Question 1

A 58-year-old woman with type 2 diabetes presents with major depression (PHQ-9 of 16) and bilateral burning pain in her feet that her primary care provider has diagnosed as diabetic peripheral neuropathy. She rates the foot pain 7/10 and says it disrupts her sleep. She is not currently on any psychotropic medications. Which antidepressant best addresses both of her diagnoses?

Accepted Answer

This is the classic duloxetine question. The patient has two diagnoses that duloxetine treats simultaneously through a single mechanism. Escitalopram (answer A) would treat the depression but SSRIs do not have meaningful evidence for neuropathic pain (serotonin alone is insufficient for descending pain modulation). Bupropion (answer C) does not treat pain and has no evidence for neuropathic pain. Gabapentin (answer D) would treat the pain but not the depression, requiring two medications where one would suffice. Duloxetine addresses both diagnoses through balanced SERT/NET inhibition that modulates mood centrally and strengthens descending pain inhibition in the spinal cord.

Question 2

A 44-year-old man with depression and fibromyalgia has been on duloxetine 60mg for 4 months with significant improvement in both mood and pain. At his follow-up visit, routine labs reveal ALT of 180 U/L (normal below 40) and AST of 145 U/L (normal below 40). He denies alcohol use and has no prior liver history. He feels well. What is the most appropriate next step?

Accepted Answer

ALT and AST elevations to 4–5 times the upper limit of normal in a patient on duloxetine are a clinically significant signal that cannot be ignored. Duloxetine's labeling specifically warns about hepatotoxicity, including rare cases of hepatic failure. Continuing the medication (answer A) risks further hepatic injury. Dose reduction (answer C) is insufficient when transaminases are this elevated because the hepatotoxicity concern is not clearly dose-dependent. Adding hepatoprotective agents (answer D) is not a substitute for removing the likely offending agent. The correct response is to stop duloxetine, evaluate for other causes of transaminitis (viral hepatitis, other hepatotoxic exposures), and select an alternative medication for both depression and fibromyalgia. Venlafaxine treats depression (and has some pain evidence) without the hepatotoxicity signal. Pregabalin treats fibromyalgia without hepatic risk.

Question 3

A patient with depression has been on venlafaxine 75mg for 8 weeks with partial response. She reports persistent fatigue, low motivation, and diffuse body aches that she attributes to her depression. She has no diagnosed pain condition. Her provider is considering increasing venlafaxine or switching to duloxetine. Which is the better pharmacological rationale?

Accepted Answer

This question tests whether students understand the dose-dependent mechanism of venlafaxine versus duloxetine's balanced profile. At 75mg, venlafaxine is functionally an SSRI (as taught on the venlafaxine page). The patient's partial response, fatigue, and somatic complaints suggest she needs norepinephrine engagement, which venlafaxine provides at 150mg+. Switching to duloxetine (answer B) would provide balanced SNRI activity, but the body aches are not a diagnosed pain condition (they may be somatic symptoms of depression that respond to any adequate antidepressant treatment). The switch adds transition complexity without a clear advantage over simply titrating the medication she is already on. Increasing venlafaxine (answer A) is correct pharmacologically but incomplete without acknowledging that switching to duloxetine is also reasonable. Bupropion (answer D) would address fatigue but would not provide the serotonergic support her depression likely still needs, and it has no pain data. The best answer acknowledges the pharmacological equivalence of the two approaches while noting the practical advantage of optimizing before switching.

Duloxetine

Side Effects Worth Knowing

Nausea: the most common early side effect

Sexual Dysfunction: SNRI class effect

Blood Pressure Elevation: norepinephrine-mediated

Dizziness: common, multifactorial

Dry Mouth: moderate

Constipation: noradrenergic contribution

Hepatotoxicity: rare but specific to duloxetine

Discontinuation Syndrome: present but generally less severe than venlafaxine

Sweating: norepinephrine-mediated

See This Medication in Action

References & Further Reading