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ABSTRACT: Variation in the corticotropin-releasing hormone receptor (CRHR1) gene has been shown to interact with early life stress to predict adult depression. This study was conducted to determine whether CRHR1 polymorphisms interact with childhood maltreatment to predict hypothalamic-pituitary-adrenal (HPA) axis reactivity, which has been linked to both depression and early life stress.
One hundred twenty-nine White, non-Hispanic adults completed the Childhood Trauma Questionnaire and the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test, and provided blood samples for genotyping of two CRHR1 polymorphisms.
Both rs110402 and rs242924 (which were in tight linkage disequilibrium, D' = .98) showed a significant interaction with maltreatment in the prediction of cortisol response to the DEX/CRH test (p < .05). For subjects with maltreatment, the GG genotype of each single nucleotide polymorphism was associated with elevated cortisol responses to the test.
Variation in the CRHR1 moderates the effect of childhood maltreatment on cortisol responses to the DEX/CRH test. Excessive HPA axis activation could represent a mechanism of interactions of risk genes with stress in the development of mood and anxiety disorders.
Biological psychiatry 07/2009; 66(7):681-5. · 8.93 Impact Factor
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Zenab Amin,
Katarzyna Kanarek,
Evgeny Krupitsky,
Espen Walderhaug,
Risto Ilomäki,
Hilary Blumberg,
Lawrence H Price,
Zubin Bhagwagar,
Linda L Carpenter, Audrey R Tyrka,
Andres Magnusson,
Nils Inge Landrø,
Edwin Zvartau,
Joel Gelernter,
C Neill Epperson,
Pirkko Räsänen,
Jari Siironen,
Jaakko Lappalainen
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ABSTRACT: Rare apoptosis-promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co-segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re-sequencing in a large sample of northern European and European-American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76-85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European-American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2009; 153B(1):332-5. · 3.70 Impact Factor
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ABSTRACT: The dexamethasone/corticotropin releasing hormone (Dex/CRH) test has been proposed as a potential tool for identifying endophenotypes relevant to mood disorders. Several studies have shown abnormal cortisol reactivity in phenotypically healthy adults without psychiatric disorders as a function of exposure to adverse early environments.
After a battery of self-report and interview assessments, 230 adults without major Axis I Disorders completed the Dex/CRH test. Childhood maltreatment was evaluated with the Childhood Trauma Questionnaire. Effect of childhood emotional abuse (EA) on cortisol responses to the Dex/CRH test was examined with repeated measures general linear models, including age, gender, and other types of maltreatment. Post hoc models examined the significant interaction between EA and age and tested the stability of the main findings with selected covariates.
A history of self-reported childhood EA independently and significantly diminished cortisol response. This effect was amplified with advancing subject age and was independent of the effects of other types of childhood maltreatment, lifetime diagnoses, and symptom scores.
Dampened cortisol reactivity might be a consequence of childhood EA that is cumulative over time. Prospective longitudinal investigation is needed to evaluate the potential of this proposed endophenotype.
Biological psychiatry 05/2009; 66(1):69-75. · 8.93 Impact Factor
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ABSTRACT: The dexamethasone/corticotropin releasing hormone (Dex/CRH) test has been proposed as a potential tool for identifying endophenotypes relevant to mood disorders. An exaggerated cortisol response to the test during major depressive episodes has been demonstrated for inpatients with melancholic or psychotic features. A diminished hormone response has been observed in chronically depressed outpatients.
Following a battery of self-report and interview assessments, 68 adults completed the Dex/CRH test. Thirty-four met structured interview criteria for current major depressive disorder and 34 age- and sex-matched control subjects had no current or lifetime DSM-IV depressive disorder. Effect of diagnosis on cortisol response to the Dex/CRH test was examined in a repeated measures general linear model.
The matched groups were equivalent with regard to childhood adversity. Cortisol response to the Dex/CRH test among subjects with current MDD was not significantly different from that seen in matched healthy controls. Independent of diagnosis, an exploratory analysis showed a trend-level association between maltreatment history and diminished cortisol response; no interactive effects with depression diagnosis were detected.
