Behavioral and physiological effects of an infant-neglect manipulation in a bi-parental, twinning primate: impact is dependent on familial factors

Experimental animal studies and epidemiological and clinical human studies demonstrate that atypical infant-caregiving can exert short- and long-term effects on offspring phenotype, including increased long-term risk of affective disorders. Whilst the early environment is therefore a major determinant of behavioral, physiological and neurobiological phenotypes, the effects of early adversity exhibit individual variation, presumably due to differences in environment-genotype interactions. Twin studies provide a powerful model with which to study such interactions. However, human twin studies rarely include analysis of genotype-environment interactions or of individuals exposed to extreme environments, and rat studies have rarely attempted to utilize littermates (i.e. dizygotic twins) to investigate environment-genotype interactions. Here, we report on the effects of repeated deprivation of caregiving in the common marmoset, a primate that exhibits dizygotic twinning and bi-parental care. Breeding pairs each contributed early deprived (ED) twins and control (CON) twins, thereby allowing for the study of effects of ED, parentage and ED-parentage interaction. Significant ED x parentage interaction effects were obtained for basal urinary, plasma and cerebrospinal-fluid cortisol titers (infancy-adolescence), and basal levels of social and maintenance behaviors (juveniles); basal urinary cortisol titers during a 2-week period of repeated psychosocial challenge (juveniles), and social and exploratory behavior during psychosocial challenge (juveniles). Significant main effects of ED were obtained for: basal levels of time spent in contact with parents (ED>CON; juveniles) and in locomotor activity (EDCON; juveniles); time spent in locomotor activity (EDCON) during psychosocial challenge (juveniles). This study provides evidence for long-term effects of early environment on bio-behavioral traits and states in marmosets specifically, and the importance of including parental factors in developmental studies in mammals generally.     

Repeated parental deprivation in the infant common marmoset (Callithrix jacchus, primates) and analysis of its effects on early development.

BACKGROUND: We describe a successful demonstration that repeated early deprivation of parental care (ED), as used to study effects of early life stress in rats, can be performed in a primate and that it constitutes an early life stressor. METHODS: Seven breeding pairs of marmoset monkeys each provided control twins (CON) and twins that were subjected to ED for 30-120 min/day on postnatal days (PND) 2-28. Urine samples were obtained to monitor the acute effect of ED on cortisol and catecholamine levels. Behavior samples were obtained in the home cage to monitor the effects of ED on infant and infant-parent behavior. RESULTS: Early deprivation of parental care caused acute increases in cortisol, epinephrine, and norepinephrine. At PND 28, basal cortisol was reduced in ED compared with CON infants, and ED infants were smaller than CON infants. Early deprivation infants tended to spend more time in the suckling position than did CON. Early deprivation infants demonstrated more distress vocalization than CON infants, even though the parental care they received in the home cage was similar. Early deprivation infants tended to play less socially than did CON. CONCLUSIONS: To our knowledge, this is the first demonstration that a repeated early life stressor of the type developed in rats can also be applied to a primate species.     

Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research

Depression is one of the most common human illnesses and is of immense clinical and economic significance. Knowledge of the neuro-psychology, -biology and -pharmacology of depression is limited, as is the efficacy of antidepressant treatment. In terms of depression aetiology, whilst the evidence for causal mechanisms is sparse, some genomic and environmental factors associated with increased vulnerability have been identified. With regards to the latter, the environments in which human infants and children develop are fundamental to how they develop, and parental loss, emotional and physical neglect, and abuse have been shown to be associated with: traits of depression, traits of predisposition to depression triggered by subsequent life events, and associated physiological abnormalities, across the life span. Studies of postnatal environmental manipulations in rodents and primates can potentially yield evidence that abnormal early-life experience leading to dysfunction of the neurobiology, physiology and behaviour of emotion is a general mammalian characteristic, and therefore, that this approach can be used to develop animal models for depression research, with aetiological, face, construct and predictive validity. The establishment of models with such validity, if at all achievable, will require a sophisticated combination of (1) appropriate postnatal manipulations that induce acute stress responses in the infant brain which in turn lead to long-term neurobiological consequences, and (2) appropriate behavioural and physiological assays to identify and quantify any depression-like phenotypes resulting from these long-term neurobiological phenotypes. Here, we review some of the evidence-positive and negative-that neglect-like environments in rat pups and monkey infants lead to long-term, depression-like behavioural traits of reduced motivation for reward and impaired coping with adversity, and to altered activity in relevant physiological homeostatic systems.     

