What's the Latest in Depression Treatment?

Table of ContentsTable of ContentsExpandHistoryPsychedelics and KetamineOther Fast-Acting TreatmentsWhat’s on the HorizonView All

Table of ContentsExpandHistoryPsychedelics and KetamineOther Fast-Acting TreatmentsWhat’s on the HorizonView All

Table of ContentsExpandHistoryPsychedelics and KetamineOther Fast-Acting TreatmentsWhat’s on the Horizon

Table of ContentsExpand

Expand

History

Psychedelics and Ketamine

Other Fast-Acting Treatments

What’s on the Horizon

View All

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 withmajor 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.

Though actual suicide rates were steady or even down in some countries, the same WHO report estimates that in the US, the incidence of suicidal thoughts went up from about 18% to around 30% in 2020 during pandemic stay-at-home orders.

The good news: there’s currently more innovation in mental health treatment than there’s been since the 1980s whenselective 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.

Depression also has a high recurrence rate. After treatment of the first episode of depression, around 50% will experience relapse. The risk for relapse increases for every subsequent episode.Research also suggests that 30.9% of people havetreatment-resistant depression. This means an estimated 8.9 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 effectiveandwork 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.

—JEFFREY BORENSTEIN, MD

At a GlanceDepression rates are at an all-time high—but new and effective treatments for this common mental health condition are on the horizon. Since the first antidepressants were introduced in the 1950s, more and more options have continued to emerge. Today, there is an increasing interest in the use of psychedelics and ketamine for depression relief. Other fast-acting options include recently introduced antidepressants and transcranial magnetic stimulation (TMS). Options that show promise as future treatments include optogenetics and stem cells.

At a Glance

Depression rates are at an all-time high—but new and effective treatments for this common mental health condition are on the horizon. Since the first antidepressants were introduced in the 1950s, more and more options have continued to emerge. Today, there is an increasing interest in the use of psychedelics and ketamine for depression relief. Other fast-acting options include recently introduced antidepressants and transcranial magnetic stimulation (TMS). Options that show promise as future treatments include optogenetics and stem cells.

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

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

The idea that the depletion of these neurotransmitters is what leads to depression is known as the monoamine hypothesis.Tricyclic antidepressants and SSRIs have also been thought to have their impact based on this theory.

The Development of TCAs and SSRIs

With the development of MAOIs and TCAs in the 1950s and 1960s, there was a significant lack of research on other types of antidepressants—untilProzac (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 asselective serotonin-norepinephrine reuptake inhibitors(SNRIs) and atypical antidepressants, still were thought to work based on the monoamine hypothesis.

How MAOIs Work and Common Side Effects

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 andtreatment 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,neuroplasticityis the brain’s ability to adapt and change to signals both within and outside of the body.

Those with depression show significantly lower levels of neuroplasticity and a decreased ability to adapt to stress.

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.

BDNFis 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 asketamineor psychedelics may help symptoms.

Timeline of Depression Research History1958: The first antidepressants, Iproniazid (MAOI) and Imipramamine (TCA)1961 MAOIs: Nardil and Partite1961-1980: tricyclic antidepressants—Elavil, Norpramin, Sinequan, Vivactil, Pamelor, Surmontil, Ludiomil1987: Prozac, the first SSRI1991-1998: SSRIs Zoloft, Paxil, Celexa; SNRIs Effexor and Serzone

Timeline of Depression Research History

1958: The first antidepressants, Iproniazid (MAOI) and Imipramamine (TCA)1961 MAOIs: Nardil and Partite1961-1980: tricyclic antidepressants—Elavil, Norpramin, Sinequan, Vivactil, Pamelor, Surmontil, Ludiomil1987: Prozac, the first SSRI1991-1998: SSRIs Zoloft, Paxil, Celexa; SNRIs Effexor and Serzone

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 ofpsilocybin(aka “magic mushrooms”) led to an 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.

It’s believed that a combination of the drug’s biological effects on the brain as well as the spiritual and mystical experience contribute to the high levels of effectiveness. The experience may give people relieffrom more existential aspects 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.

Psilocybin has already been grantedFDA Breakthrough Therapy designation, meaning that drugs that show significant 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 PTSDalso have a diagnosis of MDD.

MDMA, it is theorized, is so helpful in PTSDbecause 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 the 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.

Ketamine has received such wide attention for several reasons: first of all, it targets a completely different set of neurotransmitters in the brain than previously studied depression treatments and often begins working within hours. It also may quickly reducesuicidal ideationin some cases.

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

The fact that ketamine can work so quickly on refractory depression has the potential to be a game changer for depression.—JEFFREY BORENSTEIN, MD

The fact that ketamine can work so quickly on refractory depression has the potential to be a game changer for depression.

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.

I Tried It: At-Home Ketamine Therapy

Beyond the psychedelic space, there are several other new depression treatments that are rapid-acting, including a new protocol forTMS therapyas 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

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

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.

Moreover, according to the Stanford study, nearly 80% of people no longer met criteria for depression, meaning their symptoms were back in the “normal” range. In the “regular” treatment, only about half the people treated improve, with only a third meeting “remission.”

“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 didn’t receive a high enough frequency and density of stimulation.

Some key differences in the SAINT protocol:

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

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 will be able to positively impact specific cellular pathways in depression.

Can Depression Go Away on Its Own?

23 SourcesVerywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.World Health Organization.Mental Health and COVID-19: Early evidence of the pandemic’s impact: Scientific brief, 2 March 2022.Moriarty AS, Castleton J, Gilbody S, et al.Predicting and preventing relapse of depression in primary care. Br JGen Pract. 2020;70(691):54-55. doi:10.3399/bjgp20X707753Zhdanava M, Pilon D, Ghelerter I, et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699Barchas JD, Altemus M.Monoamine hypotheses of mood disorders.Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edition.Varghese FP, Brown ES.The hypothalamic-pituitary-adrenal axis in major depressive disorder: A brief primer for primary care physicians.Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155. doi:10.4088/pcc.v03n0401Filatova EV, Shadrina MI, Slominsky PA.Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021;10(6):1283. doi:10.3390/cells10061283Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512Agin-Liebes GI, Malone T, Yalch MM, et al.Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/0269881119897615Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512Johns Hopkins Medicine Newsroom.Psilocybin treatment for major depression effective for up to a year for most patients, study shows.Phelps J, Shah RN, Lieberman JA.The rapid rise in investment in psychedelics—cart before the horse.JAMA Psychiatry. 2022;79(3):189. doi:10.1001/jamapsychiatry.2021.3972Compass Pathways.COMPASS Pathways announces positive topline results from groundbreaking phase IIb trial of investigational COMP360 psilocybin therapy for treatment-resistant depression.Remmel A.Psychedelic drugs without the trip? This sensor could help seek them out.Nature. doi:10.1038/d41586-021-01156-yMitchell JM, Bogenschutz M, Lilienstein A, et al.MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study.Nat Med. 2021;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3Inouye A, Wolfgang A.3,4-methylenedioxymethamphetamine (Mdma)-assisted therapy in Hawaii: A brief review.Cureus. 14(6):e26402. doi: 10.7759/cureus.26402Sofia RD, Harakal JJ.Evaluation of ketamine HCl for anti-depressant activity.Arch Int Pharmacodyn Ther. 1975;214(1):68-74.Berman RM, Cappiello A, Anand A, et al.Antidepressant effects of ketamine in depressed patients.Biological Psychiatry. 2000;47(4):351-354. doi:10.1016/s0006-3223(99)00230-9Abbar M, Demattei C, El-Hage W, et al.Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial.BMJ. 2022;376. doi:10.1136/bmj-2021-067194Wei Y, Chang L, Hashimoto K.Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor.Mol Psychiatry. 2022;27(1):559-573. doi:10.1038/s41380-021-01121-1Harvard Health Publishing.Transcranial magnetic stimulation (TMS): Hope for stubborn depression.Cole EJ, Stimpson KH, Bentzley BS, et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. AJP. 2020;177(8):716-726.Fakhoury M.Optogenetics: A revolutionary approach for the study of depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2021;106:110094. doi:10.1016/j.pnpbp.2020.110094Micheli L, Ceccarelli M, D’Andrea G, Tirone F.Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise.Brain Research Bulletin. 2018;143:181-193. doi:10.1016/j.brainresbull.2018.09.002

23 Sources

Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.World Health Organization.Mental Health and COVID-19: Early evidence of the pandemic’s impact: Scientific brief, 2 March 2022.Moriarty AS, Castleton J, Gilbody S, et al.Predicting and preventing relapse of depression in primary care. Br JGen Pract. 2020;70(691):54-55. doi:10.3399/bjgp20X707753Zhdanava M, Pilon D, Ghelerter I, et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699Barchas JD, Altemus M.Monoamine hypotheses of mood disorders.Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edition.Varghese FP, Brown ES.The hypothalamic-pituitary-adrenal axis in major depressive disorder: A brief primer for primary care physicians.Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155. doi:10.4088/pcc.v03n0401Filatova EV, Shadrina MI, Slominsky PA.Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021;10(6):1283. doi:10.3390/cells10061283Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512Agin-Liebes GI, Malone T, Yalch MM, et al.Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/0269881119897615Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512Johns Hopkins Medicine Newsroom.Psilocybin treatment for major depression effective for up to a year for most patients, study shows.Phelps J, Shah RN, Lieberman JA.The rapid rise in investment in psychedelics—cart before the horse.JAMA Psychiatry. 2022;79(3):189. doi:10.1001/jamapsychiatry.2021.3972Compass Pathways.COMPASS Pathways announces positive topline results from groundbreaking phase IIb trial of investigational COMP360 psilocybin therapy for treatment-resistant depression.Remmel A.Psychedelic drugs without the trip? This sensor could help seek them out.Nature. doi:10.1038/d41586-021-01156-yMitchell JM, Bogenschutz M, Lilienstein A, et al.MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study.Nat Med. 2021;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3Inouye A, Wolfgang A.3,4-methylenedioxymethamphetamine (Mdma)-assisted therapy in Hawaii: A brief review.Cureus. 14(6):e26402. doi: 10.7759/cureus.26402Sofia RD, Harakal JJ.Evaluation of ketamine HCl for anti-depressant activity.Arch Int Pharmacodyn Ther. 1975;214(1):68-74.Berman RM, Cappiello A, Anand A, et al.Antidepressant effects of ketamine in depressed patients.Biological Psychiatry. 2000;47(4):351-354. doi:10.1016/s0006-3223(99)00230-9Abbar M, Demattei C, El-Hage W, et al.Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial.BMJ. 2022;376. doi:10.1136/bmj-2021-067194Wei Y, Chang L, Hashimoto K.Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor.Mol Psychiatry. 2022;27(1):559-573. doi:10.1038/s41380-021-01121-1Harvard Health Publishing.Transcranial magnetic stimulation (TMS): Hope for stubborn depression.Cole EJ, Stimpson KH, Bentzley BS, et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. AJP. 2020;177(8):716-726.Fakhoury M.Optogenetics: A revolutionary approach for the study of depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2021;106:110094. doi:10.1016/j.pnpbp.2020.110094Micheli L, Ceccarelli M, D’Andrea G, Tirone F.Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise.Brain Research Bulletin. 2018;143:181-193. doi:10.1016/j.brainresbull.2018.09.002

Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

World Health Organization.Mental Health and COVID-19: Early evidence of the pandemic’s impact: Scientific brief, 2 March 2022.Moriarty AS, Castleton J, Gilbody S, et al.Predicting and preventing relapse of depression in primary care. Br JGen Pract. 2020;70(691):54-55. doi:10.3399/bjgp20X707753Zhdanava M, Pilon D, Ghelerter I, et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699Barchas JD, Altemus M.Monoamine hypotheses of mood disorders.Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edition.Varghese FP, Brown ES.The hypothalamic-pituitary-adrenal axis in major depressive disorder: A brief primer for primary care physicians.Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155. doi:10.4088/pcc.v03n0401Filatova EV, Shadrina MI, Slominsky PA.Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021;10(6):1283. doi:10.3390/cells10061283Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512Agin-Liebes GI, Malone T, Yalch MM, et al.Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/0269881119897615Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512Johns Hopkins Medicine Newsroom.Psilocybin treatment for major depression effective for up to a year for most patients, study shows.Phelps J, Shah RN, Lieberman JA.The rapid rise in investment in psychedelics—cart before the horse.JAMA Psychiatry. 2022;79(3):189. doi:10.1001/jamapsychiatry.2021.3972Compass Pathways.COMPASS Pathways announces positive topline results from groundbreaking phase IIb trial of investigational COMP360 psilocybin therapy for treatment-resistant depression.Remmel A.Psychedelic drugs without the trip? This sensor could help seek them out.Nature. doi:10.1038/d41586-021-01156-yMitchell JM, Bogenschutz M, Lilienstein A, et al.MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study.Nat Med. 2021;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3Inouye A, Wolfgang A.3,4-methylenedioxymethamphetamine (Mdma)-assisted therapy in Hawaii: A brief review.Cureus. 14(6):e26402. doi: 10.7759/cureus.26402Sofia RD, Harakal JJ.Evaluation of ketamine HCl for anti-depressant activity.Arch Int Pharmacodyn Ther. 1975;214(1):68-74.Berman RM, Cappiello A, Anand A, et al.Antidepressant effects of ketamine in depressed patients.Biological Psychiatry. 2000;47(4):351-354. doi:10.1016/s0006-3223(99)00230-9Abbar M, Demattei C, El-Hage W, et al.Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial.BMJ. 2022;376. doi:10.1136/bmj-2021-067194Wei Y, Chang L, Hashimoto K.Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor.Mol Psychiatry. 2022;27(1):559-573. doi:10.1038/s41380-021-01121-1Harvard Health Publishing.Transcranial magnetic stimulation (TMS): Hope for stubborn depression.Cole EJ, Stimpson KH, Bentzley BS, et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. AJP. 2020;177(8):716-726.Fakhoury M.Optogenetics: A revolutionary approach for the study of depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2021;106:110094. doi:10.1016/j.pnpbp.2020.110094Micheli L, Ceccarelli M, D’Andrea G, Tirone F.Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise.Brain Research Bulletin. 2018;143:181-193. doi:10.1016/j.brainresbull.2018.09.002

World Health Organization.Mental Health and COVID-19: Early evidence of the pandemic’s impact: Scientific brief, 2 March 2022.

Moriarty AS, Castleton J, Gilbody S, et al.Predicting and preventing relapse of depression in primary care. Br JGen Pract. 2020;70(691):54-55. doi:10.3399/bjgp20X707753

Zhdanava M, Pilon D, Ghelerter I, et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States.J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699

Barchas JD, Altemus M.Monoamine hypotheses of mood disorders.Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edition.

Varghese FP, Brown ES.The hypothalamic-pituitary-adrenal axis in major depressive disorder: A brief primer for primary care physicians.Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155. doi:10.4088/pcc.v03n0401

Filatova EV, Shadrina MI, Slominsky PA.Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021;10(6):1283. doi:10.3390/cells10061283

Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512

Agin-Liebes GI, Malone T, Yalch MM, et al.Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.J Psychopharmacol. 2020;34(2):155-166. doi:10.1177/0269881119897615

Ross S, Bossis A, Guss J, et al.Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.J Psychopharmacol. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512

Johns Hopkins Medicine Newsroom.Psilocybin treatment for major depression effective for up to a year for most patients, study shows.

Phelps J, Shah RN, Lieberman JA.The rapid rise in investment in psychedelics—cart before the horse.JAMA Psychiatry. 2022;79(3):189. doi:10.1001/jamapsychiatry.2021.3972

Compass Pathways.COMPASS Pathways announces positive topline results from groundbreaking phase IIb trial of investigational COMP360 psilocybin therapy for treatment-resistant depression.

Remmel A.Psychedelic drugs without the trip? This sensor could help seek them out.Nature. doi:10.1038/d41586-021-01156-y

Mitchell JM, Bogenschutz M, Lilienstein A, et al.MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study.Nat Med. 2021;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3

Inouye A, Wolfgang A.3,4-methylenedioxymethamphetamine (Mdma)-assisted therapy in Hawaii: A brief review.Cureus. 14(6):e26402. doi: 10.7759/cureus.26402

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