Patient Management Exercise for Genetics and Genomics

Alison is a 24-year-old woman who was referred to you by her primary care physician for the management of major depression. She had initially sought care there but has been referred for specialty care because she is still ill despite two trials of pharmacotherapy. The patient's chief complaint is “I'm still sad and crying all the time; why can't I feel better?”

Alison is a single woman of mixed European and Native American ancestry. She reported that she had a happy childhood and adolescence, growing up in an intact nuclear family, the eldest of three children. She reported that she had some periods of emotional turmoil while in college, usually related to the end of a romantic relationship, but these were all self-limited, and each time resolved within about 3 weeks. She is now pursuing graduate studies in political science and working part-time as a research assistant in her department. Her current episode began about 6 months ago, in the wake of a boyfriend moving out of town for work and ending their relationship; this time she was unable to “bounce back,” and she sought care with her primary care physician because she developed a large number of symptoms and started to have trouble with her academic obligations. Her present symptoms include depressed mood, insomnia, guilt-filled ruminations, loss of appetite with weight loss (about 15 pounds), low energy, difficulty concentrating on her studies and job, and dramatic curtailment of any pleasurable activities (including making up excuses not to go out with her circle of friends). She denied feeling any suicidal thoughts or impulses. Aside from these periods of distress after break-ups, she has no other history of emotional, behavioral, or other neuropsychiatric condition, including no history of substance use or of any other major axis I or axis II diagnosis. Review of systems revealed cyclic low back pain with menstrual cramping. Her family history is notable for breast cancer in an aunt and for the absence of any psychiatric diagnoses.

In the consultation request and chart notes, her primary care physician indicated that prior efforts with antidepressant medication trials have been unsuccessful. These included a trial of fluoxetine, for which she could not tolerate doses greater than 20 mg/day without profound nausea and anxiety; her maximum exposure was 20 mg/day for 4 weeks. She also tried venlafaxine but also found the dose was limited by tolerability concerns and felt “buzzy” with an uncomfortable level of agitation at 75 mg and higher; her maximum tolerable experience was 37.5 mg/day for 5 weeks. She was still taking that dose at her initial visit with you.

As you collected your own history and examination data, you asked about her experience with other medications. She told you that she often has to take “baby doses” of many medications and described that when she took an over-the-counter cold preparation a few years ago, she became “loopy” and it took a few days for that side effect to wear off; you asked and she clarified that it was probably one containing dextromethorphan. She also related that, in her teen years, she sprained her ankle in a sports accident and had to go back to her pediatrician for a different pain medication when “the codeine the ER [emergency room] doctor gave me didn't do a thing.”

Alison would have to pay out of pocket for psychotherapy, a financial stretch for a graduate student, so you and she agree that a trial of mirtazapine augmentation may help address her symptoms, including insomnia, and other aspects of her current distress. She calls after 3 days, saying that she has had to stop taking mirtazapine, because she was so sedated that she missed class.

You discuss over the phone the potential for genotyping, and your suspicion that she may not metabolize medications in a typical way. She has read a lot about the science of genetics in medical care and has a friend who sent her blood away for genotyping “out of curiosity” and is intrigued. She returns to your office for phlebotomy and formal genotyping. Phenotypically, she appears to be a “slow metabolizer” in the cytochrome P450 system 2D6 enzymatic pathway, which figures prominently in the metabolism of many medications; this would explain both her difficulty in tolerating medications that are substrates for 2D6 and the lack of efficacy of codeine, which must be converted from an inactive prodrug form by 2D6 to produce analgesia.

The results of her testing confirm that she has two inactive genes for CYP2D6. You discuss with her the option to treat her with a medication that is considerably metabolized by other hepatic enzymatic pathways. You also counsel her to tell future physicians that she is a “slow metabolizer for 2D6” and should not bother trying to use codeine for pain relief.

After a discussion of the risks, benefits, and side effects of several other treatments, she opts for sertraline and over the next few weeks you have her titrate to a dose of 150 mg/day. At that point, she finds that her symptoms are resolving, and, after 6 weeks, she reports that she is in remission, with a self-rated 16-item Quick Inventory of Depressive Symptomatology score of 3.