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expert reaction to study on the clinical effectiveness of the antidepressant sertraline

A study, published in Lancet Psychiatry, reports that the antidepressant sertraline may reduce anxiety more than depressive symptoms.

 

This Roundup accompanies an SMC Briefing.

 

Prof Guy Goodwin, Emeritus Professor of Psychiatry, University of Oxford, said:

“The PANDA trial recruited patients with mainly mild symptoms of anxiety and depression because the central criterion was equipoise. That means there was uncertainty on whether or not patients merited treatment with sertraline, a commonly used SSRI. This may commonly be the case in general practice when patients seek help for persistent symptoms of negative affect. It turned out that sertraline had more effect on anxiety than depression and overall improved on a general measure of mental health more than placebo. There was no excess of adverse events in the patients treated with sertraline. Overall response rates were high in both sertraline and placebo groups. As the authors state, the findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder.

“The backdrop to this trial has been controversy over the increased use of antidepressants in general practice, in part, presumably, for exactly this kind of patient. In providing light rather than heat to the debate, the authors deserve our gratitude. More evidence on the longer term value of treatment with antidepressants and the real frequency of difficulties withdrawing from them will require a similar dispassionate approach.”

 

Dr Sameer Jauhar, Senior Research Fellow and Consultant Psychiatrist, IoPPN, King’s College and South London and Maudsley NHS Foundation Trust, said:

“This is an important study. Prescribing rates of antidepressants are higher than the numbers of people we would expect to have major depression (the main indicator for prescription). Most antidepressants are prescribed by GPs and it is important to know whether prescribing these medicines for conditions other than major depression is helpful or not. The best methodology is a placebo-controlled randomised controlled trial, in a representative population, and this is what the authors did.

“People entering this study were either uncertain themselves, or their GP was uncertain regarding prescription of an antidepressant. The findings-that anxiety symptoms, though not depressive symptoms, improved relatively quickly, and that people felt better taking these medicines, probably reflects why GP do prescribe them.

“It is not surprising that depressive symptoms did not improve to a great extent, given that only around half the people had a diagnosis of depression.

“We cannot extrapolate these findings to people with major depression because the people included in the study and the clinical measures are not compatible with the trial literature on major depression.

“This study-like any other-will require replication, though does give us some understanding of possible benefits of antidepressants, specifically SSRIs. What will be crucial for future studies is understanding for how long these medicines should be prescribed for these indications, and whether adjunctive psychotherapy has further benefits, or may help people maintain improvements after medication is stopped.

“As with all medicines, risks and benefits need to be discussed at an individual level with doctors, and carefully monitored. This study adds to that discussion.

“Finally, it is worth noting that antidepressants tend to be prescribed more to people with higher levels of deprivation-there is little doubt that this plays a role in the aetiology of a lot of symptoms measured in this trial. As ever, in medicine, prevention is better than cure, but it is worth knowing that these medicines have the potential to help a wider group of people than was originally thought.”

 

Dr Paul Keedwell, Consultant Psychiatrist, Cardiff University, said:

“This was a large and ambitious study but it would be unwise to conclude from the results that sertraline is ineffective in the treatment of depression. There are two main issues with this study that limit its scope: the population studied and the conservative dosing.

“The study included many individuals with low symptom severity, including those who did not meet diagnostic criteria for depression, and where GPs had demonstrated ‘clinical uncertainty’ about whether an antidepressant was suitable. It is not unreasonable to do this because many such individuals are prescribed antidepressants in primary care. However, the lack of significant reductions in symptom severity should not be surprising if depression scores were low to start with.

“Although most of the individuals in this study had milder or even sub-diagnostic depression severity, individuals with more severe depression were also included. When analysing the effect of severity the researchers found no evidence that these individuals fared better. However, it is not clear if there were enough severely depressed participants to have the statistical power to show a difference. Additionally, the doses required to get a response in these individuals might be higher than 100mg – the seemingly arbitrary maximum dose chosen in this study (the licensed maximum is 200mg). It is also important to note that many individuals had been depressed before, and of these many had tried antidepressants. Were some of these individuals relatively treatment resistant, thereby necessitating optimisation of the dose?

