Serotonergic Drugs Research Articles

Advantages and Disadvantages of Using St. John's Wort as a Treatment for Depression

Background and objectives: St. John's wort (SJW) extracts are currently being used to treat depression of various degrees of severity. While many studies have shown it to be superior to placebo, data regarding the effectiveness of using SJW as a stand-alone treatment compared with standard antidepressants has yet to be proven conclusively. This study aims to understand the advantages and disadvantages of SJW as a treatment modality for depression.Methods: The authors searched PubMed, JAMA network, Springer Link, Elsevier, Google Scholar, and Scientific Progress databases, from 2011 through August 2021, using the following keywords: St John’s wort, Hypericum perforatum, depression, antidepressant, complementary alternative medicine, economic evaluation depression St. wort, St John’s wort and depression, antidepressant interactions. This yielded a total of 27 papers following a thorough removal of irrelevant content and dissemination in languages other than English.Results: In patients with mild and moderate depression, SJW proved superior to placebo. Certain studies comparing the efficacy of SJW versus selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine, reported SJW to be more efficacious, while the majority reported no significant difference. Tricyclic antidepressants were also found to have similar efficacy as SJW. Moreover, treatment with SJW was also found to reduce postmenopausal depression. Regarding the safety profile, although SJW is better tolerated with fewer adverse effects when compared to standardized antidepressants, its predisposition to causing fatal serotonin syndrome, when used in conjunction with other serotonergic agents and drug interactions noted with CYP 450 drugs, raises a question in the safety profile.Conclusion: It is essential to acknowledge that SJW has been used as a treatment measure in Germany. Despite being only listed as a dietary supplement by the FDA and not a drug, SJW has shown to be comparable, if not more efficacious, than most standard treatment options for depression. SJW does prove to be an exciting piece of pharmacotherapy in the realm of mental health and post-menopausal treatment. More prospective studies will help us better understand its efficacy in mild and moderate depression and its ability to serve as a long-term agent. Considering its mechanism of action, its role in relieving patients suffering from an anxiety disorder is also worth considering.

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice.

Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT2AR) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT2AR antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT2AR agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT2AR density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT2AR, is not observable upon repeated administration of nonpsychedelic 5-HT2AR agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

Serotonergic drug repurposing in multiple sclerosis: A new possibility for disease-modifying therapy.

Investigation of neuroimmune interactions is one of the most developing areas in the study of multiple sclerosis pathogenesis. Recent evidence suggests the possibility of modulating neuroinflammation by targeting biogenic amine receptors. It has been shown that selective serotonin reuptake inhibitor fluoxetine modulates innate and adaptive immune system cells' function and can reduce experimental autoimmune encephalomyelitis and multiple sclerosis severity. This brief report discusses the immune mechanisms underlying the multiple sclerosis pathogenesis and the influence of fluoxetine on them. The retrospective data on the impact of fluoxetine treatment on the course of multiple sclerosis are also presented. The results of this and other studies suggest that fluoxetine could be considered an additional therapy to the standard first-line disease-modifying treatment for relapsing–remitting multiple sclerosis.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AimsUrethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women.MethodsWe conducted a randomized, double‐blind, placebo‐ and active‐controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine), 8 mg reboxetine (and placebocitalopram), or two placebos. Study drugs were administered at a 1‐h interval due to a difference in estimated time to peak plasma concentration (t max). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated t max for both study drugs (one timepoint).ResultsCompared to placebo, citalopram increased OUP by 6.6 cmH20 (95% confidence interval [CI] 0.04–13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH20 (95% CI: 1.3–12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH20 in resting condition compared to placebo (95% CI: 23.5–36.5, p < 0.001), and 27.0 cmH20 (95% CI: 21.2–32.8, p < 0.001) in squeezing condition.ConclusionCitalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Eating a High Fat Diet Enhances Sensitivity of Rats to 5‐HT1A Receptor‐Mediated Behavioral Effects of Serotonergic Drugs

