Ketamine: New Hope for Depression

Birth of an Anesthetic

In 1962, Calvin Stevens, a chemist at the pharmaceutical company Parke-Davis, synthesized an anesthetic that would have fewer negative side effects than the previously used compound phencycyclidine (PCP). He called his creation CI-581.

Diagnosing depression

Depression is more than just being sad. Also called major depressive disorder, it is a devastating psychiatric illness and the leading cause of disability worldwide, affecting more than 300 million people.

Clinical Blindspots

Although the DSM and ICD have been the gold standard for decades, they have been increasingly criticized for the merely descriptive way they portray the subjective symptoms of a complex disorder. Consider the misfortune of being suddenly dismissed from your job, or even experiencing the death of a loved one. Both events might lead to a mental state which technically fulfills the criteria for clinical depression. But given sufficient time you are likely to recover, and probably without professional assistance or medication.

Promises of the Past

A biological assessment of depression would provide valuable information about depression’s largely unexplained etiology, as well as new ideas for treatment. In their thoroughly researched publication on antidepressant drug development, Vitor Pereira and Vinicius Hiroaki-Sato argue for a rational, evidence-based search for pharmacological interventions against depression. This would seem like a given in a science-driven field like clinical psychiatry. Nevertheless, the historical application of antidepressants has fallen victim to overemphasis on clinical observations and the failure to acknowledge new theories.

Hopes for the Future

A possibly groundbreaking discovery emerged at the beginning of this millennium. Robert Berman and colleagues reported that a single subanesthetic dose (0.5 mg/kg) of intravenous ketamine elicited an almost immediate antidepressant response in patients which lasted for several days. Many follow-up studies confirmed and expanded this result. Ketamine treatments appeared especially promising for severely depressed patients with suicidal ideation, and it was also particularly helpful for patients who had been treated unsuccessfully with two rounds of SSRIs, so-called “non-responders”.

A New Biology of Depression

In March 2018, Panos Zanos and Ted Gould presented a detailed summary of ketamine’s proposed antidepressant mechanisms. Believing that ketamine’s dissociative properties are distinct from its antidepressant effects, they argue that the key to understanding ketamine’s effectiveness comes from enhanced neuroplasticity: Ketamine strengthens existing neuronal connections and facilitates the growth of new synapses. It does this through its pronounced activity as a non-competitive antagonist of a particular glutamatergic receptor, the NMDA receptor. In the “disinhibition hypothesis”, ketamine’s activity at NMDA receptors stimulates protein production, ultimately giving rise to new synaptic connections.

From Cell to Brain

If neuroplasticity plays a crucial role in ketamine’s antidepressant properties, how could establishing new neuronal connections help depressed patients? One speculation is that more neuronal connections allows the brain to gain more cognitive flexibility.

From Brain to Mind

In their manuscript “Ketamine for the Treatment Against Addiction: Evidence and Potential Mechanisms”, Ezquerra-Romano et al. mention Ketamine Psychedelic Therapy (KPT) as a model for using psychedelic experiences to treat depression. Mainly developed by the two Russian researchers Krupitsky and Grinenko, the theory behind KPT is that high doses of ketamine make it easier to remodel emotional beliefs related to problematic behavior, such as compulsive drug use. The treatment scheme of KPT entails positive verbal affirmations about creating meaning and a purpose in life, as well as affirmations devaluing the substance of abuse.

The Future of Ketamine

In the acclaimed Good Will Hunting, Robin Williams’ good-hearted psychotherapist gives a thoughtful lecture on the difference between knowledge and experience:

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