Effects of Bupropion Sustained-Release on Sexual Functioning and Nocturnal Erections in Healthy Men

Many antidepressants are known to cause adverse sexual effects. Bupropion is an antidepressant with fewer reported adverse sexual effects. Studies of sexual side effects are often confounded by psychiatric and medical conditions affecting sexual function. In this study, the effects of bupropion on subjective and objective sexual functioning were measured in healthy men. Thirteen men without psychiatric or medical illness completed a 2-week, placebo-controlled, double-blind, crossover trial of bupropion sustained-release 300 mg/day. Subjects had a 1-week washout period between trials. Sexual function was measured using a validated, self-administered questionnaire and the RigiScan, an instrument measuring nocturnal penile tumescence and rigidity. No differences were found in self-reported sexual function, number of erections, total erection time, or penile rigidity in subjects taking bupropion compared with those taking placebo or baseline. These findings support that bupropion does not have subjective adverse sexual side effects and does not affect nocturnal erections in healthy men.

ADVERSE SEXUAL EFFECTS are commonly associated with antidepressant treatment. Although newer antidepressants such as selective serotonin reuptake inhibitors (SSRI) are usually well-tolerated, they are frequently associated with erectile dysfunction, orgasmic delay, and decreased libido.^1-3 Unlike most antidepressants, bupropion has been reported to cause minimal sexual dysfunction in the treatment of depression,^4-6 and open-label use suggests it may treat SSRI-induced sexual dysfunction.^7,8 The effects of bupropion on erectile function, however, have not been well-studied in placebo-controlled studies.

Multiple factors, including the inherent effects of depression on sexual function,⁹ concomitant medical conditions, and the high rates of erectile dysfunction in the general male population,¹⁰ complicate evaluating whether bupropion affects sexual function. Moreover, most studies of sexual function have relied only on subject self-reports, have used varied nonvalidated instruments for evaluation, and have not used any physiologic measures.

A recent study eliminated the effects of depression on sexual function by examining the effects of bupropion in nondepressed men with erectile dysfunction as a result of diabetes mellitus.¹¹ The investigators evaluated sexual satisfaction and nocturnal penile tumescence in patients at baseline and while they were taking placebo or bupropion. The investigators found that not only did sexual satisfaction improve, but that their subjects also had a greater number of nocturnal erections while taking bupropion compared with baseline.

The effects of bupropion on nocturnal erections could be mediated through changes in rapid eye movement (REM) sleep. For example, Nofzinger and associates¹² found that bupropion shortened REM latency and increased total REM sleep in a small sample (N = 7) of depressed men. This is an important finding because REM sleep accompanies nocturnal penile tumescence (NPT), and NPT may be diminished in depressed men.⁹ It is unclear, however, whether NPT changes in depressed men are related to REM sleep abnormalities or to an independent trait of depression.

The aim of this study was to eliminate medical and psychologic contributions to sexual dysfunction and then examine the sexual effects of bupropion. Subjects were evaluated under double-blind, placebo-controlled conditions in a randomized crossover trial of bupropion versus placebo.

Methods

Subjects

Male volunteers aged 21 to 55 years were recruited through a medical school newspaper advertisement. The institutional review board approved the study. All subjects were students or employees at the Medical University of South Carolina, signed an informed consent agreement, and were paid for their participation in the study. The subjects had no history of sexual or erectile dysfunction and were in good general physical and mental health. The subjects underwent a series of assessments, including a medical history, sexual history, physical examination, urine drug screen (for cocaine, marijuana, opiates, benzodiazepines, and amphetamines) and a Structured Clinical Interview for DSM-III-R.¹³ Subjects were excluded from the study if any of the following criteria were met: (1) a current axis I psychiatric disorder; (2) a history of major depressive disorder, dysthymia, an eating disorder, or psychotic disorder; (3) a history of substance abuse or alcohol abuse/dependence (by DSM-III-R criteria) within 6 months before the start of the screening period; (4) if they were taking any medication (any psychotropic within 2 months, H₁ or H₂ blocker within 2 weeks, β-blocker within 1 week, α₁ blocker within 1 week) that affects sexual function or receiving an investigational drug within the 30 days before the beginning of the screening period; (5) if they had any systemic illness that might alter erectile functioning; (6) if they had a positive urine drug screen; (7) and a history of toxicity, hypersensitivity, or seizure as a result of bupropion administration.

A double-blind, placebo-controlled, randomized crossover study design was used to examine the effects of bupropion sustained-release (SR) on sexual functioning and nocturnal penile tumescence and rigidity. Subjects were randomly assigned to receive either 14 days of bupropion SR 300 mg (two 150 mg tablets) or identical-appearing placebo tablets. Subjects took one tablet in the morning for 3 days and then took one tablet in the morning and one tablet in the early afternoon. Subjects were called after 7 days to ensure compliance. After completing the first phase of the study, subjects underwent a 7- to 10-day washout period. They then began a 14-day course of the opposite (bupropion SR or placebo) pills from the first phase of the trial. Subjects were told not drink alcohol during the 3 days prior to measurements. Subjects were told to continue usual caffeine-containing beverage consumption. No subject reported more than three caffeinated beverages per day. One subject smoked rarely (fewer than 3 cigarettes per week).

