Molecular Testing: Adoption and Disparities in Utilization Across the United States.

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Medical Maximizing Preferences and Beliefs About Cancer Among US Adults.

Importance: Medical overutilization contributes to significant health care expenditures and exposes patients to questionably beneficial surgery and unnecessary risk. Objectives: To understand public attitudes toward medical utilization and the association of these attitudes with beliefs about cancer. Design, Setting, and Participants: In this cross-sectional survey study conducted from August 26 to October 28, 2020, US-based, English-speaking adults were recruited from the general public using Prolific Academic, a research participant platform. Quota-filling was used to obtain a sample demographically representative of the US population. Adults with a personal history of cancer other than nonmelanoma skin cancer were excluded. Statistical analysis was completed in July 2022. Main Outcome and Measures: Medical utilization preferences were characterized with the validated, single-item Maximizer-Minimizer Elicitation Question. Participants preferring to take action in medically ambiguous situations (hereafter referred to as "maximizers") were compared with those who leaned toward waiting and seeing (hereafter referred to as "nonmaximizers"). Beliefs and emotions about cancer incidence, survivability, and preventability were assessed using validated measures. Logistic regression modeled factors associated with preferring to maximize medical utilization. Results: Of 1131 participants (mean [SD] age, 45 [16] years; 568 women [50.2%]), 287 (25.4%) were classified as maximizers, and 844 (74.6%) were classified as nonmaximizers. Logistic regression revealed that self-reporting very good or excellent health status (compared with good, fair, or poor; odds ratio [OR], 2.01 [95% CI, 1.52-2.65]), Black race (compared with White race; OR, 1.88 [95% CI, 1.22-2.89]), high levels of cancer worry (compared with low levels; OR, 1.62 [95% CI, 1.09-2.42]), and overestimating cancer incidence (compared with accurate estimation or underestimating; OR, 1.58 [95% CI, 1.09-2.28]) were significantly associated with maximizing preferences. Those who believed that they personally had a higher-than-average risk of developing cancer were more likely to be maximizers (23.6% [59 of 250] vs 17.4% [131 of 751]; P = .03); this factor was not significant in regression analyses. Conclusions and Relevance: In this survey study of US adults, those with medical maximizing tendencies more often overestimated the incidence of cancer and had higher levels of cancer-related worry. Targeted and personalized education about cancer and its risk factors may help reduce overutilization of oncologic care.

Making Choices: A Multi-institutional, Longitudinal Cohort Study Assessing Changes in Treatment Outcome Valuation for Low-Risk Thyroid Cancer.

OBJECTIVE: To evaluate the relative importance of treatment outcomes to patients with low-risk thyroid cancer (TC). SUMMARY BACKGROUND DATA: Overuse of total thyroidectomy (TT) for low-risk TC is common. Emotions from a cancer diagnosis may lead patients to choose TT resulting in outcomes that do not align with their preferences. METHODS: Adults with clinically low-risk TC enrolled in a prospective, multi-institutional, longitudinal cohort study from 11/2019-6/2021. Participants rated treatment outcomes at the time of their surgical decision and again 9 months later by allocating 100 points amongst 10 outcomes. T-tests and Hotelling's T 2 statistic compared outcome valuation within and between subjects based on chosen extent of surgery (TT vs. lobectomy). RESULTS: Of 177 eligible patients, 125 participated (70.6% response) and 114 completed the 9-month follow-up (91.2% retention). At the time of the treatment decision, patients choosing TT valued the risk of recurrence more than those choosing lobectomy and the need to take thyroid hormone less ( P <0.05). At repeat valuation, all patients assigned fewer points to cancer being removed and the impact of treatment on their voice, and more points to energy levels ( P <0.05). The importance of the risk of recurrence increased for those who chose lobectomy and decreased for those choosing TT ( P <0.05). CONCLUSION: The relative importance of treatment outcomes changes for patients with low-risk TC once the outcome has been experienced to favor quality of life over emotion-related outcomes. Surgeons can use this information to discuss the potential for asthenia or changes in energy levels associated with total thyroidectomy.

