Faster and Safer Treatments for Depression

I previously wrote about Selective Serotonin Reuptake Inhibitors (SSRIs), the most commonly prescribed antidepressants. In this post, I want to discuss a novel class of compounds that may be able to treat depression faster and with fewer side effects.

Why do we need faster-acting anti-depressants?
One of the main problems with SSRIs is the time it takes for them to work (3-8 weeks). As discussed by Healy and Aldred, patients are at increased risk of suicide during this period. This is because while severely depressed people have suicidal thoughts, they generally also lack the motivation to act on them. Problems arise if they start to take an antidepressant that boosts their motivation without alleviating their depressive symptoms.

Do we have any promising leads?
You might have heard of ketamine. Originally developed for use as an anaesthetic, it is now a fairly common street drug (under the name of Special K) due to its hallucinogenic properties.

Interestingly, when people with depression were admitted to hospital and put under anaesthesia using ketamine, they often reported a dramatic improvement of their depressive symptoms.

Remember that the conventional treatments for depression work slowly so this rapid improvement (within 2 hours!) was really surprising.  To quote Thomas Insel, the director of the National Institute of Mental Health: “this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose”.

Now when scientists hear something like that, their ears perk up immediately and they start asking questions. Why did these patients report such a benefit? Was it the ketamine or something else? If it was the ketamine then what is it about that drug that produces the effect? Can we use ketamine to treat depression? If not, why not and can we make a similar drug that could be used?

What did they find?
Well it turned out that yes, it was the ketamine. When they tried to figure out its mechanism they discovered that the effects are mediated by the drug’s actions on NMDA receptors in the brain. This is a very different mechanism to most modern antidepressants.

The NMDA receptor is an ionotropic glutamate receptor. This means that when glutamate (the most common neurotransmitter in the human body) binds to the receptor, a channel opens up to allow ions flow across the cell membrane. Ionotropic receptors quickly convert the chemical signal of the neurotransmitter into the electrical signal of an action potential.

Ketamine is an antagonist at the NMDA receptor, i.e. it binds to the receptor in such a way that glutamate can no longer access its binding site. Without glutamate the channel remains closed and the electrical signal cannot be propagated.

Why does ketamine help in depression?
It is thought that ketamine’s effects on depression are a result of it increasing the activity of neural circuits in our forebrain. According to Thompson et al, ketamine “suppresses NMDAR-mediated excitation of inhibitory interneurons” which leads to “a mild disinhibition of the neuronal population”.

Why does ketamine act faster than SSRIs?
Our mood is regulated by a chain of biochemical reactions. Conventional antidepressants act early on in this chain so it takes a while for their effects to be passed down. In contrast, ketamine comes in near the end of the chain so its actions are more immediately apparent.

So what does this have to do with that novel class of antidepressants from earlier on?  
Well, unfortunately ketamine is not a suitable treatment for depression because of the whole host of side effects that come along with it. In light of this, scientists have attempted to develop new drugs that borrow from ketamine’s good points but leave out its disadvantages.

Recently, University of Maryland researchers announced their discovery of “compounds that could successfully treat depression in less than 24 hours while minimizing side effects”.  

They began their study by looking for drugs capable of increasing neuronal activity, like ketamine. The clever part is that instead of boosting excitatory signals (which can be dangerous) they decided to try reducing inhibitory signals, as this would end up having the same net effect.  

How did they do this?
The University of Maryland researchers developed drugs known as GABA-NAMs that reduce the effects of GABA, the main neurotransmitter involved in inhibitory signalling. The GABA-NAMs prevent this chemical messenger from binding to its receptor. Since there’s less inhibition, neuronal activity should increase.

Were these GABA-NAMs effective?
Tests in rodents were used to investigate the efficacy of the compounds. We know that healthy rats prefer to drink water containing sugar and that they enjoy social interaction. In contrast, depressed rats lose their preference for both of these activities. This is analogous to a characteristic symptom of depression in humans, known as anhedonia, an inability to feel pleasure.

The tests revealed that the drugs reversed signs of depression within 24 hours (compared to the weeks it would take for an SSRI). The GABA-NAMs also appeared to be safer because they only affect the regions of the brain that are involved in regulation of mood.

So are these drugs the next big thing?
Obviously it remains to be seen if the compounds will be as effective and as safe in humans but the study’s author, Scott Thompson is certainly optimistic: “If these compounds can quickly provide relief of the symptoms of human depression, such as suicidal thinking, it could revolutionize the way patients are treated.”

For more information, the original paper can be found here.

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