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Introduction and Overview¹

Major depressive disorder (MDD) is recognized worldwide as a major cause of disability, morbidity, and mortality. According to the World Health Organization’s (WHO’s) The Global Burden of Disease: 2004 Update, unipolar depressive disorders affect more than 150 million people around the world and represent the leading cause of “years lost due to disability” among both men and women and across low-, middle-, and high-income countries (WHO, 2008). In the United States alone, nearly 8 percent of persons over the age of 12 report current depression (Pratt and Brody, 2014).

The direct and indirect costs of MDD are correspondingly alarming. In 2010, the economic burden in the United States was estimated to be more than $210.5 billion, about half of that due to workplace costs generated by absenteeism and reduced productivity (Greenberg et al., 2015). This figure represented an increase of more than 20 percent in the 5 years between 2005 and 2010. Perhaps most troubling is the fact that depression often goes untreated or undertreated. The WHO World Mental Health Surveys showed that even in the United States, only about one-third of patients receive treatment in the first year of the disease, and face a median delay of 4 years before treatment is provided (Wang et al., 2007).

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¹The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus.

MDD has long been defined primarily as a mood disorder.² However, more recently people have begun to recognize effects on cognition as a major contributor to the disablement that accompanies depression and to consider this an underrecognized treatment target for depression.

WORKSHOP OBJECTIVES

On February 24, 2015, the Institute of Medicine’s (IOM’s) Forum on Neuroscience and Nervous Disorders convened key stakeholders at a workshop in Washington, DC, to explore how best to enable the discovery, development, and translation of treatments for cognitive dysfunction in depression, including a focus on the regulatory path forward (see Box 1-1).

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²According to the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (the DSM) (American Psychiatric Association, 2013), MDD is characterized by the presence of symptoms of depressed mood and/or anhedonia (loss of interest in pleasurable activities) as well as other symptoms, including “diminished ability to think or concentrate, or indecisiveness” and “psychomotor retardation,” which impairs one’s ability to function. The DSM criteria require that these symptoms persist for at least 2 weeks and that they are not attributable to normal grief, substance use, or another psychiatric or medical disorder.

Thomas Insel, director of the National Institute of Mental Health (NIMH), noted that while a broad range of treatments have been developed to treat depression, resistance to treatment is widespread and residual symptoms, particularly in the cognitive domain, often lead to incomplete recovery. Indeed, only approximately 45 percent of patients achieve remission (Simon, 2000), and those who do frequently relapse (Rush et al., 2006). As discussed in more detail later in this summary, among patients who fulfill traditional criteria for response or remission of depression, many continue to have subjective complaints that contribute to impaired function, such as the ability to return to work. Clinical and epidemiologic evidence suggests that cognitive dysfunction represents an underestimated dimension of depression that may, in part, explain patients’ inadequate response to treatment. Yet questions remain regarding the relationship between depression and cognitive dysfunction as well as how to assess cognitive dysfunction in depressed patients. Moreover, currently available pharmacologic treatments for depression may fail to address or even worsen the cognitive aspects of this crippling disease.

Pharmaceutical companies have begun to take an interest in developing drugs that target cognition in depression, said Thomas Laughren, director of Laughren Psychopharm Consulting, LLC, and formerly director of the Division of Psychiatry Products in the Office of New Drugs in the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA). Until recently, Laughren said that FDA had not been convinced of the value of targeting cognitive impairment in depression separately from other symptoms of depression, but he believes that a careful review of the data has altered that perception, and that the agency is now ready to take a new look at the issue.

ORGANIZATION OF REPORT

The following report summarizes the presentations from expert speakers and discussions among workshop participants. Chapter 2 provides the backdrop against which these discussions were framed, that is, how we define cognitive impairment in depression, its prevalence and impact on function, and neurobiological mechanisms and targets for intervention. Chapter 3 explores the state of the science in pharmacologic and nonpharmacologic treatment development. Chapter 4 discusses the challenges related to developing successful treatments for cognitive im-

pairment in depression. Chapter 5 presents regulatory challenges from the perspective of both regulators and clinical researchers. Finally, Chapter 6 discusses lessons learned from the schizophrenia field, which has grappled with many of the same issues. References are in Appendix A, the workshop agenda is in Appendix B, and the list of registered participants is in Appendix C.

TOPICS HIGHLIGHTED DURING PRESENTATIONS AND DISCUSSIONS³

Cognition is an appropriate target for treatment of depression, said many participants throughout the workshop. They discussed a number of challenges to achieving broader acceptance of this concept within the larger community and transforming this paradigm into effective treatments. The challenges and potential opportunities to address them identified by individual participants are listed here and expanded on in the succeeding chapters:

• Defining cognitive impairment in depression: The lack of a consensus definition of cognitive impairment in depression may hinder diagnosis and treatment development, said several participants. Despite increased recognition of the importance of cognitive dysfunction in depression, a precise definition of the disorder remains elusive. Both cold and hot cognition⁴ appear to be affected, leading to reduced function, and it seems important to separately consider cognitive biases and cognitive deficits.⁵ Several participants, including regulators, noted that the lack of a consensus on the cognitive domains leads to methodologic differ-

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³The following list highlights topics discussed throughout this workshop, but should not be construed as reflecting a consensus of workshop participants or any endorsement by the Institute of Medicine or the Forum on Neuroscience and Nervous System Disorders.

⁴Cold cognition refers to information processing that is independent of emotion, while hot cognition refers to constructs that are affected by emotional state. Although these terms are not universally used, they were used throughout the workshop and therefore in this summary.

⁵Cognitive biases include distorted information processing and increased attention to negative stimuli; cognitive deficits include impairments in attention, short-term memory, and executive functioning (Murrough et al., 2011).

