A new approach to 'on-demand' treatment of lifelong premature ejaculation by treatment with a combination of a 5-HT1A receptor antagonist and SSRI in rats.

Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for PE they only work after chronic treatment, or if used on-demand, less adequately than chronic SSRI treatment. It has been shown that the addition of a behaviorally silent 5-HT1A-receptor antagonist to an SSRI can generate acute inhibitory effects on male rat sexual behavior. Atlas987 is a selective 5-HT1A-receptor antagonist with equal potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. To investigate whether Atlas987 together with the SSRI paroxetine, a combination called Enduro, induces acute inhibitory effects on male rat sexual behavior, we tested Enduro in Wistar rats in a dose-dependent manner. We first tested the 5-HT1A receptor antagonist Atlas987 in 8-OH-DPAT induced serotonergic behavior in rats. Second, we tested Enduro in a dose-dependent manner in male sexual behavior. Third, we tested the effective time window of Enduro's action, and lastly, we measured the plasma levels of Atlas987 and paroxetine over an 8-h period. Results showed that Enduro acutely and dose-dependently reduced the number of ejaculations and increased the ejaculation latencies. The behavioral pattern induced reflected a specific effect on sexual behavior excluding non-specific effects like sedation or sensoric-motoric disturbances. The time-window of activity of Enduro showed that this sexual inhibitory activity was at least found in a 1-4 h' time window after administration. Plasma levels showed that in this time frame both Atlas987 and paroxetine are present. In conclusion, in rats, Enduro is successful in acutely inhibiting sexual behavior. These results may be therapeutically attractive as "on demand" treatment for life-long premature ejaculation in men.

Pharmacological Studies on the Role of 5-HT1 A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats.

Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT1 A autoreceptors and postsynaptic 5-HT1 A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT-/-) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT1 A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT1 A receptors in the pro-sexual effects of 5-HT1 A receptor agonists in SERT+/+ and in SERT-/- rats. Therefore, acute effects of the biased 5-HT1 A receptor agonists F-13714, a preferential 5-HT1 A autoreceptor agonist, or F-15599, a preferential 5-HT1 A heteroreceptor agonist, and S15535 a mixed 5-HT1 A autoreceptor agonist/heteroreceptor antagonist, on male sexual behavior were assessed. A clear and stable genotype effect was found after training where SERT+/+ performed sexual behavior at a higher level than SERT-/- rats. Both F-15599 and F-13714 induced pro-sexual activity in SERT+/+ and SERT-/- animals. Compared to SERT+/+, the F13714-dose-response curve in SERT-/- rats was shifted to the right. SERT+/+ and SERT-/- rats responded similar to F15599. Within both SERT+/+ and SERT-/- rats the potency of F-13714 was much stronger compared to F-15599. S15535 had no effect on sexual behavior in either genotype. In SERT+/+ and SERT-/- rats that were selected on comparable low sexual activity (SERT+/+ 3 or less ejaculations and SERT-/- 5 or less ejaculations in 10 weeks) S15535 also did not influence sexual behavior. The two biased compounds with differential effects on 5-HT1 A auto- and hetero-receptors, exerted pro-sexual activity in both SERT+/+ and SERT-/- rats. Applying these specific pharmacological tools has not solved whether pre- or post-synaptic 5-HT1 A receptors are involved in pro-sexual activity. Moreover, the inactivity of S15535 in male sexual behavior in either genotype was unexpected. The question is whether the in vivo pharmacological profile of the different 5-HT1 A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT1 A receptor contributions in male rat sexual behavior.

The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects.

INTRODUCTION: A new combination tablet containing sublingual testosterone and oral buspirone (T+B) was developed to benefit a subgroup of women suffering from female sexual interest/arousal disorder, caused by dysfunctionally overactive sexual inhibition. AIM: The aim of this study was to compare the effect of food intake on the pharmacokinetics of buspirone, administered as a dual-route, dual-release combination tablet containing 0.5 mg testosterone (T) and 10 mg buspirone (B). METHODS: 19 healthy women took T+B under fed and fasted conditions during 2 overnight visits. The blood was sampled over a 24-hour period to determine the pharmacokinetics of buspirone and its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP). Total testosterone levels were also assessed, at 5 time points and for quality control purposes only, as sublingual testosterone uptake is not expected to be influenced by prior food intake. MAIN OUTCOME MEASURE: PK profiles of buspirone and 1-PP. RESULTS: For buspirone, the 90% confidence intervals (CIs) of the observed fed/fasted ratios for the plasma area under the curve (AUC)0-last, AUC0-inf, and Cmax after administration of T+B were not contained within the prespecified bounds of 80% and 125%, except for the lower bound of AUC0-inf. However, the 90% CIs of the observed fed/fasted ratios for the plasma AUC0-last, AUC0-inf, and Cmax of 1-PP were contained within the prespecified bounds, with the exception of the upper bound for Cmax. The mean AUCs and Cmax for 1-PP did not differ between fed and fasted conditions. CONCLUSIONS: Administration of T+B after high-caloric food intake increased the bioavailability of buspirone but did not result in differences in Tmax when compared with fasted conditions. Both in fed and fasted conditions, T+B was generally well tolerated and safe. Exposure of 1-PP in fed and fasted conditions was comparable in both conditions. These results demonstrate that T+B can safely and effectively be used in both fed and fasted states. Gerritsen J, Bloemers J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Buspirone After Single Administration of a Sublingual Testosterone and Oral Buspirone Combination Tablet in Healthy Female Subjects. J Sex Med 2020;8:186-194.

Translational Studies in the Complex Role of Neurotransmitter Systems in Anxiety and Anxiety Disorders.

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.

The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects.

INTRODUCTION: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as T+S. AIM: The aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of T+S. METHODS: Eighteen healthy women were administered T+S under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study. MAIN OUTCOME MEASURES: The pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake. RESULTS: The observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC0-last was 1.2753 (0.9706-1.6755); for AUC0-14h, it was 1.7521 (1.0819-2.8374); and for Cmax, it was 1.5591 (0.8634-2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC0-last was 0.8437 (0.6738-1.0564); for AUC0-10h, it was 1.0847 (0.7648-1.5383); and for Cmax, it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone Cmax and Tmax under fed and fasted conditions, which is in line with expectations for a sublingual administration. CLINICAL IMPLICATIONS: The T+S combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach. STRENGTHS & LIMITATIONS: This is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon. CONCLUSION: The pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach. Bloemers J, Gerritsen J, van Rooij K, et al. The Effect of Food on the Pharmacokinetics of Sildenafil After Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects. J Sex Med 2019; 19:1433-1443.

Tramadol's Inhibitory Effects on Sexual Behavior: Pharmacological Studies in Serotonin Transporter Knockout Rats.

Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose-response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a µ-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT-/- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as "on demand" therapy for PE.

Genotype scores predict drug efficacy in subtypes of female sexual interest/arousal disorder: A double-blind, randomized, placebo-controlled cross-over trial.

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects' genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials.

BACKGROUND: In women, low sexual desire and/or sexual arousal can lead to sexual dissatisfaction and emotional distress, collectively defined as female sexual interest/arousal disorder (FSIAD). Few pharmaceutical treatment options are currently available. AIM: To investigate the efficacy and safety of 2 novel on-demand pharmacologic treatments that have been designed to treat 2 FSIAD subgroups (women with low sensitivity for sexual cues and women with dysfunctional over-activation of sexual inhibition) using a personalized medicine approach using an allocation formula based on genetic, hormonal, and psychological variables developed to predict drug efficacy in the subgroups. METHODS: 497 women (21-70 years old) with FSIAD were randomized to 1 of 12 8-week treatment regimens in 3 double-blinded, randomized, placebo-controlled, dose-finding studies conducted at 16 research sites in the United States. Efficacy and safety of the following on-demand treatments was tested: placebo, testosterone (T; 0.5 mg), sildenafil (S; 50 mg), buspirone (B; 10 mg) and combination therapies (T 0.25 mg + S 25 mg, T 0.25 mg + S 50 mg, T 0.5 mg + S 25 mg, T 0.5 mg + S 50 mg, and T 0.25 mg + B 5 mg, T 0.25 mg + B 10 mg, T 0.5 mg + B 5 mg, T 0.5 mg + B 10 mg). OUTCOMES: The primary efficacy measure was the change in satisfying sexual events (SSEs) from the 4-week baseline to the 4-week average of the 8-week active treatment period after medication intake. For the primary end points, the combination treatments were compared with placebo and the respective monotherapies on this measure. RESULTS: In women with low sensitivity for sexual cues, 0.5 mg T + 50 mg S increased the number of SSEs from baseline compared with placebo (difference in change [Δ] = 1.70, 95% CI = 0.57-2.84, P = .004) and monotherapies (S: Δ = 1.95, 95% CI = 0.44-3.45, P = .012; T: Δ = 1.69, 95% CI = 0.58-2.80, P = .003). In women with overactive inhibition, 0.5 mg T + 10 mg B increased the number of SSEs from baseline compared with placebo (Δ = 0.99, 95% CI = 0.17-1.82, P = .019) and monotherapies (B: Δ = 1.52, 95% CI = 0.57-2.46, P = .002; T: Δ = 0.98, 95% CI = 0.17-1.78, P = .018). Secondary end points followed this pattern of results. The most common drug-related side effects were flushing (T + S treatment, 3%; T + B treatment, 2%), headache (placebo treatment, 2%; T + S treatment, 9%), dizziness (T + B treatment, 3%), and nausea (T + S treatment, 3%; T + B treatment, 2%). CLINICAL IMPLICATIONS: T + S and T + B are promising treatments for women with FSIAD. STRENGTHS AND LIMITATIONS: The data were collected in 3 well-designed randomized clinical trials that tested multiple doses in a substantial number of women. The influence of T + S and T + B on distress and the potentially sustained improvements after medication cessation were not investigated. CONCLUSIONS: T + S and T + B are well tolerated and safe and significantly increase the number of SSEs in different FSIAD subgroups. Tuiten A, van Rooij K, Bloemers J, et al. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med 2018;15:201-216.

