$50M PROGRAM

Multi-Channel

Psych

Revealing Mechanisms of Anhedonia

$50M PROGRAM

Multi-Channel

Psych

Revealing Mechanisms of Anhedonia

$50M PROGRAM

Multi-Channel
Psych

REVEALING
MECHANISMS
IN ANHEDONIA

Depression is a complex biological illness.
We need treatments to match.

The latest worldwide survey of global health underscores the devastating impact of depression. Depression was ranked as the 3rd highest cause of disability across all illnesses, resulting in approximately 43 million years lost to disability (YLD). In only a single year, 264 million people suffer from depression, and 800,000 lives are lost to suicide. Narrowing in on the United States, almost 7% of adults experience an episode of depression each year, costing an estimated $210.5 billion due to the combination of treatment costs and productivity loss. Consistent with this enormous disease burden, the NIH has spent over $22 billion on depression research over the last 20 years – more than for any other mental illness, including addiction, schizophrenia, or autism. But despite this massive investment, only 1 in 3 patients substantially responds to currently available medication or psychotherapy treatments.

Why are we stuck? The modern practices of psychiatry and psychology are grounded in neuroscience and biology. We understand that synaptic connections serve as the currency of neural communication, and that strengthening or weakening these connections can facilitate learning new behavioral strategies and ways of looking at the world. Through studies in both animal models and humans, we have discovered that emotional states are encoded in complex neural network activity patterns, and that directly changing these patterns via brain stimulation can shift mood. We also know that disruption of these delicately balanced networks can lead to neuropsychiatric illness.

Based on this understanding that psychiatric symptoms are rooted in biology, all existing drug therapies for depression target biological mechanisms. Selective serotonin reuptake inhibitors (SSRIs) bind to the serotonin transporter, leading to increased serotonin concentration in the synaptic cleft and a cascade of downstream functional and structural consequences. Although the exact mechanism of action of the fast-acting antidepressant ketamine is still being investigated, it is known to be an NMDA-receptor antagonist. Brexanolone, which is the newest FDA-approved antidepressant for the indication of post-partum depression, is a neuroactive steroid that is a positive allosteric modulator of the GABA receptor. We have now even solved the crystal structures of psychiatric drugs binding to their targeted receptors. Since at least the 1960’s, with the first indications that alterations in levels of catecholamines such as dopamine can lead to depressed mood, we have known that depression is biologically based, and that treatments need to address these underlying biological problems.

Yet, these biologically based treatments are not being matched to the biology of the human beings they’re being used in. According to standard treatment guidelines currently recommended by the American Psychiatric Association, the first-line pharmacotherapeutic treatment for depression is a randomly selected SSRI. And if that doesn’t work, the next step is switching to another randomly selected SSRI, followed by augmentation with an additional agent or switching to an alternative medication class. It is a brute force process guided almost exclusively by qualitative data and subjective self-report. And the impact of each new medication change can take between 2-6 months to assess. This current state of affairs leads to time lost for both patients and their loved ones, unnecessary side effects, discouragement, and – perhaps most importantly – continued progression towards end-stage illness.

What needs to change? To make meaningful change, we need to match treatments to the specific biology of the people receiving them.

Program goals.

