1. Duloxetine
Flavio Guzman, MD

2. Overview SNRI approved for depression, GAD and pain conditions
Metabolized by CYP1A2 and CYP2D6
Avoid in patients with hepatic impairment
40-60 mg/day in depression
60 mg/day in GAD

3. Pharmacodynamics

4. Duloxetine – Pharmacodynamics
High affinity for:
SERT
NET
In vitro: more “balanced” SNRI:
Greater SERT and NET affinity than venlafaxine
Clinical significance unclear
Frampton, James E.. Plosker G. "Duloxetine." CNS drugs 21.7 (2007):

5. Indications

6. Duloxetine: FDA-Approved Indications
Major depressive disorder
Generalized Anxiety Disorder (GAD)
Pain conditions:
Diabetic Peripheral Neuropathic Pain (DPNP)
Fibromyalgia (FM)
Chronic Musculoskeletal Pain
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

7. First-line agents for generalized anxiety disorder
SSRIs
Escitalopram
Sertraline
Paroxetine
Paroxetine CR
SNRIs
Duloxetine
Venlafaxine XR
Other
Agomelatine
Pregabalin
Katzman, Martin A., et al. "Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders." BMC psychiatry 14.Suppl 1 (2014): S1.

8. Duloxetine: Off-Label Uses
Can significantly improve the quality of life of patients with SUI
Unclear whether or not benefits are sustainable.
Stress Urinary Incontinence
Mariappan, Paramananthan, et al. "Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review." European urology 51.1 (2007):

9. Pharmacokinetics

10. Duloxetine Pharmacokinetics
CYP2D6 inhibitors
Paroxetine
Fluoxetine
CYP1A2 inhibitors
Fluvoxamine
Quinolone antibiotics
Inactive metabolites
Knadler MP, et al. Duloxetine: clinical pharmacokinetics and drug interactions. Clinical pharmacokinetics. 2011;50(5):

11. Duloxetine Pharmacokinetics
moderate inhibitor
CYP2D6 substrates
Tricyclic antidepressants
Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clinical pharmacokinetics. 2011;50(5):

12. Duloxetine Adverse Effects
Common side effects:
Nausea (similar to fluoxetine and paroxetine)
Insomnia
Serotonergic adverse effects:
Sexual dysfunction
Discontinuation syndrome:
Should be tapered
Gupta S et al. Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Annals of Clin Psych. 2007;19(2):

13. Duloxetine and hypertension
Placebo
Systolic BP
0.5 mmHg
0.6 mmHg
Diastolic BP
0.8 mmHg
0.3 mmHg
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

14. Duloxetine and hypertension
“BP should be measured prior to initiating treatment and periodically measured throughout treatment”
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

15. Duloxetine – Adverse Effects
Hepatic adverse effects:
Patients with Hep C and severe alcoholism
Might exacerbate abnormal liver functions
Avoid in this population
Urinary hesitation
Rare event
NE: increase in urethral resistance
Gupta S et al. Duloxetine: review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Annals of Clin Psych. 2007;19(2):

16. Prescribing information

17. Dosage forms and strengths
20 mg
Delayed-release capsules
20 mg
30 mg
60 mg
30 mg
60 mg
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

18. Duloxetine dose range 60 mg/day 60 mg/day GAD Diabetic neuropathy
Fibromyalgia
Chronic musculoskeletal pain
Depression
40 mg/day
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

19. Depression dosing 30 mg 60 mg 30 mg 20 mg 20 mg 60 mg/day Depression
Maximum dose: 120 mg/day
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

20. Generalized anxiety disorder dosing
60 mg/day
60 mg
GAD
Maximum dose: 120 mg/day
Cymbalta (Duloxetine) [Prescribing Information] Indianapolis, IN: Eli Lilly, Inc. Accessed November 2014

21. End of presentation