The results do not support the hypothesis that elevated cortisol response to the Dex/CRH test represents a marker for major depressive episodes.
Psychoneuroendocrinology 05/2009; 34(8):1208-13. · 5.81 Impact Factor
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ABSTRACT: The present study examines the effects of different types of childhood maltreatment on personality disorder symptoms in a sample of adults with no Axis I psychopathology. Participants reporting a history of moderate to severe maltreatment on the Childhood Trauma Questionnaire (n = 70) were grouped by type of abuse and compared with a non-abused group (n = 35) with regard to the number of personality disorder symptoms endorsed. Physical/sexual abuse and emotional abuse/neglect each were associated with elevated symptoms of all three personality disorder clusters. Elevated symptoms of several specific personality disorders were also seen, including paranoid, borderline, avoidant, dependent, obsessive-compulsive, and depressive personality disorder. There were no significant differences between the maltreatment groups. These findings indicate that emotional abuse/neglect and physical/sexual abuse are risk factors for a broad array of personality outcomes in a non-clinical sample.
Psychiatry Research 02/2009; 165(3):281-7. · 2.52 Impact Factor
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Journal of Clinical Psychiatry - J CLIN PSYCHIAT. 01/2009; 70(7):1026-1031.
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Donald A Malone,
Darin D Dougherty,
Ali R Rezai,
Linda L Carpenter,
Gerhard M Friehs,
Emad N Eskandar,
Scott L Rauch,
Steven A Rasmussen,
Andre G Machado,
Cynthia S Kubu, Audrey R Tyrka,
Lawrence H Price,
Paul H Stypulkowski,
Jonathon E Giftakis,
Mark T Rise,
Paul F Malloy,
Stephen P Salloway,
Benjamin D Greenberg
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ABSTRACT: We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression.
Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF).
Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group.
Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.
Biological psychiatry 11/2008; 65(4):267-75. · 8.93 Impact Factor
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ABSTRACT: Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function that could predispose to the development of psychiatric disorders.
Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared with a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, parental care, gender, and age on the hormone responses to the Dex/CRH test.
Parental loss was associated with increased cortisol responses to the test, particularly in men. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. Adrenocorticotropic hormone responses to the Dex/CRH test did not differ significantly as a function of parental loss.
These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.
Biological psychiatry 07/2008; 63(12):1147-54. · 8.93 Impact Factor
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ABSTRACT: Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated-measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58)=4.86, p<.05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58)=5.28, p<.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53)=3.37, p<.05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.
Hormones and Behavior 04/2008; 53(4):518-25. · 3.87 Impact Factor
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ABSTRACT: Women are more likely than men to be diagnosed with depression and anxiety-related disorders, and it has been hypothesized that this difference is related to sex differences in stress reactivity. Women typically report higher levels of negative affect than men in response to psychosocial stressors, but the evidence for sex differences in physiological reactivity to stressful situations is not consistent. The present study sought to expand this work by evaluating sex differences in reactivity to a social stress challenge across neuroendocrine, autonomic and affective response domains. Participants (32 women, 30 men) completed a standardized psychosocial stress challenge (i.e., the Trier Social Stress Test (TSST)), during which several physiological (e.g., cortisol reactivity, heart rate) and psychological (e.g., depression, irritability, anger, fear) measures were assessed. The findings demonstrated that cortisol reactivity and the magnitude of autonomic responding failed to reliably discriminate between women and men. However, women reported more fear, irritability, confusion and less happiness immediately following the TSST compared to men. The broader implications of these results and how they relate to sex differences in the etiology and clinical presentation of anxiety and mood disorders are discussed.
Journal of Behavior Therapy and Experimental Psychiatry 04/2008; 39(1):87-98. · 1.86 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether childhood parental death and childhood parental separation are linked to lifetime depressive and anxiety disorders after controlling for related risk factors. Participants were 105 individuals from the community, including a group with separation/desertion from a parent, a group with childhood parental death, and a matched control group whose parents remained married and living together. Participants completed interviews and questionnaires assessing symptoms of anxiety and depression, family psychiatric history, childhood maltreatment, and childhood parental relationships. Participants with separation/desertion and those with parental death were significantly more likely than the control subjects to report the subsequent onset of symptoms of a depressive or anxiety disorder. These effects were not fully explained by parental relationships or childhood maltreatment. However, in the group with parental separation only, family history of depressive and anxiety disorders accounted for the apparent effect of parental separation. These findings indicate that parental death may be a specific risk factor for depressive and anxiety disorders. For parental separation/desertion, our results highlight the overriding influence of risk factors that commonly co-occur with this form of parental loss.
