What's the Latest in Depression Treatment?

If it’s felt to you like we’re at an inflection point with mental health, you’re not wrong.

Depression rates, which were already on the rise before the pandemic, appear to be higher than ever. One estimate from the World Health Organization (WHO) puts the global increase of people diagnosed with major depressive disorder (MDD) at a more than 25% rate from 2019 to 2020—and this doesn’t even include people who reported feelings of depression but didn’t meet the full criteria for a diagnosis.

The good news: there’s currently more innovation in mental health treatment than there’s been since the 1980s when selective serotonin uptake inhibitors (SSRIs) were originally introduced. Many of these new treatments work more quickly than those SSRIs, which can sometimes take up to four to six weeks to work.

“It’s a time of hope for many people who haven’t been helped by current treatments,” says Jeffrey Borenstein, MD, who serves as President & CEO of the Brain & Behavior Research Foundation, which funds mental health research grants.

10% of Americans will have multiple depressive episodes in their lives—but nearly half of those people have treatment-resistant depression. This means an estimated 16 million Americans will try one or more treatments for depression without achieving remission.

With this combination of factors, it’s more crucial than ever to find treatments that are effective and work quickly. Read on to learn more about the new depression treatments that are currently being used, ones that are being researched, and where future research might lead.

History of Depression Treatment

In order to understand current and future depression treatment, it’s important to know where we’ve come from to get to where we are today—and some of the conventional wisdom we may be in the process of overturning.

The Monoamine Hypothesis 

The first antidepressant, Ipronizaid, was discovered by accident when it was given to patients with tuberculosis. The patients showed a marked improvement in mood. This monoamine oxidase inhibitor (MAOI) works by preventing the body’s monoamine oxidase enzyme from breaking down dopamine, serotonin, and norepinephrine in the brain.

These three neurotransmitters, collectively known as monoamines because of their similar chemical structures, are responsible for key processes in the brain including learning, emotion, and memory. 

The Development of TCAs and SSRIs

Tricyclic antidepressants (TCAs) were developed following the introduction of MAOIs in the 1950s. They work by inhibiting the absorption of serotonin and norepinephrine, and blocking acetylcholine, another neurotransmitter.

With the development of MAOIs and TCAs in the 1950s and 1960s, there was a significant lack of research on other types of antidepressants—until Prozac (fluoxetine) was introduced in 1987.

This was the first SSRI—that is, the first antidepressant to work exclusively on blocking the reabsorption of serotonin. Increasing serotonin levels is thought to regulate mood. Additionally, SSRIs carry far fewer side effects than the earlier MAOIs/TCAs—though they are not without side effects.

Even newer classes of antidepressants, such as selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants, still were thought to work based on the monoamine hypothesis.

The Neuroplasticity Hypothesis

More modern theories look at the role of stress in depression and at the neuroplasticity hypothesis. Stress is linked to both an increased risk of major depressive episodes and treatment resistance.

It is thought that chronic stress leads to dysregulation in the hypothalmic-pituitary-adrenocortical (HPA) axis, which controls reactions to stress as well as mood and emotion, among other things. This dysregulation causes impairment in the hippocampus, which controls memory and emotion.

This leads to the neuroplasticity hypothesis of depression. Put simply, neuroplasticity is the brain’s ability to adapt and change to signals both within and outside of the body.

Looking at depression through the neuroplasticity theory broadens the focus from how a medication might affect someone’s brain from looking beyond just levels of neurotransmitters to looking at how well the neurons are communicating with each other at various parts of the process to create neuroplasticity.

BDNF and Glutamate May Be the Future of Depression Treatment

This neuroplasticity theory involves other systems and chemicals within the brain, and two major areas that are receiving particular focus right now in depression treatment are brain-derived neurotrophic factor (BDNF) and glutamate.

BDNF is a chemical in the brain that is associated with cell growth and cell death, and it is thought that lower levels of BDNF lead to lower levels of neuroplasticity, so it is an area that is receiving attention in development of depression treatment.

Glutamate is an “excitatory” neurotransmitter, meaning it is a messenger that stimulates nerve cells to be ready to receive information. It also helps nerve cells better communicate with each other.

It’s being looked at in depression treatment because optimal glutamate functioning may help facilitate, increasing neuroplasticity, so targeting the glutamate system via new treatments such as ketamine or psychedelics may help symptoms.

Psychedelics and Ketamine

Psychedelics are currently having a moment in both scientific circles and mainstream media due to their potential for rapid, significant, and long-lasting reduction in symptoms of depression.

A 2016 study of cancer patients found that just a single treatment of psilocybin (magic mushrooms) led to immediate reduction in measures of depression that were then seen to last up to six months, with nearly 80% of study participants still reporting antidepressant effect. Even in a follow-up study five years later, a majority of the study subjects still reported reduced symptoms of depression.

With that said, it so far has only been studied in very controlled clinical environments so it’s not yet known how it might work in the “real world,” and a solid framework has not yet been established on how to do this safely. Despite this, the state of Oregon and the cities of Santa Cruz and Oakland, California, among other locale, have decriminalized the use of psilocybin for therapeutic use.

Already, venture capital has been flowing into the psilocybin “market,” with investors eager to capitalize on the promise of its healing powers before it has even been widely legalized or approved by the FDA for treatment of depression. It is estimated that by 2027, psychedelics will be a multibillion dollar industry.

