New antidepressants: tackling treatment resistant depression

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 commonly 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 antidepressants are 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 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.

Treatment-resistant depression: the challenges

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 temporarily, only for them to keep on returning.

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.

“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, recent 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 ketamine, scopolamine, and psilocybin – 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.

Now, new research led by the University of Bristol has explored in detail the neuropsychological effects of these new antidepressants – including esketamine, scopolamine, and psilocybin – 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 use of ketamine as an antidepressant

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 (with 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 actually 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 is in contrast to 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 – a.k.a treatment-resistant depression.

However, Spravato 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.

Can other psychedelic drugs such as psilocybin also act as antidepressants?

Some other types of psychedelic drugs, such as psilocybin (the active compound in magic mushrooms) and MDMA (ecstasy), have shown promise as therapies for treatment-resistant depression. In November 2022, for example, a multicentre clinical trial led by COMPASS Pathways found that a 25mg dose of psilocybin – alongside psychological support – had a significant impact in reducing symptoms of depression in participants with treatment-resistant depression.

Up until a couple of years ago, despite a number of similar 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.

Additionally, a new study from researchers at the University of Georgia suggests that not only can psilocybin treat depression, but it might also be safe, presenting similar side effects to traditional antidepressant medications, including headache, nausea, anxiety, dizziness, and elevated blood pressure. Plus, these side effects were generally well tolerated by participants and faded within 24 to 48 hours. This could be a big win for advocates of using psychedelics as antidepressants, as questions around the safety of these compounds were always going to be brought into question.

Auvelity: another new antidepressant approved for major depressive disorder

As well as esketamine, Auvelity is another recently approved antidepressant, after receiving FDA approval just last year, and is a combination of dextromethorphan – best known as a cough suppressant – and bupropion – used to treat major depressive disorder and facilitate tobacco cessation. While dextromethorphan affects NMDA, glutamate-1, and sigma-1 receptors in the brain, which have all 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.

Zuranolone: a breakthrough short-course antidepressant for postpartum depression

Approved by the FDA in August last year for the treatment of postpartum depression, Zuranolone is viewed as a 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 also 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 last year 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 is being developed by Biogen and Sage Therapeutics.

Combining medication with psychological support and exercise

On top of taking antidepressants, it is important to remember that seeking psychological support is also extremely effective for people suffering from depression, as medication alone might not work if the core issues of their depression are not dealt with or made manageable.

“It is imperative first to understand the environmental risk factors for someone suffering from depression, and psychological support is often needed to identify and learn how to manage such environmental risk factors,” said Jabbi.

“For instance, if there are environmental triggers for some people’s depression, not identifying those environmental stimuli/pathogens and learning how to link those pathogens and the depressive symptoms, and ultimately developing management strategies for both the pathogens and symptoms, antidepressants may not have a lasting effect for those people.”

Furthermore, a recent study found that exercise can also be an important factor when it comes to combatting depression. In fact, some forms of exercise – namely, walking, jogging, yoga, and strength training – could be just as effective as therapy and even better than antidepressants at treating depression, with the new analysis prompting academics to say that these types of exercises should be a “core treatment” for the condition.

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 are estimated to have attempted 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 make 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.

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.