Are doses greater than 60 mg for Cymbalta (duloxetine) no more effective for MDD or GAD? Can you talk more about the studies suggesting geriatrics and pediatrics may benefit from higher doses?

Comment by InpharmD Researcher

Duloxetine has demonstrated efficacy in both older adults and pediatric patients using flexible dosing regimens ranging from 30 to 120 mg daily. In older adults, symptom improvement was observed across various dose levels, with some benefiting from doses above 60 mg daily. Pediatric studies suggest that doses of 60 mg or higher are often needed for clinical effect, though findings on efficacy have been mixed. Across both populations, the safety profile was consistent, with common adverse effects including somnolence, dry mouth, and gastrointestinal symptoms. For both major depressive disorder (MDD) and generalized anxiety disorder (GAD), doses greater than 60 mg/day of Cymbalta (duloxetine) have not been shown to provide additional clinical benefits, though some patients, such as geriatric or pediatric populations, may benefit from higher doses. Clinical trials comparing 60 mg and 120 mg doses found no significant difference in efficacy for MDD, with similar remission rates and tolerability between the two dosages. The prescribing label notes that while 120 mg/day can be effective, there is no evidence supporting greater efficacy beyond 60 mg/day for most adults.

Background

Two double-blind, randomized controlled trials investigated the efficacy and safety of duloxetine at 60 mg and 120 mg daily doses in patients with major depressive disorder (MDD). The first study focused on nonremitters and remitters after initial 6-week treatment, while the second study examined severely depressed hospitalized patients. In both trials, researchers found no significant clinical advantages of the 120 mg dose over the 60 mg dose. The first study revealed that nonremitters randomly reassigned to either 60 mg or 120 mg achieved similar remission rates (approximately 30%), with 85.5% of initial remitters maintaining their improvement. The second study, involving hospitalized patients with severe depression, demonstrated comparable outcomes across both dosage groups, with 67.3% of patients achieving remission by week 8. Adverse events were similar between groups, with minor variations such as increased hyperhidrosis and chest pain in the 120 mg group. Headache and nausea were the most frequently reported treatment-emergent adverse events. Both studies concluded that duloxetine was well-tolerated and showed comparable efficacy at 60 mg and 120 mg daily doses, suggesting that dose escalation may not necessarily provide substantial additional clinical benefits for most patients with major depressive disorder. [1], [2]

A 2014 study conducted across 47 sites in nine countries undertook a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of duloxetine in treating generalized anxiety disorder (GAD) among older adults aged 65 and above. The study employed a flexible-dose design, administering duloxetine at 30-120 mg once daily. The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) total score, with a primary endpoint at the 10-week mark. Secondary outcomes included evaluations of global functioning with the Sheehan Disability Scale (SDS), along with analysis of treatment-emergent adverse events, serious adverse events, laboratory analyses, and vital sign monitoring to assess safety and tolerability. Over the course of the trial, 48 (31.8%) patients in the duloxetine arm did not receive a dose escalation, remaining on the 30 mg dose. A total of 52 (34.4%) patients had one escalation to 60 mg, while 36 (23.8%) had two escalations to 90 mg, and 15 (9.9%) had three escalations to 120 mg. According to the findings detailed in the 2014 publication, duloxetine showed superior efficacy compared to placebo, as evidenced by significant improvement in HAM-A scores (mean change of -15.9 vs. -11.7, p<0.001) and SDS global scores (-8.6 vs. -5.4, p<0.001). These improvements were apparent from as early as four weeks and persisted throughout the 10-week study period. The incidence of treatment-emergent adverse events, such as dry mouth, constipation, and somnolence, was significantly higher among duloxetine-treated patients, though the safety profile remained consistent with previous studies. The results underscore duloxetine's potential as an effective treatment for alleviating anxiety symptoms in older adults with GAD, with manageable safety concerns. [3]

