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The Association of Serotonin Transporter Genotypes and Selective Serotonin Reuptake Inhibitor (SSRI) Associated Sexual Side Effects: Possible Relationship to Oral Contraceptives
Abstract
To study the relationship between functional variants in the serotonin transporter gene (SLC6A4) and selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction.
One hundred fifteen subjects aged 18-40 years and currently being treated with an SSRI for depression were assessed for clinical variables known to affect sexual well-being. SSRI-associated sexual difficulties were assessed with the Changes in Sexual Functioning Questionnaire (CSFQ). Subjects were subsequently genotyped for the SLC6A4 promoter region (5HTTLPR) insertion/deletion variant and a variable number of tandem repeats (VNTR) in the second intron.
The 5HTTLPR insertion/deletion variant was associated with sexual dysfunction in this study sample [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.2, 6.4; p = 0.02]. The relationship between promoter genotypes and sexual well-being differed in males and females and was related to whether females were taking an oral contraceptive (OC) medication. Females with the ll genotype were nearly eight times more likely to be categorized as having sexual dysfunction if they were taking OCs, while no relationship was observed in those not taking OCs.
These results suggest that a functional variant in the serotonin transporter gene is associated with sexual difficulties in persons taking an SSRI for depression. This relationship may differ by sex and be dependent on OC status in females.
... A total of 2737 (range: 27-1655) antidepressant-treated individuals with a psychiatric disorder were included across the 11 studies (Table 3). Five studies predominantly comprised individuals of European ancestry [8,[37][38][39][40], four studies were conducted within the Japanese population [16,[41][42][43], and one study was conducted in a North Indian population [17]. The Higuchi et al. [44] study did not specify the ancestry of the studied population. ...
... The Higuchi et al. [44] study did not specify the ancestry of the studied population. Clinical diagnoses across studies included MDD (nine studies) [8,17,37,[39][40][41][42]44], panic disorder (two studies) [16,43], and anxiety disorders (one study) [42]. Most studies used prospective study designs (10 studies) and included at least one SSRI (10 studies). ...
... Measures of antidepressant tolerability varied by study. The UKU scale was used by three studies [17,41,44] medication discontinuation/drop-out due to an ADR was used by another three studies [16,40,42], while the other studies used the changes in sexual functioning questionnaire [37], global rating of side effect burden [8], or various unspecified self-report measures [38,39,43]. The reported prevalence of ADRs ranged from 5.3-86.1% (Supplementary Table S3). ...
Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.
... 25 Antidepressant-induced SD has been reported in up to 70% of patients treated with selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs). 18,[26][27][28][29] Antidepressant medications' interference with sexual function often results specifically in orgasm or ejaculatory difficulties. There is evidence that men report more impairment in orgasm than women during SSRI treatment. ...
... Initial studies on effects of genetic regulation of serotonin and dopamine may help to explain the impact of antidepressants on specific aspects of sexual function (orgasm, arousal, or desire). 27,[38][39][40] Genetic variables associated with sexual function were assessed in 115 women being treated for depression with SSRIs. A functional variant in the 5-hydroxytryptophan-TLPR insertion/deletion region of the serotonin transporter gene was associated with SD in individuals on SSRIs. ...
... A functional variant in the 5-hydroxytryptophan-TLPR insertion/deletion region of the serotonin transporter gene was associated with SD in individuals on SSRIs. 27 In women, negative effects of SSRIs on sexual function were increased 8-fold with oral contraceptive use. 27 The genetic basis of sexual problems, such as erectile dysfunction, anorgasmia, and decreased libido, is an active area of investigation and in the future, could aid in selection of appropriate antidepressant treatment for patients with specific clinical and genetic characteristics. ...
Introduction:
Depression is one of the more prevalent mental disorders in the United States, with estimates as high as 6.7% of Americans affected annually. Consequently, antidepressant use in the United States is also widespread. Both depression and its treatments are associated with sexual dysfunction (SD) in men and women, including orgasm and arousal problems, hypoactive sexual desire, premature ejaculation, erectile difficulties, and dyspareunia. Sexual dysfunction is frequently cited as a reason for nonadherence or discontinuation of treatment for depression.
Aim:
The objective of our review is to aid physicians, including primary care physicians, psychiatrists, and urologists/gynecologists, in the multidisciplinary approach to treating patients with SD and depression.
Methods:
Our review focuses on articles published within the last 10 years on SD and depression in adults, with an emphasis on the relationship of treatments for depression on SD.
Summary:
Different classes of antidepressants vary in their ability to cause sexual side effects.
Results:
Treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) is associated with SD. Use of other antidepressants, such as bupropion, mirtazapine, nefazodone, and vilazodone, have been associated with less SD compared with SSRIs; furthermore, some of the mentioned antidepressants have been used in the treatment of SD induced by SSRIs and SNRIs.
... Pharmacogenetic research has only recently begun to identify genetic markers that may predict response to antidepressant treatment ( Lin and Chen 2008;Drago et al. 2009;Ising et al. 2009;Schosser and Kasper 2009;Uher et al. 2009bUher et al. , 2010Kato and Serretti 2010). These markers may facilitate the prediction of adverse events such as SD during antidepressant treatment ( Bishop et al. 2009). It has been hypothesised that the development of SD during treatment with serotonergic antidepressants is moderated by variations in the serotonin transporter gene ( SLC6A4 ), which encodes the serotonin transporter protein (5-HTT; Bishop et al. 2009). ...
... These markers may facilitate the prediction of adverse events such as SD during antidepressant treatment ( Bishop et al. 2009). It has been hypothesised that the development of SD during treatment with serotonergic antidepressants is moderated by variations in the serotonin transporter gene ( SLC6A4 ), which encodes the serotonin transporter protein (5-HTT; Bishop et al. 2009). The polymorphism in SLC6A4 which has been most studied for association with SD to date is the 5-HTTLPR , an insertion/deletion of 44 base pairs (bp) within the promoter region. ...
... An association has been reported between 5-HTTLPR genotype and response to antidepressant treatment, in which carriers of the long allele show a better response than short allele homozygotes ( Serretti et al. 2007;HuezoDiaz et al. 2009). Long allele homozygotes have also been shown to experience more SD during SSRI treatment for depression ( Bishop et al. 2009). Furthermore, an association has been found between the short allele and premature ejaculation (Ozbek et al. 2009), whereas Janssen et al. (2009) reported in s-carriers with premature ejaculation longer ejaculation times compared to long allele homozygotes. ...
Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant).
A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery-Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire.
The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR.
In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.
... The total number of adverse effects is a significant predictor of medication nonadherence; 36% of patients who stop their medication do so because of adverse effects [5,6]. Sexual dysfunction (SD) is commonly observed during SSRI therapy, occurring in approximately 20-70% of patients taking an SSRI [7][8][9]. These sexual side effects are particularly disconcerting to patients because they are persistent and generally do not abate like headache, nausea, insomnia, diarrhea, and other early onset side effects, which generally dissipate after the first few weeks of therapy. ...
... A follow up study by Bishop et al. was conducted to investigate variants in the serotonin transporter gene (SLC6A4) and their relationships to SSRI-associated SD [7]. Two common functional variations were assessed, the SLC6A4 promoter region (5HTTLPR) insertion/deletion variant and a variable number of tandem repeats (VNTR) in the second intron which are both associated with expression levels and function of serotonin transporters [28][29][30]. ...
... Three of the six studies of SSRIassociated sexual dysfunction were prospective, while three were point-prevalence/cross-sectional investigations. However, two of the point-prevalence/cross-sectional studies had narrowly defined inclusion/exclusion criteria and utilized the CSFQ assessment, which is a measure validated for use in the populations examined [7,23]. These studies also excluded potential subjects with concomitant disease states or drug utilization that may have confounded the evaluations of sexual well-being which were the primary goals of these investigations. ...
Sexual dysfunction (SD) is a common and disconcerting side effect of selective serotonin reuptake inhibitors (SSRIs) that often influences a patient’s desire to continue long-term antidepressant treatment. Studies specifically assessing changes in sexual well-being over time illustrate that the incidence of sexual side effects from SSRIs ranges from 20% to 70%, depending on the characteristics of the study sample assessed. Developing strategies to predict who may be at the highest risk for adverse changes in their sexual well-being is an important step in improving the quality of life and treatment of patients who require antidepressant therapy. Pharmacogenetic studies of SSRI-associated SD have identified associations between serotonin and glutamate system genes with aspects of SD. The results of studies investigating genetic variations in drug metabolism enzymes and their relationships to antidepressant-associated adverse effects have been mixed. Continued efforts to characterize the relationships between genetic markers and antidepressant outcomes, and to translate this knowledge to patient care, have the potential to significantly improve the empiric selection of antidepressant agents and to minimize the risk for intolerable side effects.
... The genotype distribution and allele frequencies of the HTR2A gene, −1438A/G and 102T/C polymorphisms, 5-HTTLPR polymorphism of SLC6A4 gene and BDNF gene Val66Met polymorphism of all the patients were in the Hardy-Weinberg equilibrium and these results were in accordance with previous studies performed in Caucasians that the −1438GG genotype was associated with increased risk of SD [21]. ...
... The relationship between a genetic variant in the SLC6A4 gene and SSRI-associated SD investigated by Bishop et al. and Garfield et al. in subjects with major depressive disorder and generalized anxiety disorder [12,21]. It was seen that individuals who were carriers of high-expression L allele of the 5HTTLPR, were more likely to be categorized as having SD. ...
Sexual dysfunction (SD) is a troublesome adverse effect of selective serotonin reuptake inhibitors (SSRIs). A variety of mechanisms might be involved in the occurrence of SD but the exact mechanism is still not clear. Genetic variations among patients treated with SSRIs are strong determinants of intolerance and poor compliance. The present study aimed to determine the relationship between serotonin‐2A receptor (HTR2A) gene −1438A/G and 102T/C polymorphisms, serotonin transporter gene (SLC6A4) 5-HTT-linked polymorphic region (5-HTTLPR) insertion/deletion variant and brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphisms and the occurrence of SD adverse effect in major depressive disorder patients treated with citalopram (CIT) or sertraline (SERT). The result from this investigation revealed that the −1438A/G and 102T/C polymorphisms appear to be associated with the SD induced by CIT. It was also demonstrated that patients receiving SERT, carrying T allele of HTR2A or L allele of 5-HTTLPR more likely to experience SD. Most important overall finding of the study is the combined effects of −1438A/G, 102T/C, and 5-HTTLPR polymorphisms. In a logistic regression model, the occurrence of SD increased with the number of risky alleles. As compared with subjects receiving SERT with few risky (≤2) alleles, those with had 5–6 alleles had an increased SD risk. After all, according to these findings, −1438A/G, 102T/C, and 5-HTTLPR polymorphisms could be considered as promising pharmacogenetic biomarkers in CIT/SERT treatment in major depressive disorder (MDD) patients to avoid the occurrence of SD.
... 55 The SLC6A4 5HTTLPR L/L polymorphism has been associated with SD based on the CSFQ in both men and women with depression who were being treated with citalopram, escitalopram, fluoxetine, paroxetine, or sertraline. 60 A lack of association between SLC6A4 5-HTTLPR and SD has been shown in men and women with major depressive disorder and depression treated with fluoxetine and escitalopram or nortriptyline, respectively. 61,62 The SLC6A4 STin2 polymorphism was also found to not be associated with SD in men and women with depression in this same subject population. ...
... 61,62 The SLC6A4 STin2 polymorphism was also found to not be associated with SD in men and women with depression in this same subject population. 60 In men with lifelong premature ejaculation responsive to sertraline, the 5-HTTLPR L A /L A polymorphism and STin2 12/12 polymorphism were associated with increased intravaginal ejaculation latency time. 63 In contrast, when Dutch men who had lifelong premature ejaculation were treated with paroxetine, the 5-HTTLPR polymorphism was not associated with intravaginal ejaculatory latency time improvement. ...
Sexual functioning is important to assess in patients with psychiatric illness as both the condition and associated treatment may contribute to sexual dysfunction (SD). Antidepressant medications, mood stabilizers, antipsychotics, and antianxiety agents may be associated with SD related to drug mechanism of action. Sexual adverse effects may be related to genetic risk factors, impact on neurotransmitters and hormones, and psychological elements. Effective strategies to manage medication-induced sexual dysfunction are initial choice of a drug unlikely to cause SD, switching to a different medication, and adding an antidote to reverse SD. Appropriate interventions should be determined on a clinical case-by-case basis.
