Depression, Glutamate, and Ketamine: A Brave New World in Antidepressant Medications
Chambers, Jennifer I.
MetadataShow full item record
Since the time of antidepressant discovery there have not been any major changes in the way the drug acts within the body. This means that for over 60 years there have been no other targets beyond the monoamine system, and no great differences in the efficacy of treatment. This review covers the transition from the relatively simplistic monoamine hypothesis of depression to the more complex hypothesis of neuroplasticity. Stress causes abhorrent neuroplasticity in the hippocampus, amygdala, and prefrontal cortex (PFC) in both animal models and humans. The effects of stress are attenuated by the currently available antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) like Prozac. However, the onset of the antidepressant effects is between 2-6 weeks. This amount of time is far too long for a person in crisis. Currently there are no acute care treatments available for individuals who are struggling with suicidal thoughts. The NMDA antagonist ketamine has been shown to provide relief from antidepressant symptoms in as little as 20 min. This may be due to its ability to rapidly activate the production of new synapse proteins, resulting in increased neurotransmission and synaptic plasticity in the PFC. This appears to occur by activating the mTOR signaling pathway and the production of brain-derived neurotrophic factor (BDNF). Because of the psychotomimetic side effects of ketamine, research has begun to focus on medications that avoid this effect. These effects include feelings of dissociation and hallucination that last for approximately as long as the drug is active in the body and can be treated with benzodiazepines, a medication for anxiety, if needed. Antagonism of the NR2B subunit of the NMDA glutamate receptor has yielded successful antidepressant results without the unwanted side effects.