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Abstract The objective of this study was to evaluate the performances of the propensity score weighted (PSW) methodology in a post-hoc re-analysis of a failed and a negative RCTs in depressive disorders. The conventional study designs, randomizations, and statistical approaches do not account for the baseline distribution of major non-specific prognostic and confounding factors such as the individual propensity to show a placebo effect (PE). Therefore, the conventional analysis approaches implicitly assume that the baseline PE is the same for all subjects in the trial even if this assumption is not supported by our knowledge on the impact of PE on the estimated treatment effect (TE). The consequence of this assumption is an inflation of false negative results (type II error) in presence of a high proportion of subjects with high PE and an inflation of false positive (type I error) in presence of a high proportion of subjects with low PE value. Differently from conventional approaches, the inverse of the PE probability was used as weight in the mixed-effects analysis to assess TE in the PSW analysis. The results of this analysis indicated an enhanced signal of drug response in a failed trial and confirmed the absence of drug effect in a negative trial. This approach can be considered as a reference prospective or post-hoc analysis approach that minimize the risk of inflating either type I or type II error in contrast to what happens in the analyses of RCT studies conducted with the conventional statistical methodology.

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these efforts by: (1) providing a more detailed analysis of standard PRT metrics—response bias and discriminability—to better understand how the task is performed; (2) analyzing the data with two computational models and providing psychometric analyses of both; and (3) determining whether response bias, discriminability, or model parameters predicted responses to treatment with placebo or the atypical antidepressant bupropion. Analysis of standard metrics replicated recent work by demonstrating a dependency between response bias and response time (RT), and by showing that reward totals in the PRT are governed by discriminability. Behavior was well-captured by the Hierarchical Drift Diffusion Model (HDDM), which models decision-making processes; the HDDM showed excellent internal consistency and acceptable retest reliability. A separate “belief” model reproduced the evolution of response bias over time better than the HDDM, but its psychometric properties were weaker. Finally, the predictive utility of the PRT was limited by small samples; nevertheless, depressed adults who responded to bupropion showed larger pre-treatment starting point biases in the HDDM than non-responders, indicating greater sensitivity to the PRT’s asymmetric reinforcement contingencies. Together, these findings enhance our understanding of reward and decision-making mechanisms that are implicated in MDD and probed by the PRT.

Recent observations suggest a role of the volume of the cerebral ventricle volume, corpus callosum (CC) segment volume, in particular that of the central-anterior part, and choroid plexus (CP) volume for treatment resistance of major depressive disorder (MDD). An increased CP volume has been associated with increased inflammatory activity and changes in the structure of the ventricles and corpus callosum. We attempt to replicate and confirm that these imaging markers are associated with clinical outcome in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study is a placebo controlled randomized study comparing sertraline vs. placebo in patients with MDD to identify biological markers of therapy resistance. Association of baseline volumes of the lateral ventricles (LVV), choroid plexus volume (CPV) and volume of segments of the CC with treatment response after 4 weeks treatment was evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline vs. placebo was observed, therefore the study characterized prognostic markers of response in the pooled population. Change in depression severity was identified by the ratio of the Hamilton-Depression rating scale 17 (HAMD-17) at week 4 divided by the HAMD-17 at baseline (HAMD-17 ratio). Volumes of the lateral ventricles and choroid plexi were positively correlated with the HAMD-17 ratio, indication worse outcome with larger ventricles and choroid plexus volumes, whereas the volume of the central-anterior corpus callosum was negatively correlated with the HAMD-17 ratio. Responders (n = 54) had significantly smaller volumes of the lateral ventricles and CP compared to non-responders (n = 117), whereas the volume of mid-anterior CC was significantly larger compared to non-responders (n = 117), confirming our previous findings. In an exploratory way associations between enlarged LVV and CPV and signs of lipid dysregulation were observed. In conclusion, we confirmed that volumes of lateral ventricles, choroid plexi and the mid-anterior corpus callosum are associated with clinical improvement of depression and may be indicators of metabolic/inflammatory activity.

Abstract Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn’t account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients’ data comparable across treatment arms.

