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How Does Ketamine Work? How Does Ketamine Prevent Deaths of Despair? 

There are numerous pathways through which ketamine appears to work to resolve depression. Ketamine demonstrates efficacy the rapid relief of suicidality, PTSD, Bipolar depression, and pain. Glutamate is the neurotransmitter that appears to be a primary molecule involved in learning and is an excitatory neurotransmitter in the cerebrum. Disorders in glutamate result in depression and mood disorders. A recent study demonstrated the importance of Serotonin 1B receptors in depression and how ketamine improves that. 

A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression 

Low Serotonin 1B receptors have been found in limbic areas of the brain in major depression disorder (MDD). Ketamine upregulates AMPA receptor activity and results in increased 5-HT1B receptor binding in the ventral striatum (involved in depression). 

In the study, PET scans were used to image serotonin receptor binding after ketamine infusions in 30 patients. Low levels of serotonin correlate with severe depression. During the study, a certain portion of the patients underwent ketamine infusions twice a week for two weeks, and 70% of those patients had improvement in their depression scores. Based in the PET scans, ketamine reduces the output of serotonin and increased dopamine (the reward molecule). Ketamine increased the number of Serotonin 1B receptors and the higher number of Serotonin 1B receptors correlates with less depression. 

Key points: 

Subanesthetic dosing of ketamine has been effective in the rapid reduction of depression over hours as opposed to weeks with traditional treatments: 

Antidepressant effects of ketamine in depressed patients 

Glutamate is the key neurotransmitter involved in mood disorders based on recent theories: 

The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects 

The NMDA receptor (N-methyl-D-aspartate ) antagonism by ketamine plays a key role in the effectiveness of ketamine’s antidepressant effect: 

 
The acute effects of NMDA antagonism: from the rodent to the human brain 

Ketamine interacts with several receptors in the brain and impacts neurotransmitters through affinity for opioid, muscarinic, nicotinic, and serotonin (5-HT)₂ receptors: 

 
Classics in Chemical Neuroscience: Ketamine 

Ketamine, much like other antidepressants, seems to increase serotonin in areas of the brain such as the prefrontal cortex and depletion of serotonin results in decreased antidepressant effects with ketamine: 

Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine 

In the positron emission tomography (PET) studies of in vivo 5-HT1B receptor binding in MDD, low binding in the hippocampus and in the anterior cingulate cortex (ACC) has been reported both in patients with recurrent MDD: 

Low serotonin1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder 

PTSD also presents with reduced serotonin 1B receptors as well: 

The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding 

In patients with a family history of depression, it is noted that 5-HT1B receptor binding was low in the ventral striatum (VST) and ventral pallidum: 

Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder 

The VST is a key structure in the reward system, implicated in anhedonia – the presence of no mood that can accompany MDD and 5-HT1B receptor binding is high in the VST: 

Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond 

Per this study, ketamine increased 5-HT_1B receptor binding in regions with reported low 5-HT_1B receptor levels, such as the hippocampus, ACC (Anterior Cingulate Cortex), and VST and this resulted in diminished depression. 

What does this mean for you? 

The bottom line is that ketamine still improved depression in 70% of treatment failures through still-debated mechanisms. The improvement of the Serotonin 1B receptor is just another piece of the puzzle.