The International Journal of Psychiatry in Medicine 02/2008; 38(3):329-44. · 1.03 Impact Factor
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ABSTRACT: Recent preclinical and clinical research has demonstrated that the neuropeptide substance P (SP) plays a role in the central nervous system (CNS) response to stress, and perhaps in the etiology of major depression and/or anxiety disorders. The nature of this role, however, is poorly understood. A limited body of evidence suggests that in medication-free depressed patients, cerebrospinal fluid (CSF) concentrations of SP may be elevated relative to healthy controls. Two studies have shown that antidepressant treatment does not significantly change CSF concentrations of SP. Using standard lumbar puncture techniques, baseline CSF samples were obtained from 19 medication-free healthy controls and 19 medicated patients with treatment-resistant depression (TRD). Mean CSF SP concentration was significantly lower in TRD patients on psychotropic medications than in the group of healthy subjects. After 10-12 weeks of treatment with adjunct vagus nerve stimulation (VNS), CSF SP concentrations were not significantly changed. Low CSF SP may reflect a biological marker of the subtype of severe and chronic depression that is resistant to standard therapies.
Psychiatry Research 02/2008; 157(1-3):123-9. · 2.52 Impact Factor
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ABSTRACT: Studies have found that a large percentage of depressed patients may have limited response and remission rates when treated with traditional antidepressants. Options for augmenting antidepressant treatment include buspirone, lithium, and triiodothyronine. There are also increasing data concerning the use of atypical antipsychotics as augmenting agents in the treatment of unipolar, nonpsychotic, treatment-resistant depression. Aripiprazole has recently received an indication from the U.S. Food and Drug Administration (FDA) for adjunctive treatment in unipolar, nonpsychotic depression, the first indication of its kind, after two double-blind trials; doses were slightly lower than those recommended for monotherapy in schizophrenia or bipolar disorder. Olanzapine and risperidone have several controlled clinical trials indicating the efficacy of both of these agents, generally at low doses. One trial of quetiapine suggested that it may not be effective in the treatment of unipolar, nonpsychotic depression. One open-label trial of ziprasidone indicated some efficacy. According to these results, aripiprazole, olanzapine, and risperidone are reasonable choices as augmentation agents, with only aripiprazole currently having an FDA indication for this use. Given the preliminary results, double-blind, placebo-controlled trials with quetiapine and ziprasidone are needed, as well as studies comparing atypical antipsychotic agents with traditional augmentation agents in the treatment of depression.
Journal of Psychiatric Practice 02/2008; 14(1):34-44. · 2.16 Impact Factor
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ABSTRACT: The aim of this study was to examine associations between childhood adversity, parental bonding, gender, depressive symptoms, and quality of life in non-treatment-seeking adults from the community.
Effects of differential parental rearing were compared in adults who reported a high degree of childhood maltreatment (n=72) and those who reported no significant adverse events in childhood (n=69). Subjects completed retrospective measures of childhood maltreatment and perceived parenting style, as well as measures of current depressive symptoms and quality of life.
The subjects without childhood maltreatment were younger and endorsed less current depressive symptomatology than did subjects with childhood maltreatment. While the subjects without a history of maltreatment reported more "optimal" bonding experiences with their parents, the maltreatment group members were more likely to characterize their early parental bonding experiences in terms of "affectionless control" (p<.001 for both maternal and paternal parenting), "affectionate constraint" (p=.025 for maternal parenting and p=.004 for paternal parenting), or "weak or absent" bonding (p<.001 for both maternal and paternal parenting). Results of a multiple regression analysis revealed that overall quality of paternal care (p=.015) and current level of depressive symptoms (p<.001) were significant independent predictors of adult quality of life. Gender effects between subjects providing parental bonding data were limited to the group with childhood maltreatment.
