ZURICH – According to the World Health Organization, depression affects an estimated 350 million people worldwide, making it one of the most prevalent psychiatric conditions. But only about half of those who try antidepressant drugs respond to them, and those who do may have to wait several weeks or even months before experiencing relief – a critical failing for people at immediate risk of suicide. Fast-acting antidepressants are thus urgently needed.
Ketamine – a drug primarily used as an anesthetic in veterinary medicine and as a short-term anesthetic and analgesic in hospitals during surgery or other painful procedures – is currently the rising star of depression research. It appears to ease depression’s most severe symptoms within minutes or hours, even in patients who have a dismal track record with other treatments.
In the first controlled study, researchers reported a 50% decline in symptoms of depression within two hours of a ketamine infusion, and one-third of patients were virtually symptom-free within a day. Moreover, patients reported diminished thoughts of suicide a mere 40 minutes after receiving an intravenous infusion of the drug. In some patients, the effects of a single dose can last more than a week.
Clinicians are not alone in studying ketamine’s potential. Neuroscientists have hailed it as the first breakthrough in depression-drug research in 50 years. Unlike conventional antidepressants – which are used to elevate concentrations of the neurotransmitters serotonin, dopamine, or noradrenaline – ketamine influences the glutamate system. Glutamate, the major excitatory neurotransmitter, plays a central role in mediating nearly all forms of brain function, including learning, memory, cognition, and emotion.
By blocking glutamate from binding to the NMDA receptor, ketamine leads to an augmented glutamate release, which activates other types of glutamate receptors and enhances the function and density of synapses (the junctions between neurons) in areas of the brain where stress or depression has caused cells to atrophy. Increased synaptic plasticity – the ability of synapses to adjust their strength, which is essential to healthy brain function – could be the neurobiological reason for the apparent therapeutic effect in patients.
But, though ketamine’s promise has stirred excitement among clinicians and neuroscientists, it has also sparked controversy, owing to the drug’s potentially harmful side effects. Depending on the dose, a patient may experience altered physical, spatial, and temporal states; larger quantities may induce hallucinations and dissolution of the self.
Intriguingly, ketamine’s psychoactive properties may be responsible for its mood-enhancing effect. Psychedelic and psycholytic treatments – popular in the 1960’s and 1970’s, before research was severely restricted and interest in the clinical use of psychedelics faded – were based on the notion that the drug-induced psychological experience was essential to facilitating the psychotherapeutic process.
According to this view, the altered state of consciousness produced by ketamine – particularly the dissolution of the self’s boundaries and the experience of union with the world – might constitute a profound and meaningful experience for a patient. Integrating this experience into the psychotherapeutic process might facilitate subsequent behavioral changes. In other words, drugs like ketamine that quickly increase neuroplasticity might be particularly clinically efficient in combination with psychotherapeutic interventions.
Unfortunately, research on ketamine addicts and those who take it in large doses as a party drug has revealed that its use may lead to learning and perception problems, as well as memory disorders. Another concern is that ketamine’s benefits may be relatively fleeting. As a result, ketamine may never develop into an accepted treatment for depression in its current form.
In fact, ketamine’s future as a therapy for depression would be uncertain even if its efficacy were more strongly established. Because ketamine has been available for decades, there is no patent for it, so pharmaceutical companies have little financial incentive to carry out research on the drug and seek approval for its use as an antidepressant.
Nonetheless, research on ketamine’s chemistry might help to identify mechanisms for addressing treatment-resistant depression that are based on glutamate-driven neuroplasticity. Indeed, pharmaceutical companies have already begun to investigate other NMDA-receptor antagonists, together with drugs that act on a different part of the glutamate system, as possible treatments for depression. This research could eventually lead to an entirely new class of antidepressant – and relief for millions of people worldwide.