Cushing’s patient’s psychiatric shifts tied to rapid Isturisa dose increase
Case report illustrates medication must be increased slowly for safety
A 43-year-old woman with Cushing’s disease developed an unusual sequence of psychiatric complications after rapid increases in her oral cortisol-lowering medication Isturisa (osilodrostat), a new case report from Japan shows.
The woman first experienced a sudden worsening of her depression symptoms early in treatment, likely due to a transient rise in cortisol. This hormone is excessively produced in Cushing’s disease. Days later, she developed delirium as her cortisol levels quickly dropped in response to the fast Isturisa dose increase.
“This case offers two clinical lessons. First, [Isturisa] should be titrated gradually according to established guidelines. Second, if psychiatric symptoms arise during treatment, they are best managed through close collaboration between endocrinology and psychiatry,” researchers wrote.
The case, “Delirium Induced by Rapid Titration of Osilodrostat in a Patient With Cushing’s Disease: A Case Report,” was published in Cureus.
Isturisa used when surgery isn’t an option
Cushing’s syndrome encompasses a group of disorders driven by excessive levels of the hormone cortisol. This condition is called hypercortisolism. Cushing’s disease is a specific form of the syndrome caused by a tumor in the brain’s pituitary gland. Hallmark symptoms include excessive weight gain, a round face, high blood pressure, and psychiatric issues such as depression, anxiety, and cognitive difficulties.
Surgery to remove the pituitary tumor is usually the first-line treatment for Cushing’s disease, but when the tumor cannot be removed or when symptoms persist, doctors turn to medications to lower cortisol levels. One such therapy is Isturisa, which is approved in the U.S. for adults with Cushing’s disease and other forms of Cushing’s syndrome for whom surgery isn’t an option or hasn’t been effective.
A rapid drop in cortisol can lead to adrenal insufficiency, a condition that may cause fever, rapid heart rate, low blood pressure, and, in severe cases, impaired consciousness or delirium. For that reason, Isturisa doses must be increased gradually and monitored closely.
In their report, researchers detailed the case of a woman in her early 40s who developed an unusual sequence of psychiatric complications after her Isturisa dose was increased too rapidly, causing abrupt shifts in her cortisol levels.
The woman had a long history, beginning in her early 20s, of major depressive disorder, for which she received long-term treatment with the antidepressant clomipramine. In her 30s, she developed treatment-resistant high blood pressure, which ultimately led to a Cushing’s disease diagnosis.
She underwent surgery to remove the pituitary tumor and started hydrocortisone replacement therapy to prevent dangerously low cortisol levels during recovery.
Despite surgery, she continued to show signs of hypercortisolism, with cortisol levels fluctuating markedly from day to day. Because her cortisol secretion remained unstable, doctors continued hydrocortisone treatment for safety.
Patient experienced depression, then delirium
Due to persistent disease activity, the woman was admitted for further evaluation. On arrival, she was alert, cooperative, and showed no active depressive or psychotic symptoms. A physical examination revealed typical Cushing’s features, and testing confirmed persistent hypercortisolism.
She was started on Isturisa at a low dose, but her cortisol levels unexpectedly rose shortly after treatment began. Between days three and five, she developed a sudden onset of psychiatric symptoms, including depressed mood, depersonalization, and suicidal ideation.
Believing the symptoms were linked to a transient rise in cortisol, her doctors rapidly increased the Isturisa dose in an effort to lower her cortisol levels.
“Although the risk of adrenal insufficiency was considered, treatment was deemed safe under hydrocortisone supplementation,” the researchers wrote.
By day nine, the dose had been escalated to a level typically reached only after weeks of gradual titration. Although the woman’s depressive symptoms eased as cortisol began to fall, she suddenly developed delirium marked by fluctuating consciousness, confusion, purposeless activity, and repetitive speech. The episode peaked on days 10 to 12.
This case highlights a rare course in which depressive symptoms during cortisol elevation and delirium during cortisol reduction occurred sequentially in the same patient following rapid titration of [Isturisa].
Her blood pressure dropped, and she developed fever and a fast heart rate, symptoms resembling adrenal insufficiency. Antipsychotic medications offered no benefit, but her symptoms resolved spontaneously by day 14.
She had no memory of the episode, and she remained stable through her hospital discharge on day 20. No delirium recurrences were reported upon follow-up.
“This case highlights a rare course in which depressive symptoms during cortisol elevation and delirium during cortisol reduction occurred sequentially in the same patient following rapid titration of [Isturisa],” the researchers wrote. “The episode suggests that even under hydrocortisone supplementation, abrupt cortisol fluctuations can induce psychiatric symptoms.”
Still, the team cautioned that the episode may not represent clear-cut phases of high and low cortisol. Instead, they suggested it may reflect a temporary state of functional adrenal dysregulation. The researchers also noted that clomipramine and antipsychotic medications may have amplified the patient’s symptoms, as these drugs can worsen confusion or agitation under hormonal stress.
In light of these findings, the researchers stressed that “clinicians should avoid rapid titration and ensure close collaboration between endocrinology and psychiatry when psychiatric symptoms arise during treatment.”
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