A 2015 randomized, placebo-controlled trial evaluated duloxetine in children and adolescents aged 7 to 17 years with GAD. Participants were randomized to receive flexibly dosed duloxetine (30-120 mg daily, n= 135) or placebo (n= 137) for 10 weeks, followed by an 18-week open-label extension with duloxetine. The mean duloxetine dose during the acute phase was 53.6 mg. At the end of the 10-week period, the last prescribed dose for duloxetine patients was 30 mg in 27.4%, 60 mg in 30.4%, 90 mg in 29.6%, and 120 mg in 12.6% of the patients. The most frequently used (modal) dose was 30 mg in 35.6%, 60 mg in 34.8%, 90 mg in 20.7%, and 120 mg in 8.9% of patients. Adherence was higher in the placebo group at the 2-week time point (98% vs. 91%, p<0.05), but no differences in adherence were observed after that. Mean Pediatric Anxiety Rating Scale (PARS) severity scores improved by -9.7 points with duloxetine compared to -7.1 points with placebo (p≤.001; Cohen's d = 0.5). Response rates (defined as ≥50% improvement on PARS) were 59% for duloxetine and 42% for placebo. Remission rates (PARS ≤8) were 50% for duloxetine and 34% for placebo, and functional remission rates (CGAS >70) were 37% and 24%, respectively (all p≤.05). No significant differences were observed between groups in blood pressure changes or discontinuation due to adverse events. However, duloxetine was associated with a higher incidence of gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations. Mean increases in pulse (+6.5 vs. +2.0 beats/min) and changes in weight (-0.1 kg vs. +1.1 kg) were significantly different between groups (p≤.01). The findings suggested that duloxetine demonstrated greater improvement in anxiety symptoms, response, and remission rates compared to placebo, with a safety profile consistent with previous findings in pediatric and adult populations. [4]

A 2004 open-label, single-arm study evaluated the long-term efficacy and safety of duloxetine in patients aged 65 and older with MDD based on DSM-IV criteria. A total of 101 patients received duloxetine at doses of 80 mg/day (40 mg twice daily) to 120 mg/day (60 mg twice daily). All patients began treatment with duloxetine 40 mg twice daily during the first week. If a patient could not tolerate this dose, it could be temporarily reduced to 20 mg twice daily, but they were required to return to 40 mg twice daily by Week 2. Patients who still could not tolerate 40 mg twice daily were withdrawn from the study. After the initial two weeks, dosing could be adjusted between 40 mg and 60 mg twice daily based on the physician’s assessment of the patient’s response and tolerability. Results showed significant reductions in mean the 17-item Hamilton Rating Scale for Depression (HAMD17) total scores from baseline to Weeks 6, 28, and 52 (-13.0, -17.4, and -17.5, respectively; all p<0.001). The the Clinical Global Impression of Severity (CGI-S) and patient-rated (PGI-I) assessments demonstrated significant improvement by Week 1, which was sustained through the end of the study. Observed case response rates were 62.9% at Week 6, 84.9% at Week 28, and 89.4% at Week 52. Remission rates at the same time points were 41.4%, 69.8%, and 72.3%, respectively. Adverse events led to treatment discontinuation in 26.7% (27 patients). Treatment-emergent adverse events reported by more than 10% of patients included dizziness, nausea, constipation, somnolence, insomnia, dry mouth, and diarrhea, most of which occurred early in treatment. Mean changes in blood pressure and body weight at study endpoint were minimal (less than 2.0 mm Hg and -0.1 kg, respectively). Overall, the study found duloxetine to be effective, safe, and well tolerated for long-term treatment of MDD in elderly patients. [5]

A 2012 open-label investigation explored the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients suffering from MDD. This study involved 72 children and adolescents aged 7 to 17 years, who were treated with a flexible dosing regimen of duloxetine ranging from 20 to 120 mg once daily. The dosage adjustments were made based on clinical improvements and individual patient tolerability. Pharmacokinetic samples were obtained intermittently across the dosing range, and the data were analyzed using population modeling techniques. Results showed that the majority of patients required doses of 60 mg or higher to achieve optimal efficacy, and the typical clearance of duloxetine in this younger cohort was notably higher than that observed in adults. An insightful discovery from this research highlights that pediatric patients generally tolerated duloxetine well within the studied dose range, although many experienced transient, potentially clinically significant elevations in blood pressure. Notably, adjustments in the daily dosage of duloxetine based on body weight or age were deemed unnecessary, suggesting that pediatric patients may not require different dosages relative to adults. The pharmacokinetic analysis revealed that factors such as age and body weight did not significantly affect duloxetine’s pharmacokinetic parameters, indicating that duloxetine’s pharmacokinetic profile is consistent across these subgroups. This foundational study provides crucial insights into the pediatric use of duloxetine for MDD, setting the stage for further extensive, controlled trials to confirm these findings and refine dosing regimens. [6]

