compared to individuals randomized to bupropion switching. However, the response rates were rather modest (22-29%) and the study population consisted mainly of older males (85.2%; mean age 54.4 years).
Nevertheless, if continuation is not possible, several switching approaches may improve treatment effects after non-response or side effects to SSRIs, e.g. switching to SNRIs 5,8 or vortioxetine 13. Regarding TCA treatment, it is often assumed that the most efficient antidepressant has been given. Therefore, it may not be beneficial to switch to a first-line antidepressant, e.g. an SSRI. Nevertheless, one large trial included chronic depressed patients who failed to respond to a 12-week treatment with the SSRI sertraline or the TCA imipramine 7. Switching from sertraline to imipramine (N=117) or imipramine to sertraline (N=51) resulted in response among more than 50% of the patients in both groups. Another trial found beneficial effects for switching to the SSRI fluoxetine (N=142) after non-response to the TCA nortriptyline 14. However, this randomized study found no difference compared to nortriptyline continuation (N=68).
Hence, more research in this clinically highly relevant area is needed and several switching combinations and specific drugs have not been investigated 10,13,15. Furthermore, many patients experience side effects, particularly to TCA treatment, necessitating switching to another antidepressant. In addition, it has been suggested that switching after 2 weeks may be beneficial among patients with early non-response 16. Other findings indicate that continuation and dose increase may lead to better response rates 5. The clinically important aspect of switching options after a failed first antidepressant treatment has to be explored in different populations and other SSRI and TCA compounds need to be studied including the effect of the timing of switching. Hence, our aim was to investigate whether switching from the TCA nortriptyline to the SSRI escitalopram or vice versa resulted in improved treatment effects among patients with MDD after a failed first antidepressant treatment.
Methods
Study design and sample
The Genome Based Therapeutic Drugs for Depression (GENDEP) study is a twelve-week partly-randomized multi-center clinical trial comparing treatment with escitalopram to nortriptyline (a detailed flow chart is available in 17). 811 adults diagnosed with MDD of at least moderate severity established in the SCAN interview 18, including both first-time depression and patients with recurrent depression who previously may have received treatment, were recruited in nine European countries. Exclusion criteria were a personal or family history (first-degree relative) of bipolar disorder or schizophrenia, a personal history of hypomanic or manic episodes or mood incongruent psychotic symptoms, active substance dependence, primary organic disease, previous non-response, side effects or contraindications to both study medications and non-caucasian ethnicity, the latter being due to the genetic part of GENDEP. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects/patients were approved by ethics boards in all participating centers. Written informed consent was obtained from all participants. Verbal consent was witnessed and formally recorded.
Interventions
Participants without contraindications for escitalopram or nortriptyline were randomly allocated to receive one of the two antidepressants using a random number generator, stratified by center and performed independently of the assessing clinician: 233 were randomized to escitalopram and 235 to nortriptyline. Patients with a history of non-response, side effects or contraindications for one of the drugs were allocated non-randomly to the other antidepressant: 225 to escitalopram and 118 to nortriptyline. Escitalopram was initiated at 10 mg daily and increased to a target dose of 15mg daily within the first two weeks and could be further increased to 20 mg daily (and up to 30 mg in cases where there was clinical agreement that a higher dose was needed).
Nortriptyline was initiated at 50 mg daily and titrated to a target dose of 100 mg daily within the first two weeks and could be further increased to 150 mg daily (and up to 200 mg in cases where there was clinical agreement that a higher dose was needed). Other psychotropic medications were not allowed with the exception of occasional use of hypnotics. Compliance was monitored weekly by self-reported pill count, and plasma levels of antidepressants were measured at week 8. Overall, individuals treated with escitalopram or nortriptyline improved to a similar degree on depressive symptoms 19. If a patient experienced poor tolerance or no response was observed during the first 12 weeks on the initially assigned drug, patients were offered to switch to the other drug. This decision was based on a clinical evaluation considering both therapeutic and adverse effects, as assessed with the antidepressant side effect checklist (ASEC), and no cut-off criteria for switching were defined. 72 patients switched from nortriptyline to escitalopram and 36 switched from escitalopram to nortriptyline and were followed for up to 26 weeks after switching. These 108 patients represent the study population for the present study.
