Antidepressant use during pregnancy and development of preeclampsia: A focus on classes of action and specific transporters/receptors targeted by antidepressants.

OBJECTIVE: The association between antidepressants and preeclampsia has been inconsistently reported. Given the compound-specific variable affinity for different transporters/receptors, their effect on preeclampsia risk could differ. Our study examined the risk of preeclampsia (and its subtypes) following exposure to different classes of antidepressants, also accounting for specific transporters/receptors targeted by antidepressants. METHODS: We conducted a cohort study, combining data from the Netherlands Perinatal Registry and the PHARMO Database Network. Exposure to antidepressants was examined from conception to week 20 of gestation; extended use thereafter was also studied. Antidepressants were categorized according to classes [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and according to target transporters/receptors. Women not using any antidepressants during 15 months before delivery were included as reference. RESULTS: We included 2,103 exposed and 95,376 reference women. Preeclampsia occurred in 70 exposed women (15 early-onset, 55 late-onset) and in 2,582 reference women (387 early-onset, 2,195 late-onset). TCA monotherapy (214 women) was associated with an increased risk of preeclampsia (n = 15, RR 2.46, 95% CI 1.51-4.02) and late-onset preeclampsia (n = 12, RR 2.41, 95% CI 1.39-4.17, early-onset could not be evaluated). No association was detected with SSRIs, SNRIs and MAOIs. We did observe an increased risk of early-onset preeclampsia following exposure to 5-HT2A antagonizing antidepressants (6/405 women, excluding TCA users, RR 3.56, 95% CI 1.60-7.94). CONCLUSIONS: Our results support an increased risk of preeclampsia and the late-onset subtype among TCA users. The association between 5-HT2A antagonists and the early-onset subtype needs to be interpreted with caution based on the relatively small number of exposed cases.

Thermodynamics of selective serotonin reuptake inhibitors partitioning into 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayers.

Knowledge of thermodynamics of lipid membrane partitioning of amphiphilic drugs as well as their binding site within the membrane are of great relevance not only for understanding the drugs' pharmacology but also for the development and optimization of more potent drugs. In this study, the interaction between two representatives of selective serotonin reuptake inhibitors, including paroxetine and sertraline, and large unilamellar vesicles (LUVs) composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) was investigated by second derivative spectrophotometry and Fourier transform infrared spectroscopy (FTIR) to determine the driving force of the drug partitioning across lipid membranes. It was found that temperature increase from 25 to 42 °C greatly enhanced the partitioning of paroxetine and sertraline into DOPC LUVs, and sertraline intercalated into the lipid vesicles to a greater extent than paroxetine in the temperature range examined. The partitioning of both drugs into DOPC LUVs was a spontaneous, endothermic and entropy-driven process. FTIR measurements suggested that sertraline could penetrate deeply into the acyl tails of DOPC LUVs as shown by the considerable shifts in the lipid's CH2 and C[double bond, length as m-dash]O stretching modes induced by the drug. Paroxetine, however, could reside closer to the head groups of the lipid since its presence caused a larger shift in the PO2 - bands of DOPC LUVs. The findings reported here provide valuable insights into the influence of small molecules' chemical structure on their molecular interaction with the lipid bilayer namely their possible binding sites within the lipid bilayer and their thermodynamics profiles of partitioning, which could benefit rational drug design and drug delivery systems.

Pontine control of ejaculation and female orgasm.

