Unexpected mechanism of action found with sertraline

By Dr. Liji Thomas, MDSep 23 2019

A new study on sertraline, which is one of the most popular drugs for depression and anxiety, shows that its efficacy is undoubted, but it operates primarily by reducing anxiety rather than depression.

What is sertraline?

Sertraline is a commonly-used antidepressant, (being just one of the almost 80 million antidepressants that are prescribed in England alone in 2018), but healthcare specialists have often worried that it is being used too much. This study, reported online in The Lancet Psychiatry on September 19, 2019, is expected to dismiss such fears, showing that it is an effective medication in anxiety and depression.

Sertraline is classified as a selective serotonin reuptake inhibitor (SSRI), which means that it prevents the reuptake of serotonin at the receptors. As a result, the levels of serotonin go up, boosting its neurological effects. Despite understanding this mechanism, researchers still don’t know much about how these drugs actually work in the body. However, it is indisputable that patients respond fast to the use of this drug when used to treat anxiety or mild depression.

Image Credit: Nevodka / Kateryna Kon

How was the study done?

The current study at University College, London, called the PANDA study, included about 650 patients, with half of them using a placebo and the other a sertraline pill. The patients had mild to severe depression (54%), or anxiety (46%), or even both (30%). 45% had mixed symptoms not amounting to a diagnosis of either anxiety or depression, while 15% would not have been diagnosed with either.

All were registered from approximately 180 GP practices in the UK. The average age was about 40 years, about 60% were women, and two-thirds were employed. These patients were not taking sertraline at the time of the start of the study and their diagnosis was uncertain.

After 6 weeks of taking the drug (at 50 mg a day) or placebo, all patients were reassessed. The dosage was then increased to 100 mg a day.

Study outcomes

In the sertraline group, there was a 21% increase in relief from anxiety; that is, patients felt less irritable, worried and nervous. This gap from the control group went up to 23% after 12 weeks.

Even at this time, however, depressive symptoms were surprisingly intact. Patients still experienced lack of focused attention, had down moods and did not enjoy life much, including previously enjoyable experiences. This improved only a little, by 13%, even after 12 weeks. However, the group on sertraline was more than two times as likely to report that they felt better mentally, overall, than the other group. Moreover, sertraline was not likely to produce significant side effects, according to the study.
In other words, the early psychological improvement was mainly due to reduced anxiety rather than an elevated mood. Thus GPs using sertraline to treat anxiety and depression of mild to moderate degree were acting appropriately and could use this drug in more patients with these symptoms.

However, researcher Glyn Lewis says that the study findings were surprising in relation to how the drug worked, even though it confirmed its efficacy. GP Helen Stokes-Lampard says, “This study gives an interesting insight into how a medication primarily used to treat depression may be improving a patients' health in other ways in the shorter term, by reducing symptoms of anxiety, which is often associated with depression.” Even though the activity of this drug on depression is low, in direct terms, it does improve depression indirectly by lowering anxiety levels, helping the patient to cope with depression better and improving mental health as a result.

Major depression, however, is a different matter, and is not likely to show any special improvement from the use of sertraline, according to psychiatrist Sameer Jauhar. He says of the study, “It is not surprising that depressive symptoms did not improve to a great extent, given that only half the people had a diagnosis of depression.” Thus the presence of mild to moderate depression in a small number of patients was not likely to show any change with the use of sertraline.

How does the study help?

Another psychiatrist, Wendy Burn, says that while the study shows sertraline is probably being used correctly, it is not the answer to all patients with depression. Instead, she says, “It reinforces the importance of combining them with other options, such as talking therapies and social prescribing.”

Another factor to consider is the long period of time required for these drugs to stabilize their levels in the body, only after which their impact can be reasonably assessed. For this reason, drugs like sertraline work best in depression only after being taken for a long period. Thus patient reviews are normally done only after prolonged periods, and prescriptions are then given for a long course of treatment if any significant benefit has been derived from the use of these drugs.

The result thus goes against the results of earlier studies on the effect of any antidepressant on acute depressive symptoms, compared to placebo. This could be because in earlier sertraline trials, all patients had major depression, and were drawn from mental health specialist centers. However, the present study design was adopted to reflect the fact that sertraline is mostly used today in GP settings, on a broad range of people with mild to severe symptoms of depression, and the aim was to evaluate its efficacy in this situation.

The intentional absence of entry criteria meant that participants were drawn from a pool of clinically uncertain diagnoses, making it more widely applicable to the population at large who receive antidepressants from their GP practice. It also reduces the chance that patients who definitely will benefit from antidepressants will be included, but this did not affect the findings significantly.

Another major advantage is that it mirrors the self-rated benefit of the drug on mental health. In fact, this is the largest trial of an antidepressant controlled by placebo that has not been funded by a drug company, giving it additional weight.