Next generation of rapid-acting antidepressants: Can ketamine help prevent suicide?

Naghmeh Nikkheslat is a Senior Research Associate at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) who is working on a project funded by the NIHR Maudsley BRC to investigate the use of ketamine as a medication for depression. In this blog, she talks about her research into depression and the immune system and what we currently know about ketamine as an anti-inflammatory antidepressant in psychiatric emergencies.

As a scientist with an interest in mental health and in particular depression, I became familiar with the devastating symptoms that people experience when they become clinically depressed and I also became aware that for nearly a third of those people, current treatments are not effective.

I study the connection between the brain and the immune system – immunopsychiatry - and there is growing evidence that changes in a number of biological processes within the body can directly contribute to depression. The hope is that these connections between physical and mental health can help develop treatments for those people with depression who have no response from current treatments.

For some people, their depression can become so severe that they experience suicidal thoughts, which can then lead to suicide. If these thoughts are detected early, then it may be possible to put in place protective measures or treatments to lessen the risk of suicide. My hope is that a new approach using ketamine, that works on the biological systems involved in depression and inflammation, could become a new way to prevent suicide. But we need research to help us find out more.                    

Inflammation

In the early stages of my career, I focused on the link between heart disease and depression, where I found that patients with heart disease produce an excessive amount of chemicals called ‘inflammatory markers’, which are released by our immune cells. The amount is even higher in those patients who also have depression.

The body usually has systems in place to regulate this overactive immune response. However sometimes, when there are too many inflammatory markers, they can disrupt the very processes that carry out this type of regulation and it can become very difficult for the production of these markers to return to the normal level.

This lack of regulation can lead to excessive levels of inflammatory markers in the body for a long period of time. Heart disease is known to be an inflammatory condition and long-term inflammation in the body can potentially affect our brain and its structure and function. This is known as ‘neuroinflammation’, which has been linked with depression.           

As much as inflammation seems to be linked with depression, it is not always due to physical conditions such as heart disease, likewise, not everyone with heart disease will develop depression.

Sometimes, people who experience depression, but not any other specific diseases, have this inflammation in their body and brain, and are not even aware of it. For example, some individuals who experienced traumatic events in their childhood, either emotionally, physically, or sexually, may also show a higher immune response and disrupted regulatory mechanisms, making them more vulnerable to depression later in life and into adulthood.

Effectiveness of antidepressants

As much as we know fair bit about the causes of depression, we still have a fair amount to discover. While there are thousands of studies in depression - its causes and what happens during the course of the disorder in the body and the brain, and how medications and therapies can be effective - we are still struggling with successfully treating about 30 per cent of those with depression.

We now know that individuals who have both inflammation and depression tend to be those who are less likely to respond to the antidepressants, and a combination of anti-inflammatory and antidepressant medications may help to improve their chance of response. However, this approach still requires time for the drugs to take effect which, for some, might be too late.

There is an urgent need for identifying alternative strategies for those patients with severe depressive symptoms, in particular suicidal ideations, who require effective but immediate intervention.

Ketamine as an antidepressant

Thanks to an NIHR Maudsley BRC Project Grant, I have started investigating ketamine as a medication for depression, which has both anti-inflammatory and anti-depressive actions. This dual effect can also help us to understand the mechanisms of action of this medication with the aim of making new antidepressants which can target both inflammation and depression.

My recently published review in Brain, Behaviour & Immunity - Health titled “Targeting inflammation in depression: Ketamine as an anti-inflammatory antidepressant in psychiatric emergency” provides a brief overview of antidepressant properties of ketamine as well as its effects on inflammation. The review aims to better understand the mechanisms underlying the potential therapeutic action of ketamine.

Ketamine has multiple rapid actions on the brain areas associated with depression. It can normalise the pathways and chemicals in the brain that have been disrupted in depression. It also helps neurons to connect with each other, so the brain cells can communicate effectively. These are required for the healthy functioning of the brain and our mental health, and it seems this is how ketamine may act as an antidepressant.

Ketamine also has anti-inflammatory properties, which makes it particularly unique for targeting the inflammatory aspects of depression. Indeed, ketamine can directly affect our immune cells to reduce the inflammation both at the level of body and the brain. It also acts on the pathways within the brain linked to neuroinflammation, decreases the production of toxic substances and increases the release of substances to promote the generation of new neurons.

But perhaps the most important overarching feature of ketamine is that it can act very rapidly. Within hours its novel dual action as an anti-inflammatory and an antidepressant can take effect. This is why it has the potential to be a valuable treatment for those severely depressed patients with suicidal thoughts and this is what I am investigating in my research. If we can use a clinically approved version of ketamine in psychiatric emergencies or design a new generation of rapid-acting antidepressants, we can give a better life to depressed patients as quickly as possible.

Ketamine, which is being sold illegally on the black market is considered as a drug of abuse and a class B drug in the UK. What scientists are trying to investigate is its use as a medication, used in smaller doses and administrated in a clinical setting under specific conditions.