Cognitive impairment related to major depressive disorder (MDD) is highly prevalent, debilitating and is lacking in effective treatments; dysregulated inflammatory physiology is a putative mechanism and may represent a therapeutic target. In depressed individuals exhibiting a pro-inflammatory phenotype who were enrolled in a 12-week randomized placebo-controlled trial of 3 doses of omega-3 polyunsaturated fatty acids (ω-3-FA), we examined: (i) the relationship between dysregulated inflammatory physiology and baseline cognitive impairment; (ii) improvement in cognitive impairment following treatment; and (iii) the association between baseline inflammatory biomarkers and change in cognitive impairment for those receiving treatment. We randomized 61 unmedicated adults aged 45.50 years (75% female) with DSM-5 MDD, body mass index >25 kg/m2, and C-reactive protein (CRP) ≥3.0 mg/L to three doses of ω-3-FA (1, 2, or 4 g daily) or matching placebo. Analyses focused on 45 study completers who had inflammatory biomarkers assessed [circulating CRP, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) as well as lipopolysaccharide (LPS)-stimulated concentrations of IL-6 and TNFα in peripheral blood mononuclear cells (PBMC)] and on the highest dose ω-3-FA (4 g daily; n = 11) compared to placebo (n = 10). Impairment in motivational symptoms (e.g., alertness, energy, enthusiasm) and higher-order cognitive functions (e.g., word-finding, memory) were assessed by a validated self-report measure. Among all 45 participants at baseline, lower concentrations of IL-6 in LPS-stimulated PBMC were associated with greater impairment in higher-order cognitive functions (r = −0.35, p = .02). Based on hierarchical linear modeling, individuals receiving 4 g/day of ω-3-FA reported significant improvement in motivational symptoms compared to placebo (B = −0.07, p = .03); in the 4 g/day group, lower baseline concentrations of TNFα in LPS-stimulated PBMC were associated with significant improvement in motivational symptoms (Ρ = .71, p = .02) following treatment. In this exploratory clinical trial, daily supplementation with 4 g of ω-3-FA improves motivational symptoms in depressed individuals exhibiting an inflammatory phenotype.

Abstract Background The literature has shown depression to be associated with an increased risk of dementia. In addition, hormone therapy can be a responsive treatment option for a certain type of depression. In this study, we examined the association between hormone therapy, including lifetime oral contraceptive (OC) use, and hormone replacement therapy (HRT) after menopause with the occurrence of dementia among female patients with depression. Methods The South Korean national claims data from January 1, 2005, to December 31, 2018, was used. Female subjects aged 40 years or older with depression were included in the analyses. Information on hormone therapy was identified from health examination data and followed up for the occurrence of dementia during the average follow-up period of 7.72 years. Results Among 209,588 subjects, 23,555 were diagnosed with Alzheimer’s disease (AD) and 3023 with vascular dementia (VD). Lifetime OC usage was associated with a decreased risk of AD (OC use for < 1 year: HR, 0.92 [95% CI, 0.88–0.97]; OC use for ≥ 1 year: HR, 0.89 [95% CI, 0.84–0.94]), and HRT after menopause was associated with a decreased risk of AD (HRT for < 2 years: HR, 0.84 [95% CI, 0.79–0.89]; HRT for 2–5 years: HR, 0.80 [95% CI, 0.74–0.88]; and HRT for ≥ 5 years : HR, 0.78 [95% CI, 0.71–0.85]) and VD (HRT < 2 years: HR, 0.82 [95% CI, 0.71–0.96]; HRT for 2–5 years: HR, 0.81 [95% CI, 0.64–1.02]; and HRT for ≥ 5 years: HR, 0.61 [95% CI, 0.47–0.79]). Conclusions In this nationwide cohort study, lifetime OC use was associated with a decreased risk of AD, and HRT after menopause was associated with a decreased risk of AD and VD among female patients with depression. However, further studies are needed to establish causality.

IntroductionAlthough people who attempted suicide tend to repeat suicide attempts, there is a lack of evidence on the association between psychiatric service factors and suicide reattempt among them.MethodsWe used a nationwide, population-based medical record database of South Korea to investigate the use of psychiatric services before and after the index suicide attempt and the association between psychiatric service factors after the index suicide attempt with the risk of suicide reattempt.ResultsAmong 5,874 people who had attempted suicide, the all-cause mortality within 3 months after the suicide attempt was 11.6%. Among all subjects who attempted suicide, 30.6% of them had used psychiatric services within 6 months before the suicide attempt; 43.7% of them had used psychiatric services within 3 months after the suicide attempt. Among individuals who had visited clinics following attempted suicide, the cumulative incidence of suicide reattempt over a mean follow-up period of 5.1 years was 3.4%. About half of suicide reattempts occurred within 1 year after the index suicide attempt. Referral to psychiatric services within 7 days was associated with a decreased risk of suicide reattempt (adjusted hazard ratio, 0.51; 95% confidence intervals, 0.29–0.89).ConclusionAn early psychiatric referral within 1 week after a suicide attempt was associated with a decreased risk of suicide reattempt.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS–SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS–SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward–behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

