Treatment-Resistant Depression and Ketamine Response in a Patient With Bilateral Amygdala Damage.

“A.M.” is a 44-year-old woman who developed treatmentresistant major depressive disorder despite a history of stable and focal bilateral amygdala lesions caused by lipoid proteinosis of Urbach and Wiethe (OMIM #247100), an extremely rare autosomal-recessive disorder resulting from mutations in the extracellularmatrix protein 1 gene (ECM1) located on chromosome 1q21 (1). We have repeatedly studied this patient and hermonozygotic twin sister, who shares the sameUrbach-Wiethephenotypeandamygdala pathology. Brain scans taken longitudinally over the past two decades have confirmed complete destruction of the basolateral amygdala bilaterally (Figure 1A; see also Figure S1 in the online supplement), and a large body of research involving the twins has helped identify brain functions and behaviors that do (2) or do not require amygdala integrity (3). In these studies,A.M.underwentextensivediagnostic screening, which confirmed preserved neuropsychological functioning, including memory, attention, and cognitive flexibility, in the absence of any psychiatric abnormalities, including no history of major depression (4, 5). Perhaps related to the extraordinarily strong, supportive bond with hermother,A.M.(butnother identical twinsister)displayed preserved recognition of fearful faces (6), but emotionally charged pictures never aroused her in a manner similar to the way they did control subjects (7). This was paralleled by a flat affect and the absence of anxiety in life situations experienced as stressful by her family (8). The onset of major depression for A.M. started 4 years ago, and it was preceded by a series of major life events, all within a 1-year period, and all related to the loss of close attachment figures whowere of central importance to her in providing support, care, and connectedness: hermother died fromcomplications from a routine diagnosticmedical procedure; she divorced her husband, who left her for anotherwoman;andher teenagesondecidedto leavehome and live with his father. Disabled by grief, broken-heartedness, and exhaustion, she stopped working and moved into her father’s house. She attempted suicide and underwent five inpatient treatments in psychiatric hospitals. Notably, she did not benefit from any of the multimodal treatment attempts, including cognitive-behavioral therapy, multiple classes of antidepressants, and bilateral electroconvulsive therapy (see Table S1 in the online supplement). On admission to our department last year, A.M. exhibited pronounced symptoms of anhedonia, loss of energy, and pervasive pessimistic thought biases expressing despair, resignation, and a passive wish to die (e.g., “I am hopeless; nothing has ever helpedmakeme feel better; my life won’t ever change for the better”). She displayed sleep disturbances, concentration deficits, and feelings of worthlessness and inferiority. Her cognitive distortions also affected her body image, evident in complaints about her appearance (e.g., “I am so ugly; I am not attractive to anybody; I will never find another partner who wants to share his lifewithme”). She refused towear glasses despite moderate myopia. Her loss of appetite resulted in a diagnosis of cachexia (wasting syndrome) on admission (body mass index, 17.75). Furthermore, she suffered from a dry mouth, salty taste, and painful oropharyngeal ulcerations typical of Urbach-Wiethe disease. Compared with a premorbid assessment 7 years earlier (6), her social network had declined both in size (the number of people in her social network was 17 in 2012, and 10 in 2018) and complexity (four embedded networks in 2012, and one in 2018; see the online supplement). In addition, she exhibited high levels of loneliness (a UCLA Loneliness Scale score of 47; see the online supplement). Clinical interviews confirmed that she had no other psychiatric disorder thanmajordepressive disorder. Ten years ago, in an exploratory positron emission tomography study using the radioligand [F]altanserin (5), we detected a significantly decreased expression of serotonin (5-HT2A) receptors throughout A.M.’s brain, whichmay be linked to her amygdala pathology in ways neither investigated nor understood. In light of the treatment-refractory and suicidal nature of A.M.’s major depression, the rationale of our