Psilocybin has already been granted FDA Breakthrough Therapy designation, which means that drugs which show a significant amount of improvement over traditional therapies in treating serious illnesses can be reviewed and approved on an expedited timeline.

However, some safety concerns do exist. In addition to physical side effects, some patients experienced an increase in suicidal behaviors and ideations. Research is also being done on how to remove the hallucinogenic properties of these drugs.

MDMA

MDMA, also known as ecstasy or Molly in its street forms, has also been granted FDA “breakthrough therapy” status after Phase 2 clinical trials where a whopping 67% of people in the trial—who entered with severe PTSD—no longer qualified for a PTSD diagnosis.

Although clinical research for MDMA for depression has not gotten as far as MDMA for PTSD, MDMA does show promise for treating major depressive disorder—and more than 50% of adults who have a diagnosis of PTSD also have a diagnosis of MDD.

MDMA works by rapidly releasing and increasing levels of serotonin and dopamine in the brain.

MDMA, it is theorized, is so helpful in PTSD because it helps people recall negative memories with the brain's fear response being better regulated. This may lead to greater self-compassion and stay with these memories safely in therapy without getting overwhelmed.

Ketamine

Of all of the “psychedelic” treatments out there, ketamine is currently the only one that is legal for treatment in all 50 states. (Experts cannot agree on whether it is a true psychedelic or not, though it does cause dissociative effects.)

Ketamine was first synthesized in the 1960s as an anesthetic and early observations showed that ketamine might work similarly to antidepressants. It wasn’t until the 1990s that ketamine would be studied in earnest to treat depression, with the first randomized controlled study showing promise of ketamine as an antidepressant being released in 2000.

Spravato (esketamine) was approved in 2019 via Fast Track status with the FDA, and it is currently administered as a nose spray that must be consumed under the monitoring of a doctor for safety reasons.

Esketamine specifies a particular type of ketamine molecule that is thought to be more potent at the NMDA glutamate receptor. IV ketamine uses a different part of the molecule and is currently used off-label for depression. It has demonstrated a more significant overall response rate than intranasal ketamine, but is more complicated to use.

As other treatments target the monoamine system (see above), ketamine is thought to create a surge of glutamate neurotransmission in the brain.

However, more research is needed to figure out how to optimally use this agent, as well as to develop agents like ketamine that don't carry the dissociative side effects and are potentially easier and safer for wide use.

Although ketamine is generally well-tolerated, it does have a number of side effects at the time of administration, such as nausea, dizziness, feeling woozy, spacey, numb, and having sensory distortions—though these side effects typically subside quickly.

Arketamine, which uses a different part of the molecule, is currently being studied as well, as it lasts longer and has fewer side effects, including less dissociative side effects. The FDA has given approval for investigational new drug clearance to study how it will work with other medications.

Other Fast-Acting Treatments 

Beyond the psychedelic space, there are several other new depression treatments that are rapid-acting, including a new protocol for TMS therapy as well as a new oral antidepressant.

“The fact that there’s these new treatments [and] that [they can] work so rapidly is something we very much need,” says Borenstein. “One of the benefits is that they’re rapidly acting to treat suicidal acts and risk, and that has the potential to be a game changer in psychiatry."

Auvelity

One of these treatments is the oral antidepressant Auvelity, approved by the FDA in August 2022. Auvelity may work within a week and targets the glutamate system, similarly to ketamine.

The medication is a combination of buproprion (the active ingredient in Wellbutrin) and dextromethorphan (commonly found in cough syrup). Its approval may open the door for a new class of medications that work to increase glutamate.

SAINT

Although transcranial magnetic stimulation (TMS) was first approved by the FDA in 2008, newer versions of the TMS protocol are found to bring results in less than a week, compared to six weeks in the older version of the protocol.

TMS therapy involves using magnetic pulses on the head to treat depression. The pulses are targeted to the area of the brain implicated in depression and they work to activate these regions. One of the major areas stimulated is the prefrontal cortex, an area of the brain associated with regulating mood.

According to some research, it has been shown to benefit somewhere between 50-60% of those who have not adequately responded to one or more antidepressant treatments.

Typically, TMS treatment takes six weeks of once-daily sessions, a major time commitment. With this Stanford accelerated intelligent neuromodulation therapy (SAINT) protocol, developed at Stanford, people receive 10 treatments per day for five days.

“The patients had remission of depression after a few days, which is tremendous,” says Borenstein.

One of the theories behind SAINT is that people who weren’t receiving a high enough frequency and density of stimulation.

Some key differences in the SAINT protocol:

• treating people multiple sessions per day with optimally spaced intervals
• applying higher levels of stimulation (1800 pulses vs 600)
• precision targeting through FMRI scans that helped the researchers find the precise location in each participants brain where the stimulation would occur 

The protocol was approved in September 2022 and is expected to launch in 2023.

What's on the Horizon

In Borenstein’s role helming the Brain & Behavior Research Foundation, he has a birds-eye view of innovation going on in mental health research, as the foundation is the nation’s largest private funder of mental health grants.

A few other possible treatment areas he’s excited about:

Optogenetics: This is a way to use light and genetic tools to control the activity of certain neurons. These techniques have been used to map connections in the brain, but there is hope that someday this technique with be able to positively impact specific cellular pathways in depression.

Stem Cells: A theory is currently being studied that stem cells may decrease depression by helping create more neurons that can form more connections in the brain. Current research includes investigating if there are new molecules that can activate stem cells to act in this antidepressant way.