Nobody knows how anti-depressants work

Awais Aftab

Lately, the public conversation around anti-depressants has focused largely on whether and how to quit them. Health Secretary Robert F Kennedy Jr has made de-prescribing, or supervised drug tapering, a focus of policy. Kennedy and other critics of antidepressants argue that the medications are overprescribed and have dangerous side effects.

The medical community, however, views them as effective and necessary treatments for people with a wide range of mental disorders, including depression, anxiety and obsessive-compulsive disorder. But underneath this debate lies a more fundamental question that science has yet to conclusively answer: How, exactly, do antidepressants work?

For decades, the public understanding of anti-depressants has been stuck in a narrative popularised by pharmaceutical advertising in the 1990s: that they work by correcting a chemical deficiency in the brain. But evidence from research studies has been clear since at least the early 2000s — if not earlier — that this is not how antidepressants work.

Doctors prescribe the drugs because decades of study data and patient reports show they can relieve people’s mental health problems. But doctors and scientists don’t have a clear understanding of how they do that. That may be surprising, but it’s the case for many kinds of medications, such as acetaminophen and general anaesthetics.

Scientists today are working with several promising explanations. No hypothesis is settled in science, and some may be disproved tomorrow. But together they reflect the strongest understanding medicine currently possesses.

Chemical imbalance?

Anti-depressants such as selective serotonin reuptake inhibitors (SSRIs), and others do increase levels of certain brain chemicals called neurotransmitters. But as far as we can tell, they aren’t correcting a chemical deficiency. Instead, their beneficial effects seem to arise from a cascade of changes they set off in nerve cells that then alter the activity of brain circuits and thought patterns.

Depression and anxiety appear to involve a shift in how a person processes emotionally significant information. Neutral facial expressions take on a more disapproving and critical vibe. Negative memories are recalled more readily than positive ones. Rewards feel muted, while criticism feels overly painful.

It is common for people with depression or anxiety to feel stuck in a persistent loop of negativity.

Researchers at the University of Oxford have shown that anti-depressants shift negative emotional information processing in a positive direction. This effect becomes evident fairly quickly after a person starts taking anti-depressants — within days, sometimes after a single dose.

But this change in how emotional information is processed isn’t enough to lift people out of a state of depression or anxiety. What typically follows is a period during which people relearn how to see themselves and the world. Once they are no longer filtering everything through negative lenses, their brains can gradually accumulate more neutral or positive experiences of themselves and the world around them.

The environment of a medicated person plays a crucial role in this relearning. People with more social support and positive interpersonal relationships, including psychotherapy, tend to gain more from the medications.

Brain rewiring

Related to these changes in emotional processing is the idea, popularised by psychiatrist Peter Kramer, that anti-depressants reduce neuroticism, a personality disposition toward worry, negative emotions and stress sensitivity.

In one clinical trial, patients on an SSRI called paroxetine showed substantial reductions in neuroticism that were not explained simply by improvement in depression.

Another way in which antidepressants may work involves the enhancement of neuroplasticity, or the brain’s ability to reorganise its structure and connections. Continued treatment with anti-depressants may bolster brain chemicals and processes that promote neuroplasticity.

Psychedelics are thought to work as a treatment for depression and anxiety, in part, for a similar reason. The hypothesis is that the drugs open a ‘window’ of plasticity through which the brain has a renewed ability to change the way it is wired.

Patients treated with anti-depressants often feel more mentally malleable and better able to move away from unhelpful thinking patterns. Some researchers have proposed that we should think about anti-depressants as relieving a kind of cognitive constipation.

The evidence for neuroplasticity is still up for debate. But the hypothesis that anti-depressants alter how readily the brain learns from experience by facilitating neuroplasticity remains a leading candidate for why they work.

Side-effects

It’s also well-recognised that anti-depressants can flatten emotions as a side effect. In one survey of more than 700 people taking an antidepressant, nearly half attributed emotional blunting to their medication, and about a third were considering stopping because of it.

On SSRIs, healthy volunteers tend to be less swayed by rewards and setbacks. There is a common meme on social media in which videos of people responding calmly to threatening situations like fire or gunshots are met with comments like “What dose of Lexapro is this?”

Some argue that this emotional blunting is how anti-depressants work, and that the drugs don’t treat mental health problems so much as dampen feelings, both positive and negative. This claim is not well supported by available studies, but it is possible that anti-depressants may nonetheless work in some patients by attenuating their emotions across the board.

Any discussion of how anti-depressants work also needs to acknowledge that research shows factors such as optimism about treatment, expectancy of relief, a positive relationship with the doctor, the passage of time and regular contact with medical staffers contribute to a substantial proportion of people’s improvement.

While anti-depressants do outperform placebos and have specific effects, the difference from placebo for the average patient is modest. Good clinicians are aware of this and pay attention to how they prescribe the drugs. They gain the trust of their patients, work collaboratively, encourage realistic hope, proactively address possible concerns, and communicate frequently and empathetically during treatment.

All these explanations are not necessarily rivals but better understood as complementary descriptions of processes unfolding at different levels in different people. A common theme among these hypotheses is that anti-depressants alter the conditions under which people interact with the world and with their emotions.

Anti-depressants can make circumstances appear less threatening; they soften sensitivity to stress and loosen rigid patterns of thoughts, allowing people to escape from them. What many of these hypotheses suggest is that medication alone is not enough; it should be complemented with the appropriate psychological and social changes.

We can think of the anti-depressant here as a cast or a scaffold: It can come off once the work of healing and repair is complete. For people with isolated episodes of depression, this strategy works best. But for others with persistent problems, grounded in temperament or environment, medication might need to be more like a buttress — a permanent and necessary support to keep the building standing.