Research report
BMI, sex, and antidepressant response

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Abstract

Background

Investigators have examined potential mechanisms for the observed differences between men and women in antidepressant response. However, to date no studies have measured the impact of body mass index (BMI) on men's and women's response to selective serotonin re-uptake inhibitors or placebo.

Methods

We evaluated the response to antidepressants and placebo of 274 non-obese (BMI < 30) and obese (BMI > 30) depressed outpatients participating in Phase II–IV clinical trials. After categorizing men and women into their respective BMI groups, we measured the amount of change each group experienced from baseline to the final visit using the HAM-D-17 and MADRS ratings scales.

Results

Compared to women, men assigned to an antidepressant had a significantly lower mean total change on both the HAM-D-17 [non-obese, F(1,88) = 5.292, p = 0.024; obese, F(1,39) = 7.040; p = 0.012] and the MADRS [non-obese, F(1,66) = 4.049, p = 0.048; obese, F(1,27) = 8.631, p = 0.007]. In fact, obese men showed the smallest difference in antidepressant-placebo response. The results of the ANCOVAs indicated significant main effects of treatment (placebo vs. antidepressant), sex of the patient, and BMI category as well as a significant interaction between all three variables.

Limitations

Patients participating in clinical trials are not necessarily representative of the entire depressed population. In addition, our results include only SSRIs, not other antidepressants.

Conclusion

Compared to the rest of the depressed sample the subgroup of depressed obese men (n = 40) showed little or no therapeutic benefit with SSRI antidepressants. Although our findings may have important clinical implications, replication and further research is warranted in order to understand their underlying mechanisms and their pertinence to dosing strategies.

Introduction

In 1977, the Food and Drug Administration (FDA) recommended that women of reproductive age be excluded from participation in the early phases of drug development due to potential birth defect or life threatening risks. The FDA revised its policy in 1993, allowing these women to participate in clinical trials (Food and Drug Administration, 1993). Since the policy change, researchers have published numerous reports on potential sex differences in clinical pharmacology, with a focus on differences in absorption, distribution, and metabolism (Anderson, 2005, Beierle et al., 1999, Bies et al., 2003, Datz et al., 1987, Harris et al., 1995, Kando et al., 1995, Meibohm et al., 2002, Yonkers et al., 1992).

Investigators have established several key differences between men and women in the rate and/or degree of absorption (Kando et al., 1995, Yonkers et al., 1992). Women tend to secrete less gastric acid and empty both solids and liquids more slowly than do men (Datz et al., 1987, Kando et al., 1995). Though the exact mechanism for this phenomenon is unknown, Datz et al. (1987) relates the effect to the impact of progesterone and estradiol on the gastrointestinal tract.

Progesterone and estrogen also affect neurotransmitter synthesis, release, and reuptake, which in turn, alters mood and behavior, particularly in women (Frackiewicz et al., 2000, O'Malley et al., 1971). A study conducted by Schneider et al. (1997) suggested combining estrogen with traditional antidepressants to increase therapeutic effects.

In addition, the acid-based and lipophilic properties of a drug will determine the percentage of the drug that the gastrointestinal tract absorbs (Yonkers et al., 1992). Women tend to absorb certain agents more quickly than do men (Beierle et al., 1999, Harris et al., 1995), increasing the bioavailability of the drug (Yonkers et al., 1992). Antidepressants are lipophilic and have a strong affinity for adipose tissue, are distributed at greater volumes, and have longer half lives in women than in men. Since women typically have a higher percentage of adipose tissue and body fat compared to men, there is a tendency for females to demonstrate a greater volume of drug distribution (Greenblatt et al., 1987, Yonkers et al., 1992). In addition, a greater potential for storage exists in persons with less lean body mass. This may also underlie the observations of prolonged drug half-lives and increases in serum levels in women (Yonkers et al., 1992).

Several investigators have focused on women and men's response to antidepressants. The evidence has been mixed on whether or not sex differences exist. Some studies indicate that men respond to tricyclic antidepressants (TCAs), specifically imipramine, to a greater degree than do women (Dawkins and Potter, 1991, Kornstein et al., 2000, Prange et al., 1969), whereas women have been shown to have a more favorable response to selective serotonin re-uptake inhibitors (SSRIs) (Baca et al., 2004, Khan et al., 2005, Kornstein et al., 2000, Sagud et al., 2002). However, other reports have not supported these findings (Hildebrandt et al., 2003, Parker et al., 2003, Quitkin et al., 2002, Thiels et al., 2005, Wohlfarth et al., 2004).

Despite the inherent differences between men and women in body weight and body mass index (BMI), no studies have examined the effect that weight, specifically BMI, has on SSRI response in men and women. We conducted the current study to explore the impact of BMI upon the relative effects of SSRI medications in men and women.

Section snippets

Materials and methods

Between 1996 and 2003, the Northwest Clinical Research Center in Bellevue, WA conducted 29 randomized, double-blind, placebo-controlled antidepressant clinical trials with adult patients meeting DSM-IV criteria for unipolar depression (moderate to severe). After 15 of the trials, we obtained data on treatment assignment from the sponsoring pharmaceutical companies.

In these 15 trials, 274 depressed outpatients received either placebo or one of the following antidepressants: citalopram,

Statistical analysis

We used the statistical program SPSS version 12.0 for all analyses. We computed the mean change in HAM-D-17 and MADRS scores for men and women assigned to either an antidepressant or placebo with regards to BMI group (Table 2).

We then conducted three-way analysis of co-variances (ANCOVA) with sex (men, women), BMI category (non-obese, obese), and treatment group (antidepressant, placebo) as the independent variables and the mean change in total HAM-D-17 and MADRS scores as the dependent

Results

Table 1 contains demographic information and means for men and women assigned to either an antidepressant or placebo based on the BMI category. Using t-test analysis, we did not observe any significant differences between men and women assigned to either an antidepressant or placebo in either BMI category with the exception of age for non-obese males. The mean age for non-obese males receiving an antidepressant was significantly higher than that for non-obese males assigned to placebo, F(1,83) = 

Discussion

We aimed to assess the impact of body mass index upon men and women's response to antidepressants. When we examined the mean change in total HAM-D-17 and MADRS scores, obese men assigned to an antidepressant experienced minimal symptom reduction, whereas females assigned to an antidepressant displayed the greatest mean change in rating scale scores regardless of their reported BMI category.

Our analysis revealed several statistically significant findings. First, treatment group (antidepressant,

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