INTRODUCTION: The physiological component of ejaculation shows parallels with that of micturition, as both are essentially voiding activities. Both depend on supraspinal influences to orchestrate the characteristic pattern of activity in the pelvic organs. Unlike micturition, little is known about the supraspinal pathways involved in ejaculation and female orgasm. AIM: To identify brainstem regions activated during ejaculation and female orgasm and to compare them with those activated during micturition. METHODS: Ejaculation in men and orgasm in women were induced by manual stimulation of the penis or clitoris by the participants' partners. Positron emission tomography (PET) with correction for head movements was used to capture the pattern of brain activation at the time of sexual climax. MAIN OUTCOME MEASURES: PET scans showing areas of activation during sexual climax. RESULTS: Ejaculation in men and orgasm in women resulted in activation in a localized region within the dorsolateral pontine tegmentum on the left side and in another region in the ventrolateral pontine tegmentum on the right side. The dorsolateral pontine area was also active in women who attempted but failed to have an orgasm and in women who imitated orgasm. The ventrolateral pontine area was only activated during ejaculation and physical orgasm in women. CONCLUSION: Activation of a localized region on the left side in the dorsolateral pontine tegmentum, which we termed the pelvic organ-stimulating center, occurs during ejaculation in men and physical orgasm in women. This same region has previously been shown to be activated during micturition, but on the right side. The pelvic organ-stimulating center, via projections to the sacral parasympathetic motoneurons, controls pelvic organs involved in voiding functions. In contrast, the ventrolateral pontine area, which we term the pelvic floor-stimulating center, produces the pelvic floor contractions during ejaculation in men and physical orgasm in women via direct projections to pelvic floor motoneurons.

High-intensity erotic visual stimuli de-activate the primary visual cortex in women.

INTRODUCTION: The primary visual cortex, Brodmann's area (BA 17), plays a vital role in basic survival mechanisms in humans. In most neuro-imaging studies in which the volunteers have to watch pictures or movies, the primary visual cortex is similarly activated independent of the content of the pictures or movies. However, in case the volunteers perform demanding non-visual tasks, the primary visual cortex becomes de-activated, although the amount of incoming visual sensory information is the same. AIM: Do low- and high-intensity erotic movies, compared to neutral movies, produce similar de-activation of the primary visual cortex? METHODS: Brain activation/de-activation was studied by Positron Emission Tomography scanning of the brains of 12 healthy heterosexual premenopausal women, aged 18-47, who watched neutral, low- and high-intensity erotic film segments. MAIN OUTCOME MEASURES: We measured differences in regional cerebral blood flow (rCBF) in the primary visual cortex during watching neutral, low-intensity erotic, and high-intensity erotic film segments. RESULTS: Watching high-intensity erotic, but not low-intensity erotic movies, compared to neutral movies resulted in strong de-activation of the primary (BA 17) and adjoining parts of the secondary visual cortex. CONCLUSIONS: The strong de-activation during watching high-intensity erotic film might represent compensation for the increased blood supply in the brain regions involved in sexual arousal, also because high-intensity erotic movies do not require precise scanning of the visual field, because the impact is clear to the observer.

Brain circuits for mating behavior in cats and brain activations and de-activations during sexual stimulation and ejaculation and orgasm in humans.

In cats, there exists a descending system that controls the posture necessary for mating behavior. A key role is played by the mesencephalic periaqueductal gray (PAG), which maintains strong specific projections to the nucleus retroambiguus located laterally in the most caudal medulla. The NRA, in turn, has direct access to motoneurons in the lumbosacral cord that produce the mating posture. This pathway is slightly different in males and females, but in females its strength fluctuates strongly depending on whether or not the cat is in heat. This way the PAG determines whether or not mating can take place. Via the PAG many other regions in the limbic system as well as in the prefrontal cortex and insula can influence mating behavior. In humans, the brain also controls responses to sexual stimulation as well as ejaculation in men and orgasm in women. Neuroimaging techniques show activations and de-activations but are not able to verify whether the PAG has a similar effect as in cats. PET-scanning results revealed that there is activation in the upper brainstem and cerebellum, as well as insula in men and in the somatomotor and somatosensory cortex in women. During sexual stimulation, but especially during ejaculation and orgasm there was strong de-activation mainly on the left side in the temporal lobe and ventral prefrontal cortex. These neuroimaging results show the importance of lowering the level of alertness regarding your immediate environment (left hemisphere) to have proper sexual behavior.