“No convincing evidence that depression is caused by low serotonin” - researchers at University College London challenge decades old theory about using antidepressants to treat depression, but should that completely change the way doctors prescribe them? By Nathan Adu-Poku.
Imagine finding out that the drugs you were prescribed might not actually work. Worse yet, that the science behind them may also have been incorrect. Alarmingly, this has become a recent reality for the millions of people suffering with depressive mood disorders who have been prescribed selective serotonin reuptake inhibitors (SSRIs) as part of their treatment, some of which are household names like Prozac or Celexa. SSRIs work by temporarily increasing the availability of a chemical called serotonin in the brain, which plays a key role in positively modulating mood. However, recent findings put to question the effectiveness of this mechanism in treating depression.
Historically, antidepressants were issued on the basis that depression is the result of a chemical imbalance in the brain; notably ‘abnormally’ lower serotonin levels amongst other neuromodulators such as noradrenaline. SSRIs, which specifically target serotonin, subsequently emerged as the first line treatment. Importantly, they are better tolerated than other antidepressants because of their high specificity to serotonin receptors and lack of interaction with other similar receptors [1].
However, a team of researchers at UCL have recently published a review contesting this common conception to suggest that, in fact, individuals with depression do not necessarily have lower levels of serotonin [2]. This was based on the following observations:
- There is little evidence to show that neither the concentration of serotonin nor its metabolites (breakdown products) in the blood or brain fluid were significantly different between those with and without depression.
- Research into 5HT receptors - proteins involved in both excitatory and inhibitory transmission of serotonin in the brain and naturally the target of most antidepressants - showed inconsistent levels of serotonin activity in depressed individuals, which questions the efficacy of SSRIs.
- At a genetic level, they found inconclusive evidence that gene variation in serotonin transporters is different between depressed and healthy individuals.
- Studies in which individuals’ serotonin levels were artificially lowered did not result in an increased risk of developing depression [3].
The clinical ramifications of this are perhaps the most interesting; should doctors still prescribe SSRIs to patients with depression now that research is unable to evidence their precise mechanism of action in the body? Does this, then, put to question one of the fundamental ethical pillars of medical practice - ‘do no harm’ - as doctors have repeatedly seen clinical evidence of SSRIs causing side effects that markedly impact patients’ quality of life. For instance, they have been shown to cause nausea, sedation, low libido, severe withdrawal effects after ceasing SSRI treatment and even life-threatening effects of Serotonin Syndrome caused by an overload of the chemical in the body.
Perhaps the solution to this is simpler than one might expect. Although SSRIs may not work like we once thought, that isn’t to say they have no benefit at all. It is simply the case that further research and understanding is needed to study the exact mechanism by which they help to relieve people of depressive moods. A similar practical example of this concerns the use of paracetamol, a standard treatment for everyday aches and pain for decades now. However, no harm has come from its use despite the lack of a definitive mechanism by which it produces its analgesic (pain relieving) effects. Looking forward, doctors should continue to prescribe SSRIs on a case by case basis provided patients are correctly monitored [4][5].
Furthermore, it is important that clinicians readdress how they explain the concept of depression and other mood disorders to patients as well as in the media. Owing to most modern textbooks and academic sources, a significant proportion of the population, some 85-90%, is still under the impression that depression is exclusively the result of a neurochemical imbalance [6]. Clinicians may also be at fault here as they often run the risk of oversimplifying concepts for patients in an attempt to achieve clarity and conciseness. Overall, a change in discourse coupled with ongoing research redefining our understanding of depression may ultimately justify abandonment from traditional pharmaceutical treatments and encourage reliance on other methods such as cognitive behavioural therapies, interpersonal psychotherapy, mindfulness and counselling.
References:
1. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001 Feb;3(1):22-27. doi: 10.4088/pcc.v03n0105. PMID: 15014625; PMCID: PMC181155.
2. Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01661-0
3. No evidence that depression is caused by low serotonin levels, finds comprehensive review [Internet]. UCL News. 2022 [cited 5 September 2022]. Available from: https://www.ucl.ac.uk/news/2022/jul/no-evidence-depression-caused-low-serotonin-levels-finds-comprehensive-review
4. Wise J. “No convincing evidence” that depression is caused by low serotonin levels, says study authors BMJ 2022; 378: o1808 doi:10.1136/bmj. 01808
5. Toussaint K, Yang XC, Zielinski MA, Reigle KL, Sacavage SD, Nagar S, Raffa RB. What do we (not) know about how paracetamol (acetaminophen) works? J Clin Pharm Ther. 2010 Dec;35(6):617-38. doi: 10.1111/j.1365-2710.2009.01143. x. PMID: 21054454.6. Depression and serotonin: Review questions decades-old theory [Internet]. Medicalnewstoday.com. 2022 [cited 5 September 2022]. Available from: https://www.medicalnewstoday.com/articles/low-serotonin-might-not-cause-depression-but-why-do-ssris-still-work
