Is Pharmacogenetic Testing Used—and Useful—in Clinical Practice?
For years, we have read articles about the promise of pharmacogenetic testing to help us choose and monitor medication treatment. But relatively few psychiatrists actually use the cytochrome P450 (CYP450) genotyping tests that are available, and the last time we wrote about the topic (TCPR, August 2007), our expert opined that they added little of value to clinical decision making.
Basically, the currently available tests can tell you whether a patient will metabolize certain drugs “rapidly” or “slowly.” Presumably, one might use this data to increase or to decrease the dose, or to switch to a different drug altogether.
But how useful has genotyping been in real psychiatric settings? In a retrospective study, a Danish group reviewed the charts of all inpatients who received CYP450 testing upon admission to a mental health center between 2003 and 2009. Of 967 patients who had received the testing, 117 (12%) were found to be either “ultrarapid” or “poor” metabolizer for CYP2D6 or CYP3C19.
Most of these (101, or 86%) were actually treated with drugs metabolized by the enzyme(s) for which they had deviant results. However, this fact was noted in the chart in only about half (53) of these cases, and only 28 received “further action,” which was usually documented as “clinical observation” or “monitor drug concentration.”
The researchers observed that CYP450 testing was poorly adopted in daily clinical practice. Psychiatrists rarely actually used the test results, due to various factors: they were ordered by a different physician than the one responsible for long-term management; the results sometimes arrived after medication decisions had been made; they may have been hidden in the electronic medical record; or there were at times combined with other test results and often ignored.
The researchers didn’t elaborate on clinical outcomes, so we don’t know whether the CYP-tested patients fared better, nor whether patients receiving CYP450-dependent drugs experienced any adverse effects. The purpose of the study was strictly to describe how testing affected medical decision-making (Jürgens G et al, Acta Psychiatr Scand 2011;1–10:online ahead of print).
TCPR’s Take: The value of CYP450 genotyping in psychiatry is still in question. Even where testing is widely performed, psychiatrists rarely use the results and appear to make medication decisions the old fashioned ways—by assessing response or getting blood levels of drugs. This study was conducted on inpatients; it’s arguable that in outpatient practice the physician who ordered the test would almost surely be the same one getting the results. It is unclear from this study whether this implies that the testing has little utility or that psychiatrists need to learn how to better use the results—or some combination of the two.
How Risky is Pregnancy for Women with a History of Mood Disorders?
We know that the postpartum period is a risky time for women who have a history of depression, especially if they experienced postpartum depression in the past. But several questions about mood and pregnancy are still unanswered. Is pregnancy itself somehow protective against depression? Are women with a history of bipolar disorder at a much higher risk of postpartum depression than women with a history of unipolar depression? Researchers recently set out to answer these questions in a retrospective study of clinical data over a thirty year period.
Researchers studied 2,252 pregnancies in the period from 1980 to 2010 in centers in two Italian cities and Boston, Mass. Women included in the study had DSM-III or DSM-IV diagnoses of bipolar I, bipolar II, or recurrent major depressive disorder, and they were all receiving psychiatric treatment, often with medications.
Among women with bipolar disorder, 23% had “illness episodes” (defined as either a depressive, manic, or severe anxiety episode; the majority were depressive episodes) during pregnancy, and 52% had illness episodes postpartum (defined as up to six months after birth). The numbers were quite different among women with unipolar depression: 4.6% of these women had episodes during pregnancy vs 30% postpartum.
The most prominent risk factors predictive of a mood episode in these women were the following: younger age at onset of mood disorder; previous postpartum episode; fewer years of diagnosed illness; and having bipolar disorder rather than unipolar depressive disorder (Viguera AC et al, Am J Psychiatry 2011;168:1179–1185).
TCPR’s Take: These figures are useful in counseling our patients about their risk for mood episodes should they become pregnant. Women with bipolar disorder have the greatest risk of doing poorly during both pregnancy and during the postpartum period. Women with a history of depression may have no greater than baseline risk of depression during pregnancy, but the postpartum risk shoots up to 30%. These figures will help us guide our patients through the tricky territory of risks vs benefits of medications during pregnancy and after delivery.
FDA Publishes Article Critical of Vilazodone Data
It has been over a year now since the approval of vilazodone (Viibryd). As you may recall from our review of the drug in TCPR April 2011, vilazodone is an SSRI with partial agonism at the 5HT1A receptor. This “dual mechanism” of action means that one can think of the drug as though it combines an SSRI with buspirone (which also is a partial 5HT1A agonist). We predicted that vilazodone would be pushed as a “low sexual side effect” alternative to standard SSRIs. While we do not allow drug reps into our offices at Carlat Publishing, our moles in the field have told us that drug reps have indeed been aggressively brandishing data regarding Viibryd’s sexual side effects.
Recently, the FDA, in what may be an unprecedented move, published an article essentially warning practitioners not to believe the hype about the drug. The article, published in the Journal of Clinical Psychiatry, summarizes various aspects of the FDA review of the vilazodone data submitted by Forest, the manufacturer. In their review, the FDA dispels two myths, and offers up one point of caution about the drug.
Myth #1: Vilazodone works faster than other antidepressants. This was based on one of Forest’s trials that showed that vilazodone separated from placebo by week one. The FDA points out two problems. First, this data was from Trial 04, which was only one of two large trials submitted as part of the new drug application. In the other trial, Trial 07, vilazodone did not separate from placebo until week four. Second, neither trial compared vilazodone with an already approved SSRI, meaning that no statements can be made about the new drug working faster than existing antidepressants.
Myth #2: Vilazodone causes less sexual dysfunction than other antidepressants. The major problem is that vilazodone was not compared to an antidepressant known to cause sexual dysfunction. Beyond that, the FDA points out that even the results comparing vilazodone to placebo were inconsistent, “showing worsening on some items and improvement on others.”
And finally, a warning: vilazodone is a dosing challenge. The 20 mg dose may not be effective, as it was not adequately tested. This is why the manufacturer states that 40 mg is the recommended dose. The problem is that in order to prevent common vilazodone GI side effects of nausea and diarrhea, we are supposed to titrate gradually by starting at 10 mg for a week, then 20 mg for a week, then ending at 40 mg. Go above 40 mg, and the drug is “poorly tolerated,” according to the FDA. What happens if a patient can’t even tolerate the bump up to 40 mg? You might be tempted to go back to 20 mg for a while, but the 20 mg dose is not clearly effective. The entire process will mean lost time for some patients who are suffering (Laughren TP et al, J Clin Psychiatry 72(9):1166–1173).
TCPR’s Take: The bottom line is that vilazodone has no proven advantages over other SSRIs, and it has special dosing issues that present challenges that are absent in other SSRIs. For these reasons, we recommend that you relegate vilazodone to second-line status in your quiver of remedies.