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A 78-year-old woman with colorectal cancer that had spread to other parts of her body developed worsening confusion over about three weeks. She then became very agitated and showed signs of psychosis, a condition that can cause people to lose touch with reality. This happened about three months after she started taking pembrolizumab, a drug that helps the immune system fight cancer. Doctors in Bern, Switzerland, found an often-overlooked cause of her mental health problems: severe hypothyroidism, meaning her thyroid gland was not making enough hormones. Her thyroid hormone levels had fallen so low that tests could not detect them. After she received thyroid hormone replacement, her hallucinations, false beliefs that others wanted to harm or poison her, and agitation disappeared completely. The case was published in Frontiers in Psychiatry on October 27, 2026. The report also describes how doctors restarted the same cancer drug later without the mental health symptoms returning.
Immune checkpoint inhibitors, such as pembrolizumab, have greatly improved treatment for several advanced cancers. These drugs work by helping the immune system attack cancer, but the immune system can sometimes attack healthy organs too. These side effects, called immune-related adverse events, can affect many parts of the body. Problems with hormone-producing glands are among the most common. Thyroid problems are especially common in people taking drugs that block a protein called programmed cell death protein 1, or PD-1. Pembrolizumab belongs to this group. In most patients, doctors find thyroid problems through regular blood tests or symptoms such as tiredness, feeling cold, or gaining weight. However, severe hypothyroidism that mainly causes an emergency involving mental health and brain function is rare. Symptoms may include extreme agitation, hallucinations, and false beliefs that others are trying to harm the person. These symptoms can be very difficult to tell apart from other brain, body chemistry, or mental health problems.
The woman had no history of mental illness and had been living on her own without help. She began receiving pembrolizumab as palliative treatment on July 4, 2025. Palliative treatment aims to control illness and improve quality of life. Before treatment, her thyroid-stimulating hormone, or TSH, level was normal at 1.99 mU/L. Her medical history included moderate chronic kidney disease and mild narrowing of the aortic valve in her heart. About three months later, after four doses of pembrolizumab, she began to experience worsening confusion and a decline in her ability to think and manage daily tasks. These changes developed over about three weeks. She then became very agitated and showed signs of psychosis, including false beliefs that people were trying to harm or poison her. On October 3, 2025, she was taken to the emergency department because she was extremely confused and agitated. She was disoriented about who she was, where she was, and other basic facts. Her answers did not make sense, but the neurological examination did not show any specific signs of damage to a particular part of the brain.
Her condition changed greatly during her hospital stay. At times, she could communicate more easily, but at other times she remained confused, moved around restlessly, and became increasingly agitated. She saw things that were not there and strongly believed that others wanted to harm or poison her. She also felt that outside forces were controlling her. Her agitation became worse in the evening and at night. She barricaded herself and became verbally and physically aggressive toward staff. Doctors diagnosed her with hyperactive delirium, a condition involving sudden changes in awareness and thinking along with increased activity and agitation. They based the diagnosis on her confusion, disorientation, disorganized thoughts and speech, restlessness, hallucinations, false beliefs, disturbed sleep patterns, and symptoms that came and went. These problems occurred alongside signs of an acute medical illness. Her thyroid gland was not enlarged or painful. Her heart and circulation examination was normal, and her neurological examination showed normal muscle strength and tone, no unusual reflexes, and no problems with coordination.
Her blood test results were striking. During a routine check on September 8, 2025, her TSH level had already risen to 41.20 mU/L. On the day she came to the emergency department, it was 37.90 mU/L. Her free T3, one of the thyroid hormones measured in the blood, was below the test's detection limit at less than 0.60 pmol/L. The normal range was 3.74 to 6.11. Her free T4, another thyroid hormone, was also below the detection limit at less than 0.5 pmol/L, compared with a normal range of 11.5 to 19.6. The authors noted that her TSH level was not as high as might be expected given how extremely low her thyroid hormone levels were. They interpreted this finding carefully. One possible explanation was that immune-related thyroid inflammation had developed quickly, before TSH levels had time to fully adjust. They could not completely rule out a partial problem involving the brain's control of the thyroid gland. Other abnormal results included moderate hyponatremia, a condition in which the blood contains too little sodium. Her sodium level had fallen from 135 mmol/L before treatment to 124–125 mmol/L when she arrived at the hospital. She also had mildly low potassium levels.
The tests doctors used to investigate her condition show how difficult it can be to identify the cause of sudden mental changes in people taking immune checkpoint inhibitors. Possible causes included inflammation of the brain linked to the cancer drug, a sudden structural problem in the brain, low adrenal hormone levels or inflammation of the pituitary gland, brain dysfunction caused by low sodium, and a primary mental health condition. Brain scans did not reveal a clear cause of the sudden changes. A CT scan showed a tiny bright spot that might have been a small bleed or a calcium deposit. A later MRI found a cavernoma in the occipital region of the brain, an area toward the back of the head, but there was no evidence of a recent bleed. The available cortisol test results did not support clear adrenal insufficiency, a condition in which the adrenal glands do not produce enough hormones. However, results for adrenocorticotropic hormone, or ACTH, and a full assessment of other pituitary hormones were not available. Doctors considered a lumbar puncture, which involves collecting fluid from around the brain and spinal cord, and an electroencephalogram, or EEG, which measures electrical activity in the brain. Neither test was performed. At first, her severe agitation made testing difficult. Later, she improved so quickly that the tests were not done. The authors acknowledge that this limits how certain the diagnosis can be, because inflammation of the brain caused by the immune system and seizure activity without obvious symptoms could not be completely ruled out.