Measurements of penile tumescence and rigidity were evaluated with a commercially available home monitor, the RigiScan (Osbon Medical Systems, Augusta, GA). The RigiScan continuously measures penile tumescence and rigidity and computes cumulative data over time. The RigiScan obtains data from the tip and base of the penis through circular strain gauges. The RigiScan monitor has been described in previous studies.^14-17 Subjects were instructed in the proper use of the monitor in the office for use at home. Overnight measurements were obtained at baseline and during the last two nights of taking placebo and bupropion. All measurements were obtained between Monday and Thursday to exclude changes related to weekend sleep patterns. Subjects also completed the Change in Sexual Function Questionnaire (CSFQ)¹⁸ at baseline and at the end of placebo and bupropion use. The CSFQ is a validated questionnaire that rates sexual desire frequency and interest, arousal, sexual pleasure, and orgasm satisfaction. Responses are on an integer scale ranging from 1 to 5. Subjects were instructed to report adverse effects from medications or use of the RigiScan monitor. The total possible score on the CSFQ was 53. The subscore upper limits for sexual arousal/excitement were 15, for sexual desire, 25, and for orgasm satisfaction, 13. The subscore for sexual pleasure was omitted because the question pertains only to people in a current sexual relationship. This omission led to a lower possible total score for our subjects.

Data analysis

Data obtained using the RigiScan monitor was analyzed using RigiScan Summary Analysis software provided by the manufacturer. The software identifies an erectile event as a 20% increase in base loop circumference for a duration of at least 3 minutes. Data include the number of erectile events per session, the duration of erectile events, the average erectile rigidity during events, and the integrated time-intensity area measurements for both tumescence and rigidity, termed TAU (tumescence activity units) and RAU (rigidity activity units), respectively, at the tip and base of the penis. TAU is defined as the duration of an erectile event multiplied by the percentage increase in tumescence over baseline expressed as a decimal. The product is calculated on a point-by-point basis and summed over time with the RigiScan sampling points every 30 seconds. RAU is the product of the rigidity value expressed in decimal form (from 0.00 to 1.0) multiplied by the number of minutes spent at a given rigidity level summed across an entire event.¹⁵ Both TAU and RUA can be interpreted as area measurements of the region bound by time-tumescence and time-rigidity tracings, respectively.

Data from the CSFQ for total score and subscores specific for sexual desire, orgasm, and arousal/excitement were recorded. Data were analyzed by comparing CFSQ responses and RigiScan results at baseline, placebo, and bupropion conditions using a one-factor, univariate, repeated-measures analysis of variance. In addition, between-subject effects dependent on whether a subject received bupropion or placebo first were analyzed. All statistics were computed using SPSS 6.1 for Windows.¹⁹

Results

Sixteen men entered the study. Thirteen subjects (mean age, 30.2 ± 6.3 years; range, 22-43 years) completed the study. Two subjects were dropped from the study because of their noncompliance with the protocol. Another ended the study during baseline measurements when he experienced penile discomfort and urethral bleeding after using the RigiScan monitor. Urological evaluation was negative, and his symptoms resolved in two days. Four patients reported side effects during treatment with bupropion or placebo. One reported feeling "jittery" for 2 days while taking bupropion; another reported feeling "energized" during the first 2 days on placebo; one reported loss of smoking interest during bupropion; and one felt "exhausted" during the placebo arm.

Sexual function measured by the CSFQ total score was unchanged during the placebo or bupropion phase of the study (df = 2, F = 0.361, p = 0.701). Subscores for sexual desire-frequency (df = 2, F = 0.195, p = 0.824), desire-interest (df = 2, F = 2.894, p = 0.077), arousal (df = 2, F = 0.342, p = 0.403), and orgasm satisfaction (df = 2, F = 0.688, p = 0.513) also showed no significant differences. Means and standard deviations of sexual function total score as well as questionnaire subscores are reported in Table 1. Between-subject effects dependent on whether a subject was randomly assigned first to placebo or bupropion also showed no significant differences for total score (df = 1, F = 0.069, p = 0.797), sexual desire-frequency (df = 1, F = 0.340, p = 0.572), sexual desire-interest (df = 1, F = 0.333, p = 0.575), arousal (df = 1, F = 2.111, p = 0.174), or orgasm satisfaction (df = 1, F = 1.094, p = 0.318).