Measures
Depression severity was measured at inclusion and weekly throughout the first 12 weeks, both during the first antidepressant trial and after switching, with a final visit 26 weeks after switching. Three established scales were applied: The clinician-rated 10-item Montgomery-Asberg Depression Rating Scale (MADRS) 20 and the 17-item Hamilton Rating Scale for Depression (HDRS) 21 including the self-report 21-item Beck Depression Inventory (BDI) 22. We included response, defined as a reduction >50% on the MADRS or HDRS, respectively, and remission, defined as MADRS <11 or HDRS <7, respectively. The rating scales were administered by trained psychologists and psychiatrists who achieved high inter-rater reliability on recorded interviews which did not differ between centers (Cronbach´s α≥0.9 for MADRS and BDI and Cronbach´s α≥0.8 for HDRS) 17. In a previous GENDEP study 19 we found that depressive symptoms could be described in more detail by three symptom dimensions derived by categorical item factor analyses: observed mood, cognitive symptoms and neurovegetative symptoms. The observed mood dimension comprises clinician-rated items assessing core mood symptoms, anxiety and activity. The cognitive symptom dimension includes items assessing pessimism, guilt, suicidality and the majority of self-reported items from the BDI. The neurovegetative symptom dimension comprises insomnia, poor appetite, weight loss and decreased libido.
Statistical analysis
To investigate treatment outcome after switching, we performed mixed effects linear regression models with full information maximum likelihood estimation and report β-coefficients including 95% confidence intervals (95%-CI). These models allow inclusion of all relevant covariates across repeated measurements and efficiently handle missing data 23. MADRS was the primary outcome measure as in previous GENDEP studies 17,19. Regarding missing data, we found no differences between the switching groups regarding early drop-out before week 12 after switching (N=40 dropped out before week 12, p=0.481 for group-difference). Furthermore, we had 26 observations with missing single visits on the MADRS, and there was a significant difference showing more missing values among those who switched to nortriptyline (n=16) compared to those who switched to escitalopram (n=10) (p=0.007).
First, we performed analyses among all 108 individuals to explore the overall effect of switching. Second, we investigated switchers to escitalopram and switchers to nortriptyline separately on the overall treatment effect and on the treatment effect at every visit during the study period. Third, we performed analyses using the HDRS and the BDI as the dependent variables including analyses on the symptom dimension scores, i.e. the observed mood, cognitive and neurovegetative symptom dimensions. Finally, we explored the effect of switching on response and remission. For this, we performed t-tests among all 108 individuals and logistic regression analyses among the 68 individuals who completed 12 weeks of follow-up after switching.
We performed all the above mentioned analyses in an unadjusted model and in a model adjusting for age, sex, severity of depression at switching, and center.
For comparison of demographic and baseline clinical characteristics we performed t-tests and report means and standard deviations (SD).
We used STATA version 14 for all analyses.
Sensitivity analyses
First, we restricted the analyses to individuals with at least 6 weeks of follow-up after switching to the second antidepressant (N=84). Second, to minimize selection bias, we performed all analyses among individuals who were randomized to treatment, i.e. excluding those 22 patients who had not been randomized. Third, we performed all analyses among individuals with non-response (N=94) to the first medication. This analysis included those individuals who experienced non-response (N=34) and those who experienced both non-response and side effects (N=60). Fourth, to explore the timing of switching, we investigated whether a specific week of switching was associated with a better response. Fifth, since the two switching groups differed regarding age at onset, we performed analyses where we additionally adjusted for age at onset. Sixth, we performed analyses among those individuals who switched due to side effects only and among those who switched due to non-response only.
