Why are placebos defeating antidepressants in clinical trials?

Depression affects around 5% of the global population, with antidepressants commonly prescribed to manage conditions like major depressive disorder, seasonal affective disorder, persistent depressive disorder, and bipolar depression. However, many candidates for depression don’t make it past clinical trials, and of late, there has been a trend of failures in the field. This is mainly due to one reason: placebos beating antidepressant treatments in efficacy studies.

In this article, we examine recent clinical failures, explore the significant impact of the placebo effect, and discuss potential pathways forward for antidepressant drug research.

J&J’s aticaprant and Neumora’s navacaprant KOR antagonists miss endpoints in depression clinical trials

The most recent drug candidate to fail in clinical trials for depression is Johnson & Johnson’s aticaprant. While the pharma giant has said that it will “explore future development opportunities for aticaprant in other areas of high unmet need,” it has washed its hands off treating depression because of the drug’s low effectiveness in phase 3 studies. 

Aticaprant is a kappa opioid receptor (KOR) antagonist. This means that it blocks KORs in the brain, which are a type of G protein-coupled receptors that play a role in regulating pain, mood, reward, and stress responses. These drugs are meant to reduce dysphoria and stress and improve mood. 

Another KOR antagonist that recently flunked a phase 3 trial was Massachusetts-based Neumora Therapeutics’ navacaprant. When this news broke out in January, the company stocks plunged by 80%. Navacaprant failed to meet the primary endpoint of reduction in depressive symptoms as measured by the MADRS total score – a scale that measures the severity of depressive symptoms – compared to placebo. Patients who received navacaprant experienced the same changes on the MADRS scale as those in the placebo group. Following this, Neumora scrapped one trial of navacaprant in bipolar depression and two in major depressive disorder (MDD). 

What does the placebo effect have to do with clinical failures in depression research?

The effectiveness of antidepressants hinges on overtaking what is called the placebo effect – a phenomenon where symptoms appear to improve in patients, which tends to be driven by their belief in the treatment’s effectiveness rather than the treatment itself.

In depression, the placebo response rate is typically reported to be between 35% and 45%, explained Dan Gloldstaub, pharma executive and scientific co-founder of PhaseV, a clinical trial optimization company.

“This is substantial compared to many other medical treatments, however, similar to the rates in several other diseases where the mental status strongly affects the disease, like in autoimmune diseases,” said Gloldstaub.

A study titled ‘Antidepressants and the Placebo Effect’ published in the National Library of Medicine in 2014 pointed out that while there is a strong therapeutic response to antidepressant medication, patient response to placebo is almost as strong.

“This presents a therapeutic dilemma. The drug effect of antidepressants is not clinically significant, but the placebo effect is,” the study read.

Depression candidate Supernus’ SPN-820 fails in phase 2b clinical trial; Alto Neuroscience and Actinogen blame placebos

This was seen with American biotech Supernus Pharmaceuticals’ depression candidate SPN-820, which tanked a phase 2b clinical trial. SPN-820 is an oral small molecule that targets synaptic function – how neurons communicate with each other – in the brain by activating the mTORC1 pathway. By boosting synaptic activity, it aims to improve brain function. 

The candidate was previously touted for showing a “rapid and substantial” effect in a phase 2a MDD trial late last year. In fact, the drug was found to improve symptoms in patients within two hours of taking the medicine, and suicidal ideation decreased by 80%.

However, SPN-820’s glory in the clinic didn’t last for long. In February, Supernus reported that patients who received the therapy showed no improvement in their MADRS at week four when compared to placebo.

This gust of failures traces back to last year. California-based Alto Neuroscience’s ALTO-100 was among them. It is an oral small molecule that is designed to enhance neural plasticity in the hippocampus, which is the region in the brain linked to both cognition and mood. According to Alto, it builds on a long-standing theory that depression is partly driven by a reduction in hippocampal neuroplasticity and is, therefore, targeted to those patients who experience this neuroplasticity deficit.

In the failed phase 2b trial, the primary endpoint was the change from baseline to the end of the six-week double-blind treatment period on the MADRS scale. This was not met, and the drug candidate did not demonstrate benefit over placebo on key secondary endpoints either.

Still, Alto has no plans to ditch ALTO-100 as it sits on the $147.9 million funding it raised when it went public last year. This will probably fuel clinical trials for its other candidates in other neuropsychiatric conditions as well as upcoming readouts of ALTO-100 in bipolar depression. 

Meanwhile, last year, Australian neurotherapeutics developer Actinogen’s cortisol blocker xanamem also failed a trial, yet again due to a higher response from the placebo group. According to the company, “the unexpectedly large placebo mean improvement” may have impaired the trial’s ability to observe the drug’s short-term pro-cognitive effects.

Xanamem works by selectively inhibiting an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the brain, which converts inactive cortisone to active cortisol, a key hormone that triggers stress responses.

