ORIGINAL RESEARCH & REVIEWS

Sexual Dysfunction and Mood Stabilizers in Long-Term Stable

Patients With Bipolar Disorder
Ana García-Blanco, MD, PhD,1 María P. García-Portilla, MD, PhD,2,3 Lorena de la Fuente-Tomás, PhD,2,3
María Batalla, MD,4 Mónica Sánchez-Autet, MD, PhD,5 Belén Arranz, MD, PhD,2,5 Gemma Safont, MD,2,6
Sergio Arqués, MD,7 Lorenzo Livianos, MD, PhD,4,8,9 and Pilar Sierra, MD, PhD4,8

ABSTRACT

Background: In addition to factors intrinsic to bipolar disorder (BD), sexual functioning (SF) can be affected by
extrinsic causes, such as psychotropic drugs. However, the effect of mood stabilizers on SF and quality of life
(QoL) is an underexplored research area.
Aim: To analyze SF in BD outpatients in euthymia for at least 6 months treated only with mood stabilizers and
the association between SF and QoL.
Methods: A multicenter cross-sectional study was conducted in 114 BD outpatients treated with (i)
lithium alone (L group); (ii) anticonvulsants alone (valproate or lamotrigine; A group); (iii) lithium plus
anticonvulsants (LþA group); or (iv) lithium plus benzodiazepines (LþB group). The Changes in Sexual
Functioning Questionnaire Short Form (CSFQ-14) was used. Statistical analyses were performed to
compare CSFQ-14 scores among the pharmacological groups. An adaptive lasso was used to identify po-
tential confounding variables, and linear regression models were used to study the association of the CSFQ-
14 with QoL.
Main Outcome Measures: Self-reports on phases of the sexual response cycle (ie, desire, arousal, and orgasm)
and QoL were assessed.
Results: The A group had better total SF scores than the L group and the LþB group. Relative to the A group,
the L and LþB groups had worse sexual desire; the L group had worse sexual arousal; and the LþA group and the
LþB group had worse sexual orgasm. Regarding sociodemographic factors, being female and older age were
associated with worse total SF and all subscale scores. Among all subscales scores, higher sexual arousal scores
were associated with better QoL.
Clinical Implications: Potential modified extrinsic factors such as psychotropic medication that can affect SF can
be addressed and adjusted to lessen side effects on SF.
Strengths & Limitations: Sample of patients with euthymic BD in treatment with mood stabilizers and no
antipsychotics or antidepressants, substance use as an exclusion criterion, and use of a validated, gender-specific
scale to evaluate SF. Major limitations were cross-sectional design, sample size, and lack of information about
stability of relationship with partner.
Conclusions: Lithium in monotherapy or in combination with benzodiazepines is related to worse total SF and
worse sexual desire than anticonvulsants in monotherapy. While the addition of benzodiazepines or anticon-
vulsants to lithium negatively affects sexual orgasm, sexual arousal (which plays a significant role in QoL) im-
proves when benzodiazepines are added to lithium. Anticonvulsants in monotherapy have the least negative

6
Received May 3, 2019. Accepted January 30, 2020. Department of Psychiatry, University Hospital Mutua Terrassa, University
1
La Fe Health Research Institute, Valencia, Spain; of Barcelona, Barcelona, Spain;
7
2
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Arnau Hospital, Valencia, Spain;
8
Madrid, Spain; Department of Medicine, University of Valencia, Valencia, Spain;
3 9
Department of Psychiatry, University of Oviedo, Oviedo, Spain; CIBERESP-17, Valencia, Spain
4
La Fe University and Polytechnic Hospital, Valencia, Spain; Copyright ª 2020, International Society for Sexual Medicine. Published by
5
Parc Sanitari Sant Joan de Deu, Barcelona, Spain; Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jsxm.2020.01.032