Treatment focused on two main steps. Doctors paused pembrolizumab and started levothyroxine, a medicine that replaces thyroid hormone, on October 3 at a dose of 50 micrograms per day. Her severe agitation during the medical hospital stay required midazolam, a calming medicine given into a vein. She was transferred to an inpatient psychiatric unit on October 12. Because her blood tests continued to show low thyroid hormone levels, doctors increased her levothyroxine dose to 100 micrograms per day on October 23 and then to 150 micrograms per day on November 6. Her mental health improved as her thyroid function was treated. On October 21, she still reported believing that others wanted to harm her. By October 27, staff had noticed fewer statements linked to psychosis and greater independence. On October 31, she said she no longer felt that others were trying to harm her. She described the earlier experience as being like a nightmare. By November 6 and 11, she was alert, calm, able to speak clearly, and no longer experiencing hallucinations or false beliefs. When she left the hospital on November 12, 2025, she was fully oriented, could manage daily activities independently, and had no active symptoms of psychosis.
The order in which events happened strongly suggested a link, the authors explain. Her thyroid function had been normal before she started pembrolizumab. Severe hypothyroidism was found when her mental and neurological symptoms became serious, and the symptoms disappeared after thyroid hormone replacement and treatment of other body chemistry problems. Her symptoms resembled a condition sometimes called myxedema psychosis, in which severe thyroid hormone deficiency causes psychosis. However, her major problems with awareness and orientation, changing mental state, physical agitation, and underlying medical issues supported a diagnosis of delirium with psychotic symptoms rather than a primary psychotic disorder. The authors are careful not to claim that hypothyroidism was the only cause. Several factors may have contributed, including low sodium, disrupted sleep, emotional and social stress, and possible effects of other medicines. Doctors did not measure thyroid antibodies during the acute illness. Tests performed later, in August 2026, found slightly raised thyroid peroxidase antibodies, while TSH receptor and thyroglobulin antibodies were negative. These results suggest that her immune system may have been reacting against her thyroid, but they cannot show whether the antibodies were present when her illness began or appeared later. Because this is a report of only one patient, the findings cannot automatically be applied to everyone.
One of the most useful parts of the case is that doctors were able to restart pembrolizumab. After her condition had stabilized and she was receiving enough thyroid hormone replacement, she resumed the cancer treatment every three weeks, with close monitoring through blood tests. Her delirium and psychotic symptoms did not return. At a follow-up visit in April 2026, she was still taking levothyroxine at 150 micrograms per day, living independently, and had experienced no return of delirium or psychosis. Tests to assess her cancer showed that the disease was stable. Doctors continued checking thyroid hormone levels, TSH, and cortisol every six weeks. Although a single case cannot support firm conclusions, the authors suggest that restarting an immune checkpoint inhibitor may be possible after hormone-related immune side effects have been brought under control. They stress that this requires careful follow-up involving different medical specialists and regular checks of thyroid function.
The main message for doctors is clear. When someone taking an immune checkpoint inhibitor develops new agitation, hallucinations, psychotic symptoms, or delirium, doctors should quickly check for hormone problems that may be caused by the treatment and could be reversed. These checks should include thyroid problems and adrenal insufficiency before the symptoms are blamed on a primary mental health disorder. This is especially important because these symptoms can look like a mental illness, particularly when hallucinations and false beliefs are the main signs. The authors argue that finding and treating the cause early may prevent long-lasting illness, avoid unnecessary increases in psychiatric medication, and reduce the risk of stopping an effective cancer treatment too soon. The case also shows that negative antibody tests do not rule out thyroid problems linked to immune checkpoint inhibitors. Having normal thyroid test results before treatment does not prevent severe thyroid dysfunction from developing later. For cancer drugs now used by very large numbers of people with advanced disease, it is important to remember that a simple blood test may reveal a treatable cause of sudden psychosis.
Subject of Research: A case report describing hyperactive delirium with psychotic symptoms linked to severe hypothyroidism during pembrolizumab treatment. The symptoms disappeared after treatment with levothyroxine and did not return when pembrolizumab was restarted.
Article Title: Case Report: Hyperactive delirium with psychotic symptoms associated with severe hypothyroidism during pembrolizumab therapy. Complete remission after levothyroxine and no recurrence after pembrolizumab rechallenge
Article References: Vieira Fregolente, E., Bühler, S., & Lahr, J. (2026). Case Report: Hyperactive delirium with psychotic symptoms associated with severe hypothyroidism during pembrolizumab therapy. Complete remission after levothyroxine and no recurrence after pembrolizumab rechallenge. Frontiers in Psychiatry, 17, 1905725. https://doi.org/10.3389/fpsyt.2026.1905725
Image Credits: AI Generated
DOI: 10.3389/fpsyt.2026.1905725
Keywords: pembrolizumab, hypothyroidism, delirium, psychosis, immune checkpoint inhibitors, immune-related adverse events, levothyroxine, hyponatremia, thyroid dysfunction, case report, oncology, neuropsychiatry