Depression is thought to affect approximately 5% of adults worldwide. It encompasses several different depressive disorders, including major depressive disorder, seasonal affective disorder, and persistent depressive disorder, all of which can bring enormous difficulty to people’s lives, resulting in symptoms like poor concentration, hopelessness about the future, feeling tired or low in energy, and suicidal thoughts.
Currently, the most prescribed type of medication used to treat depression is the class of antidepressants called serotonin reuptake inhibitors (SSRIs), which prevent neurons from removing serotonin by inhibiting a transporter protein, allowing more of the neurotransmitter to interact with neurons for longer. This means more serotonin is available to pass further messages between nearby nerve cells, ultimately leading to an increase in the levels of serotonin in the brain.
Another commonly prescribed type of antidepressant is serotonin and norepinephrine reuptake inhibitors (SNRIs), used to treat depression symptoms, as well as conditions like fibromyalgia and generalized anxiety disorder. They differ from SSRIs due to the fact that they impact both serotonin and norepinephrine – a hormone and neurotransmitter that plays a role in the body’s fight-or-flight response – rather than just serotonin.
Taking these types of antidepressants in combination with psychological counseling can help to ease the symptoms of depression for many people. However, under the category of major depressive disorder, there is what is known as treatment-resistant depression, which can be a real challenge to tackle.
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Treatment-resistant depression: The challenges of developing effective medicines
Studies have shown that about one-third of people suffering from depression do not respond to current medications, with standard treatments either not helping at all or improving symptoms only temporarily.
People are generally considered to have treatment-resistant depression if they have not responded to adequate doses of two different antidepressants taken for a sufficient duration of time, which is usually around six weeks, as SSRIs, for example, usually need to be taken for two to four weeks before the benefit can be felt.
Mbemba Jabbi, Anxiety and Depression Association of America (ADAA) board member and assistant professor of the Department of Psychiatry and Behavioral Sciences at Dell Medical School in Texas, U.S., believes that depression can be so difficult to treat due to the underlying biology and etiology of the disorder.
“Major depression, for instance, can be comorbid with many neuropsychiatric and other chronic diseases such as cardiovascular diseases, cancers, immune/inflammatory diseases, etc. In light of these intricate comorbidity pictures of depression, it is essential to note that while a diagnosis of depression can precede the onset of other comorbid disorders, depression is also often a possible, resulting factor for the diagnosis of other (possibly related) severe diseases,” he said.
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“Depression is not a simple or single origin or a simple or single biologically caused disorder, and because 20-30% of depressed individuals do not respond well to existing treatments, because the biological and environmental causes are highly variable, depression and comorbid conditions remain challenging to treat by medical practitioners and difficult for a majority of patients to overcome the various symptoms.”
Moreover, depression may have additional biological causes that are not yet fully understood. For example, research has found that serotonin levels, as well as norepinephrine levels, might not be the main or only causes of depression, as was originally thought, which could be the reason that medications such as SSRIs and SNRIs might be ineffective for some people.
How do new antidepressants work?
In recent years, there have been a number of new antidepressants reaching the market that act differently from traditional antidepressants; not only are they more effective, but they are also faster at relieving symptoms of depression.
These rapid-acting antidepressants, including psychedelics, have been found to have immediate and lasting positive effects on mood in patients with depression. However, how exactly these effects arise has been relatively unknown – until recently.
Research led by the University of Bristol has explored in detail the neuropsychological effects of these new antidepressants and has found that these drugs work by modulating affective biases associated with learning and memory. Affective biases occur when emotions alter how the brain processes information, and negative affective biases are thought to contribute to the development and continuation of depressed mood.
The rise of psychedelics for depression
A new class of antidepressants: Ketamine-based therapies
After a long period of stagnation, in which no new classes of antidepressants were approved, the U.S. Food and Drug Administration (FDA) approval of esketamine (under the brand name Spravato) in 2019 gave hope to people who had not been responding to more traditional antidepressants.
Esketamine belongs to a class of medications called N-methyl D-aspartate (NMDA) receptor blockers and is derived from ketamine, a dissociative anesthetic used in hospitals and veterinary clinics. Ketamine has a long-standing history of being used to treat depression, with studies being conducted between 2000 and 2006 showing that it was a viable alternative treatment for depression.
Ketamine can offer rapid relief for people with treatment-resistant depression, with some people potentially feeling the benefits within around 40 minutes. This contrasts with having to wait a few whole weeks for the effects of SSRIs to kick in – if they do at all.
Esketamine itself also works differently from traditional antidepressants; instead of targeting certain neurotransmitters in the brain, such as serotonin and norepinephrine, it uniquely targets the glutamate system, which is the major excitatory neurotransmitter in the brain. Essentially, esketamine binds to the inhibitory neurons in the brain, causing net excitation in the areas of the brain that are part of the depression circuit.
