We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome-technologic advances in methods to analyze millions of polymorphisms in thousands of subjects-have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.
Background Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. Methods We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Results Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP ( p < .001 for each) and normalized with antipsychotic treatment ( p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects ( p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls ( p = .01). Conclusions Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.
Abstract Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.
Background Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. Methods We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Results Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-α, 9 for interleukin (IL)-1β, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-γ. There were significantly higher concentrations of TNF-α ( p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher ( p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. Conclusions This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.
Background Little population-based data exist outside the United States on the epidemiology of binge eating disorder (BED). Cross-national BED data are presented here and compared with bulimia nervosa (BN) data in the World Health Organization (WHO) World Mental Health Surveys. Methods Community surveys with 24,124 respondents (ages 18+) across 14 mostly upper-middle and high-income countries assessed lifetime and 12-month DSM-IV mental disorders with the WHO Composite International Diagnostic Interview. Physical disorders were assessed with a chronic conditions checklist. Results Country-specific lifetime prevalence estimates are consistently (median; interquartile range) higher for BED (1.4%; .8–1.9%) than BN (.8%; .4–1.0%). Median age of onset is in the late teens to early 20s for both disorders but slightly younger for BN. Persistence is slightly higher for BN (6.5 years; 2.2–15.4) than BED (4.3 years; 1.0–11.7). Lifetime risk of both disorders is elevated for women and recent cohorts. Retrospective reports suggest that comorbid DSM-IV disorders predict subsequent onset of BN somewhat more strongly than BED and that BN predicts subsequent comorbid disorders somewhat more strongly than does BED. Significant comorbidities with physical conditions are due almost entirely to BN and to a somewhat lesser degree BED predicting subsequent onset of these conditions. Role impairments are similar for BN and BED. Fewer than half of lifetime BN or BED cases receive treatment. Conclusions Binge eating disorder represents a public health problem at least equal to BN. Low treatment rates highlight the clinical importance of questioning patients about eating problems even when not included among presenting complaints.
Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.
Abstract Background Marijuana is the most widely used illicit drug in the United States and all over the world. Reports indicate that the potency of cannabis preparation has been increasing. This report examines the concentration of cannabinoids in illicit cannabis products seized by the U.S. Drug Enforcement Administration over the last 2 decades, with particular emphasis on Δ9 -tetrahydrocannabinol and cannabidiol. Methods Samples in this report were received over time from materials confiscated by the Drug Enforcement Administration and processed for analysis using a validated gas chromatography with flame ionization detector method. Results Between January 1, 1995, and December 31, 2014, 38,681 samples of cannabis preparations were received and analyzed. The data showed that although the number of marijuana samples seized over the last 4 years has declined, the number of sinsemilla samples has increased. Overall, the potency of illicit cannabis plant material has consistently increased over time since 1995 from ~4% in 1995 to ~12% in 2014. The cannabidiol content has decreased on average from ~.28% in 2001 to <.15% in 2014, resulting in a change in the ratio of Δ9 -tetrahydrocannabinol to cannabidiol from 14 times in 1995 to ~80 times in 2014. Conclusions There is a shift in the production of illicit cannabis plant material from regular marijuana to sinsemilla. This increase in potency poses higher risk of cannabis use, particularly among adolescents.
Abstract Background Sleep disturbance is associated with inflammatory disease risk and all-cause mortality. Here, we assess global evidence linking sleep disturbance, sleep duration, and inflammation in adult humans. Methods A systematic search of English language publications was performed, with inclusion of primary research articles that characterized sleep disturbance and/or sleep duration or performed experimental sleep deprivation and assessed inflammation by levels of circulating markers. Effect sizes (ES) and 95% confidence intervals (CI) were extracted and pooled using a random effect model. Results A total of 72 studies ( n > 50,000) were analyzed with assessment of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα). Sleep disturbance was associated with higher levels of CRP (ES .12; 95% CI = .05–.19) and IL-6 (ES .20; 95% CI = .08–.31). Shorter sleep duration, but not the extreme of short sleep, was associated with higher levels of CRP (ES .09; 95% CI = .01–.17) but not IL-6 (ES .03; 95% CI: −.09 to .14). The extreme of long sleep duration was associated with higher levels of CRP (ES .17; 95% CI = .01–.34) and IL-6 (ES .11; 95% CI = .02–20). Neither sleep disturbances nor sleep duration was associated with TNFα. Neither experimental sleep deprivation nor sleep restriction was associated with CRP, IL-6, or TNFα. Some heterogeneity among studies was found, but there was no evidence of publication bias. Conclusions Sleep disturbance and long sleep duration, but not short sleep duration, are associated with increases in markers of systemic inflammation.