These findings extend previous work documenting a relationship between early life maltreatment and suboptimal parental bonding, suggesting gender-specific effects of maternal and paternal care. Effects of childhood maltreatment on quality of life in adulthood appear to be linked with the quality of childhood paternal care and the occurrence of depressive symptomatology in adulthood, suggesting possible targets for primary or secondary prevention.
Child Abuse & Neglect 01/2008; 32(1):19-34. · 2.47 Impact Factor
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ABSTRACT: Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with major depressive disorder and posttraumatic stress disorder.
Plasma adrenocorticotropin hormone (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (n = 50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL) (n = 23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL) (n = 27).
Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group x time effect characterized the relatively blunted ACTH response of the MAL group. Emotional neglect (-.34, p = .02) and sexual abuse (.31, p = .03) strongly predicted maximal cortisol release.
In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.
Biological Psychiatry 12/2007; 62(10):1080-7. · 8.28 Impact Factor
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ABSTRACT: This study assessed personality disorder symptomatology in a community sample of healthy adults without diagnosable DSM-IV-TR Axis I psychiatric disorders who reported a history of childhood abuse. Twenty-eight subjects with a history of moderate to severe physical, sexual, and/or emotional abuse according to the Childhood Trauma Questionnaire were compared to 33 subjects without an abuse history on symptoms of personality disorders. Subjects in the Abuse group were more likely to report subclinical symptoms of paranoid, narcissistic, borderline, antisocial, obsessive compulsive, passive-aggressive, and depressive personality disorders. These findings link reports of childhood abuse with symptoms of personality disorders in the absence of Axis I psychiatric disorders in a community sample of healthy adults.
Journal of Personality Disorders 09/2007; 21(4):442-7. · 2.31 Impact Factor
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New England Journal of Medicine 09/2007; 357(6):614; author reply 615-6. · 53.30 Impact Factor
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ABSTRACT: This study examined sex differences in the use of coping strategies and their relationship to depression and anxiety-related psychopathology. Responses on measures of coping strategies, depression, and anxiety were obtained from a carefully screened nonclinical sample (N = 107). The results demonstrated that women who used less positive reframing had higher levels of depressive symptoms compared with women who used more positive reframing and to men irrespective of their use of more or less positive reframing. In addition, women who reported the use of more self-blame had elevated levels of trait anxiety, although a similar effect was not found for men. The observed sex differences in the use of coping strategies and their association with depression and anxiety-related problems underscores differences in the clinical presentation of anxiety and depression between women and men.
Depression and Anxiety 07/2007; 25(10):839-46. · 4.18 Impact Factor
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ABSTRACT: To review the new findings about stress, hypothalamic-pituitary-adrenal axis and depression trying to explain a possible endophenotype prone to depression.
Nonsystematic review of the literature based on the endophenotype hypothesis.
Depression is linked to hypercortisolemia in many patients, but not all patients present these hypothalamic-pituitary-adrenal axis dysfunction. The dexamethasone suppression test is not the most accurate test to measure the hypothalamic-pituitary-adrenal axis function, and its use in the first studies published probably jeopardized the results. Hypercortisolemia frequently occurs in patients with severe depression, melancholic, either psychotic or nonpsychotic type; it is linked to the presence of a polymorphism in the promoter of the serotonin transporter gene, with a history of childhood abuse or neglect, or other significant stressful experiences like the loss of a parent during childhood and temperament leading to alterations in the response to stress.
The alterations of the hypothalamic-pituitary-adrenal axis depend on many factors like severity and type of depression, genotype, history of exposure to stress, temperament, and probably resilience. All these factors together result in an endophenotype thought to be prone to depression.
Revista Brasileira de Psiquiatria 06/2007; 29 Suppl 1:S13-8. · 1.20 Impact Factor
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ABSTRACT: Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults.
Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ).
Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment.
These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.
Psychoneuroendocrinology 11/2006; 31(9):1036-45. · 5.81 Impact Factor