J Sex Med 2020;-:1e11 1

2 García-Blanco et al
effects on SF in patients with BD. García-Blanco A, García-Portilla MP, Fuente-Tomás L de la, et al. Sexual
Dysfunction and Mood Stabilizers in Long-Term Stable Patients With Bipolar Disorder. J Sex Med
2020;XX:XXXeXXX.
Copyright  2020, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Bipolar Disorder; Sexual functioning; Lithium; Mood Stabilizers; Quality of Life
INTRODUCTION
Sexual activity is a sensitive component of social functioning
and plays a crucial role in the quality of life (QoL) of patients
with mental disorders.1,2 Sexual dysfunction has a negative
impact on mental disorder in terms of treatment compliance and
prognosis.3,4 Although sexual difficulties are common in patients
with bipolar disorder (BD),5 research on this issue is limited
because it is methodologically complex.6 On the one hand,
sexual functioning (SF) may be affected by intrinsic factors
associated with both BD (affective symptoms, age at onset, BD
type, predominant polarity, metabolic syndrome) and socio-
demographic features (age, sex, or marital status) as well as
extrinsic factors such as psychotropic medication.7e10 While
intrinsic factors cannot be modified, extrinsic factors such as
drugs can be adjusted to lessen side effects on SF. On the other
hand, sexual response is composed of different sexual phases that
could be differentially affected: sexual desire (libido), sexual
arousal (excitement, vaginal lubrication, erectile function), and
sexual orgasm.11 Therefore, determining the effects of psycho-
tropic drugs on the different phases of sexual response (after
controlling for intrinsic factors) may help improve sexual
dysfunction in patients with BD and, consequently, their QoL.
Regarding the adverse effects of psychotropic drugs on SF,
combination therapy is the rule rather than the exception, with a
mean of about 3 drugs per patient.12 Previous studies have re-
ported an incidence of 59.1% for all antidepressants
combined13e15 and up to 45% for typical antipsychotics,16,17
but only a minority of those included mood stabilizers and
anxiolytic drugs.18 Long-term stable BD patients are usually in
maintenance treatment only with mood stabilizers. Therefore,
determining their effects in euthymic BD patients would be of
interest to improve SF. Our study recruited a sample of BD
patients in euthymia for at least 6 months treated only with
mood stabilizers, with no concomitant use of antipsychotics or
antidepressants.
An association between lithium and sexual dysfunction in BD
patients has been reported, but it is unclear what percentage of
patients and what phase of SF are affected.19 As for sexual desire,
previous research found an up to 50% decrease in clinically stable
lithium-treated patients with BD.20 30 percent of BD patients
attributed their sexual problems to the introduction of lithium.21
With regard to sexual arousal, rates of sexual dysfunction in
patients undergoing treatment with lithium alone vary from
5%22 to 14%.23 In addition, a high frequency of erectile prob-
lems has been documented.24 Other researchers have found
impaired SF only in less than 5% of BD patients.25 Aizenberg
et al found that 14% of BD patients receiving lithium alone
reported having difficulties with sexual arousal, that is, achieving
and maintaining an erection. Despite this, the impact of these
difficulties on global SF was limited.26 More recent studies
indicate that 37% of these patients met threshold criteria for
sexual dysfunction, which was significantly associated with a
lower level of overall functioning, a higher number of other
adverse effects with lithium, and poor medication compliance.23
In sum, data show that a relation may exist between lithium and
SF. However, at the same time, there is not a great deal of data
on this subject, and most studies are outdated.27
Coadministration of benzodiazepines was associated with a
significantly greater risk of reported sexual dysfunction (49%) vs
patients undergoing treatment with lithium alone (14%) or with
lithium in combination with other psychotropic drugs (17%).22
Conversely, a multicenter double-blind randomized comparative
study concluded that benzodiazepines did not affect SF.28 Sexual
disinhibition and improved sexual arousal linked to reduced
anxiety have been described with benzodiazepines.29 Thus, the
findings of studies analyzing the influence on SF of lithium alone
and in combination with benzodiazepines are inconclusive.18,30
Concerning the interference of anticonvulsants with SF, the
most significant effects related to valproate in women with BD
are severely decreased libido and anorgasmia.31 Fewer side effects
and even improvement of SF have been found with lamotrigine
but in epileptic patients.32,33 It is of note that most studies have
been conducted in patients with epilepsy, so their results cannot
be generalized to BD patients. Therefore, studies with anticon-
vulsants in monotherapy are needed in BD patients.34
Another important issue is the relationship between QoL and
satisfactory sex life. A recent study found that sexual dysfunction
significantly contributed to overall functional impairment in BD
patients in clinical remission and was associated with poor leisure
time quality.35 Furthermore, it has been reported that BD pa-
tients with sexual dysfunction have lower scores on the mental
component of QoL.36 Hence, SF represents an important factor
with regard to QoL-related variables.37,38 It could be beneficial
to focus research on investigating whether different phases of
sexual response affect QoL differently. Then, in clinical practice,
we could choose drugs depending on which phase they most
