Advances in the treatment of major depression

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Major depression is the most common mood disorder in the world. Also known as clinical depression or simply depression when you have symptoms of depression or hopelessness for at least 2 weeks. Scientists still don’t know what causes it. But they know that treatment is complex and that sufferers need more avenues to get better faster.

For about half a century, scientists have expended great efforts to improve drugs that target a small group of neurotransmitters. These are chemicals in the brain — specifically serotonin, norepinephrine, and dopamine — that affect how your nerve cells communicate with each other, which in turn affects your mood.

Most people respond to standard antidepressants. But at least 30% of people who try two different types of these drugs continue to have symptoms of depression. This is called treatment-resistant depression.

So over the past two decades, scientists have changed their mindset about treating major depressive disorder as their understanding of the brain biology behind depression has changed.

The biggest change is that drug research is no longer just targeting specific neurotransmitters, says Gerard Sanacora, MD, PhD, director of the Yale Depression Research Program in New Haven, CT. “We have opened up a whole new perspective on potential targets for new drugs.”

New drugs and faster results

There’s a long-held notion that depression takes weeks or months to resolve. But new fast-acting treatments have “changed what we think is possible in this area,” says Sanacora.

In 2019, the FDA approved brexanolone (Zulresso). It’s the first drug specifically for postpartum depression, which is a type of major depression. Experts aren’t exactly sure how it works. But it is a man-made version of a steroid that your body makes naturally. It affects your GABA receptors, which help regulate mood.

Brexanolone is not as easy to take as other antidepressants. You get it through a vein in your arm at a healthcare facility over the course of 60 hours. But it can work fast. Your depression symptoms may lessen by the end of your treatment.

That same year, another breakthrough drug hit the market.

Esketamine is a prescription nasal spray. The low-dose psychedelic drug increases the activity of glutamate in parts of your brain related to mood. Glutamate’s job is to stimulate cells in the brain and nervous system. Esketamine can also trigger new connections in your brain. You can see improvements in your depression within hours or days of use, Sanacora says.

Esketamine offers life-saving hope for those with suicidal thoughts and relief for those with treatment-resistant depression. However, when used alone, symptom relief may only last a few weeks. For this reason, experts agree that you should take fast-acting medications alongside traditional treatments.

For mild or moderate depression, Sanacora still suggests cognitive behavioral therapy first, followed by conventional antidepressants, also known as selective serotonin reuptake inhibitors (SSRIs). Doctors need more information about the safety and long-term effects of newer treatments for depression.

“Over the past 20 years, we’ve seen a transformative change in the way we treat depression,” says Sanacora. “But we still need to smooth it out to understand which patients these treatments are best for and when.”

Improvements in brain stimulation

Medications are not the only treatment for depression. Electroconvulsive therapy has been around for more than 70 years. It remains one of the most effective ways to treat major depressive disorder, especially if you’re not responding to other treatments. While not new, scientists have refined the process over the past few decades.

Electroconvulsive therapy today uses less energy than it used to. The goal is to give you the same benefits but with fewer negative effects on your memory and thinking skills. “It was a tremendous improvement,” says Susan Conroy, MD, PhD, a psychiatrist and neuroscientist at Indiana University School of Medicine.

Conroy also uses transcranial magnetic stimulation to treat depression, which has fewer side effects than electroconvulsive therapy. It works by sending magnetic pulses around your skull.

Brain tissue translates these signals into electrical energy, Conroy says, changing the way areas of your brain talk to each other. “By changing these circuits, we believe that this is how transcranial magnetic stimulation relieves people of depression.”

This and other forms of brain stimulation are not suitable for everyone. But tell your doctor if other treatments aren’t helping and your depression is preventing you from daily activities, not eating, and constantly having suicidal thoughts.

“These are all signs that your treatment needs to be escalated, and fairly quickly,” says Conroy.

future treatment

Many other promising treatments for depression are on the horizon. Deep brain stimulation is one of them. In this treatment, a surgeon implants electrodes in your brain. These nodes send out painless zaps that alter the electrical activity that’s causing your symptoms.

You can think of this treatment as a pacemaker for your mood. While it’s not approved for the general public, it could be soon. “Technology is advancing very quickly,” says Conroy.

Researchers are also studying a drug called SAGE-217. According to Sanacora, there is interest in how it might help prevent a serious relapse in people with a history of depression. The idea is that you would take it as soon as your symptoms came back. “But you don’t wait until the symptoms are fully developed,” he says.

There’s also a lot of fuss around drugs like psilocybin. Studies show that these “magic mushrooms” can relieve depression about as quickly as ketamine — which is what esketamine is made from — with effects that can last longer. But when it comes to psychedelics, Sanacora says, “We need a lot more research before we can say anything with confidence.”

In his 25 years in the field, Sanacora says he’s never experienced such excitement around treating depression. But that doesn’t mean researchers have all the answers or that there’s a cure for major depression.

Still, there are steps you can take now to relieve depression or protect yourself from relapsing. This can include medication, various types of talk therapy, regular exercise, a good social life, and a healthy sleep routine. You should “do all the things that we know you can do to protect yourself as best you can,” Sanacora says.



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