Researchers are gaining exciting new insights into how the drug ketamine can rapidly treat symptoms of depression, including in people who don’t respond to other antidepressants.
Key facts about ketamine for depression:
- Ketamine is an FDA-approved anesthetic that has been found to quickly improve mood in depressed patients, including those with treatment-resistant depression.
- It works much faster than traditional antidepressants, improving symptoms within hours instead of weeks.
- Researchers think its effects come from increasing brain plasticity and connections.
- Exactly how ketamine exerts its antidepressant effects is still being investigated.
Source: Clinical Psychopharmacology Neuroscience. 2023 Aug 31; 21(3):429-446.
A New Type of Antidepressant
For years, depression has been treated with drugs that target messenger chemicals in the brain called monoamines, like serotonin.
However, at least a third of patients don’t respond fully to these traditional antidepressants.
Excitingly, in recent years the anesthetic ketamine has emerged as a new type of rapid-acting antidepressant for these hard-to-treat cases.
Ketamine has been used for anesthesia since the 1960s, but it wasn’t until the 2000s that researchers discovered it could quickly improve mood in depressed patients.
In 2019, an FDA-approved ketamine nasal spray called Spravato was approved for treating depression.
How Ketamine Works – The Leading Theories
Exactly how ketamine exerts its antidepressant effects isn’t fully understood yet.
But researchers have proposed a few leading theories based on its effects on brain cells:
Disinhibiting Brain Cells
One theory is that ketamine temporarily blocks NMDA receptors, which are involved in controlling electrical signals between brain cells.
This is thought to disinhibit certain inhibitory brain cells, leading to a rapid surge in brain cell activity that increases connections and improves mood.
Effects on Brain Plasticity
Ketamine is also thought to increase brain plasticity – the brain’s ability to make new connections and adapt.
This could help “reset” abnormal brain circuits seen in depression.
BDNF Production
Importantly, ketamine boosts production of a protein called BDNF that is key for brain cell growth and survival.
This BDNF boost may help rebuild brain cell connections disrupted in depression.
Glutamate and Synapses
Another effect of ketamine is that it rapidly increases glutamate transmission in the prefrontal cortex.
Glutamate is the brain’s main excitatory messenger.
This glutamate surge may strengthen synapses and brain circuits regulating mood.
NMDA-Independent Effects
While ketamine blocks NMDA receptors, some of its antidepressant effects may also work through other non-NMDA mechanisms researchers are still exploring.
Its effects likely involve both NMDA receptor-dependent and independent mechanisms.
Ketamine Metabolites
Ketamine is broken down into metabolites in the body that may also have antidepressant properties by increasing brain cell connections.
This suggests that ketamine’s effects aren’t only caused by NMDA receptor blockade.
Sex Differences in Response
Intriguingly, some studies have found differences in how men and women respond to ketamine treatment.
Women tend to metabolize ketamine faster, meaning they may require higher doses.
Female sex hormones may also alter ketamine’s effects.
More research is needed on how sex influences ketamine as an antidepressant.
Animal Models of Depression and Ketamine
Researchers have developed animal models of depression and treatment resistance to study ketamine’s effects.
These models try to mimic the stress and chronic mood impairments seen clinically in depressed patients.
Two main models are:
Chronic Unpredictable Stress (CUS)
Rodents exposed to various random stressors over time develop depression-like behaviors and brain changes reminiscent of human depression.
About 40-50% of stressed animals don’t respond to regular antidepressants – mimicking treatment-resistant patients.
Chronic Social Defeat Stress
Rodents exposed to aggressive “bully” mice develop social avoidance and depression-like behavior.
A subset remains depressed even after antidepressant therapy, paralleling human treatment resistance.
Researchers are now starting to investigate in these models which brain cell and molecular changes are targeted by ketamine.
Identifying these mechanisms could aid depression treatment and drug development.
The Path to Approving Ketamine for Depression
Though ketamine has only recently been approved to treat depression, it has a long history.
Here are some key events leading up to its approval as an antidepressant:
- 1960s-1970s: Ketamine is developed and begins being widely used as an anesthetic. It is valued for having fewer side effects than similar anesthetic drugs.
- 1990s: Researchers propose using NMDA receptor blockers like ketamine to treat mood disorders, but these ideas get little traction.
- 2000: A small study provides the first evidence that ketamine quickly improves mood in depressed patients. This sparks interest in ketamine for depression.
- 2006: A pioneer study shows ketamine quickly improves depressive symptoms in patients who haven’t responded to other antidepressants. This indicates its potential for treatment-resistant depression.
- 2010s: Further studies confirm ketamine’s ability to rapidly treat even severe treatment-resistant depression. Researchers begin investigating how it works.
- 2019: Based on promising clinical results, the FDA approves esketamine (a ketamine nasal spray) for treatment-resistant depression. This represents the first new class of antidepressant approved in decades.
Ongoing Questions About Ketamine
While ketamine’s ability to rapidly treat hard-to-treat depression is exciting, there are still many unknowns.
Researchers continue investigating:
- How exactly ketamine exerts its antidepressant effects in the brain
- How long its antidepressant benefits last
- Its abuse potential
- Whether other drugs that target glutamate might have similar effects
- Whether ketamine has benefits beyond mood, such as for cognition
- How to optimize ketamine’s use clinically and minimize side effects
For now, ketamine remains a promising advance for difficult-to-treat depression and has energized antidepressant research.
Discovering its mechanisms could open new avenues for better understanding and treating depression.
Ongoing research aims to harness ketamine’s benefits while minimizing its risks.
References
- Study: The Role of Glutamate Underlying Treatment-resistant Depression
- Authors: Jeongseop Kim et al. (2023)