Diet (e.g., type and amount of food consumed) has been shown to impact drug sensitivity, in ways that might be relevant for the therapeutic effects and side effects of medications. For example, previous studies have demonstrated that rats eating a high fat diet are more sensitive to some of the effects of dopaminergic drugs. Considerably less is known about how eating a high fat diet might impact sensitivity to drugs that act on serotonin (5‐HT) systems, many of which might be beneficial for the treatment of obesity, since they can decrease feeding. Drugs with agonist effects at 5‐HT receptors can produce a collection of adverse effects, known as 5‐HT syndrome. Animal models of 5‐HT syndrome include lower lip retraction, flat body posture, penile erections, and forepaw treading. To test the hypothesis that eating a high fat diet enhances sensitivity of rats to 5‐HT syndrome, male (n=16) and female (n=16) rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) laboratory chow were tested once weekly with cumulative doses of 5‐HT receptor agonists, including 8‐OH‐DPAT (0.01‐1.0 mg/kg, s.c.), lorcaserin (1.0‐32.0 mg/kg, i.p.) and WAY 163909 (1.0‐32.0 mg/kg, i.p.). Agonists were also studied in combination with antagonists selective for 5‐HT1A (WAY 100635; 0.178 mg/kg, s.c.), or 5‐HT2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Food consumption and body weight were measured throughout the study. Results were analyzed using either two‐way or three‐way mixed model ANOVAs with diet and dose, diet and day, or diet, sex, and drug as factors, and Bonferroni post hoc comparisons where appropriate. Effects mediated by the 5‐HT2C receptor (e.g, penile erections as well as decreased food consumption), were only observed following injections of lorcaserin and WAY 163909 (but not 8‐OH‐DPAT), and were not different between rats eating standard or high fat chow. Regarding 5‐HT1A receptor‐mediated effects, all three 5‐HT receptor agonists induced forepaw treading in rats; however, flat body posture and lower lip retraction were only induced by 8‐OH‐DPAT. Rats eating high fat chow were more sensitive to forepaw treading, regardless of which drug induced this behavior; however, WAY 163909 induced less forepaw treading as compared to the other two drugs, regardless of diet. Rats eating high fat chow were also more sensitive to 8‐OH‐DPAT‐induced lower lip retraction, but not flat body posture. These results suggest that eating a high fat diet can impact sensitivity of rats to some of the effects of serotonergic drugs. Additionally, these results demonstrate that while both lorcaserin and WAY 163909 decrease feeding, WAY 163909 produces less 5‐HT1A‐mediated forepaw treading than lorcaserin, which might indicate that it will produce fewer side effects in humans as well. Finally, these results suggest that dietary history could influence sensitivity of individuals to the adverse effects of serotonergic drugs, such as 5‐HT syndrome.

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes – default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization.

Serotonergic drugs modulate the phase behavior of complex lipid bilayers

Serotonin is an endogenous neurotransmitter involved in both physiological and pathophysiological processes. Traditionally, serotonin acts as a ligand for G protein-coupled receptors (GPCRs) leading to subsequent cell signaling. However, serotonin can also bind to lipid membranes with high affinity and modulate the phase behavior in 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC)/N-palmitoyl-D-erythro-sphingosylphosphorylcholine (PSM)/cholesterol model membranes mimicking the outer leaflet of the plasma membrane. Here, we investigated if serotonergic drugs containing the pharmacophore from serotonin would also modulate phase behavior in lipid membranes in a similar fashion. We used 2H NMR spectroscopy to explore the phase behavior of POPC/PSM/cholesterol (4/4/2 molar ratio) mixtures in the presence of the serotonergic drugs aripiprazole, BRL-54443, BW-723C86, and CP-135807 at a lipid to drug molar ratio of 10:1. POPC and PSM were perdeuterated in the palmitoyl chain, respectively, and prepared in individual samples. Numerical lineshape simulations of the 2H NMR spectra were used to calculate the order parameter profiles and projected lengths of the saturated acyl chains. All serotonergic drugs induce two components in 2H NMR spectra, indicating that they increased the hydrophobic mismatch between the thickness of the coexisting lipid phases leading to larger domain sizes, relatively similarly to serotonin. AFM force indentation and Raman spectral studies, which interrogate membrane mechanical properties, also indicate changes in membrane order in the presence of these drugs. These findings highlight how serotonergic drugs alter membrane phase behavior and could modulate both target and other membrane proteins, possibly explaining the side effects observed for serotonergic and other clinically relevant drugs.