At the time, Actinogen stocks dropped by 60%. However, less than two weeks later, the company released new clinical data in an attempt to revive investor confidence in the drug. Although the drug did not meet its primary endpoint, it hit secondary endpoints. Patients on Xanamem experienced a 50% higher rate of remission of depression compared to those who received the placebo. Despite its primary endpoint failure, xanamem proved to be “clinically active in the brain,” according to Steven Gourlay, chief executive officer (CEO) of Actinogen.

Relmada crashes out; proposes M&A

But not all biotechs in the neuropsychiatric space have had a comeback like Actinogen. Relmada Therapeutics has had a series of flops in recent years. The most recent debacle was reported in December when it scrapped two phase 3 trials of its depression drug REL-1017 after a data monitoring committee expressed that it didn’t have hopes that the drug would succeed in an MDD study. This led to the company announcing that it is open to potential merger and acquisition deals.

This was following setbacks in REL-1017 clinical trials back in 2022 and 2023 as the drug was unable to outperform the placebo in reducing depression symptoms. 

Antidepressants heighten placebo effect: are old studies relevant today?

All this continues to point to the effect of placebos in depression clinical trials. But is there light at the end of the tunnel? An international study published in The Lancet in 2018 comprising 16,477 participants found that 21 of the most commonly used antidepressants were more effective than placebo for the short-term treatment of depression in adults. The effectiveness ranged from small to moderate for different drugs. 

Moreover, a decade-old study demonstrated that people with depression who respond strongly to placebos actually benefit greatly from real antidepressants. Brain scans found mu-opioid system responses – plays a role in mood regulation – to antidepressants in people who previously received a placebo. So, “understanding how well a person responds to placebo could also inform a treatment plan,” a Time article stated.

Extended approval for Spravato: first monotherapy for depression

While the past year has been clouded by several clinical trial failures, there have been a few wins in the depression space. Spravato (esketamine), a nasal spray that was approved for the first time in 2019 as a combination drug for treatment-resistant depression along with an oral antidepressant, has now become the first and only monotherapy in the U.S. to address the condition. This was following the J&J drug hitting the endpoint after four weeks and showing a rapid and superior improvement against the placebo in the MADRS total score as early as 24 hours.

Spravato is derived from ketamine, an anesthetic that is used to relieve pain, and belongs to a class of drugs called N-methyl D-aspartate (NMDA) receptor blockers. Ketamine has been studied as an antidepressant for years and has proven to offer rapid relief for people with treatment-resistant depression. It works differently from traditional antidepressants as it targets the glutamate system, which is the major excitatory neurotransmitter in the brain, instead of neurotransmitters.

Besides non-traditional methods to treat depression like Spravato, deep-brain stimulation is an approach that is believed to make headway against treatment-resistant depression. American healthcare company Abbott has begun a pivotal clinical trial, having previously been successful in helping manage Parkinson’s disease and essential tremor symptoms.

Meanwhile, Neurocrine Biosciences has launched a phase 3 trial of osavampator in MDD. Osavampator is an AMPA-positive allosteric modulator (PAM), which aids in fast excitatory neurotransmission in the brain.

Clinical trials of antidepressants “screen out” ineffective drugs

Clinical trials of antidepressants are essentially a filter that screens out not only ineffective drugs but also those that don’t fit into the strict framework of the pharmaceutical business, explained Erik Larson, the owner of Larson Mental Health in Colorado in the U.S. 

“A drug may work well for some patients, but if the statistics for the group as a whole sag, the project is shut down. Depression doesn’t lend itself to a universal solution, and research requires clear, predictable results. Thus, if a drug doesn’t fit into these frameworks, it doesn’t move forward, even if it has a powerful effect on some people,” said Larson.

Another reason is side effects that can outweigh the benefits, Larson expressed. “Sometimes a drug really helps but causes something that is difficult to sell in attractive packaging. This can be severe apathy, loss of motivation, or physical discomfort. Moreover, the testing process itself is imperfect. A patient with a dynamic, ever-changing condition is offered one fixed solution, ignoring the evolution of their disorder. That’s why a large number of potentially useful drugs fail to get to market simply because they don’t fit into the predetermined framework.”

Moreover, as mentioned previously, the placebo effect seems to affect antidepressant efficacy. Gloldstaub believes that artificial intelligence (AI) tools could help distinguish between the drug and placebo effects.

“This strong interplay requires strong tools such as AI tools and a very sophisticated methodology that will be used in the clinical trial in order to minimize the masking effects of placebo from the drug effects, on the one hand, and will allow the optimal effects of the drug on the other,” said Gloldstaub.

Plus, despite many candidates not meeting expectations in late-stage MDD studies, some of these biotechs have not pulled the plug on these candidates just yet. As research continues on how to overcome placebo concerns in trials, drugs could be optimized to beat placebos and hopefully reap success in the clinic.