Assessing Fear of Thyroid Cancer in the General U.S. Population: A Cross-Sectional Study.

Background: This study aimed to measure fear of thyroid cancer in the general U.S. population and identify factors associated with a high level of thyroid cancer-specific fear that may contribute to overtreatment. Methods: We conducted a cross-sectional survey using Prolific Academic Ltd.®, an online survey platform. The survey was administered in August 2020 to English speaking adults (>17 years) in the United States who were registered with Prolific. The target sample was stratified to represent the demographics of the U.S. population. A validated, eight-item breast cancer fear scale was adapted to measure thyroid cancer-specific fear. Multivariate logistic regression identified factors significantly associated with high levels of thyroid cancer-specific fear. Results: Of the 1136 respondents (94.3% eligibility), 50.4% were female, 74.1% White, and the mean age was 45 years (SD = 16 years). Overall, 47.5% of respondents had high levels of thyroid cancer-specific fear. Multivariate regression demonstrated that age <40 years (OR = 2.46 vs. 65+ [95% confidence interval {CI} = 1.60-3.80]) and female gender (OR = 1.48 vs. male [CI = 1.13-1.93]) were associated with high levels of thyroid cancer fear. Believing thyroid cancer (OR = 2.71 [CI = 1.99-3.69]) and cancer in general are serious (OR = 1.53 [CI = 1.13-2.08]) were also associated with high levels of thyroid cancer fear. Respondents who overestimated thyroid cancer incidence (OR = 1.64 [CI = 1.25-2.13]) and believed they had a high chance of developing cancer (OR = 1.70 [CI = 1.19-2.42]) were also more likely to have high fear of thyroid cancer. Conclusion: Thyroid cancer-specific fear is prevalent in U.S. adults particularly in females and those younger than 40 years. Because disease-specific fear is associated with overtreatment, targeted education about the seriousness, incidence, and risk factors for developing thyroid cancer may decrease public fear and possibly overtreatment related to "scared decision-making."

Diagnostic Accuracy of Fine-Needle Biopsy in the Detection of Thyroid Malignancy: A Systematic Review and Meta-analysis.

Importance: Fine-needle biopsy (FNB) became a critical part of thyroid nodule evaluation in the 1970s. It is not clear how diagnostic accuracy of FNB has changed over time. Objective: To conduct a systematic review and meta-analysis estimating the accuracy of thyroid FNB for diagnosis of malignancy in adults with a newly diagnosed thyroid nodule and to characterize changes in accuracy over time. Data Sources: PubMed, SCOPUS, and Cochrane Central Register of Controlled Trials were searched from 1975 to 2020 using search terms related to FNB accuracy in the thyroid. Study Selection: English-language reports of cohort studies or randomized trials of adult patients undergoing thyroid FNB with sample size of 20 or greater and using a reference standard of surgical histopathology or clinical follow-up were included. Articles that examined only patients with known thyroid disease or focused on accuracy of novel adjuncts, such as molecular tests, were excluded. Two investigators screened each article and resolved conflicts by consensus. A total of 36 of 1023 studies met selection criteria. Data Extraction and Synthesis: The MOOSE guidelines were used for data abstraction and assessing data quality and validity. Two investigators abstracted data using a standard form. Studies were grouped into epochs by median data collection year (1975 to 1990, 1990 to 2000, 2000 to 2010, and 2010 to 2020). Data were pooled using a bivariate mixed-effects model. Main Outcomes and Measures: The primary outcome was accuracy of FNB for diagnosis of malignancy. Accuracy was hypothesized to increase in later time periods, a hypothesis formulated prior to data collection. Results: Of 16 597 included patients, 12 974 (79.2%) were female, and the mean (SD) age was 47.3 (12.9) years. The sensitivity of FNB was 85.6% (95% CI, 79.9-89.5), the specificity was 71.4% (95% CI, 61.1-79.8), the positive likelihood ratio was 3.0 (95% CI, 2.3-4.1), and the negative likelihood ratio was 0.2 (95% CI, 0.2-0.3). The area under the receiver operating characteristic curve was 86.1%. Epoch was not significantly associated with accuracy. None of the available covariates could explain observed heterogeneity. Conclusions and Relevance: Accuracy of thyroid FNB has not significantly changed over time. Important developments in technique, preparation, and interpretation may have occurred too heterogeneously to capture a consistent uptrend over time. FNB remains a reliable test for thyroid cancer diagnosis.

