Should we worry about the next generation of antidepressants?

By 2014, anyone whose depression fails to respond to Prozac or Cipramil will be given one of a new generation of triple reuptake inhibitor antidepressants . These new antidepressants, which have a similar chemical structure to cocaine (something that has led to concerns about the potential for abuse and dependency), will block the reuptake of Serotonin, Noradrenaline and Dopamine. 

The hope is that the new antidepressants will produce a much more rapid antidepressant effect than the 3-4 weeks produced by Selective Serotonin Reuptake Inhibitors (SSRIs). There is also a hope that the new antidepressants will have fewer side effects than the SSRIs, which have to carry a “black box warning” about the potential risk of suicide, and which (with the exception of Prozac/Fluoxetine) cannot be given to children and adolescents.  If that is so, then they will be a welcome addition to the armory of treatments and therapies for depression.

But the way in which our love affair with the SSRIs came to an acrimonious end suggests that we should be cautious about the process that allows drugs aimed at a mass market to be licensed.

The first problem is that in the last two decades, we have been attempting to medicate more and more socio-economic problems.  The result has been a massive rise in the numbers of us on long-term antidepressant use (with apparently little beneficial impact on our depression).  It is no accident that the most deprived areas of the country have the greatest concentration of antidepressant use, with many areas of Wales having more than 9% of the population on antidepressants (indeed, more than 10% of the population of Torfaen are taking antidepressants).

Since 1980 (when psychiatrists were first permitted to diagnose people as being mentally ill without reference to the context in which their symptoms occurred) we have seen an ever wider range of human distress, sadness, stress and discomfort being labelled as “mental illness” – so much so, that we have had to invent new categories of “severe” and “common” mental illness to separate those who always would have been treated for mental illness from those who, prior to 1980, would not.

It was entirely foreseeable that the global pharmaceutical industry would seek to cash in on this relaxing of the rules on mental illness. Overnight, the ordinary unhappiness and distress associated with divorce, redundancy, homelessness and crime became illnesses to be treated. Where once we turned to family, friends, neighbours and colleagues for understanding and support, we are now stigmatised with the label “mentally ill”, and driven into the arms of clinicians and therapists.  Where once we would have taken political action to change things for the better, we now look for pills to make our misery seem tolerable.  Everything from bed-wetting in children and shyness in adults has been defined as a mental illness so that the pharmaceutical companies can create new monopolies for old drugs.

Why don’t the politicians object? Partly because politicians have a blind spot when it comes to expensive hi-tech solutions to complex problems (just look at the billions wasted on public sector computer databases). In their heart of hearts, our political leaders have always understood that most mental illness is the entirely understandable by-product of long term structural socio-economic problems and the civic environments that these produce. But despite eighty years of social and economic benefit reforms, the problems persist. And (to quote a former Prince of Wales) “something must be done!”  So when Eli Lilly gave the world Prozac 33 years ago, we were all willing to believe that this drug was indeed the miracle cure that the marketing hype promised.

It took more than a decade for journalists and politicians to take seriously the growing patient reports of side effects and withdrawal symptoms that accompanied the new generation of SSRI antidepressants. Unfortunately, much of the coverage was sensationalised, resulting in a prolonged debate about whether antidepressants caused suicide, how great was the risk, and what (if anything) should be done. But this drew attention away from the central truth – that SSRIs don’t cure depression, and only help to improve the symptoms of those with the most severe depression.  By that time, of course, we had created a generation of long-term antidepressant users who remain on SSRIs because they remain depressed!

One change that might help us to avoid the problems of the past is the recent change to the “yellow card” scheme that now allows patients as well as clinicians to report side effects from medication. In the past, only clinicians were allowed to report side effects which, in practice, meant that first a patient had to convince a clinician that a side effect was serious enough to be worth reporting, and second, for the busy clinician to actually remember to make the report. At least patients can now make the report directly, despite this not being widely publicised.

Another proposed change which has been promised but not so far delivered is a comprehensive register of clinical trials. One of the reasons that the side effects of SSRIs, and their lack of effectiveness in mild-moderate depression took so long to emerge was publication bias. Researchers are less likely to write up trials that did not produce positive outcomes. This is implicitly encouraged by medical journals that are seldom interested in publishing papers that don’t have positive outcomes. Nor are pharmaceutical companies in any hurry to publicise bad results. Indeed, it is common for the same pharmaceutical trial to be reported several times in different journals with the result that positive results seem even better than is actually the case. So we end up seeing all of the positive trials, but very few of the negative ones. A central register of trials would at least allow us to examine those trials that have not been published, and to spot those instances where the same trial is being reported more than once.

The risk is that the manufactures of the new generation of antidepressants will get away with burying bad news because the current system prevents all but the most committed journalist from obtaining the results of unpublished trials – it took several court orders to allow access to the hidden SSRI trial results that linked these drugs to an increased suicide and self-harm risk in children.

There may already be evidence of a risk from the new triple reuptake inhibitor antidepressants. Sibutramine is a Dopamine, Noradrenaline and Serotonin Reuptake Inhibitor, although it is not licensed as an antidepressant. Until January 2010, it was licensed as an anti-obesity drug. However, in January its license was suspended by the European Medicines Agency because of concerns about increased risks of heart attacks and strokes. There are also some worrying reports of adverse side effects in psychiatric patients given Sibutramine to control their weight.

Of course, the new antidepressants may well not have such side effects, and may prove to be more effective than the current generation of SSRIs. But we need to be vigilant.

It is particularly important that clinicians follow NICE prescribing guidelines rather than falling for the sales pitch made by the pharmaceutical company reps.

It is important that we all take seriously any reports of side effects made by people who are prescribed the new drugs.

It is important that politicians and journalists avoid falling for the “miracle cure” spin that often accompanies the launch of new drugs. As we saw with SSRIs, this kind of spin prevents the concerns and experiences of patients from being heard.

Most importantly, we need to ensure that we do not use the nest generation of antidepressants as a quick-fix alternative to resolving the socio-economic and environmental factors that cause most mental illness in the first place.