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT1A receptor agonist), CP-94253 (a 5-HT1B receptor agonist), or ondansetron (a 5-HT3 receptor antagonist). These selective ligands were chosen to simulate vortioxetine's direct modulation of these receptors. Paroxetine was also included in the male study. Acute and repeated treatment with vortioxetine at doses corresponding to clinical levels (based on serotonin transporter occupancy) had minimal effects on sexual behavior in male and female rats. High dose vortioxetine plus flesinoxan (to mimic predicted clinical levels of 5-HT1A receptor occupancy by vortioxetine) facilitated male rat sexual behavior (acutely) while inhibiting female rat proceptive behavior (both acutely and after 14 days treatment). The selective serotonin reuptake inhibitor, paroxetine, inhibited male sexual behavior after repeated administration (7 and 14 days). Flesinoxan alone facilitated male sexual behavior acutely while inhibiting female rat proceptive behavior after repeated administration (7 and 14 days). CP-94253 inhibited sexual behavior in both male and female rats after repeated administration. Ondansetron had no effect on sexual behavior. These findings underline the complex serotonergic regulation of sexual behavior and indicate that the low sexual side effects of vortioxetine found in clinical studies are likely associated with its direct modulation of serotonin receptors.

Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects.

Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a µ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the µ-opioid and the 5-HT system. First the µ-opioid receptor agonist properties of tramadol were tested with naloxone, a µ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its µ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties.

The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.

Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: A role for 5-HT1A receptors?

Vilazodone (VLZ) is a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. In preclinical studies, VLZ had significantly lower sexual side effects than SSRIs and reduced serotonin transporter (SERT) levels in forebrain regions. In the current study, once-daily paroxetine (PAR, 10 mg/kg), VLZ (10 mg/kg), PAR + buspirone (BUS, 3 mg/kg; a 5-HT1A partial agonist), or vehicle (VEH) was administered to male rats for 2 weeks then switched for 7 days (eg, PAR switched to VLZ, PAR + BUS, or VEH). Sexual behavior (eg, ejaculation frequency and latency) was evaluated 1-hr postdose on days 1, 7, 14, and 21. After 2 weeks, treatment with PAR but not VLZ resulted in a significant decrease in sexual behavior. In a 30-min test, the range of ejaculation frequency was 3.08-3.5 with VLZ and 1.00-1.92 with PAR (P < 0.05 vs VEH). After switching from PAR to VEH, PAR + BUS, or VEH, sexual behaviors were normalized to control levels. In contrast, the switch from VLZ to PAR resulted in reduced sexual behaviors. This preclinical study showed that unlike PAR, an SSRI with no 5-HT1A receptor activity, initial treatment with VLZ did not result in sexual side effects at therapeutically relevant doses. Results in male rats switched from PAR to VLZ or PAR + BUS strongly suggest that activation of 5-HT1A receptors may mitigate the sexual side effects associated with conventional SSRIs.

Differential effects of vilazodone versus citalopram and paroxetine on sexual behaviors and serotonin transporter and receptors in male rats.

RATIONALE: Sexual side effects are commonly associated with selective serotonin reuptake inhibitor (SSRI) treatment. Some evidence suggest that activation of 5-HT1A receptors attenuates SSRI-induced sexual dysfunction. OBJECTIVE: This study in male rats compared the effects of vilazodone, an antidepressant with SSRI and 5-HT1A receptor partial agonist activity, with other prototypical SSRIs (citalopram and paroxetine) on sexual behaviors and 5-HT receptors (5-HT1A and 5-HT2A) and transporter (5-HTT) levels in select forebrain regions of the limbic system using quantitative autoradiography. METHODS: Rats received vilazodone (1, 3, and 10 mg/kg), citalopram (10 and 30 mg/kg), or paroxetine (10 mg/kg) treatment for 14 days. Sexual behaviors (frequency and latency of mounts, intromissions, and ejaculations) were measured in the presence of an estrous female rat on days 1 (acute), 7 (subchronic), and 14 (chronic). RESULTS: Vilazodone-treated rats exhibited no sexual dysfunction compared with controls; in contrast, the citalopram- and paroxetine-treated rats exhibited impaired copulatory and ejaculatory behaviors after subchronic and chronic treatments. Chronic vilazodone treatment markedly decreased 5-HT1A receptor levels in cortical and hippocampal regions, while the SSRIs increased levels of this receptor in similar regions. All chronic treatments reduced 5-HTT levels across the forebrain; however, the magnitude of the decrease was considerably smaller for vilazodone than for the SSRIs. CONCLUSIONS: The current studies showed that chronic treatment with vilazodone, in contrast to citalopram and paroxetine, was not associated with diminished sexual behaviors in male rats, which may be related to the differential effects of vilazodone on 5-HT1A receptor and 5-HTT levels relative to conventional SSRIs.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison.