BackgroundFew previous studies have focused on prefrontal activation in young adults diagnosed with major depressive disorder (MDD) and suicidality via functional near-infrared spectroscopy (fNIRS).Materials and MethodsA total of 59 healthy controls (HCs), 35 patients with MDD but without suicidality, and 25 patients with MDD and suicidality, between the ages of 18–34 years, were enrolled. Changes in oxygenated hemoglobin (oxy-Hb) levels of the prefrontal cortex at baseline, 4 weeks, and 8 weeks, were evaluated using a protocol consisting of three consecutively repeated trials of rest, speech, and verbal fluency test (VFT) via fNIRS. MDD was diagnosed and suicidality was evaluated based on Mini International Neuropsychiatric Interview (MINI).ResultsOxy-Hb levels were impaired in patients with MDD compared with HCs (p = 0.018 for left prefrontal cortex; p = 0.021 for right ventromedial prefrontal cortex; p = 0.002 for left frontopolar cortex). Among the three groups including HCs, MDD without suicidality, and MDD with suicidality, prefrontal oxygenation was most decreased in MDD patients with suicidality. A significantly impaired prefrontal oxygenation in the right ventrolateral prefrontal cortex (VLPFC) was detected after adjusting for covariates in MDD patients with suicidality, compared to those without suicidality.ConclusionImpaired prefrontal oxygenation during cognitive execution may serve as a diagnostic biomarker for suicidality in young adult patients with MDD.

BackgroundThere is an association between early life traumas and the development of depression in adults. Few studies have used nationwide population-based samples to investigate whether the type of early life trauma differentially influences the risk of developing depression.MethodsMajor depressive disorder and early life trauma were assessed using the Korean version of the Composite International Diagnostic Interview (K-CIDI) for DSM-IV psychiatric disorder and a questionnaire for early life trauma in the Korean Epidemiological Catchment Area Study in 2016. A total of 4,652 participants were included in the final analysis. This study evaluated the effect of the type and frequency of reported early life trauma on the risk of developing MDD and the association between reported early life trauma and differential symptoms of MDD.ResultsIndividuals with reported early life trauma had a 3.7-fold increased risk of MDD. The risk of MDD was associated with bullying trauma (odds ratio (OR) = 1.847, p = 0.005) after adjusting for age, gender, marriage, job, and education years. The risk of MDD was increased as the types of reported early life traumas increased.ConclusionBullying trauma during early life represents a risk factor for MDD, especially in individuals exposed to multiple traumas in early life.

Background: Changes in lifestyle factors are known to affect mood. However, there is insufficient evidence supporting the association between smoking, alcohol consumption, physical activity and depression in middle-aged women who are likely to experience rapid hormonal changes.Methods: We used a nationwide database of medical records in South Korea. 901,721 premenopausal and 943,710 postmenopausal women aged 40 years or older included in this study. Information on smoking, alcohol consumption, physical activity was identified from health examination data and followed up for the occurrence of depression using claims data.Results: Compared with never-smokers, ex-smokers and current smokers among premenopausal and postmenopausal women showed an increased risk of depression in a dose-dependent manner (aHR 1.13 for ex-smokers; aHR 1.23 for current smokers). Compared with non-drinkers, mild drinkers showed a decreased risk of depression (aHR 0.98 for premenopausal women; aHR 0.95 for postmenopausal women), and heavy drinkers showed an increased risk of depression both among premenopausal (aHR 1.20) and postmenopausal women (aHR 1.05). The risk of depression due to smoking and heavy alcohol consumption was higher in premenopausal women than in postmenopausal women. Compared with those who had not engaged in regular physical activity, those who had engaged showed a decreased risk of depression both among premenopausal (aHR 0.96) and postmenopausal women (aHR 0.95).Conclusions: Smoking and heavy alcohol consumption increased the risk of depression, and the increased risk was prominent in premenopausal than in postmenopausal women. Regular physical activity decreased the risk of depression both in premenopausal and postmenopausal women.

Objectives: Although obesity is associated with increased risk for depression in patients with type 2 diabetes mellitus (DM), the relationship between body weight variability (BWV) and depression remains poorly studied. This study was to investigate the incidence of depression in patients with type 2 DM according to their BWV.Methods: Intraindividual variation in body weight were measured in the nationwide, population-based retrospective cohort of 540,293 patients with type 2 DM from the Korean national health insurance system between 2009 and 2010. The diagnoses of new-onset depression occurring until the end of 2017 were ascertained. Risk of new-onset depression was examined using multivariate-adjusted Cox proportional hazards regression analysis by BWV quartile.Results: 93,149 (17.2%) patients developed new-onset depression for the follow up. BWV was significantly associated with an increased risk of depression after adjusting for confounding factors. The highest BWV quartile group had a hazard ratio (HR) of 1.17 (95% CI 1.15–1.19) compared to the lowest BWV quartile group as a reference. Obese patients in the highest BWV quartile group showed 12% increased risk of depression (HR 1.12, 95% CI 1.09–1.15) while non-obese patients in the highest BWV quartile group showed 20% increased risk of depression (HR: 1.20, 95% CI: 1.17–1.23) compared to their respective lowest BWV quartile groups.Conclusion: A higher BWV was significantly associated with an increased risk of depression in patients with type 2 DM. Thus, BWV may serve as an indicator for early detection of depression in type 2 DM patients.

