Friday, February 28, 2020

Women were more likely than men to report falling asleep after sexual intercourse, with or without orgams; postcopulatory somnolence was also enhanced by orgasm in both women & men

Gallup, G. G., Jr., Platek, S. M., Ampel, B. C., & Towne, J. P. (2020). Sex differences in the sedative properties of heterosexual intercourse. Evolutionary Behavioral SciencesFeb 2020.

Abstract: Based on a sample of 128 female and 98 male college students, there were significant sex differences in the sedative properties of vaginal intercourse. Consistent with predictions derived from an evolutionary model of sperm retention and human bipedalism, women were more likely than men to report falling asleep after sexual intercourse. Postcopulatory somnolence was also enhanced by orgasm in both women and men. However, with or without orgasm, women were more likely than men to report falling asleep after sex. Consistent with the possibility that seminal fluid may contain sedative-like properties, women who were being inseminated were also more likely to fall asleep after sex. There was no evidence for sex differences in the sedative properties of masturbation

Women who were inseminated were also more likely to fall asleep... that raises the possibility that human semen may contain sedative properties... the so-called missionary position may have evolved to promote sperm retention, and anything that postpones the sumption of an upright posture after insemination would function to increase the likelihood of sperm retention and impregnation as a consequence.

The perception of attractiveness, fertility, health, and age were influenced by size, cleft distance, ptosis, and hostile sexism; individual differences in life history and self-perceived mate value also influenced preferences

Effects of Breast Size, Intermammary Cleft Distance (Cleavage) and Ptosis on Perceived Attractiveness, Health, Fertility and Age: Do Life History, Self-Perceived Mate Value and Sexism Attitude Play a Role? Farid Pazhoohi, Ray Garza & Alan Kingstone. Adaptive Human Behavior and Physiology, February 28 2020.

Unlike other mammals, human females have evolved so that their breasts remain enlarged. Previous research has related the size and shape of women’s breasts with women’s reproductive potential and attractiveness.

Objective: To provide a more complete picture of these issues, the current study extended previous research by investigating the effects of breast size, intermammary cleft distance, and ptosis on perceived attractiveness, health, fertility, and age while also measuring individual differences in life history, self-perceived mate value, and sexism.

Method: Participants (men and women) viewed images of women’s breasts that were manipulated for size, ptosis, and intermammary cleft; and participants rated the breasts for their perceived attractiveness, fertility, health, and age.

Results: Results showed that the perception of attractiveness, fertility, health, and age were influenced by size, cleft distance, ptosis, and hostile sexism. Individual differences in life history and self-perceived mate value also influenced preferences.

Conclusion: Our results show that perceived attractiveness of breasts is associated with perceptions of fertility, health, and age. The findings from the current study represent an important step toward achieving a comprehensive account on how women’s breasts influence perception on traits associated with mate preferences, fertility, and reproductive value.

Participants were faster at detecting target faces with conspicuous sclera (white sclera or sclera colored lighter than the iris color) compared to faces with inconspicuous sclera (sclera colored similar to the iris color or darker)

Sclera color enhances gaze perception in humans. Jessica L. Yorzinski, Jacob Miller. PLOS, February 27, 2020.

Abstract: Gaze perception is an essential behavior that allows individuals to determine where others are directing their attention but we know relatively little about the ways in which eye morphology influences it. We therefore tested whether eyes with conspicuous morphology have evolved to facilitate gaze perception. During a visual search task, we recorded the eye movements of human participants (Homo sapiens) as they searched for faces with directed gaze within arrays of faces with averted gaze or the reverse; the faces were large and upright, small and upright, or large and inverted. The faces had sclera that were conspicuous (white or colored lighter than the iris color) or inconspicuous (colored the same or darker than the iris color). We found that participants were fastest and most accurate in finding the faces with conspicuous sclera versus inconspicuous sclera. Our results demonstrate that eyes with conspicuous morphology facilitate gaze perception in humans.


Our results support the hypothesis that eyes with conspicuous morphology have evolved to facilitate gaze perception. We found that eyes with conspicuous morphology are necessary for rapid gaze perception in humans: adult participants were faster at detecting target faces with conspicuous sclera (white sclera or sclera colored lighter than the iris color) compared to faces with inconspicuous sclera (sclera colored similar to the iris color or darker). These results demonstrate that conspicuous sclera, in contrast to the camouflaged sclera observed in most other primate species [6], are critical for rapid gaze perception in humans.