Here, we define a psychobiotic as a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. As a class of probiotic, these bacteria are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the brain-gut axis. Preclinical evaluation in rodents suggests that certain psychobiotics possess antidepressant or anxiolytic activity. Effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems. So far, psychobiotics have been most extensively studied in a liaison psychiatric setting in patients with irritable bowel syndrome, where positive benefits have been reported for a number of organisms including Bifidobacterium infantis. Evidence is emerging of benefits in alleviating symptoms of depression and in chronic fatigue syndrome. Such benefits may be related to the anti-inflammatory actions of certain psychobiotics and a capacity to reduce hypothalamic-pituitary-adrenal axis activity. Results from large scale placebo-controlled studies are awaited.
Abstract The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) ( Nr3c1 ). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F /17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.
Abstract Oxytocin is a nonapeptide that also serves as a neuromodulator in the human central nervous system. Over the last decade, a sizeable body of literature has examined its effects on social behavior in humans. These studies show that oxytocin modulates various aspects of social behaviors such as empathy, trust, in-group preference, and memory of socially relevant cues. Several theoretical formulations have attempted to explain the effects of oxytocin. The prosocial account argues that oxytocin mainly enhances affiliative prosocial behaviors; the fear/stress theory suggests that oxytocin affects social performance by attenuating stress; and the in-/out-group approach proposes that oxytocin regulates cooperation and conflict among humans in the context of intergroup relations. Nonetheless, accumulating evidence reveals that the effects of oxytocin are dependent on a variety of contextual aspects and the individual’s characteristics and can induce antisocial effects including aggression and envy. In an attempt to reconcile these accounts, we suggest a theoretical framework that focuses on the overarching role of oxytocin in regulating the salience of social cues through its interaction with the dopaminergic system. Crucially, the salience effect modulates attention orienting responses to external contextual social cues (e.g., competitive vs. cooperative environment) but is dependent on baseline individual differences such as gender, personality traits, and degree of psychopathology. This view could have important implications for the therapeutic applications of oxytocin in conditions characterized with aberrant social behavior.
A better understanding of the neural systems underlying impulse control is important for psychiatry. Although most impulses are motivational or emotional rather than motoric per se, it is research into the neural architecture of motor response control that has made the greatest strides. This article reviews recent developments in the cognitive neuroscience of stopping responses. Most research of this kind has focused on reactive control—that is, how subjects stop a response outright when instructed by a signal. It is argued that reactive paradigms are limited as models of control relevant to psychiatry. Instead, a set of paradigms is advocated that begins to model proactive inhibitory control—that is, how a subject prepares to stop an upcoming response tendency. Proactive inhibitory control is generated according to the goals of the subject rather than by an external signal, and it can be selectively targeted at a particular response tendency. This may have wider validity than reactive control as an experimental model for stopping inappropriate responses.
Background Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. Methods One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). Results We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. Conclusions Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.
Abstract Background The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans. Methods Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors ( n = 32), their adult offspring ( n = 22), and demographically comparable parent ( n = 8) and offspring ( n = 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements. Results Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring’s own childhood trauma, respectively. FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures. Conclusions This is the first demonstration of an association of pre-conception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects.
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.
Background Research on brain activity in schizophrenia has shown that changes in the function of any single region cannot explain the range of cognitive and affective impairments in this illness. Rather, neural circuits that support sensory, cognitive, and emotional processes are now being investigated as substrates for cognitive and affective impairments in schizophrenia, a shift in focus consistent with long-standing hypotheses about schizophrenia as a disconnection syndrome. Our goal was to further examine alterations in functional connectivity within and between the default mode network and three cognitive control networks (frontal-parietal, cingulo-opercular, and cerebellar) as a basis for such impairments. Methods Resting state functional magnetic resonance imaging was collected from 40 individuals with DSM-IV-TR schizophrenia, 31 siblings of individuals with schizophrenia, 15 healthy control subjects, and 18 siblings of healthy control subjects while they rested quietly with their eyes closed. Connectivity metrics were compared between patients and control subjects for both within- and between-network connections and were used to predict clinical symptoms and cognitive function. Results Individuals with schizophrenia showed reduced distal and somewhat enhanced local connectivity between the cognitive control networks compared with control subjects. Additionally, greater connectivity between the frontal-parietal and cerebellar regions was robustly predictive of better cognitive performance across groups and predictive of fewer disorganization symptoms among patients. Conclusions These results are consistent with the hypothesis that impairments of executive function and cognitive control result from disruption in the coordination of activity across brain networks and additionally suggest that these might reflect impairments in normal pattern of brain connectivity development.
Background Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods Participants with TRD ( n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N -methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo ( d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.
Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N -methyl-D-aspartate (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons. Results The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors. We also found that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin dependent manner.
Background Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations. Methods To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. Results We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression. Conclusions These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.