New antidepressants: tackling treatment-resistant depression


Depression is estimated to affect around 5% of adults worldwide. It includes several different depressive disorders, including major depressive disorder, seasonal affective disorder, and persistent depressive disorder, all of which can bring great difficulty to people’s lives, resulting in symptoms such as poor concentration, hopelessness about the future, feeling tired or low on energy. , and thoughts of suicide.

Currently, the most commonly prescribed type of medication used to treat depression is a class of antidepressants called serotonin reuptake inhibitors (SSRIs), which prevent neurons from getting rid of serotonin by inhibiting transport proteins, allowing more of the neurotransmitter to interact with neurons for longer. This means that more serotonin is available for further relaying of messages between nearby nerve cells, which ultimately leads to an increase in serotonin levels in the brain.

Another type of antidepressant commonly prescribed is the serotonin and norepinephrine reuptake inhibitors (SNRIs), which are used to treat symptoms of depression, as well as conditions such as fibromyalgia and generalized anxiety disorder. They differ from SSRIs in that they affect serotonin and norepinephrine — hormones and neurotransmitters that play a role in the body’s fight-or-flight response — not just serotonin.

Taking this type of antidepressant in combination with psychological counseling can help relieve 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 overcome.

Treatment-resistant depression: the challenge

Studies it has been shown that about a third of people suffering from depression do not respond to current treatment, with standard treatment either not helping at all, or temporarily improving symptoms, only for them to keep coming back.

People are generally considered to have treatment-resistant depression if they do not respond to adequate doses of two different antidepressants taken for a sufficient length of time, which is usually around six weeks, because SSRIs, for example, usually need to be taken for two to four weeks before any benefit can be seen. felt.

Mbemba Jabbi, board member of the Anxiety and Depression Association of America (ADAA) and assistant professor of the Department of Psychiatry and Behavioral Sciences at Dell Medical School in Texas, USA, believes that depression can be very difficult to treat due to its underlying biology and etiology. the disturbance.

“Severe depression, for example, can be comorbid with many neuropsychiatric and other chronic diseases such as cardiovascular disease, cancer, immune/inflammatory disease, etc. Given this complicated picture of depressive comorbidities, it is important to note that while a diagnosis of depression may precede the onset of other comorbid disorders, depression is also frequently a contributing factor to the diagnosis of other (possibly related) severe illness,” he said.

“Depression is not a simple or single cause or a single or simple biologically caused disorder, and because 20-30% of depressed individuals do not respond well to existing treatments, because biological and environmental causes vary widely, depression and comorbid conditions persist. challenging for medical practitioners to treat and difficult for the majority of patients to manage the various symptoms.”

In addition, depression may have additional biological causes that are not fully understood. For example, recent research has found that serotonin levels, as well as norepinephrine levels, may not be the main or only cause of depression – as previously thought – which may be why medications such as SSRIs and SNRIs may not be effective for some people.

How do the newer antidepressants differ from more traditional types?

After a long period of stagnation, during which no new classes of antidepressants were approved, the approval of esketamine (under the brand name Spravato) by the US Food and Drug Administration (FDA) in 2019, gives hope to people who have not responded to more. traditional antidepressants.

Esketamine belongs to a class of drugs 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 history of use to treat depression, with studies conducted between 2000 and 2006 showing that it is a viable alternative treatment for depression.

Ketamine can offer rapid relief for people with treatment-resistant depression, with some people potentially experiencing benefits in about 40 minutes. This is different from having to wait several whole weeks for the effects of an SSRI to show up – if they do.

Esketamine itself also works differently from traditional antidepressants; instead of targeting specific neurotransmitters in the brain, such as serotonin and norepinephrine, it uniquely targets the glutamate system, which is the main excitatory neurotransmitter in the brain. Essentially, esketamine binds to inhibitory neurons in the brain, causing net excitation in areas of the brain that are part of the depression circuitry.

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 drugs but are not benefiting from them – aka treatment-resistant depression.

However, Spravato is for use only under the supervision of a healthcare provider in a certified physician’s office or clinic because of the risk of serious adverse outcomes from sedation and dissociation, and the potential for drug abuse and abuse.

In addition to esketamine, Auvelity is another recently approved antidepressant, having received FDA approval 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 withdrawal. While dextromethorphan affects NMDA, glutamate-1 and sigma-1 receptors in the brain, which are all involved in the pathophysiology of depression, inhibition of cytochrome P450 bupropion increases blood levels of dextromethorphan, allowing once-daily dosing.

Auvelity is also thought to provide faster-acting relief than traditional antidepressants and can be very effective for people with treatment-resistant depression, providing relief within one week of starting.

A potential novel short-acting antidepressant for major depressive disorder

Currently, in phase 3 of clinical development for 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 in two or three days – but only a 2 week course is required, with effects lasting well beyond that two week period. This takes the burden off of having to chronically take antidepressants, and also helps minimize potential side effects.

Mona Kotecha, executive medical director of Biogen’s new neuroscience development unit, explains how Zuranolone works: “Depression can result from imbalanced signaling pathways in the brain. More and more, we understand new signaling pathways, and one of them is the GABA system. The GABA system is an important pathway in breaking down messages because the brain is really a balance between excitation and inhibition; into excitatory signaling and inhibitory signaling.

“Zuranolone specifically acts on the inhibitory signaling, or GABA pathway, and in working within these 2 weeks, we believe it has the ability, or potential ability, to reset some of the dysfunctional networks in the brain, which we think has an impact. on the mood.”

Zuranolone is currently under review by the FDA after Biogen submitted a new drug application for it. Kotecha said they expect to see an FDA decision sometime in August.

The drug is being developed by Biogen and Sage Therapeutics, and Sage is also testing Zuranolone in a phase 1 trial for treatment-resistant depression.

Combine treatment with psychological support

In addition to taking antidepressants, it is important to remember that seeking psychological support can also be very effective for people suffering from depression, because treatment alone may not work if their underlying depression is not addressed or managed.

“It is very important to first understand environmental risk factors for someone with depression, and psychological support is often needed to identify and learn how to manage these environmental risk factors,” says Jabbi.

“For example, if there are environmental triggers for some people’s depression, do not identify those environmental stimuli/pathogens and learn how to link those pathogens and depressive symptoms, and finally develop management strategies for those pathogens and symptoms, antidepressants may have no side effects. lasting effect on those people.”

A hopeful future for treatment-resistant depression

Finding new methods of dealing with major depressive disorder, especially treatment-resistant depression, is very important, because the risk of suicide is very high; an estimated 30% of people with treatment-resistant depression are thought to have attempted suicide at least once in their lifetime.

Kotecha said that Biogen firmly believes there is an urgent need for innovative therapies for all types of depression. “Depression is a very complex and very heterogeneous multifactorial disease; it affects so many people from all walks of life, and patients may experience depression in many ways.”

“Just think about the staggering number of people who are affected by depression – in Europe, potentially 6 to 7%, and of course many are undiagnosed…a large number of people create the need for multiple types of treatment in the prescription toolbox. more and more important.”

But the recent approvals and research around new antidepressants seem promising, and they may provide answers to help those with treatment-resistant depression.

In addition, Jabbi said that personalized treatment strategies using personalized genomic techniques that can shed light on a person’s genetic make-up could also provide “unprecedented breakthroughs” for treating all types of depression.

New technology on depression (powered by IN-PART)


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