Sexual dysfunction in clinically stable patients with bipolar disorder receiving valproate.

AIM: This study evaluated the prevalence of sexual dysfunction in patients with bipolar disorder, while receiving valproate monotherapy.
MATERIALS AND METHODS: Sixty-three clinically stable patients with bipolar disorder were evaluated on the Arizona sexual experience scale (ASEX), Udvalg for Kliniske Undersogelser (UKU) other side effect subscale and brief adherence rating scale.
RESULTS: The mean age of the study sample was 38.84 (standard deviation: 12.49) years. About three-fourth of the participants were male (76.2%). About one-fourth (28.6%) were found to have sexual dysfunction as per the ASEX. In terms of dysfunction in specific domain of sexual functioning, depending on the cut-off used, problem with sexual desire varied from 13.33% to 35.41% among males and 6.66%-46.66% in females. Erectile dysfunction was seen in 13.33%-31.25% of males and difficulty in vaginal lubrication was reported by 13.33%-26.66% of females. When those with and without sexual dysfunction as per the ASEX were compared, it was seen that those with sexual dysfunction had significantly longer duration of illness, higher prevalence of abnormal blood pressure and higher mean scores on the UKU other side effect subscale. Both the groups did not differ on other clinical variables.
CONCLUSION: A significant proportion of patients receiving valproate experience sexual dysfunction. Higher prevalence of sexual dysfunction was associated with longer duration of illness, higher prevalence of abnormal blood pressure, and higher mean scores on UKU other side effect subscale. Copyright:

INTRODUCTION

Sexual dysfunction is an important side effect of psychotropic medications, which can often lead to poor quality of life and poor medication compliance.[1] Almost all psychotropic medications are linked to sexual side effects. Although, it is well known that valproate and its congeners are associated with various hormonal side effects such as hyperandrogenism, polycystic ovary/polycystic ovarian syndrome, menstrual disorders, and ovulatory failure among women and abnormalities in androgens levels and sperm motility in men.[2] The effects of valproate on sexual hormones also suggest reduction in the serum testosterone levels and follicular stimulating hormones.[34] Despite these well-known hormonal side effects with valproate, little is known about sexual side effects associated with valproate. Some of the studies which have evaluated the sexual dysfunction among patients of epilepsy receiving valproate suggest the incidence of sexual dysfunctions in the form of hyposexuality[5] and erectile dysfunction to be associated with the use of valproate.[6]

One study compared the sexual functioning of patients with epilepsy receiving carbamazepine and valproate suggested that 48.1% of patients receiving valproate had erectile dysfunction and 51.9% of patients receiving carbamazepine reported the same, with no statistically significant difference between the two groups.[7] Both the groups also did not differ in terms of orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. However, higher proportion of patients on valproate reported a reduction in sexual desire. However, an important limitation of this study was it was based on a self-designed scale.[7]

In general, there is a lack of data on the incidence and prevalence of sexual dysfunction associated with the use of valproate, especially among patients with bipolar disorder (BD), receiving the same.

Valproic acid and valproate are among the most commonly used mood stabilizers among patients with BD.[8] Considering the frequent use of valproate in patients with BD and other psychiatric disorders, it is important to evaluate the prevalence of sexual dysfunction in these patients. Accordingly, this study is aimed to evaluate the prevalence of sexual dysfunction among BD on monotherapy with valproate.

MATERIALS AND METHODS

This cross-sectional study was conducted in the outpatient setting of a tertiary care teaching institute. The study was approved by the ethics committee of the institute, in which it was conducted and all the participants were recruited after obtaining written informed consent. To be included in the study, the participants were required to be diagnosed with BD-I as per the DSM-IV criteria (as assessed by using MINI-PLUS), must be in clinical remission (i.e., Hamilton depression rating scale [HDRS] score of ≤7[9]) and Young Mania Rating Scale [YMRS] score ≤7[10]) and clinically stable (i.e., no change in medications at least in the past 3 months and a Global Assessment for Functioning scale score ≥70). Other inclusion criteria for the study were: age between 20 and 60 years, married and/or in a heterosexual relationship and receiving valproate/valproic acid for at least 6 months. The study was limited to only those patients who were married or in a stable heterosexual relationship to homogenize the study sample. Those with sexual dysfunction or hypersexuality before the onset of BD (based on the history provided by the patient) were excluded. Patients with comorbid substance dependence, currently using the substance, organic brain syndrome, intellectual disability, spinal cord lesion, and stroke were excluded from the study. Patients with chronic physical illnesses such as hypertension, diabetes mellitus, and hypothyroidism were not excluded. However, patients with fluctuation of blood pressure or fluctuation in blood glucose levels in the past 3 months were excluded. This was based on the history provided by the patient and the review of treatment records.

