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 differ from more traditional types?
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 to 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 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.
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.
Potential new short-course antidepressant for major depressive disorder
Currently, in phase 3 of clinical development for both major depressive disorder and postpartum depression, if approved, Zuranolone could be 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, executive medical director of Biogen’s emerging neurosciences development unit, explained how Zuranolone 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.”
Zuranolone is currently under review by the FDA after Biogen filed a new drug application for it. Kotecha said that they hope to see the FDA’s decision sometime in August.
The drug is being developed by both Biogen and Sage Therapeutics, and Sage is also testing Zuranolone in a phase 1 trial for treatment resistant depression.
Combining medication with psychological support
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.”
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 seems promising, and they may well provide the answer to helping those suffering with 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.
New technologies related to depression (powered by IN-PART)
- A Method to Control Spreading Depression in the Brain – Penn State University
- Selective Melanotropin Ligands for Neurodegeneration, Depression, or Mood Disorders – University of Arizona
- Natural Compounds to Regulates Winter Depression-like Behavior – Nagoya University
- Kappa Opioid Receptor Ligands for the Treatment of Depression and Anxiety Disorders – University of Kansas
- Neuroimaging Biomarkers for Diagnosing Depression Subtypes and Predicting Treatment Response – Cornell University