D. Jeffrey Newport

The link between childhood trauma and depression: insights from HPA axis studies in humans.

Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge. However, not all of depression is related to childhood trauma and our results suggest the existence of biologically distinguishable subtypes of depression as a function of childhood trauma that are also responsive to differential treatment. Other risk factors, such as female gender and genetic dispositions, interfere with components of the stress response and further increase vulnerability for depression. Similar associations apply to a spectrum of other psychiatric and medical disorders that frequently coincide with depression and are aggravated by stress. Taken together, this line of evidence demonstrates that psychoneuroendocrine research may ultimately promote optimized clinical care and help prevent the adverse outcomes of childhood trauma.

Influence of child abuse on adult depression: Moderation by the corticotropin-releasing hormone receptor gene

CONTEXT Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression. OBJECTIVE To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene. DESIGN Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms. SETTING General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia. PARTICIPANTS The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished). MAIN OUTCOME MEASURES Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders. RESULTS Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199). CONCLUSIONS These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Neurobiology of posttraumatic stress disorder

Exposure to a traumatic event is required for the diagnosis of posttraumatic stress disorder (PTSD). The symptoms of PTSD are believed to reflect stress-induced changes in neurobiological systems and/or an inadequate adaptation of neurobiological systems to exposure to severe stressors. More recently, there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD, such as altered mechanisms of learning and extinction, sensitization to stress, and arousal. Furthermore, there have been efforts to understand whether certain neurobiological changes in PTSD reflect preexisting vulnerability factors rather than consequences of trauma exposure or correlates of PTSD. Genetic variability, sex differences, and developmental exposures to stress influence neurobiological systems and moderate PTSD risk. On the basis of these findings, important hypotheses for developing novel strategies to identify subjects at risk, promote resilience, and devise targets for the prevention or treatment of PTSD can be derived.

Maternal depression and infant cortisol: influences of timing, comorbidity and treatment

BACKGROUND The current study examines the relationship between maternal depression and infant cortisol concentrations. The potential roles of comorbid maternal anxiety disorders, timing of maternal depression, and maternal treatment with psychotropic medications during pregnancy are addressed. METHODS Women with 6-month-old infants (105 boys and 84 girls) participated in a laboratory paradigm that included infant saliva collection at six points, noise burst and arm restraint stressor tasks, and a diagnostic interview of the mother. RESULTS Lifetime history of maternal depression was associated with increased baseline and mean (average) infant cortisol levels. Comorbidity with anxiety disorder was related to infant cortisol reactivity. Peripartum (prepartum and/or postpartum) maternal depression, rather than a pre-pregnancy history of disorder, was associated with higher infant cortisol reactivity. Prenatal and postnatal exposure to maternal disorder had similar effects, but prenatal maternal psychotropic medication treatment appeared to attenuate infant cortisol increases associated with prenatal maternal disorder exposure. CONCLUSIONS These data suggest that exposure to maternal depression and anxiety during pregnancy and the postpartum period may increase infant salivary cortisol. This maternal depression-infant cortisol association is independent of the effects of delivery complications, and appears to be modulated by prenatal maternal psychotropic treatment.

Assessment and treatment of depression in the cancer patient

The prevalence, diagnosis, and treatment of depression in the cancer patient are reviewed. Although frequently encountered in the cancer patient population, depression often remains undiagnosed and untreated. This carries grave consequences in that depressed cancer patients experience a poorer quality of life, are less compliant with medical care, have longer hospital stays, and have higher mortality rates. Diagnostic assessment of depression in the cancer patient raises difficulties both upon phenomenological and etiological grounds. In particular, the presence of neurovegetative symptoms which may be secondary to either cancer or depression may cloud the diagnostic picture. Due to the serious consequences of unrecognized depression, a more sensitive inclusive approach to diagnosis is recommended in the clinical setting. Finally, the limited data regarding treatment of depression in patients with cancer is reviewed. This includes a discussion of both psychosocial and pharmacological interventions which are shown to alleviate depression, improve quality of life measures, improve immune function, and lengthen survival time.

Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse

BACKGROUND Previous studies indicate that adverse childhood events are associated with persistent changes in corticotropin-releasing factor neuronal systems. Our aim was to determine whether altered glucocorticoid feedback mediates the neuroendocrine sequelae of childhood trauma. METHODS Standard and low-dose dexamethasone suppression tests (DST) were performed in women with a history of child abuse (n=19), child abuse and major depression (n=16), major depression and no childhood trauma (n=10), and no history of mental illness or childhood trauma (n=19). Secondary analysis with posttraumatic stress disorder (PTSD) as the organizing diagnosis was also conducted. RESULTS In the low-dose DST, depressed women with a history of abuse exhibited greater cortisol suppression than any comparator group and greater corticotropin suppression than healthy volunteers or nondepressed abuse survivors. There were no differences between nondepressed abuse survivors and healthy volunteers in the low-dose DST or between any subject groups in the standard DST. The PTSD analysis produced similar results. CONCLUSIONS Cortisol supersuppression is evident in psychiatrically ill trauma survivors, but not in nondepressed abuse survivors, indicating that enhanced glucocorticoid feedback is not an invariable consequence of childhood trauma but is more related to the resultant psychiatric illness in traumatized individuals.

