Association of Thyrotoxicosis With Mania

"Ms. F," a 24-year-old female with no known medical history, was brought to the emergency department by emergency medical services for agitation and disorganized behavior. On the way to the hospital, she was given 10 mg of haloperidol, 4 mg of lorazepam, and 50 mg of diphenhydramine intramuscularly. Ms. F reported that she was "chosen by God" and "haunted by demons." For more than 2 weeks, she had been sleeping 2–3 hours at night and experiencing hyperreligiosity. She stated that was reading the Bible more than usual, speaking in tongues, and crying for her past sins.

A review of systems was significant for weight loss, anxiety, emotional lability, alternating bouts of diarrhea and constipation, and heat intolerance for the past few weeks.

She reported no family history of mood disorders; however, she reported thyroid disease in her grandmother. Physical examination was significant for tachycardia, temperature 99.1° F (37.3°C), and fine tremors in her bilateral upper extremities. There was no observable proptosis. Thyroid was nontender and without palpable abnormality. Skin was dry, and nonpitting edema was observed in her lower extremities. Her physical and neurological exams were otherwise unremarkable.

Ms. F was alert and oriented to person, place, and time. She was well-groomed and in appropriate dress. She was cooperative, but psychomotor agitation was noted as she was constantly rocking back and forth. Her speech was pressured. She described her mood as "great," and her affect was labile. She denied suicidal and homicidal ideation. Her thought process was notable for circumstantiality, looseness of association, and delusions of grandiosity. No paranoia or ideas of reference were apparent. She denied hallucinations and did not appear to be responding to internal stimuli. Ms. F was easily distractible, with a short span of attention. Her memory was intact. Insight and judgment were impaired.

Complete blood count, basic metabolic panel, and antinuclear antibody were ordered to rule out infection or autoimmune disorder and found to be unremarkable. Urine pregnancy and toxicology studies were also unremarkable. Electrocardiogram showed normal sinus tachycardia. Thyroid function testing was ordered given the patient's presentation (Table 1).

Endocrinology was consulted, and those clinicians noted no history of radiation and thyroid-toxic medication exposure, including amiodarone and lithium. Because the patient's thyroid-stimulating hormone (TSH) was low, with elevated free triiodothyronine (T3) and thyroxine (T4) and positive thyrotropin receptor antibody, Ms. F was diagnosed as having thyrotoxicosis without thyroid storm, possibly due to Graves' disease. Endocrinology recommended initiating methimazole 10 mg twice daily and propranolol 60 mg four times daily for heart rate control. The endocrinology clinicians did not feel that a medical inpatient admission would be beneficial, because her vital signs were stable and she did not require fluids, telemetry, or monitoring for autonomic instability.

Ms. F was admitted to the psychiatry inpatient unit with a diagnosis of bipolar and related disorder due to another medical condition. In the unit, she continued to experience elevated energy with decreased need for sleep. She displayed flight of ideas, tangentiality, grandiosity, hyperreligiosity, and delusional thinking. Her affect remained labile. The emergency psychiatric physician had initially prescribed 40 mg of lurasidone daily with breakfast. Because of a lack of therapeutic response, lurasidone was discontinued 3 days after hospital admission.

The patient's manic symptoms were then targeted with a combination of risperidone and lamotrigine. Risperidone 2 mg nightly and lamotrigine 25 mg daily were initiated together as a means of both acute symptom management and subsequent maintenance. She developed a rash, which led to discontinuation of lamotrigine. She was then prescribed divalproex sodium 1,500 mg daily (weight-adjusted dose), because lithium was an additional risk to her thyroid health. During hospitalization, risperidone was titrated to 4 mg nightly, and divalproex sodium was increased to 2,000 mg to achieve symptom management. She developed sialorrhea from risperidone and was cross-tapered to quetiapine 200 mg every morning and 400 mg nightly because this medication is less likely to cause sialorrhea. Ms. F tolerated quetiapine and divalproex sodium without any significant side effect.

After 12 days of inpatient treatment, follow-up labs showed that TSH was 0.01, free T3 had come down to 593, and T4 had decreased to 2.93. These results indicated a response to antithyroid medication. After 20 days of hospitalization, Ms. F was discharged on quetiapine 200 mg every morning and 400 mg nightly, divalproex sodium 2,000 mg daily, methimazole 10 mg twice daily, and propranolol 60 mg four times daily. At the time of discharge, her sleep was improved, mood was euthymic, affect was appropriate to mood, and delusion was resolved. Two days after discharge, her follow-up labs revealed that the free T3 had come down to 320 and the free T4 to 0.963—both within normal range.