Symptom profile of major depressive disorder in women with eating disorders

OBJECTIVE: Based on the well-documented association between eating disorders (EDs) and affective disorders, the patterns of comorbidity of EDs and major depressive disorder (MDD) were investigated. The temporal relation between EDs and MDD onset was analyzed to determine differences in the course and nature of MDD when experienced prior to versus after the onset of the ED. METHOD: Lifetime MDD and depressive symptoms were assessed in 1371 women with a history of ED. The prevalence of MDD was first explored across ED subtypes, and ages of onset of MDD and EDs were compared. Depressive symptoms were examined in individuals who developed MDD before and after ED onset. RESULTS: The lifetime prevalence of MDD was 72.9%. Among those with lifetime MDD (n =963), 34.5% reported MDD onset before the onset of ED. Those who experienced MDD first reported greater psychomotor agitation (OR =1.53; 95%CI =1.14-2.06), and thoughts of own death (but not suicide attempts or ideation; OR =1.73; 95%CI =1.31-2.30). Among individuals who had MDD before ED, 26.5% had the MDD onset during the year before the onset of ED; 67% of individuals had the onset of both disorders within the same 3 year window. CONCLUSION: Clinicians treating individuals with new-onset ED or MDD should remain vigilant for the emergence of additional psychopathology, especially during the initial 3 year window following the onset of the first disorder.     

Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies

Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE/DA. Available depletion studies found conflicting results in heterogeneous populations: healthy controls, patients with previous MDD in remission and patients suffering from MDD. The decrease in mood after 5-HT and NE/DA depletion in humans is reviewed and quantified. Systematic search of MEDLINE and EMBASE (1966-October 2006) and cross-references was carried out. Randomized studies applying ATD, PCPA, APTD or AMPT vs control depletion were included. Pooling of results by meta-analyses was stratified for studied population and design of the study (within or between subjects). Seventy-three ATD, 2 PCPA, 10 APTD and 8 AMPT studies were identified of which 45 ATD and 8 APTD studies could be meta-analyzed. 5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.     

A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals.

BACKGROUND: The ventromedial prefrontal cortex (VMPFC) is a region implicated in the assessment of the rewarding potential of stimuli and may be dysfunctional in major depressive disorder (MDD). The few studies examining prefrontal cortical responses to emotive stimuli in MDD have indicated increased VMPFC responses to pleasant images but decreased responses to sad mood provocation when compared with healthy individuals. We wished to corroborate these results by examining neural responses to personally relevant happy and sad stimuli in MDD and healthy individuals within the same paradigm. METHODS: Neural responses to happy and sad emotional stimuli (autobiographical memory prompts and congruent facial expressions) were measured using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in MDD (n = 12) and healthy (n = 12) individuals. RESULTS: Increased and decreased responses in VMPFC were observed in MDD and healthy individuals, respectively, to happy stimuli, whereas the pattern was reversed for MDD and healthy individual responses to sad stimuli. These findings were not explained by medication effects in depressed individuals. CONCLUSIONS: These findings indicate a double dissociation of the pattern of VMPFC response to happy and sad stimuli in depressed and healthy individuals and suggest abnormal reward processing in MDD.     

Major depressive disorder, suicidal ideation, and suicide attempt in twins discordant for cannabis dependence and early-onset cannabis use

