Researchers are on the hunt for better drugs to treat depression, a leading cause of disability worldwide.

Current treatments all work in the same way, and haven't changed significantly in 35 years. Plus, they don't help as many as 1 in 3 patients.

Some new drug candidates draw inspiration from psychedelics like hallucinogenic mushrooms and ketamine. Another works on a brain network called Gaba that other medications ignore.

As many as one in every three people with depression does not get relief from their condition with common medications like Celexa and Prozac. When they do work, these antidepressants take 4 to 6 weeks to have an effect — an unfathomable hold-up for those with severe forms of the illness that can include thoughts of suicide.

Yet these drugs are currently among the best treatments we have for depression, which is also a leading cause of disability across the globe.

Researchers are on the hunt for better options.

This year saw a resurgence of interest in new depression drugs that target parts of the brain that current medications ignore. Going into 2019, some of the most promising candidates are drugs inspired by psychedelic compounds such as psilocybin, the active ingredient in magic mushrooms, and ketamine, an anesthetic that has long been dismissed by the general public as a "party drug."

An anesthetic with a reputation as a 'party drug'

A widely used anesthetic that is also known as a party drug, ketamine was shown to have benefits as a rapid-fire antidepressant nearly a decade ago. ravipat/Shutterstock A widely used anesthetic that is also considered a party drug, ketamine was shown to have benefits as a rapid-fire antidepressant nearly a decade ago. Early studies suggest that ketamine may be especially helpful to people dealing with suicidal thoughts since it works so quickly.

The authors of one paper called ketamine "the most important discovery in half a century."

Read more: A 'party drug' with potential to be the next blockbuster antidepressant is edging closer to the mainstream, but it could set you back $9,000

As opposed to existing antidepressants, ketamine acts on a brain mechanism that scientists have only recently begun to explore that involves what are known as NMDA receptors. Homing in on this channel appears to provide relief from depression that is better, arrives faster, and works in far more people than current drugs.

Pharmaceutical companies like Allergan and Johnson & Johnson are in hot pursuit of new depression drugs that take after ketamine.

Allergan's drug is in the last phase of clinical trials and has received a key FDA designation designed to speed it through the approval process. Johnson & Johnson filed for FDA approval of its drug — a nasal spray made with the chemical mirror image of ketamine — this year, meaning it could be on the market as early as 2019.

In addition, a growing list of academic medical centers now offer ketamine infusions for depression, including Columbia University, which began offering the drug to patients with severe depression this fall.

A drug that might not require patients to take a pill every day

Sage-217 could offer patients the ability to take the drug once a month instead of daily. Hollis Johnson/Business Insider Made by Sage Therapeutics, a new drug candidate known only as Sage-217 works in a fundamentally different way than all of the past 35 years' worth of antidepressants.

Unlike the medications doctors have been prescribing for nearly a half century, all of which target the brain's serotonin system, Sage's drug targets a brain network called Gaba. As a result, the drug appears to work faster and last longer. Some early research suggests it may even be possible for patients to go several weeks without taking the drug — as opposed to being tied to a daily pill.

Experts who study depression say they've been cheered by preliminary study results on Sage-217. And although it truly appears to be a blockbuster in several ways, it's worth noting that it would likely not work as a sort of one-and-done treatment in the way Sage CEO Jeff Jonas described over the summer. Instead of taking the drug once, patients would likely take it episodically, or as frequently as once a month.

Wall Street analysts see a huge market potential for the new drug.

"The possibility of having something that impacts the Gaba system is attractive because if you were to launch it tomorrow, there’s likely going to be lots of patients who’ve failed with anything that’s available," Paul Matteis, the managing director of biotech research with brokerage firm Stifel, told Business Insider.

More conclusive results on Sage-217 are expected to be released in 2019.

A compound from magic mushrooms that can be made in a lab

Psilocybin, the main ingredient in hallucinogenic mushrooms, has been likened to a "surgical intervention" for depression. Shutterstock Researchers studying psilocybin, the main psychoactive ingredient in hallucinogenic mushrooms, have likened its quick effects on cancer patients to a "surgical intervention" for depression.

Brain scan studies suggest that depression ramps up the activity in brain circuits linked with negative emotions, and weakens the activity in circuits linked with positive ones. Psilocybin appears to restore balance to that system.

Two for-profit companies lead the research in the space. The first, called Compass Pathways, is backed by entrepreneur Peter Thiel and began work on a handful of clinical trials of psilocybin for depression earlier this year.

"We're on a mission to create solutions for patients who don’t have any other options," Compass co-founder and chief medical officer Ekaterina Malievskaia told Business Insider this fall. "There hasn't been a meaningful development in the field for decades."

The second, a biotech startup launched in October called Atai, is focused on financing more of the kind of research that Compass is doing. Atai has already raised $25 million from investors like ex-hedge fund manager Mike Novogratz and Icelandic entrepreneur Thor Bjorgolfsson.

Read more: A new biotech company has raised $25 million to help unleash a 'virgin market' of psychedelic research

Some researchers have high hopes that a psilocybin-inspired drug will get approved within a decade. David Nutt, director of the neuropsychopharmacology unit at Imperial College London, told Business Insider last year that he believed psilocybin would become an "accepted treatment" for depression before 2027. Malievskaia said she hopes to bring the treatment to market in 5-10 years.