Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) is a common and serious medical illness that negatively affects how individuals feel, the way they think, and how they act. Symptoms include sad mood, loss of interest in activities that were once enjoyed, changes in appetite, fatigue, and suicidal thoughts (APA, 2017). This condition is one of the leading causes of disability worldwide, affecting about 16 million adults every year. In the last 20 years, the instances of suicide have increased by more than 30% in 25 states, making depression a large concern in modern times.

The traditional treatments for depression, such as talk therapies, antidepressant medicines, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT) often take weeks or months to take effect and do not always succeed in alleviating symptoms (Meisner, 2017). Not only does Ketamine work more rapidly, sometimes showing beneficial effects within one hour (Niesters, Martini, & Dahan, 2014), it can succeed when other treatments fail. Individuals that are not satisfied with traditional plans of care may respond to Ketamine.

In 2000, one of the first studies about Ketamine and depression revealed that the drug has a strong, immediate, long-lasting effect on an individual’s mental health. In this randomized, placebo-controlled, crossover design study, patients with depression received 0.5 mg/kg of Ketamine or saline on the first day of testing. Participants in group 1, receiving Ketamine initially, endorsed antidepressant effects within 4 hours of their first treatment. Benefits peaked at 72 hours, and lasted for 1 to 2 weeks thereafter (Psychiatry Advisor, 2019). This study was replicated in 2006 with 18 patients with MDD who were resistant to other treatments. Compared with participants who received placebo, those who received Ketamine showed significant improvement in symptoms within 110 minutes, with 35% maintaining significant responses for at least 1 week (Psychiatry Advisor, 2019).

Since then, similar studies redemonstrated these findings, indicating that Ketamine is effective in providing fast-acting, lasting relief for depression. A single dose of Ketamine can reduce suicidal ideation, fatigue, and anhedonia within hours to days of administration (Psychiatry Advisor, 2019).

Major Depressive Disorder And Ketamine Theories

It is unclear exactly how Ketamine alleviates symptoms of depression, however, there are a few theories as to how this novel treatment takes effect. Ketamine blocks glutamatergic N-methyl-D-aspartate (NMDA) receptors, whereas antidepressants target serotonin, norepinephrine, or adrenaline. By binding to NDMA receptors within the brain, Ketamine increases the concentration of Glutamate, the primary excitatory neurotransmitter used in the nervous system, within synapses. Glutamate then activates AMPA receptors in the postsynaptic neuron. This leads to the release of other molecules that increase communication between neurons, creating new neural pathways (Meisner, 2017). This process, synaptogenesis, likely affects mood, thought patterns, and cognition.

Another theory is that Ketamine dampens neural signaling of inflammation, which has been linked to mood disorders (Meisner, 2017). Researchers have also noted that Ketamine is a weak agonist at the mu, delta, and kappa opioid receptors (Psychiatry Advisor, 2019). Ketamine may also alleviate depression by working as an agonist at dopamine receptors, an antagonist at the M1-3 muscarinic receptors, and as an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. In addition, Ketamine enhances the transmission of gamma-aminobutyric acid (GABA), which decreases symptoms of depression (Psychiatry Advisor, 2019). Ketamine’s mood enhancing abilities may be attributed to any one of these mechanisms, although it is likely that all of them play a role.

Most prior research targeted racemic Ketamine infusions, not the more recently FDA approved intranasal Ketamine. Therefore, the mechanisms and side effects of Spravator are not as well known (Meisner, 2017).