BackgroundTelehealth has provided many researchers, especially those conducting psychosocial research, with the tools necessary to transition from in-person to remote clinical trials during the COVID-19 pandemic. A growing body of research supports the effectiveness of telemental health for a variety of psychiatric conditions, but few studies have examined telemental health for individuals with comorbid medical diagnoses. Furthermore, little is known about the remote implementation of clinical trials examining telemental health interventions. ObjectiveThis paper outlines the procedural modifications used to facilitate conversion of an in-person randomized controlled trial of cognitive behavioral therapy (CBT) for depression in individuals with traumatic brain injury (TBI; CBT-TBI) to a telemental health study administered remotely. MethodsGiven the nature of remote implementation and specific challenges experienced by individuals with TBI, considerations related to treatment delivery, remote consent, data management, neuropsychological assessment, safety monitoring, and delivery of supportive material have been discussed. Feasibility, acceptability, and safety were evaluated by examining attendance and participant responses on self-report measures of treatment satisfaction and suicidal behavior. ResultsHigh rates of treatment attendance, assessment completion, study retention, and satisfaction with the intervention and modality were reported by participants who completed at least one telemental health CBT-TBI session. ConclusionsStudy modifications are necessary when conducting a study remotely, and special attention should be paid to comorbidities and population-specific challenges (eg, cognitive impairment). Preliminary data support the feasibility, acceptability, and safety of remotely conducting a randomized controlled trial of CBT-TBI. Trial RegistrationClinicalTrials.gov NCT03307070; https://clinicaltrials.gov/ct2/show/NCT03307070

Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (rg = 0.299 ± 0.026, p = 9.10 × 10–31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA→MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10–5; βMD→OA = 0.19, SE = 0.026, p < 2.67 × 10–13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (Pmeta ≤ 5 × 10–8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted “mechanosensory behavior” genes (GO:0007638; Pgene_set = 2.45 × 10–8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.

Background: To investigate the neurobiological evidence supporting the adaptogenic effects of Korean Red Ginseng in reducing the harmful consequences of stress using a double-blind, placebo-controlled trial. Method: Sixty-three subjects with high stress levels were randomized to receive an orally administered, double-blind, 6-week treatment with Korean Red Ginseng (n = 32) or placebo (n = 31). All participants underwent a comprehensive psychological evaluation using Beck Depression Inventory and Stress Response Inventory, cognitive evaluation using the continuous performance test, biological evaluation by measuring blood levels of lipids, catecholamines, inflammation markers, and heart rate variability at baseline and after 6 weeks. Results: At baseline, both groups showed no significant differences in age, sex, years of education, Beck Depression Inventory, and Stress Response Inventory. After 6 weeks, triglyceride levels were significantly increased within the normal limit in theKorean Red Ginseng group (F = 4.11, p = 0.048), and the epinephrine level was decreased in this group (F = 4,35, p = 0.043). The triglyceride increase was significantly associated with epinephrine decrease (B = −0.087, p = 0.041), suggesting that Korean Red Ginseng may stabilize the sympathetic nervous system. In addition, we detected a significant group by time effect in the visually controlled continuous performance test, suggesting positive effects of Korean Red Ginseng on cognition. Conclusion: Korean Red Ginseng might help to stabilize the sympathetic nervous system and improve cognition in individuals with high stress. Keywords: Adaptogenic effect, Epinephrine, Korean Red Ginseng, Stress management, Triglyceride

Objective: Somatic pain is an important risk factor for suicide and suicidal behaviors. However, the association between the number of somatic pain conditions and lifetime suicide attempts (LSA) has not been well established yet. Therefore, the objective of this study was to examine associations between LSA and multiple somatic pain (MSP), singe pain, and no pain in a nationwide survey. Methods: A total of 12,532 adults were randomly selected from the population using the one-person-per-household method. Each participant completed a face-to-face interview using the Korean Composite International Diagnostic Interview (K-CIDI) with Suicide Module, and the Barratt Impulsiveness Scale 11 (BIS-11). The MSP was defined as pain in two or more parts of one's body, including abdominal pain, back pain, arthralgia, arm or leg pain, chest pain, headache, menstrual pain, dysuria, genital pain, and other pain. Results: Among 12,532 subjects, 858 (6.85%) had MSP. Among the three groups (MSP, single pain, and no pain) of subjects, the MSP group had higher percentages of females, those with lower education, and divorced/widowed/separated individuals. However, there were no significant differences in monthly income or residence among the three groups. The MSP group showed four times higher suicide attempts and six times higher multiple attempts than did the no pain group. The BIS total score of the MSP group was the highest among the three groups. Genital pain showed the highest odds ratio for LSA. The higher the number of somatic pain, the higher the odds ratios were for LSA, major depressive disorder (MDD), and anxiety disorders. Subjects having both MSP and MDD showed a significant association with LSA (AOR = 14.78, 95% CI 10.08–21.67, p

Background: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could “accurately” identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. Methods: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the “preferred” treatment. Remission rates were calculated for participants “accurately” treated based on the composite moderator (lucky) versus “inaccurately” treated (unlucky). Findings: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. Interpretation: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. Funding: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center.Trial Registration.Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.

