Table 2.

Recommendations for the Design of Clinical Research Studies of Hypothyroidism-Associated Brain Fog

Population-specific issues

Focus on dissatisfied patients with persistent cognitive symptoms

Consider only including patients with little endogenous thyroid function

Ensure that research participants have well-documented and persistent hypothyroidism

Include relevant demographic and clinical parameters in research design and analysis (e.g., age, sex, gender, BMI, mood, sleep disturbances, exercise patterns)

Include well-characterized and well-matched control groups (e.g., people without thyroid disorders, and/or treated hypothyroid people without cognitive symptoms)

Research design issues

Determine a standard definition of hypothyroid-associated brain fog

Agree on a validated PRO instrument to quantitate hypothyroid-associated brain fog, include fatigue as an outcome

Utilize PROs in large-scale studies, but conduct smaller scale, more intensive studies for objective corroboration of cognitive deficits using validated tests and functional imaging techniques that are sufficiently sensitive and linked to cognitive domains likely to be affected by thyroid dysfunction

Determine minimally clinically important differences in outcome measures and adequately power clinical studies based on this

Conduct longitudinal studies to determine the trajectory of cognitive symptoms

Include control group in repeated-measures designs to account for practice effects

Clinical trials must be blinded and placebo-controlled

Assess patient preference for type of treatment (or overall satisfaction with treatment) as an outcome measure in clinical trials

Power clinical studies to analyze outcomes by serum T3 levels, Thr92Ala polymorphisms, and TPOAb titers, or stratify by these factors.

BMI, body mass index; PRO, patient-reported outcome; T3, triiodothyronine; TPOAb, thyroid peroxidase antibody.