BACKGROUND: Previous research has reported both a moderate degree of comorbidity between cannabis dependence and major depressive disorder (MDD) and that early-onset cannabis use is associated with increased risks for MDD. OBJECTIVE: To examine whether associations between both lifetime cannabis dependence and early cannabis use and measures of MDD, suicidal ideation, and suicide attempt persist after controlling for genetic and/or shared environmental influences. DESIGN: Cross-sectional survey of twin pairs discordant for lifetime cannabis dependence and those discordant for early cannabis use. SETTING: General population sample of twins (median age, 30 years). PARTICIPANTS: Two hundred seventy-seven same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17 years). MAIN OUTCOME MEASURES: Self-report measures of DSM-IV-defined lifetime MDD, suicidal ideation, and suicide attempt. RESULTS: Individuals who were cannabis dependent had odds of suicidal ideation and suicide attempt that were 2.5 to 2.9 times higher than those of their non-cannabis-dependent co-twin. Additionally, cannabis dependence was associated with elevated risks of MDD in dizygotic but not in monozygotic twins. Those who initiated cannabis use before age 17 years had elevated rates of subsequent suicide attempt (odds ratio, 3.5 [95% confidence interval, 1.4-8.6]) but not of MDD or suicidal ideation. Early MDD and suicidal ideation were significantly associated with subsequent risks of cannabis dependence in discordant dizygotic pairs but not in discordant monozygotic pairs. CONCLUSIONS: Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.     

Biogenic amine activity in response to fluoxetine and desipramine in differentially reared rhesus monkeys.

BACKGROUND: It has been hypothesized that adverse early experience may be a mechanism by which children become vulnerable to later psychopathology via alteration of neurochemical or hormonal systems associated with such disorders. Such effects may in turn affect later responses to pharmacologic agents that act on these systems. METHODS: In this study, 18 mother-reared (MR) and 18 peer-reared (PR) rhesus monkeys experienced six 1-week separations from cagemates interspersed with 1-week reunions, while housed in like-reared groups of 3. Within rearing groups, equal numbers of animals received either fluoxetine (2 mg/kg), desipramine (5 mg/kg) or placebo delivered daily beginning 4 weeks before the first separation. Levels of norepinephrine (NE), the NE metabolite MHPG, the dopamine metabolites DOPAC and HVA, and the serotonin metabolite 5HIAA were measured in CSF samples collected approximately every 2 to 3 weeks during these procedures. RESULTS: Following treatment, DMI increased NE and decreased MHPG in the DMI-treated groups, while 5HIAA was decreased in the fluoxetine-treated groups following treatment. The increase in NE was followed by a sharp decline over the course of treatment, which was accompanied by an increase in MHPG. The rearing groups did not show a differential response to the drug treatments, and the separation manipulation itself had few effects. The mother-reared group showed higher levels of NE and DOPAC over all samples and higher levels of HVA in most samples. CONCLUSIONS: These rearing effects on biogenic amine activity were observed even in the presence of pharmacologic treatments that effectively altered the activity of these systems, and are consistent with previous findings from the same subject. The higher NE values observed in mother-reared infants over separations and reunions may have been due to higher basal levels of NE than peer-reared monkeys or to greater responsiveness to the stress of repeated social disruption or both. These findings agree with other primate studies showing that rearing differences persist beyond the infancy period and add to growing evidence of the important influence of the early social environment on neurobiologic development in primates.     

Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression

Stress has been shown to interact with genetic vulnerability in pathogenesis of psychiatric disorders. Here we investigated the outcome of interaction between genetic vulnerability and early-life stress, by employing a rodent model that combines an inherited trait of vulnerability in Flinders Sensitive Line (FSL) rats, with early-life stress (maternal separation). Basal differences in synaptic signaling between FSL rats and their controls were studied, as well as the consequences of early-life stress in adulthood, and their response to chronic antidepressant treatment (escitalopram). FSL rats showed basal differences in the activation of synapsin I and Erk1/2, as well as in αCaM kinase II/syntaxin-1 and αCaM kinase II/NMDA-receptor interactions in purified hippocampal synaptosomes. In addition, FSL rats displayed a blunted response of Erk-MAP kinases and other differences in the outcome of early-life stress in adulthood. Escitalopram treatment restored some but not all alterations observed in FSL rats after early-life stress. The marked alterations found in key regulators of presynaptic release/neurotransmission in the basal FSL rats, and as a result of early-life stress, suggest synaptic dysfunction. These results show that early gene-environment interaction may cause life-long synaptic changes affecting the course of depressive-like behavior and response to drugs.     

Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.     