Lastly, a 2014 double-blind study evaluated the efficacy and safety of flexible-dose duloxetine in children and adolescents with major depressive disorder over a 36-week period, including a 10-week acute phase and 26-week extension. A total of 337 patients were randomized to receive duloxetine (60-120 mg once daily, n= 117), fluoxetine (20-40 mg once daily, n= 117), or placebo (n= 103). Patients initiated duloxetine at 30 mg or fluoxetine at 10 mg daily, with automatic escalation to duloxetine 60 mg or fluoxetine 20 mg at Week 2. Duloxetine could be increased to 90 mg at Week 4 and 120 mg at Week 7 or later; fluoxetine could be increased to 40 mg at Week 4 or later. Placebo patients were transitioned to duloxetine at the start of the extension period, beginning at 30 mg daily with automatic escalation and flexible dosing thereafter. Neither duloxetine nor fluoxetine separated significantly from placebo on the primary efficacy endpoint: change in Children’s Depression Rating Scale-Revised (CDRS-R) total score from baseline to Week 10 (p<0.05). There were no statistically significant differences between treatment groups in serious adverse events, total treatment-emergent adverse events, or discontinuations due to AEs during the acute phase. No completed suicides, deaths, or clinically significant ECG abnormalities were observed. The trial results were deemed inconclusive, as neither active treatment demonstrated a statistically significant advantage over placebo at 10 weeks; however, the safety profile of duloxetine was consistent with that seen in adults, with no new safety concerns identified. [7]

References:

[1] Kornstein SG, Dunner DL, Meyers AL, et al. A randomized, double-blind study of increasing or maintaining duloxetine dose in patients without remission of major depressive disorder after initial duloxetine therapy. J Clin Psychiatry. 2008;69(9):1383-1392. doi:10.4088/jcp.v69n0905
[2] Brecht S, Desaiah D, Marechal ES, Santini AM, Podhorna J, Guelfi JD. Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for severe depression: a double-blind randomized trial. J Clin Psychiatry. 2011;72(8):1086-1094. doi:10.4088/JCP.09m05723blu
[3] Alaka KJ, Noble W, Montejo A, et al. Efficacy and safety of duloxetine in the treatment of older adult patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2014;29(9):978-986. doi:10.1002/gps.4088
[4] Strawn JR, Prakash A, Zhang Q, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2015;54(4):283-293. doi:10.1016/j.jaac.2015.01.008
[5] Wohlreich MM, Mallinckrodt CH, Watkin JG, Hay DP. Duloxetine for the long-term treatment of major depressive disorder in patients aged 65 and older: an open-label study. BMC Geriatr. 2004;4:11. Published 2004 Dec 7. doi:10.1186/1471-2318-4-11
[6] Prakash A, Lobo E, Kratochvil CJ, et al. An open-label safety and pharmacokinetics study of duloxetine in pediatric patients with major depression. J Child Adolesc Psychopharmacol. 2012;22(1):48-55. doi:10.1089/cap.2011.0072
[7] Atkinson SD, Prakash A, Zhang Q, et al. A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder. J Child Adolesc Psychopharmacol. 2014;24(4):180-189. doi:10.1089/cap.2013.0146

Relevant Prescribing Information

Dosage for Treatment of Major Depressive Disorder in Adults: [8]
While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment.

Dosage for Treatment of Generalized Anxiety Disorder: [8]
Adults: While a 120 mg once daily dosage was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment.
Geriatrics: Patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day.
Pediatrics: Some patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. The maximum dose studied was 120 mg per day.

Clinical Studies [8]
Generalized Anxiety Disorder
GAD Trial in Geriatric Patients
The efficacy of duloxetine in the treatment of patients greater than or equal to 65 years of age with GAD was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults greater than or equal to 65 years of age meeting the DSM-IV criteria for GAD (Study GAD-5). In Study GAD-5, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week acute treatment phase was 51 mg. Patients treated with duloxetine (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the HAM-A total score.