Spravato is a nasal spray to be used in conjunction with an oral antidepressant for the treatment of depression in adults who have tried other antidepressant medications but have not benefited from them.
However, the spray is only to be used under the supervision of a healthcare provider in a certified doctor’s office or clinic due to the risk of serious adverse outcomes resulting from sedation and dissociation, and the potential abuse and misuse of the drug.
Other psychedelic drugs, like psilocybin and MDMA, can also act as antidepressants
Some other types of psychedelic drugs, such as psilocybin (the active compound in magic mushrooms) and lysergic acid diethylamide (LSD), have also shown promise as therapies for treatment-resistant depression.
Up until a couple of years ago, despite several studies showing that psilocybin can rapidly treat depression, little was known about how psilocybin actually works to relieve depression in the brain. But, eventually, two studies – one published in The New England Journal of Medicine and one in Nature Medicine – managed to shed some light on how psilocybin and other psychedelics might work on the brain.
Psilocybin appears to reduce activity in the medial prefrontal cortex, an area of the brain that helps regulate certain cognitive functions, including attention, inhibitory control, habits, and memory. The compound decreases connections between this area and the posterior cingulate cortex, which is an area that is thought to play a role in regulating memory and emotions. An active connection between these two areas is usually a feature of the brain’s “default mode network”, which is active when people rest and focus internally. By reducing the activity of the network, psilocybin may work by removing the constraints of the internal “self”, as users reported an “opened mind” with an increased perception of the world around them, therefore reducing symptoms of depression.
From a clinical perspective, there is one standout psychedelic company currently developing a drug for treatment-resistant depression. Compass Pathways, which has come up with a synthetic form of psilocybin, announced in February that a phase 3 trial of its lead candidate COMP006 for treatment-resistant depression achieved its primary endpoint. This was the second of two phase 3 trials, both of which have confirmed a highly differentiated profile for COMP360, demonstrating a level of clinical effect that has historically been extremely difficult to achieve in treatment-resistant depression. Compass has now requested a meeting with the FDA to discuss a rolling submission and review, and it expects to complete a New Drug Application (NDA) submission in Q4 of 2026.
Meanwhile, another company worth mentioning, which is developing an optimized form of the hallucinogenic drug lysergic acid diethylamide (LSD), is Definium Therapeutics (previously called MindMed). Although its lead candidate MM120 is in phase 3 for generalized anxiety disorder and major depressive disorder, rather than specifically for treatment-resistant depression, it has generated a lot of attention. In fact, we listed the company as “one to watch” in 2026, as it has not faced the setbacks of other psychedelic drug companies, and its generalized anxiety disorder studies are expected to produce topline results in the first and second half of 2026, while results of the major depressive disorder study are also expected to come in the second half of this year.
Next-generation neuroplastogens: A push toward non-hallucinogenic alternatives
Neuroplastogens are a novel class of compounds inducing rapid and enduring neuroplasticity – which is essentially the brain’s ability to regrow and reform lost connections.
While traditional psychedelics like those already mentioned have emerged as some of the most potent known neuroplastogens, they have also come under fire as experts have said these drugs have a higher risk of triggering a psychotic or manic episode in people who have a personal or family history of schizophrenia or bipolar disorder.
This has led to a growing wave of “next-generation” neuroplastogens that separate the therapeutic neuroplastic effects of psychedelics from their hallucinogenic properties. These compounds are widely viewed as more commercially viable because they could potentially be prescribed in more conventional clinical settings, integrated into existing healthcare systems more easily, and administered without extensive psychological support infrastructure.
Two notable companies working on these types of compounds are Enveric Biosciences and Elkedonia. Both are developing therapies for treatment-resistant depression and other neuropsychiatric disorders; however, both are yet to reach the clinic due to the field still being in its infancy.
Enveric’s lead candidate, EB-003, is a novel neuroplastogen that engages both the 5-HT2A and 5-HT1B receptors, a dual mechanism that may define a new class of neuropsychiatric treatments. This pharmacological profile is designed to promote adaptive rewiring of brain circuits while stabilizing emotional and behavioral regulation, potentially enabling durable recovery in patients with post-traumatic stress disorder (PTSD), treatment-resistant depression, and generalized anxiety. It has shown promising preclinical results in models relevant to depression and post-traumatic stress disorder (PTSD), with a focus on oral dosing and scalability, which differentiates it from more clinic-intensive approaches.
Elkedonia, meanwhile, closed an €11 million ($12.68 million) seed round in June last year to identify and optimize drug-like small molecule inhibitors of Elk1. According to the company, supporting evidence from preclinical and clinical studies suggests that Elk1 inhibition is a therapeutic lever in depression, with rapid efficacy, and is devoid of sedation, dependence, hallucinations, or other side effects commonly associated with existing antidepressant treatments.
