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According to the World Health Organization, approximately 280 million people worldwide experience depression at any point in time.

In the United States, 21 million people suffer from major depressive disorder (MDD), a heterogenous brain disorder characterized by the presence of any grouping of symptoms from at least five out of nine specific domains, spanning from dysphoric mood and somatic complaints to hopelessness and suicide ideation.

Working, caring for family, and even getting out of bed can become extremely difficult during a major depressive episode. Insomnia can set in and finding pleasure in everyday activities is a challenge. Yet, each person is unique, and the symptoms of MDD — and how people experience the condition — can manifest differently across individuals.

Some depressive symptoms commonly persist despite treatment with currently available antidepressant therapies.1 Nearly 70% of people with MDD treated with antidepressant drugs from the selective serotonin reuptake inhibitor class (SSRIs; the most commonly prescribed agents for MDD) experience residual symptoms like anxiety, impaired cognition, insomnia, fatigue, and anhedonia — a loss of interest in activities that were previously enjoyed.2 For these people, there remains an unmet need for differentiated, new treatments that effectively address residual symptoms and promote remission.

Fortunately, neuroscience is entering a new era of precision medicine based on scientific and digital advances. Scientists are evaluating how to recognize illness subtypes and predict which people with MDD will respond to a particular treatment.

The challenges of treating a heterogenous nervous system disorder

MDD is diagnosed by the presence of multiple patient-reported symptoms that reflect a change in the individual’s usual function, which endure over time. This approach leads to a clinical diagnosis that encompasses a syndrome emanating from a group of related disorders, which are described according to the individual’s experiences and their ability to identify and convey them.

Developing treatments for MDD has been challenging, in part because of our limited understanding of the neurobiology underlying its symptoms. Thus, only a few pharmacologic mechanisms have become available to clinicians, of which nearly all focus on enhancement of the biogenic amine neurotransmitters: serotonin, norepinephrine, and dopamine.

Individuals with MDD do not manifest abnormalities in biogenic amine systems that are detectable using biomarker measures available as part of routine clinical laboratory tests. Without a way to predict which people will respond best to a particular treatment, providers rely heavily on experience, beginning with the treatments with which they are most familiar, and often combining two or more drugs and psychotherapeutic approaches in search of an optimal effect.

Current treatments are sufficiently effective for only a limited number of people, as about one-third of depressed individuals experience either nonresponse or inadequate (partial) response after multiple treatment trials.3,4 About half of individuals who respond to available treatments experience relapse or recurrence of MDD symptoms within 12 months despite continued use.4

By targeting well-understood biological mechanisms to discover new treatments, we can identify illness subtypes more likely to respond to those treatments. Such precision approaches are particularly under development to address residual symptom clusters that commonly persist in people receiving standard-of-care treatments, like anxiety, insomnia, fatigue, and anhedonia.

Precision medicine approaches for treating MDD offer renewed hope

Researchers are conducting clinical trials and developing differentiated treatments in multiple patient subtypes by taking precision medicine approaches.

Precision medicine is moving beyond conventional treatments that target biogenic amines to address MDD symptoms using novel pharmacological approaches that alter function in the brain circuits thought to produce specific symptom clusters in the disorder. These endeavors capitalize on emerging science characterizing the neuroreceptor proteins expressed in these circuits that modulate their function.

One neurotransmitter system of interest is the orexinergic system, which mediates both arousal during sleep-wake cycles and behavior under conditions of high motivational relevance, like stress, threat, and opportunities for reward. One target of interest is the orexin-2 receptor — a protein found in the brain circuits that regulate biogenic amine neurotransmitter release, autonomic function, and stress hormone release.

When orexin-2 receptors are stimulated for too long or at inappropriate times, their activation can cause hyperarousal manifestations, including insomnia and excessive cortisol release, which contribute to depression.

A second neurotransmitter system under investigation is the kappa-opioid receptor (KOR) system, which is activated by one of the brain’s endogenous opioid peptides, dynorphin. Clinical trials are underway for KOR antagonists in individuals with MDD who have experienced inadequate response to current antidepressant treatment and whose depressive symptoms include residual anhedonia, a symptom complex thought to reflect excessive kappa receptor stimulation.

Activation of kappa receptors by dynorphin release occurs during chronic stress and other conditions that are associated with depressive symptoms.

It is hypothesized that individuals with MDD and anhedonia emanating from excessive kappa receptor stimulation will be less likely to respond completely to SSRI antidepressants, which block the reuptake of serotonin and thus depend upon normal release of serotonin.

Digital technologies offer another new frontier in neuropsychiatry. Researchers are exploring approaches for leveraging electronic health records, smart phone-based assessments and digital sensors to better understand long-term outcomes for people who suffer from MDD along with residual insomnia and anhedonia as they receive various treatments that are currently available.

It is anticipated that by using a combination of clinical trial and electronic health record data, researchers can better understand how these novel therapies compare with current treatment options with respect to safety, side effects, and socio-occupational function.

The goal of precision medicine approaches for MDD and other complex disorders of the brain is to identify treatments suited to the unique symptom experience of people suffering from MDD. Learn more.


1. Goldberg D. The heterogeneity of “major depression”. World Psychiatry. 2011;10(3):226-228. doi:10.1002/j.2051-5545.2011.tb00061.x
2. Israel JA. The impact of residual symptoms in major depression. Pharmaceuticals (Basel). 2010;3(8):2426-2440.
3. Nemeroff CB. Prevalence and management of treatment-resistant depression.  J Clin Psychiatry. 2007;68 Suppl 8:17-25.
4. 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. Am J Psychiatry. 2006;163(11):1905-1917. doi:10.1176/ajp.2006.163.11.1905