Human participants rapidly fixated target faces with conspicuous sclera. Regardless of whether participants were searching for the face with directed gaze among faces with averted gaze or the face with averted gaze among faces with directed gaze, they quickly found the target face with conspicuous sclera. In contrast, when the sclera was inconspicuous, participants spent more time searching for those faces compared to the faces with conspicuous sclera. These patterns were similar for the large faces, which simulated close-up interactions, as well as small faces, which simulated distant interactions. They were also similar for the inverted faces, which preserved low-level visual properties (such as luminance) but disrupted facial configuration [26]. Because visual attention can be strongly influenced by bottom-up processes (such as contrast; [27,28]), it is not necessarily surprising that participants were fast to fixate target faces with conspicuous sclera that exhibit high contrast. Importantly, participants were equally rapid at fixating faces with naturally-colored sclera and faces with sclera color that were lighter than the iris color; this demonstrates that digitally manipulating sclera color does not necessarily alter fixation latencies. We also found that participants were quicker to fixate target faces with light versus dark colored irises; future experiments can assess how iris color interacts with sclera color to influence gaze perception.

After participants fixated target faces with conspicuous sclera, they were quick to manually indicate that they had found the target faces (via a key press). However, when the sclera was inconspicuous, participants were much slower to manually indicate that they had found the target faces; their manual response times were especially slow for the small faces with sclera color that were darker than the iris color. These slower manual responses likely indicate that the participants were less certain of their decisions and therefore taking more time to indicate their responses. Their manual response times for faces with naturally-colored sclera and faces with sclera color that were lighter than the iris color were similar, indicating that digitally manipulating sclera color does not necessarily alter manual response latencies.

Participants were highly accurate in selecting the target faces. With the exception of the small faces with sclera that were darker than the iris color, participants were over 98% accurate in finding the correct target face. Therefore, even though participants spent more time searching for the target face when the face had inconspicuous sclera (see above), they were accurate in ultimately identifying the correct face. The only target faces that participants had difficulty in correctly identifying were the small faces with dark sclera color: they were 90% accurate in finding these target faces. Previous work found that humans are only 52% accurate in gaze perception when the sclera are darker than the iris (black sclera, white pupil, and white iris [7]). In contrast, we found that accuracy in gaze perception was over 90% regardless of sclera color. Rather than presenting stimuli in which the sclera and iris color were polar opposites [7], our stimuli only adjusted sclera color (rather than simultaneously adjusting sclera, pupil and iris color) and we did so relative to the natural iris color. Given that most primate species have sclera that closely match their iris color [6], our stimuli in which the sclera color matched the iris color closely simulated the eye morphology of these other primate species. Furthermore, our study used a gaze search task while previous work used a gaze discrimination task, which could also account for differences in accuracy levels.

Surprisingly, search efficiency was generally similar for faces with naturally-colored sclera and faces with sclera that matched the iris color. When the faces were large and upright as well as large and inverted, participants were equally efficient at searching for these faces. However, participants were less efficient at searching for faces with sclera that matched the iris color versus naturally-colored sclera when the faces were small, suggesting that sclera color in gaze perception may be especially important during distant interactions. The ability of humans to communicate with each other over large distances is likely critical to many types of interactions. This ability may be especially useful during a hunt when silent communication is critical for a successful outcome [5,29]. Previous work has shown that humans are able to reliably detect gaze direction from as far away as 10 meters [30,31] and our results suggest that sclera color contributes to this ability.

Our results support the gaze enhancement hypothesis by demonstrating that eyes with conspicuous morphology facilitate gaze perception. Humans are fastest and most accurate in gaze perception when faces have naturally-colored sclera (or sclera that are lighter than the iris color). When faces are modified so that eye morphology is less conspicuous (sclera that match the iris color or are darker than the iris color), gaze perception is slower. Given that 99% of nonhuman primates have eye morphology that is less conspicuous (with sclera color that closely matches their iris color; [6]), future experiments that examine nonhuman primates’ ability to perceive gaze would be informative. Our results demonstrate that eye morphology plays a critical role in human gaze perception and therefore impacts the evolution of social cognition.

Lottery participation increased the happiness of participants before the draw; winning a small prize had no effect on happiness; people may not only care about the outcomes of the lottery, but also enjoy the game

The joy of lottery play: evidence from a field experiment. Martijn J. Burger, Martijn Hendriks, Emma Pleeging & Jan C. van Ours. Experimental Economics, February 27 2020.

