Depression Cures

Dr. Eric Nestler

Dr. Eric Nestler

By Eric Nestler, M.D., Ph.D., Nash Family Professor and Chair, Department of Neuroscience; Director, Brain Institute; Mount Sinai School of Medicine

Depression is a serious illness that has an enormous impact on humanity: one in six individuals will experience clinical depression at some point during their lifetime, with depression ranked, by the World Health Organization, as the number one cause of disease burden worldwide. Sadly, a “cure” for depression does not yet exist. But, despite the limitations of today’s treatments, recent strides in depression research show hope for the eventual development of cures for depression.

All of today’s antidepressant medications are based on the older tricyclic antidepressants (e.g., amitriptyline, imipramine), whose antidepressant activity was discovered by serendipity roughly 6 decades ago (3). Newer medications, such as the selective-serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline) or serotonin-norepinephrne reuptake inhibitors (SNRIs; e.g., venlafaxine, duloxetine), have the same mechanism of action as the older medications and therefore treat the same range of patients. Indeed, limitations of today’s antidepressants are indicated by the observation that fewer than half of all depressed individuals show a full remission even after optimal treatment. Another major limitation of today’s treatments is that they require several weeks of administration before any clinical benefit is seen.

Despite the great need for more effective antidepressants, progress has been relatively slow in developing antidepressant medications with fundamentally novel mechanisms of action. There are many reasons for this slow progress, but perhaps the most important is the far greater complexity of the brain compared to all other organs. A single human brain is composed of ~100 billion nerve cells or neurons with each neuron forming connections (called synapses) with thousands of other neurons. It has been estimated that the total number of synapses in a single human brain exceeds the total number of stars estimated to be in the entire universe! Furthermore, unlike diseases of other organs (e.g., heart disease, diabetes, and cancer), which can be modeled accurately in laboratory animals such as rats and mice, key features of depression and other psychiatric illnesses (e.g., guilt, suicidality, sadness) are not accessible in animals. The difficulty in establishing bona fide animal models of depression has no doubt been a major impediment to the generation of improved treatments.

Recent advances in basic neuroscience promise to overcome some of these obstacles. First, while some key symptoms of depression cannot be modeled in animals, other core symptoms of depression, such as anhedonia (loss of interest in pleasurable activities, e.g., food, sex, and social interaction), reduced motivation, social withdrawal, and impairments in appetite, sleep, energy level, and circadian rhythms, can be measured in rodents. As well, recent work has shown that chronic exposure of rats and mice to different forms of chronic stress induce abnormalities in the aforementioned symptoms and that these symptoms can be treated effectively by repeated, but not acute, administration of clinically available antidepressant medications. Interestingly, depression symptoms can be induced in rodents both by chronic active stress (for example, repeated social defeat, where an animal is repeatedly subordinated by a larger, aggressive animal) (4) and by chronic social isolation (for example, where an animal is housed for several weeks in isolation from other animals) (5). It is possible that the distinct syndromes exhibited in these two depression models correspond to different subtypes of human depression characterized by different forms of long-term stress (3).

The availability of these new animal models, of greater etiological, face, and predictive validity, is now allowing, for the first time, detailed studies of the changes that chronic stress induces in the brain to cause these depression-like symptoms as well as how today’s antidepressants reverse these symptoms at the molecular level. Such work is allowing investigators to design new ways of inducing such antidepressant-like adaptations in the brain, efforts which are pointing the way toward fundamentally novel type of antidepressant treatments (1). Since some rats and mice in these studies do not show symptoms of depression in response to chronic stress-these animals, like most humans, appear resilient-it is possible for investigators to also understand the molecular basis of resilience and to design new antidepressants aimed at fostering such resilience-associated changes in the brains of more vulnerable individuals (12).

Translating these discoveries made in animal models to the clinic will take many years, but there should now be great hope that the impressive strides made over the past decade in understanding brain function will lead to more rapidly acting and more effective antidepressant treatments. We refer to depression today as a chronic illness. Yet, the only reason depression is chronic is because we have not yet found a cure. We believe that depression cures will be possible through animal research that is closely tied to clinical investigations of people currently suffering from this potentially fatal illness.

Eric J. Nestler
New York, NY
March 15, 2010


  1. Covington HE, 3rd, Vialou V, Nestler EJ (2009) From synapse to nucleus: Novel targets for treating depression. Neuropharmacology, in press.
  2. Feder A, Nestler EJ, Charney DS (2009) Psychobiology and molecular genetics of resilience. Nature Rev Neurosci 10:446-457.
  3. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894-902.
  4. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A, Eisch AJ, Self DW, Lee FS, Tamminga CA, Cooper DC, Gershenfeld HK, Nestler EJ (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391-404.
  5. Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Iniguez SD, Cao JL, Kirk A, Chakravarty S, Kumar A, Krishnan V, Neve RL, Cooper DC, Bolanos CA, Barrot M, McClung CA, Nestler EJ (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12:200-209.

For further information, see

Eric J. Nestler, M.D., Ph.D.
Nash Family Professor and Chair, Department of Neuroscience
Director, Brain Institute
Mount Sinai School of Medicine
One Gustave L. Levy Place, Box 1065
New York, NY 10029
Tele 212-659-5656
Fax 212-659-8510

8 Responses to “Depression Cures”

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  2. S. C.
    May 18, 2012 at 1:40 pm #

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  3. W. Birmingham
    May 22, 2012 at 11:59 am #

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  4. Anonymous
    May 23, 2012 at 3:45 pm #

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  5. Sade Aten
    May 24, 2012 at 4:52 pm #

    I’ve been coping with depressive disorder for just about two years ever since my hubby Ben passed away, and one of the ways I’ve tried to recover is by finding out as much about depression as I can. I’m presently leading a discussion group for women who are experiencing depression, and I came upon your blog post while searching for materials to go over in this thursday’s meeting. I don’t know how it works for other people, but for me, knowledge is strengthening, and the more I learn the nearer I get to feeling normal again.

    • wendy
      May 25, 2012 at 7:34 pm #

      Thanks so much for reading and for your comments. So sorry to hear about your husband but continue your journey in finding out more about this disorder and how it’s helped you.

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