Patients receiving concomitant antidepressants, antipsychotics, phosphodiesterase inhibitors, or any other medications that could increase or decrease the sexual desire or sexual functioning were also excluded.

The study participants were recruited by convenient sampling technique during their routine follow-up. Sexual dysfunction was assessed using Arizona sexual experience scale (ASEX) Questionnaire.[11] In addition, different types of sexual dysfunction (decreased/increased libido, delayed orgasm, lack of orgasm, decreased vaginal lubrication, increased sexual desire, erectile dysfunction, and premature ejaculation) was recorded in the form of “present” or “absent,” based on a semi-structured interview with the patient and spouse/partner wherever available.

Brief Adherence Rating Scale (BARS)[12] was used to evaluate the medication adherence in the previous month. Udvalg for Kliniske Undersogelser (UKU)[13] side effect rating scale was used to assess other side effects of valproate.

Residual psychopathology was rated on HDRS[9] and YMRS.[10]

ASEX is a short 5 items, self-report questionnaire, which is used to evaluate the sexual dysfunction associated with the use of psychotropic medications. It evaluates sexual dysfunction in five domains, i.e., drive, arousal, penile erection/vaginal lubrication, ability to reach orgasm, and satisfaction from orgasm. Each item of ASEX is rated on a 6-point scale, with higher scores suggestive of the higher level of sexual dysfunction. Clinical sexual dysfunction is indicated by a total score of ≥19 or a score of ≥5 on any one item or a score of ≥4 on any 3 items of ASEX. The scale has good internal consistency (alpha value − 0.9) and excellent test-retest reliability (0.8–0.89).[11] For the current study, the Hindi translated version, which is available, was used.

BARS[12] is a clinician-administered scale to record medication adherence. Medication adherence is rated based on the number of days and the amount of medication missed and also in the form of overall medication adherence by using a visual analog scale.

UKU side effect rating scale[13] is a comprehensive scale to assess side effects associated with psychotropics. It has adequate psychometric properties and has been used extensively among patients with BD and schizophrenia.

Analysis of the data analysis involved the calculation of mean and standard deviation (SD) with range for continuous variables and frequency and percentages for categorical variables. Comparisons of continuous variables were made using t-test or the Mann–Whitney “U” test. Ordinal and nominal variables were compared by using the Chi-square test and Fisher's exact test. Yate's correction was used, when needed.

RESULTS

The study included 63 participants, of which 18 (28.6%) were found to have sexual dysfunction as per ASEX.

The mean age of the study sample was 38.84 (SD: 12.49) years and the mean number of years of education was 11.69 (SD 3.73) years. About three-fourth of the participants were male (76.2%). The majority of the participants were currently married (85.7%), from joint families (60.3%) of urban background (61.9%). When those with and without sexual dysfunction as per ASEX were compared, no significant difference was seen between the two subgroups on any of the demographic variables.

The mean age of onset of BD was 26.05 (SD: 9.79) years and the mean duration of illness at the time of assessment was 153.54 (SD: 107.87) months. Comorbid substance dependence in the past was present in 11 (17.5%) participants and comorbid physical illness was present in 7 (11.1%) of the participants. The mean HDRS and YMRS scores were 0.95 (1.145) and 0.48 (1.13), respectively. The mean Global Assessment of Functioning score for the study sample was 89.07 (SD: 7.35).

