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Biomedical subjects

M D Waldinger

Publications and source records attributed to M D Waldinger.

At least 19 recordsLinked to original sources
PubMed2005

Effects of chronic paroxetine pretreatment on (+/-)-8-hydroxy-2-(di-n-propyl-amino)tetralin induced c-fos expression following sexual behavior.

Chronic treatment with the selective serotonin reuptake inhibitor paroxetine impairs the functioning of 5-HT(1A) receptors involved in ejaculation. This could underlie the development of delayed ejaculation often reported by men treated with paroxetine. The neurobiological substrate linking the effects of selective serotonin reuptake inhibitor-treatment and 5-HT(1A) receptor activation with ejaculation was investigated. Male Wistar rats that were pretreated with paroxetine (20 mg/kg/day p.o.) or vehicle for 22 days and had received an additional injection with the 5-HT(1A) receptor agonist 8-OH-DPAT ((+/-)-8-hydroxy-2-(di-n-propyl-amino)tetralin; 0.4 mg/kg s.c.) or saline on day 22, 30 min prior to a sexual behavior test, were perfused 1 h after the sexual behavior test. Brains were processed for Fos-, and oxytocin immunohistochemistry. The drug treatments markedly changed both sexual behavior and the pattern and number of Fos-immunoreactive cells in the brain. Chronic pretreatment with paroxetine caused delayed ejaculation. Acute injection with 8-OH-DPAT facilitated ejaculation in vehicle-pretreated rats, notably evident in a strongly reduced intromission frequency, whereas 8-OH-DPAT had no effects in paroxetine-pretreated rats. Chronic treatment with paroxetine reduced Fos-immunoreactivity in the locus coeruleus, and prevented the increase in Fos-immunoreactive neurons induced by 8-OH-DPAT in the oxytocinergic magnocellular part of the paraventricular nucleus as well as in the locus coeruleus. Since oxytocin and noradrenalin facilitate ejaculation, the alterations in Fos-IR in these areas could connect selective serotonin reuptake inhibitor treatment and 5-HT(1A) receptor activation to ejaculation. Chronic paroxetine treatment and 8-OH-DPAT changed c-fos expression in a number of other brain areas, indicating that Fos-immunohistochemistry is a useful tool to find locations where selective serotonin reuptake inhibitors and 8-OH-DPAT exert their effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Animal models of ejaculatory behavior.

Premature ejaculation is generally regarded the most frequent male ejaculatory complaint and has been considered a psychosexual disorder with psychogenic aetiology. The efficacy of various antidepressants, however, to delay ejaculation in men and to pharmacologically treat premature ejaculation suggests a strong neurobiological involvement. Most of our current understanding of the neurobiology and neuroanatomy of sexual behavior and ejaculatory function has been derived from preclinical studies using several laboratory species. In the present paper we will review the various animal models that have been developed to further study ejaculatory function in the laboratory rat. In addition, we will briefly review the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior. Together, these preclinical studies may contribute to a better understanding of the neurobiology of ejaculation and help the development of novel drug targets to treat ejaculatory disorders such as premature ejaculation.

Animals↗
PubMed2004

Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis is to evaluate whether the design and methodology of drug-treatment studies of premature ejaculation affect the efficacy outcome differently. Therefore, methodological, design and efficacy data from 79 studies (3034 males), published between 1943 and 2003, are reviewed. A meta-analysis is performed on 43 selective serotonin reuptake inhibitors (SSRIs) and clomipramine studies (1514 males), published between 1973 and 2003; these studies were pooled to provide a summary variance-weighted effect size. The antidepressant-induced percentage increase of the intravaginal ejaculation latency time (IELT) was calculated and examined against various methodological items. A significant difference in efficacy between SSRIs was observed. Using daily treatment, paroxetine appeared more effective than the other SSRIs. Retrospective use of a questionnaire, subjective reports, single-blind and open study designs generate far greater variability of ejaculation time both at baseline and during active drug treatment than real time assessment by stopwatch. In conclusion, at daily treatment, the overall efficacy of paroxetine, clomipramine, sertraline and fluoxetine is comparable, but paroxetine exerts the strongest ejaculation delay. Only eight (18.5%) studies on antidepressant treatment fulfilled all criteria used in evidence-based medicine, for example, randomised, double-blind studies with prospective real time (stopwatch) assessment of the IELT at each intercourse. Single-blind studies, open designs, retrospective reporting, or the use of a questionnaire to assess ejaculation time should be avoided.

