Selective Serotonin Reuptake Inhibitors (SSRIs)

Disclaimer: I am not a doctor and this is not medical advice. I am writing this as a knowledge synthesis for my own benefit.

Depression is the most common psychiatric problem for which people seek help and is projected to become the second leading cause of disability in the world by 2020.

Currently, the most popular treatments for depression are a class of drugs known as the Selective Serotonin Reuptake Inhibitors (SSRIs).
Examples include escitalopram which is found in Lexapro and fluoxetine which is found in Prozac (fluoxetine has a slightly different mechanism but I won’t go into that here).

Do SSRIs even work?
They certainly aren’t miracle drugs but the evidence shows that they are better than placebo.

How well they work is another matter, one which is still being debated in the literature.

We know that a benefit exists because there is a statistically significant difference between drug and placebo. What people can’t agree on is whether or not this benefit is clinically significant i.e. will SSRIs help patients enough to justify the side effects?

Irving Kirsch states that “there is a strong therapeutic response to antidepressant medication. But the response to placebo is almost as strong”. In another paper, he claims that 80% of the improvement observed on treatment is attributable to placebo. He then puts this in context: “the effect of placebo on pain is estimated to be about 50% of the response to pain medication”.

It has been shown that people who respond better to placebo will also respond better to SSRIs than those patients who get no benefit from placebo, suggesting that some people are just more likely than others to respond to treatment, regardless of what the treatment is.

Some scientists, including Kirsch, argue that antidepressants do more harm than good so they should only be used in the most severe cases. The problem with this is that even if true, many patients with depression would happily accept that harm in exchange for relief of their symptoms.  

How do SSRIs work?
I’m going to deal with this in two parts. Part 1 will explain the mechanism by which the drugs act. Part 2 looks more at what we know about how they affect depression.

As the name implies, SSRIs inhibit the reuptake of serotonin. Serotonin is a neurotransmitter, meaning that it transmits messages between neurons across a junction known as the synapse. Neurotransmission includes the following steps:

  • Release: A signal causes the presynaptic neuron to release the neurotransmitter which diffuses across the synaptic cleft (the gap between two neurons).
  • Receptor Activation: Receptors on the postsynaptic neuron recognise the neurotransmitter such that the signal is propagated.
  • Reuptake: Afterwards, the neurotransmitters can either be enzymatically degraded or they can be taken back up into the presynaptic neuron.

There are over one hundred different known neurotransmitters and they are all involved in various different processes. Serotonin is known to regulate emotion, reproduction, attention, sleep, learning and memory.

How SSRIs affect depression 
So why do we want to inhibit the reuptake of serotonin?
The conventional explanation is that depression is caused by a deficiency in serotonin so the more serotonin that there is acting on the postsynaptic neuron, the better. This can be achieved by inhibiting its reuptake. SSRIs ensure that serotonin hangs around for longer in the synaptic cleft such that its action on the receptors is maintained. An analogy would be a boss convincing her employees to work overtime in order to compensate for falling profits.

While this explanation still gets trotted out, it really doesn’t hold water. The fact that SSRIs work is the main evidence in favour of it but in actuality, some drugs (e.g. tianeptine) which increase serotonin reuptake (the opposite effect to SSRIs) nevertheless help with treating depression.

The honest answer then is that we don’t know. One of the more in vogue explanations at the moment is that depression is related to inflammation but this isn’t much more than an admission of our ignorance since inflammation is such a catch-all term.

It has also been suggested that SSRIs strengthen and heal the brain so that it becomes less susceptible to depression but if anything, the opposite appears to be true (See Increased Risk of Relapse later). The reason that this hypothesis was first put forward was because some studies indicated that antidepressants stimulated neurogenesis, the growth of new neurons.

However, the method that they used to test this can’t distinguish between neurogenesis and neuronal death. It turns out that antidepressants actually cause neuronal damage so if neurogenesis does occur, it is probably the brain trying to make up for the harm done by SSRIs.

What are the problems associated with SSRIs?
While these anti-depressants are widely prescribed, they have a number of limitations. These include:

  • Delayed action. It can often take several weeks for the drugs to start working. To compound matters, symptoms (including suicidal ideation) often get worse initially.
  • Side effects. These are generally milder than for other antidepressants but since serotonin is involved in the regulation of so many physiological processes, the range of side effects is quite broad. Sexual dysfunction and weight gain are particularly common while both drowsiness and insomnia have been known to occur in different patients.
  • Increased risk of relapse. Antidepressants get less effective with prolonged use so ideally we’d like to discontinue therapy once the patient has stabilised. If the risk of relapse is substantial however, discontinuation could do more harm than good.
    Getting concrete figures on the size of the risk is tricky but Andrews et al found that the 3 month risk of relapse increased from 4% for patients who had been given a placebo to 43.3% for SSRIs and to 61.8% for fluoxetine. Unfortunately they don’t discuss how clinically meaningful this is.
  • Difficulty concentrating. You know how a computer with low RAM can’t do many things at once? Depression causes a similar problem because serotonin is involved with working memory. In theory, we would expect SSRIs to alleviate this but as we’ve seen so many times, the theory doesn’t translate. Patients might get a short respite but their attention spans seem to get worse in the long-term.

Are SSRIs only effective in severe cases?
You may have heard that SSRIs are ineffective in patients with mild depression. For example, Kirsch found that “efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication”.

However, this may have more to do with the quantification of efficacy than the drugs themselves. Essentially, it’s easier to quantify an improvement in patients with major depression than those with a less severe form.

When clinicians want to grade a patient’s depression, they often use the Hamilton Depression (HAM-D) scale. The minimum score on the HAM-D scale is 0 (no depression) while the maximum score is 52. It seems to make sense then that researchers would consider the size of the reduction in a patient’s HAM-D score on treatment to be indicative of how effective the medication was. Unfortunately, this isn’t necessarily the case.

Consider a drug which relieves depression by 20%. If a patient with a HAM-D score of 25 (very severe depression) is given this drug, then their score should decline to 20 (severe depression). That’s pretty impressive. However, if the same drug is given to someone with a HAM-D score of 12 then their score only falls to 9.6. Both 12 and 9.6 are in the same category, mild depression.
It should be clear then that the results will always look more impressive when the drug is given to a more severely depressed patient.

On the other hand, larger fluctuations in the HAM-D score can occur quite naturally. Kirsch writes that “a six-point difference can be obtained just by changes in sleep patterns, with no change in any other symptom of depression”. He also points out that the drug-placebo difference was below the level of clinical significance even when he just analysed patients with very severe depression.

The problem with this is that ‘clinical significance’ was defined completely arbitrarily by guidelines such as NICE in the UK who later admitted that their choice was based more on picking a round number than picking one that was meaningful.  

I can’t finish this without highlighting one critical point: SSRIs do work but that doesn’t mean that they are the best option for every patient. Goodwin et al, writing in relation to the use of the drugs in bipolar disorder, emphasise the gap that exists between physicians who are happy to prescribe anti-depressants and researchers who “agonize over whether antidepressants should be offered at all, at least as monotherapy”. 

What this all suggests is that SSRIs probably shouldn’t be first-line treatment for mild depression but they can be a valuable therapy for patients with moderate depression. Physicians should remember that prescribing an SSRI straight away might not be the safest option. Patients should remember that multiple options exist; there are other drugs and other therapies. Cognitive Behavioural Therapy (CBT) in particular is a well-tolerated treatment.


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