When those with and without sexual dysfunction as per the ASEX were compared, it was seen that those with sexual dysfunction had a significantly longer duration of illness, higher prevalence of abnormal blood pressure, and higher mean scores on UKU other side effects subscale [Table 1]. Both groups did not differ on other clinical variables.

Table 1

Sociodemographic and clinical profile of study sample

Variables	Mean (SD)/n (%)			t/χ2 (P)
	Whole sample (n=63)	With sexual dysfunction (n=18)	Without sexual dysfunction (n=45)
Age (years)	38.84 (12.49)	41.44 (11.84)	37.80 (12.72)	1.04 (0.29)
Gender
Male	48 (76.2%)	12 (66.7%)	36 (80%)	1.26 (0.26)
Female	15 (23.8%)	6 (33.3%)	9 (20%)
Marital status
Single	9 (14.3%)	2 (11.1%)	7 (15.6%)	0.003$ (0.955)
Married	54 (85.7%)	16 (88.9%)	38 (84.4%)
Education (years)	11.69 (3.73)	11.22 (3.77)	11.89 (3.88)	0.63 (0.52)
Family type
Nuclear	25 (39.7%)	6 (38.9%)	18 (40%)	0.242 (0.623)
Joint/extended	38 (60.3%)	12 (66.6%)	27 (60%)
Locality
Rural	24 (38.1%)	7 (38.9%)	18 (40%)	0.007 (0.935)
Urban	39 (61.9%)	11 (61.1%)	27 (60%)
Age of onset of bipolar disorder	26.05 (9.79)	26.55 (9.84)	24.77 (9.81)	0.648 (0.519)
Duration of illness (months)	153.41 (107.87)	208.88 (123.98)	131.22 (93.24)	2.71 (0.009)**
Comorbid substance dependence in the pasta	11 (17.5%)	3 (16.66%)	6 (13.33%)	0.000$ (1.00)
Comorbid physical illnessb	7 (11.1%)	6 (13.33%)	1 (5.55%)	0.197$ (0.657)
HDRS total	0.95 (1.45)	1.5 (2.06)	0.73 (1.07)	336.5@ (0.246)
HDRS after subtracting the sexual dysfunction item	0.84 (1.22)	1.27 (1.63)	0.66 (0.97)	330.5@ (0.202)
YMRS total	0.48 (1.13)	0.50 (1.47)	0.47 (0.99)	384.0@ (0.651)
GAF total	89.07 (7.35)	86.88 (7.76)	89.95 (7.08)	1.15 (0.13)
BARS total	96 (12.80)	92.61 (17.26)	97.35 (10.45)	1.33 (0.186)
ASEX total score	14.47 (5.45)	21.27 (3.51)	11.75 (3.28)	10.21 (<0.001)***
Mean height (cm)	166.02 (7.74)	163.87 (8.84)	166.88 (7.17)	1.40 (0.165)
Mean weight (kg)	74.38 (14.5)	72.96 (9.82)	74.94 (16.06)	0.48 (0.62)
BMI	27.06 (5.50)	27.31 (4.15)	26.96 (6.00)	0.22 (0.82)
Abnormal BMI (i.e., BMI >25)	38 (60.31%)	12 (66.66%)	26 (57.77%)	0.424 (0.515)
Mean waist circumference	96.5 (12.39)	97.25 (10.45)	96.21 (13.55)	0.298 (0.766)
Waist circumference above the cut off (>90 for males, >80 for females)	48 (76.2%)	15 (83.33%)	33 (73.33%)	0.709 (0.40)
Mean systolic BP	123.56 (14.20)	127.22 (14.29)	122.09 (14.06)	1.30 (0.19)
Mean diastolic BP	82.09 (10.30)	83.00 (8.00)	81.73 (11.15)	0.43 (0.66)
Abnormal blood pressure (systolic≥130 and/or diastolic≥85)	31 (49.2%)	13 (72.22%)	18 (40%)	5.34 (0.021)*
Mean number of tablet per day	1.36 (0.67)	1.27 (0.57)	1.40 (0.72)	0.64 (0.52)
Dose of valproate mg/d	1010.31 (231.95)	958.33 (214.37)	1031.1 (237.71)	1.12 (0.264)
Duration of valproate (months)	46.67 (45.44)	61.44 (51.28)	40.95 (41.86)	−1.65 (1.10)
Adverse effect profile as per UKU
Psychic	0.81 (1.35)	0.64 (1.06)	1.22 (1.86)	349.5@ (0.343)
Neurologic	0.13 (0.38)	0.22 (0.54)	0.08 (0.28)	371.5@ (0.350)
Autonomic	0.21 (0.70)	0.50 (1.15)	0.09 (0.35)	340.0@ (0.07)
UKU others total	2.68 (3.03)	5.50 (4.06)	1.55 (1.42)	160.5@ (<0.001)***
UKU total excluding sexual dysfunction	2.61 (3.00)	5.33 (4.14)	1.53 (1.37)	176.5@ (<0.001)***

