Advances in Treatment for Major Depressive Disorder

Major depressive disorder is the most prevalent mood disorder in the world. Also called clinical depression, or just depression, it occurs when you have symptoms of low mood or hopelessness for at least 2 weeks. Scientists still don’t know what causes it. But they know it’s complicated to treat and people who have it need more ways to feel better faster.

For nearly half a century, scientists have devoted considerable effort to improving drugs that target a small set of neurotransmitters. They are chemicals in the brain – serotonin, norepinephrine, and especially dopamine – that affect how your nerve cells communicate with each other, which then affects your mood.

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

So, over the past 2 decades, scientists have changed the way they think about treating major depressive disorder as their understanding of the brain biology behind depression has changed.

The biggest change, says Gerard Sanacura, MD, PhD, director of the Yale Depression Research Program in New Haven, CT, is that drug research targets only specific neurotransmitters. “We’ve opened up a whole new vista of potential targets for new drugs.”

New drugs and faster results

A long-held belief is that depression takes weeks or months to resolve. But Sanacura says the new rapid treatment has “changed what we think is possible in the field.”

In 2019, the FDA approved braxenolone (Zolriso). It is the first drug specifically for postpartum depression, 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 60 hours. But it can work faster. Your symptoms of depression may begin to disappear by the end of your treatment.

Another successful drug came out in the same year.

Esketamine is a prescription nasal spray. Low-dose psychedelic drugs increase glutamate activity in parts of your brain related to mood. Glutamate’s function is to stimulate cells in the brain and nervous system. Esketamine can also stimulate new connections in your brain. You may start to see an improvement in your depression within hours or days of using it, Sanakura says.

Esketamine offers life-saving hope for people with suicidal thoughts and relief for people with treatment-resistant depression. But when used alone, symptom relief may last only a few weeks. That’s why experts agree that you should take fast-onset medications alongside conventional treatments.

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

“Over the past 20 years, there has been a transformational change in the way we treat depression,” Sanakura says. “But we still have to refine our understanding of which patients these treatments are best for and when.”

Improved brain stimulation

Medication is not the only treatment for depression. Electroconvulsive therapy has been around for over 70 years. It’s one of the most effective ways to treat major depressive disorder, especially if you don’t respond to other treatments. Although it is not new, scientists have refined this method over the past decades.

Today, electroconvulsive therapy uses less energy than in the past. The goal is to give you the same benefits but with less negative effects on your memory and thinking skills. “It’s a huge improvement,” says Susan Conroy, MD, PhD, a psychiatrist and neuroscientist at the 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 scalp.

Brain tissue converts these signals into electrical energy, which changes the way your brain communicates with each other, Conroy says. “By changing this circuitry, we think about how transcranial magnetic stimulation improves people with depression.”

These and other forms of brain stimulation are not right for everyone. But tell your doctor if other treatments don’t help and your depression prevents you from doing daily activities, you’re not eating, and you have persistent suicidal thoughts.

“These are all signs that you need to speed up your treatment and do it very quickly,” says Conroy.

Future treatment

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

You can think of this treatment as a pacemaker for your mood. Although this is not yet approved for the general public, it may be soon. “Technology is advancing really quickly,” says Conroy.

Researchers are also studying a drug called SAGE-217. There’s interest in how it might help prevent relapse in people with a history of depression, Sanakura says. The idea is that you take it as soon as your symptoms return. “But you don’t wait until the symptoms are completely gone,” he says.

There is also a lot of buzz about drugs like psilocybin. Studies show that these “magic mushrooms” can reduce depression as quickly as ketamine — which makes esketamine — and the effects last longer. But when it comes to psychedelics, Sanakura 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 seen such enthusiasm about treating depression. But that doesn’t mean researchers have all the answers or a cure for major depressive disorder.

Still, you can take steps now to reduce depression or prevent relapse. This can include medication, different types of talk therapy, regular exercise, a good social life, and a healthy sleep routine. Sanacora says you should “do all the things we know you can do to protect yourself as much as possible.”

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