In a prospective and naturalistic setting, two samples representing 209 depressed inpatients were assessed for thyroid functioning at admission before antidepressant treatment, and for depression before and after 1 month of antidepressant treatment. We hypothesized that serum thyroid-stimulating hormone (TSH) elevation > or = upper 25th percentile of the normal reference range is associated with poorer response to antidepressant therapy and differences between tricyclic antidepressants (TCA) and other antidepressants. Screening for mild thyroid failure defined as serum TSH concentrations > or = upper 25th percentile of the normal range may provide clues to the clinician. Such patients have a more severe form of depression and a slower or impaired response to antidepressant therapy. It is also possible that they would benefit preferentially from TCA rather than other antidepressants.