It’s now 64 years since the US Food & Drug Administration (FDA) approved the first antidepressant drug – imipramine. Yet six decades later, scientists remain divided about how and more fundamentally if standard antidepressants solve the underlying causes of depression.

They clearly improve symptoms for many people. But the exact mechanisms of why they work remain unclear thanks to the huge gaps in our understanding about how the brain works.

Most existing antidepressants, including imipramine, are based on the monoamine theory: that depression is caused by deficiencies and imbalances in the brain’s key neurotransmitters (chemical signallers): serotonin, noradrenaline and dopamine, which all influence mood and alertness.

Over the last few years, a new line of research has been opening up around psychoactive compounds. These have a different effect on the brain and are generating plenty of excitement about the potential for the first new pharmaceutical avenue to treat depression in half a century.

But they’re also proving more controversial since the compounds involved, including ketamine, MDMA (better known as ecstasy) and psilocybin (the active element in “magic mushrooms”) are popularly associated with recreational drug use rather than as therapeutic treatments.

When it comes to effectiveness, a major 2018 report published in the Lancet found that all 21 of the existing antidepressants reviewed were better than a placebo. But some were ranked more highly than others, based on a combination of effectiveness in reducing depressive symptoms and dropout rates (ie fewer side effects).

The top five were: three SSRIs (escitalopram, paroxetine and sertraline), one NaSSA (mirtazapine) and one drug in its own unique class (agomelatine).

Thanks to recent research regarding psychoactive compounds, there are now a range of emerging pharmaceutical options for treating depression in addition to non-drug related ones such as exercise and therapy:

1. Selective serotonin reuptake inhibitors (SSRIs)

SSRIs first came on the market in the 1980s, led by fluoxetine, marketed as Prozac. Today, they’re the most widely prescribed antidepressants of all because they’re better tolerated.

SSRIs are a type of monoaminergic drug, which blocks the re-absorption of serotonin into the nerve cells that release it. In doing so, it leaves more serotonin circulating in the brain to lift mood.

2. Serotonin-noradrenaline reuptake inhibitors (SNRIs)

This class of drugs are similar to SSRIs. In addition to blocking the reuptake of serotonin, they also act on noradrenaline, enabling the brain to benefit from both for longer.

3. Noradrenaline and specific serotonergic antidepressants (NaSSAs)

The most well known drug in this class is mirtazapine. It has a slightly different mechanism to SSRIs and SNRIs, making certain chemical signals stronger so they can pass on more messages.

4. Tricyclic antidepressants (TCAs)

Thanks to imipramine and its successors, these are the oldest antidepressants in use. However, they’re generally only prescribed as a last response since they have more side effects. They work by increasing serotonin and noradrenaline levels, while blocking another neurotransmitter called acetylcholine.

5. Monoamine oxidase inhibitors (MAOs)

This type of antidepressant prevents the monoamine oxidase enzyme from breaking down noradrenaline and serotonin so both stay active for longer.

Like TCAs, they’re no longer commonly administered since they can also interact dangerously with other types of medication including some cold and allergy medications.

6.  Psychoactive antidepressants

Recent research has focused on trying to stimulate the brain’s most abundant neurotransmitter, glutamate and brain-derived neurotropic factor (BDNF), a protein that acts on certain neurons in the central nervous system.

Working together, the two increase connections between brain cells and improve plasticity, the brain’s ability to change and adapt to new information. Studies show that people with depression can, for example, experience a 20% reduction in the size of hippocampus, the part of the brain responsible for learning and memory.

Unlike antidepressants, which can take weeks to kick in, psychoactive drugs take immediate effect. Indeed, their ability to instantly alter perception and reality is how they can help people suffering from depression to find a pathway out of it.

The drugs act as a key that unlocks a door into the subconscious. As such, they’re being prescribed in combination with therapy so that sufferers can resolve what comes out.

Psychoactive antidepressants also differ from their forebears because they cannot be taken at home. Administration in a clinical setting prevents recreational misuse and the clear dangers of letting someone take mind-altering drugs while going about their day-to-day life.

Here are a few recent developments:

Esketamine: in 2019, the FDA approved a chemical cousin of ketamine, which was originally used as an anaesthetic for animals back in the 1960s. It’s administered through a nasal spray in a clinical setting.

Psilocybin: there are now more than half a dozen clinical trials evaluating the active ingredient in magic mushrooms. One2021 study by Imperial College London demonstrated how it helped 59 patients with moderate to severe depression.

The psilocybin group not only recorded an improvement in immediate symptoms, but a longer remission than the group taking a standard antidepressant. Scientists believe that it works by helping people gain cognitive control over emotions, breaking negative emotions and thought processes.

Nitrous oxide: A 2021 study by Washington University in St Louis demonstrated how the naturally occurring gas (also known as laughing gas) helps to lift depression. It does this in similar way to psilocybin – giving the brain a “factory reset”: by breaking negative thought patterns.