Background: Attachment, or affiliative bonding among conspecifics, is thought to involve neural mechanisms underlying behavioral responses to threat and reward-related social signals. However, attachment-oriented responses may also rely on basic sensorimotor processes. One sensorimotor system that may play a role in attachment is the parietofrontal cortical network that responds to stimuli that are near or approaching the body, the peripersonal space (PPS) monitoring system. We hypothesized that this network may vary in responsivity to such potentially harmful stimuli, particularly those with social salience, based on individual differences in attachment styles. Methods: Young adults viewed images of human faces or cars that appeared to move towards or away from them, while functional magnetic resonance imaging data were collected. Correlations between each of four adult attachment styles, measured using the Relationship Questionnaire, and responses of the PPS network to approaching (versus withdrawing) stimuli were measured. Results: A region-of-interest (ROI) analysis, focused on six cortical regions of the PPS network that showed significant responses to approaching versus withdrawing face stimuli in an independent sample (n = 80), revealed that anxious attachment style (but not the other 3 attachment styles) was significantly positively correlated with responses to faces (but not to cars) in all six ROIs (r = 0.33–0.49, p = 0.01–0.0001, n = 50). Conclusions: These findings suggest that anxious attachment is associated with over-responsivity of a sensorimotor network involved in attending to social stimuli near the body.

Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BPND) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al. (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A 11C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BPND computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using 11C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach.

ObjectivesChronic use of benzodiazepines and zolpidem (BDZ/Z-drugs) leads to dependency, cognitive impairment, and falls. Although controlled-release melatonin (Melatonin CR) may be an alternative, a switch in clinical settings has proven difficult. We investigated the factors associated with successful switch to Melatonin CR in patients with major depressive disorder (MDD) and insomnia.MethodsThis retrospective observational study involved 170 patients diagnosed with MDD and insomnia, and aged older than 55 years, who were treated with BDZ/Z-drug for at least the past 90 days and never before exposed to Melatonin CR. All patients were treated with a standard antidepressant therapy and Melatonin CR for their insomnia. A successful switch was defined as three or more consecutive prescriptions of Melatonin CR separated by at least one-month interval, after discontinuation of the BDZ/Z-drug.ResultsSeventy-nine patients (46.5%) who switched successfully showed no significant differences in sex, age, education, and occupational status compared with the unsuccessful group. The types of antidepressants used or BDZ/Z-drug treatment did not differ significantly between the two groups. Fewer somatic symptoms were observed in the successful group. In the multivariate analysis, the successful group showed significantly less somatic anxiety, shorter duration from first BDZ/Z-drug use to the first antidepressant use, and shorter total duration of BDZ/Z-drug therapy.ConclusionsA successful switch from BDZ/Z-drug to Melatonin CR was associated with less baseline somatic anxiety, earlier use of antidepressants, and shorter total duration of BDZ/Z-drug use, but was less strongly associated with the type of antidepressants in MDD patients with insomnia.

Relapse to smoking after initial abstinence is a major clinical challenge with significant public health consequences. At the brain and behavioral level, those who relapse to tobacco smoking have both greater cue-reactivity and lower inhibitory control than those who remain abstinent. Little is known about neural activation during inhibitory control tasks in the presence of drug-related cues. In the current study, tobacco smokers (SMK; n = 22) and non-smoking controls (CON; n = 19) completed a Go/NoGo task involving smoking cues during a functional magnetic resonance imaging (fMRI) scan. Following the scan session, smokers were required to quit smoking, and maintenance of abstinence was evaluated as part of a 12-week smoking cessation trial. We evaluated pre-cessation brain activity during NoGo trials in smokers who were versus were not able to quit smoking. We then compared fMRI and inhibitory control measures between smokers and non-smokers. We did not find differences between SMK and CON in performance or activation to smoking or neutral cues. However, compared to SMK who relapsed, SMK who attained biochemically-validated abstinence at the end of the smoking cessation trial had greater neural activation in the anterior insula during NoGo trials specifically with smoking-related cues. Results indicate that within SMK, decreased inhibitory control activation during direct exposure to drug-related stimuli may be a marker of difficulty quitting and relapse vulnerability. Keywords: Smoking cessation, Tobacco, fMRI, Insula, Cue, Relapse, Anterior cingulate cortex, ACC