Results
Sample characteristics
A total of 72 patients switched from nortriptyline to escitalopram after a mean of 6.2 weeks and 36 from escitalopram to nortriptyline after a mean of 7.0 weeks (range 1-12 weeks for both groups; no difference in switching week, p=0.197) (Table 1). The reasons for switching were side effects (N=12), non-response (N=34) or both (N=60), whereas 2 individuals had no information regarding reason for switching (Table 2). Commonly reported adverse reactions to escitalopram included nausea and vomiting (15%) and sexual dysfunction (30%). Common adverse effects of nortriptyline included dry mouth (80%), orthostatic dizziness (32%), drowsiness (27%) and constipation (24%). Individuals who switched from nortriptyline to escitalopram were more often female (71% vs. 47%; p=0.013), had a younger age at onset of depressive symptoms (29.5 vs. 36.8 years; p=0.003), and were more often randomized to treatment (86.1% vs. 66.7%; p=0.035) (Table 1). The mean MADRS score at switching was 21.5 (SD=8.3) for those switching from nortriptyline to escitalopram and 24.2 (SD=7.7) for those switching from escitalopram to nortriptyline (Table 3). We found no significant differences in MADRS, HDRS, BDI, observed mood or cognitive symptoms at the time of switching, but those who switched from escitalopram to nortriptyline had higher neurovegetative symptoms (0.6 vs. 0.1; p=0.0009) (Table 3).
Table 1. Characteristics of the study population at study entry, i.e. at the initiation of the first antidepressant trial.
| Total N=108 |
Nortriptyline → Escitalopram N=72 |
Escitalopram → Nortriptyline N=36 |
Significance | |
|---|---|---|---|---|
| Female, N (%) | 68 (63%) | 51 (70.8%) | 17 (47.2%) | p=0.013 |
| Age, mean years (SD) | 43.1 (11.5) | 42.0 (11.7) | 45.2 (10.8) | p=0.164 |
| Randomized, N (%) | 86 (79.6%) | 62 (86.1%) | 24 (66.7%) | p=0.035 |
| Education, mean years (SD) | 12.0 (3.1) | 12.0 (3,3) | 11.9 (2.7) | p=0.927 |
| Occupation, N (%) | p=0.878 | |||
| Full time work | 37 (34.3%) | 26 (36.1%) | 11 (30.6%) | |
| Part-time work | 13 (12.0%) | 8 (11.1%) | 5 (13.9%) | |
| Student | 5 (4.6%) | 4 (5.6%) | 1 (2.8%) | |
| Home-maker | 5 (4.6%) | 3 (4.2%) | 2 (5.6%) | |
| Retired | 16 (14.8%) | 11 (15.2%) | 5 (13.9%) | |
| Unemployed | 32 (29.6%) | 20 (27.8%) | 12 (33.2%) | |
| Marital status, N (%) | p=0.405 | |||
| Married/cohabitant | 57 (52.8) | 35 (48.5%) | 22 (58.3%) | |
| Separated/divorced | 17 (15.7) | 13 (18.1%) | 4 (11.1%) | |
| Widowed | 4 (3.7) | 3 (4.2%) | 1 (2.8%) | |
| Single | 30 (27.8) | 21 (29.1%) | 9 (27.8%) | |
| Age at onset, mean years (SD) | 31.9 (11.9) | 29.5 (11.4) | 36.8 (11.6) | p=0.003 |
| Episodes, N (%) | p=0.392 | |||
| 1 | 35 (32.4%) | 23 (31.9%) | 12 (33.3%) | |
| 2 | 53 (49.1%) | 34 (47.2%) | 19 (52.8%) | |
| 3+ | 20 (18.5%) | 15 (20.9%) | 5 (13.9%) | |
| Mean (SD) | 1.86 (0.70) | 1.89 (0.72) | 1.81 (0.67) | |
| Current episode duration, mean weeks (SD) | 22.4 (17.3) | 21.5 (16.8) | 24.2 (18.4) | p=0.488 |
Table 2. Clinical characteristics of individuals who switched from nortriptyline to escitalopram (N=72) or escitalopram to nortriptyline (N=36) after non-response or side effects to the first medication.