Abstract: Buying lottery tickets is not a rational investment from a financial point of view. Yet, the majority of people participate at least once a year in a lottery. We conducted a field experiment to increase understanding of lottery participation. Using representative data for the Netherlands, we find that lottery participation increased the happiness of participants before the draw. Winning a small prize had no effect on happiness. Our results indicate that people may not only care about the outcomes of the lottery, but also enjoy the game. Accordingly, we conclude that lottery participation has a utility value in itself and part of the utility of a lottery ticket is consumed before the draw.

Discussion and conclusions

From a financial point of view buying a lottery ticket is not a rational investment as the average ex-post value of a ticket is just over half the price of that ticket. Nevertheless, many people participate in lotteries. There are two popular explanations in the economics literature for this: (1) low cost opportunities to improve one’s financial position if there are few opportunities to do this otherwise and (2) prospect theory according to which people overweight the small probability of winning a lottery. The first explanation suggests that participation would be predominantly among lower social classes which is not the case since lottery play takes place across the whole income distribution. The second explanation is at odds with the finding that most lottery participants have quite accurate expectations about the probability to win a prize. Although there is some empirical support for both the Friedman–Savage theory and prospect theory, these theories only partly explain people’s propensity to gamble.
We studied lottery participation using a field experiment in which some participants of a regular household survey received a state lottery ticket for free, while other participants had no ticket or only a purchased ticket, or both a free and a purchased ticket. This allows us to investigate to what extent participating in a lottery increases momentary happiness. If so, this supports a third explanation of lottery participation, i.e. people deriving non-monetary utility from participating in a lottery play. This could be because of the hope of winning a large prize, the fun and excitement of the game, or because of social bonding activities when playing the lottery together with family or friends.
In our field experiment, momentary happiness is measured at three moments in time, i.e. before free lottery tickets are issued, after providing some individuals with a free lottery ticket but before the draw, and after the draw. We study the change in momentary happiness between the first two moments to investigate whether playing in the lottery increases momentary happiness, regardless of whether the ticket was bought or free. We also study the change in momentary happiness between the first and third moment to investigate to what extent winning a small lottery prize matters.
Our main finding is that participants in a lottery derive procedural utility from playing the game. This is irrespective of whether the lottery ticket was bought or received for free due to the experiment. On a scale from 1 to 10, participating in a lottery increases momentary happiness with 0.25–0.40 (approximately 1/5–1/3 standard deviation increase). These results may be driven by the hope and expectations about financial gains, the thrill of a potential win, and social bonding when playing as a group. However, the procedural utility that players derive from winning a small prize is limited. In sum, we conclude that lottery participation seems to be at least partly driven by the joy of lottery play, i.e. lottery participants may be hoping for financial gains but gamble for fun. More generally, our research shows the importance of taking in procedural utility in modeling decisions of consumers since consumers do not only care about outcomes, but also about the process. Accordingly and in line with previous work, seemingly irrational decisions such as lottery play could be considered rational from the perspective of procedural utility (see also Benz 2005).
It is important to note that our results are related to the probability of winning which is about 50% in the State Lottery. For lotteries with a smaller winning probability the magnitude of the happiness effects are smaller. It is also important to note that our article has focused on the short-term positive impact on lottery play through procedural utility and does not pay attention to the potential negative long-term effects of lottery play, especially in the case of problem and pathological gambling (Lorenz 1990). In this regard, lottery gambling has been associated with psychological, social, and economic problems. Hence, procedural utility may induce sub-optimal decision-making in the long-run. At the same time, the number of problem lottery gamblers among the population is relatively small (Hendriks et al. 1997) and the overall long-term effects of lottery play on overall well-being or experienced quality of life seem to be limited (Burger et al. 2016). However, more research on the consequences of lottery play are needed to examine the long-term effects of lottery play.

Bias in Bias Recognition: People View Others but Not Themselves as Biased by Preexisting Beliefs and Social Stigmas

Wang, Qi, and Hee J. Jeon. 2020. “Bias in Bias Recognition: People View Others but Not Themselves as Biased by Preexisting Beliefs and Social Stigmas.” PsyArXiv. February 27. doi:10.31234/ Final version Wang Q, Jeon HJ (2020) Bias in bias recognition: People view others but not themselves as biased by preexisting beliefs and social stigmas. PLoS ONE 15(10): e0240232, Oct 2020.