Antidepressant medications are commonly used to treat depression, but only about 30% of patients reach remission with any single first-step antidepressant. If the first-step treatment fails, response and remission rates at subsequent steps are even more limited. The literature on biomarkers for treatment response is largely based on secondary analyses of studies designed to answer primary questions of efficacy, rather than on a planned systematic evaluation of biomarkers for treatment decision. The lack of evidence-based knowledge to guide treatment decisions for patients with depression has lead to the recognition that specially designed studies with the primary objective being to discover biosignatures for optimizing treatment decisions are necessary. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is one such discovery study. Stage 1 of EMBARC is a randomized placebo controlled clinical trial of 8 week duration. A wide array of patient characteristics is collected at baseline, including assessments of brain structure, function and connectivity along with electrophysiological, biological, behavioral and clinical features. This paper reports on the data analytic strategy for discovering biosignatures for treatment response based on Stage 1 of EMBARC.

Background The Anxiety Symptoms Questionnaire (ASQ) is a brief self-report questionnaire which measures frequency and intensity of symptoms and was developed to improve assessment of anxiety symptoms in a clinical setting. We examined the reliability and validity of the ASQ in patients with anxiety disorders and/or depression, non-clinical control subjects and college students.Methods 240 outpatients with generalised anxiety disorder, social anxiety disorder, panic disorder or major depressive disorder were administered the ASQ and additional questionnaires measuring depression and anxiety, as were 111 non-clinical control subjects and 487 college students. Factor analysis, Pearson’s correlation coefficients and logistic regression were used to assess reliability and validity. Test–retest reliability of the ASQ was measured using a subset who were re-administered the ASQ after 4 weeks.Results Factor analysis revealed measurement of a single dimension by the ASQ. Internal consistency and test–retest reliability were strong. The ASQ total score also significantly distinguished patients with an anxiety disorder from the clinical controls above and beyond the clinician-rated Hamilton Anxiety Scale.Conclusions The ASQ is a valid, reliable and effective self-rated measure of anxiety and may be a useful tool for screening and assessing anxiety symptoms in psychiatric as well as college settings.

Objective: Peripheral biomarkers have been studied to predict treatment response of panic symptoms. We hypothesized that depressive disorder (MDD) vs. panic disorder (PD) would exhibit different peripheral biomarkers, and their correlation with severity of panic attacks (PA) would also differ. Methods: Forty-one MDD patients, 52 PD patients, and 59 healthy controls were followed for 12 weeks. We measured peripheral biomarkers along with the Panic Disorder Severity Scale (PDSS) at each visit—pre-treatment, 2, 4, 8, and 12 weeks on a regular schedule. Peripheral biomarkers including serum cytokines, plasma and serum brain-derived neurotrophic factor (BDNF), leptin, adiponectin, and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA). Results: Patients with MDD and PD demonstrated significantly higher levels of pre-treatment IL-6 compared to controls, but no differences were seen in plasma and serum BDNF, leptin, adiponectin, and CRP. Pre-treatment leptin showed a significant clinical correlation with reduction of panic symptoms in MDD patients at visit 5 (p = 0.011), whereas pre-treatment IL-6 showed a negative correlation with panic symptom reduction in PD patients (p = 0.022). An improvement in three panic-related items was observed to be positively correlated with pre-treatment leptin in MDD patients: distress during PA, anticipatory anxiety, and occupational interference. Conclusion: Higher pre-treatment leptin was associated with better response to treatment regarding panic symptoms in patients with MDD, while higher IL-6 was associated with worse response regarding panic symptoms in PD patients. Different predictive peripheral biomarkers observed in MDD and PD suggest the need for establishing individualized predictive biomarkers, even in cases of similar symptoms observed in different disorders. Keywords: Panic attack, Major depression disorder, Panic disorder, IL-6, Leptin

Objective: It has been suggested that patients' perception of treatment assignment might serve to bias results of double blind randomized controlled trials (RCT). Most previous evidence on the effects of patients' perceptions and the mechanisms influencing these perceptions relies on cross-sectional associations. This re-analysis of a double blind, placebo controlled RCT of pharmacological treatment of major depression set out to gather longitudinal evidence on the mechanism and effects of patients' perceived treatment assignment in the pharmacological treatment of major depression.Methods: One-hundred eighty-nine outpatients with DSM-IV diagnosed major depression were randomized to SAMe 1,600–3,200 mg/d, escitalopram 10–20 mg/days, or placebo for 12 weeks. Data on depressive symptoms (17-item Hamilton Depression Scale; HDRS-17), adverse events and patients' perceived treatment assignment was collected at baseline, week 6, and week 12. The re-analysis focused on N = 166 (out of the originally included 189 participants) with available data on perceived treatment assignment.Results: As in the parent trial, depressive symptoms (HDRS-17) significantly decreased over the course of 12 weeks and there was no difference between placebo, SAMe or escitalopram. A significant number of patients changed their perceptions about treatment assignment throughout the trial, especially between baseline and week 6. Improvement in depressive symptoms, but not adverse events significantly predicted perceived treatment assignment at week 6. In turn, perceived treatment assignment at week 6, but not actual treatment, predicted further improvement in depressive symptoms at week 12.Conclusions: The current results provide longitudinal evidence that patients' perception of treatment assignment systematically change despite a double blind procedure and in turn might trigger expectancy effects with the potential to bias the validity of an RCT.Parent study grant number: R01 AT001638 Parent study ClinicalTrials. gov Identifier: NCT00101452

