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Written by Andrew Neff

Edited by Maisha Razzaque

July 2019

Treating Depression

The 6 best biological treatments for major depressive disorder, and the systematic reviews & meta-analyses that tell us whether they work.

Human Brain Art

Looking for 2019’s hottest new depression treatments, but tired of one-hit-wonder experiments, industry-biased interpretations, and overstatement from tenure-chasing university faculty? Then try some meta-science on for size. Along with a list of six biological treatments for major depressive disorder, we’ve compiled the systematic reviews and meta-analyses that (kinda) tell us whether they work.




Way more exciting than SSRI’s is the club-drug, ketamine (aka “special K”). Ketamine is great at inducing feelings of sedation, pain relief, and memory changes: the three key elements to a great night at a David Guetta concert. It also increases blood pressure, can be addictive, or even lethal. Maybe most frighteningly, ketamine can transport users into a terrifying hallucination-trance-state referred to as the “K-hole.” 




But ketamine, often, really does make people feel good. So maybe, scientists thought, this NMDA receptor blocker could effectively treat depression if done in a controlled setting?



Psychiatry’s go-to pharmaceutical treatment for Major Depressive Disorder has been fraught with controversy. Blocking the reuptake of Serotonin, this drug is thought to improve mood by promoting the global signaling of this neurotransmitter. Since 1987, we’ve been super-amped about the drug, it has fewer side-effects and better efficacy than the old stuff (like MAOI’s and Tricyclics). 


The SSRI train seemed like the way to go… until we found out it kind of doesn’t work. In the biggest systematic review to date, it appears that SSRI’s, on average, have a small but not clinically significant impact on depressive symptoms (Jakobson, 2017).


And it turns out, the evidence is beginning to mount in the favor of  Ketamine; it’s somewhat effective albeit short-lived (likely only a week) (Caddy, 2015). Rogue physicians have already begun setting up ketamine infusion clinics, and in the United States, the FDA has even approved it as a nasal spray.


But we approach this enthusiasm with caution. It’s a story as old as time. A new treatment comes out and everyone’s really excited about it. Then time passes, more science emerges, and the treatment no longer looks so effective. Right now, we can only trust that time will tell.




A heavy dose of LSD or magic mushrooms will rock your world. Stripping away your ego, it will dissolve your being into a state of oceanic boundlessness (literal descriptors used in modern scientific surveys). Like SSRI’s, hallucinogens work through serotonin, although they more specifically target the magical serotonin 2A receptor. 


In the 1950s, shady U.S. government scientists thought that psychedelic-induced ego-obliteration would make people more vulnerable to suggestion, and therefore, change (yes, MK Ultra, 10 history points to you). Might we apply this same logic towards helping people overcome their psychiatric funks?

Only small studies have been conducted on people with terminal illnesses, but at least in this population, decently-controlled research has been pretty successful (Reiche, 2018).


But a major scientific obstacle remains. Might it be that acid trips are only successful because people expect they should be? Or, does that even really matter? It turns out that people know when they’re tripping on acid and when they’re not, which means that researchers can’t really include a placebo control in their experiments.


For information on getting involved in a non-IRB approved study on hallucinogens, please contact the author of this post.


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If scientists are right, and there’s very little evidence that they are, gut bacteria are impacting our moods. By producing, guess which neurotransmitter okay I’ll tell you serotonin, intestinal nerves are stimulated, brains are changed, and depressions are overcome.


The idea makes perfect sense because there’s loads of research supporting the idea that intestinal serotonin is the key to happiness. At one time, scientists used to think that brain lesion studies and deep brain stimulation and optogenetics and fMRI and EEG and intracerebral pharmacological interventions supported the idea that emotion was the product of the central nervous system - the brain. How naive.

Anyways, to the evidence. As of 2018, there were 10 randomized controlled trials looking at the effects of probiotics on depression. And the result? Some studies showed an effect, most didn’t, and on average, there was no significant effect of probiotics on mood (Ng, 2018). 


For a longer rant, see an animation on the gut-brain-axis that is honestly breaking youtube it’s so trending.

Deep Brain Stimulation


Or maybe we could just get into the brain. I mean, the absolute horror of the whole situation aside, there is a risk to open brain surgery. But when you’re not far from taking your own life, and nothing else has helped, it’s a risk some consider worth taking. 


By implanting a metal probe into a part of the brain called the subcallosal cingulate, and providing periodic electrical stimulation, people with depression have reported improved outcomes. Some of the videos showing what happens when you turn on the probe are pretty incredible.


In a recent study, researchers implanted an electrode into a group of people’s brains, but only in half of the participants did they turn on the electrode. Those with active electrodes reported improved moods, but so did those without, suggesting the effect was more likely the result of participant expectations (Holztheimer, 2017).

Deep Brain Stimulation

Deep brain stimulation is almost certainly the future, but so many questions remain, like where to zap, and with what sort of stimulation pattern, and whether our current equipment is accurate enough to make a lasting and nuanced impact on human emotion.

Transcranial Magnetic Stimulation

TMS (Transcranial Magnetic Stimulation)


But that electrode implantation stuff isn’t for everyone. Fortunately, we can electromagnetically stimulate the brain without invasive surgery. The device, which you can make at home, is a sort of magic wand that’s waved over parts of the head and has an impact on the brain cells below. 


As of 2016, 23 randomized controlled trials have looked at the effect of TMS on depression. On average, there appears to be a positive effect, except the improvement is minimal and therefore unlikely to be clinically relevant (Health Quality Ontario, 2016). 


For information on getting involved in another non-IRB approved study using homemade TMS equipment, please contact the author of this article.


  1. Caddy, Caroline, et al. "Ketamine and other glutamate receptor modulators for depression in adults." Cochrane Database of Systematic Reviews 9 (2015).

  2. Health Quality Ontario. (2016). Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Ontario health technology assessment series, 16(5), 1.

  3. Holtzheimer, Paul E., et al. "Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial." The Lancet Psychiatry 4.11 (2017): 839-849.

  4. Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., ... & Krogh, J. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC psychiatry, 17(1), 58.

  5. Ng, Q. X., Peters, C., Ho, C. Y. X., Lim, D. Y., & Yeo, W. S. (2018). A meta-analysis of the use of probiotics to alleviate depressive symptoms. Journal of affective disorders, 228, 13-19.

  6. Reiche, Simon, et al. "Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: a systematic review." Progress in neuro-psychopharmacology and biological psychiatry 81 (2018): 1-10.


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Skeptical Science

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Humanistic Touch

A Psychology and Neuroscience Blog


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5% of our annual proceeds are donated to the John Templeton Foundation.

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