Abstract: Biases perpetuate when people think that they are innocent whereas others are guilty of biases. We examined whether people would detect biased thinking and behavior in others but not themselves as influenced by preexisting beliefs (myside bias) and social stigmas (social biases). The results of three large studies showed that, across demographic groups, participants attributed more biases to others than to themselves and that this self-other asymmetry was particularly salient among those who hold strong beliefs about the existence of biases (Study 1 and Study 2). The self-other asymmetry in bias recognition dissipated when participants made simultaneous predictions about others’ and their own thoughts and behaviors (Study 3). People thus exhibit bias in bias recognition and this metacognitive bias may be remedied by highlighting to people that we are all susceptible to biasing influences.

The Sexual Victimization Experiences of Men Attending College: A Mixed Methods Investigation

The Sexual Victimization Experiences of Men Attending College: A Mixed Methods Investigation. Heather Littleton, Emily Downs & Kelly Rudolph. Sex Roles, February 27 2020.

Abstract: Emerging research supports that men attending college are at elevated sexual assault risk. However, research is limited by assessment issues as well as a lack of examination of how men conceptualize their experiences. The current study sought to expand our understanding of college men’s sexual assault experiences via a mixed methods study. Fifty-eight U.S. college men (11.2% of a sample of 518 men) reported a sexual assault history since age 14 and completed measures of their assault characteristics, psychological adjustment, and alcohol use. A total of 44 also provided a written narrative of the assault. Results supported that men’s assaults often occurred in party/drinking contexts and that many were impaired from substances. Over two-thirds were assaulted by a female perpetrator, with the most common form of assault involving “mismatched intentions” where a perpetrator engaged in nonconsensual sexual behavior during an initially consensual encounter. Substance use interfered with effective resistance for many, and some also stated that they did not resist even though they were able. A total of 43% (n = 19) said the assault had a long-term negative impact, whereas 52% (n = 23) reported a minimal or neutral impact. Overall, findings support a need for sexual assault interventions tailored for male survivors.


Like prior studies, the current study supported that men attending college are vulnerable to sexual assault, with over 11% of men reporting a history of some form of sexual assault, either in high school or college (or both). Further, over 5% of men reported a history of completed rape. Notably, this prevalence is higher than found in prior U.S. epidemiologic studies, with these studies finding a prevalence of attempted or completed rape among men ranging from 1.4% to 3.0% (International Society for Traumatic Stress Studies, Sexual Violence Briefing Paper Working Group 2018). In contrast, our findings are generally in line with prior studies of sexual assault among men attending college, which similarly find an elevated prevalence of sexual assault when compared to the general population (Forsman 2017). Sexual minority men were also more likely than heterosexual men to report a sexual assault history, like prior research findings (Coulter et al. 2017; Edwards et al. 2015; Ford and Soto-Marquez 2016; Hines et al. 2012; Navarro and Clevenger 2017). However, no differences in sexual assault history were found among White and racial minority men, unlike what was found by Tewksbury and Mustaine (2001). Findings also supported that men with a sexual assault history reported much higher levels of current depression than men with no sexual assault history and were more likely to report problematic current alcohol use. Finally, 28% scored above the cut-off for sexual assaultrelated PTSD. Thus, men attending college who have experienced sexual assault are at elevated risk of adjustment difficulties, including clinically elevated depression and PTSD. Further, the frequency with which men in the current sample reported a history of multiple assaults (62%) and their high rates of current hazardous drinking support that many men with sexual assault histories attending college are vulnerable to experiencing additional assaults while enrolled.

Examination of both our quantitative and qualitative data supported that men’s sexual assaults frequently occurred in party contexts and during the course of casual sexual encounters. Many participants were impaired or incapacitated by alcohol and/or other substances during the assault. Participants were also more likely to report that the perpetrator was a woman than a man, with all survivors of impaired and incapacitated assaults reporting a female perpetrator. Overall, findings support that participating in a party subculture while in high school and college not only normalizes and encourages sexual aggression and victimization of women, but also sexual aggression targeting men, including that perpetrated by women. Until now, this risk associated with participating in the party subculture has gone largely ignored.

Physical force was used in just under half of the assaults. This could be because female perpetrators are less likely to have a size or strength advantage in relation to a male victim and thus may not utilize forceful strategies. Instead, perpetrators frequently took advantage of the victim when he was incapacitated or highly impaired from substances and/or used threats or blackmail (e.g., threatening to spread rumors about the individual) in order to perpetrate the assault. However, it should be noted that men assaulted by male perpetrators more frequently reported that the perpetrator used physical force, with 77% of men assaulted by a man reporting he used physical force, as compared to 36% of men assaulted by a woman.

