"TREATMENT-RESISTANT DEPRESSION" AND USE OF INTRAVENOUS KETAMINE AND INTRANASAL ES-KETAMINE

Treatment-Resistant Depression (TRD) is defined as major depression characterized by the unsatisfactory response of two or more antidepressant therapies (adequate for dosage and duration), associated with a high incidence of comorbidities, with more marked impairment of functioning socio-occupational and greater risks of relapse, recurrence and suicidality. The high incidence of TRD has advanced scientific research towards the study of molecules with antidepressant action and with different mechanisms of action than those based on the monoaminergic theory. Ketamine is one of these molecules. A non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, ketamine is mainly used in clinical practice as an anaesthetic and analgesic agent. It has recently been shown that it exerts an antidepressant activity with few and transient side effects at sub anaesthetic doses. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Although the complete molecular mechanism of ketamine is very complex and still partly unknown, it appears that NMDA blockade induces a modulation of several synaptogenic signalling pathways, such as brain-derived neurotrophic factor (BDNF), improving synaptic plasticity of the prefrontal cortex and hippocampus. The design of the observational and retrospective study object of this thesis is evaluating the clinical response following repeated administration of intravenous ketamine (off-label use) and intranasal esketamine in a sample of 16 patients referring to the Psychiatric Clinic of the Siena University Hospital suffering from TRD. The efficacy assessment was performed by administering the Montgomery-Asberg Depression Rating Scale (MADRS) by an expert clinician before and during each entire treatment cycle of ketamine or esketamine intake. The data appeared to be significant in terms of benefit deriver from intravenous ketamine or intranasal S-ketamine therapy. In particular on the core symptoms of depression, such as sadness, apathy, inability to concentrate and fatigue, as shown by a reduction in the total score MADRS at last dose> 27% of baseline score. The most significant effects were achieved in the first 4 weeks of administration. The study limit is the small number of samples, which are still being implemented. To date, ketamine and S-ketamine are proven to be one of the few innovative drug therapies effective and safe for the treatment of TRD.