| Total N = 108 | Nortriptyline → Escitalopram N=72 |
Escitalopram → Nortriptyline N=36 |
Significance |
|---|---|---|---|
| Dose before switch | Nortriptyline 109.3 mg (SD: 34.8) | Escitalopram 19.6 mg (SD: 7.6) | |
| Switch < week 8, N (%) | 40 (55.6%) | 16 (44.4%) | p=0.325 |
| Mean (SD) switching week | 6.2 (2.8) | 7.0 (3.3) | p=0.197 |
| Mean (SD) weeks follow-up after switching | 10.0 (3.2) | 8.7 (4.4) | p=0.099 |
| Follow-up after switching | |||
| ≥6 weeks | 59 (81.9%) | 25 (69.4%) | p=0.141 |
| 12 weeks | 47 (65.3%) | 21 (58.3%) | p=0.481 |
| Switching due to | p=0.079 | ||
| Side effects | 10 (13.9%) | 2 (5.5%) | |
| Non-response | 18 (25.0%) | 16 (44.4%) | |
| Both | 43 (59.7%) | 17 (47.2%) | |
| Missing information | 1 (1.4%) | 1 (2.8%) | |
| Mean (SD) weeks follow-up based on reason for switching | |||
| Side effects | 10.1 (3.1) | 6.5 (7.8) | p=0.323 |
| Non-response | 8.8 (3.6) | 9.5 (3.9) | p=0.391 |
| Both | 10.4 (3.0) | 8.0 (4.6) | p=0.186 |
Table 3. Treatment effects among individuals switching from nortriptyline to escitalopram (N=72) or escitalopram to nortriptyline (N=36) after non-response or side effects to the first medication.
| Total N = 108 | Nortriptyline → Escitalopram N=72 |
Escitalopram → Nortriptyline N=36 |
Significance | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Response HDRS1, N (%) | 43 (59.7%) | 18 (50.0%) | p=0.347 | |||||||
| Remission HDRS1, N (%) | 42 (58.3%) | 17 (47.2%) | p=0.283 | |||||||
| Response MADRS1, N (%) | 43 (59.7%) | 15 (41.7%) | p=0.080 | |||||||
| Remission MADRS1, N (%) | 46 (63.9%) | 18 (50.0%) | p=0.178 | |||||||
| At study | Baseline2 | End Point | Improvement | At study2 | Baseline2 | End Point | Improvement | Mean across groups | ||
| Entry2 | Sign. | entry | Sign. |
Baseline Sign. |
Endpoint Sign. |
|||||
| MADRS, mean (SD) | 29.6 (7.4) | 21.5 (8.3) | 15.1 (11.4) | 6.9 (10.1) ** | 30.1 (5.5) | 24.2 (7.7) | 18.2 (10.4) | 7.3 (12.2) ** | p=0.094 | p=0.165 |
| HDRS-17, mean (SD) | 22.0 (6.0) | 16.4 (6.4) | 11.1 (8.4) | 5.6 (7.4) ** | 22.4 (4.7) | 17.9 (6.0) | 13.4 (8.6) | 4.2 (8.4) ** | p=0.231 | p=0.211 |
| BDI, mean (SD) | 30.9 (10.7) | 23.3 (12.2) | 16.4 (13.1) | 7.3 (11.6) ** | 30.6 (8.8) | 25.9 (9.8) | 17.9 (10.1) | 9.4 (10.6) ** | p=0.247 | p=0.533 |
| Observed mood, mean3 (SD) | 1.0 (0.6) | 0.4 (0.7) | −0.4 (1.1) | 0.8 (1.1) ** | 1.0 (0.5) | 0.5 (0.7) | −0.1 (1.0) | 0.6 (1.2) ** | p=0.677 | p=0.185 |
| Cognitive, mean3 (SD) | 0.9 (0.7) | 0.4 (0.9) | −0.3 (1.2) | 0.8 (1.0) ** | 0.9 (0.6) | 0.4 (0.8) | −0.1 (0.8) | 0.5 (1.0) ** | p=0.892 | p=0.167 |
| Neurovegetative, mean3 (SD) | 0.8 (0.6) | 0.1 (0.8) | −0.1 (0.9) | 0.2 (0.8) ** | 0.8 (0.6) | 0.6 (0.6) | 0.1 (0.9) | 0.6 (0.9) ** | * | p=0.440 |
HDRS = Hamilton Depression Rating Scale, 17-item; MADRS = Montgomery Aasberg Depression Rating Scale; BDI = Beck Depression Inventory; SD = Standard deviation; Sign. = Significance of improvement.
