ISOLATED ADRENOCORTICOTROPIC HORMONE (ACTH) deficiency is a rare pituitary disorder characterized by decreased secretion of ACTH, but not of the other hormones of the anterior pituitary and causes secondary adrenal insufficiency.1 Since isolated ACTH deficiency gradually and latently develops and shows non-specific symptoms, it is easily misdiagnosed. We report a case of middle-aged-onset isolated ACTH deficiency that showed a severe major depressive episode. A 62-year-old man was admitted to our hospital due to suicidal behavior. He did not have any previous history of neuropsychiatric or endocrine disorders. From 6 months before the admission, he complained of mild general fatigue, depressed mood, loss of pleasure, psychomotor retardation, insomnia, decrease in appetite, and weight loss. He was diagnosed as having major depressive disorder. A dose of 100 mg/day of sertraline did not relieve him of his depressive symptoms at all. At the time of admission, he was fully conscious and showed a severe major depressive episode with suicidal ideas. He did not show any symptoms suggestive of atypical depression or chronic fatigue syndrome, such as hypersomnia, lead paralysis, mood reactivity, rejection sensitivity, muscle pain, lymph node swelling, and fever. Magnetic resonance imaging of his brain did not show any structural abnormality, including an empty sella. Blood test revealed anemia (red blood cell count, 3.24 × 106/µL; hemoglobin, 10.0 mg/dL) and hyponatremia (117 mEq/L). Thyroid function studies were consistent with hypothyroidism: thyroid-stimulating hormone (TSH), 49.8 µIU/mL (normal range, 0.6–5.1); fT3, 2.45 pg/mL (2.47–4.34); and fT4, 0.71 ng/dL (0.97–1.79). Rheumatoid factor and antinuclear, antithyroglobulin, anti-thyroid peroxidase, TSH-receptor, and antipituitary antibodies were negative. Both serum ACTH (<2.0 pg/mL; normal range, 7.2–63.3) and cortisol (0.2 µg; 3.7–19.4) were extremely low, whereas aldosterone (61.6 pg/mL; 38.9–307.0) was within normal range. Neither ACTH nor cortisol responded to corticotrophin-releasing hormone stimulation test, showing that he suffered from secondary adrenocortical insufficiency. Thyrotropin-releasing hormone test, gonadotrophin-releasing hormone test, and growth hormone-releasing hormone test showed normal responses, revealing that his secondary adrenocortical insufficiency was caused by isolated ACTH insufficiency. We discontinued sertraline and started to administer him 5 mg/day of hydrocortisone. Three days later, his symptoms mimicking major depressive episode were dramatically resolved. As in our case, isolated ACTH deficiency may be comorbid with primary hypothyroidism although the mechanism of the coexistence is unknown.2 However, the comorbid hypothyroidism did not seem to induce his depressive state as hypothyroidism was recovered 4 months after rapid relief of his psychiatric state. Relationships between glucocorticoid function and symptoms mimicking major depressive episodes are complex but might reflect insufficient glucocorticoid signaling. Some major depressive episodes might be associated with the insufficient glucocorticoid signaling by decrease of glucocorticoid production or decrease of sensitivity of glucocorticoid receptors.3 Our case suggests that isolated ACTH deficiency should be added into a differential diagnostic list of major depressive disorder. The patient gave the authors informed consent to publish this letter.