Patient perception of receiving a thyroid cancer diagnosis.

PURPOSE OF REVIEW: This review describes the current state of the literature on patients' perceptions of receiving a diagnosis of thyroid cancer. The evaluation progresses from people's understanding about thyroid cancer in general to the lived experiences of those receiving an initial diagnosis or one of recurrence. The implications on patients' quality of life and treatment decisions are also discussed. RECENT FINDINGS: Receiving a diagnosis of thyroid cancer often elicits intense and immediate emotions of shock and fear evoked by the word 'cancer,' which may be related to lack of knowledge about thyroid cancer specifically. Describing thyroid cancer as the 'good cancer' in an attempt to reassure patients is not necessarily reassuring and can inadvertently minimize the impact of a patient's diagnosis. Fear and worry about cancer in general and the possibility for recurrence contribute to lasting psychological distress and decreased quality of life. Patients' perceptions of their diagnosis and resulting emotional reactions influence treatment decision-making and have the potential to contribute to decisions that may over-treat a low-risk thyroid cancer. SUMMARY: Understanding patients' experience of receiving a thyroid cancer diagnosis is critical because their emotional reactions can have a profound impact on treatment decision-making and quality of life.

Active surveillance for thyroid Cancer: a qualitative study of barriers and facilitators to implementation.

BACKGROUND: The 2015 American Thyroid Association guidelines supported active surveillance (AS) as a strategy for managing select low-risk thyroid cancers. Data examining physicians' attitudes about the acceptability of this option are limited. This study aimed to characterize the barriers and facilitators to implementing AS as perceived by practicing endocrinologists and surgeons in the United States. METHODS: We conducted 24 semi-structured interviews probing physicians' attitudes toward AS for patients with small, low-risk thyroid cancer. We used deductive content analysis guided by a well-known model of guideline implementation. Analysis characterized concepts and themes related to AS implementation as physician, guideline, or external factors. We performed member checking to validate results. RESULTS: The most prominent barriers to AS were related to physician factors, although guideline-specific and external barriers were also observed. Physician attitudes towards AS comprised the majority of physician-related barriers, while lack of knowledge about the guideline was also discussed. Participants' concerns about the potential negative outcomes resulting from observing a cancer were notable as were the lack of confidence in performing and offering surveillance. Beliefs about patient expectations and lack of knowledge about the guideline were also identified as barriers to offering surveillance. Guideline-specific and external barriers included the vagueness of surveillance protocols, lack of data supporting active surveillance, and societal beliefs about cancer. Facilitators of active surveillance included patients' desire to avoid surgery and shared decision-making. CONCLUSIONS: Barriers and facilitators of active surveillance for low-risk thyroid cancers exist at multiple levels. Strategies to increase adoption of active surveillance should focus on physicians' attitudes, patient expectations, data supporting surveillance outcomes, and promoting societal-level acceptance of surveillance.

NATIONAL SURVEY OF ENDOCRINOLOGISTS AND SURGEONS REGARDING ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER.

