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Antidepressants work, but just not how scientists thought they worked

Most clinical trials of antidepressants were done decades ago in people with severe depression recruited from specialist mental health services. Yet most people who take these drugs have mild to moderate depression. We wanted to know whether a common antidepressant called sertraline works for this group. We found that, indeed, it does work, but differently from how we expected.

Prescriptions for antidepressants have risen substantially in wealthy countries over the past two decades (the rate has doubled in the last ten years), and this has led to concerns that they are being over-prescribed. The vast majority of antidepressants are prescribed by GPs for patients with mild to moderate symptoms of anxiety or depression, even if these patients don’t have enough symptoms for a clinical diagnosis of depression or anxiety.

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Our new study, published in The Lancet Psychiatry, investigated the effectiveness of sertraline in primary care patients with symptoms of depression, ranging from mild to severe. We did not set any severity criteria because we wanted a sample similar to the people who receive antidepressants now.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) – drugs that increase levels of a chemical called serotonin in the brain – and one of the most commonly prescribed drugs for depression and anxiety.

Our study recruited more than 650 people aged 18-74 from 179 GP surgeries in England. They had all reported symptoms of depression to their doctor – such as low mood, loss of pleasure, difficulty concentrating and sleep problems – and were seeking treatment. We randomly allocated patients to one of two groups: they either received sertraline for 12 weeks or they received a placebo that was identical to the sertraline pill.

Neither researchers nor patients knew which group people were allocated to. This type of “double-blind study” helps to reduce bias. After the study started, we collected data from participants at regular intervals: two, six and 12 weeks after they started the trial.

Difficulty sleeping is a depressive symptom. amenic181/Shutterstock

Reducing anxiety

The results surprised us. Our theory was that depressive symptoms would be improved on sertraline by six weeks, but we found no evidence this was the case. Any effect on depressive symptoms happened later and was smaller and less convincing. In contrast, sertraline led to an early reduction in anxiety symptoms several weeks before any improvement in depressive symptoms.

Most people with depressive symptoms also have anxiety symptoms, and it would be unusual for someone to have depressive symptoms but no anxiety symptoms. By reducing anxiety symptoms, the antidepressant made people with depression feel better. Those taking the antidepressant were twice as likely to say they felt better compared with those taking the placebo. Even if depressive symptoms take longer to respond, early effects on anxiety lead to improvements in a person’s quality of life.

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There has been a long-running debate about whether antidepressants help people with mild symptoms. Our study included people with a wide range of severity and we saw no evidence that the effect of the antidepressant was smaller in those with mild or moderate symptoms. Sertraline seems to benefit a wider group of people than previously believed. Our study alone cannot rule out the possibility that sertraline might be less effective in people with mild symptoms, but we found no evidence for this.

Our findings support the continued prescription of sertraline and other similar antidepressants for people with depressive symptoms. As with any medication, the benefits have to be set against any side effects and the possibility of withdrawal symptoms when coming off the drug.

This study was carried out in the UK, which has a strong primary care system. But there are similarities between the behaviour of doctors and patients in all wealthy countries, whatever the health system. For example, the increase in antidepressant prescription has occurred in all wealthy countries. We think our findings also apply to other countries.

Antidepressants are one of the most commonly prescribed drugs in the world, but we are still developing our understanding of how they work. Overall, this study is reassuring. On average, people who are receiving antidepressants in UK primary care are benefiting, even if the benefit is more for anxiety symptoms than depressive symptoms.

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