... Selective serotonin reuptake inhibitors (SSRIs) are currently first line antidepressant therapies for the treatment of Major Depressive Disorder (MDD) (Gelenberg, 2010). Unfortunately, a high proportion of patients choose to discontinue their medication due to adverse effects (Bull et al., 2002a;Bull et al., 2002b;Rush et al., 2006) with sexual dysfunction reported as a common bothersome outcome from these medications (Hu et al., 2004) and an estimated prevalence of 20-70% (Bishop et al., 2009;Montejo et al., 2001). ...
... Samples analyzed for this study were collected as part of a previously enrolled and evaluated cohort of participants (Bishop et al., 2009). Potential participants were 18-40 years old, taking an SSRI medication for least 6-weeks, and free from any kind of sexual dysfunction before they started therapy. ...
We examined whether polymorphisms in the GRIK2, GRIA3 and GRIA1 genes were associated with selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction in 114 participants treated for depression. One polymorphism in GRIA1 (rs1994862) was associated with arousal dysfunction, providing further evidence for the role of GRIA1 in mechanisms underlying SSRI-associated sexual side effects.
... Different pharmacogenomic studies have been reported for these SNPs (rs6295 and rs6311) in the literature [16][17][18][19][20][21][22][23][24]. Inconsistencies in the findings of association studies have commonly been attributed to inter-ethnic variation in allele and genotype frequencies, differences in medications, variability in treatment outcome phenotype, and diagnostic categories of patients evaluated [25][26][27][28]. ...
The polymorphisms of the 5HTR1A and 5HTR2A receptor genes (rs6295C/G and rs6311G/A) have been evaluated for association with SSRI treatment outcome in various populations with different results. The present study was carried out to determine the association between genotypes of HTR1A-rs6295 and HTR2A-rs6311 with SSRI treatment outcome among the ethnic Malay patients diagnosed with first-episode major depressive disorder (MDD). The patients were recruited from four tertiary hospitals in the Klang Valley region of Malaysia. Predefined efficacy phenotypes based on 25% (partial early response) and 50% (clinical efficacy response) reduction in Montgomery Asberg Depression Rating Scale-self Rated score (MADRS-S) were adopted for assessment of treatment efficacy in this study. Self-reporting for adverse effects (AE) was documented using the Patient Rated Inventory of Side Effect (PRISE) after treatment with SSRI for up to 6 weeks. Adjusted binary logistic regression between genotypes of the polymorphism obtained using sequencing technique with the treatment outcome phenotypes was performed. The 142 patients recruited were made up of 96 females (67.6%) and 46 males (32.4%). Clinical efficacy and Partial early response phenotypes were not significantly associated with genotypes of HTR1A and HTR2A polymorphism. The GG genotype of HTR2A polymorphism has decreased odds for dizziness (CNS) and increased odds for poor concentration. The GA genotype increases the odd for excessive sweating, diarrhoea, constipation and blurred vision. The CC genotype of HTR1A-rs6295 decreases the odd for nausea/vomiting and increases the odd for anxiety. Thus, some genotypes of HTR1A and HTR2A polymorphism were associated with SSRI treatment outcomes in ethnic Malay MDD patients.
... Individuals with genotypes associated with inefficient serotonin transport (e. g., 5HTTLPR) have been shown to have significantly higher risk of experiencing antidepressant sexual side effects (Bishop, Moline, Ellingrod, Schultz, & Clayton, 2006;Clark et al., 2012;Huezo-Diaz et al., 2009). Women with the short form of this allele are at even higher risk if they also take hormonal contraceptives (Bishop, Ellingrod, Akroush, & Moline, 2009), suggesting possible interactions with endocrine factors. Similarly, older adults (60+) with high-expressing genotypes for serotonin transporter and autoreceptors are at particular risk of diminished sexual desire following antidepressant treatment (Garfield et al., 2014). ...
... However, intriguingly, the reason for that is not known. For example, women who take antidepressants are particularly susceptible to the sexual side effects of HCs, so checking whether a patient uses antidepressants may help [29]. ...
Purpose of Review
The purpose of this review is to discuss controversies about hormonal contraception (HC) and sexuality, as well as to analyze sexual function according to the type of HC.
Recent Findings
HC has negative effects on sexual desire and lubrication, and may contribute to increased vestibular pain. Although there are several different types of HC, all alter the androgenic environment, which may have negative effects on sexual function. On the other hand, there may be reasons to support the use of HCs, and there can be improvement in sexuality associated with their use. For instance, there may be benefits for benign gynecological disorders such as endometriosis, menorrhagia, and dysmenorrhea. In addition, owing their contraceptive capacity, HC helps alleviate the fear of pregnancy, increasing the pleasure of the sexual experience. Another important aspect may be the relationship between hormonal contraceptives, body image and appearance, self-esteem, and sexuality.
Summary
There is sufficient evidence that HC may have both a positive and a negative impact on female sexuality. Additional research is needed on several key issues: searching for an HC without negative effects on sexuality, or with as little effect as possible; detecting women at risk of sexual dysfunction following initiation of HC; and finally, the possibility of adding androgens to HCs to minimize sexual side effects.
... On the other hand, if ethnicity does indeed interact with 5-HTTLPR, it is important to note that available studies are almost exclusively comprised of non-Hispanic Caucasian and east Asian populations [7,8]. In addition to ethnicity, some researchers have hypothesized about differential effects of genotype by sex [6,11]. ...
... These markers may facilitate the prediction of adverse events such as SD during antidepressant treatment (30). In a study of the treatment of premature ejaculation, long allele homozygotes showed a better SSRI treatment response than short allele carriers (31)(32)(33)(34). The major effects of hyperprolactinemia in women are amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism, and increased longterm risk of osteoporosis. ...
The psychotic drug agents are linked and believed to increase risk of sexual dysfunction by increasing prolactin levels. Ginkgo Biloba Extract (GBE) is reported much effected in treating antidepressant induce sexual dysfunction. The current study was carried out in two phases. In first phase of study we did the evaluation of effect of hyperprolactinemia caused by CPZ(Chlorpromazine)on ovarian follicular growth, gonadotrophin and changes in ovarian hormone in adult female rats while in second phase investigation of prophylactic role of GBE against testicular damage, oxidative stress and caudal sperm indices in CPZ treated rodent model was done. In 1 st study we divided the animals in 4 groups, each group was consisting of 5 rats.1 st group was control while other three groups were treated with different doses of CPZ e. g 5mg/kg/day,15mg/kg/day, and 30mg/kg/day respectively for 2 weeks, CPZ was given via gavage. On 15 th day, the animals were sacrificed by decapitated, ovaries were removed and stained with H&E and later their histomorphometric examination was done. The serum levels of LH (Luteinizing hormone), FSH (Follicle Stimulating Hormone), Estradiol (E2), Progesterone and Prolactin levels were measured. CPZ treated groups showed varied amount and size of atretic follicle. The Higher rate of dysfunctional ovaries were seen in those groups which were treated with higher doses of CPZ. Similarly, higher concentration of progesterone and prolactin while lower concentration of FSH, E2, LH in sera and decreased rate of pregnancy was also observed in treated groups. The rate of toxicity was directly proportion to quantity of CPZ dose. In 2 nd phase of study the animals were divide into 5 groups and each had 5 rats.1 st was control,2 nd was treated with CPZ alone while other 3 were firstly treated with single dose of CPZ (30 mg/kg) and then treated with different doses of GBE i-e 45mg/kg,90mg/kg, and 200mg/kg respectively for 20 days. CPZ and GBE were given via gavage. On 21st day, at the end of experiment, the animals were sacrificed by de-capitated using guillotine and then their reproductive organs (testis, epididymis) were removed for further study. Decreased weight of testis and epididymis was also noted in CPZ treated groups. Moreover, degeneration of seminiferous tubules, reduction in sperm motility and count was also observed after CPZ toxicity. In addition to this, increase in the germ cell apoptosis was also noted; the levels of SOD, Testosterones, and CAT got reduced while MDA was increased in treated groups. The groups treated with GBE showed visible and significant improvement in all above said pathological alterations. The results of current study showed that 200mg/kg dose of GBE was more effective in protecting rodents against reproductive toxicity caused by CPZ.
... 8e11 First, very little empirical or clinical data support or validate the new DSM-5 diagnostic classification. Second, the distinction between female sexual desire and female sexual arousal as distinct dysfunctions is supported by several lines of evidence, including genetic evidence from twin studies, 12 studies of specific single-nucleotide polymorphisms, 13 studies of the use of serotonergic antidepressant medications, 14 and neuroimaging studies (for review, see 15,16 ). To address the controversial classification of female sexual dysfunctions in the DSM-5, the ISSWSH expert consensus panel met again in January 2016 and included 13 researchers and clinicians who are experts in female sexual dysfunction. 1 The ISSWSH report reads as follows: ...
Introduction:
Recent advances in neuroimaging offer an unprecedented window into the female sexual brain. The small samples and poor statistical power of individual functional magnetic resonance imaging studies have limited what can be gleaned about the systematic brain network that is involved in female sexual desire and female sexual dysfunction (eg, hypoactive sexual desire disorder [HSDD]).
Aim:
To quantitatively determine the brain network involved in HSDD.
Methods:
Systematic retrospective review and statistical meta-analysis of pertinent neuroimaging literature.
Main outcome measures:
Review of published literature on functional magnetic resonance imaging studies illustrating brain regions associated with female sexual desire and female HSDD.
Results:
HSDD is associated with a specific fronto-limbic-parietal dysfunction characterized by (i) lower blood oxygen level-dependent responses in the sexual desire brain network and (ii) higher blood oxygen level-dependent responses in the self-referential brain network.
Conclusion:
The meta-analytic results are in line with a top-down neurofunctional model of HSDD in which inspecting, monitoring, and evaluating oneself (rather than sensory experience) before or during sexual activities interfere with sexual desire. These results raise new questions regarding the necessity and sufficiency of dysfunctional activation in the sexual desire and self-referential brain networks, whose answers bear on the development and evaluation of personalized treatments for HSDD. Cacioppo S. Neuroimaging of Female Sexual Desire and Hypoactive Sexual Desire Disorder. Sex Med Rev 2017;X:XXX-XXX.
... En contraste, la categoría propuesta para la ICD-11 Disfunción por deseo sexual hipoactivo se puede aplicar tanto a hombres como a mujeres, en tanto que la disfunción de la excitación sexual femenina se clasifica por separado. La separación de deseo y la excitación en las mujeres en disfunciones diferentes está respaldada por varios tipos de evidencia, incluida la evidencia genética derivada de estudios en gemelos 36 , estudios específicos de polimorfismos de un solo nucleótido y la utilización de medicamentos antidepresivos serotoninérgicos 37,38 , así como estudios con neuroimágenes 39 . Así mismo, hay evidencia de que el trastorno por deseo hipoactivo en las mujeres y los hombres responden a tratamientos similares 40 , y que estos son diferentes de los tratamientos que son eficaces para el trastorno de la excitación sexual femenina [41][42][43] . ...
En la próxima undécima revisión de la Clasifcación Internacional de las Enfermedades y Problemas de Salud Relacionados (ICD-11) de la Organización Mundial de la Salud, se han propuesto cambios sustanciales a la clasificación de los trastornos mentales y conductuales relacionados con la sexualidad y la identidad de género de la ICD-10. Estos conciernen a los siguientes agrupamientos de trastornos de la ICD-10: F52 Disfunciones sexuales no causadas por enfermedades o trastornos orgánicos; F64 Trastornos de identidad de género; F65 Trastornos de preferencia sexual; y F66 Trastornos psicológicos y conductuales asociados al desarrollo y orientación sexual. Se han propuestos cambios con base en los avances en la investigación y en el ejercicio clínico, y cambios importantes en las actitudes sociales y en la normativa, leyes y normas de derechos humanos relevantes. Este artículo describe los principales cambios recomendados, la fundamentación y evidencia considerada y diferencias importantes con respecto al DSM-5. Se ha propuesto una clasificación integrada de disfunciones sexuales para un nuevo capítulo sobre Trastornos Relacionados con la Salud Sexual, que supera la separación mente/cuerpo inherente a la ICD-10. Se han reconceptuado los trastornos de identidad de género en la ICD-10 como incongruencia de género y también se ha propuesto que se cambien a un nuevo capítulo sobre salud sexual. La clasificación propuesta de los trastornos parafílicos distingue entre trastornos que son relevantes para la salud pública y la psicopatología clínica y los que simplemente reflejan conductas privadas. Se ha recomendado que se eliminen de la ICD-11 las categorías de la ICD-10 relacionadas con la orientación sexual.
