**4. Anorexia Nervosa**

Anorexia nervosa (AN) has the highest mortality of any psychiatric disorder, with a standardised mortality rate of between 3.2 and 10.5 [39,40]. It is characterised by dietary restriction and weight loss behaviours (e.g., exercise), leading to significantly low weight. Prognosis is often poor, with estimates of relapse including 59% at nine years of illness [41] and 30% at 15 years of illness [42]. There are several biopsychosocial models that seek to explain the aetiology of AN, such as the Cognitive Interpersonal Maintenance Model [43]. Nevertheless, the neurobiological underpinnings of the disorder remain ambiguous. There are no approved psychopharmacological medications for AN, and the treatment options are otherwise limited [44]. Moreover, a large proportion of patients are treatment-resistant

and therefore fail to gain weight. Treatment options are limited for this patient group [45], which has been described as a "crisis" in the field [46].

Psychiatric comorbidity is common in AN, even after the eating disorder has been resolved [47]. A study of 11,588 adults in eating disorder clinics in Sweden was conducted, with comorbidities including mood disorders (33–50%), generalised anxiety disorder (28–35%), social phobia (14–17%), obsessive-compulsive disorder (7–8%), post-traumatic stress disorder (PTSD; 3–7%) and substance use disorder (4–11%) [48]. Other data from separate geographical locations support similar prevalence rates [49–52], although other estimates of anxiety disorder comorbidity have been higher at ~55–85% of patients [53]. Features of autism spectrum disorder (ASD) are also highly prevalent in AN, with one study finding a 16.3% prevalence in a sample of 92 participants [54].

Patients with AN often report anhedonia, a lack of self-compassion, feelings of failure and suicidal ideation [49,55,56], and AN is associated with a higher risk of suicide [57]. Comorbid depression is linked to poor outcomes in patients, particularly those with severeenduring AN (SE-AN), whereby patients with comorbid depression are six times more likely to remain unrecovered at a 22-year follow-up [58]. Individuals with AN often report that engaging in disordered eating behaviours allows them to cope with or avoid difficult emotions; affect regulation may be a maintaining factor for the disorder [59]. Additionally, anxiety is a feature within the syndrome of AN, with high levels of fear and anxiety around food, weight and body shape and stereotyped eating behaviours. In the majority of cases, symptoms of anxiety disorders (e.g., generalised anxiety disorder, social phobia and obsessive-compulsive disorder) precede the onset of AN [60,61]. Moreover, symptoms of anxiety as measured by the State-Trait Anxiety Inventory [62] often remain high even after recovery [63,64]. Another risk factor for the development of AN is childhood trauma, most of which are related to negative sexual experiences [65].

Genetic studies suggest overlapping aetiology between AN and some psychiatric comorbidities (e.g., depression and obsessive-compulsive disorder) [66–68]. However, psychopharmacological drugs often show little efficacy in terms of weight gain in AN; a meta-analysis found no benefit in the weight outcomes from both antipsychotics and antidepressants in comparison to the placebo [69]. New approaches to the management of comorbidities, such as depression, in AN are warranted, which may, in turn, alleviate eating disorder (ED) symptoms. The evidence for the use of ketamine in the treatment of each respective comorbidity will be addressed in the following sections.
