Meta-Analysis of Antidepressant Augmentation: Piling on in the Absence of Evidence

By Yury, Craig A.; Fisher, Jane E. et al. | Ethical Human Psychology and Psychiatry, October 1, 2009 | Go to article overview

Meta-Analysis of Antidepressant Augmentation: Piling on in the Absence of Evidence


Yury, Craig A., Fisher, Jane E., Antonuccio, David O., Valenstein, Marcia, Matuszak, Jeremy, Ethical Human Psychology and Psychiatry


Background : Treatment of depression with a single pharmaceutical agent often does not work, and several agents may be tried or combined to increase efficacy. Augmentation involves the addition of one or more medications to an existing antidepressant monotherapy to enhance mood and overall antidepressant response. Approximately 22% of individuals with unipolar depression are prescribed augmentation strategies. This study examined the effectiveness of augmentation strategies. Methods : A Medline search of studies published before January 1, 2007 was conducted to assess the extent of published data on the most frequently prescribed augmentation strategies. Studies with completed original data, sufficient efficacy data, and participants diagnosed with unipolar depression were included. Letters to the editor, preliminary data, data only presented at conferences, and small uncontrolled case reports were excluded. Results: 13 studies contained sufficient data to calculate an effect size. Mean estimated effect size of all 13 studies calculated with random effects was 0.1782 with a 95% confidence interval of -0.2513-0.6076. Conclusions : There are minimal published data examining antidepressant augmentation, and augmentation is a minimally effective treatment option.

Keywords: meta-analysis; depression; antidepressant; augmentation

Major depressive disorder affects approximately 14.8 million adults in the United States (Kessler, Chiu, Demler, & Walters, 2005) and is the leading cause of disability in the United States for persons between 15 and 44 years of age (World Health Organization [WHO], 2004). The volume of antidepressants sold, and presumed to be consumed, per day in the major developed world is reflective of the prevalence of depression. A comparison of retail and hospital sales of antidepressants in eight major developed countries in 1998 revealed an average of 28 defined daily doses (DDDs) per 1,000 population per day (McManus et al., 2000). The volume of antidepressants sold meets the recommended daily dosage for approximately 3% of the developed world's population.

Antidepressant therapy can be administered as a monotherapy, a series of monotherapies, or as augmentation. Monotherapy is defined as a patient taking only one prescribed antidepressant. A series of monotherapies occurs when administration of one antidepressant is stopped and a new antidepressant is administered. This pattern may repeat itself several times. Augmentation involves the addition of one or more medications to an existing antidepressant monotherapy to enhance mood and overall antidepressant response.

Treatment-resistant depression is commonly defined as an inadequate clinical response, including nonresponse, following at least two trials of properly prescribed antidepressant therapy among patients suffering from depression (Fava & Rush, 2006). It is estimated that at least 50% of individuals who begin treatment with antidepressant monotherapy do not respond, and as many as 30% of individuals treated for major depressive disorder do not benefit from a series of monotherapy trials (Thase, 2004). In addition, full and persistent remissions are uncommon in acute depression trials (Thase, 2004). For example, selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors tend to show remission rates of 25% to 45% in acute trials (Thase, Entsuahm, & Rudolph, 2001). Only 20% to 30% of patients experience a full remission of their depressive symptoms during the first antidepressant trial (Fava & Davidson, 1996; Fava et al., 2003).

Prescribers may pursue a variety of strategies to increase the probability of full remission with antidepressant monotherapy (Fava & Rush, 2006). These options include (a) psychoeducation, (b) enhancing treatment adherence, (c) ensuring adequacy of antidepressant dose, (d) ensuring adequacy of antidepressant treatment duration, (e) prescribing antidepressant medications with relatively greater efficacy in specific subtypes or populations, and (f) psychotherapy (Fava & Rush, 2006). …

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