Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects

Current available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects.