All the brain's a stage for serotonin: the forgotten story of serotonin diffusion across cell membranes.

In the conventional model of serotonin neurotransmission, serotonin released by neurons in the midbrain raphe nuclei exerts its actions on forebrain neurons by interacting with a large family of post-synaptic receptors. The actions of serotonin are terminated by active transport of serotonin back into the releasing neuron, which is mediated by the serotonin reuptake transporter (SERT). Because SERT is expressed pre-synaptically and is widely thought to be the only serotonin transporter in the forebrain, the conventional model does not include serotonin transport into post-synaptic neurons. However, a large body of evidence accumulating since the 1970s has shown that serotonin, despite having a positive charge, can cross cell membranes through a diffusion-like process. Multiple low-affinity, high-capacity, sodium-independent transporters, widely expressed in the brain, allow the carrier-mediated diffusion of serotonin into forebrain neurons. The amount of serotonin crossing cell membranes through this mechanism under physiological conditions is considerable. Most prominent textbooks fail to include this alternative method of serotonin uptake in the brain, and even most neuroscientists are unaware of it. This failure has limited our understanding of a key regulator of serotonergic neurotransmission, impeded research on the potential intracellular actions of serotonin in post-synaptic neurons and glial cells, and may have impeded our understanding of the mechanism by which antidepressant medications reduce depressive symptoms.

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis.

BACKGROUND: Antidepressants (ADs) are commonly prescribed medications, but their long-term health effects are debated. ADs disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. However, many ADs also have anticlotting properties that can be efficacious in treating cardiovascular disease. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples. METHODS: Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD-related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class. We conducted mixed-effect meta-analyses testing sample type and AD class as moderators of all-cause mortality and new cardiovascular events. RESULTS: Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27). Only "other ADs" were differentiable from TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased when we analyzed the subset of studies controlling for premedication depression, suggesting the absence of confounding by indication. CONCLUSIONS: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.

Using Evolutionary Theory to Guide Mental Health Research.

Evolutionary approaches to medicine can shed light on the origins and etiology of disease. Such an approach may be especially useful in psychiatry, which frequently addresses conditions with heterogeneous presentation and unknown causes. We review several previous applications of evolutionary theory that highlight the ways in which psychiatric conditions may persist despite and because of natural selection. One lesson from the evolutionary approach is that some conditions currently classified as disorders (because they cause distress and impairment) may actually be caused by functioning adaptations operating "normally" (as designed by natural selection). Such conditions suggest an alternative illness model that may generate alternative intervention strategies. Thus, the evolutionary approach suggests that psychiatry should sometimes think differently about distress and impairment. The complexity of the human brain, including normal functioning and potential for dysfunctions, has developed over evolutionary time and has been shaped by natural selection. Understanding the evolutionary origins of psychiatric conditions is therefore a crucial component to a complete understanding of etiology.

Population-level effects of suppressing fever.

Fever is commonly attenuated with antipyretic medication as a means to treat unpleasant symptoms of infectious diseases. We highlight a potentially important negative effect of fever suppression that becomes evident at the population level: reducing fever may increase transmission of associated infections. A higher transmission rate implies that a larger proportion of the population will be infected, so widespread antipyretic drug use is likely to lead to more illness and death than would be expected in a population that was not exposed to antipyretic pharmacotherapies. We assembled the published data available for estimating the magnitudes of these individual effects for seasonal influenza. While the data are incomplete and heterogeneous, they suggest that, overall, fever suppression increases the expected number of influenza cases and deaths in the US: for pandemic influenza with reproduction number , the estimated increase is 1% (95% CI: 0.0-2.7%), whereas for seasonal influenza with , the estimated increase is 5% (95% CI: 0.2-12.1%).

An experimental paradigm for triggering a depressive syndrome.

Research investigating whether depression is an adaptation or a disorder has been hindered by the lack of an experimental paradigm that can test causal relationships. Moreover, studies attempting to induce the syndrome often fail to capture the suite of feelings, thoughts, and behaviors that characterize depression. An experimental paradigm for triggering depressive symptoms can improve our etiological understanding of the syndrome. The present study attempts to induce core symptoms of depression, particularly those related to rumination, in a healthy, nonclinical sample through a controlled social experiment. These symptoms are sad or depressed mood, anhedonia, feelings of worthlessness or guilt, and difficulty concentrating. One hundred and thirty-four undergraduate students were randomly assigned to either an exclusion (E) or control (C) group. Participants in the exclusion group were exposed to a modified Cyberball paradigm, designed to make them feel socially excluded, followed by a dual-interference task to assess whether their exclusion interfered with their working memory. Excluded participants: (a) self-reported a significant increase in sadness and decrease in happiness, but not anxiety or calmness; (b) scored significantly higher in four of five variables related to depressive rumination; and (c) performed significantly worse on a dual-interference task, suggesting an impaired ability to concentrate. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cognitive Behavior Therapy for Depression From an Evolutionary Perspective.

Evolutionary medicine attempts to solve a problem with which traditional medicine has struggled historically; how do we distinguish between diseased states and "healthy" responses to disease states? Fever and diarrhea represent classic examples of evolved adaptations that increase the likelihood of survival in response to the presence of pathogens in the body. Whereas, the severe mental disorders like psychotic mania or the schizophrenias may involve true "disease" states best treated pharmacologically, most non-psychotic "disorders" that revolve around negative affects like depression or anxiety are likely adaptations that evolved to serve a function that increased inclusive fitness in our ancestral past. What this likely means is that the proximal mechanisms underlying the non-psychotic "disorders" are "species typical" and neither diseases nor disorders. Rather, they are coordinated "whole body" responses that prepare the individual to respond in a maximally functional fashion to the variety of different challenges that our ancestors faced. A case can be made that depression evolved to facilitate a deliberate cognitive style (rumination) in response to complex (often social) problems. What this further suggests is that those interventions that best facilitate the functions that those adaptations evolved to serve (such as rumination) are likely to be preferred over those like medications that simply anesthetize the distress. We consider the mechanisms that evolved to generate depression and the processes utilized in cognitive behavior therapy to facilitate those functions from an adaptationist evolutionary perspective.

Evolutionary theory and the treatment of depression: It is all about the squids and the sea bass.

According to the analytical rumination hypothesis, depression is an evolved adaptation (like pain or anxiety) that served in our ancestral past to keep people focused on complex interpersonal problems until they could arrive at a resolution (spontaneous remission). If this is true, then those clinical treatments that most facilitate the functions that depression evolved to serve are likely to be more advantageous in the long run than others that simply relieve distress. For example, antidepressant medications may be efficacious in the treatment of depression but only work for so long as they are taken. They may also have an iatrogenic effect that prolongs the duration of the underlying episode. Cognitive and behavioral interventions are as efficacious as medications in terms of reducing acute distress and also appear to have an enduring effect that protects against the return of subsequent symptoms. However, the bulk of the evidence for this effect comes from comparisons to prior medication treatment and it remains unclear whether these psychosocial interventions are truly preventative, or antidepressant medications iatrogenic. A study is described that could resolve this issue and test evolutionary theory with respect to the purported role of rumination in bringing about spontaneous remission.

Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.

Importance: Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. Objective: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data Sources: Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Study Selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. Data Extraction and Synthesis: Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Main Outcomes and Measures: Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. Results: In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02). Conclusions and Relevance: Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

Disordered doctors or rational rats? Testing adaptationist and disorder hypotheses for melancholic depression and their relevance for clinical psychology.

Most clinicians view depression as a painful disorder in which motivation to pursue adaptive goals is lacking and cognition is impaired. An alternative hypothesis-grounded in a common evolutionary approach-suggests that depression is inherently motivational and evolved to motivate avoidant learning of harmful situations. Testing these hypotheses requires a clear definition of "disorder". Wakefield's harmful dysfunction evolution-based definition proposes that all unambiguous cases of disorder involve a malfunctioning adaptation. These hypotheses-functional adaptation and malfunctioning adaptation-are mutually exclusive and require a common research strategy. One must identify and map out the relevant adaptation-characterized by a high degree of non-random organization and coordination for promoting a function-which will eventually result in a conceptual blueprint of where and how the adaptation can malfunction. Using inescapable shock in rats and physicians' emotional responses to medical errors to provide context, we show how the symptoms of melancholic depression exhibit signs of adaptation for motivating a time-consuming, attentionally-demanding, energetically-expensive avoidant learning style after experiencing a harmful event. We discuss how this adaptationist approach may provide insight into spontaneous remission and the effects of psychotherapies and antidepressant medications.

Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.

Importance: Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors. Objectives: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication. Data Sources: Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals. Study Selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point. Data Extraction and Synthesis: Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. Main Outcomes and Measures: With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. Results: In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent. Conclusions and Relevance: Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.

Testing the Analytical Rumination Hypothesis: Exploring the Longitudinal Effects of Problem Solving Analysis on Depression.

Depression is a mental health condition for which individuals commonly seek treatment. However, depressive episodes often resolve on their own, even without treatment. One evolutionary perspective, the analytical rumination hypothesis (ARH), suggests that depression occurs in response to complex problems. According to this perspective, depressive symptoms promote analytical rumination, i.e., distraction-resistant thoughts about the causes of problems [causal analysis (CA)] and how they can be solved [problem-solving analysis (PSA)]. By helping individuals solve complex problems, analytical rumination may contribute to remission from depression. The aim of this study was to investigate (1) whether clinically-depressed individuals have more complex problems and engage in more CA and PSA than non-depressed and (2) the effects of CA and PSA on decreases in problem complexity, depressive symptoms, and remission from the depression. Samples of 85 patients were treated for depression with antidepressants and psychotherapy, and 49 healthy subjects were assessed three times over a 4-month period (at Weeks 1, 5, and 16). At each assessment, they completed measures of depression, analytical rumination, and problem complexity. Depressed individuals reported having more complex problems and engaging in more CA than non-depressed participants. The two groups engaged in a similar degree of PSA. Findings from a multiple regression suggested that more PSA at Week 1 was related to a decrease in depressive symptoms at Week 5, even after controlling for baseline depression, problem number, and complexity. PSA at Week 1 did not predict the remission after hospitalization or at follow-up; however, having less complex problems at the baseline made it more likely that a patient would later remit. Engaging in more CA or PSA at Week 1 did not affect perceived problem complexity at Week 5 or at follow-up. However, these findings were not statistically significant when influential observations (or outliers) were included in the analysis. Our findings suggest that PSA may contribute to a decrease in symptoms of depression over time. However, alleviations in problem complexity and remission might only be achieved if problems are initially less complex. Future directions involve exploring how PSA might contribute to decreases in depressive symptoms and other mechanisms underlying remission from depression.

The bright side of being blue: depression as an adaptation for analyzing complex problems.

Depression is the primary emotional condition for which help is sought. Depressed people often report persistent rumination, which involves analysis, and complex social problems in their lives. Analysis is often a useful approach for solving complex problems, but it requires slow, sustained processing, so disruption would interfere with problem solving. The analytical rumination hypothesis proposes that depression is an evolved response to complex problems, whose function is to minimize disruption and sustain analysis of those problems by (a) giving the triggering problem prioritized access to processing resources, (b) reducing the desire to engage in distracting activities (anhedonia), and (c) producing psychomotor changes that reduce exposure to distracting stimuli. As processing resources are limited, sustained analysis of the triggering problem reduces the ability to concentrate on other things. The hypothesis is supported by evidence from many levels-genes, neurotransmitters and their receptors, neurophysiology, neuroanatomy, neuroenergetics, pharmacology, cognition, behavior, and efficacy of treatments. In addition, the hypothesis provides explanations for puzzling findings in the depression literature, challenges the belief that serotonin transmission is low in depression, and has implications for treatment.

Recent Developments in the Treatment of Depression.

The cognitive and behavioral interventions can be as efficacious as antidepressant medications and more enduring, but some patients will be more likely to respond to one than the other. Recent work has focused on developing sophisticated selection algorithms using machine-learning approaches that answer the question, "What works best for whom?" Moreover, the vast majority of people suffering from depression reside in low- and middle-income countries where access to either psychotherapy or medications is virtually nonexistent. Great strides have been made in training nonspecialist providers (known as task sharing) to overcome this gap. Finally, recent work growing out of evolutionary psychology suggests that antidepressant medications may suppress symptoms at the expense of prolonging the underlying episode so as to increase the risk of relapse whenever someone tries to stop. We address each of these developments and their cumulative implications.

Sex Differences in Detecting Sexual Infidelity : Results of a Maximum Likelihood Method for Analyzing the Sensitivity of Sex Differences to Underreporting.

Despite the importance of extrapair copulation (EPC) in human evolution, almost nothing is known about the design features of EPC detection mechanisms. We tested for sex differences in EPC inference-making mechanisms in a sample of 203 young couples. Men made more accurate inferences (φmen = 0.66, φwomen = 0.46), and the ratio of positive errors to negative errors was higher for men than for women (1.22 vs. 0.18). Since some may have been reluctant to admit EPC behavior, we modeled how underreporting could have influenced these results. These analyses indicated that it would take highly sex-differentiated levels of underreporting by subjects with trusting partners for there to be no real sex difference. Further analyses indicated that men may be less willing to harbor unresolved suspicions about their partners' EPC behavior, which may explain the sex difference in accuracy. Finally, we estimated that women underreported their own EPC behavior (10%) more than men (0%).

The sensitivity of variance component estimates to underreporting: method and application to substance abuse data.

Many studies of human behavior and psychological constructs rely on subjects' willingness to disclose information about themselves. This is problematic for phenotypes that require the disclosure of sensitive information, such as sexual behavior or illicit drug use, which are likely to be underreported. We describe a method for evaluating how sensitive variance component estimates are to underreporting. The method involves estimating, by maximum likelihood, the original population proportions of the response classes, and adjusting them for a set of hypothesized underreporting parameters. If the true values of the underreporting parameters were known, the researcher could estimate the variance components based on these values. Usually, underreporting levels are not known with certainty. However, it is possible to assume a specific value for the underreporting rate, obtain response pattern proportions adjusted for this rate, and then to conduct the analyses on these revised estimates. By repeating the procedure across the range of plausible underreporting values, the researcher can assess how sensitive the variance component estimates are to variation in underreporting. We apply this method to a sample of male-male twin pairs who reported on themselves and their co-twins for illicit drug abuse and dependence (DAD). We show how underreporting influences estimates of additive genetic, common environment, and specific environment variance components (A, C, and E) obtained for DAD in a classical twin design.

Parent-offspring conflict and cost-benefit analysis in adolescent suicidal behavior : Effects of birth order and dissatisfaction with mother on attempt incidence and severity.

Data on birth order and parent-offspring relations for 1,601 adolescents participating in the National Longitudinal Study of Adolescent Health were used to test hypotheses about the role of adolescent suicidal behavior in parent-offspring conflict. Among adolescents highly dissatisfied with their mothers, the odds that middleborns would make at least one suicide attempt was 23% that of first- and lastborns (p<.001), but their odds of receiving medical treatment for their attempts was 8.5 times greater than the odds for first- and lastborns (p=.032). The results are tentatively interpreted as supporting the hypothesis that adolescents use suicide attempts to leverage investment from their parents.

The source dilemma hypothesis: Perceptual uncertainty contributes to musical emotion.

Music can evoke powerful emotions in listeners. Here we provide the first empirical evidence that the principles of auditory scene analysis and evolutionary theories of emotion are critical to a comprehensive theory of musical emotion. We interpret these data in light of a theoretical framework termed "the source dilemma hypothesis," which predicts that uncertainty in the number, identity or location of sound objects elicits unpleasant emotions by presenting the auditory system with an incoherent percept, thereby motivating listeners to resolve the auditory ambiguity. We describe two experiments in which source location and timbre were manipulated to change uncertainty in the auditory scene. In both experiments, listeners rated tonal and atonal melodies with congruent auditory scene cues as more pleasant than melodies with incongruent auditory scene cues. These data suggest that music's emotive capacity relies in part on the perceptual uncertainty it produces regarding the auditory scene.

Reverse Engineering the Febrile System.

Fever, the elevation of core body temperature by behavioral or physiological means, is one of the most salient aspects of human sickness, yet there is debate regarding its functional role. In this paper, we demonstrate that the febrile system is an evolved adaptation shaped by natural selection to coordinate the immune system to fight pathogens. First, we show that previous arguments in favor of fever being an adaptation are epistemologically inadequate, and we describe how an adaptationist strategy addresses this issue more effectively. Second, we argue that the mechanisms producing fever provide clear indications of adaptation. Third, we demonstrate that there are many beneficial immune system responses activated during fever and that these responses are not mere byproducts of heat on chemical reactions. Rather, we show that natural selection appears to have modified several immune system effects to be coordinated by fever. Fourth, we argue that there are some adaptations that coordinate the febrile system with other important fitness components, particularly growth and reproduction. Finally, we discuss evidence that the febrile system may also have evolved an antitumor function, providing suggestions for future research into this area. This research informs the debate on the functional value of fever and antipyretic use.

Genetic and environmental influences on the frequency of orgasm in women.

This study reports on genetic and environmental influences on the frequency of orgasm in women during sexual intercourse, during other sexual contact with a partner, and during masturbation. Participants were drawn from the Australian Twin Registry, and recruited from a large, partly longitudinal twin-family study. Three thousand and eighty women responded to the anonymous self-report questionnaire, including 667 complete monozygotic (MZ) pairs and 377 complete dizygotic (DZ) same-sex pairs, 366 women from complete DZ opposite-sex pairs, and 626 women whose co-twins did not participate. Significant twin correlations were found for both MZ and DZ twin pairs for all three items of interest. Age effects were statistically significant for some items. Models incorporating additive genetic, shared and nonshared environmental influences provided the best fit for Items 1 and 3, while a model with additive and nonadditive genetic influences along with nonshared environment fitted the data from Item 2. While an independent pathway model fits the data most par-simoniously, a common pathway model incorporating additive genetic (A), shared environment (C), and unique environment (E) effects cannot be ruled out. Overall, genetic influences account for approximately 31% of the variance of frequency of orgasm during sexual intercourse, 37% of the variance of frequency of orgasm during sexual contact other than during intercourse, and 51% of the variance of frequency of orgasm during masturbation. Following Baker (1996), we speculate that this additive genetic variance might arise from frequency-dependent selection for a variety of female sexual strategies.