Adult↗
PubMed2004

Lifelong premature ejaculation: from authority-based to evidence-based medicine.

Historically, four periods can be distinguished in the approach to and treatment of lifelong premature ejaculation. Although drug treatment has been an option for many decades, psychotherapy prevailed as the first choice of treatment. However, the application of the principles of evidence-based medicine shows that there is little evidence to support the psychological approach and behavioural treatment. In contrast, controlled trials with selective serotonin reuptake inhibitors, clomipramine and anaesthetic ointments have repeatedly shown the efficacy of both daily and 'as-needed' drug treatment to delay ejaculation. Currently, an evidence-based approach is gradually replacing the authority-based psychological attitude that characterized the view of premature ejaculation. Based on psychopharmacological studies there is evidence that premature ejaculation is related to a diminished serotonergic neurotransmission, and 5-HT2C or 5-HT1A receptor disturbances. Moreover, animal studies show the presence of a distinct ejaculation-related neural circuit in the central nervous system; its role in premature ejaculation remains to be elucidated.

Age Factors↗
PubMed2003

Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology.

In the last decade, an increasing number of drug studies on premature ejaculation have been published. The methodology used in these studies differed widely. In this review, it is therefore questioned as to how far the differences in methodology could have influenced clinical outcomes. The aim of the present review was to compare the different methodologies that were used in drug studies on premature ejaculation. The majority of these studies were conducted between 1973 and 2003 and were strikingly different in study design and in the quantification of clinical outcomes. It appeared that in some of these studies, placebo and active drug effects were neglected due to an erroneous methodology. The few studies that were using stopwatch assessment at each intercourse at baseline and during treatment and in which the intravaginal ejaculation latency time (IELT) was included appeared to be comparable in their results. The use of a well-defined definition of premature ejaculation, for example, an IELT of less than 1 min revealed reproducible results. Finally, the retrospective use of a questionnaire or a subjective report on ejaculation time induced higher effects with regard to placebo effects and an underestimation of active drug effects. In conclusion, for drug treatment research of premature ejaculation it is recommended to use a randomized double-blind prospective design, the use of the IELT, the use of a stopwatch at each coitus both during a baseline period and during drug treatment and a definition of premature ejaculation as an ejaculation that occurs within 1 min after vaginal penetration.

Evidence-Based Medicine↗
PubMed2001

Antidepressants and ejaculation: a double-blind, randomized, placebo-controlled, fixed-dose study with paroxetine, sertraline, and nefazodone.

Antidepressant medication is often associated with sexual side effects. A double-blind, placebo-controlled study in men with lifelong rapid ejaculation was performed to assess the effects of two selective serotonin (5-HT) reuptake inhibitors--paroxetine and sertraline--and the 5-HT2 antagonist and 5-HT/noradrenaline reuptake inhibitor nefazodone on the latency to ejaculate. Forty-eight men with an intravaginal ejaculation latency time (IELT) of a maximum of 1 minute were randomly assigned to receive paroxetine (20 mg/day), sertraline (50 mg/day), nefazodone (400 mg/day), or placebo for 6 weeks. During the 1-month baseline and 6-week treatment period, IELTs were measured at home with a stopwatch. The trial was completed by 40 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was stable at approximately 20 seconds. Analysis of variance revealed a between-group difference in the evolution of IELT delay over time (p = 0.002); the IELT after paroxetine and sertraline gradually increased to approximately 146 and 58 seconds, respectively, compared with 28 seconds in the nefazodone group. The paroxetine and sertraline groups differed significantly (p < 0.001 and p = 0.024, respectively) from placebo, but the nefazodone group did not (p = 0.85). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, whereas sertraline delayed it only moderately. There was no clinically relevant delay in ejaculation with nefazodone.

Adolescent↗
PubMed2001

SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram.

Selective serotonin reuptake inhibitors (SSRIs) are known to induce delayed orgasm and ejaculation. However, different SSRIs may differentially delay ejaculation. A double-blind, fixed-dose study in healthy men with lifelong rapid ejaculation was performed to evaluate potential differences between clinically relevant doses of two selective serotonin reuptake inhibitors, paroxetine and citalopram, in their effects on ejaculation. Thirty men with an intravaginal ejaculation latency time (IELT) less than 1 minute were randomly assigned to receive paroxetine (20 mg/day) and citalopram (20 mg/day) for 5 weeks, after taking half the dosage in the first week. During the 1-month baseline and 6-week treatment period, IELTs were measured at home by using a stopwatch procedure. The trial was completed by 23 men. Analysis of variance revealed a between-group difference in the evolution of IELT delay over time (p = 0.0004); the IELT after paroxetine and citalopram gradually increased from 18 and 21 seconds to approximately 170 and 44 seconds, respectively. Paroxetine 20 mg/day exerted a strong delay (8.9-fold increase), whereas citalopram 20 mg/day mildly delayed ejaculation (1.8-fold increase). These results indicate that paroxetine leads to a significant delay in orgasm and ejaculation, whereas citalopram seems to have less of an effect on it.

Adolescent↗
PubMed2000

Treatment of hot flushes with mirtazapine: four case reports.

OBJECTIVE: To evaluate the effect of mirtazapine on the severity of hot flushes and bouts of perspiration in women. METHOD: In two women with depression a reduction in hot flushes was noticed by serendipity during treatment with mirtazapine 15-30 mg/daily. On the basis of this observation clinical studies were extended with two non-depressed and non-anxious women with hot flushes. Both subjects were prescribed mirtazapine daily. RESULTS: Four cases are described as case reports. All subjects reported a practically complete disappearance of hot flushes and associated perspiration, within the first week of treatment. CONCLUSION: Mirtazapine appears to have a substantial ameliorating effect on hot flushes and perspiration bouts. It is postulated that the 5-HT(2A) blocking properties of mirtazapine is accounted in the symptomatic relief of hot flushes. In addition it is hypothesized that the serotonergic system is crucially involved in the pathogenesis of hot flushes and perspiration bouts. Further evaluation in double-blind placebo-controlled studies is encouraged.

Adult↗
PubMed1999

[Sexual side effects of antidepressants].

Most antidepressant drugs have some sexual side effects. These side effects are caused by an increased neurotransmission of serotonin in the central nervous system, a stimulating effect at postsynaptic serotonin receptors and effects on the peripheral nervous system. Antidepressant-induced sexual disorders may impair patient compliance. Publications on sexual side effects are mainly case reports and few double blind placebo-controlled trials. This hampers generalisation of findings. The best treatment consists of prescribing another antidepressant which probably has hardly any or no sexual side effects. However, this entails the risks of reduced antidepressant effects and of non-sexual side effects. The extent of sexual side-effects among the serotonin reuptake inhibitor seems to differ. Antidepressants with few or no sexual side effects include those with noradrenergic and dopaminergic action (some tricyclic antidepressants, bupropion), as well as antidepressants with a postsynaptic receptor blocking action (nefazodone and mirtazapine).

Antidepressive Agents↗
PubMed1999

A comparison of the effects of different serotonin reuptake blockers on sexual behaviour of the male rat.

In human males, SSRIs differentially affect (premature) ejaculation; paroxetine and fluoxetine markedly and sertraline, moderately inhibited ejaculation latency, whereas fluvoxamine did not inhibit this parameter (Waldinger, M.D., Hengeveld, M.W., Zwinderman, A.H., Olivier, B., The effect of SSRI antidepressants on ejaculation: a double-blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J. Clin. Psychopharmacol. (in press)). The present studies tried to investigate, using sexual behaviour in male rats, whether such differences could also be found in animal paradigms of sexual behaviour. In a series of three experiments we compared various specific serotonin reuptake inhibitors (SSRIs) for their ability to suppress sexual behaviour in male rats. In the first experiment sexually experienced rats were tested 60 min after oral administration of clomipramine, fluvoxamine, fluoxetine (all in a range of 0, 3, 10 and 30 mg/kg p.o.), sertraline or paroxetine (both in a range of 0, 1, 3 and 10 mg/kg p.o.). Clomipramine, paroxetine and fluvoxamine did not significantly inhibit male sexual behaviour, although some trends were observed. Sertraline inhibited sexual behaviour at 3 and 10 mg/kg p.o., the effects being stronger at 3 mg/kg p.o. Fluoxetine (3 mg/kg p.o.) facilitated sexual behaviour, while at 30 mg/kg p.o. a modest increase in the postejaculatory interval was noted. In the second experiment, sexual behaviour of sexually naive male rats was slightly inhibited by paroxetine 10 mg/kg p.o., but sertraline (range 1-10 mg/kg p.o.), fluvoxamine and fluoxetine (both in a range of 3-30 mg/kg p.o.) were ineffective. In the last experiment the effects of paroxetine (0-10 mg/kg p.o.), fluvoxamine and fluoxetine (both 0-30 mg/kg p.o.) were studied during an exhaustion design in sexually experienced male rats. As rats get more 'sluggish' when they have had multiple ejaculations, we hoped to see stronger inhibitory effects in the last cycle prior to exhaustion. None of the drugs dose-dependently inhibited the pattern of sexual behaviour during the first sexual cycle. In the last cycle the patterning of sexual behaviour differed, but only paroxetine (10 mg/kg p.o.) inhibited sexual behaviour significantly. The total number' of ejaculations during the test was not reduced by any of the SSRIs tested. Contrary to human findings, we did not find major inhibitory effects of SSRIs on male rat sexual behaviour at non-sedative doses. The only differentiation that could be made is that paroxetine and sertraline had slightly stronger effects than the other 5-HT reuptake inhibitors. Masculine sexual behaviour in rats does not constitute a suitable model to investigate the differential mechanism of sexual inhibition of SSRIs that have been described in human males.

Animals↗
PubMed1998

Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system.

Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying ejaculation. We describe here the neurophysiology and the peripheral neuroanatomy of ejaculation and provide a review of the involvement of serotonin in the central nervous system in relation to serotonergic nuclei and their projections. A hypothesis of the role of 5-HT1A and 5-HT2C receptors in premature ejaculation is postulated.

Animals↗
PubMed1998

Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline.

Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT < or = 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients had IELTs of more than 1 minute (group 2). The geometric mean IELT was 14 seconds in group 1 and 83 seconds in group 2. Twelve patients in group 1 and five in group 2 were randomized to the paroxetine 20 mg/day. The percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% (95% confidence interval [CI], 216-758%) in group 1 and 480% (95% CI, 177-1,118%) in group 2 (p = 0.81). After 6 weeks of treatment with paroxetine, the geometric mean IELT was 92 seconds in group 1 and 602 seconds in group 2 (p < 0.001). Therefore, the paroxetine-induced percentage increase in IELT seems to be independent of the baseline IELT. This suggests that ejaculation-delaying side effects of some SSRIs investigated in men with lifelong rapid ejaculation may be generalized to men with less-rapid ejaculation.

Adolescent↗
PubMed1998

Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour.

The serotonergic system in the brain modulates many types of behavioural and physiological processes. An example of this modulatory function is seen with the selective serotonin reuptake inhibitors (SSRIs) which enhance serotonin transmission and influence mood, anxiety states, aggression, feeding and sexual behaviour. At present, 14 different serotonin receptors have been described and, although the function and localization of many of these receptors is becoming increasingly clear, much remains unknown. The SSRIs are intriguing drugs; by blocking presynaptic and somatodendritic serotonin transporters, they enhance serotonergic neurotransmission and thereby activate serotonin receptors. It is this effect which leads to the characteristic effects of the SSRIs. Theoretically, however, it appears possible that they may have differential effects on the various subpopulations of serotonin receptors. Differences between the SSRIs have recently been reported in males with rapid ejaculation; fluvoxamine, in contrast to other SSRIs, did not affect rapid ejaculation. What difference in the mechanism of action between the SSRIs is responsible for this differential profile? A conditioned taste aversion procedure has been used in mice to investigate the discriminatory stimuli (cues) of fluvoxamine and fluoxetine. It appeared that the discriminatory stimulus of fluvoxamine is primarily mediated via 5-hydroxytryptamine (HT)1A receptors, whilst that of fluoxetine is primarily mediated via 5-HT2C receptors. Both types of receptors have been implicated in depression and it is conceivable that different SSRIs have intrinsic activity at these receptors. Investigations are now ongoing to determine whether this differential mechanism of action also applies to the other SSRIs and whether there are differences between the SSRIs with respect to their effect on sexual behaviour in rodents.

Animals↗
PubMed1998

Selective serotonin reuptake inhibitor-induced sexual dysfunction: clinical and research considerations.

Antidepressants, including the tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs), cause sexual dysfunctions such as decreased sexual desire, erectile difficulties and delayed ejaculation. Such sexual side-effects affect quality of life and may result in non-compliance with medication and the associated risk of recurrence of depression. Depression may also be associated with sexual disturbances, especially reduced libido. It is important to unravel the origin of sexual problems during depression and determine whether they were present before depression started, whether they are associated with the depression, or whether they are an effect of medication. Baseline measurements, objective measures and accurate instruments are all essential for scientific research into the sexual side-effects of antidepressants. Various human factors that may influence measurements of sexual behaviour must also be taken into account. Considering all these provisos, the ejaculation delaying effects of the SSRIs (fluvoxamine, fluoxetine, paroxetine and sertraline) have been investigated in a double-blind, placebo-controlled study in men with rapid ejaculation. The SSRIs were given at their recommended daily dosages for 6 weeks and the men measured their intravaginal ejaculation latency time at home using a stopwatch. The results showed a clear difference between the SSRIs, fluvoxamine having by far the least disturbing effect on ejaculation.

Ejaculation↗
PubMed1997

Ejaculation-retarding properties of paroxetine in patients with primary premature ejaculation: a double-blind, randomized, dose-response study.

OBJECTIVE: To compare the influence of a daily dose of 20 or 40 mg of the serotonergic antidepressant drug paroxetine in delaying ejaculation in patients with primary premature ejaculation. PATIENTS AND METHODS: Thirty-four patients with primary premature ejaculation were randomly assigned to receive 20 mg or 40 mg daily of paroxetine for 7 weeks in a double-blind fixed-dose trial after an initial dose of 20 mg/day in the first week. Patients and their female partners were interviewed separately. In the group receiving 20 mg, one of two capsules consisted of placebo and in the group receiving 40 mg, both capsules contained active drug. RESULTS: The trial was completed by 27 men; both groups showed a statistically significant difference from the baseline values of ejaculation latency (P < 0.001) and a clinically relevant improvement in ejaculation time. The increase in the intravaginal ejaculation latency time was not statistically significant different between the groups. The patient's assessments were confirmed independently by their partners. CONCLUSIONS: The daily use of 20 mg paroxetine may be considered as an adequate treatment for primary premature ejaculation. Increasing the dose may lead to a further increase in ejaculation latency.

Adolescent↗
PubMed1994

Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study.

Seventeen male outpatients with premature ejaculation were randomly assigned to treatment with paroxetine (N = 8) or placebo (N = 9). After a first week dose of 20 mg/day, the paroxetine regimen was increased to 40 mg/day for 5 weeks. Patients and their female partners were interviewed separately. Patients treated with paroxetine had significantly greater clinical improvement than the patients given placebo.

Adult↗