Selective serotonin reuptake inhibitors, more commonly referred to as SSRIs, are a class of drugs involved in the treatment of conditions such as depression, generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD), and eating disorders, among others. They work by reducing the neuronal uptake of serotonin which results, in turn, in higher synaptic concentrations. This leads to downregulation of the 5HT1 presynaptic inhibitory autoreceptors. SSRIs are well absorbed from the gut and metabolised in the liver. Some, such as paroxetine, have a long half-life of 10-20h. First, though, let’s look a little closer at the pharmacology of SSRIs.
Pharmacology of SSRIs
The mechanism of action of SSRIs is remarkably simple. It derives from the monoamine hypothesis which states, roughly, that a deficit of monoamines in the central nervous system is responsible for disabling biological states. There are others, however, who voice concern about this increasingly narrow focus – some interpreting it as a myopic means in the treatment of depressive states. In terms of pharmacology, SSRIs increase synaptic concentrations of serotonin which leads to a downregulation of 5HT1 presynaptic inhibitory receptors. Prolonged synaptic serotonin concentrations also downregulate postsynaptic 5HT2 receptors.
Why are SSRIs used?
SSRIs are among the most widely prescribed medicines in the world, used for a wide array of mental disorders:
- Generalised anxiety disorder (GAD)
- Obsessive compulsive disorder (OCD)
- Eating disorders
SSRIs are indicated for use in patients with severe, as well as mild-to-moderate, depression. Studies show that SSRIs have quite a limited, if perhaps placebo-type, effect in patients with mild-to-moderate depression. Patients with generalised anxiety disorder (who have not responded to non-pharmacologic therapies) typically experience a mild-to-moderate reduction in symptoms. SSRIs have also proven efficacious in the treatment of eating disorders, but not in terms of long-term treatment.
Pharmacokinetics & Drug Interactions
SSRIs are generally well absorbed from the gut, and are primarily metabolised via hepatic routes. They also vary in terms of half-life. Paroxetine has, for example, a half-life of 10-20h, compared to citalopram, fluoxetine and sertraline – which have half-lives ranging from 1-3 days. The half-life of paroxetine may be prolonged in poor metabolisers of CYP2D6. The pharmacology of SSRIs is such that it is associated with numerous, significant drug interactions.
The most serious drug interaction is between SSRIs and MAOIs, a combination which may trigger serotonin syndrome. Examples of MAO inhibitors include moclobemide, tranylcypromine, phenelzine and selegiline. Fluoxetine and paroxetine, among other SSRIs, are potent inhibitors of CYP2D6, meaning substrates of this enzyme (such as opioids, beta blockers, class I antiarrhythmics, and ondansetron, among others) are significantly affected.
SSRIs, unlike their TCA cousins, are associated with few antimuscarinic adverse effects. They also tend to cause less sedation and less weight gain in comparison to many other antidepressants. SSRIs are, though, associated with their own range of potential side effects not least nausea, insomnia, anxiety, dry mouth and constipation (paroxetine). A minority of patients also report suicidal ideation. Other adverse effects associated with SSRI use include sexual dysfunction, increased risk of GI bleeding (when taken with anticoagulant drugs), and serotonin syndrome in overdose.
Test your knowledge of the pharmacology of SSRIs with this quiz – ten questions that examine the whole spectrum of SSRIs and questions that are ideal for students at every level.