Effectiveness of antidepressant medication: Implications of recent meta-analytic findings

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1 Effectiveness of antidepressant 1 Effectiveness of antidepressant medication: Implications of recent meta-analytic findings Alan Scoboria, PhD, C.Psych University of Windsor A recent meta-analysis upon the effectiveness of antidepressant medication has received considerable media attention (Kirsch, Deacon, Huedo-Medina, Scoboria, Moore & Johnson, 2008). The following summary is provided to clarify and contextualize the study and related issues. The paper is open-access and can be viewed on-line at: This article is for informative purposes, and is not intended to provide specific treatment recommendations or medical advice. What did this study find? This study shows that while modern antidepressants do produce substantial improvements in depression, people receiving a placebo improved nearly as much as those receiving the drug. Only for the most severe depressions did drug show an advantage over placebo. The finding that placebo response is high in antidepressant trials is consistent with prior research (Joffe, Sokolov, & Streiner, 1996; Kirsch & Sapirstein, 1998; Kahn et al., 2000; Kirsch et al., 2002; Walsh et al., 2002). What is novel about this study? This study analyzed drug trials from arguably the most comprehensive dataset available. The Federal Drug Administration in the United States requires that drug manufacturers report all data available when evaluating the effectiveness of a new drug. Thus some of the problems with publication bias, where studies which show effects are published and those which do not show effects are not published, are avoided (Turner et al., 2008). The analyses were conducted for modern antidepressant drugs in the FDA database for which all data was reported. This results in the most objective estimate of drug and placebo effects possible.

2 Effectiveness of antidepressant 2 The study then examined drug and placebo effects based upon the severity of initial depression. Analyses showed that the clinical significance of the difference between drug and placebo was not meaningful for mildly to highly depressed patients. Only for the most severely depressed patients did drug show a notable clinical difference over placebo. However, this was not due to drug being more effective, but rather because the placebo response was lower for severely depressed people. Why do physicians, researchers, and patients think these drugs are effective? Because they appear to be effective some people do report feeling quite a bit better. However, the data indicate that it is questionable whether this is due to the pharmacology of the drug. Improvement in depressive symptoms are highly influenced by people s beliefs that they are receiving an effective treatment. It is important to note that this study does not prove that drugs do not have a pharmacological effect; rather it shows that other factors produce effects that are equally strong. So why were these drugs approved as being more effective than placebo? Central to this issue is the distinction between statistical and clinical significance. In many studies drugs do result in greater change on average than placebo, using conventional statistical significance criteria. However, the magnitude of the difference between drug and placebo tends to be small. For example, in this study the average difference between drug and placebo groups was a rather small 1.8 points on the Hamilton Rating Scale of Depression (HRSD). Consider two groups of individuals whose scores on the HRSD are 20 on average prior to treatment. Half receive drug and half receive placebo. After 6 weeks of treatment, the drug group s average score on the HRSD is 9 and the placebo group s average score is These two scores may be statistically different. However, from the point of view of clinical utility the changes in scores are virtually identical both groups improved substantially. It has also been suggested that these drugs may not in fact produce long term improvements in mood, but rather provide mild non-specific stimulating and sedating effects. If this is the case, these drugs may be helpful early in treatment to reduce distress, agitation, and sleep problems, but these types of issues are not specific to depression (Moncreiff, 2007) Why do depressed people respond to placebos? The reasons behind the placebo response for depression are complex. Clearly, expecting that one is receiving a beneficial treatment is helpful. Depression is a disorder that is characterized by hopelessness for some patients (Abramson, Metalsky, & Alloy, 1989; Joiner et al., 2001). The very act of seeking help and receiving a treatment from an expert likely instils hope which may spur improvement for some individuals.

3 Effectiveness of antidepressant 3 Furthermore, the very side effects that the drugs produce may enhance someone s belief that they are receiving a beneficial treatment (Moncrieff, Wessely, & Hardy, 2004). Someone who takes an antidepressant and begins to experience side effects is more likely to believe they are getting a treatment that will help. This may also explain the small differences that are observed on average between drug and placebo groups in clinical trials: individuals with side effects (on drugs) may have stronger beliefs that they are receiving a beneficial treatment than those without side effects (on placebo). The status that people ascribe to drugs due to factors such as marketing, prestige of brand names, or cost likely influence beliefs about the effectiveness of drugs. For example, a recent study showed that people reported lower levels of pain when administered an expensive placebo pain medication as contrasted with an inexpensive placebo medication (Waber, Shiv, Carmon, & Ariely, 2008). One clear message that this and similar work conveys: depression is highly related to one s beliefs about being depressed and one s beliefs about treatment. Changing how one thinks about and experiences one s depression can result in improvement. How is depression treated most effectively? A variety of treatments are available. To understand which treatments may be most beneficial, it is important to understand the nature of depression. Depression is a cyclical disorder: 85% of people who have a diagnosable major depressive episode will have another episode at some point in the future. The median number of lifetime episodes for individuals experiencing one episode is 4. (Judd, 1997; Mueller et al., 1999). Furthermore, the natural course of the first untreated depressive episode is estimated to be from 3 to 9 months (Solomon et al., 1997; Eaton et al., 1997). Thus demonstrating that any treatment affects a current episode is difficult. Presumably individuals are feeling depressed for some period of time prior to seeking help. In fact, the DSM-IV-TR (American Psychiatric Association, 2000) criteria for major depressive episode requires that symptoms are present at minimum two weeks prior to diagnosis. Thus any treatment that is thought to takes 8-12 weeks to show effectiveness may reflect change that would have occurred if the disorder was permitted to run it s course. This is the case for both drug and therapy administration. When first prescribed, a drug is typically tried for 6-8 weeks. If benefit is not observed, the dosage is revised, or a second drug is attempted. The same of course holds for therapies for example, 12 weeks of CBT is common for the treatment of depression. It is thus difficult to demonstrate that a treatment has an effect on the current depressive episode. In light of these observations, the treatment of depression is best targeted at preventing future depressive episodes. In preventing relapse, therapy has proven to be an essential component: therapy alone and drug therapy combinations produce the best results in terms of preventing re-occurrence (Evans et al., 1992; Thase et al., 1997; Jarrett et al, 2001; Hollon et al., 2006).

4 Effectiveness of antidepressant 4 What alternative treatments are available? There are a variety of treatments for depression which show benefits similar to drugs, without the associated side effects. For further information about each approach and why they are thought to work, please see the cited material. This is not intended to represent an exhaustive list of options. Exercise. A highly effective treatment for depression is exercise. Recent work suggests that exercise provides a variety of benefits when treating depression. (Stathopoulou et al., 2006). Therapy. A variety of psychological treatments have been demonstrated to effectively treat depression. Examples with clearly demonstrated efficacy include: cognitive behavioural therapy (Beck, 1976), emotion focused therapy (Greenberg & Watson, 2005), and interpersonal therapy (Klerman et al., 1999). Bibliotherapy. A number of self-administered workbook based therapies for depression have shown efficacy, when adherence is sufficient (see Gregory, Schwer Canning, Lee, & Wise, 2004). What should people who are taking one these drugs do? Nobody should stop taking any prescribed medication without consulting with their treatment provider(s). Remember, this research does not say that antidepressants never work. People should talk with their treatment providers about seeking the combination of treatment options which they believe will work best for them. Should these drugs be used to treat depression? These drugs are effective, but not necessarily due to their pharmacological characteristics. Their primary disadvantages are cost, and that they cause side effects which many patients find seriously discomforting. Because there are highly effective and safe alternative treatments, medication might be reserved for cases in which alternative treatments do not work, or in cases of severe depression. Other treatments appear to be more cost effective than drug treatment. For example, therapy has been shown to be more cost effective than antidepressant medication (Dobson, et al., in press). Antidepressant drugs will continue to serve an important role in the treatment of depression, particularly with severe, chronic, and recurrent cases. However, moving away from medically based models and towards comprehensive healthbased models which consider the costs and benefits of all available treatment options and the rights of individuals to choice are needed. References Abramson, L.Y., Metalsky, G.I. & Alloy, L.B. (1989). Hopelessness depression: A theory-based subtype of depression. Psychological Review, 96, American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, 4 th ed., Text Revision. Beck, A.T. (1976). Cognitive therapy and the emotional disorders. New York: International Universities Press.

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