OBJECTIVE: Active surveillance for low-risk papillary thyroid cancer (PTC) was endorsed by the American Thyroid Association guidelines in 2015. The attitudes and beliefs of physicians treating thyroid cancer regarding the active surveillance approach are not known. METHODS: A national survey of endocrinologists and surgeons treating thyroid cancer was conducted from August to September 2017 via professional society emails. This mixed-methods analysis reported attitudes toward potential factors impacting decision-making regarding active surveillance, beliefs about barriers and facilitators of its use, and reasons why physicians would pick a given management strategy for themselves if they were diagnosed with a low-risk PTC. Survey items about attitudes and beliefs were derived from the Cabana model of barriers to guideline adherence and theoretical domains framework of behavior change. RESULTS: Among 345 respondents, 324 (94%) agreed that active surveillance was appropriate for at least some patients, 81% agreed that active surveillance was at least somewhat underused, and 76% said that they would choose surgery for themselves if diagnosed with a PTC of ≤1 cm. Majority of the respondents believed that the guidelines supporting active surveillance were too vague and that the current supporting evidence was too weak. Malpractice and financial concerns were identified as additional barriers to offering active surveillance. The respondents endorsed improved information resources and evidence as possible facilitators to offering active surveillance. CONCLUSION: Although there is general support among physicians who treat low-risk PTC for the active surveillance approach, there is reluctance to offer it because of the lack of robust evidence, guidelines, and protocols.

Perceptions of HPV vaccination and pharmacist-physician collaboration models to improve HPV vaccination rates.

BACKGROUND: Human Papillomavirus (HPV) is the most common sexually transmitted disease in the United States (US), with 12 cancer causing strains. Vaccination rates in the southern US fall below the national average. Pharmacists provide an opportunity to improve vaccination rates. OBJECTIVES: The objectives of this study were to 1) identify barriers and facilitators to providing the HPV vaccine and Vaccines for Children (VFC) program participation in pharmacies and clinics, and 2) assess pharmacy staff, clinic staff, and parent perceptions of 3 collaboration models to improve HPV vaccination. METHODS: A developmental formative evaluation was conducted with pharmacy staff, primary care clinic staff, and parents of adolescent children. Interview guides were informed by the Consolidated Framework for Implementation Research (CFIR). Barriers and facilitators to HPV vaccination and VFC participation were explored. Additionally, acceptability of 3 collaboration models were explored: 1) a shared-responsibility model in which a physician provides the first dose of HPV vaccine with the second provided in the pharmacy, 2) a pharmacy-based model in which a clinic refers patients to the pharmacy to receive both doses, and 3) an insourced model in which pharmacists schedule days to provide the vaccine in the collaborating clinic. RESULTS: Twenty-nine interviews were conducted between August 2019 and June 2020. Both pharmacy and clinic staff had positive views toward the HPV vaccine and vaccinations in general. Pharmacists and physicians reported parental awareness and education as a barrier to HPV vaccination. Counseling about HPV vaccine was reported as being more time-consuming because of the stigma associated with the vaccine. Parents were willing to have their children vaccinated for HPV in the pharmacy but desired their child's physician be involved in the immunization process. The shared-responsibility model was the most favored of the 3 collaboration models. CONCLUSION: Perceptions of the HPV vaccine and vaccination in pharmacies were positive. Collaboration between clinics and pharmacies to improve HPV vaccination rates is viewed positively by pharmacy staff, clinic staff, and parents. This study will guide implementation of pharmacist-physician collaborative models to improve vaccination through pharmacy participation in the VFC program and HPV vaccination.

Factors associated with physicians' recommendations for managing low-risk papillary thyroid cancer.

BACKGROUND: The 2015 American Thyroid Association endorsed less aggressive management for low-risk papillary thyroid cancer (LR-PTC). We aimed to identify factors influencing physicians' recommendations for LR-PTC. METHODS: We surveyed members of three professional societies and assessed respondents' recommendations for managing LR-PTC using patient scenarios. Multivariable logistic regression models identified clinical and non-clinical factors associated with recommending total thyroidectomy (TT) and active surveillance (AS). RESULTS: The 345 respondents included 246 surgeons and 99 endocrinologists. Physicians' preference for their own management if diagnosed with LR-PTC had the strongest association with their recommendation for TT and AS (TT: OR 12.3; AS: OR 7.5, p < 0.001). Physician specialty and stated patient preference were also significantly associated with their recommendations for both management options. Respondents who received information about AS had increased odds of recommending AS. CONCLUSIONS: Physicians' recommendations for LR-PTC are strongly influenced by non-clinical factors, such as personal treatment preference and specialty.