Men responded to the assault attempt in a variety of ways. Perhaps in part because of their physical size and strength advantage relative to a female perpetrator, a number of men reported that they were able to end the assault through engaging in a verbal refusal or by telling some sort of lie to the perpetrator (e.g., that the police were there, that they were not feeling well). A minority of men also reported using physical resistance to end the assault. In contrast, a number of men stated that they did not engage in physical resistance, with some stating that they did not resist due to fear of what would occur if they resisted or because they dissociated during the assault. However, some survivors seemed unsure as to why they did not resist and asserted that they were capable of ending the assault but did not do so.

There are a number of possible reasons for men’s lack of more assertive resistance, despite their likely superior or equivalent physical size and strength relative to the perpetrator. For one, men may have underestimated the extent to which their ability to recognize risk and resist effectively was impaired from alcohol or drug use. Second, some men may have experienced tonic immobility, defined as an involuntary temporary state of immobility and muscle rigidity in response to threat (Coxell and King 2010). Indeed, prior studies of female sexual assault victims have supported that many reported experiencing tonic immobility during the assault (Coxell and King 2010). Third, men may have been unsure how to respond to a sexual assault attempt because they may not have considered themselves to be vulnerable to sexual assault. Finally, social norms that dictate that it is not acceptable for a man to be physically aggressive toward a woman may have inhibited men’s use of physical resistance in the case of female-perpetrated assaults (Basow et al. 2007).

Men also reported a range of responses following the assault. Just over 40% reported the assault had a significant and lasting negative impact on their mental health and well-being. Additionally, several men reported feelings of emasculation and questioning of their sexuality after the assault. Conversely, slightly over half the men reported that the assault had no long-term impact on them and regarded the assault as not a serious event. Perhaps because their assaults frequently did not involve physical force as well as an oftentimes physically smaller perpetrator, some men did not experience fear and helplessness during and after the assault, which could have facilitated their successful adjustment post-assault. Also, of note, only 27.5% of men acknowledged the assault as some type of sexual victimization, as compared to nearly 40% of female sexual assault victims on average (Wilson and Miller 2016). Additionally, only slightly over half the men had ever disclosed the assault, whereas approximately 80% of college women who experienced sexual assault have disclosed (Orchowski et al. 2013). It is likely that male rape myths in part contributed to men’s lack of acknowledgment and disclosure. Thus, male assault victims experiencing distress may face additional barriers to acknowledgment, disclosure, help seeking, and recovery.

Limitations of our study should be noted. First, the overall sample size was small and primarily made up of White, firstyear, U.S. college students. As such, it is unclear the extent to which the current findings are representative of the experiences of men attending college more broadly. Additionally, not all men provided an assault narrative, with racial minority men as well as those who never disclosed the assault less likely to do so. Men also were identified as sexual assault victims using a screening measure. Although this measure was designed to be gender-neutral and utilized behaviorally specific terms, it has not been extensively used to screen for sexual assault experiences among men. As a result, it is possible that the items may not have comprehensively captured men’s sexual assault experiences. Likewise, some men may have reported experiences on the screening measure that did not constitute sexual assault. However, because only two men provided narratives of consensual experiences, false positives to this screening appeared uncommon. Finally, although participants were encouraged to provide a detailed narrative of their assault, narratives varied in the level of detail provided. This resulted in some inconsistencies between participants’ responses on the ACQ and their narratives. For example, two survivors who provided a narrative reported that the perpetrator used severe force on the ACQ, but their narratives did not include a description of severe force by the perpetrator.

Future Research Directions
Bearing these limitations in mind, findings support an urgent need for more work focused on the experiences of men attending college who have experienced sexual assault. There is a need for research focused on the experiences of diverse groups, particularly racial and sexual minority men, who may be more likely to experience sexual assault. Future studies should utilize a longitudinal methodology to evaluate the impact of sexual assault among men over time, as well as men’s risk for re-victimization. Qualitative methods should also be utilized in future research to elucidate men’s conceptualizations of, and responses to, their assault experiences. Additional work exploring beliefs about sexual assault and acceptance of rape myths is also likely important to understand factors impeding disclosure, acknowledgment, and help-seeking among men experiencing adjustment difficulties.

