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New approaches to antidepressant drug discovery: beyond monoamines

Key Points

  • All antidepressant medications in use today are based on serendipitous discoveries, made more than 50 years ago, of the clinical efficacy of tricyclic and monoamine oxidase inhibitor antidepressants, both of which were later found to target the brain's serotonin or noradrenaline systems.

  • As only about half of all individuals with depression show full remission in response to these mechanisms, there has been intense interest in developing novel antidepressants with non-monoamine-based mechanisms. Although this work has led to impressive gains in understanding the molecular basis of adaptive and maladaptive responses to chronic stress, and in identifying numerous targets for the development of novel antidepressant treatments, it is striking that no non-monoamine-based antidepressant has yet been released onto the market.

  • We summarize the obstacles responsible for this lack of progress, including the difficult chemistry involved in most non-monoamine-based targets, limitations in animal models of depression, our still limited knowledge of the aetiology and pathophysiology of human depression, the heterogeneity and imprecise diagnosis of depression, and the exorbitant cost and risks of antidepressant clinical trials.

  • We go on to provide a progress report of some of the most promising current strategies aimed towards the development of non-monoamine-based antidepressants. Because a large subset of individuals with depression show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, the development of corticotropin-releasing factor (CRF) receptor antagonists has been a high priority. It is sobering, however, that despite decades of research, we still do not have a clear proof of concept demonstration of the efficacy of CRF antagonists in human depression. By contrast, there is increasing evidence for the possible antidepressant effects of glucocorticoid receptor antagonists.

  • By analogy with CRF antagonists, experience with substance P (or neurokinin, NK) receptor antagonists has been similarly frustrating. After an initial positive report almost a decade ago, more recent clinical evidence has been inconsistent, and the future of NK receptor antagonists in the treatment of depression remains uncertain.

  • More recent studies in animal models have shown putative roles for glutamate receptors, neurotrophic factors (such as brain-derived neurotrophic factor), the intracellular cyclic AMP pathway, hypothalamic feeding peptides, circadian genes, and many others in animal models of depression. These discoveries have defined new potential targets for antidepressant drug discovery, but real challenges remain in translating these to the clinic.

  • The identification of new targets such as these is cause for optimism. Nevertheless, past failures and frustrations in antidepressant drug development mean that a careful analysis of future advances is required.


All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.

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Figure 1: The corticotropin-releasing factor system in depression.
Figure 3: Neurotrophic mechanisms in depression and antidepressant action.
Figure 2: CREB and dynorphin in the nucleus accumbens in depression.


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Preparation of this review was supported by grants from the National Institute of Mental Health, USA.

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Corresponding author

Correspondence to Eric J. Nestler.

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Competing interests

E.J.N. receives consultancy income from several pharmaceutical and biotechnology companies with active antidepressant drug discovery programmes. He is Chair of a neuroscience Scientific Advisory Board of Eli Lilly, USA, and a member of the Scientific Advisory Boards of Neurogen, Helicon, Neurologix, Neuromolecular, RxGen and Intracellular Therapies (all USA). He is also co-founder and Scientific Advisory Board Chair of PsychoGenics, USA.

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Nestler's laboratory



Decreased interest in, and ability to experience, pleasure. A common symptom of depression.

Monoamine neurotransmitters

Small molecule neurotransmitters that contain a single amine group. Monoamines include dopamine, serotonin, noradrenaline and adrenaline, and histamine is sometimes included in this group of neurotransmitters as well.

Electroconvulsive therapy

(ECT). Repeated generalized seizures, induced electrically, as a treatment for depression. A form of somatic therapy.

Somatic therapies

Refers to non-medication, non-psychotherapy treatments for depression. Such therapies include ECT and several more experimental treatments such as magnetic stimulation (transcranial magnetic stimulation, TMS, and magnetic seizures) and vagal nerve stimulation.

Tricyclic antidepressants

Refers to a group of structurally related compounds that were developed in the 1950s and later shown to possess antidepressant activity in humans. Prototypical tricyclic antidepressants include amitriptyline, imipramine and desipramine.

Atypical antidepressants

Clinically effective antidepressants for which the mechanisms of action are unknown (for example, bupropion, mirtazapine and tianeptine).

Stress models

The application of any of several aversive or nociceptive stimuli (physical or psychological stressors) to an animal. Examples include restraint stress, foot shock, social defeat and chronic mild stress.

Monoaminergic depletion

Tryptophan depletion lowers serotonin levels in the brain. This treatment increases anxiety-related behaviours in rodents and increases immobility in the forced swim test. No clear effects of antidepressants have been reported.

Olfactory bulbectomy

Causes degeneration of neurons connecting the olfactory bulbs to the limbic system. This is associated with several behavioural abnormalities that can be normalized by chronic, but not acute, antidepressant treatment.


(Novelty-suppressed feeding). Inhibition of feeding produced by exposure to a novel environment provides an anxiety-related measure that is sensitive to the effects of chronic, but not acute, antidepressant treatment. The test also responds to anxiolytic drugs, such as benzodiazepines.

Learned helplessness

Reduced escape behaviour in response to stress after prior exposures to unavoidable stressors. Responds to acute or subchronic antidepressant administration.

Chronic mild or unpredictable stress

Involves relatively prolonged exposure to various relatively mild stressors. Reported to induce an anhedonia-like state, which can be reversed by chronic antidepressant treatment. However, these findings have not been replicated by all laboratories.

Chaperone proteins

Proteins that bind to other proteins to regulate their folding, trafficking among intracellular compartments, and degradation.

Cushing syndrome

Medical consequences of hypersecretion of glucocorticoids from the adrenal cortex, which can be caused by several conditions.

Distress vocalizations

Ultrasonic vocalizations produced by young rodents lost outside the nest or by adults in aversive contexts. Acute treatment with several types of antidepressant inhibits the production of these calls.

Forced swim test

Rodents immersed in a vessel of water develop an immobile posture after initial struggling. Most antidepressants, administered acutely before the test, reverse the immobility and promote struggling. Advantages of this technique include low cost, high throughput and predictive validity; disadvantages include the fact that acute antidepressant administration, which is not effective in human depression, is effective in the test

Social defeat

Prolonged exposure to an aggressor causes several depression-like behavioural abnormalities in animals, which can be reversed by chronic, but not acute, antidepressant treatment. Social defeat is an example of chronic psychosocial stress.

Psychotomimetic drug

A drug that induces psychosis. Prototypical examples include NMDA receptor antagonists (for example, phencyclidine and ketamine) and psychostimulants administered repeatedly at high doses (for example, amphetamine).

Tail suspension test

Mice suspended by their tails develop an immobile posture after initial struggling. Acute administration of most antidepressants before the test reverses immobility and promotes struggling. Advantages of this technique include low cost, high throughput and predictive validity; disadvantages include the fact that acute antidepressant administration, which is not effective in human depression, is effective in the test.

Brain stimulation reward

Rodents will work (press a lever) to pass electric current into specific brain areas. A change in the threshold current for such intracranial self-stimulation is reported to provide a measure of affective state, with an increase in threshold current reflecting a depressed affect.

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Berton, O., Nestler, E. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7, 137–151 (2006).

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