affect and thus their repercussion on QoL. The same would
apply to physical and mental components of QoL.
The purpose of our study was to analyze SF in long-term
euthymic patients with BD treated with mood stabilizers.
J Sex Med 2020;-:1e11
Sexual Dysfunction and Mood Stabilizers
Based on previous studies,23,31 we expected different levels of SF
depending on the type of treatment (ie, lithium, lithium plus
benzodiazepines, anticonvulsants, lithium plus anticonvulsants)
and a different impact on QoL. First, we hypothesized that
lithium monotherapy can affect all phases of sexual
response.19,21,24,26 Second, we expected patients treated with
lithium together with benzodiazepines would have lower SF
scores on the desire and orgasm subscales,22 but not on arousal as
a result of improved anxiety.28,29 Third, we expected that anti-
convulsants would affect desire and orgasmic function.31 Finally,
as sexual dysfunction has a negative impact on QoL,35 we hy-
pothesized a positive association between SF and QoL, with
higher SF scores associated with better mental and physical
components of QoL.
METHOD
Design
In this cross-sectional study, we compared the effect of
medication on SF in euthymic BD patients classified into 4
groups: BD patients in lithium monotherapy (L group); BD
patients treated with one or more anticonvulsants (A group); BD
patients treated with lithium together with one or more anti-
convulsants (LþA group); and BD patients treated with lithium
together with one or more benzodiazepines (LþB group). Sub-
sequently, we examined the association between SF and mental
and physical dimensions of QoL.
Participants
Patients were recruited from outpatient mental health centers
at 4 participating hospitals in Spain: University and Polytechnic
Hospital La Fe (Valencia), Oviedo Hospital (Oviedo), Sant Joan
de Deu Parc Sanitari (Barcelona), and University Hospital
Mutua de Terrassa (Terrassa, Barcelona). Eligible patients were
outpatients diagnosed with BD (n ¼ 114). Inclusion criteria
were (1) currently meeting DSM-IV-TR criteria for BD type I or
II; (2) aged 18e65 years; (3) in treatment with lithium alone,
one or more anticonvulsants, lithium together with one or more
anticonvulsants, or lithium together with one or more benzodi-
azepines in a stable phase of the disease defined as having a
Young Mania Rating Scale (YMRS)39 score  7 and a Hamilton
Depression Rating Scale (HDRS)40 score  8 for at least
6 months; (4) at least 6 months of treatment (per 3 above) before
enrolment; (5) no changes in pharmacological treatment for the
last 3 months; and (6) sexual interactions regularly and often
enough to be evaluated.
Exclusion criteria were (1) clinically significant history of
diabetes, neurological or endocrine disorder, or genital disease;
(2) other psychiatric disorders; (3) substance use within
3 months of the study; and (4) taking antidepressants or
antipsychotics.
The Clinical Research Ethics Committee of Central Univer-
sity Hospital of Asturias in Oviedo approved the study protocol
J Sex Med 2020;-:1e11
3
(Ref. 36/2012). Written informed consent was obtained from all
subjects before enrolment.
Selection Criteria
Patients meeting DSM-IV-TR criteria for BD41 were invited
by their attending clinicians to participate in the study. The
treating psychiatrist corroborated the diagnosis based on a case
note review and an in-depth intake interview at the clinic. The
assessment included all pertinent items from the Structured
Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I).42
BD patients who met the criteria for a manic or a depressive
episode were excluded. To ensure the exclusion of manic or
depressive episodes, the YMRS39,43 and the HDRS40,44 were
used (YMRS scores < 7 and HDRS scores < 8, respectively). See
Table 1 for sociodemographic and clinical data for the final
sample.
INSTRUMENTS
Sexual Functioning
SF was assessed using the Changes in Sexual Functioning
Questionnaire Short Form (CSFQ-14). This is a self-report
instrument that has previously been validated and has
demonstrated good construct validity and internal reli-
ability.45 It has separate versions for males and females with
gender-specific questions and yields scores for 3 scales cor-
responding to the phases of the sexual response cycle (ie,
desire, arousal, and orgasm). For each subscale, a higher
score indicates better functioning. We used the Spanish
version.46
Quality of Life
The 36-item Short-Form Health Survey (SF-36) is a multi-
purpose, short-form health survey.47 The survey contains 36
items that are scored in 8 scales: physical functioning (PF), role
limitations due to physical health problems (RP), bodily pain
(BP), general health (GH), vitality (VT), social functioning (SF),
role limitations due to emotional problems (RE), and mental
health (MH). Scores on the 8 SF-36 scales were further aggre-
gated to produce a physical component summary (PCS) and a
mental component summary (MCS) of health status. Partici-
pants completed the SF-36 Health Survey version adapted for the
Spanish population.48
Clinical Variables
The case note review and clinical interview were examined to
collect the following data: age, sex, marital status, education level,
type of BD, dominant polarity, duration of euthymia, length of
illness, age at diagnosis, number of hospitalizations, number of
episodes, comorbid personality disorders, comorbid substance
use disorders, comorbid anxiety disorders, metabolic syndrome,
and family psychiatric history.
 4
Table 1. Sample description
Lithium (n ¼ 57) Anticonvulsants (n ¼ 20) Lithium þ anticonvulsants (n ¼ 17) Lithium þ benzodiazepines (n ¼ 20)

Mean (SD)/n (%) Mean (SD)/n (%) Mean (SD)/n (%) Mean (SD)/n (%)

Variable Median (1st, 3rd Q.) Median (1st, 3rd Q.) Median (1st, 3rd Q.) Median (1st, 3rd Q.)

Age 40.42 (12.86) 49 (8.69) 46.35 (8.87) 47.3 (10.01)

39 (29, 52) 48 (44.75, 52.75) 49 (39, 55) 47.5 (39.75, 54.5)
Sex
Male 33 (57.89%) 8 (40%) 9 (52.94%) 5 (25%)
Female 24 (42.11%) 12 (60%) 8 (47.06%) 15 (75%)
Marital status
Never married 33 (57.89%) 14 (70%) 11 (64.71%) 9 (45%)
Married or living with partner 4 (7.02%) 2 (10%) 3 (17.65%) 5 (25%)
Separated/divorced 20 (35.09%) 4 (20%) 3 (17.65%) 6 (30%)
Type of bipolar disorder
Type 1 49 (85.96%) 10 (50%) 13 (76.47%) 15 (75%)
Type 2 8 (14.04%) 10 (50%) 4 (23.53%) 5 (25%)
Dominant polarity
Depressive 11 (19.64%) 9 (47.37%) 6 (37.5%) 9 (45%)
Manic/hypomanic 45 (80.36%) 10 (52.63%) 10 (62.5%) 11 (55%)
Age at diagnosis 28.39 (9.48) 34.35 (14.91) 33.18 (9.11) 30.9 (11.15)
25 (24, 33) 37 (19.25, 42) 31 (29, 39) 30 (20.75, 41.25)
Length of illness, years 12.21 (11.68) 15.05 (13.39) 13.18 (6.39) 16.4 (13.08)
6 (3, 18) 10.5 (4, 26.75) 11 (9, 18) 13 (6.5, 25.25)
Number of hospitalisations 2.26 (2.17) 1 (0.79) 2.35 (2.55) 1.95 (1.73)
2 (1, 3) 1 (0.75, 1) 2 (1, 3) 1.5 (1, 3)
Number of manic episodes 2.39 (2.36) 0.55 (1) 2.82 (3.07) 1.75 (1.71)
2 (1, 3) 0 (0, 1) 2 (1, 4) 1.5 (0.75, 2.25)
Number of hypomanic episodes 1.11 (1.41) 2.65 (1.6) 1.76 (2.19) 1.6 (1.7)
1 (0, 2) 3 (1, 4) 1 (0, 3) 1 (0, 3)
Number of depressive episodes 1.6 (2.23) 2 (2.2) 3.65 (2.52) 4 (5.51)
1 (0, 2) 1 (0, 4) 4 (2, 5) 3 (1, 5)
Number of mixed episodes 0.39 (1) 0.1 (0.31) 0.41 (0.62) 0.4 (1.35)
0 (0, 0) 0 (0, 0) 0 (0, 1) 0 (0, 0)
Metabolic syndrome 7 (12.3%) 3 (15%) 4 (23.5%) 3 (15%)
HDRS 2.49 (1.96) 2.47 (2.00) 3.90 (2.45) 4.91 (4.64)
J Sex Med 2020;-:1e11

2 (1, 4) 2 (1, 4) 4 (2, 5.75) 4 (2, 8)

García-Blanco et al
YMRS 1.37 (1.81) 0.47 (0.80) 2.10 (3.95) 1.18 (2.17)
1 (0, 2) 0 (0, 1) 0.5 (0, 2) 0 (0, 2)
CSFQ-14
Total 43.51 (10.34) 47.65 (8.04) 41.76 (13.28) 39.3 (8.4)
45 (38, 49) 46.5 (44.75, 53) 43 (33, 53) 39.5 (33.75, 42.25)
(continued)
J Sex Med 2020;-:1e11

Sexual Dysfunction and Mood Stabilizers

Table 1. Continued
Lithium (n ¼ 57) Anticonvulsants (n ¼ 20) Lithium þ anticonvulsants (n ¼ 17) Lithium þ benzodiazepines (n ¼ 20)

Mean (SD)/n (%) Mean (SD)/n (%) Mean (SD)/n (%) Mean (SD)/n (%)

Variable Median (1st, 3rd Q.) Median (1st, 3rd Q.) Median (1st, 3rd Q.) Median (1st, 3rd Q.)
Sexual desire 14.16 (3.9) 15.95 (2.61) 14.65 (5.38) 12.6 (3.36)
14 (12, 17) 15.5 (15, 16) 15 (10, 19) 12 (10.75, 14.25)
Sexual arousal 10.11 (3.4) 10.9 (2.73) 9.59 (4.02) 9.6 (2.84)
10 (8, 13) 11 (10.75, 12) 9 (6, 13) 9.5 (7, 11.25)
Sexual orgasm 10.63 (2.94) 11.2 (3.04) 9.12 (3.89) 9.3 (3.37)
11 (9, 13) 13 (10.75, 13) 10 (6, 13) 9.5 (7.5, 12)
Global sexual dysfunction (n)
SF-36 28 6 10 17
PCS 71.87 (19.38) 67.23 (25.34) 65.84 (21.1) 61.6 (21.15)
76 (60.4, 86) 73 (46, 86.55) 76 (48, 82.5) 63.6 (49, 80.5)
MCS 65.38 (16.59) 67.8 (20.37) 55.98 (20.66) 57.28 (22.25)
67.73 (55.37, 79.8) 71.8 (57.09, 85.57) 51.93 (42.97, 72.9) 57.38 (41.12, 78.53)
CSFQ-14 ¼ Changes in Sexual Functioning Questionnaire Short-Form; HDRS ¼ Hamilton Depression Rating Scale; MCS ¼ Mental Component Summary; PCS ¼ Physical Component Summary;
SF-36 ¼ Short-Form Health Survey; YMRS ¼ Young Mania Rating Scale.
Bolded data represent statistically significant results. Data are shown as mean (standard deviation) and median (first and third quartiles) for continuous variables and relative and absolute frequencies for
categorical variables.

5
6 García-Blanco et al
Procedure
After signing an informed consent form, all participants were
rated with the HDRS, YMRS, CSFQ-14, and SF-36 scales, and
sociodemographic data were collected. The timing of the ques-
tionnaires was the same between groups. In addition, patients
completed an individual semi-structured interview to record
clinical data, which was compared with their case note review.
Data Analysis
Clinical data were summarized using mean (standard de-
viation) and median (first and third quartiles) for continuous
variables and relative and absolute frequencies for categorical
variables (Table 1). The effect of medication on the CSFQ-14
and its subscales was assessed by means of ordinal regression
models owing to the nature of the variables.49 An adaptive
lasso was used to identify potential confounding variables and
select the associated CSFQ-14 scales. This statistical tech-
nique determines the associated demographic and clinical
variables by means of penalized regression models. The pa-
rameters of convexity and penalization were selected by the
algorithm using 10-fold cross-validation. Furthermore, to
study the association of CFSQ-14 subscales with QoL (PCS/
MCS), linear regression models were used controlling for
potential confounding factors. Ordinal regression models and
linear regression models are reported in the Supplementary
Material Section. All analyses were performed using R soft-
ware (version 3.4.3) and ordinal (version 2015.6-28) and
clickR (version 0.3.41) packages. A P value lower than 0.05
was considered statistically significant.
RESULTS
Effect of Medication on Sexual Function
To assess the true effect of medication on SF, we adjusted
penalized ordinal regression models including demographic and
clinical variables to identify potential confounders. HDRS score,
YMRS score, age at onset, type of BD, predominant polarity,
metabolic syndrome, age, sex, and marital status were included in
the models. The A group was chosen as the reference group to be
compared with the rest of the groups, as the A group had the best
SF scores (Table 1). The confounding variables selected by
adaptive lasso—age, sex, marital status, YMRS, HDRS, and
metabolic syndrome—were included in the total sexual function
scale (Supplementary Table S1). For sex, males were chosen as
the reference group to be compared with females. For marital
status, married or living with partner was chosen as the reference
group to be compared with the rest of the groups. Being female
(OR ¼ 0.19, 95% CI [0.079, 0.45], P < .001) and older age
(OR ¼ 0.94, 95% CI [0.90, 0.98], P ¼ .006) were associated
with worse SF scores. For medication effect, both the L group
and the LþB group had worse SF than the A group (OR ¼ 0.31,
95% CI [0.11, 0.90], P ¼ .032; and OR ¼ 0.27, 95% CI
[0.080, 0.89], P ¼ .032, respectively). On the sexual desire
subscale, being female (OR ¼ 0.28, 95% CI [0.12, 0.62],
P ¼ .002) and older age (OR ¼ 0.94, 95% CI [0.89, 0.97],
P < .001) were associated with worse sexual desire scores. For
medication effect, both the L group and the LþB group had
worse sexual desire than the A group (OR ¼ 0.26, 95% CI
[0.09, 0.74], P ¼ .012; and OR ¼ 0.20, 95% CI [0.06, 0.64],
P ¼ .007, respectively) (Supplementary Table S2). On the sexual
arousal subscale, being female (OR ¼ 0.27, 95% CI [0.12,
0.62], P ¼ .002) and older age (OR ¼ 0.92, 95% CI [0.88,
0.96], P < .001) were associated with worse sexual arousal
scores. For medication effect, the L group had worse sexual
arousal than the A group (OR ¼ 0.32, 95% CI [0.11, 0.89],
P ¼ .029) (Supplementary Table S3). On the sexual orgasm
subscale, being female (OR ¼ 0.36, 95% CI [0.16, 0.80],
P ¼ .014) and older age (OR ¼ 0.94, 95% CI [0.90, 0.98],
P ¼ .003) were associated with greater difficulty achieving sexual
orgasm. For medication effect, the LþA and LþB groups had
greater difficulty achieving sexual orgasm than the A group,
although these differences did not reach the level of significance
(OR ¼ 0.27, 95% CI [0.07, 1.13], P ¼ .074; and OR ¼ 0.32,
95% CI [0.09, 1.17], P ¼ .086, respectively) see Supplementary
Table S4).
Association Between SF and QoL
For the association between SF and QoL, age, sex, YMRS,
HDRS, metabolic syndrome, marital status, and predominant
polarity were introduced as confounding factors selected by
adaptive lasso in both MCS and PCS. For predominant polarity,
depressive polarity was chosen as the reference group to be
compared with manic/hypomanic polarity. In the penalized
regression model for MCS (Supplementary Table S5), higher
sexual arousal scores were associated with better MCS
(OR ¼ 2.85, 95% CI [0.99, 4.71], P ¼ .003). Similarly, in the
penalized regression model for PCS (Supplementary Table S6),
the higher the sexual arousal score, the better the PCS
(OR ¼ 2.18, 95% CI [0.24, 4.12], P ¼ .028). Furthermore,
higher manic symptoms were associated with higher PCS
(OR ¼ 2.10, 95% CI [0.48, 3.72], P ¼ .012).
DISCUSSION
Our study examines SF and its association with QoL in
euthymic patients with BD treated with mood stabilizers and no
antipsychotics or antidepressants. Thus, we compared patients
treated with anticonvulsants alone, lithium alone or with one or
more anticonvulsants, or lithium plus benzodiazepines. Our
main findings can be summarized as follows. Patients on lithium
monotherapy or added to benzodiazepines had worse total SF
than the group treated only with anticonvulsants. Similarly,
lithium monotherapy or with added benzodiazepines was asso-
ciated with worse sexual desire. However, lithium monotherapy
was associated with lower sexual arousal, but not when benzo-
diazepines were added. Once again, when combined with anti-
convulsants or benzodiazepines, patients treated with lithium had
greater difficulty on the sexual orgasm subscale. After controlling
J Sex Med 2020;-:1e11
Sexual Dysfunction and Mood Stabilizers
for other variables, being female and older age were associated
with worse total SF and sexual desire, arousal, and orgasm sub-
scale scores. Regarding the association between SF and QoL,
higher sexual arousal scores were associated with better MCS and
PCS. In other words, mood stabilizers affect SF differently, and
depending on the affected phase of SF, QoL is also affected
differently.
First, regarding treatment with lithium in monotherapy, our
findings agree with previous authors who find worse SF associ-
ated with lithium monotherapy,23 especially on the arousal and
desire subscale.20,21,50 According to our findings, several mech-
anisms have been postulated as responsible for the undesirable
effects of lithium on SF. The most accepted is that lithium
probably causes arousal dysfunction in terms of erectile
dysfunction through impairment of endothelial-mediated relax-
ation of the corpus cavernosa,51,52 and that is the reason why
aspirin effectively improves lithium-related sexual dysfunction in
men with stable BD.53 Although more research is needed, similar
mechanisms in corresponding structures have been suggested in
women treated with lithium.54 Other researchers find that all
phases of sexual response can be affected, so lithium may reduce
sexual thoughts and desire, worsen erectile function and arousal,
and reduce frequency of orgasm during sex.19,21,26
Second, regarding treatment with lithium in combination
other drugs, we agree with previous reports that show that the
combination of lithium plus benzodiazepines is related to worse
SF scores, specifically on the desire subscale. A previous study
found that coadministration of benzodiazepines was associated
with a significantly greater risk of sexual dysfunction (49%) than
lithium alone (14%) or lithium in combination with other
psychotropic drugs (17%).22 It is not clear if this effect is in-
dependent of lithium or due to a combined effect of benzodi-
azepines and lithium, and the possible hypothesis is that lithium
may potentiate the effect of benzodiazepines on SF.55 In line
with this hypothesis, when benzodiazepines were administered in
monotherapy, they did not affect SF.28 It is not known if ben-
zodiazepines can affect desire and orgasm, but as pathological
levels of anxiety appear to have a negative influence on sexual
arousal,56 it can be hypothesized that the use of benzodiazepines
would have a positive effect on arousal. Based on our results, the
combination of lithium plus benzodiazepines or anticonvulsants
does not affect arousal. Thus, the capacity of both drugs to
improve anxiety would imply positive effects on sexual arousal.
Third, for BD patients treated with anticonvulsants, we ob-
tained the best scores on desire, arousal, and orgasm subscales as
compared with the groups treated with lithium in monotherapy
or in combination with anticonvulsants or benzodiazepines.
Although the findings are hardly comparable as the treated dis-
eases are different, our results for anticonvulsants seem incon-
sistent with the previous literature on epilepsy where
anticonvulsants are often associated with sexual dysfunction
mainly in male epilepsy patients, but the underlying mechanism
is unknown.57 A potential explanation is that patients treated
J Sex Med 2020;-:1e11
7
with anticonvulsants experience hormonal changes. In fact, val-
proate negatively affects the release of such female hormones as
luteinizing and follicle-stimulating hormones and prolactin, and
it exerts an inhibitory action that can lead to high serum con-
centrations of testosterone and other male hormones. The effect
on GABAergic transmission induced by valproate and its broad
inhibitory action on cytochrome and glucuronidation systems
could result in abnormal secretion of gonadotropins.58 However,
the association between these hormonal changes and SF is
difficult to establish. Indeed, there are substantial differences
among the different anticonvulsants, and fewer side effects on
reproductive hormones have been described for lamotrigine in
male epileptic patient.33,59 In fact, lamotrigine has even been
associated with a favorable effect on SF in epileptic patients,
especially in women.60 Importantly, most cases of sexual
dysfunction occurring with valproate have been reported in
epileptic patients, and evidence in patients with BD is limited, so
previous studies cannot be generalized to BD.2 In our study,
anticonvulsants were the mood stabilizers with the least negative
effects on SF in stable BD patients.
Regarding demographic and clinical variables, neither de-
mographic variables such as marital status nor clinical ones such
as affective symptoms, age at illness onset, type of BD, pre-
dominant polarity, or metabolic syndrome provided significant
results. With respect to sex, we found a higher rate of sexual
dysfunction in women, with worse scores in overall SF, desire,
arousal, and orgasm. Other studies justify a higher prevalence of
sexual dysfunction in women based on the presence of mood and
anxiety symptoms.61,62 However, our findings indicate that BD
women had poorer SF than BD men, regardless of the presence of
mood symptoms. As for age, older age was associated with worse
SF scores in all phases of sexual response. Similarly, Cutler report
worse SF in older psychiatric patients, probably related to greater
neurological or cognitive impairment than in the nonpsychiatric
population.63
Finally, another objective of our study was also to evaluate the
impact of SF on QoL in BD patients due to SF is considered an
essential part of QoL.64 We found that arousal scores (vaginal
lubrication or erectile function) were positively associated with
both the mental and physical components of QoL. Similar results
have been described in schizophrenia.65 A recent article evalu-
ating SF in euthymic BD patients treated with lithium showed
greater sexual dysfunction (desire, arousal, and orgasm) during
periods of clinical remission than the general population.23
