David Antonuccio, PhD

It is estimated that at least half of persons who begin antidepressant treatment will not respond to monotherapy.

 When a single antidepressant is ineffective, the addition of 1 or more medications to enhance mood and overall antidepressant response is common.

 While it is hoped that such augmentation strategies will be effective, drug augmentation has drawbacks, including increased cost, unclear dosing strategies, and the possibility of drug-drug interactions.

 A review of augmentation strategies by Fava and Rush

 indicates that current evidence is primarily based on open, uncontrolled studies. The review further stated that lithium augmentation is well supported by controlled studies but was more common in the 1980s than today.

 detailed the frequency of antidepressant augmentation strategies used in 244,859 patients with a diagnosis of unipolar depression for whom antidepressants were prescribed in Veterans Affairs mental health settings. Twenty-two percent of patients were receiving an augmenting agent, most commonly a second antidepressant (11%) or a second-generation antipsychotic (7%). Based on this sample, it appears that antidepressant augmentation is common practice. The authors concluded that although lithium augmentation is the most well-supported approach, it is rarely prescribed. It is important to understand whether the most frequent augmentations are supported by scientific evidence. With that in mind, we examined the literature on augmentation strategies for the most frequently prescribed augmentations for unipolar depression as identified by Valenstein and associates.

We conducted a PubMed search of studies published before January 1, 2007, to find articles containing medications (using the generic name) or class of drug in the title, abstract, or keywords. Only completed original data articles with efficacy data and that studied participants with a diagnosis of depression were included.	

We found 22 studies for the most common augmentation strategies. 

 displays the most common augmentation classes according to Valenstein and associates

 and the percentage of patients for whom these augmentations were prescribed, as well as the number of studies using these augmentations.

The most commonly prescribed classes of augmentation with a second antidepressant are not well supported. Two of the most frequently prescribed of these combinations-addition of a noradrenergic and specific serotonergic antidepressant (NaSSA) to a norepinephrine-dopamine reuptake inhibitor (NDRI) and addition of an NDRI to a serotonin-norepinephrine reuptake inhibitor (SNRI)-have no published data to support them.

The augmentation of an SSRI with an atypical antipsychotic had the most evidence, with 11 studies, 3 of which used a placebo control. The second-most frequently prescribed antidepressant-antipsychotic augmentation strategy (adding an atypical antipsychotic to an NDRI) has no published data available.

The limited amount of available data is problematic, as is the design or quality of the research. Comparisons vary widely, including studies comparing augmentation strategies with other combination strategies, individual drugs, the augmentation drug by itself, and placebo control groups. Only 6 studies used a placebo control-3 with augmentations with antidepressants and 3 with augmentations with antipsychotics. Of the placebo controls, 5 studies used a placebo augmentation and 1 used a monotherapy placebo group.

Although data from a class of drugs are considered applicable for specific drugs within that class, we examined whether the most frequently prescribed drugs are also the most frequently studied drugs. 

displays the top augmentations and the number of times results of an examination of each combination was published in an article.

Using our search strategy, we were unable to locate any published studies for the most frequently prescribed antidepressant augmentation (bupropion augmented with sertraline), and 4 of the 9 most frequently prescribed antidepressant augmentations do not appear to have any published data. We were unable to locate any published studies on the top 2 antipsychotic augmentations (sertraline augmented with risperidone or with olanzapine), and 7 of the 10 most frequently prescribed antipsychotic augmentations do not appear to have any published data available. With the possible exception of the combination of fluoxetine and olanzapine, no combination appears to have sufficient published data to meet the FDA standard for initial approval of at least 2 positive placebo-controlled studies.

Safety was rarely the focus of these studies; most emphasized efficacy issues. We attempted to evaluate the quality of the presentation of the safety data when available. Of the 22 studies, 3 had no safety data, 8 had a safety section, 3 had a comparison with a placebo group, 16 had safety statistics, and 17 had a description of the adverse effects or events (some studies fit more than one of these categories).

It is important to specifically mention the STAR*D study, a large trial that included some augmentations.

 The STAR*D was a practical effectiveness trial that had no placebo comparisons. In the trial, patients whose depression had failed to respond to citalopram and who agreed to be randomized to augmentation strategies received either 12 weeks of bupropion or buspirone added to citalopram in phase 2 of the trial. Such augmentation resulted in up to 39% remission, with a subsequent relapse rate of up to 67%.

Subsequent augmentations in the STAR*D study had even lower remission and higher relapse rates. Without a placebo comparison, the interpretation of these results is difficult. It could be argued that any further response was positive among patients who had failed to respond to prior trials. However, one might also consider these results disappointing and conclude that they reflect an unfavorable risk-benefit ratio, given that about 4% of patients experienced a serious adverse event from the first augmentation and that about 13% had to discontinue participation because of intolerance of adverse effects.

In the modern era of evidence-based medicine, augmentation should ideally be guided by existing evidence. Researchers have noted a lack of studies to guide the sequence of augmentation strategies and the identification of patients for whom specific strategies might be most helpful.

 The data summarized here show that more than 40% of the most popular classes of augmentation strategies and more than 55% of the most frequently prescribed combinations of drugs used for augmentation for unipolar depression have no published scientific support. In addition, placebo-controlled comparisons are rare. Statements about safety and efficacy for almost all the most commonly used augmentation strategies appear to be premature. The strategy with the most scientific support (ie, lithium augmentation) is relatively rarely used.	

Many of these medications have been available for 2 decades, yet data on the most common augmentation strategies continue to be extremely limited. The recent publication of a major augmentation study on bipolar patients offers some hope that the science of drug augmentation is beginning to evolve.

 For now, it may be prudent for clinicians and patients to consider the sparse scientific data supporting most augmentation strategies when deciding whether to augment antidepressants. A clinical approach geared to "first do no harm" would suggest that most common augmentation strategies be used judiciously until there are more data to support the practice. It will be important to conduct future scientific studies of efficacy and safety in order to understand the risk of unknown harm for augmentation treatment strategies of unknown benefit.

 Thase ME. Therapeutic alternatives for difficult- to-treat depression: a narrative review of the state of the evidence. 

 DeBattista C. Augmentation and combination strategies for depression. 

 Antonuccio DO, Burns D, Danton WG. Antidepressants: a triumph of marketing over science? 

http://www.antidepressantsfacts.com/2002-07-15-Antonuccio-therapy-vs-med.htm

 Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. 

 Valenstein M, McCarthy JF, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings. 

 Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. 

 Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. 

 Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. 

 Stimpson N, Agrawal N, Lewis G. Randomised controlled trials investigating pharmacological and psychological interventions for treatment-refractory depression. Systematic review. 

 Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. 

Articles

Common Augmentation Strategies for Depression: Findings Show Lack of Evidence

(This is a preview of the Rumble in Reno II scheduled for Oct. 18. The debate between Kirsch and Thase will focus on the issues highlighted in these point/counterpoint articles. Brochures for this conference are available online at 

Antidepressants are widely believed to be exceptionally effective medications. The data, however, tell a different story. Kirsch et al. (2002a) analyzed the data sent to the U.S. Food and Drug Administration by the manufacturers of the six most widely prescribed antidepressants (fluoxetine [Prozac], paroxetine [Paxil], sertraline [Zoloft], venlafaxine [Effexor], nefazodone [Serzone] and citalopram [Celexa]). Their research showed that although the response to antidepressants was substantial, the response to inert placebo was almost as great. The mean difference was about two points on the Hamilton Rating Scale for Depression (HAM-D). Although statistically significant, this difference is not clinically significant (Jacobson et al., 1999). More than half of the clinical trials sponsored by the pharmaceutical companies failed to find significant drug/placebo difference, and there were no advantages to higher doses of antidepressants. The small difference between antidepressant and placebo has been referred to as a "dirty little secret" by clinical trial researchers (Hollon et al., 2002), a secret that was believed by FDA officials to be "of no practical value to either the patient or prescriber" (Leber, 1998, as cited in Kirsch et al., 2002b). 

Previous reports of vanishingly small drug/placebo differences (Kirsch and Sapirstein, 1998) were met with skepticism (e.g., Klein, 1998). In contrast, the basic findings from this new meta-analysis have been accepted as accurate (e.g., Thase, 2002). The dispute is no longer about the small size of the average drug/placebo difference, but rather about how to interpret this fact and what to do about it. 

Various interpretive possibilities have been raised. One of the most popular theories is that there may be a subset of patients for whom at least some antidepressants are very effective, but that their relative lack of efficacy with other patients masks effect (e.g., Thase, 2002). Specifically, whereas mildly depressed patients respond to both drugs and placebos, more severely depressed patients respond only to active drugs. The FDA data contradict this hypothesis. Although severely depressed patients benefited more from medication than mildly depressed patients due to a phenomenon known as regression toward the mean, they also benefited more from placebo than their more mildly depressed counterparts. 

Of course, one can never rule out the possibility of undetected moderator variables. But if there are hidden moderators, the overall mean difference between drug and placebo (two points on the HAM-D) constrains the conclusions that can be drawn from them. If the mean drug/placebo difference is greater than two points for a subset of medications or patients, then it must be less than two points for the others. For example, if the mean difference between drug and placebo is four points for half of the patients (which is still a rather small drug effect), then the mean effect of antidepressants on the other patients must be zero, and if it is more than four points for half the patients, then the medications must be interfering with responsiveness in at least some others who would fare better on placebo.

Another popular hypothesis is that drug effects are more stable than placebo effects, resulting in lower relapse rates. This hypothesis is also contradicted by the data. A meta-analysis of relapse prevention trials published between 1973 and 1990 indicated that 71% of the drug response was duplicated by placebo (Walach and Maidhof, 1999). Kirsch et al.'s meta-analysis also examined response to treatment as a function of the duration of the trial. The data indicated that responses to both drug and placebo decrease over time. Contrary to conventional wisdom, however, the correlation between duration of the trial and response to treatment was higher for active medication (

=-0.62), suggesting a steeper decline in effectiveness for active drugs than for placebo (Kirsch et al., 2002b). 

In light of these data, what should be done in clinical contexts? Some have suggested that antidepressants continue to be prescribed, even if their effects are largely placebo effects. If nothing else, these agents can be used as active placebos. Given the side effects of these medications, we suggest an alternative approach. There are many interventions that seem to be as effective or nearly as effective as antidepressants. These include physical exercise, bibliotherapy and psychotherapy (Kirsch et al., 2002b). Psychotherapy has the further advantage of demonstrated superiority to medications in long-term comparative studies (Antonuccio et al., 2002). Given these data, antidepressant medication might best be considered a last resort, restricted to patients who refuse or fail to respond to other treatments. 

 Antonuccio DO, Burns DD, Danton WG (2002), Antidepressants: a triumph of marketing over science? Prevention & Treatment 5:Article 25. Available at: journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2. 
 

 Hollon SD, DeRubeis RJ, Shelton RC, Weiss B (2002), The emperor's new drugs: effect size and moderation effects. Prevention & Treatment 5:Article 28. Available at: journals.apa.org/ prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
 

 Jacobson NS, Roberts LJ, Berns SB, McGlinchey JB (1999), Methods for defining and determining the clinical significance of treatment effects: description, application, and alternatives. J Consult Clin Psychol 67(3):300-307.
 

 Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002a), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23. Available at: journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2. 
 

 Kirsch I, Sapirstein G (1998), Listening to Prozac but hearing placebo: a meta analysis of antidepressant medication. Prevention & Treatment 1: Article 0002a. Available at: journals.apa.org/prevention/volume-1/toc-jun26-98.html. Accessed Aug. 2, 2002.
 

 Kirsch I, Scoboria A, Moore TJ (2002b), Antidepressants and placebos: secrets, revelations, and unanswered questions. Prevention & Treat-ment 5:Article 33. Available at: www.journals. apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2. 

 Klein DF (1998), Listening to meta-analysis but hearing bias. Prevention & Treatment 1:Article 0006c. Available at: www.journals.apa.org/prevention/volume 1/toc-jun26-98.html. Accessed Aug. 2, 2002. 
 

 Thase ME (2002), Antidepressant effects: the suit may be small, but the fabric is real. Prevention & Treatment 5:Article 32. Available at:. Accessed Aug. 2. 
 

 Walach H, Maidhof C (1999), Is the placebo effect dependent on time? A meta-analysis. In: How Expectancies Shape Experience, Kirsch I, ed. Washington, D.C.: American Psychological Association, pp321-332.

The slight difference between antidepressant and placebo has been referred to as a "dirty little secret" by researchers, a secret that was believed by FDA officials to be "of no practical value."

David Antonuccio, PhD

Articles

Common Augmentation Strategies for Depression: Findings Show Lack of Evidence

Antidepressants Versus Placebos: Meaningful Advantages Are Lacking