Neural correlates of antidepressant-related sexual dysfunction: a placebo-controlled fMRI study on healthy males under subchronic paroxetine and bupropion

Abstract

Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning.

Figure 1

Study design. To each of the three randomization arms, six subjects were assigned.

Figure 2

(a) Group-averaged cumulative rating scores obtained from the five-item Massachusetts General Hospital Sexual Function Questionnaire (MGH SFQ). Overall, subjective sexual dysfunction was significantly (^*p<0.05) increased under paroxetine during the past week. A minimal cumulative score of 5 indicates increased sexual interest when compared with normal; ‘average' cumulative score of 10 indicates no change in sexual functioning compared with before (dashed black line); scores above 10 indicate decreased sexual functioning; the maximal cumulative score of 30 has the meaning of no sexual interest. (b) Group-averaged ratings for each subscale. MGH-SFQ subscales ratings indicate diminished (^*p<0.05) ability to get sexually aroused and to achieve orgasm under paroxetine when compared with enrollment, placebo (arousal and orgasm), and bupropion (orgasm only).

Figure 3

Significant treatment effects (p<0.05 FDR corrected) along the anterior cingulate gyrus as revealed by an appropriate omnibus F-test on treatment effects for placebo, bupropion, and paroxetine (for demonstration purposes, the threshold was lowered to p<0.005 uncorrected). Parameter estimates of modeled effects were extracted from the peak voxel of each cluster, that is, the subgenual anterior cingulate cortex (sgACC), the pregenual anterior cingulate cortex (pgACC), the anterior midcingulate cortex (aMCC), and the posterior midcingulate cortex (pMCC). Activation decreased under paroxetine when compared with placebo and bupropion in sgACC, pgACC, and pMCC. In aMCC, activation decreased under both drugs compared with placebo.

Figure 4

Statistical parametric maps (SPMs) and fMRI signal time courses extracted from three prototypical regions significantly associated with erotic visual stimulation with differential drug effects in an omnibus F-test (p<0.05 FDR corrected): midbrain with decreased activation under paroxetine, sublenticular extended amygdala (SLEA) with increased and prolonged activation under bupropion, and decreased activation under paroxetine; anterior midcingulate cortex (aMCC) with decreased activation under both drugs compared with placebo. The depicted SPMs are thresholded at p<0.005 uncorrected for demonstration purposes. Mean first eigenvariate values were extracted from the clusters for each subject and then averaged. ^*Significant difference at p<0.05 in a paired t-test of the fMRI signal at each time point.

Figure 5

Significant (p<0.05) correlations of fMRI activation in the pMCC region of interest (parameter estimates: placebo >paroxetine) with (a) increases in ratings of subjective sexual dysfunction under paroxetine relative to placebo and (b) with paroxetine blood levels.