We envision a world in which diagnosing anhedonic depression is as straightforward as getting a mammogram, and stratification into a treatment plan has the same speed as current algorithms after breast biopsy. This necessitates a general shift of mindset in an important way. Depression can be a terminal illness, just like breast cancer. Rapid, targeted intervention is therefore vital to prevent progression. Initially selecting the treatment with the highest likelihood of working for an individual patient based on their specific biology is therefore of high value, because in addition to decreasing the total time of suffering, key goals include avoiding unnecessary side effects and limiting treatment-associated risks. To that end, our goals are to achieve:
1. Rapid patient stratification and treatment matching: Develop an integrated model of anhedonic depression capturing both internal biological factors and externally-manifested and quantifiable symptom-correlated biometrics and behavioral measures. This model should stratify people into those who will be treatment sensitive and those who will be treatment resistant with 80% accuracy, consistent with the current 20% false negative rate for mammograms. The model should also be sufficient to match responsive patients to their appropriate treatment regimen rapidly, including novel or existing behavior modification, psychotherapy, medication, and neurostimulation options. Currently 33% of depressed people have significant symptom reduction with the initial treatment selected, while an additional 21-33% of people require between 2-4 treatment trials to achieve remission. Our goal is to double the number of people who receive an effective treatment on the first try.
1a. The model should capture multiple levels of investigation (e.g. genome, phenome, network connectivity, metabolome, microbiome, reward processing, plasticity levels, HPA axis function).
1b. The model should seek to leverage high frequency patient-worn or in-home measurements in addition to those obtained in the clinic, hospital, or laboratory.
1c. The integrated model should predict the relationship between genome, metabolome (particularly, but not exclusively, from CSF), microbiome, and resting-state connectivity to anhedonia symptoms, reward processing, and treatment response in depressed individuals.
1d. Predictive validity should be verified in new cohorts either held out from existing samples or collected during the study period.
2. Identification of mechanisms underlying treatment-resistant anhedonic depression: Define the biological basis of anhedonic depression with the goal of identifying effective treatments for half of non-responsive patients, as measured by a decrease of ≥50% on current gold-standard suicidality, depression, and anhedonia scales (HAM-D, BDI, SHAPS). We are particularly interested in developing patient-personalized data-driven “Intensive Care” treatment regimens – inclusive of both new and existing lifestyle, drug, psychotherapy, and device interventions – that reduce suicide risk in the top quintile of patient severity. High density behavioral measures should be used in this high-risk population to intensively track symptoms and environmental factors (exercise, sleep, social interactions, etc.) in those who are the most likely to progress to terminal illness, with a goal of developing patient-controlled “alarms” to trigger suggestions to seek help or more intensive interventions. Our intent is to have the same impact on the survivability of severe, treatment-resistant depression that advances in diagnostics and treatment have had on the survivability of breast cancer. Namely, we want 85% of people to survive their suicidal anhedonic depression for at least 5 years– and perhaps a full lifetime– after diagnosis.
Note that a cross-disciplinary and cross-institutional collaborative effort focusing on anhedonic depression will allow us to build bridges between experts in different areas, and synchronize investigations across levels (e.g. genes, molecules, cells, animal models, humans) from the very beginning of the program. Thus, it is not necessary or desired to form a large consortium or team to address all facets of the program goals (see Thrusts in full program announcement), since the strength of this approach will manifest through program-level integration of efforts from individuals and small agile teams with deep and sometimes narrow expertise. Across all projects, Wellcome Leap will facilitate iterative and collaborative integration of findings to refine models and improve and validate predictive measures, and adapt approaches as our teams make progress together towards our shared goals.

Program Director.

Susanne Ahmari, MD, PhD is a practicing psychiatrist and neuroscientist with expertise in translating findings between humans and model systems. She uses a variety of advanced technical approaches to manipulate and monitor circuits to investigate mechanisms underlying mental illness, including the neural substrates of obsessive compulsive disorder. She established the Translational OCD Laboratory in 2013 to conduct interdisciplinary research that will lead to better treatments for patients. She earned her MD and PhD in Molecular and Cellular Physiology from Stanford University and completed her residency in Psychiatry at Columbia University.

Process and timeline

Program announcement.

30 DAYS FOR PREPARATION AND SUBMISSION OF ABSTRACT

15-Day Abstract review round.

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Day 1

Submission deadline: 22 July 2021

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Day 1

Submission deadline: 22 July 2021

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Day 1

Submission deadline:

22 July 2021

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Day 13

Abstract feedback sent: 4 August 2021

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Day 13

Abstract feedback sent: 4 August 2021

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Day 13

Abstract feedback sent:

4 August 2021

All submissions will receive technical and/or programmatic feedback as well as a recommendation to submit or not submit a full proposal.

30 DAYS FOR PREPARATION OF FULL PROPOSALS AFTER ABSTRACT FEEDBACK

30-Day Full proposal review round.

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Day 43

Submission deadline: 3 September 2021

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Day 43

Submission deadline: 3 September 2021

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Day 43

Submission deadline:

3 September 2021

25-page full proposals including technical approach, milestones, costs, and key personnel submitted. Proposals should specifically address abstract feedback.

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Day 71

Proposal decision sent: 1 October 2021

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Day 71

Proposal decision sent: 1 October 2021

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Day 71

Proposal decision sent:

1 October 2021

All submissions will receive a ‘selected for funding’ or ‘not selected for funding’ decision. Those selected will proceed to contract signature as the final gate with work expected to commence within approximately 30 days.

Mechanics of applying

Who is eligible?

Performers from universities and research institutions: small, medium and large companies (including venture-backed); and government or non-profit research organizations are invited to propose. 

It is not necessary to have submitted an abstract in order to submit a full proposal.

