MHM Magazine

A second SSRI is likely a better option than an SNRI (Serotonin and Noradrenalin reuptake inhibitor) if an adolescent does not respond to the initial SSRI treatment, but a sizeable portion of children and adolescents with depression don’t respond to first line treatments. Ketamine, a dissociative anaesthetic has emerged as a promising alternative for treatment resistant depression in adolescents, so it’s important to examine the available evidence. The challenges with Depression in Adolescents: The Current Landscape There are multiple challenges with treating adolescent depression and there are challenges with current available antidepressant medication. Current treatment can be effective for many, but a substantial proportion of patient’s fail to experience a sustained remission. Approximately 40% remain depressed despite treatment. One in four patients don’t achieve remission with available treatment strategies and one in four of those who respond can expect to relapse within a year. The current available treatments for depression take a long time to work and don’t work on many patients, and there is a challenge if one of these medications doesn’t work as they all work on similar mechanisms. There are few useful antidepressant trials in children and there are no fixed dosed studies, limited head- to-head trials of medications and poor data especially in younger children. This highlights the need for novel treatments to treat adolescent depression that target distinct neurochemical systems that are considered in a developmental context. One such alternative gaining attention is ketamine, a dissociative anaesthetic. While traditionally used in surgical settings, ketamine has emerged as a promising option for treatment-resistant depression (TRD) in adults. Its potential effectiveness offers hope for those who have not responded to conventional treatments. Treatment Resistant Depression in Adolescents and what we Know About Ketamine from Adult Studies Treatment resistant adolescent depression is defined as depression symptoms despite an adequate trial of an evidence- based psychotherapy and an antidepressant with Grade A evidence for treating depression in adolescents (fluoxetine, sertraline, escitalopram). Ketamine improves a range of depressive symptoms in adults, and it notably reduces anhedonia, a symptom associated with poor therapeutic response in adolescent major depression. Ketamine also appears to have effectiveness in reducing suicidality in adults, a dimension of adolescent major depression that has shown controversial associations with SSRIs. This makes ketamine a potentially valuable new treatment option for the adolescent population. Safety and success in treating adult treatment resistant depression, makes it a potential for consideration for use in severe treatment resistant depression in adolescents. Ketamine treatment is typically administered intravenously or intranasally under medical supervision and requires referral by a psychiatrist for the administration of its use. Ketamine as an Alternative Treatment Ketamine entered medical use in 1964 and gained FDA approval as an anaesthetic for adults in 1970 and quickly showed promise for various clinical applications beyond anaesthesia. Despite its versatility, recreational use emerged in the 1970s, escalating in the 1980s. In response, the DEA classified it as a controlled substance in 1999, with its psychotropic effects being formally studied in the same year. In a pivotal moment in 2019, the FDA approved intranasal ketamine for adult treatment-resistant depression (TRD), marking its first psychiatric indication. The eventual off label usage in adolescents is inevitable and anticipated and poses challenges. The relative ease of administration as compared to IV infusion may also make it more popular and accessible adolescent treatment modality. Mechanism of Action Ketamine’s mechanism of action is intricate, involving interactions with various neural systems. Research has suggested that depressed adolescents exhibit increased intracortical facilitation, indicating excessive glutaminergic activity compared to controls. Considering the unique pharmacological landscape of the adolescent brain, which undergoes active maturation of monoaminergic, glutaminergic, and GABAergic systems, it's essential to contextualise the developmental pharmacology when testing novel therapeutics. The primary mechanisms by which ketamine exerts its effects are as follows: 1. N-Methyl-D-Aspartate (NMDA) Receptor Antagonism: Ketamine is a non-competitive antagonist of NMDA receptors, which are involved in synaptic plasticity, learning, and memory processes. It binds to the phencyclidine (PCP) site within the NMDA receptor complex and blocks the channel and prevents calcium influx. 2. Glutamate Modulation: Ketamine’s blockade of NMDA receptors leads to a subsequent increase in glutamate release in the prefrontal cortex. This stimulates AMPA receptors, resulting in enhanced synaptic plasticity and the induction of synaptic changes that may underlie the antidepressant effects of ketamine. 3. Synaptic Remodelling: Ketamine triggers a cascade of molecular and cellular events, including the activation of neurotrophic factors like brain- derived neurotrophic factor (BDNF) and the mechanistic target of rapamycin pathway. These processes promote synaptic growth, increase the number and function of dendritic spines, and facilitate the formation of new connections in brain circuits associated with mood regulation. 4. Modulation of GABAergic Interneurons: Ketamine affects the inhibitory GABAergic neurotransmission by dampening the activity of GABAergic interneurons in the prefrontal cortex. This disinhibition increases excitatory glutamatergic output, thereby enhancing synaptic MHM | 2024 | Volume 11 | Issue 2 | The Use of Ketamine in Adolescents with Treatment Resistant Depression: Where are we and what does the current evidence say? MHM Is ue 2 | 2024 | MENTAL HEALTH MATTERS | 11 MHM