Practice Implications
Results support a critical need for the development of tailored interventions for men who have experienced sexual assault which are designed to address issues including feelings of emasculation, rape myth adherence, and lack of disclosure and support-seeking. Clinicians working with male college students should routinely screen men for sexual assault histories. Further, clinicians working with male survivors should probe for the aforementioned issues among sexual assault survivors and provide survivors with psycho-education about these issues (e.g., that erections can be triggered via a spinal reflex) as a first step. More broadly, it is clear that sexual assault prevention interventions at the high school and college level should be gender-inclusive by focusing on issues related to obtaining clear consent for all sexual activities and emphasizing that both men and women can be victims and perpetrators of sexual assault. Prevention programs should also include tailored content addressing the needs of vulnerable groups, such as sexual minorities.

Depression appears characterised by a homogenously pro-inflammatory state: Patients show increases in pro-inflammatory immune markers mean levels, and reductions in anti-inflammatory IL-4

Inflammatory Markers in Depression: a Meta-Analysis of Mean Differences and Variability in 5,166 Patients and 5,083 Controls. Emanuele F. Osimo et al. Brain, Behavior, and Immunity, February 27 2020.

• Patients with depression show reduced variability in pro-inflammatory immune measures.
• Patients with depression show increases in pro-inflammatory immune markers mean levels, and reductions in anti-inflammatory IL-4.
• Depression appears characterised by a homogenously pro-inflammatory state.

Importance: The magnitude and variability of cytokine alterations in depression are not clear.

Objective: To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation.

Data Sources: Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined.

Study Selection: Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected.

Data Extraction and Synthesis: Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.

Main Outcomes and Measures: Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR).

Results: A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g=0.71; 95%CI: 0.50-0.92; p<0.0001); IL-3 (g=0.60; 95%CI: 0.31-0.89; p<0.0001); IL-6 (g=0.61; 95%CI: 0.39-0.82; p<0.0001); IL-12 (g=1.18; 95%CI: 0.74-1.62; p<0.0001); IL-18 (g=1.97; 95%CI: 1.00-2.95; p<0.0001); sIL-2R (g=0.71; 95%CI: 0.44-0.98; p<0.0001); and TNFα (g=0.54; 95%CI: 0.32-0.76; p<0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR=0.85; 95%CI: 0.75-0.98; p=0.02); IL-12 (CVR=0.61; 95%CI: 0.46-0.80; p<0.01); and sIL-2R (CVR=0.85; 95%CI: 0.73-0.99; p=0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α.

Conclusions and Relevance: Acute depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.

Keywords: DepressionInflammationMeta-analysisHeterogeneityCytokineCRP

4. Discussion

Our meta-analysis finds evidence that mean-scaled variability, measured as CVR, is reduced in patients with depression for CRP, IL-12 and sIL-2R, while it is unchanged for IL-3, IL-6, IL-18 and TNF α. In the same sample, we also find that blood levels of CRP, IL-3, IL-6, IL-12, IL-18, sIL-2R and TNF α are significantly elevated in patients with depression with medium-large effect sizes (range 0.54-1.97), and that these findings are robust to a range of potential confounds and moderators. See Table 1 for a summary of our findings.
Our study is, to our knowledge, the first meta-analysis of variability of immune parameters in individuals with depression compared to matched controls. Mean differences in inflammatory markers in depression have been meta-analysed before (Howren et al., 2009Dowlati et al., 2010Haapakoski et al., 2015Goldsmith et al., 2016Köhler et al., 2017). However, as shown in Supplementary Table 1, this study is by far the largest meta-analysis of immune markers in depression, including a sample 1.48 times larger than the largest previous one. In addition to this, this is one of the first studies to systematically consider the effect on immune markers of excluding patients not experiencing an active depressive episode (previously only considered in a much smaller study by Goldsmith et al), duration of illness (previously only considered descriptively), study quality (previously only considered in a smaller study by Haapakoski et al), and smoking (previously only considered by Kohler et al). Furthermore, our findings of increased mean levels of CRP, IL-6, IL-12 and TNF α in depression replicate previous meta-analytical findings; the same can be said of no changes in levels of TGF β (Table 2). Reductions in IL-4, found in our study with an effect size of -0.73 and resistant to most sensitivity analyses, were not significant in Kohler et al, 2017 nor in (Dowlati et al., 2010), however both these studies were based on considerably smaller samples, which could explain the difference. More controversial is the result for IFNγ, which we find not significantly altered in our main analysis and increased in patients when excluding studies not matched for smoking levels between cases and controls. Given that previous, smaller meta-analyses were also non-concordant with regards to IFNγ (Dowlati et al., 2010Goldsmith et al., 2016Köhler et al., 2017), we believe therefore that more research is needed to establish the relationship between IFNγ levels and depression.

