Antidepressant drugs have unfairly been the target of suspicion and stigma over the years, and there’s no doubt that for some people they can have life-changing effects. There are many different types, and they’re not only used to treat depression, so let’s break down what the latest science says about these medications.

What conditions are antidepressants used for?

Antidepressants are some of the most widely prescribed drugs, used by millions of people every day – but not all of these people will have a diagnosis of depression.

Although depression is the most common condition these drugs are used for, they’re also often part of treatment for other mental health conditions like anxiety, post-traumatic stress disorder, and obsessive-compulsive disorder.

Certain antidepressants – we’ll come on to the different classes in a minute – are also prescribed to treat chronic pain. People with conditions such as complex regional pain syndrome, trapped nerves, and neuropathic pain due to multiple sclerosis, can benefit from the use of specific antidepressants where traditional painkillers have not worked.

Doctors may also try antidepressants for patients with non-neuropathic chronic pain, such as fibromyalgia, but some are moving away from this in light of evidence – such as a 2023 Cochrane review – that they may be no better than a placebo.

And there’s another less obvious use for antidepressants. According to the UK’s National Health Service, some kids may be treated with antidepressants to help deal with bedwetting, as they can relax the muscles of the bladder and decrease the urge to urinate.

What classes of antidepressants are there?

SSRIs and SSNIs

If you’re diagnosed with depression and are offered the option of medication, the first drug your doctor will suggest will likely be an SSRI – a selective serotonin reuptake inhibitor. You may have heard some of the brand names of these drugs before, like Lexapro (escitalopram), Prozac (fluoxetine), and Zoloft (sertraline).

Aside from having peculiar effects on fish, SSRIs work by stopping the transport of serotonin out of synapses, the spaces between neurons where messages pass, thereby increasing the amount of serotonin hanging around in the brain. A longstanding hypothesis in psychiatry states that low serotonin levels are partly to blame for depression.

Although more recent research indicates that low serotonin alone may not be enough to cause depression in the first place, it does seem to play a role in relapses for those with the condition, so SSRIs will most likely remain a key part of the psychiatrist’s toolkit for some time to come.

That doesn’t mean we can’t update them, though. There’s a newer class of drugs that work similarly to SSRIs, called serotonin-norepinephrine reuptake inhibitors (SNRIs). As well as helping boost serotonin levels, SNRIs also increase the levels of another neurochemical, norepinephrine (also called noradrenaline). Some examples of these drugs include venlafaxine and duloxetine – incidentally, one of the few that the 2023 Cochrane review found does seem to have some efficacy for non-neuropathic pain.

While SSRIs and SNRIs are similar, patients may find the side effects of one class more difficult to tolerate than the other. And even within each class, the drugs vary in terms of the nuances of how they work in the body and how often you need to take them. Finding the best drug for each person is often a matter of trial and error.

TCAs

Tricyclic antidepressants (TCAs) first came to market in the US in 1959, but since the advent of SSRIs, they’ve been considered a second-line treatment for depression. Drugs in this class include amitriptyline and imipramine, the first to be developed.

The “tricyclic” refers to the three rings of atoms these drugs have in their chemical structures. Like SNRIs, they also work by blocking the uptake of serotonin and norepinephrine. TCAs have a low therapeutic index, meaning that even a small overdose could lead to dangerous symptoms. There’s also some evidence that TCAs tend to cause more side effects than SSRIs and are less well tolerated by patients overall.

TCAs are the class of antidepressants that are usually prescribed for neuropathic pain, but the evidence on their efficacy is mixed. A 2015 Cochrane review looking specifically at amitriptyline found that it “probably does give really good pain relief” to a minority of people, so again it's likely to be a process of trial and error when searching for the best medications for a particular patient.

Other classes

There are other antidepressants that doctors may turn to in specific cases, such as when other treatments have not worked.

Monoamine oxidase inhibitors (MAOIs) are one example. Although they were the first antidepressants to be discovered, they have been used less and less as alternative drugs have been developed. A big reason for this is that they can interact with lots of other medications and certain foods. The symptoms of these interactions can be life-threatening for patients, but also tricky to spot for medical professionals.

Some examples of MAOIs are selegiline and isocarboxazid. They work by targeting the enzyme monoamine oxidase, stopping it from breaking down serotonin, norepinephrine, and dopamine.

There are also various drugs that can be classed as “atypical antidepressants”, which work in a variety of ways. But for all of these, the goal remains to keep as much serotonin, norepinephrine, and to a lesser extent dopamine, in the brain for as long as possible.

Why do some antidepressants take so long to kick in?

One of the difficulties faced by patients when they start taking antidepressants is that they can take several weeks to start working. It’s a conundrum that has plagued the medical establishment.

Some have argued this is evidence that the serotonin hypothesis is flawed, and that SSRIs only work in some people because they’re doing something else in the brain that we’ve not fully understood yet.

Others have suggested that the lag is due to the brain’s homeostatic systems rebalancing things after an initial spike in serotonin when someone starts to take an SSRI. The brain responds by decreasing the production of the neurotransmitter for a time, meaning there’s no net increase in serotonin for several weeks while things settle down.

But last year, one group of scientists put forward a new idea. Their study looked at the effects of one SSRI, escitalopram, in 32 people without any history of mental health disorders. After taking the drug or a placebo for three to five weeks, positron emission tomography (PET) scans revealed a time-dependent increase in new synapses forming in certain areas of the brain.

Commenting on the study, cognitive neuroscientist Jonathan Roiser, who was not involved in the work, told Wired: “It's a different perspective to what's come before. It gives the additional weight to this idea that you need the cumulative changes over time in order to shift the environment to be more positive, which can then explain how people are then going to recover from depression.”

The study was small and included only healthy people, so it’s too soon to draw broad conclusions yet. The authors told Wired that the next phase of their work is already underway, including studies on people with depression, so hopefully, more pieces of this puzzle will soon be falling into place.

What’s the latest research into antidepressants?

In the meantime, other exciting research is opening up the possibility of alternative antidepressant medications.

One of the newest drugs on the block is esketamine – and if you’re thinking that name sounds familiar, you’d be right. Esketamine has a similar structure to ketamine, and its approval for use in treatment-resistant depression sparked excitement and controversy in equal measure.

Esketamine is given in the form of a nasal spray. The drug kicks in quickly, orders of magnitude faster than an SSRI, so it’s designed to complement traditional medications by filling the gap until they start to work.

Some scientists are also working on new compounds that refine our existing treatments even further. In 2022, a study reported on a drug called ZZL-7, which targets the serotonin system but – crucially – seems to be able to do so more quickly. That study was only on mice, however, so it’s a long way off use in human patients.

Another big, exciting frontier in this field is the world of psychedelics. Psilocybin, the stuff that puts the magic in magic mushrooms, has been showing great potential for the most difficult-to-treat depression cases. How it works is still a matter of some debate, but now these drugs are becoming more accessible, both for research purposes and limited therapeutic uses, our understanding of them can only increase.

Drugs are not the only treatment option for depression; but with so many people around the world taking these medications every day, it’s good to be informed about what they are, how they work, and how this landscape could change in the coming years.

All “explainer” articles are confirmed by fact checkers to be correct at time of publishing. Text, images, and links may be edited, removed, or added to at a later date to keep information current. 

The content of this article is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of qualified health providers with questions you may have regarding medical conditions.