Opioid and Benzodiazepine Substitutes: Impact on Drug Overdose Mortality in Medicare Population

IntroductionGabapentinoids (GABAs) and serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]/serotonin and norepinephrine reuptake inhibitors [SNRIs]) are increasingly being prescribed as potential substitutes to opioids and benzodiazepines (benzos), respectively, to treat co-occurring pain and anxiety disorders. The toxicities of these drug classes and their combinations are not well understood. MethodsWe conducted a matched case-control study using 2013-2016 Medicare files linked to the National Death Index. Cases were enrollees who died from drug overdose. Controls were enrollees who died from other causes. Cases and controls were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzos, and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death. ResultsAmong 4323 matches, benzo possession was associated with twice the risk for drug overdose death in cases vs controls. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs). Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations. ConclusionsBenzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death. SSRIs/SNRIs were associated with lower risk of overdose death vs benzodiazepines. GABAs were not associated with decreased risk compared with opioids, raising concerns for GABAs’ perceived relative safety.

Maternal Prepregnancy 5-Hydroxytryptamine Exposure Affects the Early Development of the Fetus.

In recent decades, the increasing incidence of depression has contributed to an increase in the use of serotonergic drugs, such as antidepressants, which predisposes humans to serotonin syndrome. Serotonin syndrome is caused by elevated serotonin levels in the central and peripheral nervous systems. It has been well documented that the development of offspring can be affected by maternal exposure to environmental challenges, such as stress, diseases, or an unhealthy diet during pregnancy. Serotonin, also called 5-hydroxytryptamine (5-HT), is widely expressed in the female reproductive system and plays an important role in the development of follicles and embryos. However, whether the suffering of the mother from serotonin syndrome before pregnancy affects fetal development is still uncertain. In the present study, to explore the effect of maternal prepregnancy 5-HT exposure on the fetus, intraperitoneal injection of 5-HT was used to change maternal prepregnancy 5-HT levels. It was found that maternal prepregnancy 5-HT exposure significantly reduced the body weight and liver weight and the levels of estrogen and progesterone in female mice. Although there was no significant difference in the cleavage rate and blastocyst rate between the 5-HT and control groups, maternal prepregnancy 5-HT exposure increased the percentage of embryo resorption, decreased placental weight, and led to placental inflammation at E13.5. Notably, 5-HT exposure caused weight loss in the offspring at 2 weeks. These results suggested that maternal prepregnancy 5-HT exposure could affect the development of the offspring, which was partly caused by reduced hormonal secretion and placental inflammation.

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity.

Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery. There is a great deal of interest in determining whether commonly prescribed pharmacological interventions that influence these neuromodulatory networks would similarly impair VNS effects. Here, we sought to directly test the effects of three common pharmaceuticals at clinically relevant doses that target neuromodulatory pathways on VNS-mediated plasticity in rats. To do so, rats were trained on a behavioral task in which jaw movement during chewing was paired with VNS and received daily injections of either oxybutynin, a cholinergic antagonist, prazosin, an adrenergic antagonist, duloxetine, a serotonin-norepinephrine reuptake inhibitor, or saline. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate reorganization of motor cortex representations, with area of cortex eliciting jaw movement as the primary outcome. In animals that received control saline injections, VNS paired with training significantly increased the movement representation of the jaw compared to naïve animals, consistent with previous studies. Similarly, none of the drugs tested blocked this VNS-dependent reorganization of motor cortex. The present results provide direct evidence that these common pharmaceuticals, when used at clinically relevant doses, are unlikely to adversely impact the efficacy of VNS therapy.

Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice

Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the homeostatic regulation of neuronal activity and synaptic plasticity. However, it remains largely unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 h after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow-wave activity. However, psilocin decreased the recovery rate of sleep slow-wave activity following sleep deprivation in the local field potentials of electrodes targeting the medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.

Post-Marketing Safety Profile of Vortioxetine Using a Cluster Analysis and a Disproportionality Analysis of Global Adverse Event Reports.

IntroductionVortioxetine, a multimodal serotonergic drug, is widely used as treatment for major depressive disorder. Although on the market since late 2013, the data of the relative safety of vortioxetine, especially compared to selective serotonin reuptake inhibitors, are still scarce.ObjectiveThe aim of this study was to explore the adverse event reporting pattern of vortioxetine through a cluster analysis. Furthermore, to compare the adverse event reporting pattern for vortioxetine with that of the selective serotonin reuptake inhibitors.MethodsIndividual case safety reports for vortioxetine in VigiBase up to 1 November, 2019 were subjected to consensus clustering, to identify and describe natural groupings of reports based on their reported adverse events. A vigiPoint exploratory analysis compared vortioxetine to the selective serotonin reuptake inhibitors in terms of relative frequencies for a wide range of covariates, including patient sex and age, reported drugs and adverse events, and reporting country. Important differences were identified using odds ratios with adaptive statistical shrinkage.ResultsThirty-six clusters containing at least five reports were identified and analysed. The two largest clusters included 48% of the vortioxetine reports and appeared to represent gastrointestinal adverse events and hypersensitivity adverse events. Other distinct clusters were related to, respectively, fatigue, aggression/suicidality, convulsion, medication errors, arthralgia/myalgia, increased weight, paraesthesia and anticholinergic effects. Some of these clusters are not labelled for vortioxetine, such as arthralgia/myalgia and paraesthesia, but are known adverse events for selective serotonin reuptake inhibitors. A vigiPoint analysis revealed a higher proportion of reports from consumers and non-health professionals for vortioxetine as well as higher relative reporting rates of gastrointestinal symptoms, pruritus and mood-related symptoms, consistent with the cluster analysis.ConclusionsA pattern of co-reported adverse events that is consistent with labelled adverse events for vortioxetine and the safety profile for selective serotonin reuptake inhibitors in general was revealed. Clusters of unlabelled adverse events were identified that reflect clinical entities that might represent signals of previously unknown adverse events. More extensive analyses of spontaneous reports may help to further understand the reporting pattern of adverse events.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01139-y.

Clinical considerations with use of psychotropic medications in COVID-19 patients

Clinical considerations with use of psychotropic medications in COVID-19 patients

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Chapter 17 - Better language through chemistry: Augmenting speech-language therapy with pharmacotherapy in the treatment of aphasia

Speech and language therapy is the standard treatment of aphasia. However, many individuals have barriers in seeking this measure of extensive rehabilitation treatment. Investigating ways to augment therapy is key to improving poststroke language outcomes for all patients with aphasia, and pharmacotherapies provide one such potential solution. Although no medications are currently approved for the treatment of aphasia by the United States Food and Drug Administration, numerous candidate mechanisms for pharmaceutical manipulation continue to be identified based on our evolving understanding of the neurometabolic experience of stroke recovery across molecular, cellular, and functional levels of inquiry. This chapter will review evidence for catecholaminergic, glutamatergic, cholinergic, and serotonergic drug therapies and discuss future directions for both candidate drug selection and pharmacotherapy practice in people with aphasia.

Increasing Central Serotonin with 5-hydroxytryptophan Disrupts the Inhibition of Social Gaze in Nonhuman Primates.

