**5. The Use of Ketamine in Commonly Comorbid Psychiatric Disorders** *5.1. Depression*

Patients with treatment-resistant depression defined as those who have failed to achieve remission (or at least a 50% improvement in mood) after two antidepressants, are candidates for esketamine nasal spray therapy in conjunction with an antidepressant. Notably, the National Institute of Care Excellence (NICE) in the United Kingdom do not recommend nasal spray esketamine for depression on the grounds of poor cost-effectiveness [70]. This is currently being reviewed. In research, the most common administration route in clinical trials is intravenous (IV) ketamine [71]. Studies show that IV ketamine elicits a rapid antidepressant response in major depressive disorder and treatment-resistant depression, acting within 24 h and providing a response after a single IV administration of subanaesthetic doses (0.5 mg/kg) for 4–7 days [72]. There has been extensive research investigating ketamine as a treatment option for this population. For example, it has been found that a third of patients with treatment-resistant depression achieve remission [10], with higher rates of remission associated with repeated administrations. All symptoms of depression have been found to be reduced, including suicidality [25]. Additionally, improvements in aspects of memory and learning have been found in patients with depression after ketamine treatment, such as working memory and visual learning memory [73]. Studies of ketamine for depression have, for the most part, used adult samples, although a systematic review found reductions in depressive symptoms, suicidality and mood lability

in adolescents given ketamine for treatment-resistant psychiatric conditions [74]. Thus, there is emerging evidence for its use in adolescents, although, notably, esketamine is only licensed for use in adult patients.

Whilst esketamine has fewer psychotomimetic effects than R-ketamine, it has been suggested that these psychotomimetic effects may increase the antidepressant efficacy [75,76]. Whilst considered a side effect, the psychotomimetic effects can have transformative psychological effects akin to those elicited from other psychedelic experiences (e.g., psilocybin [77,78]). Additionally, there have been concerns raised regarding the cognitive effects of ketamine, since it tends to produce impairments in cognitive function, although the majority of this evidence is in chronic users [79]. However, in acute doses, it appears that neurocognitive function is sustained or even improved [80]. More research should be conducted to ascertain the impact of therapeutic ketamine on cognition in patients with depression.