Leap agrees not to use any confidential information disclosed to it in a submitted proposal for any purpose other than the review of a proposal. Leap will not use the information contained in a proposal for Leap’s direct or indirect personal or financial benefit and will not make such information available for the direct or indirect personal or financial benefit of any other organization or individual.

Leap shall not disclose or permit disclosure of any confidential information with anyone who has not been officially designated by Leap to participate in a review and completed a confidentiality agreement. Leap agrees that it shall take all reasonable measures to protect the secrecy of and avoid disclosure or use of confidential information in order to prevent it from falling into the public domain or the possession of unauthorized persons. Such measures shall include, but not be limited to, the same degree of care that Leap utilizes to protect its own confidential information, which shall be no less than reasonable care. Leap further agrees to promptly notify in writing of any actual or suspected misuse, misappropriation or unauthorized disclosure of submitted confidential information which may come to Leap’s attention.

Notwithstanding the above, Leap shall have no liability to Leap with regard to any information which Leap can prove:

(i) was in the public domain at the time it was disclosed or has entered the public domain through no fault of Leap;

(ii) was known to Leap, without restriction, at the time of disclosure, as demonstrated by files in existence at the time of disclosure;

(iii) is disclosed with the prior written approval of the submitter;

(iv) becomes known to Leap, without restriction, from a source other than Leap without breach of this statement; or

(v) is disclosed pursuant to the order or requirement of a court, administrative agency, or other governmental body; provided, however, that Leap shall provide prompt notice of such court order or requirement to submitter to enable submitter to seek a protective order or otherwise prevent or restrict such disclosure.

Furthermore, please recognize that Leap may already be funding, or considering funding, the same or similar technology as covered by a submitted proposal—or have previously received from third parties—information or proposals similar to that which was submitted, that was not subject to confidentiality.

Leap’s adherence to the above use of confidential information shall continue for a period of three (3) years from the receipt date of a submitted proposal.

Proposal application steps.

  1. Download proposals
  2. Download proposal template (and cost and schedule template )
  3. Upload your proposal and submit your application before 3 September at 11:59pm ET.

Frequently asked questions.

If you have questions, please review our FAQ section.

Send inquiries to MCPsych@wellcomeleap.org

Note that while there are many definitions of anhedonia, we are less interested in the investigation of reduced consummatory pleasure, the general experience of pleasure, or the inability to experience pleasure. Rather, as per the description above, we will prioritize investigations of anhedonia as it relates to impairments in the effort-based reward system– e.g. reduced motivation to complete tasks and decreased capacity to apply effort to achieve a goal.

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 [ii] NIH Reporter, https://reporter.nih.gov/, accessed March 2021.

 [iii] Turner EH et al. Selective publication of antidepressant trials and its influence on apparent efficacy. New England J. Med. 358 (3): 252-260 (2008).

 [iv] Cuijpers P et al. Interpersonal psychotherapy for mental health problems: a comprehensive meta-analysis. Am. J. Psychiatry. 173 (7): 680-687 (2016).

[v] Hillhouse TM & Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp.Clin.Psychopharmacology. 23:1: 1-21 (2015).

[vi] Nutt DJ et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur.Neuropsychopharmacol. Suppl 3:S81-6 (1999).

[vii] Murrough J, Abdallah C, & Mathew S. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 16: 472–486 (2017).

[viii] Meltzer-Brody S et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet. 392 (10152): 1058-1070 (2018).

[ix] Coleman J, Green E, & Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature. 532: 334–339 (2016).

[x] Schildkraut JJ. The catecholamine hypothesis of affective disorder: A review of supporting evidence. American Journal of Psychiatry. 122: 509-522 (1965).

[xi] Practice Guideline for the Treatment of Patients with Major Depressive Disorder (3rd Edition). American Psychiatric Association (2010).

[xii] Pentland S. Honest Signals: How they shape our world. MIT Press (2008).

[xiii] Pan LA et al. Neurometabolic Disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. American Journal of Psychiatry. 174 (1): 42-50 (2017).

[xiv] Drysdale et al. Neurometabolic Disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Nature Medicine. 174 (1): 42-50 (2017).

[xv] Moda-Sava et al. Neurometabolic Disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Science. 174 (1): 42-50 (2019).

[xvi] Kupfer DJ, Frank E, & Perel J.M. The advantage of early treatment intervention in recurrent depression. Arch.Gen.Psychiatry. 46: 771-775 (1989).

[xvii] Seely JM & Alhassan T. Screening for breast cancer in 2018– What should we be doing today? Curr.Oncol. 25:S115-S124 (2018).

[xviii] Rush et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry. 163(11):1905-1917 (2006).

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