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted amongst patient populations treated with serotonergic drugs. However, those in the field lack a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze responses, making them worse at flexibly switching between orienting and inhibiting behaviors. Furthermore, the effects of 5-HTP on performance correlated with a constriction of the pupil, an increased time to initiate trials, and an increased reaction time, suggesting that the disruptive effects of 5-HTP on social gaze behaviors are likely driven by a downregulation of arousal and motivational states. Together, these findings provide causal evidence for a modulatory relationship between 5-HTP and social gaze behaviors in nonhuman primates and offer translational insights for the role of the serotonergic system in social gaze.SIGNIFICANCE STATEMENT Behavioral changes arising from pharmacological agents that target serotonergic functions are complex and difficult to predict. Here, we examined the causal impacts of administering the direct precursor of serotonin, 5-HTP, on orienting and inhibiting social gaze in nonhuman primates. 5-HTP increased central concentrations of serotonin and selectively impaired the ability of monkeys to inhibit orienting to faces while similarly impairing the ability of monkeys to orient to face and control images. These behavioral gaze impairments were systematically associated with a downregulation of arousal and motivational states, indexed by pupil constriction, increased time to initiate trials, and increased reaction time. These findings provide a causal link between 5-HTP and social gaze behaviors in nonhuman primates and provide translational insights about serotonergic interventions.

Trends in the Use of Benzodiazepines, Z-Hypnotics, and Serotonergic Drugs Among US Women and Men Before and During the COVID-19 Pandemic

The ongoing COVID-19 pandemic and associated mitigation measures have disrupted access to psychiatric medications, particularly for women. To assess the sex differences in trends in the prescribing of benzodiazepines, Z-hypnotics and serotonergic (selective serotonin reuptake inhibitors [SSRIs] and serotonin and norepinephrine reuptake inhibitors [SNRIs]), which are commonly prescribed for anxiety, insomnia, and depression. This cohort study used data from Clinformatics Data Mart, one of the largest commercial health insurance databases in the US. Enrollees 18 years or older were required to have complete enrollment in a given month during our study period, January 1, 2018, to March 31, 2021, to be included for that month. Prescription of a benzodiazepine, Z-hypnotic, or SSRI or SNRI. For each month, the percentage of patients with benzodiazepine, Z-hypnotic, or SSRI or SNRI prescriptions by sex was calculated. The records of 17 255 033 adults (mean [SD] age, 51.7 [19.5] years; 51.3% female) were examined in 2018, 17 340 731 adults (mean [SD] age, 52.5 [19.7] years; 51.6% female) in 2019, 16 916 910 adults (mean [SD] age, 53.7 [19.8] years; 51.9% female) in 2020, and 15 135 998 adults (mean [SD] age, 56.2 [19.8] years; 52.5% female) in 2021. Compared with men, women had a higher rate of prescriptions for all 3 drugs classes and had larger changes in prescription rates over time. Benzodiazepine prescribing decreased from January 2018 (women: 5.61%; 95% CI, 5.60%-5.63%; men: 3.03%; 95% CI, 3.02%-3.04%) to March 2021 (women: 4.91%; 95% CI, 4.90%-4.93%; men: 2.66%; 95% CI, 2.65%-2.67%), except for a slight increase in April 2020 among women. Z-hypnotic prescribing increased from January 2020 for women (1.39%; 95% CI, 1.38%-1.40%) and February 2020 for men (0.97%; 95% CI, 0.96%-0.98%) to October 2020 (women: 1.46%; 95% CI, 1.46%-1.47%; men: 1.00%; 95% CI, 0.99%-1.01%). Prescribing of SSRIs and SNRIs increased from January 2018 (women: 12.77%; 95% CI; 12.75%-12.80%; men: 5.56%; 95% CI, 5.44%-5.58%) to April 2020 for men (6.73%; 95% CI, 6.71%-6.75%) and October 2020 for women (15.18%; 95% CI, 15.16%-15.21%). In this cohort study, coinciding with the COVID-19 pandemic onset was an increase in Z-hypnotic as well as SSRI and SNRI prescriptions in both men and women along with an increase in benzodiazepine prescriptions in women, findings that suggest a substantial mental health impact of COVID-19-associated mitigation measures.

