Could ketamine be the next big thing in depression?

Will Frostick | 20th July 2017

Depression is a leading cause of disability worldwide and with more than 1 in 10 suffering from symptoms, it is likely to affect many of us in some way over our lifetimes.

However, despite the large public health burden of depression, therapeutic discovery in this field has lagged significantly behind other areas of medicine and our ability to combat depression and relieve its symptoms is limited.

Antidepressant treatment: a history

For the last 50 years, antidepressant research and medicine has been dominated by the monoamine hypothesis. This theory links depression to the depletion or perturbation of signals from certain neurotransmitters, such as serotonin and norepinephrine, whose chemical structures belong to a class of molecules known as monoamines.

The theory suggests we can reduce depression by strengthening signals through these neurotransmitters and this approach has been the backbone of anti-depression medication ever since.

Like many scientific breakthroughs, the monoamine hypothesis was found by chance. Doctors noticed that tuberculosis patients treated with isoniazid showed signs of improved mood.

Isoniazid is antituberclular but it also interferes with monoamine metabolism, slowing neurotransmitter breakdown once it is released. As a result, more monoamines are left active in the brain for longer periods of time. It was also observed that reduced monoamine levels could predict suicidality.

Based on this evidence, the monoamine hypothesis has risen to the forefront of depression science.

Stagnation, stagnation, stagnation

Since the isoniazid discovery, an abundance of antidepressants based on the monoamine hypothesis have entered the market.

While there is some variance in the molecular mechanism, these drugs still work on the same general principle. For example, Prozac (fluoxetine) is a selective serotonin reuptake inhibitor, or SSRI.

SSRIs inhibit brain cells’ natural process of ‘vacuuming-up’ (reuptake) a specific monoamine (serotonin). Much like isoniazid, this has the overall effect of increasing the amount of monoamine left hanging around (see figure above).

This general model has been used to treat millions of patients and was the first major breakthrough in depression medicine. However, there has been little to revolutionise the field in the half century since.

Nearly all the treatments entering the market have been ‘me too’ drugs, and while second generation therapies have demonstrated improved tolerability and more specific biological actions, the approach has failed to generate notably more effective therapies.

Response rates have stagnated over the years and tricyclic clomipramine, one of the oldest antidepressant drugs, remains one of the most effective.

What are we missing?

There is more to be concerned about than inertia. Although antidepressants reliably increase neurotransmitter levels in the brains of patients, this does not always translate into symptom relief.

Response rates are often only marginally greater than placebo, and much of the symptom relief can be linked to an active placebo effect. Even though neurotransmitter levels rise within hours, it can take 4-6 weeks to see any therapeutic benefit (although not to see the side effects). Further still, pharmacological depletion of monoamines in healthy volunteers does not cause depression either. These criticisms call into question the presumption that depression is caused by an impairment of monoaminergic neurotransmitter function. 

This clearly suggests the monoamine model is insufficient. Limited efficacy combined with painstakingly long onset times are letting down vulnerable patients. Fortunately, a new approach is emerging and excitement is building about “the most important breakthrough in antidepressant treatment in decades”. Ketamine as a depression treatment may seem unorthodox to some but the early results are remarkable.

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