AN presents clinicians with significant challenges due to its chronicity, high relapse risk, and considerable morbidity and mortality rates [5–8]. The ego-syntonic nature of the disorder, characterized by denial and lack of treatment motivation, distinguishes AN from other mental disorders [3, 4]. Despite limited scientific evidence on SE-AN treatments, the future holds encouraging prospects for developing more effective therapeutic approaches [19, 20]. The present review examined various treatment options for individuals with SE-AN; in particular, psychotherapeutic, pharmacological, and neurostimulation approaches were identified.

Various reports on treatment effectiveness in individuals with chronic AN evaluate CBT and its greater effectiveness compared to SSCM [9, 32, 36, 40, 65]. Similarly, several studies have reported that inpatient CBT-E is well-accepted and effective [9, 32, 36, 37]. Only the more recent study by Frostad et al., regarding the therapeutic potential of outpatient CBT-E, reported an elevated dropout rate, suggesting that CBT is more tolerated when carried out in an inpatient setting [46]. Nonetheless, the group of patients that completed the treatment achieved significant weight gain both at EOT and after a one-year follow-up (80% had a BMI ≥ 18.5), proving that outpatient CBT-E is a valid alternative to hospitalization [46]. Le Grange et al. identified predictors and moderators of outcome at the end of treatment: worse depression level, older age, more severe ED-related symptoms, and AN-BP subtype (binge eating/purging) [40].

When considering pharmacological treatments, research on dronabinol, antipsychotics, and ketamine showed some mixed results regarding the often complementary areas of weight gain and improvement in ED-related symptoms [26, 43, 44, 49, 51, 56]. Some medications showed positive effects on weight gain [26, 43, 49, 51, 56], and others on ED psychopathology [43, 44, 49, 51]. Dronabinol, a synthetic orexigenic cannabinoid, showed some modest effects on weight gain and metabolic changes [56]. Conversely, it was found to be ineffective in improving ED psychopathology. Such a profile could hold clinical importance for patients with SE-AN even in the absence of notable changes in psychopathological symptoms [56].

Regarding antipsychotics, some studies showed that olanzapine and haloperidol can have the potential to induce weight gain [26, 49, 51]. These results, however, show some contradictions, such as the fact that olanzapine offered modest benefits in weight gain, considerably less than the substantial weight gain observed in treating other disorders using the same pharmacological therapy [26]. Moreover, evidence for olanzapine's significant impact on AN-psychopathological features, such as excessive concerns about weight gain and obsessiveness, is conflicting [26, 66]. Regarding haloperidol, some small studies showed how low-dose inpatient treatment exhibited improvements in BMI and ED psychopathology, particularly in delusional symptoms and drive for thinness [49, 51].

With respect to ketamine, some studies indicated promising treatment approaches for SE-AN and its comorbid conditions. In fact, research showed that intramuscular ketamine had a beneficial effect on depressive symptoms, revealing high efficacy in reducing depressive symptoms and the risk of suicide [44]. Minor improvements were observed in controlling anxiety and ED-related symptoms [44]. It was also demonstrated that combining ketamine infusions with a therapeutic ketogenic diet can be safe and effective in reducing ED-related symptoms and psychopathology, despite a lack of significant weight restoration [43].

Combining TKD with ketamine may help normalize impaired dopaminergic function in AN, potentially improving brain circuit function and behaviors. Although the underlying mechanisms remain unclear, the results suggest that this approach is effective in AN patients who have restored weight but continue struggling with body image concerns and self-acceptance issues [67–69]. Similarly, with regard to nutritional supplements, tyrosine has shown potential therapeutic efficacy in improving psychological traits associated with AN, such as depressed mood and cognitive function [58, 59, 70, 71].

Finally, on the subject of brain stimulation therapies, such as repetitive rTMS and DBS, we found promising results in improving ED-related psychological traits (such as mood and anxiety), affective regulation, and quality of life [34, 42, 47, 48, 52]. However, we have observed divergent results regarding outcome measures such as BMI and weight gain. Some authors reported significant improvements in this regard [35, 48, 52, 53], while others described small ones, if any [33, 34, 53]. Similarly, discordant findings were reported about ED symptoms, with some moderately positive results [42, 48, 50, 53] and some not significant findings [33–35].

In particular, the use of rTMS on DLPFC seems to hold potential therapeutic effects. Its action in this cortical area can lead to emotional regulation, cognitive flexibility, and response inhibition [72–75]. Even in this field, research shows conflicting results regarding ED psychopathology, weight, and food intake: some studies reported no clinical improvement, while others observed reductions in food cravings and binge eating episodes [50]. Moreover, some authors suggested that rTMS is most effective as an addition to psychological therapy and/ or cognitive training [76–78].

On the other hand, stereotactic neurosurgery acts through neuromodulation of targeted limbic structures such as the subcallosal cingulate [48, 79–81]. The two main types of stereotactic neurosurgery are simulating surgery, involving DBS, and ablative surgery, by means of thermocoagulation and radiosurgery. Stereotactic neurosurgery for psychiatric disorders aims to treat specific symptoms like anxiety, aggression, obsession and compulsion by interrupting neural circuits in the limbic system through surgical blocks using functional neuroimaging, particularly tractography. Chronic DBS stimulation in these regions lead to reduced activity near the target and hyperactivity of parietal structures involved in the limbic and parietal regions, thus leading to impairments in affective functioning [80]. These results were found in both patients with the active disease and those who recovered and restored weight [82, 83]. The cingulate in fact plays a part in attributing reward value to environmental stimuli and affective processing, both of which are impacted in SE-AN [84]. Recent research has also explored neurosurgical procedures like anterior capsulotomy for obsessive symptomatology and anterior cingulotomy for anxious symptomatology [85, 86].

By acknowledging the patient as the central figure in the therapy, interventions should involve intrapersonal work, collaboration with significant others, and identity development beyond the confines of Anorexia Nervosa. Factors identified by Starzomska et al., including enhanced insight, externalization and devaluation of the disorder, and improved interpersonal understanding, play crucial roles in fostering self-determined recovery efforts [87]. Furthermore, therapeutic strategies should extend beyond towards the patient’s interpersonal relationships, involving caregivers and family members, in order to embrace the recent Maudsley AN treatment approach in adults [88]. This approach implies intrapersonal exploration, collaboration with significant others, examination of identity beyond AN, questioning the value of AN, and externalizing its impact on the individual's life.