One of the main challenges with ketamine treatment can be the length of time that the antidepressant effects lasts after finishing a course of treatment. A possible option may be maintenance therapy with ketamine which usually runs twice a week to once in two weeks. Ketamine may decrease suicidal thoughts for up to three days after the injection.An enantiomer of ketamine – esketamine commercially sold as Spravato – was approved as an antidepressant by the European Medicines Agency in 2019. Esketamine was approved as a nasal spray for treatment-resistant depression in the United States and elsewhere in 2019 (see Esketamine and Depression). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends esketamine as a third-line treatment for depression.A Cochrane review of randomized controlled trials in adults with unipolar major depressive disorder, found that when compared with placebo, people treated with either ketamine or esketamine experienced reduction or remission of symptoms lasting 1 to 7 days. There were 18.7% (4.1 to 40.4%) more people reporting some benefit and 9.6% (0.2 to 39.4%) more who achieved remission within 24-hours of ketamine treatment. Among people receiving esketamine, 2.1% (2.5 to 24.4%) more encountered some relief at 24-hours and 10.3% (4.5 to 18.2%) more had few or no symptoms. These effects did not persist beyond one week, although higher dropout rate in some studies mean that the duration of benefit remains unclear.Ketamine may partially improve depressive symptoms among people with bipolar depression, at 24 hours after treatment, but not 3 or more days.
Moreover, animal studies and at least three human case reports have found no interaction between ketamine and the monoamine oxidase inhibitor (MAOI) tranylcypromine, which is of importance as the combination of a monoamine reuptake inhibitor with an MAOI can produce severe toxicity such as serotonin syndrome or hypertensive crisis. Collectively, these findings shed doubt on the involvement of monoamine reuptake inhibition in the effects of ketamine in humans. Ketamine has been found to increase dopaminergic neurotransmission in the brain, but instead of being due to dopamine reuptake inhibition, this may be via indirect/downstream mechanisms, namely through antagonism of the NMDA receptor.Whether ketamine is an agonist of D2 receptors is controversial. Early research by the Philip Seeman group found ketamine to be a D2 partial agonist with the potency similar to that of its NMDA receptor antagonism. However, later studies by different researchers found the affinity of ketamine of >10 μM for the regular human and rat D2 receptors, Moreover, whereas D2 receptor agonists such as bromocriptine are able to rapidly and powerfully suppress prolactin secretion, subanesthetic doses of ketamine have not been found to do this in humans and in fact, have been found to dose-dependently increase prolactin levels. Imaging studies have shown mixed results on inhibition of striatal [11C] raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect. However, changes in [11C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2 receptor.