Is Hypothyroidism-Depression Link as Strong as We Think?

There was a link between hypothyroidism and clinical depression, although the association was modest and possibly limited to women, according to a systematic review and meta-analysis.

The meta-analysis of 25 studies (n=348,014 participants) found a modest link between hypothyroidism and clinical depression overall (OR 1.30, 95% CI 1.08-1.57), reported Christopher Baethge, MD, of the University of Cologne in Germany, and colleagues.

Subgroup analyses found depression was more strongly associated with overt hypothyroidism (OR 1.77, 95% CI 1.13-2.77) than with subclinical hypothyroidism (OR 1.13, 95% CI 1.01-1.28), suggesting a dose-effect relationship, they stated in JAMA Psychiatry.

And the association was strongest in females (OR 1.48, 95% CI 1.18-1.85) and non-significant in males (OR 0.70, 95% CI 0.40-1.25), the authors said.

“In this systematic review and meta-analysis, the effect size for the association between hypothyroidism and clinical depression was considerably lower than previously assumed, and the modest association was possibly restricted to overt hypothyroidism and female individuals,” Baethge’s group wrote.

“It may be time to reconsider the paradigm of a strong connection between hypothyroidism and depression,” they added. “The results of other groups and our own findings indicate the contribution of hypothyroidism to the pandemic of depression is probably small. This is good news for patients with hypothyroidism or, in particular, with thyroid autoimmunity. In counseling, we may not be able to rule out depression as a comorbidity, but it is not looming large as a very likely threat.”

The study also found a weak and “inconclusive” link between autoimmunity, defined as thyroid peroxidase antibody positivity, and clinical depression (OR1.24, 95% CI 0.89-1.74). “Possibly, it is not the disturbance of the immune system that explains the comorbidity. Hypothyroidism may work differently,” the researchers said, noting that many chronic disorders increase the risk for depression in an unspecified way.

“Regarding research, it appears autoimmunity is not a forceful driver of affective symptoms,” they added. “A more promising link seems to be the level of thyroid hormones and disturbances of the hypothalamic pituitary adrenal/hypothalamic pituitary thyroid axis.”

The meta-analysis included epidemiological and population-based studies on the association of hypothyroidism and depression. These studies provided laboratory diagnoses, International Statistical Classification of Diseases and Related Health Problems diagnoses, or Diagnostic and Statistical Manual of Mental Disorders diagnoses of hypothyroidism and/or clinical depression.

Two reviewers independently extracted data and evaluated the studies based on the Newcastle-Ottawa Scale. Odds ratios were calculated in random-effects meta-analyses. The prespecified primary outcomes were the association of clinical depression with either hypothyroidism or autoimmunity.

Baethge and colleagues noted their results were at odds with a 2018 meta-analysis that reported a substantial association of subclinical and clinical depression with hypothyroid autoimmunity (OR 3.31). and those authors estimated that each year, more than 20% of patients with autoimmune thyroiditis experience depression.

However, the 2018 meta-analysis had some important limitations, Baethge’s group explained, such as the “combination of population-based studies with results from outpatient clinics, with their bias toward more severely affected patients. Since the authors associated thyroid status with any change of depression scores, including and especially changes below cutoffs for clinically relevant depression, the practical significance of the results is uncertain,” they said.

Limitations to the current study included the fact that only four of the analyzed studies reported results by sex, and several studies adjusted for sex, so the finding of a stronger association between hypothyroidism and depression for women could be a “false positive,” they said.

Another limitation was the varying designs and methodologies of the studies analyzed, as most studies consisted of random samples or complete registers of a population, but others recruited participants from a primary or ambulatory care setting, possibly introducing biases. However, leaving out such studies did not substantially change the results, they said.

In addition, some studies included patients taking thyroid medication, which could have blurred an association of underlying hypothyroidism with depression. However, when the researchers contrasted studies with and without patients taking thyroid medication, they found a stronger association with medication. “Therefore, in these studies, thyroid medication may be an indicator of severe thyroid disorder rather than a successful treatment of depression,” they said.

Last Updated September 15, 2021