aComorbid substance dependence in the past: Without sexual dysfunction group: Only alcohol dependence (n=2), Only tobacco dependence (n=3), both alcohol and tobacco dependence (n=2), With sexual dysfunction group: Only alcohol dependence (n=2), only tobacco dependence (n=1), both alcohol and tobacco dependence (n=1), bComorbid physical illness: Without sexual dysfunction group: diabetes mellitus (n=1), hypertension (n=4), hypothyroidism (n=1), With sexual dysfunction group: Hypertension (n=1), hypothyroidism (n=1), seizure disorder (n=1). BMI – Body mass index; HDRS – Hamilton Depression Rating Scale; ASEX – Arizona Sexual Experiences Scale; YMRS – Young Mania Rating Scale; GAF – Global Assessment of Functioning; BP – Blood pressure; UKU – Udvalg for Kliniske Undersogelser; BARS – Brief Adherence Rating Scale; $Chi-square with Yate’s correction, @Mann Whitney U Test, *P<0.05; **P<0.01;***P<0.001

When the sexual dysfunction was assessed in the form of ASEX score of ≥4 on at least 1 domain of ASEX, 47.62% of the participants fulfilled this criterion. In terms of the type of sexual dysfunction, among both, the genders decrease in sexual derive was the most common type of sexual dysfunction. The second most common type of sexual dysfunction among males was the problem in penile erection, whereas in females, there was equal prevalence of decreased in sexual drive and arousal. There was no significant difference between the two genders in terms of the type of sexual dysfunction, except for the fact that there was a trend for the higher prevalence of problems with arousal among females [Table 2]. When the cut-off score of ≥5 for each domain was used for the presence of sexual dysfunction, difficulty in reaching orgasm and lack of satisfaction with orgasm were the most common form of sexual functions in males, however, none of the female patients reported problems with orgasm. Among females, the most common sexual dysfunction was problem with vaginal lubrication [Table 2].

Table 2

Sexual dysfunction as per Arizona Sexual Experiences Scale

Variables Sexual dysfunction as per ASEX	Males (n=48), n (%) Scoring≥4 on the item	Females (n=15), n (%) Scoring≥4 on the item	χ2 (P)
Drive	17 (35.41)	7 (46.66)	0.61 (0.43)
Arousal	11 (24.44)	7 (46.66)	3.15 (0.07)
Penile erection/vaginal lubrication	15 (31.25)	4 (26.66)	0.00 (0.988)
Ability to reach orgasm	11 (24.44)	2 (13.33)	0.18 (0.663)
Satisfaction with orgasm	11 (24.44)	2 (13.33)	0.18 (0.663)
Dysfunction in>1 domain	16 (33.33)	8 (53.33)	1.93 (1.63)
Variables Sexual dysfunction as per ASEX	Males (n=48), n (%) Scoring≥5on the item	Females (n=15), n (%) Scoring≥5on the item	χ2 (P)
Drive	6 (13.33)	1 (6.66)	0.20 (0.87)$
Arousal	5 (10.41)	3 (6.7)	FE=0.38
Penile erection/vaginal lubrication	6 (13.33)	2 (13.33)	0.00 (0.93)$
Ability to reach orgasm	8 (17.77)	0	1.55 (0.21)$
Satisfaction with orgasm	8 (17.77)	0	1.55 (0.21)$
Dysfunction in>1 domain	8 (17.77)	2 (13.33)	0.00 (0.95)$