Functional reorganization of intra‐ and internetwork connectivity in major depressive disorder after electroconvulsive therapy

Electroconvulsive therapy (ECT) is an effective and rapid treatment for major depressive disorder (MDD). However, the neurobiological underpinnings of ECT are still largely unknown. Recent studies have identified dysregulated brain networks in MDD. Therefore, we hypothesized that ECT may improve MDD symptoms through reorganizing these networks. To test this hypothesis, we used resting‐state functional connectivity to investigate changes to the intra‐ and internetwork architecture of five reproducible resting‐state networks: the default mode network (DMN), dorsal attention network (DAN), executive control network (CON), salience network (SAL), and sensory‐motor network. Twenty‐three MDD patients were assessed before and after ECT, along with 25 sex‐, age‐, and education‐matched healthy controls. At the network level, enhanced intranetwork connectivities were found in the CON in MDD patients after ECT. Furthermore, enhanced internetwork connectivities between the DMN and SAL, and between the CON and DMN, DAN, and SAL were also identified. At the nodal level, the posterior cingulate cortex had increased connections with the left posterior cerebellum, right posterior intraparietal sulcus (rpIPS), and right anterior prefrontal cortex. The rpIPS had increased connections with the medial PFC (mPFC) and left anterior cingulate cortex. The left lateral parietal had increased connections with the dorsal mPFC (dmPFC), left anterior prefrontal cortex, and right anterior cingulate cortex. The dmPFC had increased connection with the left anterolateral prefrontal cortex. Our findings indicate that enhanced interactions in intra‐ and internetworks may contribute to the ECT response in MDD patients. These findings provide novel and important insights into the neurobiological mechanisms underlying ECT.     

Disrupted reward circuits is associated with cognitive deficits and depression severity in major depressive disorder

Neuroimaging studies have demonstrated that major depressive disorder (MDD) patients show blunted activity responses to reward-related tasks. However, whether abnormal reward circuits affect cognition and depression in MDD patients remains unclear. Seventy-five drug-naive MDD patients and 42 cognitively normal (CN) subjects underwent a resting-state functional magnetic resonance imaging scan. The bilateral nucleus accumbens (NAc) were selected as seeds to construct reward circuits across all subjects. A multivariate linear regression analysis was employed to investigate the neural substrates of cognitive function and depression severity on the reward circuits in MDD patients. The common pathway underlying cognitive deficits and depression was identified with conjunction analysis. Compared with CN subjects, MDD patients showed decreased reward network connectivity that was primarily located in the prefrontal-striatal regions. Importantly, distinct and common neural pathways underlying cognition and depression were identified, implying the independent and synergistic effects of cognitive deficits and depression severity on reward circuits. This study demonstrated that disrupted topological organization within reward circuits was significantly associated with cognitive deficits and depression severity in MDD patients. These findings suggest that in addition to antidepressant treatment, normalized reward circuits should be a focus and a target for improving depression and cognitive deficits in MDD patients.     

Major depressive disorder is characterized by greater reward network activation to monetary than pleasant image rewards

Anhedonia, the loss of interest or pleasure in normally rewarding activities, is a hallmark feature of unipolar Major Depressive Disorder (MDD). A growing body of literature has identified frontostriatal dysfunction during reward anticipation and outcomes in MDD. However, no study to date has directly compared responses to different types of rewards such as pleasant images and monetary rewards in MDD. To investigate the neural responses to monetary and pleasant image rewards in MDD, a modified Monetary Incentive Delay task was used during functional magnetic resonance imaging to assess neural responses during anticipation and receipt of monetary and pleasant image rewards. Participants included nine adults with MDD and 13 affectively healthy controls. The MDD group showed lower activation than controls when anticipating monetary rewards in right orbitofrontal cortex and subcallosal cortex, and when anticipating pleasant image rewards in paracingulate and supplementary motor cortex. The MDD group had relatively greater activation in right putamen when anticipating monetary versus pleasant image rewards, relative to the control group. Results suggest reduced reward network activation in MDD when anticipating rewards, as well as relatively greater hypoactivation to pleasant image than monetary rewards.     

