Sex differences in pharmacokinetics of antidepressants

Abstract

Although the available pharmacokinetic evidence indicates that women should receive lower doses of antidepressants and men should receive higher doses, current guidelines do not recommend dose adjustment, because these sex differences are considered to be clinically insignificant. Unless we understand the link between pharmacokinetics and pharmacodynamics of antidepressants, it will be difficult to determine whether sex differences are of clinical importance or not. Thus, further systematic and particularly focused research is needed on sex differences in pharmacokinetics.

Sex differences in animal models of psychiatric disorders

“…Also, often, treatment response is affected by sex-dependent differences in baseline behaviour, whereas the response to psychotropic drugs masks sex differences post-treatment. Importantly, sex differences in response to psychotropic drugs, are often related to pharmacokinetic sex differences and this should be taken into account when results from animal and human studies are interpreted (Nabeshima et al, 1984; Andine et al, 1999;Shelnutt et al, 1999;Hodes et al, 2010;Kokras et al, 2011a).…”

“…Also, often, treatment response is affected by sex-dependent differences in baseline behaviour, whereas the response to psychotropic drugs masks sex differences post-treatment. Importantly, sex differences in response to psychotropic drugs, are often related to pharmacokinetic sex differences and this should be taken into account when results from animal and human studies are interpreted (Nabeshima et al, 1984; Andine et al, 1999;Shelnutt et al, 1999;Hodes et al, 2010;Kokras et al, 2011a).Behavioural sex differences usually result from sex differences in neural underpinnings and/or are linked with sex differences in brain structure, neurochemistry, neuroendocrinology and neurobiology (Cahill, 2006;Cosgrove et al, 2007;Solomon and Herman, 2009). Sex differences result from chromosome effects, organizational effects of sex hormones during development of the brain and/or activational effects of sex hormones (McCarthy et al, 2012).…”

Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice

“…Indeed, sex differences in response to ketamine in rodents are most likely dependent on the sex-specific levels of estrogen and progesterone, as it was recently reported that the female-specific rapid antidepressant effects of a low acute dose of ketamine were completely abolished in ovariectomized rats subjected to FST, but emerged again upon restoration of physiological levels of estrogens and progesterone [17]. Notably, sex differences in response to antidepressant treatments have been largely attributed to the sexdifferentiated pharmacokinetic disposition of psychotropic agents [41,42]. Following the demonstration by our lab and others that female mice and rats are more sensitive to the antidepressant effects of ketamine, Zanos et al (2016) most recently reported that sex differences in response to acute administration of this drug may be partly due to the sexdifferentiated metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) [43].…”

Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones

“…For instance, chronic fluoxetine improves extinction recall in females but not in males and facilitates extinction learning in low estrogen rats while having no effect on high estrogen rats (Lebrón-Milad, Tsareva, Ahmed, & Milad, 2013). In addition to fear extinction, sex differences have also been reported in the effect of antidepressants on stress and associative learning, as well as their overall pharmacokinetics; studies suggest that females respond better to selective serotonin reuptake inhibitors (SSRIs), a response that may be attributed to the known interactions between estrogen and serotonin (Dalla, Pitychoutis, Kokras, & Papadopoulou-Daifoti, 2010; Damoiseaux, Proost, Jiawan, & Melgert, 2014; Keers & Aitchison, 2010; Kokras, Dalla, & Papadopoulou-Daifoti, 2011; Leuner, Mendolia-Loffredo, & Shors, 2004). Interestingly, some of these effects have been associated with naturally cycling female sex hormones, which may be influencing the differences in therapeutic response to antidepressant pharmacotherapy (Frackiewicz, Sramek, & Cutler, 2000).…”