Evaluation of the 5α-reductase inhibitor finasteride on reproduction and gonadal development in medaka, Oryzias latipes.

5-α reductase (5αR) inhibitors have an anti-androgenic effect in mammals because they inhibit the conversion of testosterone to the potent androgen, dihydrotestosterone. Finasteride is a type-2 5αR inhibitor that is used as a human pharmaceutical for the treatment of prostate cancer, benign prostate hyperplasia and male pattern baldness. This study evaluated the impacts of finasteride (50, 500 and 5000µg/L) on the development and reproduction of medaka (Oryzias latipes) exposed continuously over multiple generations (F0, F1 and F2). The exposure was initiated with reproductively mature fish (F0 generation) and continued until the hatching of the F2 generation. There were no significant effects on survival, fecundity or fertility in the F0 (50, 500, 5000µg/L) and F1 (50, 500µg/L) generations. The F1 generation exposed to 5000µg/L exhibited significant mortality. Histopathology of the gonads demonstrated that medaka and pre-clinical species respond similarly to finasteride exposure. Intersex condition and maldeveloped gonads were observed in F0 generation males exposed to 5000µg/L and F1 generation males exposed to 500µg/L. F1 generation males exposed to 500µg/L displayed reduced gonadosomatic index with an increased incidence of testicular degeneration. Males in both generations exhibited an increased incidence of Leydig cell hyperplasia at concentrations ⩾500µg/L. F0 generation females exposed to 5000µg/L exhibited increased gonadosomatic index. An increased prevalence of accelerated post-ovulatory follicle involution was observed in females at concentrations ⩾500µg/L in both generations. The gonadal changes induced by finasteride support the idea that 5-α reductase inhibition impacts androgen signaling in fish. Results from this study are discussed in the context of differential expression of the androgen receptor between species of fish.

Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder.

BACKGROUND: The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. METHODS: Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). RESULTS: Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. CONCLUSIONS: These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.