Weak reward source memory in depression reflects blunted activation of VTA/SN and parahippocampus

Reward responses in the medial temporal lobes and dopaminergic midbrain boost episodic memory formation in healthy adults, and weak memory for emotionally positive material in depression suggests this mechanism may be dysfunctional in major depressive disorder (MDD). To test this hypothesis, we performed a study in which unmedicated adults with MDD and healthy controls encoded drawings paired with reward or zero tokens during functional magnetic resonance imaging. In a recognition test, participants judged whether drawings were previously associated with the reward token (‘reward source’) or the zero token (‘zero source’). Unlike controls, depressed participants failed to show better memory for drawings from the reward source vs the zero source. Consistent with predictions, controls also showed a stronger encoding response to reward tokens vs zero tokens in the right parahippocampus and dopaminergic midbrain, whereas the MDD group showed the opposite pattern—stronger responses to zero vs reward tokens—in these regions. Differential activation of the dopaminergic midbrain by reward vs zero tokens was positively correlated with the reward source memory advantage in controls, but not depressed participants. These data suggest that weaker memory for positive material in depression reflects blunted encoding responses in the dopaminergic midbrain and medial temporal lobes.     

Psychosocial adjustment in young adulthood of women who experienced an eating disorder during adolescence

OBJECTIVE: To examine the impact of an adolescent eating disorder on psychosocial adjustment in young adulthood. METHOD: A randomly selected sample of high school girls was assessed on a wide array of psychosocial and diagnostic variables twice during adolescence (n = 891, n = 810), and a stratified subset (n = 539) was assessed during their 24th year. Based on their history of psychopathology before age 19, participants were categorized into (1) partial- or full-syndrome eating disorder (ED; n = 36); (2) non-comorbid major depressive disorder (MDD; n = 95); (3) non-mood disorder without ED or MDD (NMD; n = 64); and (4) no disorder (ND; n = 138). RESULTS: Discriminant function analysis identified a single significant function (variance = 57%) in which the ED group was significantly elevated (mean = 0.87, SD = 1.20) compared with the other three groups; the MDD (mean = 0.14, SD = 1.00) and NMD (mean = 0.17, SD = 0.99) group means were intermediary and differed from the ND group (mean = -0.40, SD = 0.95). CONCLUSION: Despite apparent recovery of ED symptoms among most ED cases, women with a history of adolescent ED evidenced significant impairments in health, self-image, and important areas of social functioning. These findings underscore the clinical significance of adolescent ED.     

Autoimmunity against myelin oligodendrocyte glycoprotein is dispensable for the initiation although essential for the progression of chronic encephalomyelitis in common marmosets

To elucidate the pathogenetic significance of myelin/oligodendrocyte glycoprotein (MOG)-specific autoreactivity in a genetically and immunologically heterogeneous nonhuman primate model of multiple sclerosis, we analyzed experimental autoimmune encephalomyelitis (EAE) in the outbred common marmoset (Callithrix jacchus). One sibling each of 5 bone marrow chimeric marmoset twins was immunized with myelin derived from wild-type (WT) C57BL/6 mice (WT myelin); the other sibling was immunized with myelin from MOG-deficient C57BL/6 mice (MOG -/- myelin). One twin pair developed acute EAE simultaneously; the 4 remaining twin siblings immunized with WT myelin developed chronic progressive EAE, whereas siblings of these 4 monkeys remained free of clinical disease signs. Many EAE-related abnormalities were identified in the CNS of both groups by magnetic resonance imaging and histologic analysis, but mean percentages of spinal cord demyelination were lower in monkeys immunized with MOG -/- myelin (8.2%) than in WT myelin-immunized animals (40.5%). There was a strong correlation between the development of overt clinical EAE and seropositivity for anti-MOG antibodies, but blood and lymph node T-cell proliferative responses showed no relationship to disease. These results indicate that the initiation of CNS inflammation and demyelination can take place in the absence of detectable autoimmunity against MOG, but the clinical progression and histopathologic severity depends on the presence of antibodies against MOG in this multiple sclerosis model.     