Table 1

Mean RigiScan penile rigidity and tumescence measurements and comparisons among measurements are reported in Table 2. There were no significant differences while subjects were taking bupropion compared with baseline or placebo in terms of the number of erection events per night (df = 2, F = 0.811, p = 0.457), erections per 100 minutes of sleep (df = 2, F = 0.939, p = 0.406), erectile event duration (df = 2, F = 0.486, p = 0.621), time erect per 100 minutes of sleep (df = 2, F = 0.170, p = 0.845), average erectile rigidity-base (df = 2, F = 0.343, p = 0.713), average erectile rigidity-tip (df = 2, F = 0.022, p = 0.978), RAU-base (df = 2, F = 0.553, p = 0.583), RAU-tip (df = 2, F = 0.470, p = 0.631), TAU-base (df = 2, F = 1.267, p = 0.301) and TAU-tip (df = 2, F = 0.175, p = 0.841). Again, data were analyzed to determine whether there were between-subject effects depending on their initial randomization to placebo or bupropion, and no significant differences were found for the number of erections per night (df = 1, F = 0.037, p = 0.850), erections per 100 minutes of sleep (df = 1, F = 0.642, p = 0.440), total erectile event duration (df = 1, F = 0.000, p = 0.999), time erect per 100 minutes of sleep (df = 1, F = 0.122, p = 0.734), average rigidity-base (df = 1, F = 1.576, p = 0.235), average rigidity-tip (df = 1, F = 0.014, p = 0.907,), RAU-base (df = 1, F = 0.214, p = 0.652), RAU-tip (df = 1, F = 0.026, p = 0.875), TAU-base (df = 1, F = 0.388, p = 0.546), or TAU-tip (df = 1, F = 0.162, p = 0.695).

Table 2

Discussion

The findings support that usual clinical doses of bupropion for 2 weeks have little to no effect on sexual function in healthy male subjects without psychiatric or medical disease. This was true for self-reported arousal/excitement, orgasm satisfaction, and sexual desire, as well as for physiologic measures of nocturnal penile tumescence and rigidity. The baseline results obtained using the CSFQ are comparable to previously published means for normal subjects.¹⁸ Baseline RigiScan results are also comparable to data published in earlier studies of normal subjects.^{15, 16}

This study did not corroborate a previous report²⁰ suggesting that bupropion has prosexual effects. The study by Modell and associates,²⁰ however, was open-label and studied depressed patients. If bupropion has prosexual effects, it may only be evident in depressed patients. Bupropion SR, however, did not cause erectile dysfunction, orgasm delay, or decrease in sexual desire. This is in contrast to the SSRIs, which seem to cause alterations in orgasm, erectile functioning, and libido.^1-3 Our findings corroborate reports that bupropion does not delay orgasm⁶ or adversely effect erectile response.^{4, 11} Most likely, normal baseline sexual functioning reported by our subjects at baseline on the CSFQ made measurable improvement in sexual function difficult. Similarly, normal levels of baseline nocturnal erectile function and rigidity may have left little room for improvement.

Evaluating healthy men allows for the isolation of the effects of bupropion from many of the psychologic and physiologic factors that complicate the evaluation of an individual's sexual function. This study shows that bupropion does not cause antidepressant-induced sexual dysfunction in men without the complicating factors of a psychiatric disorder or preexisting erectile dysfunction.

There are several limitations to the study. First, the sample size was small, but using subjects as their own control partially mitigates this problem. A larger sample may have revealed differences. Second, crossover studies may have the potential for "carryover" effects. In this study, these effects were minimized by the use of a washout period between bupropion and placebo trials. Third, our study did not include electroencephalographic measures of sleep, and we were therefore unable to analyze bupropion's effects on REM sleep, a sleep stage often associated with nocturnal penile tumescence. It is unclear whether REM sleep defects in depression are related to NPT abnormalities. NPT abnormalities, however, may be trait-related to depression in men, and these abnormalities do not resolve when depression remits with cognitive therapy.¹² Moreover, nocturnal erections remain a proxy measure of erectile function during sexual intercourse. Fourth, we did not obtain plasma samples to corroborate bupropion use, although subjects claimed they took medication as scheduled. The nocturnal tumescence and rigidity results were not adjusted for age, but given the small range of subject ages and the emphasis on within-subject effects of our analysis, age-related changes were not likely a significant factor.

This study did not examine the effects of bupropion in older men, and the findings cannot be extrapolated to women. Significant changes in erectile or sexual function may have also been limited by the period of time that subjects were receiving bupropion. A longer study may have shown beneficial or adverse effects, although a previous study of nefazodone, buspirone, and trazodone on nocturnal penile tumescence found changes over shorter drug administration periods.²¹ The administration of bupropion for longer than 2 weeks may yield different results.

In conclusion, our findings substantiate earlier studies that found a lack of significant adverse sexual effects with the use of bupropion. Bupropion seems to be a reasonable drug to switch to when others cause sexual dysfunction. A study evaluating the effects of bupropion or SSRIs on erectile function in depressed men is warranted.

Acknowledgment

Many thanks to Randy B. Holton for his expert administrative assistance.