• ences in studies that obscure the reasons for different results and impedes the regulatory path forward.

• Understanding the neurobiology of cognitive impairment: An incomplete understanding of the neurobiology underlying cognitive impairment in depression appears to be impeding the development of new treatments, noted some participants. Ongoing research to define the brain circuits affected in depression could help to explain the suboptimal effectiveness of current treatments and identify potential targets for novel treatments.
• Targeting cognition to improve treatment efficacy: Targeting cognition in depression could improve the efficacy of treatment for depression, suggested several participants. They said the reason for the high rate of treatment resistance in depression may relate to the failure of treatments to target cognition, yet no new drugs have been approved by FDA for the treatment of cognitive impairment in depression. Although cognition has been assessed in many treatment studies, the effects on cognition have been nominal. Furthermore, most studies have looked only at cold cognition, yet some participants said hot cognition may be the more important target.
• Using holistic approaches and combining treatments: These approaches appear promising, said some participants. After discussing a range of pharmacologic and nonpharmacologic treatment approaches, including neurostimulation and cognitive remediation, several participants concluded that effective treatment will require combinations of drugs and other treatments that target multiple neurobiological mechanisms and cognitive domains and that ensure good functional outcomes in the workplace and home environments.
• Improving early diagnosis and early treatment: Earlier diagnosis of depression and early effective treatment could improve response to treatment, emphasized some participants, noting that delayed treatment leads to poorer response to antidepressant therapy and more frequent relapses. Tools are needed to enable earlier detection as well as to predict the response to treatment.
• Developing biomarkers: Biomarkers would be valuable, and cognition potentially could be used as a surrogate biomarker, said a few participants. These biomarkers include genetic, neuroimaging, cognitive, and other physiologic measures, and could not only enable earlier identification of persons with depression,

• but also improve the efficiency of clinical trials by identifying appropriate candidates for trials and by providing indicators of target engagement and treatment response.

• Using experimental model approaches: Experimental model approaches can be helpful for screening and predicting the effects of antidepressant treatments on cognition, said some participants. For example, early changes in emotional processing (hot cognition) are seen with antidepressant drug treatments, and this is predictive of later therapeutic response. Modeling the disease process in humans may provide answers to questions about the neurobiologic effects of a treatment early in the drug development process, before billions of dollars have been spent on a treatment that ultimately fails to show efficacy. One experimental model discussed at the workshop is already being used by pharmaceutical companies to screen candidate treatments.
• Heterogeneity and stratifying study participants: Heterogeneity presents challenges in developing treatments, and stratifying study participants into subgroups can be beneficial although it limits generalizability, noted various workshop participants. Patients with depression constitute a diverse group in terms of both symptomatology and response to treatment, and these aspects also vary with gender and across the lifespan. Moreover, heterogeneity has a huge impact on clinical trials, creating “noise” that obscures treatment benefits. Several participants discussed different approaches to stratification of study participants into subgroups that could provide clearer answers in trials and enable the identification of interventions appropriate for different subgroups.
• Addressing pseudo-specificity: Pseudo-specificity may be a major roadblock to the design of clinical trials and regulatory approval, recognized many participants. In order for a treatment to be approved for cognitive dysfunction in depression, regulators likely will ask for data showing that the drug works only or better in patients with depression-related cognitive impairment as opposed to cognitive impairment in general or depression in the absence of cognitive impairment.
• Employing novel trial designs: Novel trial designs could be useful, said some participants. They suggested a number of modifications to existing trial designs, as well as innovative new designs such as adaptive trials, which could address some unique

• concerns raised by targeting cognition in depression, expedite drug development, and increase the likelihood of success. Several participants also emphasized the need for patient engagement and real-world studies that take a holistic approach.

• Improving assessment tools: Improved tools to assess cognition in patients with depression would be useful, some participants said. A number of batteries are available for testing cognition in patients with depression, yet not all test the same domains or employ the same neuropsychological tests. Several participants acknowledged both the advantages and disadvantages of a standardized battery, using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery as a point of reference. Other major issues discussed with regard to assessment were the use of objective versus subjective and cognitive versus functional measures. As mentioned by some participants from regulatory agencies, clinical meaningfulness is paramount. In other disease conditions such as Alzheimer’s disease and schizophrenia, regulators have required demonstration of efficacy on a co-primary endpoint, such as a functional or global measure. Whether a similar requirement would be made for cognitive impairment in depression remains to be determined.
• Embracing innovative technologies: These technologies could help to improve assessment and could also be used in treatment, said some participants. Examples include a number of innovative technologies, such as tracking tools available on smartphones and in-home devices that could provide continuous functional measures of disease progression across all stages of disease and with a high degree of clinical meaningfulness.
• Enhancing clarity in the regulatory pathway: Clarity in the regulatory pathway for approval of treatments would be beneficial, noted some participants. No treatment targeting cognitive impairment in depression has yet received regulatory approval. Regulators participating in the conference expressed willingness and flexibility with regard to many aspects of trial design and encouraged investigators to meet with them early in the process of developing their trials.
• Learning from the MATRICS program: Many lessons can be learned from the MATRICS program, said some participants who had worked on the MATRICS initiative, which was designed to address the roadblocks to developing treatments for

In his concluding remarks, Insel said he was initially skeptical that there was a need for new cognitive interventions and cognitive measures for depression. However, he said the proceedings had convinced him that even cognitive interventions that have been available for some time may not be adequate to address the cognitive concerns of patients with depression. He also expressed concern about how little is actually known about the current set of interventions, noting that the meta-analyses that have been published are “underwhelming” and limited by issues of heterogeneity. However, he noted that there are many directions for further exploration and potential opportunities to improve the treatment of cognitive dysfunction in depression, as mentioned above and described in more details in subsequent chapters.