Sleep EEG,depression and gender

Despite clear evidence of an intimate connection between sleep, major depressive disorders (MDD) and gender, few studies have explored gender differences in either sleep or in wakefulness in patients as a means of better understanding the psychogenic components of MDD. Indeed, few sleep studies focus on characterising gender differences in any population. This paper will present a review of the literature on gender differences in sleep and depression. The theoretical and clinical implications of the findings will also be discussed. The premise of the present review is that there is an inherent increased vulnerability to depression in women that arises out of basic gender differences in brain organisation and state regulation, particularly in response to a "biological challenge" during sleep. It is argued that the inherent properties of organisation and regulation of sleep EEG in healthy men and women, elicited under challenge conditions, show gender-specific vulnerability to organisational abnormalities that model homeostatic abnormalities in depressed men and women and contribute to the genesis of depression. 2001 Harcourt Publishers Ltd     

Eating disorder recovery is associated with absence of major depressive disorder and substance use disorders at 22-year longitudinal follow-up

BackgroundPsychiatric comorbidity is common in eating disorders (EDs) and associated with poor outcomes, including increased risk for relapse and premature death. Yet little is known about comorbidity following ED recovery.MethodsWe examined two common comorbidities, major depressive disorder (MDD) and substance use disorder (SUD), in adult women with intake diagnoses of anorexia nervosa and bulimia nervosa who participated in a 22-year longitudinal study. One hundred and seventy-six of 228 surviving participants (77.2%) were interviewed 22 years after study entry using the Eating Disorders Longitudinal Interval Follow-up Evaluation to assess ED recovery status. Sixty-four percent (n = 113) were recovered from their ED. The Structured Clinical Interview for DSM-IV was used to assess MDD and SUD at 22 years.ResultsAt 22-year follow-up, 28% (n = 49) met criteria for MDD, and 6% (n = 11) met criteria for SUD. Those who recovered from their ED were 2.17 times more likely not to have MDD at 22-year follow-up (95% CI [1.10, 4.26], p = .023) and 5.33 times more likely not to have a SUD at 22-year follow-up than those who had not recovered from their ED (95% CI [1.36, 20.90], p = .008).ConclusionCompared to those who had not fully recovered from their ED, those who had recovered were twice as likely not to be diagnosed with MDD in the past year and five times as likely not to be diagnosed with SUDs in the past year. These findings provide evidence that long-term recovery from EDs is associated with recovery from or absence of these common major comorbidities. Because comorbidity in EDs can predict poor outcomes, including greater risk for relapse and premature death, our findings of reduced risk for psychiatric comorbidity following recovery at long-term follow-up is cause for optimism.     

Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects

Plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenethylene glycol (MHPG), and binding of tritiated yohimbine to platelet membranes were measured in 14 patients with generalized anxiety disorder (GAD), who were matched for age and sex with 14 patients with unipolar major depressive disorder (MDD) and 14 normal subjects. Plasma NE and MHPG levels were increased and the number of alpha2-adrenoreceptors (Bmax) was decreased in GAD patients compared with MDD and normal subjects. No differences were found between MDD patients and normal subjects for plasma NE, MHPG, and alpha2-adrenoreceptor binding. Plasma NE and MHPG were significantly correlated in MDD patients and tended toward a significant positive correlation in GAD patients. Plasma MHPG and affinity of binding platelet alpha2-adrenoreceptors (Kd) were significantly correlated in normal subjects. Thus, noradrenergic activity seems to be increased in patients with GAD, but not in patients with MDD. In GAD patients, higher levels of catecholamines may lead to a down-regulation of presynaptic alpha2-adrenoreceptors.     

Early-life origin of adult insomnia: does prenatal–early-life stress play a role?

Insomnia is very common in the adult population and it includes a wide spectrum of sequelae, that is, neuroendocrine and cardiovascular alterations as well as psychiatric and neurodegenerative disorders. According to the conceptualization of insomnia in the context of the 3-P model, the importance of predisposing, precipitating, and perpetuating factors has been stressed. Predisposing factors are present before insomnia is manifested and they are hypothesized to interact with precipitating factors, such as environmental stressful events, contributing to the onset of insomnia. Understanding the early-life origins of insomnia may be particularly useful in order to prevent and treat this costly phenomenon. Based on recent evidence, prenatal–early-life stress exposure results in a series of responses that involve the stress system in the child and could persist into adulthood. This may encompass an activation of the hypothalamic–pituitary–adrenal axis accompanied by long-lasting modifications in stress reactivity. Furthermore, early-life stress exposure might play an important role in predisposing to a vulnerability to hyperarousal reactions to negative life events in the adult contributing to the development of chronic insomnia. Epigenetic mechanisms may also be involved in the development of maladaptive stress responses in the newborn, ultimately predisposing to develop a variety of (psycho-) pathological states in adult life.