Although these next-generation neuroplastogens are still in preclinical stages, they could become extremely promising new antidepressants for treatment-resistant depression if they live up to expectations in clinical trials.
Other new antidepressants recently approved for major depressive disorder: Auvelity and Zuranolone
Auvelity is another new antidepressant that has received the green light in recent years, after gaining FDA approval in 2022. It is a combination of dextromethorphan, best known as a cough suppressant, and bupropion, which is used to treat major depressive disorder and facilitate tobacco cessation. While dextromethorphan affects NMDA, glutamate-1, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression, bupropion’s cytochrome P450 inhibition boosts dextromethorphan’s blood levels, allowing for once-daily dosing.
Auvelity is also thought to provide faster-acting relief than traditional antidepressants and could be especially effective for people with treatment-resistant depression, providing relief within one week of commencement.
Furthermore, upon its approval by the FDA in 2023 for the treatment of postpartum depression, Zuranolone was viewed by many as another potentially groundbreaking new antidepressant.
This is because, not only is it fast-acting – some people may feel better within two or three days – but only a 2-week course is required, with the effects being sustained well beyond the period of those two weeks. This takes away the burden of having to take antidepressants chronically and helps to minimize any potential side effects.
Mona Kotecha, M.D., executive medical director, head of Zuranolone clinical development, explained how the new antidepressant works: “Depression may result from imbalanced signaling pathways in the brain. More and more, we’re understanding new signaling pathways, and one of those is the GABA system. The GABA system is a pathway that is important in tampering down messaging because the brain is really a balance of excitation and inhibition – so, excitatory signaling and inhibitory signaling.
“Zuranolone specifically works on inhibitory signaling, or the GABA pathway, and in working in these 2 weeks, we believe that it has an ability, or potential ability, to reset some of the dysfunctional networks in the brain, which we think have an impact on mood.”
Its FDA approval made Zuranolone the first oral treatment for postpartum depression, as treatment for the indication had previously only been available as an IV injection given by a health care provider in certain health facilities.
The drug was developed by Biogen and Sage Therapeutics.
A hopeful future for treatment-resistant depression
Finding new methods of tackling major depressive disorder, particularly treatment-resistant depression, is imperative, as the suicide risk is extremely high; an estimated 30% of people with treatment-resistant depression attempt suicide at least once in their lifetime.
Kotecha said that Biogen strongly believes there is an urgent need for innovative therapies for all types of depression. “Depression is a very complex, multifactorial disease and is very heterogeneous; it affects so many people from different walks of life, and patients may experience depression in a multitude of ways.”
“Just thinking about the staggering number of people who are affected by depression – in Europe, potentially 6 to 7%, and certainly many are going undiagnosed…the sheer number of people makes the need for a variety of types of treatments in the prescriber’s toolbox ever more important.”
But the recent approvals and research around new antidepressants certainly seem promising, and they may well provide the answer to helping those suffering from treatment-resistant depression.
Additionally, the recent executive order signed by Donald Trump in April 2026 aimed at accelerating research, regulatory review, and access to psychedelic drugs to treat serious mental health conditions is driving renewed investor and industry attention.
“I think the recent executive order has driven meaningful renewed interest in the field because it created both the perception, and probably the reality, that some of the historical regulatory barriers, timelines, cost, and risk associated with neuropsychiatric drug development may start to come down,” Joseph Tucker, chief executive officer (CEO) of Enveric Biosciences, told Labiotech. “You have potentially better agency coordination, broader use of expedited pathways, and a more obviously supportive top down (i.e. federal) stance toward the field in general, all of which could meaningfully improve development efficiency over time. All of this is ramping up investor attention, and possibly even renewed pharma interest, in the space.”
He added that he thinks this may benefit next-generation neuroplastogenic compounds, like Enveric’s EB-003, over first-generation psychedelic-assisted therapies. “If timelines compress and more capital enters the field, scalability and commercial practicality should become increasingly important in terms of differentiating innovative therapies. Treatments requiring lengthy in-clinic monitoring, multiple healthcare providers, and physical infrastructure can become expensive and difficult to deploy at a large scale, even if they are clinically effective.
“In my opinion, this situation will create a growing advantage for companies developing compounds that may be able to deliver neuroplasticity and therapeutic benefit while fitting more naturally into scalable pharmaceutical treatment models, such as oral outpatient therapies with less functional impairment and reduced monitoring requirements. I think investors and pharma companies will increasingly focus on differentiation, scalability, and overall healthcare system fit, not just whether a compound is psychedelic.”
Moreover, Jabbi said that personalized treatment strategies using personalized genomics techniques that could account for an individual’s genetic makeup may also provide “never-before-achieved breakthroughs” for treating all kinds of depression.
Ultimately, with all the activity going on in the field, it seems that the future could indeed be hopeful for patients suffering from depression.
This article was originally published in May 2023 and has since been updated by Willow Shah-Neville in May 2026.