Response: MADRS or HDRS reduced ≥ 50%; Remission: MADRS ≤ 11, HDRS ≤ 7.
Study entry is before start of the first drug. Baseline is after treatment with the first drug and before switch to the second drug.
The score for the symptom dimensions was based on the item response theory (IRT) approach including the score of the several items from the three applied rating scales, i.e. the MADRS, HDRS and the BDI.
* p < 0.005; ** p < 0.0001.
Treatment effect after switching
Of the 108 individuals, a total of 84 (77.8%), 81 (75.0%) and 68 (63.0%) completed 6, 8 and 12 weeks of follow-up after switching medication, respectively. In addition, 40 (37.0%) individuals completed the additional follow-up visit 26 weeks after switching. The mean follow-up after switching was 9.5 weeks (SD=3.7). We found no difference regarding length of follow-up after switching or reason for switching between the two switching groups (Table 2). Similar proportions of individuals who switched due to non-response, side effects or both completed 6 weeks (p=0.458) or 12 weeks (p=0.559) of the second course of treatment, respectively.
No significant difference was found at the end point between the two switching groups on the three rating scales or the three symptom dimensions (Table 3). The development of symptom scores on the MADRS, HDRS, BDI and the three symptom dimensions before and after switching is illustrated in Figure 1. Overall, switching resulted in a significant decrease on the MADRS among all 108 patients as indicated by an adjusted β of -0.35 (95%-CI=-0.41 to -0.28; p<0.001). Both groups improved similarly on the MADRS (escitalopram to nortriptyline: N=36, β=-0.38, 95%-CI=-0.51 to -0.25, p<0.001; nortriptyline to escitalopram: N=72, β=-0.34, 95%-CI=-0.41 to -0.26, p<0.001). We found significant improvements on the HDRS and BDI for both switching groups (Table 3 and Figure 1, all p<0.001). Furthermore, both switching groups significantly improved on the three symptom dimensions, i.e. on observed mood, cognitive and neurovegetative symptoms (Figure 1, all p<0.001). All analyses were adjusted for age, sex, severity of depression at switching, and center.
Figure 1.
The development of mean scores on three standard rating scales (A-C) and three symptom dimension scores (D-F) among patients with MDD before (week 0-8) and after (week 13-38) switching from nortriptyline to escitalopram (N=72) or from escitalopram to nortriptyline (N=36).
Abbreviations: MDD=Major Depressive Disorder; MADRS=Montgomery-Aasberg Depression Rating Scale; HDRS=Hamilton Depression Rating Scale; BDI=Beck Depression Inventory.
1 Weeks 9-12 before switching are not shown due to few individuals.
2 The score for the symptom dimensions was based on the item response theory (IRT) approach including the score of specific items from the three applied rating scales, i.e. the MADRS, HDRS and the BDI.
Response and remission
During the entire follow-up period after switching, a total of 58 (53.7%) individuals achieved response on the MADRS and 61 (56.5%) on the HDRS, respectively, whereas 64 (59.3%) achieved remission on the MADRS and 59 (54.6%) on the HDRS, respectively. We found no significant differences between the two switching groups regarding response and remission based on t-tests (Table 3).
When analyzing the 68 individuals who completed 12 weeks of follow-up after switching (47 switched to escitalopram and 21 switched to nortriptyline), a total of 28 (59.6%) switchers to escitalopram experienced response on the MADRS and 22 (46.8%) experienced remission. Among individuals who switched to nortriptyline, 7 (33.3%) experienced response and 8 (38.1%) remission. Fully adjusted logistic regression showed no difference between the two switching groups regarding response (p=0.125) or remission (p=0.440) after 12 weeks, respectively.