It is well accepted that disturbances in thyroid metabolism in a mature brain may significantly alter mental function, influencing cognition and emotion (1). From earliest reports to the present day, the strongest association between thyroid dysfunction and psychopathology has been in the area of mood disorders (2). Patients with thyroid disease, especially primary hypothyroidism, often have depressive symptoms. Conversely, many patients with affective disorders have noticeable abnormalities in the hypothalamic-pituitary-thyroid axis (3).

In psychiatric practice, obtaining thyroid function tests for patients newly diagnosed with depression is often routine. Although the association of depression with hypothyroidism has been well studied, the relationship between manic symptoms and hyperthyroidism remains incompletely understood.

Thyrotoxicosis—an excess of thyroid hormones in the bloodstream—is characterized by anxiety, fatigue, generalized weakness, insomnia, weight loss despite increased appetite, tremulousness, palpitations, and increased perspiration. Serious psychiatric symptoms include manic excitement, delusions, and hallucinations (4). According to DSM-5, mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood lasting at least a week and, during that period of mood disturbance, of increased goal-directed activity or energy, inflated self-esteem or grandiosity, decreased need for sleep, more talkative or pressured speech, distractibility, and flight of ideas. The episode is not due to the physiological effects of substances or any other medical condition (5).

In terms of pathophysiology, TSH stimulates the thyroid gland to produce T4 and T3. The production and secretion of TSH is regulated by the hypothalamus via thyrotropin-releasing hormone. TSH production is inhibited via a negative feedback loop by T3 and T4 (4). Thyrotoxicosis in Graves' disease is caused by autoantibodies to the thyrotropin receptor that activate the receptor, thereby stimulating thyroid hormone synthesis and by negative feedback lowering the TSH hormone (6).

In our case, Ms. F experienced physical symptoms of hyperthyroidism, such as tachycardia, fine tremors, and dry skin, with concomitant manic symptoms—elevated mood, grandiosity, pressured speech, distractibility and increased energy. It is unclear whether the resolution of the patient's manic symptoms occurred from the treatment of thyrotoxicosis or the treatment of mania, because both conditions were treated concurrently.

The literature notes that thyroid diseases can trigger psychiatric illness (anxiety, depression, mania and psychosis) (7). Our case raises the question as to whether the patient's manic episode was a manifestation of her thyroid dysfunction. Manic symptoms have been known to occur with hyperthyroidism but are rare (8). In hyperthyroidism, late-onset mania is more commonly detected than early-onset mania (9).

A retrospective review based on 18 patients described manic symptoms occurring shortly after the initiation of thyroid replacement in patients with hypothyroidism (10). Most of the patients experiencing mania were female; they often had concurrent psychotic symptoms and frequently had a personal or familial history of psychiatric disorders. The authors suggested that rapid administration of thyroxine could abruptly augment catecholamine receptor sensitivity, thereby causing manic symptoms. Another study suggested that the modulation by thyroid hormones of the B-adrenergic receptor response to catecholamines may contribute to the affective changes seen in thyroid disease (11).

Although there are no well-established guidelines for treatment of mania associated with thyrotoxicosis, some studies suggest that patients with this condition should first be treated by restoring them to euthyroid states (1, 7). Additional treatment with beta-adrenergic antagonists is also helpful. Antimanic agents are required when symptoms fail to respond to these measures (8). Several studies have investigated the timeline of symptoms resolution and found that symptoms tend to disappear with successful treatment (12). Wallace et al. (13) stated that the effects of hyperthyroidism on the brain return to normal more slowly than other systemic effects. Prospective studies of patients with hyperthyroidism suggest that remission of affective and cognitive symptoms usually occurs within a few months of patients' becoming euthyroid. Some studies suggest that an episode of hyperthyroidism influences affective modulation in a time frame that exceeds the period of thyroid hormone excess (1). Cross-sectional studies suggest that there may be long-term effects on cognitive function and affective modulation following hyperthyroidism (7).

A link between thyrotoxicosis and mania could consist of a direct comorbidity between the disorders and similarities in presentation. Alternatively, manic symptoms may gradually develop in the wake of thyroid hormone excess. Future research is warranted to elucidate the relationship of affective disorders to central thyroid hormone functioning and pathological processes involved. Such research should also be aimed at developing clear treatment guidelines, which will lead to a more specific approach in the management of patients with this type of presentation.

The author thanks her attending, Dr. Jon Corey Jackson, Clinical Psychiatrist at Mississippi State Hospital, Pearl, Miss., and Adjunct Professor, Department of Neural and Behavioral Science, William Carey University College of Osteopathic Medicine, Hattiesburg, Miss., for his assistance.