Following a review of clinical trial results and consultation with external advisors, the Food and Drug Administration (FDA) has granted approval for Spravato to be used in patients with treatment-resistant depression in the United States. Spravato is a nasal spray produced by Janssen Pharmaceuticals Inc. that contains esketamine hydrochloride, a chemical mirror to the anaesthetic and dissociative psychedelic ketamine.
"There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment.”
Trials consisted of short-term and long-term studies in which one group of patients were given esketamine nasal spray alongside a traditional antidepressant, while a placebo group received saline and a traditional oral antidepressant. Individuals taking esketamine showed significantly more improvement, occurring in less than 24 hours after the first dose, and a greater length of time to relapse of depressive symptoms than those taking placebo.
Medical ketamine treatments in the US date back to 1970 when the FDA first approved its use as an anaesthetic. Many ketamine clinics have since emerged though to offer intravenous (IV) administrations ‘off-label’ – meaning for a different medical use than the FDA has approved and not covered by health insurance plans –as a fast-acting treatment for severe depression. This follows the results of numerous published studies since 2000 showing significant decrease in depression symptoms in patients who felt no meaningful improvement on other antidepressant medications.
“This is a game changer,” said John Krystal, M.D., chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the US. He calls ketamine “the anti-medication” medication working differently than those used previously to treat depression.
In other treatments SSRIs – serotonin reuptake inhibitors – are used based on the ‘chemical imbalance’ hypothesis that people with depression have a deficit of serotonin. However, this hypothesis may not fully explain depression with growing research showing a link to a build up of proteins in the brain under stress. This makes neurons less adaptable and less able to communicate with other neurons.
Ketamine works by triggering glutamate production, which prompts the brain to form new neural connections to repair the damage. The new pathways give patients the opportunity to develop more positive thoughts and behaviours.
While SSRIs tend to work as long they are in your system and can be difficult to come off, the effects of ketamine continue afterwards. ”It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” said Dr. Krystal.
Although esketamine works similarly to ketamine – its mirror molecule - Janssen Pharmaceuticals opted to pursue approval by the FDA for its use rather than ketamine for a number of reasons. Importantly, its chemical makeup allows it to bind more tightly to the glutamate receptors, making it two to five times more potent, meaning patients need a lower dose. It was also patentable and therefore profitable in contrast to ketamine that is widely used. And it escapees the baggage associated with ketamine as a ‘club drug’.
Still, the approval comes with a number of regulations. The drug must only be administered as a nasal spray in a certified clinically supervised setting and used in conjunction with oral antidepressants. It can only be given to patients who have not responded successfully to two previous antidepressant treatments.
Because of the risk of sedation and dissociation, patients must stay in the doctor’s office for at least two hours of monitoring after receiving their Spravato dose until the doctor determines the patient is ready to leave. The Spravato never leaves the facility.
In all, this is a significant advancement for helping people struggling with treatment-resistant depression and an exciting step in the discovery of the medical potential of ketamine and other psychedelic drugs.