Dogs bark,but the caravan goes on: A discussion on the meta-analysis of antidepressants by Andrea Cipriani et al.

1. Introduction

Clinical neuro-pharmacologist and retired clinical psychiatrist Ken Gillman wrote: “…caveats and limitations rightly expressed by the authors about the validity and generalisability of their data and results (published in the largest meta-analysis of about 21 antidepressants by Andrea Cipriani et al. [1]) will soon, as usual, be forgotten in the oversimplified implementation resulting from insufficiently informed or critical use of ‘guidelines”’ [2].

In the world in which Max Weber’s idea of instrumental rationality has been turned upside down: “rather than in purposes seeking the most effective means, it now consists in the means that seeks, and more often than not finds, suitable applications” [3]. We can easily read this thought as: rather than in disease seeking the most effective remedy, it now consists in the remedy that seeks (and often finds) a suitable disease. It is possible to imagine this idea as a groundwork for creating a syntagma of a drug-based disease [4]. First SSRI AD fluoxetine was launched in 1987, more than two decades after the monoamine hypothesis of depression had been put into words. Namely, in the late 1960s, a post-mortem study showed a diminished level of serotonin in depressive suicides [5] but the idea that serotonin levels might be lowered in depression was omitted [6] and tricyclic antidepressants continue to be a drug of choice for treating severe depression. When in 1980s benzodiazepines as addictive drugs were attempted to be supplanted by the serotonergic drug buspirone, this idea flopped. Instead, SSRIs were marketed for treating depression despite being weaker than older tricyclic ADs. That strategy was a great success, central to which was the belief that SSRIs restore the serotonin level in synapses to normal. This notion later metamorphosed into the definition that SSRIs cure chemical imbalance in the brain.

2. Birth of mythology

Fluoxetine was created and established to block the serotonin transporter and presynaptic reuptake and therefore elevate serotonin content in synapses [7]. Accordingly, the drug-centred model was created: depression is a lack of serotonin in synapses. The disease-centred model advocates that antidepressants work because they reverse the processes in the disease that give rise to the appearance of depression-characteristic symptoms. Until now, nobody has proven this model [8]. On the other hand, “the ‘drug-centred’ model suggests that far from correcting an abnormal state, as the disease model suggests, psychiatric drugs induce an abnormal or altered state. Psychiatric drugs are psychoactive substances, like alcohol and heroin. Psychoactive substances modify the way the brain functions and by doing so produce alterations in thinking, feeling and behaviour. The drug-centred model suggests that the psychoactive effects produced by some drugs can be useful therapeutically in some situations. They do not do this in the way the disease-centred model suggests by normalising brain function. They do it by creating an abnormal or altered brain state that suppresses or replaces the manifestations of mental and behavioural problems” [9].

The ‘drug-centred’ story of depression began in the 1950s with a doubtful experiment with reserpine. It postulated the paradigm that the decreased level of serotonin was the cause of depression disorder. The theory still persists even though a single proof to support the theory has not yet been found. Its life will also be additionally preserved by the article published in The Lancet in February 2018. Immediately after the publication of the largest meta-analysis, The Times in the article entitled “More people should get pills to beat depression” wrote for the Sunday Times: “Millions of sufferers would benefit, doctors told. More than a million extra people should be offered antidepressants after the largest study of its kind concluded that they worked, experts have said. Patients and GPs must not be squeamish about treating mental health problems with drugs, according to scientists who found that every one of 21 common antidepressants was better than a placebo”.

The National Health Service (www.nhs.uk) under the title “Big new study confirms antidepressants work better than placebo” wrote: “Antidepressants are highly effective and should be prescribed to millions more people with mental health problems, researchers declared last night”, reports the Mail Online and continues the article in a more sober way: “However, that does not mean they are “highly effective” – it means people are more likely to see their symptoms improve if they take an antidepressant than if they take a placebo”.

Despite the fact that Cipriani et al. wrote that summary effect sizes were “mostly modest” [1], some popular media concluded the article had proven that antidepressants work, any debates over these drugs are now over and declared that “happy pills” are here again. The soundbite “antidepressants work” will remain in public mind and, unfortunately, even in the minds of psychiatrists and GPs. Nevertheless, the defined daily doses are rising and in the USA, UK, Iceland, Australia and Portugal are over 100 per 1000 inhabitants. Most people are put on these drugs in primary care, after a very brief visit and without clear symptoms of clinical depression. Usually there is some improvement, and it is often based on the passage of time or placebo effect [10,11]. The value of Cipriani’s study must be questioned again for many reasons. Firstly, the drawback of randomized controlled trials is the selection of population by a contract research organisation which provides high responders, who are additionally selected by the run-in phase of trials. There is only a few ten percent match between participants in trials and patients with a prescription for AD in their hands. Secondly, the duration of trials also does not correspond to the duration of administrating the drug. Whereas in 522 trials in the article the exposure lasts 4–8 weeks, less than 6% of the population takes AD for 8 weeks or less and 26% for 2 months-2 years, 24% 2–5 years, 19% 5–10 years and 25% takes AD for more than 10 years respectively (in the period 2011–2014) [12]. Side effects and risk factors of long term use are an important drawback and are rarely mentioned. Some lesser known effects are depicted below.

3. Conclusion

Given these circumstances, it is obvious that debates around effectiveness and odds ratios in antidepressants therapy, considering the methodological flaws, reanalysis of a network meta-analysis, which are the main themes in articles that put under question Cipriani’s article, are irrelevant. Even the name itself, namely ‘antidepressants’, is wrong because it suggests that these medications correct the biological basis of depressive disorder, which is far from the truth. We can speculate that not only akathisia, which is connected to CYP P450 poor metabolizers, but also other side effects are a consequence of high concentrations of antidepressants in blood due to slow metabolism with cytochrome P450 enzymes. Additionally, can we even speculate that fast metabolizers have the lowest antidepressants concentrations in blood and therefore the weakest side effects and consequently the highest decrease on the Hamilton Depression Rating Scale?

Finally, Eric Nestler, the Dean for the Academic and Scientific Affairs and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York, wrote: “…after more than a decade of PET studies (positioned aptly to quantitatively measure receptor and transporter numbers and occupancy), monoamine depletion studies (which transiently and experimentally reduce brain monoamine levels), and genetic association analyses examining polymorphisms in monoaminergic genes, there is little evidence to implicate true deficits in serotonergic, noradrenergic, or dopaminergic neurotransmission in the pathophysiology of depression. This is not surprising, as there is no a priori reason that the mechanism of action of a treatment is the opposite of disease pathophysiology” [42]. Furthermore, regarding devastating side effects and despite many biases, which raise the effectiveness of these drugs, the odds ratios are still only statistically significant, the risk/benefit ratio is far on the risk side. Therefore we can say that prescribing antidepressants to patients is not in line with the Hippocratic Oath and Cipriani’s article should be retracted.