GAD Trial in Pediatric Patients 7 Years to 17 Years Old:
The efficacy of duloxetine in the treatment of pediatric patients 7 years to 17 years of age with GAD was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria) (Study GAD-6).

In Study GAD-6, the starting dosage was 30 mg once daily for 2 weeks. Further dosage increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score.

References:

[8] Cymbalta (duloxetine hydrochloride capsule, delayed release). Prescribing information. Eli Lilly and Company; 2024

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are doses greater than 60 mg for Cymbalta (duloxetine) no more effective for MDD or GAD?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


Use of effect size to determine optimal dose of duloxetine in major depressive disorder
Design

Analysis of 6 acute phase III clinical trials

N= 1619

Objective To determine the optimal dose of duloxetine in MDD.
Study Groups

Placebo (n= 632)

Duloxetine 40 mg/day (n= 177)

Duloxetine 60 mg/day (n= 251)

Duloxetine 80 mg/day (n= 363)

Duloxetine 120 mg/day (n= 196)

Inclusion Criteria

Outpatients aged ≥18 years meeting DSM-IV criteria for MDD, CGI-S score ≥4, HAMD17 total score ≥15

Exclusion Criteria

Primary Axis I disorder other than major depression, Axis II disorder interfering with compliance, treatment-resistant depression, serious medical illness, substance abuse or dependence within the prior year, positive drug screen, use of CNS medication, antihypertensive medication use

Methods

Effect size for duloxetine 40 mg, 60 mg, 80 mg, and 120 mg per day estimated using pooled data from 6 studies. Primary efficacy measure was HAMD17 total score. Tolerability assessed using pooled data.

Duration

8 or 9 weeks for acute therapy

Outcome Measures

Primary: HAMD17 total score change

Secondary: Response rates (50% reduction from baseline), remission rates (HAMD17 total score ≤7)

Baseline Characteristics Characteristics Placebo (n= 632) Duloxetine 40 mg/day (n= 177) 60 mg/day (n= 251) 80 mg/day (n= 363) 120 mg/day (n= 196)
Age (years), Mean (SD) 42.4 (13.0) 42.0 (13.0) 41.6 (13.1) 43.5 (12.6) 44.34 (10.7)
Female (%) 68.4 62.1 65.7 65.8 75.0
Ethnicity - Caucasian (%) 86.9 83.1 82.5 91.7 99.5
HAMD17 total score, Mean (SD) 19.7 (4.2) 18.1 (5.6) 20.9 (3.8) 19.2 (4.4) 20.8 (4.0)
CGI-severity, Mean (SD) 4.2 (0.6) 4.0 (0.8) 4.3 (0.5) 4.2 (0.6) 4.3 (0.7)
Results Endpoint Placebo (n= 632) Duloxetine 40 mg/day (n= 177) 60 mg/day (n= 251) 80 mg/day (n= 363) 120 mg/day (n= 196)
Effect size for change in HAMD17 total score 0 0.2 0.4 0.3 0.5
Effect size for remission rate 0 0 0.3 0.2 0.4
Effect size for response rate 0 0 0.3 0.2 0.4
Adverse Events

Discontinuation due to adverse events higher in duloxetine-treated patients compared to placebo. Common adverse events: nausea, dry mouth, dizziness, constipation. No clear dose-response relationship for TEAEs.

Study Author Conclusions

The effect size analyses demonstrate that duloxetine 40 mg has minimum efficacy, and that duloxetine 60–120 mg/day is effective in the treatment of patients with MDD. An initial dose less than 60 mg/day might provide better tolerability for some patients diagnosed with MDD.

Critique

The study effectively uses effect size analysis to determine optimal dosing of duloxetine, providing valuable insights into dose-efficacy relationships. However, the analysis is limited by the lack of direct statistical comparisons between doses due to study design, and the potential variability in pharmacokinetics across individuals, which may affect generalizability of the findings.