4.1. Interpretations and Implications

4.1.1. Meta-analysis of Heterogeneity

In a previous study we have shown that patients with depression show a proportion of high CRP levels at different cut-offs (CRP >1mg/L, >3mg/L and >10mg/L) that is similar to matched controls (Osimo et al., 2019); this supported the hypothesis that the shape of the CRP distribution curve is similar in patients and controls. In this study we find that mean-scaled variability of CRP and of a number of other immune markers is either reduced or unchanged in patients with depression as compared to healthy controls. A reduced variability implies a narrower distribution in patients than in controls, and possibly even a greater homogeneity in the inflammatory phenotype in depression. Therefore, the findings to date, at least for markers that show elevations of the mean and reductions in heterogeneity such as CRP, support a narrower distribution that is shifted to the right in depression. This is important as in the past there have been suggestions that inflammation in depression could be due to a sub-group of “inflamed and depressed” subjects, who might potentially be part of a separate sub-group of the depressed population (Miller and Cole, 2012). Our findings, instead, point in the direction of a continuous distribution of inflammatory markers in the depressed population, which is more homogenous than the healthy population.
The reduction in variability in CRP is worthy of a special mention here, as CRP is the main inflammatory marker routinely measured in clinical practice (Yeh, 2004;109(21_suppl_1):), and it is commonly used to stratify patients based on peripheral inflammatory levels in immunopsychiatric studies. Activation of the inflammatory system is thought to underlie antidepressant resistance (Chamberlain et al., 2018Benedetti et al., 2002Lanquillon et al., 2000Carvalho et al., 2013), highlighting a potential involvement in treatment response (Carvalho et al., 2013Maes et al., 1997O’Brien et al., 2007Yoshimura et al., 2009). Therefore, whether targeting inflammatory cytokines could provide therapeutic benefit for patients with depression is a key question that is being investigated in ongoing trials (e.g. NCT02473289; ISRCTN16942542). Our findings will be relevant for future studies assessing inflammation in depression, especially those recruiting patients based on their baseline inflammatory status.

4.1.2. Meta-analysis of mean differences

We found increases in the average levels of type I and other pro-inflammatory cytokines such as IL-3, IL-6, IL-12, IL-18 and TNF α; we also found reductions in IL-4, one of the main anti-inflammatory and immune-modulatory cytokines; finally, we found mean increases in CRP, which is one of the best characterised inflammatory markers in medical (Danesh et al., 2000Visser et al., 1999) and psychiatry conditions (Fernandes et al., 2016von Känel et al., 2007Fernandes et al., 2016). Taken together, these results confirm that acute depression is associated with a pro-inflammatory state.
CRP is one of the best studied inflammatory markers in the field of medicine. Higher levels of CRP have been consistently found in cross-sectional studies and in population-based longitudinal studies of depression, often preceding the onset of illness (Gimeno et al., 2009Khandaker et al., 2014Wium-Andersen et al., 2013Zalli et al., 2016), suggesting that inflammation could be a cause rather than simply a consequence of the illness; supporting this hypothesis, recently Mendelian randomization analyses of the UK Biobank sample found that IL-6 and CRP are likely to be causally linked with depression (Khandaker et al., 2019). Furthermore, elevated peripheral CRP levels have been found to correlate with its level in the central nervous system, with a strong correlation between plasma and CSF CRP (r = 0.855, p < 0.001) (Felger et al., 2018).
TNF α is one of the major pro-inflammatory cytokines; it is produced by dendritic cells and macrophages and is a major activator of downstream inflammatory cascades with multiple effectors (Abbas et al., 2014). During acute infection dendritic cells and macrophages also produce IL-6 and IL-12; both are type I cytokine family members, secreted in response to an acute inflammatory stimulus (Abbas et al., 2014). IL-12 plays a central role in responses to active infection promoting Th1 responses and, hence, cell-mediated immunity (Stern et al., 1996). TNF α, IL-6 and IL-12 increases in current depressive episodes underline the systemic nature of the inflammatory status, showing some similarity to the immune reaction to an active infection.
For markers found to be overall not different between patients and controls, but with variable results in sensitivity analyses (IL-5, IFNγ and TGF β), our results encourage further research, aiming to disentangle their potential tole in mediating effects of treatment (IL-5), smoking (IFNγ) or BMI differences (TGF β).
Finally, IL-2 and IL-8 were found to be increased in patients in our main analysis, but produced discordant results in sensitivity analyses due to the effect of BMI-matching; future studies should carefully match participants for BMI as this appears to be a particularly relevant factor affecting immune status.

