Pulse-dosing and conventional application of doxepin: Effects on psychopathology and hypothalamus-pituitary-adrenal (HPA) system

It has been shown that a single pulse-dosing (PD) dose of clomipramine improves depressive symptoms. However, so far PD and conventional (CONV) application of antidepressants have never been directly compared for an extended period. We performed a double-blind study of PD and CONV application of doxepin (DOX) in depressed patients. After a 1-week placebo treatment, nine patients in the PD group received 250 mg of DOX every 6 days and placebo on the other days until day 39. Ten patients in the CONV group received increasing dosages of DOX until day 7 and 250 mg DOX on the other days for 39 days. Three dexamethasone (DEX)-suppression/corticotropin-releasing hormone (CRH)-stimulation tests were completed: (1) during the initial placebo period; (2) on day 9; and (3) on day 21. In the PD group, scores on the Hamilton Rating Scale for Depression (HAM-D) differed from baseline only after day 36 (17.1 ± 7.0 vs. 22.7 ± 2.8, p < 0.03). In the CONV group, however, HAM-D scores improved significantly after 2 days (22.8 ± 7.2 vs. 26.5 ± 5.7, p < 0.02) and continued to improve until day 39 (7.3 ± 5.8). From day 25 to 39, there were significant differences between the HAM-D scores of the two groups. In the PD group, the decline of cortisol after DEX pretreatment was nonsignificant (NS) at both follow-up test occasions (35.9 ± 40.7 vs. 24.0 ± 20.7 vs. 23.6 ± 26.6 μg/mL). In the CONV group, a significant decrease was observed at the second test (61.8 ± 61.9 vs. 10.7 ± 4.2 vs. 19.8 ± 19 μg/mL, p < 0.05, respectively, NS). The area-under- the-curve cortisol response after CRH was attenuated in the PD group (5,667 ± 2,910 vs. 1,883 ± 2,178 vs. 2,239 ± 2,583 [arbitrary unit], p < 0.01, respectively, p < 0.01) and in the CONV group (5,710 ± 4,734 vs. 1,267 ± 2,053 vs. 445 ± 1,016 [arbitrary unit], NS, respectively, p < 0.02). We conclude that CONV application of DOX is clinically superior compared with PD and that both modes of application have attenuating effects on hypothalamus- pituitary-adrenal system activity.