... In contrast, the proposed ICD-11 category Hypoactive sexual desire dysfunction can be applied to both men and women, while Female sexual arousal dysfunction is classified separately. The separation of desire and arousal in women into distinct dysfunctions is supported by several lines of evidence, including genetic evidence from twin studies 36 , studies of specific single nucleotide polymorphisms and the use of serotonergic antidepressant medications 37,38 , and neuroimaging studies 39 . There is also evidence that Hypoactive desire disorder in women and men respond to similar treatments 40 , and that these are different from treatments that are effective for Female sexual arousal disorder [41][42][43] . ...
In the World Health Organization's forthcoming eleventh revision of the International Classification of Diseases and Related Health Problems (ICD-11), substantial changes have been proposed to the ICD-10 classification of mental and behavioural disorders related to sexuality and gender identity. These concern the following ICD-10 disorder groupings: F52 Sexual dysfunctions, not caused by organic disorder or disease; F64 Gender identity disorders; F65 Disorders of sexual preference; and F66 Psychological and behavioural disorders associated with sexual development and orientation. Changes have been proposed based on advances in research and clinical practice, and major shifts in social attitudes and in relevant policies, laws, and human rights standards. This paper describes the main recommended changes, the rationale and evidence considered, and important differences from the DSM-5. An integrated classification of sexual dysfunctions has been proposed for a new chapter on Conditions Related to Sexual Health, overcoming the mind/body separation that is inherent in ICD-10. Gender identity disorders in ICD-10 have been reconceptualized as Gender incongruence, and also proposed to be moved to the new chapter on sexual health. The proposed classification of Paraphilic disorders distinguishes between conditions that are relevant to public health and clinical psychopathology and those that merely reflect private behaviour. ICD-10 categories related to sexual orientation have been recommended for deletion from the ICD-11.
... Relatively fewer studies genotyped the triallelic locus and they did not support a substantial role of the polymorphism on antidepressant efficacy (Fabbri et al. 2013a). Several pharmacogenetic studies (Perlis et al. 2003;Murphy et al. 2004;Popp et al. 2006;Hu et al. 2007;Smits et al. 2007;Maron et al. 2009) and one meta-analysis (Kato and Serretti 2010) reported that the S allele may also be a risk factor for the development of SSRI-induced side effects in Caucasian populations, though not for sexual dysfunction (Bishop et al. 2009;Strohmaier et al. 2011). ...
Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.
... Certain genetic polymorphisms related to inefficient serotonin transport (eg, 5-HTTLPR) are associated with significantly higher risk of adverse sexual effects. 43 Women with vulnerable polymorphisms are at significantly increased risk of adverse sexual effects if they take hormonal contraceptives, 44 suggesting that switching to a low-dose or nonhormonal contraceptive method may improve sexual function in a subset of female antidepressant users. However, this recommendation is speculative and further research is needed to examine the efficacy of this strategy. ...
Because 1 in 6 women in the United States takes antidepressants and a substantial proportion of patients report some disturbance of sexual function while taking these medications, it is a near certainty that the practicing clinician will need to know how to assess and manage antidepressant-related female sexual dysfunction. Adverse sexual effects can be complex because there are several potentially overlapping etiologies, including sexual dysfunction associated with the underlying mood disorder. As such, careful assessment of sexual function at the premedication visit followed by monitoring at subsequent visits is critical. Treatment of adverse sexual effects can be pharmacological (dose reduction, drug discontinuation or switching, augmentation, or using medications with lower adverse effect profiles), behavioral (exercising before sexual activity, scheduling sexual activity, vibratory stimulation, psychotherapy), complementary and integrative (acupuncture, nutraceuticals), or some combination of these modalities.
... The possibility of using a genetic marker for screening patients at increased risk for AASD prior to prescribing an antidepressant could mitigate side effects experienced by those taking SSRIs. In another study on the genetics of AASD in a larger patient population taking SSRIs, the research team found SD associated with the serotonin transporter promoter insertion/deletion genotype in both male and female patients, but to different degrees, and especially among women who took oral contraceptives compared with those who did not [74]. ...
Sexual dysfunction is a common symptom in patients with depression and a frequent, poorly tolerated side effect of antidepressants used in treating their condition. The severity of this impairment can lead to non-adherence to the very medications prescribed for these patients and interfere with their recovery. Antidepressant-associated sexual dysfunction reduces patients' quality of life and therapeutic efficacy, yet physicians may not appreciate the prevalence of this side effect and how severely it can affect treatment adherence. In untreated patients with depression, the incidence of sexual dysfunction can be very high, but estimates have varied widely depending on the assessment method used, and evaluation of global sexual dysfunction (35-45%) versus specific phases of the sexual function cycle (60-80%). This paper provides a brief overview of current sexual dysfunction assessment tools. Patient factors and antidepressant selection affecting patient adherence are reviewed and the potential for individualized antidepressant treatment is discussed. The paper also offers potential options, including genetic identification, for managing antidepressant-associated sexual dysfunction in the hopes of improving patient adherence and treatment success.
... Considering side effects, females with the LL genotype were more likely to be categorized as having SSRI-associated sexual dysfunction if they were taking oral contraceptive (OC) medication, whereas no relationship was observed in those not taking OCs and in men (Bishop et al., 2009). ...
Background:
Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders.
Methods:
A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT.
Results:
5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations.
Limitations:
The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender.
Conclusions:
5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR×gender on the modulation of affective disorders.
... One distinct 5-HT2A receptor SNP, 5-HT2A-1438 GG, appears to correlate with lower scores of sexual arousal compared with alternate genotypes [81]; a more recent Malaysian study failed to replicate this finding but was limited by sample size [82]. A larger study linked SD with a particular insertion/deletion variant within the promoter region of the SLC6A4 serotonin transporter gene; this effect was most striking in female patients that were concurrently prescribed oral contraceptives [83]. Research has also demonstrated a connection between SNPs of glutaminergic genes and an array of sexual problems, including decreased libido, erectile dysfunction and difficulty achieving orgasm [84]. ...
Introduction:
There is a well-established relationship between sexual functioning and quality of life. Depression can cause sexual dysfunction (SD) and its treatment can often lead to restoration of sexual functioning. Use of antidepressants has also been associated with SD, with implications for treatment compliance and creation of further distress for the patient.
Areas covered:
This review evaluates available information regarding SD related to both depression and antidepressant treatment, including literature up to June 2014. It includes eligible published studies that investigated antidepressant-associated SD (AASD).
Expert opinion:
Depression and SD have a bidirectional association. When screening for depression, baseline sexual functioning should be assessed with validated rating scales. If sexual side effects develop with antidepressant treatment, management options include waiting for spontaneous remission, decreasing the medication dose, switching to an alternative drug or adding an augmentation agent or antidote. Research suggests that bupropion and newer antidepressants exhibit a more favorable SD profile compared with other antidepressants, especially selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. Bupropion, mirtazapine and buspirone have been studied as augmentation agents/antidotes or substitution agents in management of AASD. Future studies validating genetic factors could enable personal genotyping to guide individualized treatment and also facilitate the development of enhanced therapeutic guidelines to avoid or manage AASD.
... However, numerous concerns have arisen regarding the well-known side effect of decreased sexual desire and orgasm among those taking SSRIs (48)(49)(50)(51). This side effect points to the potential role of serotonin in human sexual behaviors, yet associations between allelic variants of the serotonin transporter and human sexuality have not been well explored (34,52,53). Furthermore, while current research has provided general support for both dopamine and serotonin's role in human sexual experience, when explored, results have been less conclusive for females (33,34), emphasizing the need for further research on biological aspects of female sexual experience and how they may influence behavior. ...
Background:
Sexuality-related constructs, such as sexual arousal, sexual sensation seeking (SSS) and sexual satisfaction, have been related to sexual behaviours that place one at risk of adverse consequences, such as sexually transmissible infections, HIV and unintended pregnancy. The biopsychosocial model posits an array of factors, ranging from social environmental factors to biological and psychological predispositions, that may be associated with these sexuality constructs in adolescents.
Methods:
Female African Americans aged 14-20 years were recruited from reproductive health clinics for an HIV intervention. Baseline survey and follow-up DNA data (n=304) were used to assess biological, psychological and social environmental associations with the sexuality constructs of arousal, SSS and sexual satisfaction.
Results:
Multivariate linear regression analysis revealed that a higher depressive symptom rating was associated with higher arousability, whereas short serotonin transporter gene allele(s) status was associated with lower arousability. Impulsivity and perceived peer norms supportive of unsafe sexual behaviours were associated with increased SSS, whereas short serotonin transporter gene allele(s) status was associated with lower SSS. Higher social support was associated with higher levels of sexual satisfaction, whereas short serotonin transporter gene allele(s) status was associated with lower satisfaction. The sexuality constructs were also significantly related to the number of sex partners, the frequency of vaginal sex and the number of unprotected vaginal sex acts in the past 6 months.
Conclusions:
The findings emphasise the importance of understanding biopsychosocial factors, including the role of serotonin as an indicator of natural variations in sexual inclination and behaviours, that influence sexuality constructs, which, in turn, are associated with sexual behaviours, to allow further refinement of sexual health clinical services and programs and promote the development of healthy sexuality.
... There is little doubt that pharmacological manipulations leading to alterations in the serotonergic system can influence female sexual behavior in a variety of species, including humans. Recent attempts to identify 5-HT system relevant genetic polymorphisms (Kroeze et al., 2012;Sghendo and Mifsud, 2011) and their association with female HSDD and/or after treatment with 5-HT system altering drugs (Bishop et al., 2009;Bishop et al., 2006;Burri et al., 2012;Serretti et al., 2007) may begin to offer a profile about which components of the 5-HT system are especially important in female sexual behavior. However, in spite of a considerable amount of data, there are still many limitations to our current knowledge. ...
In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed. Evidence is presented that drugs which increase 5-HT have negative effects on female sexual behavior while a decrease in 5-HT is associated with facilitation of sexual behavior. Studies with compounds that act on 5-HT1, 5-HT2 or 5-HT3 receptors are discussed. Most evidence indicates that 5-HT1A receptor agonists inhibit sexual behavior while 5-HT2 or 5-HT3 receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual behavior, but studies on the role of 5-HT in other elements of female sexual behavior (e.g. desire, motivation, sexual appetite) are few. Future studies should be directed at determining if these additional components of female sexual behavior are also modulated by 5-HT.
... Since other factors such as age, gender, smoking, diet, co-medication and disease symptoms also infl uence drug response and side effects, well controlled studies will be required in addition to cost-benefi t analyses. Given that other genes will ultimately also modulate response and side effects to psychotropic medication ( Bishop et al., 2009), the ' ideal ' genetic test will be based on an algorithm including several genes and multiple gene variants, and once validated, such test will signifi cantly improve psychiatric drug treatment. Our experiences in our Pharmacogenetics Research Clinic (CAMH, Toronto) have shown that physicians and patients are willing to adopt genetic testing and suggest that implementation in routine clinical practice is feasible. ...
Abstract Genetic testing may help to improve treatment outcomes in order to avoid non-response or severe side effects to psychotropic medication. Most robust data have been obtained for gene variants in CYP2D6 and CYP2C19 enzymes for antipsychotics and antidepressant treatment. We reviewed original articles indexed in PubMed from 2008-2013 on CYP2D6 and CYP2C19 gene variants and treatment outcome to antidepressant or antipsychotic medication. We have started providing CYP2D6 and CYP2C19 genotype information to physicians and conducted a survey where preliminary results are reported. Studies provided mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Plasma levels were mostly found associated with CYP metabolizer status. Higher occurrence/severity of side effects were reported in non-extensive CYP2D6 or CYP2C19 metabolizers. Results showed that providing genotypic information is feasible and generally well accepted by both patients and physicians. Although currently available studies are limited by small sample sizes and infrequent plasma drug level assessment, research to date indicates that CYP2D6 and CYP2C19 testing may be beneficial particularly for non-extensive metabolizing patients. In summary, clinical assessment of CYP2D6 and CYP2C19 metabolizer status is feasible, well accepted and optimizes drug treatment in psychiatry.
