Early studies using the insulin tolerance test (ITT) in affective disorders reported a blunted GH response in some depressed patients. However, results from subsequent studies were less consistent. These discrepancies resulted in part from limited sample sizes causing diagnostic heterogeneity. In the present study we examined hormonal response patterns during the ITT in 25 bipolar patients (19 depressed and 6 hypomanic), 91 unipolar depressives, and 51 healthy volunteers to determine whether distinct neuroendocrine response patterns characterized specific diagnostic subgroups. We measured the glucose, GH, PRL, and cortisol responses during a 75-min ITT and observed a diminished cumulative GH response in bipolar hypomanic patients compared to bipolar depressives (P = 0.004) and healthy volunteers (P less than 0.001), and a larger cumulative GH response in bipolar depressives compared to unipolar patients (P = 0.02). No differences were observed in either PRL or cortisol responses among subject groups. The present findings suggest that GH responses during the ITT may be more complex than initially described and partially dependent upon affective disorder subtype. Thus, bipolar patients may have distinctive GH response patterns compared to those of unipolar depressives and healthy controls. Moreover, some of the difference observed in the GH response to the ITT may result from the phase of the manic-depressive illness. These data indicate differences in neuroendocrine substrates between affective disorder subtypes.