 

References:

Pritchett YL, Marciniak MD, Corey-Lisle PK, Berzon RA, Desaiah D, Detke MJ. Use of effect size to determine optimal dose of duloxetine in major depressive disorder. J Psychiatr Res. 2007;41(3-4):311-318. doi:10.1016/j.jpsychires.2006.06.013

Acute and Long-term Treatment of Late-Life Major Depressive Disorder: Duloxetine Versus Placebo
Design

Multicenter, 24-week (12-week short-term and 12-week continuation), randomized, placebo-controlled, double-blind trial

N= 370

Objective To compare the efficacy of duloxetine with placebo on depression in elderly patients with major depressive disorder
Study Groups

Duloxetine (n= 204)

Placebo (n= 95)

Inclusion Criteria Age 65 years or more with major depressive disorder diagnosis (one or more previous episode); Mini-Mental State Examination score ≥20; Montgomery-Asberg Depression Rating Scale total score ≥20
Exclusion Criteria History of bipolar, panic, or obsessive-compulsive disorder, psychosis, or schizophrenia; current primary axis I diagnosis other than MDD; serious suicidal risk; lack of response to two or more adequate doses of antidepressant therapy, or an adequate trial of duloxetine at any time; serious unstable medical illness or clinically significant laboratory abnormality
Methods Patients were randomized 2:1 to duloxetine (30 mg/day for 1 week, forced titration to 60 mg/day) or placebo for 12 weeks. Placebo rescue or duloxetine dose optimization was available if the patient had less than 50% improvement from baseline on the HAMD-17 Total score at week 12 or HAMD-17 total score more than 10 at weeks 16 or 20. Duloxetine-treated patients receiving treatment optimization received dose increases from 60 to 120 mg/day
Duration 24 weeks (12-week short-term and 12-week continuation)
Outcome Measures

Primary: Maier subscale of the 17-item Hamilton Depression Rating Scale (HAMD-17) at week 12

Secondary: Geriatric Depression Scale, HAMD-17 total score, Brief Pain Inventory (BPI), Numeric Rating Scales (NRS) for pain, Clinical Global Impression-Severity scale, Patient Global Impression of Improvement

Baseline Characteristics Characteristic Placebo (n= 95) Duloxetine (n= 204)
Age, years, mean (SD) 73.1 (5.64) 73.01 (6.26)
Female, n (%) 56 (58.9) 135 (66.2)
White, n (%) 70 (73.7) 160 (78.4)
Mini-Mental State Examination total score 28.4 (1.7) 28.6 (1.8)
HAMD-17, total score 19.3 (5.8) 19.4 (5.6)
BPI 24-hour average pain score 3.48 (2.6) 3.48 (2.7)
Results Endpoint Placebo (n= 95) Duloxetine (n= 204) p-value
HAMD-17 Maier subscale score at week 12 -3.90 (0.44) -4.34 (0.29) 0.397
GDS at week 24 -3.66 (1.00) -7.02 (0.58) 0.004
BPI average pain score (acute phase) -0.14 (0.18) -0.83 (0.13) <0.001
BPI average pain score (acute plus continuation phase) -0.37 (0.18) -0.87 (0.12) 0.013
Adverse Events

A significantly higher percentage of duloxetine-treated patients versus placebo discontinued due to adverse event (15.3% versus 5.8%). Common adverse events included dry mouth, constipation, diarrhea, and dizziness. Statistically significant pulse increase was observed in duloxetine-treated patients. A higher percentage of duloxetine-treated patients reported falls compared to placebo.

Study Author Conclusions

Although the antidepressant efficacy of duloxetine was not confirmed by the primary outcome, several secondary measures at multiple time points suggested efficacy. Duloxetine had significant and meaningful beneficial effects on pain.

Critique

The study provided valuable insights into the efficacy of duloxetine in elderly patients with MDD, particularly in terms of pain management. However, the primary outcome did not confirm antidepressant efficacy, and the study's design allowed for dosage adjustments that may have influenced results. The study's generalizability may be limited due to the specific inclusion criteria and the predominantly white study population.

References:

Robinson M, Oakes TM, Raskin J, Liu P, Shoemaker S, Nelson JC. Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo. Am J Geriatr Psychiatry. 2014;22(1):34-45. doi:10.1016/j.jagp.2013.01.019