Depression is a serious issue that requires serious solutions, yet too many with major depressive disorder have tried a whole host of medicines to no avail, eventually moving toward Treatment-resistant depression or TRD. 

TRD does not necessarily mean that depression cannot be treated, but rather that it does not respond to the usual treatments, meaning people with TRD have often tried a good deal of treatments. This is where ketamin comes in–not as a party drug or anesthetic, as many might initially think of it, but rather an ‘antidepressant’ for those who have tried many antidepressants. 

Mental health professionals, from those with a Masters in School Counseling online to those treating elderly patients, know that the scope for mental health treatment is vast and complex, and while a ketamine-related medication might seem unconventional, it’s always about doing what’s best for the patient.

Ketamin as Treatment 

For depression, ketamine is given in a sub-anesthetic dose and is thought to work through several methods of action (MOA), first and foremost, by blocking NMDAR receptors, which increases glutamate release and activates other receptors. This MOA emphasizes the increase in excitatory glutamate, which is thought to enhance synaptic plasticity and neural connectivity, potentially reversing depression-related deficits. 

At the same time, ketamine boosts brain-derived neurotrophic factor (BDNF) signaling, promoting neurogenesis and resilience in key brain areas like the prefrontal cortex. The big difference between these effects and traditional antidepressants is time. Some selective serotonin uptake inhibitors (SSRIs) take weeks before effects are noticed, ketamine can work in minutes.

Finding Alternatives 

Ketamine has derivatives, many with the potential for fewer unwanted side effects, reduced dangers for abuse, and improved formulas. A commonly used ketamine alternative is Esketamine, which is essentially a more refined version of ketamine. Esketamine is used in place of ketamine for psychiatric purposes. It has also received FDA approval for TRD in the form of a nasal spray.   

Eskatamine offers a similar rapid-acting antidepressant effect with potentially fewer side effects and a reduced risk of abuse via the nasal spray delivery system. Although it is only FDA-approved and administered in a few highly controlled settings, ensuring its use for mental health treatment is safe and monitored. 

Esketamin is still no perfect drug, and the fact that it is so heavily regulated limits its use. This is where (2R,6R)-Hydroxynorketamine or RR-HNK comes into play. 

RR-HNK is a metabolite of ketamin, meaning it is a compound produced when the body processes ketamine–although it can be synthesized by itself. Unlike ketamine, RR-HNK has been found to retain therapeutic effects, such as alleviating symptoms of depression, while potentially minimizing risks like dissociation and abuse. This makes it a promising candidate for safer and more targeted treatments.

The RR-HNK Trial 

A recent drug trial organized by the National Institute of Health looked at the safety and tolerability of RR-HNK by studying its pharmacokinetics and pharmacodynamics in vivo–in other words, how the drug moves through and affects the living body. 

74 participants aged between 18 and 65 were placed in three randomized trials with placebos. After weeks of trials and data collection, it was determined that RR-HNK was safe and caused no serious side effects. Safety aside, the drug lived up to expectations–with participants reporting no symptoms of sedation or dissociation. 

The Findings 

The Phase 1 assessment found that adverse events referred to as AEs were mild, resolving within a day without treatment, and occurred in 13 drug recipients and five placebo recipients. No serious side effects or mood-related issues arose. Drug levels in the blood increased predictably with higher doses, peaking about 0.7ng/mL–1-hour post-infusion and clearing within seven to eight hours. Repeated doses showed consistent results without significant drug buildup.

The data for safety looks bright, but what about the efficacy? Unfortunately, the previous study is the first of many–most drugs have about five phases of development that can each take years before they hit the shelf, and quantifying depression can be challenging. 

If further tests prove RR-HNK acts on the same glutamate and BDNF pathways to alleviate even the most severe symptoms of depression without the unwanted side effects or possibility for abuse, then this drug will be a real game changer. 

Other Research on Ketamine to Treat Depression 

At the end of the day, RR-HNK is just one ketamine alternative, there are currently trials for other drugs that mimic ketamine action on NMDA and glutamate pathways. Recent trials on another drug, L-655,708, have shown promise. Previously tested as a cognitive performance enhancer that acts as a selective inverse agonist at a subtype of the GABA receptor—an inhibitory neurotransmitter that can work to increase glutamate levels. It has been found to produce sustained antidepressant effects by increasing activity in the hippocampus, similar to ketamine and RR-HNK, but without their psychotic or addictive side effects, making it a promising candidate for treating TRD.

Depression is an issue that will not go away anytime soon, and clinicians need more tools to address the systematic challenges of TRD. More research is needed, but there is certainly promise for new cures, so whether you are a mental health professional or someone in need of help, rest assured that bright minds are working hard to create solutions.