From Overdiagnosis to Overtreatment of Low-Risk Thyroid Cancer: A Thematic Analysis of Attitudes and Beliefs of Endocrinologists, Surgeons, and Patients.

Introduction: The optimal management for patients with small, low-risk thyroid cancer is often debated. We aimed to characterize the attitudes and beliefs of providers and patients about management of small, low-risk thyroid cancer and how they relate to overtreatment. Methods: We conducted 34 semi-structured interviews with surgeons (n = 12), endocrinologists (n = 12), and patients with <1.5 cm papillary thyroid cancer (n = 10). Interviews probed about diagnosis and treatment decision-making, including nonoperative options. We used thematic analysis to identify themes related to overtreatment and created concept diagrams to map observed relationships between themes. Results: When providers discussed management of small, low-risk thyroid cancer, most felt that overtreatment was a problem, and some brought it up without prompting. Providers often believed that overtreatment results from overdiagnosis and relayed how the process commonly starts with incidental discovery of a thyroid nodule on imaging. Providers viewed biopsy of the nodule as a reflexive or habitual action. They ascribed inappropriate biopsy to lack of adherence to or knowledge of guidelines, radiologist recommendations, and the desire of patients and physicians to minimize diagnostic uncertainty. Providers described subsequent cancer diagnosis as an event that "opens Pandora's box" and often provokes a strong instinctive, culturally rooted need to proceed with surgery-specifically total thyroidectomy. Consequently, most providers felt that it is easier to prevent overdiagnosis than overtreatment and recommended strategies such as improving guideline adherence, resetting patients' expectations, and engaging the media. In contrast, patients did not bring up or openly discuss overtreatment or overdiagnosis. Some patients described the seemingly automatic process from an incidental finding to surgery. Their statements confirmed that the "need to know" was a major motivation for biopsying their nodule. Patients felt that once they had a cancer diagnosis, surgery was a foregone conclusion. Patients admitted their knowledge about thyroid nodules and cancer was low, leaving room for education about the need for biopsy and less extensive treatment options. Conclusions: Surgeons' and endocrinologists' attitudes and beliefs about overtreatment focus on the automaticity of overdiagnosis. Both patients and providers are cognizant of the cascade of clinical events that propel patients from incidental discovery of a thyroid nodule to surgery.

Epigenetic and Neurodevelopmental Perspectives on Variation in Parenting Behavior.

Mother-infant interactions in rodents can be used to explore the biological basis of postnatal parental effects. There is emerging evidence from laboratory studies that variation in early life experiences can induce molecular changes in the developing brain which lead to activation or silencing of genes. These epigenetic effects may account for the stability of the effects of parenting on offspring development and the transmission of parenting from one generation to the next. In this article, we highlight evidence supporting a role for epigenetic mechanisms in the consequences, transmission, and variability in parenting. Although primarily drawn from laboratory studies in rodents, this evidence may also provide some insights into key questions within the study and practice of human parenting. We discuss these questions, highlighting both the challenges and benefits of using translational approaches.

Altered 5-HT2C receptor agonist-induced responses and 5-HT2C receptor RNA editing in the amygdala of serotonin transporter knockout mice.

BACKGROUND: The serotonin 5-HT2C receptor (5-HT2CR) is expressed in amygdala, a region involved in anxiety and fear responses and implicated in the pathogenesis of several psychiatric disorders such as acute anxiety and post traumatic stress disorder. In humans and in rodent models, there is evidence of both anxiogenic and anxiolytic actions of 5-HT2C ligands. In this study, we determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors. RESULTS: In the three-chamber social interaction test, the 5-HT2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT2C-mediated response was absent in SERT-/- mice. Likewise, in the open field test, the selective 5-HT2C agonist RO 60-0175 induced an anxiogenic response in SERT+/+ mice, but not in SERT-/- mice. Since 5-HT2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT2CR RNA editing profiles of SERT+/+ and SERT-/- mice in amygdala. Compared to SERT+/+ mice, SERT-/- mice showed a decrease in less edited, highly functional 5-HT2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency. CONCLUSIONS: These results indicate that the 5-HT2CR in the amygdala of SERT-/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT2C agonists in SERT-/- mice. These alterations in 5-HT2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors.

Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating.

Long-term weight management by dieting has a high failure rate. Pharmacological targets have focused on appetite reduction, although less is understood as to the potential contributions of the stress state during dieting in long-term behavioral modification. In a mouse model of moderate caloric restriction in which a 10-15% weight loss similar to human dieting is produced, we examined physiological and behavioral stress measures. After 3 weeks of restriction, mice showed significant increases in immobile time in a tail suspension test and stress-induced corticosterone levels. Increased stress was associated with brain region-specific alterations of corticotropin-releasing factor expression and promoter methylation, changes that were not normalized with refeeding. Similar outcomes were produced by high-fat diet withdrawal, an additional component of human dieting. In examination of long-term behavioral consequences, previously restricted mice showed a significant increase in binge eating of a palatable high-fat food during stress exposure. Orexigenic hormones, melanin-concentrating hormone (MCH) and orexin, were significantly elevated in response to the high-fat diet only in previously restricted mice. Furthermore, administration of the MCH receptor-1 antagonist GSK-856464 [4-(4-ethyl-5-methylsulfanyl-1,2,4-triazol-3-yl)pyridine] significantly reduced total caloric intake in these mice during high-fat access. These results reveal reprogramming of key central pathways involved in regulating stress responsivity and orexigenic drives by moderate caloric restriction experience. In humans, such changes would be expected to reduce treatment success by promoting behaviors resulting in weight regain, and suggest that management of stress during dieting may be beneficial in long-term maintenance.

Epigenetic influences on brain development and plasticity.

A fine interplay exists between sensory experience and innate genetic programs leading to the sculpting of neuronal circuits during early brain development. Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the formation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood.

Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice.

The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/-) and knockout (-/-) mice. Comparisons were made with SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviours in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT-/- mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT-/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/- mice.

Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice.

RATIONALE: Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life. OBJECTIVES: To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice. RESULTS: 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.5- to 11.7-fold increases in SERT-/- mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT-/-, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT-/- mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT-/- mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/- mice with no effect in SERT-/- mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT-/- mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT+/- and -/- mice. CONCLUSIONS: These studies demonstrate that SERT-/- mice have exaggerated neurochemical, behavioral, and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT-/- mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice.

A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric illness with strong segregation data indicative of major genetic contributions. Association analyses of common functional variants of the serotonin transporter gene (SLC6A4), a long-standing OCD candidate, have so far been inconsistent. Here, we set out to investigate the role of additional functional SLC6A4 loci in OCD. We describe a common, functional C > T single nucleotide polymorphism, rs25532, located less than 150 nucleotides centromeric of the serotonin transporter-linked polymorphic region indel known as 5-HTTLPR. The minor allele of rs25532 significantly decreased luciferase reporter gene expression levels by 15-80%, depending on 5-HTTLPR allele background and cell type. Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus association with OCD in a large case-control sample. Remarkably, the haplotype significantly overrepresented in probands contained the higher-expressing allele at each locus, supporting the notion of increased serotonin transporter functioning being pathogenetically involved in OCD. Conditional haplotype analyses with the software WHAP revealed that this association is primarily driven by 5-HTTLPR, rs25532 and rs16965628. Our results contribute to a better understanding of SLC6A4 expression genetics and provide a functional haplotype framework for future serotonin-related studies.

Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice.

Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/-) and knockout (-/-) mice. In SERT -/- mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1mg/kg) or the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/- mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT -/- mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/- and -/- mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT -/- mice.