Sensitivity analyses
When only analyzing individuals with at least 6 weeks of follow-up after switching, we found significant treatment effects on the MADRS scale among switchers from nortriptyline to escitalopram (N=59, β=-0.34, 95%-CI=-0.41 to -0.26, p<0.001) and switchers from escitalopram to nortriptyline (N=25, β=-0.35, 95%-CI=-0.49 to -0.22, p<0.001).
Second, when restricting to individuals who were randomized to treatment, we found significant treatment effects on the MADRS among switchers from nortriptyline to escitalopram (N=62, β=-0.34, 95%-CI=-0.42 to-0.26, p<0.001) and switchers from escitalopram to nortriptyline (N=24, β=-0.41, 95%-CI=-0.58 to -0.24, p<0.001).
Third, we found effects for switching among those 94 individuals who switched due to non-response, which was present among individuals who switched from nortriptyline to escitalopram (N=61, β=-0.39, 95%-CI=-0.47 to -0.31, p<0.001) and individuals who switched from escitalopram to nortriptyline (N=33, β=-0.37, 95%-CI=-0.49 to -0.25, p<0.001).
Fourth, we performed analyses based on the week of switching (Supplementary Table 1). We found no indication that a specific period, e.g. early or late switching, showed a better response pattern. Switching in all weeks was associated with better response except for the 5 individuals who switched in week 4.
Fifth, analyses additionally adjusting for age at onset supported the primary results. Switchers to escitalopram improved by β=-0.38 (95%-CI=-0.51 to -0.25, p<0.001), whereas switchers to nortriptyline improved by β=-0.34 (95%-CI=-0.41 to -0.26, p<0.001).
Sixth, analyses among those individuals who switched due to side effects only (N=12) showed improved treatment effects in both groups (nortriptyline to escitalopram, N=2, β=-1.03, 95%-CI=-1.87 to -0.19, p=0.016; escitalopram to nortriptyline, N=10, β=-0.34, 95%-CI=-0.50 to -0.17, p<0.001), and 9 (75%) out of the 12 achieved remission. The 34 individuals who switched due to non-response only showed improved treatment effects in both groups (nortriptyline to escitalopram, N=18, β=-25, 95%-CI=-0.35 to -0.15, p<0.001; escitalopram to nortriptyline, N=16, β=-0.38, 95%-CI=-0.47 to -0.29, p<0.001), and 17 (50%) out of the 34 achieved remission.
Discussion
Among 108 individuals with MDD who experienced non-response or side effects to a first treatment course with escitalopram or nortriptyline, switching to the other drug resulted in significant improvement in depression scores and more than 50% of patients achieving response or remission. We found significant improved treatment effects on several rating scales and different symptom dimensions. Particularly, our finding that switching from a TCA to an SSRI improved treatment outcomes is contra intuitive to clinical consensus but in line with two previous trials 7,14. However, we had no control group, e.g. individuals randomized to continuation treatment. Nevertheless, our results suggest that switching from nortriptyline to escitalopram or vice versa may be a viable approach to improve treatment outcomes after non-response or side effects to a first antidepressant treatment course. Our finding that individuals who switched to escitalopram were younger may be explained by the fact that the first treatment assignment was based on a clinical evaluation, and the rate of contraindications for TCAs increases with age.
Evidence of switching between antidepressants
Clinicians frequently encounter the situation where continuation with an antidepressant is not possible due to non-response or side effects. It is important to choose an evidence-based switching strategy with the potential of improving treatment effects. Switching to an antidepressant targeting the same receptors, e.g. from one SSRI to another SSRI, may seem less likely to result in fewer side effects and better treatment response. The GENDEP study was designed to investigate two drugs with different mechanisms of action, i.e. escitalopram targeting mainly serotonergic pathways versus nortriptyline mainly targeting noradrenergic pathways. Hence, the important finding of the present study is that switching to an antidepressant with a different receptor profile can improve the antidepressant treatment effects. This is supported by a meta-analysis of clinical trials 24. Although only including four trials, the results indicated that after SSRI non-response, switching to a different class of antidepressants showed better response rates compared to switching to a different SSRI. In addition, two prior trials found beneficial effects after switching between a TCA and an SSRI 7,14. However, the only randomized trial found no differences between switching to the SSRI fluoxetine (N=142) and nortriptyline continuation (N=68) 14.Finally, the timing of switching represents an important clinical aspect. A small study found that among early non-responders to sertraline (≤20% reduction in MADRS within the first 2 weeks), randomization to paroxetine switching (N=20) after 2 weeks resulted in better response and remission compared to sertraline continuation (N=21) 16. On the other hand, a larger randomized trial found that after non-response to 2 weeks on escitalopram, continuation and up-titration (N=229) resulted in better response compared to duloxetine switching (N=245) 5. In the present study, we could not identify any timing of switching that indicated a better response; however, we were not able to investigate specific hypotheses as the before mentioned studies. Hence, present evidence supports following guidelines before considering switching. Guidelines recommend antidepressant continuation for at least 4-6 weeks to be able to evaluate clinical response 1. Indeed, continuation and up-titration can lead to response as late as after 8 weeks 25.
Future trials may investigate mechanisms potentially explaining better response after switching to specific antidepressant drugs and whether an earlier time of switching may result in better treatment response. Particularly the finding that switching from a TCA to an SSRI improved treatment outcome was unexpected and may be explained by many factors, e.g. hepatic metabolism or effects on the immune system.
Strengths and limitations
GENDEP is a large, real-world partly-randomized trial, representing patients seen in everyday practice, i.e. with comorbid disorders, prior (failed) antidepressant treatment attempts and suicidal ideation. The close monitoring with weekly visits during 12 weeks of treatment and the large study population (only slightly smaller compared to previous trials that investigated switching between TCAs and SSRIs 7,14) support our findings. Furthermore, the investigated drugs escitalopram and nortriptyline target different receptors, which is an important clinical aspect to consider when switching medication.
Regarding limitations, we did not compare the effect of switching with patients randomized to continuation treatment or other approaches such as augmentation. Hence, we are not able to distinguish specific drug response from spontaneous remission and we cannot evaluate whether other treatment approaches, e.g. augmentation, may have resulted in better treatment response. Furthermore, patients switched at very different time points based on clinical evaluation. This limited the possibility to investigate whether switching at specific time points may result in better treatment effects. In addition, compliance was high (98.4%) but primarily measured via self-reported pill counts.
Conclusion
In the case of a patient with side effects or non-response despite sufficient dose and treatment duration, switching to an antidepressant with a different receptor profile may be one strategy to improve antidepressant treatment response. Our findings indicate that even switching from a TCA to an SSRI may improve the antidepressant treatment effects. Future large trials need to include patients with MDD and non-response after antidepressant treatment of sufficient length and dose and compare 1) different randomized intervention groups (e.g., continuation/up-titration, augmentation, or switching), 2) include several antidepressant drugs with different receptor profiles, and 3) explore the importance of specific timing of the new intervention (e.g., early versus late switching).
Supplementary Material
Acknowledgements
None.
Funding:
The Genome-Based Therapeutic Drugs for Depression (GENDEP) study was funded by a European Commission Framework 6 grant (EC Contract Ref LSHB-CT-2003-503428). Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. The funders had no role in the design and conduct of the study, in data collection, analysis, or interpretation, or in writing the report.
Footnotes
Conflicts of interest:
Dr. Aitchison holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. Dr. Aitchison has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. Dr. Souery has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. Drs. Farmer and McGuffin have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline. The other authors report no financial relationships with commercial interests.
Authors contributions:
OKF, ERL, OM, and RU designed the present study. OKF performed all analyses with help from RU and ERL. OM supervised all steps. The other authors were principal investigators on the GENDEP study. The results were discussed with all authors. OKF wrote the first draft of the manuscript which was reviewed and approved of all authors.
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