... As a key regulator of SERT activity, 5-HTTLPR may also influence the risk of SSRI induced side effects. Available studies mainly suggested the S allele as risk factor [Perlis et al., 2003;Murphy et al., 2004;Popp et al., 2006;Hu et al., 2007;Smits et al., 2007;Maron et al., 2009], while only one study found an opposite result for sexual dysfunction in females taking oral contraceptives [Bishop et al., 2009]. On the other hand, studies reporting no association between 5-HTTLPR and antidepressant side effects were mainly performed in non-Caucasian samples Ng et al., 2006;Hougardy et al., 2008;Higuchi et al., 2009;Lee et al., 2010;Strohmaier et al., 2011], further suggesting a population-specific effect of the polymorphism (Supplementary Table I). ...
Major depressive disorder (MDD) is an emergent cause of personal and socio-economic burden, both for the high prevalence of the disorder and the unsatisfying response rate of the available antidepressant treatments. No reliable predictor of treatment efficacy and tolerance in the single patient is available, thus drug choice is based on a trial and error principle with poor clinical efficiency. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter-individual variability. The present review collected the main pharmacogenetic findings primarily about antidepressant response and secondly about antidepressant induced side effects, and discussed the main strengths and limits of both candidate and genome-wide association studies and the most promising methodological opportunities and challenges of the field. Despite clinical applications of antidepressant pharmacogenetics are not available yet, previous findings suggest that genotyping may be applied in the clinical practice. In order to reach this objective, further rigorous pharmacogenetic studies (adequate sample size, study of better defined clinical subtypes of MDD, adequate covering of the genetic variability), their combination with the results obtained through complementary methodologies (e.g., pathway analysis, epigenetics, transcriptomics, and proteomics), and finally cost-effectiveness trials are required. © 2013 Wiley Periodicals, Inc.
... The factors responsible for resistance to these sexual side effects is not known. However, Bishop and colleagues have described evidence that genetic polymorphisms in the promoter regions of the 5-HT 2A receptor gene or in the SERT gene may influence vulnerability to SSRI-associated sexual dysfunction [62,63] but not all reports agree [64]. Other investigators have implicated individual differences in the effect of SSRIs on the P450 2D6 isoenzyme leading to accumulation of higher concentrations of the drugs [65]. ...
Introduction. The selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5-HT1A receptor has been implicated in this sexual dysfunction. Whether this association with 5-HT1A receptors holds for other rat strains is not known.
Aim. The effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5-HT1A receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined.
Methods. Proestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI.
Main Outcome Measures. Lordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague-Dawley and Fischer females were compared on each of these measures. The IC50 for inhibition of lordosis behavior was determined.
Results. In both the intact and the hormonally primed, ovariectomized model, Sprague-Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose dependency in behavioral inhibition, but a higher dose was required for Sprague-Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5-HT1A receptor agonist.
Conclusions. Acute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague-Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5-HT1A receptor agonist. Fluoxetine's inhibition of female rat sexual behavior may involve effects of the SSRI in addition to activation of the 5-HT1A receptor. Miryala CSJ, Hiegel C, and Uphouse L. Sprague-Dawley and Fischer female rats differ in acute effects of fluoxetine on sexual behavior. J Sex Med **;**:**–**.
... Subjects included in this study were originally recruited for a point prevalence "health and well-being study" of SSRI use. 3 In the original study, 122 outpatients with depression treated with an SSRI, were recruited through local advertisements. Potential research subjects were screened by telephone for eligibility. ...
Objective:
The adrenergic beta-1 receptor gene (ADRB1) Ser49Gly and Arg389Gly variants differentially affect blood pressure response to beta-blocker therapy. Binding site prediction results for fluoxetine and paroxetine in a bioinformatics model estimated that each of these particular selective serotonin reuptake inhibitors (SSRIs) have high receptor affinity as an "Adrenergic (beta) Blocker," which was confirmed in vitro. This pilot study was conducted to understand the relationship between these "beta-blocking" SSRIs (fluoxetine and paroxetine) and cardiac vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)), when subjects are stratified by ADRB1 genotype. Previously ascertained DNA and clinical data was examined from 122 subjects recruited for a cross-sectional study of health and well being during SSRI pharmacotherapy. A multivariate linear regression analysis was used to determine which variables affected cardiac vital signs. There was a significant interaction between Arg389Gly variant status and "beta-blocking" SSRIs [p = 0.0353] in relation to SBP. Specifically in homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs had significantly lower SBP (mean 104 mmHg) compared to the group taking other SSRIs (mean 122 mmHg) [p = 0.0437]. In these same homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs also had lower HR (mean 60 bpm) compared to the other SSRIs (mean 79 bpm) [p = 0.00877]. Future prospective studies of this phenomenon are necessary to identify all genetic markers that can predict SSRI-associated cardiovascular effects that may be related to the SSRI discontinuation syndrome and potentially influence pharmacotherapy decisions.
![Гарник [Garnik] Суренович [Surenovich] Кочарян [Kocharyan]](https://i1.rgstatic.net/ii/profile.image/808187276038144-1569698270660_Q64/Garnik-garnik-Kocaran-kocharyan.jpg)
The article deals with clinical manifestations of diminished libido as well as definitions of hypoactive sexual desire disorder (HSDD) in the International Classification of Diseases, 10th Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders, Fourth and Fifth Editions (DSM-4 and DSM-5) (USA). Its corresponding code in ICD-10 is F52.0 (“Lack or loss of sexual desire”), which is common for both men and women. DSM-4 has code 302.71 (“Hypoactive Sexual Desire Disorder”), which is common for persons of both sexes too. The point to note is that the above classification considers the presence of distress or difficulties in interpersonal communication, caused by hyposexuality, as one of indicators for diagnosing this disorder. DSM-5 uses diagnosis “Male Hypoactive Sexual Desire Disorder” (code 302.71), whereas for revealing this disorder in women general diagnosis “Female Sexual Interest/Arousal Disorder” (code 302.72) is used, since in compliance with the opinion, present in the above guide, women are characterized by difficulties in differentiation and a frequent comorbidity of disorders of sexual interest and sexual excitement. Also, attention is called to the fact of substitution of the term “sexual desire” with the term “sexual interest”, thereby giving some psychological tint to the first part of the diagnosis and reducing its biological background. Both DSM-5 codes (for men and for women) also provide for a diagnostic criterion, according to which hypoactive sexual manifestations cause a clinically significant distress. The author also informs about existence of an autonomous classification of female sexual dysfunctions by two international panels of experts in sexual medicine (Nomenclature Committee of the International Society for the Study of Women’s Sexual Health and the International Consultation in Sexual Medicine), who believe that preservation of the separate diagnosis “Hypoactive sexual desire disorder” for women is reasonable. It is reported that ICD-11 will use diagnosis “Hypoactive sexual desire dysfunction” not only for men, but for women too. The given data demonstrate scientific substantiation for such a decision. Attention is called to the fact that the above classification has fully absolutized the subjective perception of hyposexuality. For example, it is reported that the proposed diagnostic guide takes aim at the absence of any norms for sexual activity. It is suggested to regard as “satisfactory” the sexual activity, which satisfies the given person. If the individual is satisfied with his/her sexual activity, the possibility of diagnosing his/her sexual dysfunction is excluded at once. Validity of such an approach is discussed. Besides the described hypoactive sexual manifestations, the article also lists the clinical phenomena, which are associated with the above manifestations and accompany them.
Key words: diminished libido, manifestations, hypoactive sexual desire disorder, definitions, women, men.
В статье приводятся клинические проявления ослабленного либидо, а также определения гипоактивного расстройства полового влечения в Международной классификации болезней десятого пересмотра (МКБ-10), Диагностическом и статистическом руководстве по психическим расстройствам четвертого и пятого пересмотра (DSM-4 и DSM-5) (США). В МКБ-10 ему соответствует шифр F52.0 («Отсутствие или потеря полового влечения»), который является общим как для мужчин, так и для женщин. В DSM-4 есть шифр 302.71 («Гипоактивное расстройство полового влечения»), который также является общим для лиц обоего пола. Следует обратить внимание, что одним из индикаторов для определения этого расстройства в данной классификации называют наличие из-за гипосексуальности дистресса или трудностей в межличностном общении. В DSM-5 используется диагноз «Male Hypoactive Sexual Desire Disorder» (шифр 302.71), а для определения этого расстройства у женщин уже применяется общий диагноз «Гипоактивное расстройство сексуального интереса/возбуждения» (шифр 302.72), так как по мнению, отраженному в данном руководстве, у женщин существует сложность дифференциации и частая коморбидность расстройств полового интереса и сексуального возбуждения. Также обращает на себя внимание замена термина «половое влечение» на термин «сексуальный интерес», что придает некоторый психологический оттенок первой части диагноза и уменьшает его биологичность. В обоих шифрах DSM-5 (для мужчин и для женщин) также предусмотрен диагностический критерий, согласно которому гипоактивные сексуальные проявления вызывают клинически значимый дистресс. Автор сообщает о существовании автономной классификации женских сексуальных дисфункций двух международных групп экспертов в области медицинской сексологии («Номенклатурного комитета Международного общества по изучению сексуального здоровья у женщин» и «Международного комитета по вопросам сексуальной медицины»), которые считают обоснованным сохранение отдельного диагноза гипоактивное расстройства полового влечения у женщин. Сообщается, что в МКБ-11 будет использоваться диагноз «Гипоактивная дисфункция полового влечения» не только для мужчин, но и для женщин. Приводятся данные, свидетельствующие о научной обоснованности такого решения. Обращает на себя внимание тот факт, что в данной классификации произошла полная абсолютизация субъективного восприятия гипосексуальности. Так, сообщается, что предлагаемое диагностическое руководство нацеливает на то, что не существует никаких нормативов сексуальной активности. «Удовлетворительной» сексуальной активностью предлагается считать такую, которая удовлетворяет данного конкретного человека. Если индивид удовлетворен своей сексуальной активностью, то возможность установления диагноза сексуальной дисфункции сразу исключается. Обсуждается правомерность такого подхода. Также в статье, помимо описанных гипоактивных сексуальных проявлений, называются связанные с ними и сопутствующие им клинические феномены.
Ключевые слова: ослабленное либидо, проявления, гипоактивное расстройство полового влечения, определения, женщины, мужчины.
Introduction:
Sexual dysfunction (SD) is a symptom of depression in ≈70% of patients presenting with major depressive disorder (MDD). Antidepressant medications (AD) and adjunctive treatments may further contribute to SD and complicate evaluation and management.
Areas covered:
A systematic literature search of PubMed, Ovid MEDLINE and Cochrane databases for MDD, SD, classes of antidepressants, etc. was performed with a focus on 2014 to June 2021. SSRIs are associated with 70% treatment-emergent sexual dysfunction (TESD), SNRIs and tricyclics have rates of TESD of 40 - 45%, and antidepressant medications without SRI effects or with additional unique mechanisms of action have rates similar to placebo (<10%). Appropriate assessment at baseline and throughout treatment, consideration of patient preferences in prescribing, addressing modifiable factors (comorbid medical/psychiatric conditions, substances, relationship difficulties), and utilizing management strategies of switching to an AD with less SD, adding an antidote/adjunctive therapy or lowering the dose are discussed.
Expert opinion:
MDD and antidepressant treatment contribute to SD in a high percentage of patients. Treating to remission reduces SD as a symptom of depression. Frequent assessment and targeted management strategies may be effective in preventing or addressing SD. Secondary outcomes like impact on adherence, relationships and self-image should also be considered.
Background
Patients being treated with SSRIs who experience intolerable Adverse Effects (AEs) have a penchant for discontinuing treatment, inevitably jeopardizing any probability for treatment response.
Aim
This study aims to identify the Single Nucleotide Polymorphisms (SNPs) that are associated with certain AEs of SSRI treatment in Major Depression Disorder (MDD).