AIM: The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme. METHODS: Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil. RESULTS: Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06 ng ml(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml(-1)  h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml(-1) (95% CI 4.63, 6.69) and 5.12 ng ml(-1)  h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml(-1) (95% CI 126, 220) and a lower AUC, 476 ng ml(-1)  h (95% CI 401, 551) than formulation 1, 268 ng ml(-1) (95% CI 188, 348) and 577 ng ml(-1)  h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10). CONCLUSIONS: The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues. WHAT THIS STUDY ADDS: A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies.

The many different faces of major depression: it is time for personalized medicine.

First line antidepressants are the so-called SSRIs (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram. Unfortunately, these drugs mostly do not provide full symptom relief and have a slow onset of action. Therefore other antidepressants are also being prescribed that inhibit the reuptake of norepinephrine (e.g. reboxetine, desipramine) or the reuptake of both serotonin (5-HT) and norepinephrine (e.g. venlafaxine, duloxetine, milnacipran). Nevertheless, many patients encounter residual symptoms such as impaired pleasure, impaired motivation, and lack of energy. It is hypothesized that an impaired brain reward system may underlie these residual symptoms. In agreement, there is some evidence that reuptake inhibitors of both norepinephrine and dopamine (e.g. methylphenidate, bupropion, nomifensine) affect these residual symptoms. In the pipeline are new drugs that block all three monoamine transporters for the reuptake of 5-HT, norepinephrine and dopamine, the so-called triple reuptake inhibitors (TRI). The working mechanisms of the above-mentioned antidepressants are discussed, and it is speculated whether depressed patients with different symptoms, sometimes even opposite ones due to atypical or melancholic features, can be matched with the different drug treatments available. In other words, is personalized medicine for major depression an option in the near future?

Psychogenic fever, functional fever, or psychogenic hyperthermia?

Psychogenic fever reflects a phenomenon where core body temperature is high (up to 41°C) or low-grade high (37-38°C) during either acute or chronic stress. Underlying mechanisms are distinct from infection-induced fever and involve the central and sympathetic nervous systems. Psychogenic fever appears a complex psychological, physiological and endocrinological phenomenon.

Lifelong, central corticotropin-releasing factor (CRF) overexpression is associated with individual differences in cocaine-induced conditioned place preference.

Stress, through corticotropin-releasing factor (CRF), influences all aspects of cocaine addiction. Earlier studies suggest that individual differences in responsivity to stress affect susceptibility to develop addiction. We have previously found that CRF over-expression alters individual differences in behavioural responses to novelty stress in mice. Therefore, we hypothesised that post-natal, long-term over-expression of brain CRF may alter the rewarding effects of cocaine in a manner that is sensitive to individual differences. In this study we specifically investigated cocaine-induced conditioned place preference (CPP) in transgenic mice over-expressing CRF (CRF-OE) and in wild-type (WT) littermates after determining their individual locomotor and emotional responsivity to inescapable novelty. CRF-OE mice showed decreased overall locomotor activity and increased anxiety-like behaviour in response to novelty compared to WT mice. Low behavioural reactivity to novelty (LR) was associated with heightened anxiety-like behaviour in CRF-OE, but not in WT, mice. WT and CRF-OE mice developed CPP equally to both low (5mg/kg) and high (20mg/kg) doses of cocaine. However, LR CRF-OE mice expressed significantly stronger cocaine CPP than transgenic mice with high locomotor response to novelty (HR). In WT mice, on the other hand, stronger CPP induced by 20mg/kg of cocaine was found in the HR animals. Furthermore, there was a strong negative correlation between locomotor reactivity to novelty and CPP in CRF-OE, but not in WT, mice. Collectively, these results suggest that long-term, post-natal CRF over-expression increases the rewarding effects of cocaine in individuals with high emotional response to stress.

Food restriction does not relieve PTSD-like anxiety.

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment. Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala. Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS.