Antidepressant prescribing is showing no signs of slowing down, increasing year on year. The total number of prescribed antidepressants increased by 4.6million between the years 2015/2016 to 2016/2017, with the total number of treated patients over 18 years old increasing by 300,000 during the same period. In the year ending March 2017, the total number of prescribed antidepressant items was 65.6million in the United Kingdom, more than one for every man, woman and child*.

So surely these widely prescribed medications have a solid foundation of evidence on which to propagate their usage?

Well, the neuropharmacology jury is still out on this issue. In this article, I hope to discuss some of the evidence to support both sides of the argument and some of the practical issues which arise from the use of these serotonergic medications.

But let’s start at the beginning – The monoamine hypothesis.

This hypothesis proposes that a person with depression will show depleted levels of one or more of the monoamine neurotransmitters (serotonin, noradrenaline and dopamine). A simple and elegant idea. This hypothesis primarily came from serendipitous discoveries in the 1950s when Reserpine was being used as a treatment of hypertensive vascular disease. In some of these patients, the treatment precipitated depression. The symptoms resolved once treatment was withdrawn before a period of rest or electric shock therapy (2, 3). Reserpine was found to sequester neurotransmitters such as serotonin and the catecholamines (Dopamine, noradrenaline and adrenaline etc) into pre-synaptic storage vesicles, allowing the breakdown and subsequent depletion of synaptic concentrations of these neurotransmitters. So, it’s understandable that a logical leap was taken to connect the depressive symptoms associated with Reserpine’s use with this neurotransmitter depletion.

Furthermore, during the 1950s Iproniazid (a derivative of Isoniazid) and a monoamine oxidase inhibitor was being tested for use in tuberculosis. Similar to the story above serendipitous events occurred (as is often the case in the history of drug discovery) and patients began presenting with side effects such as euphoria, increased appetite and improved sleep. Initially, this wasn’t considered as a therapeutic opportunity but shortly after in 1958 Iproniazid was trailed in patients with depression for several weeks with significant improvements being noted in 70% of patients (5). It was subsequently used ‘off-label’ in the treatment of major depressive disorder.

Taken together – these two pieces of evidence spawned the monoamine hypothesis and provided the basis of the intellectual arguments needed for the pharmaceutical industry to pursue the creation of medications to treat depression.

The ‘game-changer’ was the marketing of the first selective serotonin re-uptake inhibitor (SSRI) – Fluoxetine (Prozac) in 1988 (2). This reduced the troubling side effects associated with the older antidepressants (MAOI’s and TCA’s) and gave the general practitioner their first depression tackling tool kit. Prozac has now become synonymous around the world with mental health and antidepressant use, featuring in many news articles, more often than not to the detriment of patients. One article by a large tabloid press company in 2013 branded the UK a ‘Prozac nation’ (6). If mental health treatment could do with anything, it’s a reduction in the stigma surrounding it.

That leads us to where we are today with huge numbers of prescriptions for these items. Health Care Professionals will know some patients respond very well to treatment with SSRI’s, others not so much. But what evidence is there to support their use and are they the best thing for depression?

What do we know and how can that inform our practice?

The most up to date meta-analysis on the subject compared 21 different antidepressants, across 522 trials, including upwards of 120,000 patients. It found that overall all 21 antidepressants were more efficacious in treating major depressive disorder than placebo, with a varying level of efficaciousness and tolerability.

To summarise, the overall most favourable (most efficacious and most tolerable) were; Escitalopram, Sertraline, Mirtazapine, Paroxetine and Agomelatine.

The overall most efficacious were; Agomelatine, Amitriptyline, Escitalopram, Mirtazapine, Paroxetine, Venlafaxine and Vortioxetine.

The overall most tolerable were; Fluoxetine and Agomelatine.

As we know, each antidepressant comes with its own use related issues which need to be discussed in a patient-centred approach. However, having an evidence based to guide discussions is extremely useful. It is also worth keeping in mind that the different trials included varied in the risk of bias, largely being funding by pharmaceutical companies. The evidence was also classed as being moderate to low in terms of certainty, so take the results with a pinch of salt (9).

An important caveat when prescribing antidepressants is to remember that the current NICE guidelines state they are best used in combination with psychological intervention in people with moderate to severe depression (7). We need to move away from the pervading approach of depression treatment ‘take this pill and come back in 2 weeks’ type approach and encourage holistic care, like that of MSK pathologies. Pain killers are no good at improving long term outcomes without a good course of physiotherapy. Here I cite one meta-analysis that found that CBT was as effective as treating depression as antidepressant medication (8).

The brain is far more complex than initially stipulated by the monoamine hypothesis and how antidepressants elicit their beneficial effects is still up for debate. But at least we have evidence that their use is justified. The trick now is to incorporate this into an ever more patient-centred approach, to gain every morsel of benefit we can out of the medication we use.

In the next article, we will discuss how genetics can affect antidepressant use and how in the future this may be used to tailor medication to each patient.

*It’s important to note here that the term antidepressant used is for any medication within the BNF section 4.3: Antidepressant drugs.

Author: MJ Burgoyne


  1. The number of antidepressant items and patients receiving them (prescribed in England and dispensed in the community) Years ending March 2016 and March 2017. NHSBSA. DATA extracted from ePACT 2 as per 08/03/2018. Available:
  2. M Hillhouse et al. A brief history of the development of antidepressant drugs: From monoamines to glutamate. Exp Clin Psychopharmacol. 2015 Feb; 23(1): 1–21. Available:
  3. Kelly Brogan MD. Depression: It’s not your serotonin. Available:
  4. Drug bank. June 13, 2005 07:24 / Updated on April 03, 2019. Available:
  5. Loomer, H. P., Saunders, J. G, and Kline, N. S.: A clinical and pharmaco-dynamic evaluation of iproniazid as a psychic energizer. Psychiatric Res. Rep. 8:129–141, 1957.Google Scholar
  6. Prozac Nation: Use of antidepressants in the UK has soared by 500% in the past 20 years. Mail Online July 5, 2013. Available:
  7. National insitutue for clinical excellence. Depression in adults: recognition and management. CG90. Available:
  8. Amick Halle R, Gartlehner Gerald, Gaynes Bradley N, Forneris Catherine, Asher Gary N, Morgan Laura C et al. Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis BMJ 2015; 351.
  9. Andrea Cipriani, Prof Toshi A Furukawa, Georgia Salanti, Anna Chaimani, Lauren Z Atkinson, Yusuke Ogawa et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet. Volume 391, ISSUE 10128, P1357-1366, April 07, 2018


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