Antidepressant and anxiolytic compounds isolated from Salvia elegans interact with serotonergic drugs.

Salvia elegans belongs to a genus plants with biological activities in central nervous system. In this work, the purpose was to evaluate the anxiolytic and antidepressant effects of fractions and compounds isolated from S. elegans and its interaction with serotoninergic drugs by using behavioral tests in mice. Fractions from aerial parts of S. elegans were obtained by column chromatography, SeF1, SeF2, SeF3, and SeF4. Each of them was administered to 25mg/k in ICR mice subject to forced swimming test (FST), or elevated plus maze test (EPM), or open field test (OFT). The most active fractions were chemically separated until compounds, which were analyzed as anxiolytic or antidepressant and the coadministration of these treatments with 5-HT1A and 5-HT2 drugs was measured in the different biological tests. All fractions were anxiolytic and antidepressant, oleanolic acid (OA) was found in SeF2, and from SeF3, a mixture of terpenes was found; a GC-MS analysis confirmed the presence of two main compounds: rosifoliol and agaraspirol (TM, mixture of terpenes). TM (doses-response curve, 0.01, 0.1, 0.5, 1.0, and 2.0mg/kg) and OA (5mg/kg) were also evaluated demonstrating an antidepressant and anxiolytic effect, respectively. The combination of TM (0.5mg/kg) with 8-OH (selective 5-HT1A receptoragonist) induced an increment of antidepressant activity, while with the antagonist WAY-100635, the effect diminished. But with DOI (5-HT1c/5-HT2receptor agonist), there was no change, and with KET (5-HT2 receptor antagonist), the activity was increased. When OA is co-administered with 8-OH or with DOI, the anxiolytic activity of this terpene, diminished; but with the combination with antagonists, the effect of OA shows no change. TM and OA were antidepressant and anxiolytic, respectively, on mice exposed to different tests, and these are able to interact with serotoninergic drugs.

Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease

Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.

P-MD006. Serotonin syndrome - case series

Introduction. Serotonin syndrome (SS) is a life threatening condition caused by serotonin toxicity, and usually involves a combination of drugs that increase serotonergic transmission. Methods. All patients admitted with a clinical diagnosis of serotonin syndrome in KIMS hospital between april 2019 and September 2019 were studied. A total of 3 patients were diagnosed with Serotonin syndrome over a period of 6 months. Results. Case 1: 58-year-old male patient, diabetic and hypertensive, on Amantadine and Rasagiline for complaints of tremors, slowness of gait and activities since 3 months. Escitalopram and clonazepam with amitriptyline was advised by the treating doctor. Olanzapine was given for psychosis. Patient’s tremors increased further. CPK was 839 U/L. Considering possibility of Serotonin syndrome, patient was treated with cyproheptadine and clonazepam. Patient improved symptomatically and was discharged. Case 2: 70-year-old male patient presented with complaint of involuntary movements of both upper limbs of 5 days duration. Patient was on multiple antipsychotic drugs for psychiatric disorder. On examination, patient had rigidity of both upper limbs with rest and postural tremor both upper limbs with restless behaviour, agitation, decreased sleep and hallucinations. On evaluation CPK was 2413 U/L. Considering possibility of serotonin syndrome, all offending medications were stopped and patient was treated with cyproheptadine, clonazepam, and levodopa. Case 3: 69- year-old male patient with psychiatric disorder on multiple antipsychotics presented with complaint of tremors all over body, irrelevant talk, and auditory hallucinations since 2 days. He had history of right thalamic infarct in 2015. Considering possibility of serotonin sundrome, antipsychotics were stopped and treated with cyproheptadine, clonazepam and levodopa. Conclusion. The incidence of serotonin syndrome is rising, reflecting the growing number of serotonergic drugs available and the increased use of these agents in clinical practice.