Depression is a chronic disease characterized by recurrent episodes that interfere with daily life and normal functioning, exacting high costs for individuals and society. James McNulty, Vice President of Peer Support at the Depression and Bipolar Support Alliance, presented data from the World Health Organization (WHO) revealing that depression is the primary cause of disability in the United States and Canada for individuals aged 15–44 (WHO, 2002). Indeed, depression and other mental illnesses result in a more significant loss of healthy life years to disability and death than cardiovascular disease, cancer, or diabetes (WHO, 2004).
However, the onset of mental illness occurs primarily at a young age—by age 24 in 75 per cent of cases (Kessler et al., 2005)—but can strike at any age. Regardless of age at onset, a study by the Council of Medical Directors of the National Association of State Mental Health Program Directors showed that individuals who receive treatment for a severe mental illness still die 25 years earlier than the average population (NASMHPD, 2006). Disconcertingly, similar statistics are not available for those who do not receive care for a mental illness.
The Knowledge Base of Depression
The neuroscience knowledge base underlying the study of depression has been growing since the emergence of biochemical pharmacology and molecular technologies in the 1970s and 1980s. Over this same period, pharmaceutical companies, the National Institutes of Health’s (NIH’s) National Institute of Mental Health (NIMH), and patient advocacy groups have aggressively pursued new treatments for the disease. The success of selective serotonin reuptake inhibitors (SSRIs) and the many structurally similar drugs that followed improved the lives of many patients. However, William Potter, most recently Vice President of Translational Neuroscience at Merck Research Labs, Merck & Co., Inc., explained that a genuinely novel antidepressant had not been introduced in the last 40 years.
According to Potter, the period of SSRI development established a level of comfort in the mental health community that may have temporarily hindered the development of new and better antidepressants. Today, significant effort is focused on understanding the challenges to developing novel antidepressant therapies and designing the informative clinical trials necessary to test the effectiveness of discoveries.
Issues in conducting Clinical Trials in Depression
According to Madhukar Trivedi, Professor and Chief of the Division of Mood Disorders in the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas, two of the greatest challenges in depression research are (1) the lack of a definitive marker for diagnosing depression—a pathophysiologic “smoking gun,” as he described it; and (2) the fact that a significant number of trials in depression are not focused on answering the most important clinical questions—that is, there are many uninformative trials in the field.
Trivedi further explained that there is very little scientific evidence regarding which patients will respond to which of 25 to 30 treatments for depression. Treatments are similar but may be different in important ways. The result is substantial variation in clinical practice patterns for depression. It is unclear in many cases which antidepressant a clinician should choose for a patient, as well as how long to treat the patient with a given drug.
Identifying a Study Population for a Heterogeneous Disease
First, as suggested above, the diagnosis of depression is less technical and more subjective than that of other diseases. Moreover, changes in the way depression has been diagnosed over time call into question the use of large, historical databases. There is significant uncertainty as to whether a population diagnosed with depression in 1990 would be comparable to a population diagnosed with depression in 2000.
The criteria for diagnosing depression require that the patient have a depressed mood or a markedly diminished interest in pleasure (anhedonia). Hypothetically, one depressed patient could have a depressed mood as well as weight gain, hypersomnia, and recurrent thoughts of death, while another could have anhedonia, weight loss, and insomnia. Both of these patients would be diagnosed with depression and yet have no symptoms in common, and both could be enrolled in a clinical trial for depression. This treatment of a heterogeneous disease as if it were homogeneous is one reason clinical research in depression struggles to distinguish among antidepressants.
Clinical Trial Methodologies and Placebo Response
The effect of placebo response rates in clinical trials for depression has added a layer of complexity and difficulty to the process of designing trials and interpreting the trial results. Placebo response refers to a patient’s clinical improvement in response to an inactive substance (e.g., sugar pill). Most clinical trials in depression are placebo-controlled. The ethical issue of whether placebo-controlled trials should be conducted when effective therapies are available remains contentious. McNulty noted that while placebo-controlled studies are not required by the FDA, it is difficult to design a trial the FDA will accept without including a placebo study arm.
Placebo response rates in clinical trials for depression have been increasing, but variable, over time. The paper cited by Potter (Walsh et al., 2002) reports that the response to placebo across trials varied significantly—from approximately 10 percent to more than 50 percent—and was frequently substantial: in approximately half of the studies, 30 percent or more of patients assigned to placebo exhibited a clinically significant improvement. In addition, over the course of 2 decades (1980–2000), the proportion of patients responding to placebo increased at the rate of approximately 7 percent per decade (Walsh et al., 2002). The proportion of patients responding to active medication over this time period showed a similar increase. It should be noted that placebo response is a significant issue in the design of trials in many different disease areas.
Developing Informative Clinical Trials for Depression
A number of workshop participants noted that the current state of research in depression is marked by an inability to effectively distinguish one antidepressant treatment from another and identify the patient populations best served by a particular drug. In discussing how best to advance clinical research in depression, presenters and audience members raised a number of issues and possibilities.