Background There is concern that selective serotonin reuptake inhibitors (SSRIs) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRIs in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRIs. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF. Over a mean 1.6 years of follow‐up, the rate of major/nonmajor clinically relevant bleeding was 18.57 events/100 patient‐years for SSRI users versus 16.84 events/100 patient‐years for matched comparators, adjusted hazard ratio (aHR) of 1.16 (95% confidence interval [CI], 0.95–1.43). The aHRs were similar in patients taking rivaroxaban (aHR 1.11 [95% CI, 0.82–1.51]) and those taking warfarin (aHR 1.21 [95% CI, 0.91–1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRIs was 1.13 (95% CI, 0.62–2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI, 0.96–2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRIs were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRIs added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRIs can be safely added to anticoagulants in patients with atrial fibrillation. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Eating disorders comorbid with depression are an established risk factor for suicide. In this study, we aimed to determine the effects of binge eating (BE) symptoms on suicidality and related clinical characteristics in major depressive disorder (MDD). A total of 817 community participants with MDD were included. We compared two groups (with and without lifetime BE symptoms). The MDD with BE group was subdivided into a frequent BE (FBE) subgroup (BE symptoms greater than twice weekly) and any BE (ABE) subgroup (BE symptoms greater than twice weekly). The MDD with BE group comprised 142 (17.38%) patients. The FBE and ABE subgroups comprised 75 (9.18%) and 67 (8.20%) patients, respectively. Comorbid alcohol use disorder, anxiety disorder, post-traumatic stress disorder (PTSD) and history of suicide attempt were significantly more frequent in the MDD with BE group than MDD without BE group. Sexual trauma was also reported more frequently in MDD with BE group. No significant differences were observed between the ABE and FBE subgroups. Multivariate logistic regression revealed an association of suicide attempt with BE symptoms and sexual trauma. Structural equation modeling showed that sexual trauma increased BE (β = 0.337, P

Internet addiction (IA) is defined as a psychological dependence on the internet, regardless of the type of activities once logged on, and previous studies have focused on adolescents and young adults. The aim of this study was to investigate the association between suicide attempts and sleep among community-dwelling adults with IA.The Young's Internet Addiction Test (IAT), the Korean version of the Composite International Diagnostic Interview (K-CIDI) and a suicide questionnaire were used in this cross-sectional multistage, cluster sampling population-based study. A total of 3212 adults aged 18-64 years were interviewed face-to-face, and they had been randomly selected through a one-person-per-household method.Of the 3212 adults, 204 were assessed as having IA (6.35%). Adults with IA were younger, and more frequently male, unmarried, and unemployed, and had poorer sleep quality than adults without IA (32.8% vs. 19.8%), whereas there was no significant difference in the absolute duration of sleep between the two groups. Adults with IA showed more frequent difficulty initiating and maintaining sleep, non-restorative sleep, daytime functional impairment, and duration of sleep more than 10 hours on weekdays than adults without IA. IA with poor sleep quality was significantly associated with lifetime suicide attempts (AOR = 3.34, 95% CI 1.38-8.05) after adjusting for demographic covariates. Adults with IA who had more sleep problems showed more severe IA, especially those who experienced a previous suicidal attempt. Among mental disorders, IA with poor sleep quality was significantly associated with anxiety disorder and overall psychiatric disorders.Among adults with IA, poor sleep quality was found to be associated with more severe IA and lifetime suicide attempt.