Results
Patients with the short (SS) genotype (44 base pair deletion) and those with the long along with guanine substitution (LgLg - 44 base pair insertion with rs25531- guanine substitution variant) of the serotonin transporter gene (STG) have substantially been reported with a higher incidence of AEs to SSRI. While variants of glutamate receptor ionotropic genes have been found to be linked with different domains of sexual dysfunction, polymorphisms of 5-HT2A gene - rs6311 (G > A), the long allele (L) of STG, rs6295 (C > G) polymorphism of HTR1A and polymorphism rs1160351 (A > C) of MAM domain-containing glycosyl-phosphatidyl inositol anchor 2 (MDGA2) gene have also been found to be associated with sexual dysfunction. The rs4680 (G>A; Val > Met) polymorphism of catechol-O-methyltransferase (COMT), AA genotype of rs18532 polymorphism of tryptophan hydroxylase, the rs6318 (C > G) polymorphism of the serotonin receptor 2C (HTR2C), and S allele of STG were found to be associated with weight gain following SSRI treatment. The sanctity of these results is limited by the inability of some researchers to replicate these association findings.
Conclusion
This review highlights a number of polymorphisms associated with some of the key AEs encountered in SSRI treatments. Standardized study designs in pharmacogenomic evaluations hold great promise for replication of association findings.
Major Depressive Disorder(MDD) is serious psychiatric condition and they affect one in five people during their lifetime, the annual prevalence rates for the US population are 7.1% among adults, slightly more common among women (8.7%) than men (5.3%). Selective serotonin reuptake inhibitors are among the pharmacological agents most commonly used in the treatment of MDD.
The mechanism of action of antidepressants is not yet fully understood. Currently, it is believed that the mechanism of the so-called down-regulation, i.e. reducing the density of receptors in the postsynaptic membrane, in this case mainly 5HT2 receptors. All of the antidepressants in use today have some common side effects. The side effect that will be discussed in the broadest possible way in this paper are sexual dysfunctions appearing during the therapy. Measuring the degree to which a given substance affects the sexual function of a patient diagnosed with MDD encounters many difficulties on its way. There are currently several questionnaires enabling such an assessment, the most common are CSFQ, ASEX and SexFX. Also the major problem is Post SSRI Sexual Disfunction. A number of animal studies have proven that prolonged exposure to SSRIs leave permanent changes in the CNS, but unfortunately, similar studies have not yet been conducted in humans. The aim of this study is to present the problem of sexual dysfunction as a side effect of SSRI therapy, to present the causes and to propose a strategy to combat SSRI-induced sexual dysfunctions.
Sexual dysfunction (SD) is a frequent and distressing side effect of many psychotropic medications, including serotonergic antidepressants, antipsychotic medications, and mood stabilizers. Psychotropic medications may negatively influence any of the areas of sexual functioning, including libido, arousal, and orgasm. Sexual dysfunction is a threat to patients’ quality of life and frequently affects partners’ quality of life as well. Yet, SD is often underestimated both in clinical trials and in clinical practice. In fact, many patients feel embarrassed to spontaneously discuss side effects that involve sexual functions, and many study designs and clinicians rely only on spontaneous reports. This chapter provides an overview of medication-induced SD and examines the prevalence, clinical characteristics, causes, and treatment options for this burdensome condition.
For patients with mental health disorders treated with psychotropic medications, contraceptive management can be challenging for the primary care provider. Effectiveness of the combined oral contraceptive may decrease with concomitant use of certain psychotropic medications, although notably SSRIs do not have this interaction. Certain psychotropic medications may convey sexual side effects or hormonal effects such as elevated prolactin levels, elevated androgen levels, and decreased sex hormone-binding globulin, which may lead to clinical symptoms. The lack of effective contraception in patients on psychotropic medications may lead to teratogenic effects in the event of an unplanned pregnancy. Long-acting reversible contraceptives may be a preferred contraceptive method in these patients for improved rate of pregnancy prevention and the avoidance of pharmacologic interactions.
Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability studies. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. METHODS: Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 utilizing a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. The S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence including assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs This article is protected by copyright. All rights reserved.
Pharmacogenomics is a rapidly growing field dedicated to identifying genetic markers that will allow practitioners to identify safe and effective therapy that is tailored to the individual patient. As a result, pharmacogenomic testing has the potential to optimize drug therapy for a variety of disease states. The landmark Sequenced Treatment Alternatives to Relieve Depression trial, commonly known as the STAR*D trial, showed that only a disappointing 30 % of patients experience remission from depression symptoms with their initial trial of antidepressant therapy. Furthermore, other studies have shown that 70 % of patients not remitting after their first medication trial may endure symptoms for months before experiencing relief secondary to drug therapy. In the future it is hoped that advancing pharmacogenomics research will help identify the safest and most effective medication for each patient-not only for the treatment of depression but for other disease states as well. Currently pharmacogenomic testing is not widely implemented; however, this is likely to change as clinicians become increasingly familiar with this field. This chapter will familiarize clinicians with the field of pharmacogenomics by (1) building a simple understanding of how genetic variability can alter drug response, (2) discussing current approaches in pharmacogenomics research, (3) describing helpful resources for practitioners, (4) providing an overview of the clinical application of pharmacogenomics and the associated issue of reimbursement, and (5) reviewing opinions on the future of pharmacogenomics in the clinical setting.
How contraceptives affect women's sexual well-being is critically understudied. Fortunately, a growing literature focuses on sexual aspects of contraception, especially hormonal contraception's associations with libido. However, a more holistic approach to contraceptive sexual acceptability is needed to capture the full range of women's sexual experiences. We conducted a narrative literature review of this topic, working with an original sample of 3,001 citations published from 2005 to 2015. In Part 1, we draw from a subset of this literature (264 citations) to build a new conceptual model of sexual acceptability. Aspects include macro factors (gender, social inequality, culture, and structure), relationship factors (dyadic influences and partner preferences), and individual factors (sexual functioning, sexual preferences, such as dis/inhibition, spontaneity, pleasure, the sexual aspects of side effects, such as bleeding, mood changes, sexual identity and sexual minority status, and pregnancy intentions). In Part 2, we review the empirical literature on the sexual acceptability of individual methods (103 citations), applying the model as much as possible. Results suggest contraceptives can affect women's sexuality in a wide variety of positive and negative ways that extend beyond sexual functioning alone. More attention to sexual acceptability could promote both women's sexual well-being and more widespread, user-friendly contraceptive practices.
Selective serotonin reuptake inhibitors (SSRIs) induced delayed ejaculation as an adverse effect. Cause of this they have been used to treat Premature Ejaculation. Recent studies have suggested that sildenafil, a selective inhibitor of cyclic GMP specific phosphodiesterase type 5, could be beneficial in the treatment of PE. However, some studies demonstrated that sildenafil is helpfull in the treatment of SSRI induced delayed ejaculation. In the present study, we examined the effects of administration of the SSRIs plus sildenafil combination on vas deferens contractions on isolated rat vas deferens. Saline (10ml/kg) was administered to the control group rats for 15 days intraperitoneally (i.p). Fluoxetine (20 mg/kg), sertraline (10 mg/kg) or citalopram (10mg/kg) were administered to the SSRI groups for 14 days i.p and 10 ml/kg saline was administered at 15th day. SSRIs were administered to the combination groups for 14 days i.p. and 10 ml/kg sildenafil was administered at 15th day. Saline (10ml/kg) was administered to the sildenafil group for 14 days i.p and at 15th day, 10 mg/kg sildenafil was administered. Rats were exposed to the forced swimming test. After the test rats vas deferens were removed and placed in organ baths and the contraction responses induced by electrical field stimulation (EFS) were recorded. The contraction responses induced by EFS were inhibited by SSRIs. This inhibition effect was antagonized by sildenafil when administered with fluoxetine or citalopram but not with sertraline. The results thought that sildenafil could have limited the 5-HT increasing effects of fluoksetin and citalopram, having lower potency for binding to the 5-HTT in synaptic cleft, whereas could not have limited this effect of sertraline, having more potency for binding to the 5-HTT. We suggest that 5-HTT may have a role on differantiated effects of SSRIs plus sildenafil combination on vas deferens contractions.
Background and aim:Sexual dysfunction could be most important side effect of selective serotonin reuptake inhibitors (SSRIs). Sexual dysfunction is common among both men and women with major depressive disorder. Propose of this study is to evaluate the effect of SSRIs drug on sexual tendency and ability. Method:Present study was conducted during November 211to January 2012. Sample consisted of 584 subjects. All patients attending psychiatry clinic. 247subjects used SSRIs drug and 337 subjects used other psychiatry drugs. Results:Results of the research indicated that out of 247subjects used SSRIs drug 93people(38%) did not show drug side effects, but from other subjects; 60people (24%) reduced sexual tendency, 25people(10%) total disruption of sexual tendency, 33people(13%) lack of sexual tendency before onset of treatment, 10 people (4%) reduced sexual tendency before beginning of treatment, 10people(4%) increased sexual tendency, 7 people (3%) lack of satisfaction, 2people(0.08%) reduced or delayed satisfaction were reported. Discussion and Conclusion: The results of studies investigating correlation of SSRIs drugs and Sexual Dysfunction, which there are significant relation between consumption of SSRIs drugs and reduce or disruption of sexual tendency that may be one the most important problem among the couples.
Objective: To investigate the distribution characteristics and research direction of SSRIs pharmacogenetics for providing a basic for further research. Methods: Articles were searched and analyzed by bibliometrics. Results: A total of 83 references of pharmacogenetics were recorded. The total number has increased quickly during the recent years. The core journals have not yet formed, but the core writers have been formed preliminarily. The gene loci were focused gradually. Conclusion: The pharmacogenetics of SSRIs has attracted more and more attention. We should pay more attention to it.
Nowadays antidepressants are still administrated by a trial and error principle and a substantial proportion of patients does not benefit from treatment or suffers from significant side effects. Clinical features failed to predict the antidepressant response and tolerability, so pharmacogenetic seems to be the most promising way to achieve the target of an individualized therapy. The aim of this paper is to review the current knowledge of findings in pharmacogenetic of antidepressant, and to analyze how they could impact the everyday clinical practice. We mainly focused on pharmacodynamics associated genes where promising results have been found, although still poor replicated to allow clinical applications. On the other hand evidences regarding pharmacokinetics genes, although consistent enough to allow the design of genetic chips, seem to have less relevance to predict antidepressant response. The main results are underlined, new promising polymorphisms are suggested. Finally, the clinical impact of pharmacogenetic studies is debated.
Sexual dysfunction is a troubling obstacle for individuals being treated for depression and can be caused by both depressive symptoms as well as antidepressant drugs. Selective serotonin reuptake inhibitors (SSRIs) represent a class of antidepressants commonly associated with sexual dysfunction, even after symptomatic improvement. Candidate gene studies have identified associations between sexual dysfunction and altered SSRI pharmacokinetics or to the neurotransmitter systems affected by depression and SSRI treatment. The multifactorial nature of this phenotype and study heterogeneity are currently limitations to the translation of these findings to clinical use. Larger, prospective studies of genetic-guided antidepressant selection may help to clarify the clinical utility of pharmacogenetics in minimizing sexual side effects.
Objective:
Major depressive disorder is the most common psychiatric disorder, worldwide, yet response and remission rates are still unsatisfactory. The identification of genetic predictors of antidepressant (AD) response could provide a promising opportunity to improve current AD efficacy through the personalization of treatment. The major steps and findings along this path are reviewed together with their clinical implications and limitations.
Method:
We systematically reviewed the literature through MEDLINE and Embase database searches, using any word combination of "antidepressant," "gene," "polymorphism," "pharmacogenetics," "genome-wide association study," "GWAS," "response," and "adverse drug reactions." Experimental works and reviews published until March 2012 were collected and compared.
Results:
Numerous genes pertaining to several functional systems were associated with AD response. The more robust findings were found for the following genes: solute carrier family 6 (neurotransmitter transporter), member 4; serotonin receptor 1A and 2A; brain-derived neurotrophic factor; and catechol-O-methyltransferase. Genome-wide association studies (GWASs) provided many top markers, even if none of them reached genome-wide significance.
Conclusions:
AD pharmacogenetics have not produced any knowledge applicable to routine clinical practice yet, as results were mainly inconsistent across studies. Despite this, the rising awareness about methodological deficits of past studies could allow for the identication of more suitable strategies, such as the integration of the GWAS approach with the candidate gene approach, and innovative methodologies, such as pathway analysis and study of depressive endophenotypes.
