When I was a fellow in the late 1980s, a geriatric woman was referred to the endocrinology department with a thyroid stimulating hormone (TSH) level of about 6 mIU/mL, a common cause of referral then and now. today. Her family also reported that she was incapacitated, with common symptoms of dementia. His doctor could not decide to offer levothyroxine.
I was unable to show any symptoms of hypothyroidism. His thyroxin (T4)/triiodothyronine absorption (T3U), the measurements used at the time, were average. I recommended not to treat her to the treating endocrinologist. Although he agreed that the likelihood of correcting obvious dementia by pushing the TSH down was low, he said there was nothing else to offer him as a means of reversal. He thought the drug’s safety and the reliability of the lab tests warranted at least one therapeutic trial.
Over the following decades, the United States Food and Drug Administration approved a number of drugs to stabilize Alzheimer’s disease. These probably have better efficacy than levothyroxine, but none are as safe and economical, and none result in a clear reversal of disability.
Could levothyroxine be the poor man’s option, not only for cognitive decline but also for affective disorders? Thyroid hormones have long been used to improve mood, often in addition to conventional antidepressants.
Decades later, the effects of thyroid function on the mind — whether achieved through normal physiology, disease, or a pill — remain less than completely settled.
What has changed are formal organizational guidelines for dealing with minimally elevated TSH values and advances in the technological ability to pool large amounts of data to generate more conclusive answers. Over the past year, several studies have assessed the impact of thyroid function on dementia and depression.
The prototype study, a randomized controlled trial called TRUST, as reported by Medscape in 2017, examined the effect of using levothyroxine to normalize low-level TSH among a geriatric cohort of approximately 700 participants. The study found no symptomatic benefit, primarily on quality of life measures.
Another subgroup analysis participants who had depression assessments before and after treatment focused more specifically on whether mild depression could be alleviated by TSH correction with levothyroxine. The use of antidepressants was not an exclusion criterion. No effect was found on depression scores, using two different scales depending on participants’ geographic location. Development of new mild depression was also likely whether or not participants were taking levothyroxine. But this analysis also found a higher dropout rate from the study among patients with the highest baseline depression scores. Also, the population included too few people with moderate to major depression (the situation in which psychiatrists are most likely to consider adding thyroid hormones) to draw a conclusion on effectiveness.
While depression has many safe and effective interventions, progressive cognitive impairment has no such treatments, not even therapies that allow further medical advancements.
To assess the effect of thyroid dysfunction on cognition, van Vliet and colleagues, as reported in September 2021, conducted a multicohort data analysis of 23 cohorts with data on thyroid function and cognitive impairment. A spectrum of thyroid function emerged, including overt hypothyroidism, hyperthyroidism, subclinical and normal thyroid dysfunction. Various clinical psychometric tests were performed to assess mental status and executive function, and diagnoses of dementia were included in several of the captured studies.
The combination of 23 studies allowed investigators to amass data on approximately 75,000 people, with a large number of people having data from cognitive tests or formal screening for dementia.
Subclinical two-way thyroid dysfunction had little impact on cognitive function or dementia. Indeed, some executive functions appeared to be unexpectedly improved in hyperthyroid patients, but not by an amount that would improve their ordinary activities. Moreover, since very large populations tend to amplify small differences between groups, the absence of differences in large populations reinforces confidence that treatment of minor TSH elevations offers little benefit. .
But for those who need it, mono- or combined therapy? Or None?
While the therapeutic advantages and disadvantages compared to replacement with pure levothyroxine [T4] or a mixture of T4 with triiodothyronine [T3] have generated a consensus in favor of levothyroxine alone, we are still struggling with treated patients who complain of impaired well-being.
Despite the clinical use of thyroid hormone replacement for over 100 years and levothyroxine monotherapy for about 50 years, when to use a mixture, if any, remains controversial despite numerous comparative trials.
A recent U.S. military-sponsored trial perhaps offers the branching point that affects prescription. The group studied about 75 people with established hypothyroidism that was corrected to normal TSH with medication. They also administered a variety of quality of life and skill measures. Using a crossover design, they identified people who performed poorly on the quality of life assessment when taking levothyroxine alone, then offered a T3-containing alternative and saw the quality of life score improves. But again, measures of well-being and some cognitive symptoms remained mostly independent of the type of thyroid hormone that produced the therapeutic TSH.
As thyroid assessment progressed from basal metabolic rate testing to T4/T3U, and now TSH, each step made the physician seem more astute; but as the studies suggest, we may have gotten a little too shrewd, forcing people to take drugs and do lab tests with little profit.
We still prescribe a lot of thyroid hormones; in most years it is among the most commonly prescribed drugs in America. A recent analysis of new prescriptions for levothyroxine between 2008 and 2018, as reported by Medscape, showed that only 8% were for overt hypothyroidism; 60% had subclinical hypothyroidism and 30% had normal TSH, presumably postoperative thyroidectomy users.
The average TSH prompting a new treatment was 5.8 mIU/mL. About 60% of new prescriptions came from general practitioners and about 10% from endocrinologists.
While concerns about cardiac protection or lowering lipids might prompt some of the prescriptions, the data on the negligible effects of the thyroid on mind and mood suggest we may need more restraint.