April 21, 2015

expert reaction to editorial on serotonin and depression

In an editorial published in The BMJ, the treatment of patients with depression has been discussed with regard to serotonin and pharmaceuticals which attempt to control its levels.

Prof. Sir Simon Wessely, President of the Royal College of Psychiatrists, said:

“That antidepressants are helpful in depression, together with psychological treatments, is established. How they do this is not. Most researchers have long since moved on from the old serotonin model.

“Most important of all, the newer drugs (the SSRIs) are safer if taken in overdose than the older tricyclics.

“People should not change their current medication on the basis of this editorial alone.”

Prof. David Taylor, Director of Pharmacy and Pathology and Head of Pharmaceutical Sciences Clinical Academic Group, King’s Health Partners, South London and Maudsley NHS Foundation Trust, said:

“Professor Healy makes a forceful but poorly supported argument against something which doesn’t and has never really existed: the idea that SSRIs ‘correct’ an ‘imbalance’ of serotonin in the brain.

“Researchers and psychiatrists alike know that SSRIs are effective in a number of disorders but no one is sure exactly how they work. Their readily demonstrable effect is on serotonin but they have many indirect secondary effects in the brain. Professor Healy also ignores very strong evidence that tryptophan depletion (which reduces serotonin production) reverses the beneficial effects of antidepressants with a variety of modes of action. He fails to mention that SSRIs supplanted earlier tricyclics largely because of their relative safety in overdose, not because of any conspiracy concerning a theory of serotonin’s involvement in depression.”

Dr Paul Keedwell, Consultant Psychiatrist and Specialist in Mood Disorders, said:

“Most psychiatrists are quite happy to admit to patients that they do not know precisely how antidepressants work. Their primary focus is on treating depression effectively and safely. They take into account evidence from trials but also recognise individual differences in response to different medications.

“In the real world of the clinic, SSRIs are undeniably effective in treating individuals with major depression. They have become the first line treatment of choice because they have fewer troublesome side-effects than their predecessors, and are safer in overdose. There is no evidence to suggest that they are less effective than the old tricyclics in general, although this could be true in individual cases.

“Exactly how SSRIs work could only be irrefutably proven by opening up someone’s brain.  Even then, methods of observation would be likely to affect what we observe. Animal evidence and tests of blood, urine and spinal fluid of humans strongly suggests that serotonin function is affected in some way by these drugs. However, the profession is well aware of the fact that other systems are likely to be involved.

“Many individuals do not achieve complete remission with the first SSRI that is trialled, but this is also true of other types of antidepressant. We know from the large STAR-D trial that switching to a different type can bring about a successful outcome in many of these cases.

“There remain a significant number of people who are resistant to all existing forms of antidepressant, which is why more research is needed.

“The idea that a ‘serotonin myth’ is somehow restricting such research is simply not true. Ketamine, which is thought to work predominantly through glutamate receptors, had been shown in independent trials to bring about a rapid remission in at least a third of previously treatment-resistant individuals. Other drugs in development work on the interplay between noradrenaline and serotonin, or on novel manipulations of dopamine, melatonin, glutamate and the stress hormone cortisol. Psychiatrists have long known that therapeutic success likely involves a complex interplay between all of these brain chemicals.

“Hence, Healy’s assertion that disturbed serotonin function is not sufficient to completely explain depression is not news. However, his assertion that SSRIs may be less effective than older drugs is not supported by the evidence from clinical trials or the real world of the clinic.

“David Healy has previously claimed that SSRIs cause dependence or provoke suicide.  In so doing he has risked deterred individuals with severe depression from getting the help they need and this latest article just adds to this problem. The risk of suicide from untreated depression is much greater than the risk of treating it with antidepressants, and yes, this includes SSRIs.

Dr Clare Stanford, Reader in Experimental Psychopharmacology, UCL, said:

“Prof David Healy’s article treads a path that is well-worn but out of date. He argues that selective serotonin re-uptake inhibitors (SSRI) antidepressants are used because of a pervasive myth that they boost serotonin levels, but this is something of a straw man. He makes the mistake of assuming that antidepressants reverse a functional abnormality in the brain that causes depression. Actually, the theory that low ‘levels’ of serotonin in the brain (whatever that means, functionally) causes depression died many years ago, in spite of the fact that a deficit in the synthesis of serotonin in the brain can trigger relapse of depression in some patients who are in remission: a fact which he also fails to mention.

“By contrast, the monoamine theory of ‘anti-depression’ is alive and kicking. There is plenty of evidence that SSRIs increase communication from neurones that release serotonin, as well as other monoamine transmitters, and that the ensuing downstream changes, such as creation of new neurons (neurogenesis) or modification of gene expression, can ameliorate depression.

“In short, SSRIs probably switch-on anti-depression, rather than switch-off depression (which could explain the rapid efficacy of ketamine).”

“I am sure that most clinicians and scientists will be dismayed that a flawed argument is used to underpin a suggestion that the use of older tricyclic antidepressants, which are so dangerous in overdose, is always preferable to the SSRIs.”

‘Serotonin and depression: The marketing of a myth’ by Healy published in The BMJ on Tuesday 21^st April. 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/?s=SSRI&cat

Declared interests

Prof. Simon Wessely: None declared

Prof. David Taylor: I am employed by the NHS, King’s College London, Mental Health Research Network, Department for Transport and Driver and Vehicle Licensing Agency (DVLA). I am an Advisory Board member for Lundbeck, Servier and Sunovion. I receive research funding from Bristol-Myers Squibb, Janssen and Lundbeck. I have given lectures for Janssen, Otsuka, Servier and Lundbeck.  Of these companies, Lundbeck market several SSRIs and Servier market an antidepressant with a different mode of action.

Dr Paul Keedwell: None to declare

Dr Clare Stanford: Fellow of the British Pharmacological Society and Past President of the British Association for Psychopharmacology