Sexual dysfunction is a potential side effect of antidepressant drugs: this article presents a critical review of the current literature. Although many studies have been published on this subject, only some have used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antidepressants are limited by other methodological flaws. However, there is consistent evidence to suggest that antidepressant medication adversely affects one or more of the 3 phases of sexual response (desire, arousal and orgasm). Antidepressants with strong serotonergic properties have the highest rate of sexual side effects. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences on clinical management and compliance.
Background:
Antidepressant medication is a major cornerstone in treatment of mood and anxiety disorders. Numerous substances are available on the market; however, only 60% of treated patients show sufficient response to medication and side effects are common. Lengthy trials are not uncommon until the optimized drug and dose is found and unfortunately, no valid predictors to match the 'right' drug to the 'right' patient exist nowadays. Genetic factors are thought to be involved as evidenced by numerous pharmacogenetic studies. This comprehensive review summarizes the most interesting findings and discusses clinical implications of pharmacogenetic results.
Methods:
We reviewed available literature on pharmacogenetics of antidepressant response and side effects until summer 2011 using the PubMed database.
Results:
Promising findings exist for several variants in candidate genes involved in the pharmacokinetics or pharmacodynamics of antidepressants. These include association findings in the serotonin transporter gene (5-HTT), serotonin receptor genes, a gene coding an efflux pump in the blood-brain-barrier (ABCB1), and genes involved in the HPA axis. Promising candidate genes increasing risk for side effects include some of the genes associated with treatment response and cytochrome P450 genes.
Conclusion:
A high number of studies on pharmacogenetics of antidepressants have been published during the past decades. However, contradictory results still limit clinical use of these findings. Future studies should include functional analyses and consider gene-gene and gene-environment interactions. This will aid in facilitating a future use of pharmacogenetics in clinical practice, likely leading to improved patient care.
Introduction:
To date, few studies have specifically investigated the genetic determinants of antidepressant-induced sexual dysfunction (SD).
Aim:
The aim of this prospective study was to examine whether the 5-HT2A receptor -1438 G/A polymorphism has functional consequences on sexual well-being in young adult men presenting with their first episode of major depressive disorder (MDD) after serotonergic antidepressant treatment.
Methods:
Between May 2010 and June 2011, a total of 56 drug-naïve patients presenting with their first episode of MDD were recruited from a psychiatric hospital and received either a selective serotonin reuptake inhibitor or venlafaxine monotherapy; the patients were then genotyped. Over the course of antidepressant treatment, the population was divided into a SD group (N=16) and a non-SD group (N=29) based on the Arizona Sexual Experience Scale (ASEX). Participants who did not achieve a significant improvement, as assessed by the Hamilton Depression Rating Scale (HAMD-17), were excluded from the final data analysis.
Main outcome measures:
The primary outcome measures were the differences in the genotype distribution and allele frequencies between groups.
Results:
In the SD group, the AA genotype was significantly overrepresented (P=0.004), and the mean baseline HAMD-17 score, the mean baseline ASEX score, and the mean end-point ASEX score were significantly higher than those in the non-SD group (P=0.026, P=0.004, and P<0.001, respectively). The mean end-point HAMD-17 score (P=0.115) did not differ significantly between the two groups.
Conclusion:
These results suggest that the AA genotype may be a genetic trait offering an opportunity to strengthen early detection of serotonergic antidepressant-induced SD in young adult male patients with MDD, whereas the G allele is protective against SD in this population.
To evaluate sexual function in midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms. Selective serotonin reuptake inhibitors effectively treat vasomotor symptoms but adversely affect sexual function in depressed populations. Information on sexual function in nondepressed midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms is lacking; any treatments that might impair function are of concern.
This was a randomized controlled trial comparing 8 weeks of escitalopram with placebo in women ages 40-62 years with 28 or more bothersome vasomotor symptoms per week. Change in Female Sexual Function Index composite score (ranges from 2 [not sexually active, no desire] to 36) and six sexual domains (desire, arousal, lubrication, orgasm, satisfaction, pain) and the Female Sexual Distress Scale, and a single-question of sexually-related personal distress from the Female Sexual Distress Scale, were compared between groups.
Among all women, median composite baseline Female Sexual Function Index score was 18.1 (interquartile range 2.4-26.5, n=200) and among sexually active women was 22.8 (interquartile range 17.4-27.0, n=75) in the escitalopram group and 23.6 (interquartile range 14.9-31.0, n=70) in the placebo group. Treatment with escitalopram did not affect composite Female Sexual Function Index score at follow-up compared with placebo (P=.18 all women; P=.47 sexually active at baseline). Composite mean Female Sexual Function Index change from baseline to week 8 was 0.1 (95% confidence interval [CI] -1.5 to 1.7) for escitalopram and 2.0 (95% CI 0.2-3.8) for placebo. The Female Sexual Distress Scale results did not differ between groups (P=.73) nor did adverse reports of sexual function. At week 8, among those women sexually active at baseline, there was a small difference between groups in Female Sexual Function Index domain mean score change in lubrication (P=.02) and a marginal nonsignificant difference in orgasm (P=.07).
Escitalopram, when used in the treatment of vasomotor symptoms, did not worsen overall sexual function among nondepressed midlife women.
Existing psychotropic medications for the treatment of mental illnesses, including antidepressants, mood stabilizers, and antipsychotics, are clinically suboptimal. They are effective in only a subset of patients or produce partial responses, and they are often associated with debilitating side effects that discourage adherence. There is growing enthusiasm in the promise of pharmacogenetics to personalize the use of these treatments to maximize their efficacy and tolerability; however, there is still a long way to go before this promise becomes a reality. This article reviews the progress that has been made in research toward understanding how genetic factors influence psychotropic drug responses and the challenges that lie ahead in translating the research findings into clinical practices that yield tangible benefits for patients with mental illnesses.
To review recent publications in the area of sexual dysfunction in females including the adolescent age group.
Though as many as 40% of adult females have a sexual dysfunction, the incidence among adolescent females is unknown. Though over half of adolescents are sexually active, sexual dysfunction is not a term universally accepted among the general public as well as researchers. Research on sexual dysfunction in females typically starts with age 18 years or over. Causes of sexual dysfunction include medical disorders, gynecological problems, which started from the adolescent age, psychiatric disorders, and complications of medications such as selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and others. Management includes identification of the specific sexual dysfunction and treatment of the underlying condition, including surgical treatment in such cases as absent vagina or obstetrics fistula. Psychological therapy is helpful when psychological factors are contributory to the dysfunction. Pharmacologic principles of management cases can, for example, include treatment of gynecological problems such as pelvic inflammatory disease (PID) or endometriosis as a cause of sexual dysfunction or include removal of the offending drug, use of glutamatergic strategies or trazodone in SSRI-association dysfunction, and addition of bupropion or other medications in select cases. No medication is FDA-approved for sexual dysfunction in females.
Sexual dysfunction in females includes lack of sexual desire, sexual pain disorders (as dyspareunia), anorgasmia, and sexual arousal dysfunction. Acceptance of the high incidence of sexual dysfunction in all female populations is necessary to appreciate this phenomenon in the adolescent cohort, because some gynecological disease can arise from the adolescent age and can cause sexual dysfunction. Some sexual dysfunctions require immediate treatment, including surgical in the case of congenital anomaly, ovarian cyst, or tumor. Current understanding is based on extrapolation of research in the adult population. Management principles include removal of offending drugs and treatment of underlying disorders. Research in the adolescent population is recommended for more understanding and acceptance of this phenomenon in this age group.
Context While recent pharmacological advances have generated increased public interest and demand for clinical services regarding erectile dysfunction, epidemiologic data on sexual dysfunction are relatively scant for both women and men. Objective To assess the prevalence and risk of experiencing sexual dysfunction across various social groups and examine the determinants and health consequences of these disorders. Design Analysis of data from the National Health and Social Life Survey, a probability sample study of sexual behavior in a demographically representative, 1992 cohort of US adults. Participants A national probability sample of 1749 women and 1410 men aged 18 to 59 years at the time of the survey. Main Outcome Measures Risk of experiencing sexual dysfunction as well as negative concomitant outcomes. Results Sexual dysfunction is more prevalent for women (43%) than men (31%) and is associated with various demographic characteristics, including age and educational attainment. Women of different racial groups demonstrate different patterns of sexual dysfunction. Differences among men are not as marked but generally consistent with women. Experience of sexual dysfunction is more likely among women and men with poor physical and emotional health. Moreover, sexual dysfunction is highly associated with negative experiences in sexual relationships and overall wellbeing. Conclusions The results indicate that sexual dysfunction is an important public health concern, and emotional problems likely contribute to the experience of these problems.
Polymorphic regions consisting of a variable number of tandem repeats within intron 2 of the gene coding for the serotonin transporter protein 5-HTT have been associated with susceptibility to affective disorders. We have cloned two of these intronic polymorphisms, Stin2.10 and Stin2.12, into an expression vector containing a heterologous minimal promoter and the bacterial LacZ reporter gene. These constructs were then used to produce transgenic mice. In embryonic day 10.5 embryos, both Stin2.10 and Stin2.12 produced consistent β-galactosidase expression in the embryonic midbrain, hindbrain, and spinal cord floor plate. However, we observed that the levels of β-galactosidase expression produced by both the Stin2.10 and Stin2.12 within the rostral hindbrain differed significantly at embryonic day 10.5. Our data suggest that these polymorphic variable number of tandem repeats regions act as transcriptional regulators and have allele-dependent differential enhancer-like properties within an area of the hindbrain where the 5-HTT gene is known to be transcribed at this stage of development.
Traditionally, DNA used for PCR-based diagnostic analysis has originated from white cells fractionated from whole blood. Although this method yields substantial quantities of DNA, there are some drawbacks to the procedure, including the inconvenience of drawing blood, risk of exposure to blood-borne pathogens, liquid sample handling, and the somewhat involved extraction procedure. Alternatively, DNA for genetic diagnosis has been derived from finger stick blood samples, hair roots, cheek scrapings, and urine samples. Oral saline rinses have also been used extensively as a means of collecting buccal epithelial cells as a DNA source. However, this method still requires liquid sample handling. Herein, we present our results involving the rapid extraction of DNA from buccal cells collected on cytology brushes and swabs for use in PCR reactions, specifically the multiplex amplification of 5 exons within the CFTR gene. The quality of DNA isolated from buccal cells, collected in this manner, has been sufficient to reproducibly support multiplex amplification. Cheek cell samples and the DNA prepared from them as described here are highly stable. The success rate of PCR amplification on DNA prepared from buccal cells is 99%. In a blind study comparing the analysis of 12 mutations responsible for cystic fibrosis in multiplex products amplified with DNA from both blood and buccal cell samples from 464 individuals, there was 100% correlation of results for blood and cheek cell DNA, validating the use of DNA extracted from cheek cells collected on cytology brushes for use in genetic testing.
BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder.
A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders.
We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]).
This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.
Unlabelled:
The authors analyze the incidence of sexual dysfunction (SD) with different SSRIs (Fluoxetine, Fluvoxamine, Paroxetine and Sertraline) and hence the qualitative and quantitative changes in SD throughout time 308 outpatients (169 women, 139 men; mean +/- SD age = 41 +/- 7) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors including questions about the following items decreased libido, delayed orgasm or anorgasmia, delayed ejaculation inability to ejaculation, impotence and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRIs intake, exclusive treatment with SSRIs or associated with benzodiazepines, previous heterosexual or self-orone current sexual practices. We excluded patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recently hormone intake and significant medical illnesses.
Results:
There is a significant increase in the incidence of SD when the physicians ask the patients direct questions (55.29%) versus spontaneous SD reported (14.2%). There are some significant differences among different SSRIs paroxetine provoked more delay of orgasm/ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (Chi square p < 0.05). Only 22.6% of the patients had a good tolerance about their sexual dysfunction. SD has positive correlation with the dose. The patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women but women's sexual dysfunction was more intense than men. Seven of nine patients (77.7%) experienced total improvement when the treatment was changed to Moclobemide (450 mg/day) and two of four patients (50%) improved when treatment was changed to Amineptine.
We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.
