7 Common Mistakes With Antidepressants

Nearly half of patients with depression have significant anxiety.¹ Buproprion is often avoided in these cases out of concern that it won’t work or will make the anxiety worse. Why is this a mistake? Because patients miss out on buproprion’s favorable tolerability, which stands out for its low incidence of sexual dysfunction, fatigue, weight gain, and withdrawal problems. Also, the evidence doesn’t support those concerns about anxiety.

Buproprion may not treat anxiety disorders, but it’s nearly as good as the SSRIs at relieving anxiety when it’s part of a major depressive episode. The SSRIs do have an advantage in anxious depression, but it’s very slight – you’d need to treat 17 patients to see a difference in 1 – according to a meta-analysis of 10 randomized controlled trials of depression with anxiety, several of which were head-to-head active comparison trials.²

In terms of sleep, buproprion causes initiation insomnia at about the same rate of other antidepressants, but unlike the SSRIs it improves sleep quality.

When treating depression, tricyclics, antipsychotics, and paroxetine are the main drivers of anticholinergic effects, but nearly all the antidepressants have some anticholinergic effects. Those effects add up with polypharmacy, including over-the-counter medications like diphenhydramine (Benadryl) and doxylamine (Unisom). The Anticholinergic Burden score (ACB) helps you gauge the problem.

Dry mouth, constipation, memory problems, falls, urinary tract infections, and a worsening of cardiac and respiratory health are among the ways that they wear down the body. These problems don’t tend to get better with time but do worsen with advancing age. An Anticholinergic Burden Score above 3 was associated with a 50% increase in the rate of death over a 3 month period in depressed residents of nursing homes over age 65.3

Among patients who take serotonergic antidepressants, 1 in 2 will encounter discontinuation issues and the problem will be severe for 1 in 4.⁴ The shorter the half life, the bigger the problem. One exception to this rule is paroxetine, which has a decent half-life (21 hours) but ranks alongside venlafaxine for the worst discontinuation challenges. The likely reason is that paroxetine inhibits its own metabolism at the CYP-2D6 enzyme, and that enzyme revs up when paroxetine is stopped, effectively shortening its half life.⁵

Extended release coatings don’t reduce discontinuation issues, much because they slow down the rate of entry but not the rate of exit.

The SSRIs are all about equal in terms of efficacy and tolerability. Instead, it’s drug interactions and withdrawal problems that set them apart. Fluoxetine, paroxetine, duloxetine, and high-dose sertraline (≥ 150 mg/day) are potent inhibitors at a metabolic enzyme that claims many victims in the pharmacopeia: CYP-2D6. That leaves citalopram and escitalopram as the safer alternatives, and with citalopram’s black-box warning about QTc prolongation only escitalopram is standing.⁵

CYP-2D6 inhibitors usually raise the levels of other drugs, but there is an important exception in the opioid category. Codeine, oxycodone, hydrocodone, and tramadol are all prodrugs that are converted into active metabolites by CYP-2D6*, which means these pain medications are likely to lose their analgesic effects when patients start an antidepressant that inhibits their conversion at CYP-2D6.⁶

*These opioids are metabolized into morphine (from codeine), oxymorphone (from oxycodone), hydromorphone (from hydrocodone), and O-desmethyl-tramadol (from tramadol).

^References

^{1. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn't bupropion the most frequently prescribed antidepressant? J Clin Psychiatry 2005;66(5):603-610.}

^{2. Papakostas GI, Stahl SM, Krishen A, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies. J Clin Psychiatry, 2008;69(8):1287-1292.}

^{3. Chatterjee S, Bali V, Carnahan RM, Chen H, Johnson ML, Aparasu RR. Risk of mortality associated with anticholinergic use in elderly nursing home residents with depression. Drugs Aging. 2017;34(9):691-700.}

^{4. Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav. 2019;97:111-121.}

^{5. Carlat D (2015). Drug Metabolism in Psychiatry: A Clinical Guide, 3rd Edition. Carlat Publishing, Newburry MA.}

^{6. Ruano G, Kost JA. Fundamental considerations for genetically-guided pain management with opioids based on cyp2d6 and oprm1 polymorphisms. Pain Physician. 2018;21(6):E611-E621.}

^{7. Womersley K, Ripullone K, Agius M. What are the risks associated with different selective serotonin reuptake inhibitors (SSRIs) to treat depression and anxiety in pregnancy? An evaluation of current evidence. Psychiatr Danub. 2017;29(Suppl 3):629-644.}

^{8. Turner E, Jones M, Vaz LR, Coleman T. Systematic review and meta-analysis to assess the safety of bupropion and varenicline in pregnancy. Nicotine Tob Res. 2019;21(8):1001-1010.}

^{9. Kato M, Hori H, Inoue T, Iga J, Iwata M, et al. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2020 Jul 23.}

^{10. Trivedi MH, Dunner DL, Kornstein SG, Thase ME, Zajecka JM, et al. Psychosocial outcomes in patients with recurrent major depressive disorder during 2 years of maintenance treatment with venlafaxine extended release. J Affect Disord. 2010 Nov;126(3):420-9.}

^{11. Baldessarini RJ, Lau WK, Sim J, Sum MY, Sim K. Duration of initial antidepressant treatment and subsequent relapse of major depression. J Clin Psychopharmacol. 2015;35(1):75-6.}

^{12. Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010 Aug;167(8):934-41.}

^{13. Groot PC, van Os J. Outcome of antidepressant drug discontinuation with taperingstrips after 1-5 years. Ther Adv Psychopharmacol. 2020 Sep 2;10:2045125320954609.}