When I was a fellow in the late 1980s, a geriatric woman was referred to the endocrinology service with a thyroid stimulating hormone (TSH) level of about 6 mIU/mL, a common cause of referral then and now. Her family also reported that she was incapacitated, with common dementia symptoms. Her doctor could not decide whether to offer levothyroxine.
I could not elicit any symptoms of hypothyroidism. Her thyroxine (T4)/triiodothyronine uptake (T3U), the measurements used at the time, were mid-normal. I recommended not treating her to the attending endocrinologist. Although he concurred that the likelihood of correcting an obvious dementing illness by nudging the TSH downward was small, he said there was nothing else to offer her as a means of reversal. He believed that the safety of the medicine and the reliability of the lab testing justified at least a therapeutic trial.
In the ensuing decades, the US Food and Drug Administration has approved a number of drugs for stabilizing Alzheimer’s disease. These probably have better efficacy than levothyroxine, but none are as safe and economical, and none result in any clear reversal of disability.
Could levothyroxine be the poor man’s option, not just for cognitive decline but for affective disorders? Thyroid hormones have a long history of being used to elevate mood, often as supplements to conventional antidepressants.
Decades later, the effects of thyroid function on the mind — whether achieved through normal physiology, a disease, or a pill — remain less than fully settled.
What has changed are formal organizational guidelines for dealing with minimally elevated TSH values and advances in the technological capacity to pool large amounts of data to generate more conclusive answers. In 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, looked at the effect of using levothyroxine to normalize a minimally elevated TSH among a geriatric cohort of about 700 participants. The study found no symptomatic benefit, primarily on quality-of-life measures.
A further subgroup analysis of participants who had assessments of depression pre- and post treatment focused more specifically on whether mild depression could be alleviated with TSH correction with levothyroxine. Use of antidepressants was not an exclusion criterion. No effect was found on depression scores, using two different scales depending on the geographic location of the participants. The development of new mild depression was equally 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. Moreover, the population included too few people with moderate to major depression (the situation in which psychiatrists are most likely to consider adding thyroid hormone) to reach a conclusion on efficacy.
While depression has many safe and effective interventions, progressive cognitive impairment does not have such treatments, not even therapies that provide incremental medical progress.
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, overt hyperthyroidism, subclinical thyroid dysfunction, and normal. Various clinical psychometric testing had been performed to assess mental status and executive function, and diagnoses of dementia were included in several of the captured studies.
Combining 23 studies allowed investigators to amass data on about 75,000 people, with large numbers of people having data from cognitive testing or formal dementia screening.
Subclinical thyroid dysfunction in either direction had little bearing on cognitive function or dementia. Indeed, some executive functions unexpectedly seemed improved in the hyperthyroid patients, though not by an amount that would enhance their ordinary activities. Moreover, because very large populations tend to magnify small differences between groups, lack of differences in large populations enhances confidence that treating minor TSH elevations offers little benefit.
But for Those Who Need It, Mono- or Combo Therapy? Or None?
While the therapeutic advantages and disadvantages over replacement with pure levothyroxine [T4] or a mixture of T4 with triiodothyronine [T3] have generated a consensus in favor of levothyroxine alone, we still grapple with treated patients who complain of impaired well-being.
Despite thyroid hormone replacement’s clinical use for over 100 years and levothyroxine monotherapy for about 50 years, when to use a mixture, if ever, remains contentious despite numerous comparison trials.
A recent trial sponsored by the US military perhaps offers the branch point that affects prescribing. 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 measurements. Using a crossover design, they identified people who scored poorly on the quality-of-life assessment when taking levothyroxine alone, and then offered a T3-containing alternative, and saw the quality-of-life score improve. But again, measurements of well-being and a few cognitive symptoms remained mostly independent of the type of thyroid hormone that produced the therapeutic TSH.
As assessment of the thyroid has advanced from the basal metabolism test to the T4/T3U, and now to the TSH, each stage made the doctor appear to be more astute; but as the studies suggest, we may actually have become a little too astute, committing people to medication and lab testing with little gain.
We still prescribe quite a lot of thyroid hormone; most years it is among the most commonly prescribed medications 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% were for subclinical hypothyroidism, and 30% had a normal TSH, presumably post-op thyroidectomy users.
The mean TSH prompting a new treatment was 5.8 mIU/mL. About 60% of the new prescriptions came from primary care physicians and about 10% from endocrinologists.
While concerns about cardiac protection or lipid reduction could prompt some of the prescriptions, the data on negligible effects of thyroid on mind and mood suggest that perhaps we need more restraint.