Doubt about antidepressant-like effect

Dear Editor: Extensive studies have measured antidepressant-like effects of chemical compounds to discover new drugs for depression treatment or to clarify the molecular mechanisms of depression. Most useful anti-depressants including tricyclics, selective serotonin reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (NRIs), serotonin and noradrenaline re-uptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) exert antidepressant-like effects in forced swimming test (FST) in mice and rats [1]. However , it remains unanswered whether the observed antidepressant-like effects are real antidepressant effects as seen in those by antidepressant drugs used in clinic. Two questions emerge from this topic: the first question is whether the molecular signaling pathway of antidepressant-like effect is the same as that of antidepressant effect; the second question is whether all compounds having antidepressant-like effects can exert antidepressant effect in animal tests and in clinic. Major depression is a mental illness influenced by genetic and environmental factors. The pathophysiol-ogy of depression includes decreased concentration of monoaminergic transmitters, low levels of nerve growth factors, hyperactivation of the hypothalamic-pituitary-adrenal axis, impaired neuronal plasticity and reduced adult neurogenesis. The disease is chronic and mainly caused by long-term, severe life stress. Moreover, current antidepressant drugs need at least 3 to 4 weeks to correct these changes and improve depressive symptoms [2]. Although it may be an impossible quest to mimic major depressive disorders completely in rodents, many models have been established to reproduce the pathophysiology of depression in animals, among which the chronic mild stress (CMS) model has been widely used. The model can induce most of the neurobiological alterations of depression referred above and cause main symptoms of depression, including decreased responsiveness to rewards, anhedonia, decreased appetite and weight loss, which can be reversed by treatment with a wide spectrum of antidepressants for 2 to 4 weeks [3]. In fact, it was demonstrated in our experiment that 3 weeks of CMS procedures (various stimuli including restraint, forced swimming, wet cage, deprivation of food and water, reversal of light/dark cycle and tilted cage, Fig. 1A) were sufficient to induce depressive behaviors in tail suspension test (TST), FST, sucrose preference test (SPT) as well as novelty suppressed feeding test (NSFT) (Fig. 1B-E) [4-6] and induced physical impairment in mice. It required at least two weeks to reverse behavioral despair after the end of two-week treatment with fluoxetine (Fig. 1F-G). In our experiment, fluox-etine cannot ameliorate depressive symptoms acutely and antidepressant potential of 7-NI under CMS condition …