The authors analyzed the incidence of sexual dysfunction (SD) with different selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, paroxetine, and sertraline) and hence the qualitative and quantitative changes in SD throughout time in a prospective and multicenter study. Outpatients (192 women and 152 men; age = 39.6 +/- 11.4 years) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors and that included questions about the following: decreased libido, delayed orgasm or anorgasmia, delayed ejaculation, inability to ejaculate, impotence, and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRI intake, exclusive treatment with SSRIs or treatment associated with benzodiazepines, previous heterosexual or self-erotic current sexual practices. Excluded were patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recent hormone intake, and significant medical illnesses. There was a significant increase in the incidence of SD when physicians asked the patients direct questions (58%) versus when SD was spontaneously reported (14%). There were some significant differences among different SSRIs: paroxetine provoked more delay of orgasm or ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (chi 2, p < .05). Only 24.5% of the patients had a good tolerance of their sexual dysfunction. Twelve male patients who suffered from premature ejaculation before the treatment preferred to maintain delayed ejaculation, and their sexual satisfaction, and that of their partners, clearly improved. Sexual dysfunction was positively correlated with dose. Patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's. In only 5.8% of patients, the dysfunction disappeared completely within 6 months, but 81.4% showed no improvement at all by the end of this period. Twelve of 15 patients experienced total improvement when the treatment was changed to moclobemide (450-600 mg/day), and 3 of 5 patients improved when treatment was changed to amineptine (200 mg/day).
The Changes in Sexual Functioning Questionnaire (CSFQ), a structured interview/questionnaire designed to measure illness- and medication-related effects on sexual functioning, is presented with initial evidence of its clinical usefulness in differentiating between those who have sexual dysfunction and those who have no dysfunction. Individuals from clinical and nonclinical samples completed the CSFQ. The sample groups were compared on mean scores on the CSFQ and its subscales. Comparative findings indicate that psychiatric patients diagnosed with a mood disorder have significantly lower sexual functioning when compared with nonpsychiatric outpatients, medical students, and psychiatry residents combined. The CSFQ is a useful measure for assessing medication- or illness-related effects on sexual functioning in a systematic way.
The Changes in Sexual Functioning Questionnaire (CSFQ), a structured interview/questionnaire designed to measure illness- and medication-related changes in sexual functioning, is presented with evidence of its validity and reliability. Medical students (n = 122) and psychiatry residents (n = 33) completed the CSFQ on two separate occasions. Residents also completed the Derogatis Interview for Sexual Functioning-Self-Report (DISF-SR), a reliable, validated measure used in research on sexual functioning in patient populations. Concurrent validity was established between the CSFQ and the DISF-SR and test-retest reliability was high. The CSFQ is a reliable and valid measure of sexual functioning, useful in both clinical and research settings.
While recent pharmacological advances have generated increased public interest and demand for clinical services regarding erectile dysfunction, epidemiologic data on sexual dysfunction are relatively scant for both women and men.
To assess the prevalence and risk of experiencing sexual dysfunction across various social groups and examine the determinants and health consequences of these disorders.
Analysis of data from the National Health and Social Life Survey, a probability sample study of sexual behavior in a demographically representative, 1992 cohort of US adults.
A national probability sample of 1749 women and 1410 men aged 18 to 59 years at the time of the survey.
Risk of experiencing sexual dysfunction as well as negative concomitant outcomes.
Sexual dysfunction is more prevalent for women (43%) than men (31%) and is associated with various demographic characteristics, including age and educational attainment. Women of different racial groups demonstrate different patterns of sexual dysfunction. Differences among men are not as marked but generally consistent with women. Experience of sexual dysfunction is more likely among women and men with poor physical and emotional health. Moreover, sexual dysfunction is highly associated with negative experiences in sexual relationships and overall well-being.
The results indicate that sexual dysfunction is an important public health concern, and emotional problems likely contribute to the experience of these problems.
This article provides a review of the past and current literature on the neurobiology of sexual function. The influence of endocrine, neurotransmitter, and central nervous system influences on male and female sexual function are discussed for sexual desire, arousal, and orgasm or ejaculation stages of sexual responding. Endocrine factors reviewed include the following: androgens, estrogens, progesterone, prolactin, oxytocin, cortisol, and pheromones. Neurotransmitters and neuropeptides discussed include nitric oxide, serotonin, dopamine, epinephrine, norepinephrine, opioids, acetylcholine, histamine, and gamma-aminobutyric acid. Central nervous system influences on sexual function are discussed briefly with reference to brainstem regions, the hypothalamus, and the forebrain.
Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and clomipramine, are frequently associated with sexual dysfunction. Other antidepressants (nefazodone, mirtazapine, bupropion, amineptine, and moclobemide) with different mechanisms of action seem to have fewer sexual side effects. The incidence of sexual dysfunction is underestimated, and the use of a specific questionnaire is needed.
The authors analyzed the incidence of antidepressant-related sexual dysfunction in a multicenter, prospective, open-label study carried out by the Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. The group collected data from April 1995 to February 2000 on patients with previously normal sexual function who were being treated with antidepressants alone or antidepressants plus benzodiazepines. One thousand twenty-two outpatients (610 women, 412 men; mean age = 39.8 +/- 11.3 years) were interviewed using the Psychotropic-Related Sexual Dysfunction Questionnaire, which includes questions about libido, orgasm, ejaculation, erectile function, and general sexual satisfaction.
The overall incidence of sexual dysfunction was 59.1% (604/1022) when all antidepressants were considered as a whole. There were relevant differences when the incidence of any type of sexual dysfunction was compared among different drugs: fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction.
The incidence of sexual dysfunction with SSRIs and venlafaxine is high, ranging from 58% to 73%, as compared with serotonin-2 (5-HT2) blockers (nefazodone and mirtazapine), moclobemide, and amineptine.
To describe reasons for discontinuing or switching selective serotonin-reuptake inhibitors (SSRIs) at 3 and 6 months after starting treatment, and to identify information provided to patients that may help prevent premature discontinuation of medication.
Telephone surveys were conducted at 3 and 6 months after patients (n = 672) were started on an SSRI for a new or recurrent case of depression.
Significantly more patients discontinued or switched their SSRI because of an adverse effect within the first 3 months of starting (43%) compared with the second 3 months (27%; p = 0.023). The adverse effect most frequently reported as the reason for early discontinuation or switching was drowsiness/fatigue (10.2%), followed by anxiety, headache, and nausea - all at just over 5%. The odds ratio for discontinuation was 61% less in patients who recalled being told to take the medication for at least 6 months compared with those who did not (OR 0.39; p < 0.001). Patients who recalled being informed of potential adverse effects increased their reported incidence of mild to moderate adverse effects by 55% (OR 1.55; p < 0.05) without affecting rates of premature discontinuation (OR 1.06; p = 0.77).
Adverse effects are the most frequent reason for discontinuing or switching SSRIs within the first 3 months of treatment. Patients are more likely to continue taking their antidepressant if they fully understand how long to take the medication. Informing patients of potential adverse effects does not appear to prevent premature discontinuation, but may increase the patient's awareness and reporting of mild to moderate adverse effects.
Major depression is frequently associated with sexual dysfunction (over 70% of patients), and the antidepressant medications used to treat the illness may exacerbate pre-existing sexual dysfunction, or induce sexual dysfunction not present on diagnosis. In women, sex hormones that change across the life cycle, menstrual cycle, and diurnally have direct effects on sexual functioning, and indirect effects via modulation of neurotransmitter systems. These complex neuroendocrine effects lead to the sexual dysfunction seen with antidepressants. Strategies to manage these effects have had some success. They include switching to antidepressants with minimal sexual side effects, addition of hormones and/or antidotes, and lowering the dose of medication. Emerging data on the pathophysiology of sexual function and dysfunction, and new treatment options may lead to improved quality of life for women diagnosed with depression.
The Changes in Sexual Functioning Questionnaire (CSFQ) is a 36-item clinical and research instrument identifying five scales of sexual functioning. This study documents the internal consistency and factor structure of a 14-item version of the CSFQ (CSFQ-14), which yields scores for three scales corresponding to the phases of the sexual response cycle (i.e., desire, arousal, and orgasm) as well as the five scales of the original CSFQ. Factor analysis confirms the construct validity of the CSFQ-14 as a global measure of sexual dysfunction. The CSFQ-14 and the individual scales exhibit strong internal reliability.
The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A -1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18-40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A -1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR=3.6; 95% CI 1.03, 12.6; p=0.046). Furthermore, the 5HT2A -1438 GG genotype was a significant predictor of lower arousal scores (p=0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.
The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P<0.0001) and both s/s and s/l variants with response rate (P=0.0002). Response rate within 4 weeks was associated in both models (P=0.003-P<0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.
Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive–compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.
Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5′-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.
The Changes in Sexual Functioning Questionnaire (see Appendix) was developed as a brief clinical and research instrument to measure sexual function changes accompanying illness or the administration of medications. In a pilot study of patients with major depression being treated with paroxetine, the instrument was useful in delineating three groups of patients: patients who reported increased libido without sexual dysfunction, patients who developed anorgasmia with possible spontaneous resolution (medication side effect and development of tolerance), and patients with long-term sexual dysfunction unaffected by the medication. Change scores accurately differentiated global elements, changes associated with specific factors of sexual response, and drug-specific side effects. All patients had a therapeutic response to treatment with experiences of sexual functioning that could be categorized into one of the three groups.
Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.
It has been widely hypothesized that the ovarian steroids, estrogen (E) and progesterone (P), act on serotonin neurons to modulate mood and increase prolactin secretion in women. However, information is needed on the molecular consequences of ovarian hormone action in serotonin neurons. This study examined the effect of E and P on the expression of mRNA for the serotonin re-uptake transporter (SERT) in monkeys using in situ hybridization and a 253 bp human SERT cRNA probe. Monkeys (n=5 animals/group) were ovariectomized and hysterectomized (spayed) and then untreated (control), or treated, with E for 28 days (E treated) or treated with E for 28 days and supplemented with P for the last 14 days of the E regimen (E+P treated). Densitometric analysis of autoradiographs with gray-level thresholding was performed at five levels of the dorsal and median raphe. The number of pixels exceeding background in defined areas was obtained (pixel number). The average pixel number for spayed, E- and E+P-treated groups was 22 280+/-3517, 15 227+/-1714, and 14 827+/-2042, respectively, in the combined dorsal and median raphe. In the E- and E+P-treated groups compared to the control group, there was a 32% and 33% decrease in SERT mRNA signal represented by pixel number (ANOVA, P<0.05). Hence, E- and E+P-treated groups were significantly less than the control group, but they were not different from one another. Also, there were significantly fewer SERT mRNA-positive cells in the dorsal raphe of E- and E+P-treated groups (ANOVA, P<0.001). Therefore E, with or without P, reduces SERT mRNA expression. These results suggest that the ability of P to increase prolactin secretion in E-primed monkeys does not involve an action at the level of SERT gene transcription. Hence, the mechanism by which the CNS transduces the action of P on prolactin secretion remains to be elucidated. However, these data suggest that one action of E replacement therapy in postmenopausal women may be to decrease expression of the SERT gene.
The effect of short-term (Sprague-Dawley rats, two weeks) and long-term ovariectomy (Sprague-Dawley and Fischer rats, three months) on serotonin 5-hydroxytryptamine2A receptors in different regions of the brain and its possible correction with an 17 beta-estradiol treatment (10 micrograms, b.i.d., two weeks) were studied in comparison to intact rats. Saturation binding assays were performed using [3H]ketanserin to estimate 5-hydroxytryptamine2A receptor density and affinity in tissue homogenates of frontal cortex of Fischer rats and quantitative autoradiography was performed to evaluate receptor specific binding in frontoparietal cortex, nucleus accumbens, striatum and dorsal raphe nucleus of Fischer rats, and in frontal cortex of the two strains of rats. Messenger RNA levels of 5-hydroxytryptamine2A receptors were measured by in situ hybridization in frontal cortex of the two strains of rats. An overall decrease of 5-hydroxytryptamine2A receptor densities was found in all the brain regions of ovariectomized Fischer rats assayed, and this could be restored towards control levels by estradiol treatment. No change in the 5-hydroxytryptamine2A receptor affinity was measured in the frontal cortex. A similar pattern of changes was observed for the messenger RNA levels encoding the 5-hydroxytryptamine2A receptors and receptor density, suggesting the implication of a genomic mechanism. Experiments in Sprague-Dawley rats confirmed and extended the results obtained with Fischer rats. By analogy, in humans, this 5-hydroxytryptamine2A receptor modulation may underlie the mood and movement disorders associated with menopause.
Sexual dysfunction side effects have been associated with antidepressant medication, especially with serotonin reuptake inhibitors. Neurotransmitters appear to be involved, especially dopamine and serotonin, but the processes by which they influence sexual dysfunction are not clear.
The serotonin neural system originates from ten nuclei in the mid- and hindbrain regions. The cells of the rostral nuclei project to almost every area of the forebrain, including the hypothalamus, limbic regions, basal ganglia, thalamic nuclei, and cortex. The caudal nuclei project to the spinal cord and interact with numerous autonomic and sensory systems. This article reviews much of the available literature from basic research and relevant clinical research that indicates that ovarian steroid hormones, estrogens and progestins, affect the function of the serotonin neural system. Experimental results in nonhuman primates from this laboratory are contrasted with studies in rodents and humans. The sites of action of ovarian hormones on the serotonin neural system include effects within serotonin neurons as well as effects on serotonin afferent neurons and serotonin target neurons. Therefore, information on estrogen and progestin receptor-containing neurons was synthesized with information on serotonin afferent and efferent circuits. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact mood, cognition, pain, and numerous other autonomic functions.
Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive-compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.
Variable number tandem repeats (VNTR) within non-coding regions of a number of genes have been correlated with susceptibility to various disease states. In particular, a VNTR polymorphism of a 16 or 17 bp element within intron 2 of the human serotonin transporter gene has been correlated with a predisposition to affective disorders. We have demonstrated that this region will support differential levels of reporter gene expression in differentiating embryonic stem cells, this being dependent on the presence of 10 or 12 copies of the repeat. The VNTR domain can therefore act as a transcriptional regulator, a property which potentially contributes to disease susceptibility.
Sexual dysfunction commonly occurs during antidepressant treatment. However, the reported rates of sexual dysfunction vary across antidepressants and are typically underreported in product literature. The objectives of this study were (1) to estimate the prevalence of sexual dysfunction among patients taking newer antidepressants (bupropion immediate release [IR], bupropion sustained release [SR], citalopram, fluoxetine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine, and venlafaxine extended release [XR]) and (2) to compare physician-perceived with patient-reported prevalence rates of antidepressant-associated sexual dysfunction.
This cross-sectional, observational study was conducted in 1101 U.S. primary care clinics. Adult outpatients (4534 women and 1763 men) receiving antidepressant monotherapy were enrolled. The prevalence of sexual dysfunction was measured using the Changes in Sexual Functioning Questionnaire.
In the overall population, bupropion IR (22%) and SR (25%) and nefazodone (28%) were associated with the lowest risk for sexual dysfunction, whereas selective serotonin reuptake inhibitor (SSRI) antidepressants, mirtazapine, and venlafaxine XR were associated with higher rates (36%-43%). In a prospectively defined subpopulation unlikely to have predisposing factors for sexual dysfunction, the prevalence of sexual dysfunction ranged from 7% to 30%, with the odds of having sexual dysfunction 4 to 6 times greater with SSRIs or venlafaxine XR than with bupropion SR. Physicians consistently underestimated the prevalence of antidepressant-associated sexual dysfunction.
Ours is the first study to assess sexual dysfunction across the newer antidepressants using consistent methodology and a validated rating scale. Overall, SSRIs and venlafaxine XR were associated with higher rates of sexual dysfunction than bupropion or nefazodone. Because antidepressant-associated sexual dysfunction is considerably underestimated by physicians, greater recognition and education are imperative when prescribing antidepressant treatment.
Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).
The serotonin transporter (5HTT; chromosomal location 17q12) is an important regulator of serotonergic neurotransmission and is the site of action for a number of antidepressant medications. Sequence variation at a VNTR known as the 5HTTLPR, which is 1.4 kb upstream of the translation start of 5HTT, has been associated in some studies with increased vulnerability to depression, neuroticism, and autism. Support for these clinical observations has included laboratory findings that 5HTTLPR variation is associated with changes in 5HTT gene translation. We re-examined these earlier laboratory findings by directly measuring 5HTT mRNA levels and genotyping four loci spanning the 5HTT gene using RNA and DNA prepared from 85 independent lymphoblast cell lines. Using this data, haplotypes were inferred and the resulting single point and haplotypes data analyzed by univariate and regression analyses. Consistent with the original findings, we found a significant effect of the 5HTTLPR on mRNA production. In contrast to previous reports, the effect on 5HTT mRNA production appeared to be mediated through an additive, not dominant, mechanism. Neither genotype nor haplotype at three other 5HTT loci were associated with alterations in mRNA production, although the small number of samples homozygous for the three most common haplotypes limits these findings. We conclude that further examination of the role of 5HTT sequence variation in regulating 5HTT mRNA production is warranted.
The human serotonin transporter gene (SLC6A4, 5-HTT) possesses several polymorphic loci that affect its expression or function. Rare gain-of-function coding mutations such as Ile425Val and Gly56Ala have recently been discovered,1, 2 while common noncoding polymorphisms that impact transcription include an intron 2 VNTR and the 5-HTT-linked polymorphic region (5-HTTLPR).3, 4 The latter polymorphism is commonly subdivided into S (short, lesser expressing) and L (long, greater expressing) alleles based on the presence of a 43 bp indel (initially described as 44 bp)3, 5, 6 and has been extensively analyzed in over 300 behavioral, psychiatric, pharmacogenetic and other medical genetics papers over the past 10 years.7, 8
This study examines phase-specific sexual dysfunction among patients who are being treated for major depression and who do not meet criteria for global sexual dysfunction.
6297 adult outpatients receiving antidepressant monotherapy completed the Changes in Sexual Functioning Questionnaire (CSFQ). The sub-sample for this study (n = 3114) comprises participants who were receiving treatment with a SSRI or SNRI and did not meet the gender-specific criterion for global sexual dysfunction on the CSFQ.
Among this sub-sample, 95.6% of women and 97.9% of men exhibited impairment in at least one phase of sexual functioning. Men were significantly more likely than women to experience dysfunction in the desire phase (91.2% vs. 79.0%; OR = 2.76; 95% C.I. = 2.14 to 3.5) and the orgasmic phase (85.1% vs. 45.4%; OR = 6.9; 95% C.I. = 5.6 to 8.4) but were significantly less likely than women to experience dysfunction in the arousal phase (71.9% vs. 83.3%; OR = .51; 95% C.I. = .43 to .62). The prevalence of phase-specific dysfunction did not vary significantly by SSRI/SNRI for males or females.
Among patients who do not experience clinically significant global sexual dysfunction on SSRI/SNRI monotherapy, dysfunction in at least one phase of the sexual response cycle is very common and may reduce sexual health-related quality of life.
To assess the influence of the serotonin transporter variable number of tandem repeat (HTT-VNTR) polymorphism and the serotonin transporter-gene-linked polymorphic region (HTTLPR) polymorphism on development of side effects under antidepressant therapy.
A total of 109 depressive in-patients treated with various antidepressants according to local clinical practice were included in the investigation. Four weeks after admission to hospital, side effects were assessed by using a modified version of the dosage record and treatment emergent symptoms scale (DOTES). Differences in side effects between the genotype groups of both polymorphisms were analyzed using the Fisher's exact test.
A total of 65 patients received mirtazapine (25 of them in combination with other antidepressants), and 44 patients were predominantly treated with antidepressants acting via HTT, such as selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). When patients were treated with HTT-blocking antidepressants, a significantly higher occurrence of side effects in patients with the HTTVNTR 2.10/2.10 genotype (52.6%) than in patients with the 2.10/2.12 (12.5%) and 2.12/2.12 (0%) genotypes (p = 0.004) was found. With regard to the HTTLPR polymorphism, patients predominantly on HTT-blocking antidepressants with the s/s genotype suffered more frequently from side effects (50.0%) than heterozygotes (40.0%) and homozygotes for the l-allele (0%) (p = 0.002). In contrast, no association of the HTTVNTR polymorphism was found in patients treated with mirtazapine. The risk groups defined by a combined genotype from both polymorphisms demonstrated a major effect on the incidence of adverse drug events in patients treated with predominantly HTT-blocking antidepressants (p = 0.00018; low risk: 0%, 0/13, medium risk: 13.3%, 2/15, high risk: 62.5%, 10/16).
These results support the hypothesis that both polymorphisms influence tolerability to drugs primarily acting via HTT inhibition, such as SSRIs, TCAs and venlafaxine. Tolerability to mirtazapine was not influenced, probably owing to a different mode of action. As there are limitations due to the heterogeneity of treatment and concomitant therapy, further studies are required to confirm the obtained results.
During treatment with selective serotonin reuptake inhibitors, some patients experience adverse events whereas others do not. Assessment of predictors for selective serotonin reuptake inhibitors-induced adverse events would be useful for the identification of patients likely to develop these events. This study evaluates the association between adverse events during selective serotonin reuptake inhibitor treatment and two polymorphisms in the serotonin transporter (5-HTTLPR and STin2) gene. We included 214 patients meeting Diagnostic and statistical manual of mental disorder-IV criteria for major depression and using an selective serotonin reuptake inhibitor for at least 6 weeks. Blood samples or buccal swabs were taken to determine 5-HTTLPR and STin2 genotype. Information on adverse events was gathered through interviews and general practitioners' files. The association between serotonin transporter genotype and adverse events was assessed by use of logistic regression. Patients with the 5-HTTLPR s/s or s/l genotype appeared to have an increased risk of adverse events, especially general adverse events (dermatologic reactions, weight change and fatigue); odds ratio 1.77 (95% confidence interval 0.80-3.92) for the s/s genotype, odds ratio 2.37 (95% confidence interval 1.13-4.96) for the s/l genotype. For STin2, results were inconsistent and observed associations were weak and statistically nonsignificant. Our findings indicate that patients with the 5-HTTLPR s/s or s/l genotype have an increased risk of developing adverse events during selective serotonin reuptake inhibitor treatment.
Serotonin Transporter (5HTT or SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the "Long G" allele on mRNA transcription. We also found that CpG methylation was higher (P < 0.0008) and mRNA production (P < 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated.
Most preclinical studies examining the mechanism(s) of action of antidepressants are carried out using male animals. Blockade of serotonin transporter (SERT) function by selective serotonin reuptake inhibitors (SSRIs) is the initial event that triggers a not completely understood process that results in clinical improvement in depression. To investigate whether there are differences in the ability of SSRIs to inhibit the SERT between male and female rats at different phases of the estrous cycle, clearance of locally applied serotonin (5-HT) was measured by in vivo chronoamperometry. Local application of the SSRI, fluvoxamine, directly into the CA3 area of hippocampus increased significantly 5-HT clearance time parameters in male rats and female rats in estrus or diestrus, but not in proestrus. The contribution of ovarian steroids to this result was investigated in ovariectomized (OVX) rats treated with estradiol benzoate (EB) and/or progesterone (P). In OVX-control rats, fluvoxamine increased clearance time parameters, whereas EB and/or P treatment blocked this effect, consistent with what was seen in female rats in proestrus. This effect was gender-specific, since treatment of castrated rats with EB/P had no effect on the ability of fluvoxamine to slow 5-HT clearance. The time course of hormonal effects showed that 1-60 min after local application of 17-beta-estradiol (E(2)) into the CA3 region of OVX rats, fluvoxamine had no effect on clearance time of 5-HT. E(2)-BSA mimicked E(2)'s effects at 10 min but not at 60 min. Pretreatment with estrogen receptor antagonists blocked the effects of E(2). The finding that acutely both estradiol and progesterone can inhibit the ability of an SSRI to slow the clearance of 5-HT, may have important implications for the use of SSRIs in women.
Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531
- Jr Wendland
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Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531
- Wendland
Gonadal hormones modulate 5-hydroxytryptamine2A receptors: emphasis on the rat frontal cortex
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Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic‐Related Sexual Dysfunction [see comment]
- Montejo AL
Comparison of sexual functioning in clinical and nonclinical populations using the Changes in Sexual Functioning Questionnaire (CSFQ)
- Clayton AH