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Abstract:
Major depression (MD) is one of the most common psychiatric disorders,
severely affecting the quality of life of millions of people worldwide.
Despite the availability of several classes of antidepressants,
treatment efficacy is still very variable and many patients do not
respond to the treatment. Clomipramine (CMI), a classical and widely
used antidepressant, shows widespread interindividual variability of
efficacy, while the environmental factors contributing to such
variability remain unclear. We investigated whether chronic stress
modulates the bio-distribution of CMI, and as a result the behavioral
response to CMI treatment in a mouse model of chronic social defeat
stress (CSDS). Our results show that stress exposure increased
anxiety-like and depressive-like behaviors and altered the stress
response. Chronic defeat stress furthermore significantly altered CMI
bio-distribution. Interestingly, CMI bio-distribution highly correlated
with anxiety-like and depressive-like behaviors only under basal
conditions. Taken together, we provide first evidence demonstrating that
chronic stress exposure modulates CMI bio-distribution and behavioral
responses. This may contribute to CMI's broad interindividual
variability, and is especially relevant in clinical practice.