“Unlike most other SSRIs the dosing strategy for sertraline (50mg-200mg) is not straightforward and there are marked individual differences in doses required to achieve a response.

“Most psychiatrists would say that sertraline is an effective antidepressant provided there is flexibility to increase the dose up to the maximum of 200mg per day, especially in people with more severe depression. This could also be true in a primary care setting, depending on the individual.

“Finally, the study did show a subtle trend towards both response and remission at 12 weeks, but not at 6 weeks. On the whole, quality of life improved. Individuals felt better. To me this indicates that a stepping up of the dose might have brought about further improvements. Importantly, sertraline was prescribed at 50mg for the first week, meaning that by 6 weeks participants had been treated for only 5 weeks at the higher (but still moderate) dose of 100mg. Clinical experience and trial data suggest that for treating depression, as opposed to anxiety, longer trials and higher doses might be required.

“What I think can be concluded from this study, is that moderate doses of sertraline are of questionable value in treating depression in a cohort of people with predominantly low depression severity. Further research is needed in this important primary care population, with individuals grouped according to severity, and a more flexible dosing regimen.”

 

Prof David Nutt, The Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Division of Brain Sciences, Dept of Medicine, Imperial College London, said:

“There are hundreds of papers showing increasing serotonin reduces anxiety and stress responses and sertraline – a type of drug known as a selective serotonin reuptake inhibitor (SSRI) which act on serotonin levels – is licensed for several anxiety disorders because of this. The lack of impact on depression scores in this study probably reflects both positive placebo effects plus a floor effect (meaning the scores for depression in the participants are low so there was little room for them to change).

“This study helps explain why so many GPs use SSRIs to promote wellbeing in their patients with intractable life stressors.  Also, I hope this trial continues to collect data on relapse prevention and withdrawal in this well studied population as this would help resolve the current dispute over their frequency and severity.”

 

Prof Wendy Burn, President of the Royal College of Psychiatrists, said:

“This trial is an interesting and important addition to the evidence base underpinning the use of antidepressants for patients suffering from depression and anxiety.

“Sertraline had beneficial effects on anxiety and wellbeing measures greater than placebo at six weeks, although this was not so for depression. There was some reduction of depressive symptoms at 12 weeks.

“These data are important because they confirm the benefits of treatment with an antidepressant in a group of patients in NHS general practice and will be reassuring for both doctors and patients. It also shows that antidepressants are not the solution for everyone and reinforces the importance of combining them with other options such as talking therapies and social prescribing.

“As with all antidepressants, it is vital that people prescribed them are monitored closely, made aware of possible side effects and know how to seek help if they experience them.”

 

‘The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomized trial’ by Gemma Lewis et al. was published in Lancet Psychiatry  at 23:30 UK time on Thursday 19th September. 

DOI: 10.1016/S2215-0366(19)30366-9

 

Declared interests

Prof Guy Goodwin: Currently consultant to companies developing new antidepressants (Lundbeck, Janssen, Sage) and hold shares in P1vital products.

Dr Sameer Jauhar: Sameer Jauhar is Co-investigator on a research study in psychosis, funded by Alkermes. Sameer has not received fees for being a Co PI or any expenses for this.

King’s College, London, has received fees from Lundbeck for lectures Sameer Jauhar has given on psychosis.

Funding: National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London SJ is funded by a JMAS (John, Margaret, Alfred, and Stewart) Sim Fellowship from the Royal College of Physicians, Edinburgh.

Dr Paul Keedwell: No declarations

Prof David Nutt: I have in the past advised Pfizer who used to market sertraline plus many of the other pharmaceutical companies who developed and marketed other anti-depression and anxiety medicines.

Prof Wendy Burn: No declarations of interest

None others received.

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