$Chi-square with Yate’s correction. FE – Fischer’s exact value; ASEX – Arizona Sexual Experiences Scale

In terms of other side effects as assessed by the UKU side effect scale, which could influence the sexual functioning were evaluated, weight gain was the most commonly reported side effect among both the genders (males −56.25%; females −80%). Among males, weight gain was followed by erectile dysfunction (33.33%), orgasmic dysfunction (24.44%), and ejaculatory dysfunction (18.75%); whereas in females, weight gain was followed by dry vagina (26.66%), increased sexual desire (13.33%) and decreased sexual desire (13.33%).

On semi-structured interview, before assessment on ASEX, out of the 18 patients who had sexual dysfunction as per ASEX, only five patients, reported the same on their own and when asked, whether they discussed the same with their treating psychiatrist, only 6 answered in affirmation. When asked to report the type of sexual dysfunction experienced, erectile dysfunction (17.77%) was the most common complaint in males. Females most commonly reported decreased libido (13.33%). Very few patients were distressed with their sexual dysfunction (males −15.55%; females −6.66%), neither did they face any adverse comments from their partner (males −95.56%; females −100%). Among the causes, sexual dysfunction was most commonly attributed to medication (males −13.33%; females −6.66%), and some of the patients did intermittently discontinue the valproate due to sexual dysfunction. However, these variables did not differ significantly between subjects of either gender.

In terms of treatment adherence as assessed on BARS, a small proportion of the patients had poor adherence to medication, but adherence did not differ significantly between those with and without sexual dysfunction [Table 3].

Table 3

Comparison of treatment compliance of patients with and without sexual dysfunction as per Arizona Sexual Experiences Scale

Clinical profile of patients Adherence as per BARS	Mean (SD)/n (%)			t/χ2 (P)
	Whole sample (n=63)	With sexual dysfunction (n=18)	Without sexual dysfunction (n=45)
Number of days on which patient did not take medications
<7	59 (93.7%)	16 (88.9%)	43 (95.6%)	FE=0.57
7-13	4 (6.3%)	2 (11.1%)	2 (4.4%)
Took less than the prescribed dose
Never/almost never	55 (87.3%)	14 (77.8%)	40 (88.88%)	FE=0.26
Missed few doses	8 (12.7%)	4 (22.2%)	5 (11.12%)
Percentage of medications taken in last 1 month	96 (12.80)	92.61 (17.26)	97.35 (10.45)	−1.33 (0.186)

BARS – Brief Adherence Rating Scale; SD – Standard deviation; FE – Fischer’s exact value

DISCUSSION

The present study evaluated the prevalence of sexual dysfunction in a sample of patients with BD on monotherapy with valproate by using ASEX. Previous studies which have evaluated the prevalence of sexual dysfunction in patients receiving valproate have mostly relied on self-designed scale among patients with epilepsy. The present study shows that 28.6% of patients of BD receiving valproate develop sexual dysfunction as per the ASEX. In terms of dysfunction in the specific domain of sexual functioning, depending on the cut-off used, the problem with sexual desire varied from 13.33% to 35.41% among males and 6.66%–46.66% in females. In terms of difficulty in arousal, the prevalence of dysfunction among males was 10.41%–24.44% and in females, it ranged from 6.66% to 46.66%. Erectile dysfunction was seen in 13.33%–31.25% of males and difficulty in vaginal lubrication was reported by 13.33%–26.66% of females. In terms of problems with orgasm, 17.77%–24.44% of males reported difficulty in reaching orgasm, and a similar percentage of males reported dissatisfaction with orgasm. When the ASEX score of ≥4 was used as a cut-off for each item, 13.33% of females reported difficulty in reaching orgasm and dissatisfaction with orgasm. However, when the ASEX score of ≥5 was used as a cut-off for each item, none of the females reported problems with orgasm. When the cut-off score of ≥4 was used for each domain for the presence of sexual dysfunction, 33.33% of males and 53.33% of females had dysfunction in more than one domain. However, when the cut-off score of ≥5 was used for each domain for the presence of sexual dysfunction, 17.77% of males and 13.33% of females had dysfunction in more than one domain. There are limited data on the prevalence of sexual dysfunction among patients receiving valproate. One study, which evaluated the sexual functioning of patients receiving valproate reported erectile dysfunction in 48.1% of patients,[7] whereas the prevalence of erectile dysfunction in the present study was 13.33%–31.25% of males. This difference in the prevalence could be due to the assessment method. Previous study relied on a self-designed scale, whereas the present study relied on ASEX, which is considered to be a standard scale to assess, sexual dysfunction among patients receiving psychotropics. As previous studies have not reported the prevalence of sexual dysfunction in other domains, it is not possible to compare the findings of the present study with the existing literature.