Este estudio exploró la viabilidad del uso de redes sociales en Internet para llevar a cabo un programa de detección del Trastorno Depresivo Mayor (TDM) y proporcionar psicoeducación a estudiantes universitarios. Se publicó un anuncio en Facebook dirigido a estudiantes en cinco universidades en los Estados Unidos para que completaran una encuesta de salud mental para la detección de TDM usando el Patient Health Questionnaire-9 (PHQ-9). A los estudiantes que dieron positivo para el TDM se les ofreció otra encuesta de seguimiento ocho semanas después. De los 259 estudiantes quienes accedieron a participar en este estudio, 26,7% dieron positivo para el TDM, pero solo 14,2% estaban recibiendo tratamiento. El uso de Facebook para anunciar la encuesta para la detección de TDM requirió poco tiempo de inicio y el coste promedio fue de $11,45 por sujeto. Es factible utilizar redes sociales comercialmente disponibles en Internet como Facebook para detectar el TDM en estudiantes universitarios. Sin embargo, la realización de la encuesta en Internet y provisión de recursos de tratamiento no fueron suficientes para aumentar las tasas de tratamiento en este grupo. © 2012 Asociación Española de Psicología Conductual. Publicado por Elsevier España, S.L. Todos los derechos reservados.

The annual suicide rate in South Korea is the highest among the developed countries. Paraquat is a highly lethal herbicide, commonly used in South Korea as a means for suicide. We have studied the effect of the 2011 paraquat prohibition on the national suicide rate and method of suicide in South Korea. We obtained the monthly suicide rate from 2005 to 2013 in South Korea. In our analyses, we adjusted for the effects of celebrity suicides, and economic, meteorological, and seasonal factors on suicide rate. We employed change point analysis to determine the effect of paraquat prohibition on suicide rate over time, and the results were verified by structural change analysis, an alternative statistical method. After the paraquat prohibition period in South Korea, there was a significant reduction in the total suicide rate and suicide rate by poisoning with herbicides or fungicides in all age groups and in both genders. The estimated suicide rates during this period decreased by 10.0% and 46.1% for total suicides and suicides by poisoning of herbicides or fungicides, respectively. In addition, method substitution effect of paraquat prohibition was found in suicide by poisoning by carbon monoxide, which did not exceed the reduction in the suicide rate of poisoning with herbicides or fungicides. In South Korea, paraquat prohibition led to a lower rate of suicide by paraquat poisoning, as well as a reduction in the overall suicide rate. Paraquat prohibition should be considered as a national suicide prevention strategy in developing and developed countries alongside careful observation for method substitution effects.

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs.

Background. A steady rise in the prevalence of depression among college students has negatively affected student quality of life. This study investigates the feasibility and acceptability of a Web-based model, including Skype, to screen and provide psychiatric consultation to depressed college students. Methods. Students completed the 9-item Patient Health Questionnaire (PHQ-9) online; those who screened positive (PHQ-9 ≥ 10) or endorsed any level of suicidal ideation were offered Web-based psychiatric consultation using Skype. After the consultation, students filled out a 7-item satisfaction questionnaire to report on the acceptability of this Web-based method. Results. A total of 972 students consented to the online depression screening and 285 screened positive. Of those, 69 students consented and 17 students successfully completed the psychiatric consultation via Skype. Thirteen (76.4%) students found the interview useful in helping them understand their depression. Fifteen (88.2%) students thought that psychologists and psychiatrists could successfully see patients via videoconferencing. Conclusions. Current online technologies can provide depression screening and psychiatric consultation to college students; those who participated reported a positive experience. Future studies will need to address the low levels of participation among college students and attract students who are underserved, as well as use a videoconferencing platform that adequately protects data confidentiality.

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.

BackgroundApproach and avoidance behavior provide a means for assessing the rewarding or aversive value of stimuli, and can be quantified by a keypress procedure whereby subjects work to increase (approach), decrease (avoid), or do nothing about time of exposure to a rewarding/aversive stimulus. To investigate whether approach/avoidance behavior might be governed by quantitative principles that meet engineering criteria for lawfulness and that encode known features of reward/aversion function, we evaluated whether keypress responses toward pictures with potential motivational value produced any regular patterns, such as a trade-off between approach and avoidance, or recurrent lawful patterns as observed with prospect theory.Methodology/principal findingsThree sets of experiments employed this task with beautiful face images, a standardized set of affective photographs, and pictures of food during controlled states of hunger and satiety. An iterative modeling approach to data identified multiple law-like patterns, based on variables grounded in the individual. These patterns were consistent across stimulus types, robust to noise, describable by a simple power law, and scalable between individuals and groups. Patterns included: (i) a preference trade-off counterbalancing approach and avoidance, (ii) a value function linking preference intensity to uncertainty about preference, and (iii) a saturation function linking preference intensity to its standard deviation, thereby setting limits to both.Conclusions/significanceThese law-like patterns were compatible with critical features of prospect theory, the matching law, and alliesthesia. Furthermore, they appeared consistent with both mean-variance and expected utility approaches to the assessment of risk. Ordering of responses across categories of stimuli demonstrated three properties thought to be relevant for preference-based choice, suggesting these patterns might be grouped together as a relative preference theory. Since variables in these patterns have been associated with reward circuitry structure and function, they may provide a method for quantitative phenotyping of normative and pathological function (e.g., psychiatric illness).