Health:Depression’s Psychedelic Solution? – 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

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.

Simone Grimm is a researcher in the Department of Psychiatry, Psychotherapy, and
Psychosomatics at the University of Zurich.

Project Syndicate,