The Neural Correlates of Social Anxiety Disorder and Response to Pharmacotherapy

This study attempted to define further the neural processing events underlying social anxiety in patients with social anxiety disorder (SAD) and their response to pharmacotherapy. Social anxiety-related changes in regional cerebral blood flow were defined by [15O]H2 positron emission tomography (PET) in medication-free individuals with generalized SAD (gSAD), and age- and sex-matched comparison subjects, and analyzed using a linear mixed effects model. PET studies were again acquired in the gSAD individuals following an 8-week, flexible dose treatment trial of nefazodone. Both script-guided mental imagery of an anxiogenic social situation and a confrontational mental arithmetic task were associated with marked increases in self-rated anxiety in both subject groups. For gSAD subjects, social anxiety induced by guided mental imagery was associated with increased activity in the left postcentral gyrus and lenticulate, and the right inferior frontal and middle temporal gyri. Social anxiety induced by the mental arithmetic task was associated with activation of the medial and left dorsolateral prefrontal cortex, cerebellum, thalamus, insula, and ventral striatum. Both tasks were associated with relative decreases in activity in the right amygdala and the hippocampus. A direct group comparison indicated that comparison subjects exhibited a differing pattern of social anxiety-related neural activations. Nefazodone treatment was associated with marked clinical improvement. Comparison of social anxiety-related neural activations prior to and after nefazodone administration indicated greater activity in the precentral gyrus, insula, midbrain/hypothalamus, and middle frontal and anterior cingulate gyrus prior to treatment, and greater activity in the left middle occipital and bilateral lingual gyri, postcentral gyrus, gyrus rectus, and hippocampus after treatment. The results of an analysis relating neural activity and treatment-related changes in symptom severity indicated differential neural responses associated with states of symptom remission vs partial response. The observed social anxiety-related changes in distributed neural activity are consistent with cognitive models of SAD and adaptive decreases in amygdala activity in response to social anxiogenics, and support the association of altered frontal cortical responses with treatment response.

The impact of maternal childhood abuse on maternal and infant HPA axis function in the postpartum period

BACKGROUND Early life trauma, particularly child abuse, has been associated with aberrations in hypothalamic-pituitary-adrenal (HPA) axis functioning in adulthood. However, the relationship of early abuse and later adult neuroendocrine changes may be moderated by additional factors such as comorbid psychopathology and recent life stress. Parental exposure to child abuse may have transgenerational effects, with offspring of abuse victims showing similar neuroendocrine profiles as their mothers. The majority of previous studies in this area focus on adult offspring, and the degree to which the effects of parental child abuse can be detected earlier in the development of the offspring remains obscure. METHODS The current study utilized a clinical sample of women with a history of MDD (N=126), to examine the effects of maternal early life sexual and physical abuse (Childhood Trauma Questionnaire (CTQ)) on both maternal and infant salivary cortisol levels during a laboratory stress paradigm at 6 months postpartum. RESULTS Maternal child abuse was associated with steeper declines in cortisol in the mothers and lower baseline cortisol in their infants. Comorbid maternal PTSD, current maternal depressive symptoms, and recent life stressors were significant moderators of maternal cortisol change. Maternal abuse history was associated with increases in cortisol levels in those mothers who experienced these additional stressors. Similarly, a history of early maternal abuse and comorbid PTSD was associated with greater increases in infant cortisol levels. CONCLUSIONS Maternal childhood abuse was associated with HPA axis function in both the mother and the infant during the postpartum period.

Validity of depression rating scales during pregnancy and the postpartum period: Impact of trimester and parity

The objective of the current study was to delineate the optimal cutpoints for depression rating scales during pregnancy and the postpartum period and to assess the perinatal factors influencing these scores. Women participating in prospective investigations of maternal mental illness were enrolled prior to 28 weeks gestation and followed through 6 months postpartum. At each visit, subjects completed self-rated depression scales--Edinburgh Postnatal Depression Scale (EPDS) and Beck Depression Inventory (BDI) and clinician-rated scales--Hamilton Rating Scale for Depression (HRSD(17) and HRSD(21)). These scores were compared to the SCID Mood Module for the presence of fulfilling diagnostic criteria for a major depressive episode (MDE) during 6 perinatal windows: preconception; first trimester; 2nd trimester; 3rd trimester; early postpartum; and later postpartum. Optimal cutpoints were determined by maximizing the sum of each scales sensitivity and specificity. Stratified ROC analyses determined the impact of previous pregnancy and comparison of initial to follow-up visits. A total of 534 women encompassing 640 pregnancies and 4025 follow-up visits were included. ROC analysis demonstrated that all 4 scales were highly predictive of MDE. The AUCs ranged from 0.857 to 0.971 and were all highly significant (p < .0001). Optimal cutpoints were higher at initial visits and for multigravidas and demonstrated more variability for the self-rated scales. These data indicate that both clinician-rated and self-rated scales can be effective tools in identifying perinatal episodes of major depression. However, the results also suggest that prior childbirth experiences and the use of scales longitudinally across the perinatal period influence optimal cutpoints.

Lamotrigine in Breast Milk and Nursing Infants: Determination of Exposure

OBJECTIVE. Although lamotrigine use during pregnancy has substantially increased over the past decade secondary to accumulated reproductive safety data, systematic data on lamotrigine during breastfeeding remains sparse. We sought to characterize the determinants of lamotrigine concentrations in breast milk and nursing-infant plasma. PATIENTS AND METHODS. Women who enrolled in a prospective investigation of perinatal medication pharmacokinetics, were treated with lamotrigine, and chose to continue lamotrigine while breastfeeding were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient and serial samples over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Lamotrigine concentrations in all of the samples were determined by using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. RESULTS. Thirty women and their nursing infants participated in the study, providing a total of 210 breast milk samples. The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants. CONCLUSIONS. Consistent with previous investigations of medications in breast milk, the lamotrigine milk/plasma ratio is highly variable. The rate of lamotrigine excretion into human breast milk is similar to that observed with other antiepileptic drugs. These data expand the extant literature on lamotrigine in breastfeeding and demonstrate relatively comparable nursing-infant exposure to lamotrigine compared with other antiepileptic drugs.