Tuesday, 10 January 2012
IN THE NAME OF ALLAH – THE SOURCE OF MERCY – THE MOST MERCIFUL
Is Depression caused by a lack of Serotonin in the brain, or are we being conned?
I feel like I need to start this post with a caveat: I am in no way saying that depression does not have biological correlates, or that medication is a useless route for depression. No no no! I am simply taking a look at why serotonin has found its way to the forefront of public consciousness when talking about depression, and if there are drugs which target other neurotransmitters which may be just as good as, or better, than the classical SSRI antidepressants. Ok cool.
In the 1950s, scientists accidentally discovered that increasing levels of the monoamines (serotonin, dopamine and noradrenaline) in the brain was associated with increased positive mood, and the hypothesis was made that depression is due to decreased levels of neural monoamines, particularly serotonin. To what extent is this correct and to what extent are we being deceived by ‘Big Pharma’?
The pharmaceutical industry is estimated to be worth over $600 billion and, of this, over $3.1 billion is due to sales of the antidepressant Zoloft the seventh best selling drug in the world. Arguably, it is in the best interests of this industry not to highlight and even to suppress the efficacy of other drugs which do not conform to the depleted serotonin hypothesis which has served drugs like Zoloft so well, for not doing so would mean remarketing their stance on the cause of depression, branding a new drug, and advertising it to the public – all of which are costly endeavours.
Hundreds of studies have demonstrated that antidepressant administration increases mood, affects cognition & reduces fear responses in the depressed & the healthy, but why do they not work in all people? Although antidepressants which serve to increase monoamine levels are effective, their immediate chemical effects take weeks to be translated into increased positive mood (average 6 weeks) - surely if depression was due to not having enough serotonin, we would all be happy as soon as we took an antidepressant pill, as they increase serotonin levels immediately.
Latency aside, some recent studies have proposed that the antidepressants currently on the market are not as effective as pharmaceutical companies would have us believe. Kirsch et al (2002) found, through analysis of all antidepressant clinical trials submitted to the FDA for approval, that the antidepressant response was matched by 80% of the placebos used, and in 57% of the trials there was no significant difference between antidepressant and placebo. Let’s just consider that for a second: 8 out of every 10 placebos they used worked just as well as antidepressants - that’s a huge number. Is simply being told you are taking something which will make you happier enough to make you happier? Lacasse and Leo (2002) contrast this with trials concerning insulin imbalance in studies aiming to find relevant medications for diabetics. In these trials, they claim, there is no such modest efficacy or high placebo response…so why should antidepressants be approved by the FDA with less evidence for their efficacy? Perhaps what they are hinting at is that although antidepressants have mild side effects such as dry mouth, anxiety, constipation and weight gain, incorrect adjustment of blood sugar levels can lead to coma and even death; so drug companies can successfully market antidepressants - even though the research to support their efficacy is not as well replicated as one would desire – because the negatives of doing so are less than for other disorders and medications.
Also troublesome are the findings of the efficacy of drugs which do not directly target the serotonergic system. For example, bupropion, reboxetine, and even St. John’s Wort have performed as well as or even better than SSRIs in recent randomised controlled studies. Most interesting perhaps is tianeptine, which is actually a selective serotonin reuptake enhancer. This actually reduces the available serotonin in your brain, so it would make you more sad, right? - Wrong: it has found to be clinically efficacious in the treatment of depression, with few side-effects. It even alleviates comorbid anxiety without sedation. This is an advantageous property, considering the high comorbidity of anxiety and depression (as high as 50%).
Regardless of whether we should be looking to increase or decrease serotonin, the question remains: can biology ever truly be a cause? Given that biological factors don’t necessarily lead to depression (they often provide only a vulnerability which must be ‘triggered’ by environment), it is too hasty for drug companies to claim that depression is caused by a lack of serotonin.
So why have antidepressants and a serotonin explanation come to the forefront in advertising literature and the minds of medical professionals and the general public if there are other plausible candidate mechanisms at play in depression? Turner et al (2008) highlighted a ‘publication bias’ prevalent in the scientific literature by comparing published and unpublished outcomes of 12 antidepressant studies involving 12,564 patients submitted to the FDA. 31% (3449 patients) were not published, and this was significantly associated with study outcome: out of 74 studies, 37 with a positive result were published as opposed to only 1 with a positive result that was not published. It therefore appeared, according to the published literature, that 94% studies were positive. However, when they returned to all the available literature, including the studies that were refused publication, only 51% were positive. That’s no better than chance! We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. What does seem clear, though, is that there is a publication bias prevalent in the FDA and academic journal system, which may have skewed evidence more towards the pharmaceutical companies’ opinions.
Another important aspect at play here is journalism and the media, which Leo & Lacasse (2008) recognised in their study in which they looked to the media for support of their hypothesis that, whilst the cause of mental disorders such as depression is unknown, “the idea that neurotransmitter imbalances cause depression is vigorously promoted by pharmaceutical companies and the psychiatric profession at large”. They received responses from multiple sources, including practicing psychiatrists, clients, and a major pharmaceutical company. The evidence offered was “not compelling”, and several of the cited sources flatly stated that the proposed theory of serotonin imbalance was known to be incorrect. When they asked one particular journalist about why she had said in an article that depression was due to a “chemical imbalance”, ”the author mentioned that: psychiatrists would be the best people to talk with about chemical imbalances; mental illnesses have been linked to chemical imbalances; psychiatrists are trained to figure this out through a variety of tests; and that “numerous studies have been done” and “the research is definitely available.” We pointed out to her that, if there are “numerous studies” which are “definitely available,” then it should be relatively easy to cite at least one article. She did not reply.” In this way, journalists are the main link between scientific researchers and the general public, and careless writing can easily influence common thought about this disorder.
In summary then, I do not dispute that there is indeed convincing and statistically significant evidence within studies to support the hypothesis that a lack of serotonin has a role to play in depression, but rather I wish to show that such evidence may have been shown favouritism both in the media and in publication biases present in many of the most prominent scientific journals. I am drawn to agree with the recent literature, which suggest that the view of the cause of depression as a “chemical imbalance” is oversimplified at best: we have insufficient evidence to view it as a cause and, until we can, this may even be detrimental to patient recovery. As proponents of Cognitive Behavioural Therapy would argue, viewing oneself as the passive ‘victim’ of one’s own biology may even be detrimental to recovery.