This is the case of a 24-year-old woman referred to our outpatient psychiatry clinic for depression-like symptoms in the context of multiple hormonal deficits and a lesion in hypothalamus and pituitary gland. A prior diagnostic workup had identified multisystem Langerhans cell histiocytosis (LCH) with neurologic and neuroendocrine involvement. The patient was treated with hormonal replacement, corticosteroids, chemotherapy, and antidepressant medication, however, the neuropsychiatric syndrome persisted and appeared exacerbated by challenging family dynamics. Apathy was the predominant clinical feature, pointing to a distinct phenotype that is differentiable from depression. Mild improvement was noted after initiation of therapy with dexmethylphenidate, and consideration was given to oxytocin treatment, although the latter was not pursued owing to the lack of an established protocol. This case illustrates a striking neuropsychiatric phenotype of treatment-resistant apathy occurring in the setting of neuro-LCH with localized hypothalamic-pituitary lesion and multi-endocrine deficiency. The apathy syndrome was refractory to treatments targeting LCH, hormone replacement, and antidepressants, highlighting the need for a tailored approach. The potential role of psychostimulants and oxytocin replacement as therapeutic avenues in apathic patients warrants further research.