Depression is a common, recurrent, disabling and potentially life-threatening disorder that accounts for much misery worldwide. Current treatments are imperfect: most studies suggest that chemical antidepressant or psychological therapies, though broadly equally effective when properly delivered, help at best only around half of those suffering in the short to medium term.
For psychological therapies, there are difficulties surrounding access to therapy and ensuring their quality, while for antidepressant drugs there are concerns about their efficacy compared to placebos and how quickly they start to work.
It usually takes up to four weeks to see meaningful benefits in patients who respond to drugs (though chemical and some psychological changes can be detected within hours). While drugs act significantly faster than a full course of cognitive therapy, the delay in response is nonetheless unwelcome.
It may also be unnecessary. In the last decade, antidepressant agents such as ketamine with a much faster onset (hours to days) have been described. Unfortunately, these experimental treatments come with serious side-effects that preclude everyday clinical use, and their antidepressant effects tend not to be sustained.
Mice with depression
Now a team from the University of Chicago have claimed that a class of chemicals that selectively act on particular brain receptors for serotonin may have faster, safer antidepressant properties. Serotonin, a chemical messenger in the brain also known as 5HT, is known to regulate mood and has long been implicated in depressive illness. The researchers say that selectively blocking (antagonising) the action of serotonin on these 5HT2c receptors produces antidepressant-like effects in laboratory mice in only five days, while citalopram, a widely used antidepressant that works by preventing serotonin reuptake into neurons in the brain.
The tests used by the researchers to measure the functional effect of the drug are established but relatively crude. They used stress-related behavioural investigations which were developed to detect possible antidepressant activity in novel compounds such as the chronic forced swim test. Here putative antidepressant activity is inferred when a drug reduces the amount of time a mouse spends immobile, having stopped struggling when repeatedly immersed inescapably in a cylinder of water.
The Chicago researchers then went on to compare the effects of the 5HT2c-blocking drugs with citalopram on other molecular and micro-structural aspects of brain function that are believed to be associated with antidepressant activity – some of which may be seen as a “signature” that they will work quickly because the changes can be induced by rapidly acting antidepressant agents such as ketamine.
Here, the results are less clear cut. Citalopram shared some, but not all, of the rapidly induced changes the researchers explored. Because citalopram is not a “fast-acting” drug, the researchers interpret the findings as suggesting that some effects induced by experimental fast-acting drugs are not, after all, the hallmark of rapidly acting agents.
Aside from the obvious limitations of translating simple behavioural tests in mice to complex clinical effects in humans, there are other considerations that call for caution in interpreting these findings.
How to interpret these findings
First, many clinically available antidepressant drugs already possess 5HT2c-blocking activity – for example, fluoxetine, otherwise known as Prozac. But this drug doesn’t usually begin to work rapidly (in the case of fluoxetine it may take between two to four weeks).
Similarly, agomelatine, which also blocks 5HT2c receptors in the brain, was once touted as a rapid-acting antidepressant, but more recent and considered evaluation doesn’t recognise this. Indeed, a recent meta-analysis has called into question whether the drug has any significant therapeutic activity.
Established drugs like fluoxetine and agomelatine do not act selectively on 5HT2c receptors like the experimental drugs studies here (fluoxetine also blocks serotonin re-uptake like citalopram, and agomelatine also affects melatonin systems in the brain), and they differ in the potency with which they bind to 5HT2c receptors. These factors might account for differences in the speed of action among the experimental and established drugs.
Nonetheless, it is disappointing that the researchers didn’t generally use established antidepressants with known 5HT2c antagonist properties as comparison agents alongside citalopram in their study. This would have been a good test of the validity of their experimental set-up and the soundness of their conclusions.
Second, the authors suggest that the fast-acting class of antidepressants that they describe may prove to be safer than other agents, because blocking receptor response is “much more of an innocuous target than others that have been identified”. This is almost undoubtedly true in comparison to an anaesthetic like ketamine, but again, caution is advised – another antidepressant with 5HT2c-blocking activity, nefazodone, was withdrawn from clinical use more than a decade ago because of its propensity to cause liver damage.
The potential antidepressant properties of blocking 5HT2c have been known for many years; the new finding in this study is the speed with which 5HT2c receptor blockers appear to act in pre-clinical animal studies. But there is nothing in the study to suggest that such drugs will prove to be more effective overall than existing treatments.