Lead Investigator: Amit Etkin, Alto Neuroscience, Inc
Title of Proposal Research: Role of clinical, historical and demographic factors in the response to antidepressants versus placebo
Vivli Data Request: 7541
Funding Source: Employee salaries at Alto Neuroscience, Inc. are supported by internal Alto funds
Potential Conflicts of Interest: Full-time employee of Alto Neuroscience-work being proposed is part of the job responsibilities for Alto. Alto is supporting this project. Adam Savitz owns stock in Johnson&Johnson and was a full time employee of J&J (Janssen Research & Development) until July 2021. No conflict with this project. J&J has no involvement in the project.
Summary of the Proposed Research:
Antidepressant selection is presently a trial-and-error process. One of the most common treatments for depression are selective serotonin reuptake inhibitors (SSRI), which are believed to act by increasing levels of serotonin to the brain. Data from seminal clinical trials, such as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, demonstrates that after failure of an SSRI, there is an equal probability of response to another SSRI, a serotonin norepinephrine reuptake inhibitor (SNRI), or bupropion. Antidepressants work by increasing the levels of key neurotransmitters in the brain. Common targets include: serotonin, a chemical produced by nerved cells and considered to be a mood stabiliser; norepinephrine, a chemical released by the nervous system in response to stress; and dopamine, produced by the nervous system to send messages between nerve cells. SSRIs increase serotonin levels, whereas SNRIs increase serotonin and norepinephrine, and bupropion increases norepinephrine and dopamine. These are all key neurotransmitters that help improve mood and other symptoms of depression. Despite these similarities and differences in the mechanisms of each of these classes of drugs, we still know relatively little about who responds best to antidepressants and why. As such patients may go through many successive trials of antidepressant medications (ADMs) before finding an effective one for them, without any information to guide this process. This unguided process of treatment selection results in substantial morbidity, increased mortality (including risk of suicide), tremendous patient and provider frustration, and a high risk of the patient dropping entirely out of treatment. As such, the need to establish which treatments are most effective for a patient with major depressive disorder (MDD) is a deeply pressing clinical and societal issue.
Little is known about whether clinical or demographic variables differentially predict treatment outcome. Information gained on this question would further our understanding of the impact and relevance of non-traditional antidepressant mechanisms of action, may help select patients who may optimally respond to one treatment or the other, or guide the development of future novel medicines. We will address this question using aggregated analyses of clinical and demographic data from randomized clinical trials treating MDD. Pooling datasets will allow high statistical power, should reduce bias from specific site / study effects, and allow a broad exploration of different drugs and drug classes. Our statistical methods will be ones common to clinical trial research, as well as those more closely related to simple forms of machine learning. Given the broad relevance of the proposed analyses, meaningful impact is expected for the general population of depressed patients (22M in the US alone), as well as patients with anxiety or trauma-related disorders in which antidepressant treatment is also a mainstay (10M’s in the US). Indeed, at present it is estimated that one in eight in the US is on an antidepressant at any given time, thus illustrating both the breadth and need for a precision approach such as that described herein.
Requested Studies:
Duloxetine Versus Placebo in the Long-Term Treatment of Patients With Late-Life Major Depression
Data Contributor: Lilly
Study ID: NCT00406848
Sponsor ID: 10815
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to Evaluate the Efficacy and Safety of Once Daily Oral Lu AA21004 in Patients With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT02389816
Sponsor ID: LuAA21004/CCT-004
A Phase 3, Randomized, Placebo-Controlled, Double-Blind, Parallel-Design Study to Evaluate the Short-Term, Fixed Dose Efficacy and Safety of LY110140 Once Daily Dosing in Japanese Patients With Major Depressive Disorder
Data Contributor: Lilly
Study ID: NCT01808612
Sponsor ID: 14595
A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Flexible Dose Study on the Efficacy of Lu AA21004 on Cognitive Dysfunction in Adult Subjects With Major Depressive Disorder (MDD)
Data Contributor: Takeda
Study ID: NCT01564862
Sponsor ID: LuAA21004_202
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase III Study to Assess the Efficacy and Safety of Lu AA21004 in Patients With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT01355081
Sponsor ID: LuAA21004/CCT-003
A Multinational, Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Assess the Efficacy and Safety of Lu AA21004 in Patients With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT01255787
Sponsor ID: LuAA21004/CCT-002
A Phase 3, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed-Dose Study Comparing the Efficacy and Safety of 2 Doses (10 and 15 mg) of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT01179516
Sponsor ID: LuAA21004_317
A Phase 3, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed-Dose Study Comparing the Efficacy and Safety of 2 Doses (10 and 20 mg) of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT01163266
Sponsor ID: LuAA21004_316
A Phase 3, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Duloxetine-Referenced, Fixed-Dose Study Comparing the Efficacy and Safety of 2 Doses (15 and 20 mg) of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT01153009
Sponsor ID: LuAA21004_315
A Double-Blind, Efficacy and Safety Study of Duloxetine Versus Placebo in the Treatment of Children and Adolescents With Major Depressive Disorder
Data Contributor: Lilly
Study ID: NCT00849901
Sponsor ID: 6223
A Double-Blind, Efficacy and Safety Study of Duloxetine Versus Placebo in the Treatment of Children and Adolescents With Major Depressive Disorder
Data Contributor: Lilly
Study ID: NCT00849693
Sponsor ID: 7109
A Randomized, Double-blind, Parallel-Group, Placebo-Controlled, Fixed-Dose Study Comparing the Efficacy and Safety of 3 Doses of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT00735709
Sponsor ID: LuAA21004_305
A Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed-dose Study Comparing the Efficacy and Safety of Lu AA21004 Versus Placebo in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT00672958
Sponsor ID: LuAA21004_303
A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Fixed-Dose Study Comparing the Efficacy and Safety of 2 Doses of Lu AA21004 in Acute Treatment of Adults With Major Depressive Disorder
Data Contributor: Takeda
Study ID: NCT00672620
Sponsor ID: LuAA21004_304
Duloxetine Versus Placebo in Patients With Major Depressive Disorder (MDD): Assessment of Energy and Vitality in MDD
Data Contributor: Lilly
Study ID: NCT00536471
Sponsor ID: 11669
Duloxetine Versus Placebo in the Treatment of Elderly Patients With Major Depressive Disorder
Data Contributor: Lilly
Study ID: NCT00062673
Sponsor ID: 6091