Similarly, the greater the sexual dysfunction, the lower the
level of functioning and QoL, especially in quality of leisure
time.35 In any event, not all previous studies find significant
relationships between the different phases of SF and QoL in
psychiatric patients, probably due to 2 factors. First, the prob-
lems with defining QoL, as it is difficult to conceptualize the
relationship of clinical variables to measures of QoL and inter-
vening variables that mediate these effects,66 and second, due to
the limitations of the current assessment tools.67
8 García-Blanco et al
The main strength of our study was to obtain a BD sample in
treatment with mood stabilizers and no antipsychotics or anti-
depressants, given the current tendency to use combination
therapy in BD. In addition, our sample was composed only of
euthymic patients. This is an important advantage because mania
and depression have different effects on sexual behavior. It is
known that the prevalence of sexual dysfunction in major
depression is high,68 and hypersexuality is a common symptom
in manic episodes.69 Another advantage of the sample is that
substance use was an exclusion criterion because of its deleterious
effect on SF.70 Similarly, physical comorbidities were an exclu-
sion criterion (diabetes, neurological or endocrine disorder, or
genital disease). For the assessment of SF, we used the CSFQ-14,
which is a well-validated, gender-specific scale, addressing phase-
specific functioning and monitoring changes over time.46
The results of the present study should be interpreted with
caution in light of several limitations. The rigorous exclusion
criteria limit the generalizability of the results and also reduces
the sample size, which increases the chance of false negatives
(some true associations might not be detected). The cross-
sectional design hinders to obtain information about patients
own sexuality before taking psychotropic drugs. Furthermore, a
retrospective assessment of baseline sexual function could be
distorted by memory bias and potential mood disturbance.
Although marital status was introduced as a potential confounder
with no significant results, we did not take into account stability
of relationship with partner. Furthermore, SF was assessed using
a self-report scale, which does not provide information about the
existence or type of sexual activity, and it is not possible to
determine whether patients adequately understood the content of
the questions nor to collect relevant information about their
sexual activity.
In sum, stable BD patients showed significant sexual
dysfunction, whose severity was dependent on mood stabiliser
treatment. Treatment with lithium in monotherapy or in com-
bination with benzodiazepines was associated with worse total
SF. In contrast, BD patients treated only with anticonvulsants
showed lower sexual dysfunction. Furthermore, when benzodi-
azepines were added to lithium, BD patients showed lower
arousal dysfunction. It is of note that arousal dysfunction was
associated with low QoL in both physical and mental compo-
nents. Thus, we can conclude that we must be especially aware of
negative effects on arousal because its association with QoL is the
highest, compared with the other phases of sexual response.
Hence, the impact of mood treatment on SF in BD patients
should be assessed in daily practice. As is well known, psychiatric
patients rarely speak of their sexual difficulties spontane-
ously,13,71 so all patients should be asked about sexual problems
both before starting treatment with lithium and periodically
during treatment. Taking the effects of mood treatment on SF
into consideration would help improve treatment compliance4,72
and decrease lifetime suicide attempts73 and consequently opti-
mize the quality of life of BD patients.
CONCLUSION
Lithium in monotherapy or in combination with benzodi-
azepines is related to worse total SF and worse sexual desire
than anticonvulsants in monotherapy. While the addition of
benzodiazepines or anticonvulsants to lithium negatively af-
fects sexual orgasm, sexual arousal (which plays a significant
role in QoL) improves when benzodiazepines are added to
lithium. Anticonvulsants in monotherapy have the least
negative effects on SF in BD patients. In sum, assessing the
effects of mood treatment on SF should be part of daily
practice for potential improvement of QoL.
Corresponding Author: Pilar Sierra, MD, PhD, Department of
Psychiatry, La Fe University and Polytechnic Hospital, Avda
Fernando Abril Martorell 106 46026, Valencia, Spain; E-mail:
sierra_pil@gva.es. Ana García-Blanco, MD, PhD, La Fe Health
Research Institute, Valencia, Spain. Tel: 687770381; Fax: (39)
961244367; E-mail: ana.garcia-blanco@uv.es
Conflict of Interest: The authors report no conflicts of interest.
Funding: This study (FIS PI11/02493; JR17/00003) was sup-
ported by the Instituto de Salud Carlos III (ISCIII; Plan Estatal
de IþDþi 2013-2016) and cofinanced by the European
Development Regional Fund ‘‘A way to achieve Europe’’
(ERDF). The sponsors had no involvement in the study design,
the collection, analysis, or interpretation of data, or the writing
and submission of the manuscript.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Pilar Sierra; Ana García-Blanco; María P. García-Portilla
(b) Acquisition of Data
María Batalla; Lorena de la Fuente-Tomás; Mónica Sánchez-
Autet; Belén Arranz; Gemma Safont; Sergio Arqués
(c) Analysis and Interpretation of Data
Pilar Sierra; Ana García-Blanco; Lorenzo Livianos
Category 2
(a) Drafting the Article
Pilar Sierra; Ana García-Blanco
(b) Revising It for Intellectual Content
Pilar Sierra; Ana García-Blanco
Category 3
(a) Final Approval of the Completed Article
Pilar Sierra; Ana García-Blanco
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SUPPLEMENTARY DATA
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jsxm.2020.01.032.