When the prevalence of sexual dysfunction in patients receiving valproate was compared with those receiving lithium, findings of the present study are comparable with a previous study which reported sexual dysfunction as per the ASEX score of ≥19 and other suggested cut-offs in 37% of patients receiving lithium.[14] When the sexual dysfunctions in various domains were compared with the previous study, it is apparent that the prevalence of the dysfunction in various domains is comparable for lithium and valproate.[14]

When the sexual dysfunction was assessed as per the UKU side effect scale, 10.41% and 13.33% of males and females respectively reported increased sexual desire. The prevalence of erectile dysfunction and orgasmic dysfunction as assessed by using the UKU side effect scale was comparable to that found with ASEX. Similarly, prevalence of vaginal lubrication was comparable as assessed on both the scales.

When the association of sexual dysfunction with demographic and clinical profile was evaluated, none of the variables, except for the longer duration of illness, abnormal blood pressure and higher prevalence of other side effects as assessed by using the UKU scale were associated with a higher prevalence of sexual dysfunction. These findings suggest that patients on valproate for a longer duration, those having comorbid hypertension and those experiencing other side effects should be regularly evaluated for the presence of sexual dysfunction. Sexual dysfunction was not associated with poor medication adherence in patients receiving valproate. Similar findings have been reported for patients developing sexual dysfunction while receiving lithium.[14]

The present study has certain limitations. These include small sample size and cross-sectional assessment. The small sample size was guided by difficulty in finding patients on monotherapy, as polypharmacy is a rule for patients with BD, rather than an exception. The study sample mainly comprised patients of BD, receiving valproate for a long duration. Accordingly, these findings cannot possibly be generalized to other groups, such as those recently started on valproate, receiving valproate for a short duration or receiving valproate as part of polypharmacy.

The study was limited to clinically stable patients on regular follow-up. Hence, the findings cannot be generalized to other group of patients receiving valproate. Due to the use of multiple comparisons, the possibility of a type I error is present. Valproate is known to cause hormonal disturbances. However, in the present study, hormonal assays were not done. Similarly, the association of prevalence of sexual dysfunction with serum valproate levels was not done. No effort was made to evaluate the relationship issues with the spouse, which can also influence the sexual relationship. No comparison group was included. Future studies must attempt to evaluate patients receiving valproate as monotherapy longitudinally along with carrying out hormonal assays and serum valproate levels to understand the relationship of valproate with sexual dysfunction.

CONCLUSION

The present study suggests that one-fourth of the patients on valproate experience sexual dysfunction. There is no difference in the prevalence of sexual dysfunction among subjects of either gender. Sexual dysfunction is seen in all the phases of the sexual cycle and many patients have dysfunction in more than one domain. Most of the patients who experience sexual dysfunction while receiving valproate, usually do not discuss with their treating clinician and are not distressed due to the same. Longer duration of illness is associated with the presence of sexual dysfunction. However, the prevalence of sexual dysfunction is not influenced by the sociodemographic variables, clinical variables, residual depressive and manic symptoms, dose and duration of use of valproate. Higher numbers of other side effects as assessed on UKU side effects are associated with higher prevalence of sexual dysfunction. Sexual dysfunction is not associated with poor medication adherence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.