4.2. Strengths and Limitations

The main strength of this work is the use of the largest sample of studies of inflammatory markers in depression to date; the same large sample was used to study heterogeneity and mean differences in patients as compared to controls. Even if we could not make inferences on the shape of the distribution, such as modality, as this would require individual subject data, we were able to obtain the first measure to date of the variability of inflammatory markers in depression.
A further strength of this paper is the employment of a systematic approach to the analysis of potential confounds. Given the large number of studies that focussed on inflammatory markers in depression, we were able to investigate the effect of potential psychiatric (e.g. treatment status, current depressive episode at time of sampling and duration of illness) and lifestyle confounds (e.g. age, BMI and smoking status), as well as statistical and sampling confounds (e.g. data skew and study quality). Sensitivity analyses focussing on studies with strict environmental and physiological matching provided us with greater confidence that depression is associated with the elevation of some immune parameters. Use of a multivariate meta-analytic approach to reduce the influence of multiplicity is a further strength.
Among our limitations, we included cross-sectional studies which used different tools to diagnose depression, even if only studies using ICD or DSM diagnostic criteria were included. Inconsistency between studies was moderate to high. This could reflect methodological factors, e.g. differences in assay sensitivity. However, the random-effects model used is robust to inconsistency, and would not explain our variability findings, because these reflect within-study variation (with methodologic factors common to patient and control groups in any given study). Due to data unavailability, some sensitivity analyses might be subject to type II error, i.e. false negatives; for example, BMI-matched sensitivity analyses often included samples much smaller than that of the main analysis. Furthermore, sensitivity analyses of antidepressant naïve and treatment resistant patients were not possible owing to insufficient studies.
Although all studies included in analyses used well validated quantification techniques, insufficient assay sensitivity may have limited the ability to detect subtle differences in immune parameters between patients and controls, particularly for titres beneath the limit of assay detection. Unfortunately, very few studies (2 out of 106) reported the number of samples below the limit of assay detection, so this factor could not be taken into account. Positive data skew can inflate standard deviation due to outliers within the ‘tail’ of the data (Fayers, 2011). However, we demonstrated no significant difference in the proportion of skewed data sets between patients and controls, suggesting that influence of skew was equal. Thus, excessive skew in healthy controls compared with patients was not likely contributing to results.
We excluded papers that only included patients and controls presenting the same co-morbidity or physiological state in addition to depression (such as studies in autoimmune disorders or pregnancy) to reduce the risk of bias. Most included studies excluded participants with co-morbid medical conditions, and the presence of co-morbidity in participants was assessed as one of the items of our quality assessment of papers. It was not possible to exclude all co-morbidity due to original data quality, but we are confident this issue is not going to significantly affect results as a) we used random effect models to account for additional variation; b) co-morbidity is likely to be equally distributed between cases and controls; and c) our large sample (the largest to date) allows for more individual variation without affecting results.
A very limited number of studies on CRP excluded participants presenting with an acute infection (CRP >10 mg/L); we decided to include these studies because we previously found that the odds ratio of inflammation in patients vs controls is very similar if considering all patients (OR=1.46) or excluding patients and controls with CRP >10 mg/L (OR=1.44) (Osimo et al., 2019), thus suggesting that an equal proportion of patients and controls present with acute inflammation.

4.3. Conclusions and future directions

In this study we found a reduction in mean-scaled variability in CRP, IL-12 and sIL-2R. We found increases in the mean levels of CRP, IL-3, IL-6, IL-12, IL-18, sIL-2R and TNF α in patients with depression. These results survived sensitivity analyses for psychiatric and lifestyle predictors, influence of skew, influence of poor-quality studies and publication bias.
Our results confirm that acute depression is a pro-inflammatory state, and lend support to the hypothesis that inflammatory marker elevations in depression are not due to an inflamed sub-group, but rather to a right shift of the immune marker distribution. However, future research should specifically address the inflammatory sub-group hypothesis of depression, which can only be directly tested in an individual-patient meta-analysis.