Antidepressant medication exposure and 5-HT1A autoreceptor binding in major depressive disorder.

OBJECTIVE: We have previously reported higher brain serotonin 1A (5-HT1A ) autoreceptor binding in antidepressant-naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5-HT1A receptor binding after medication discontinuation. METHODS: Positron emission tomography (PET) imaging with the 5-HT1A receptor radioligand [11 C]WAY-100635 was performed in 66 individuals with current DSM-IV MDD to examine relationships between 5-HT1A binding and time since most recent antidepressant treatment. All subjects were medication-free for at least 2 weeks prior to scanning. Thirty-two additional MDD comparison subjects were antidepressant naïve. RESULTS: No differences in [11 C]WAY-100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [11 C]WAY-100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. CONCLUSION: These results indicate that any antidepressant-associated downregulation of 5-HT1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness-related binding levels.

Primary cesarean section and adverse delivery outcomes among women of very advanced maternal age.

OBJECTIVE: To assess associations between primary cesarean delivery and adverse delivery outcomes with very advanced maternal age. STUDY DESIGN: We conducted a population-based cohort study including 78,880 births to mothers 25 years and older with singleton births from 2003 to 2012 using Washington State birth certificates and hospital discharge data, excluding births to women with a prior cesarean section. The primary outcome was mode of delivery. Secondary outcomes included maternal transfusion, chorioamnionitis, severe perineal lacerations and prolonged length of stay. Outcomes of births to women of advanced maternal age (35 to 39, 40 to 44) and very advanced maternal age (45 to 49, ⩾50) were compared with referent births among women aged 25 to 34 years. General linear models with a log-link function were used to calculate unadjusted and adjusted relative risks and 95% confidence intervals (CIs). RESULT: Proportions and risks of primary cesarean section increased with age (25 to 34 years, referent: 20.0%; 35 to 39 years: 25.9%, relative risk (RR)=1.25 (95% CI=1.20 to 1.29); 40 to 44 years: 30.9%, RR=1.45 (95% CI=1.40 to 1.50); 45 to 49 years: 35.7%, RR=1.59 (95% CI=1.45 to 1.75); and ⩾50 years: 60.7%, RR=2.44 (95% CI=1.95 to 3.05); P-trend <0.001). Associations did not differ between primiparous and multiparous women. No differences were noted for measures of maternal morbidity, except there was a trend of increasing risk of prolonged length of stay among births to older women (P-trend <0.001). CONCLUSION: Primary cesarean delivery risk continues to increase above age 35 regardless of prior vaginal birth, with the highest risk among women aged 50 years and older.

Neuropsychological deficits in past suicide attempters with varying levels of depression severity.

BACKGROUND: Our previous work identified deficits in interference processing and learning/memory in past suicide attempters who were currently depressed and medication-free. In this study, we extend this work to an independent sample studied at various stages of illness and treatment (mild symptoms, on average) to determine if these deficits in past suicide attempters are evident during a less severe clinical state. METHOD: A total of 80 individuals with a past history of major depression and suicide attempt were compared with 81 individuals with a history of major depression and no lifetime suicide attempts on a battery of neurocognitive measures assessing attention, memory, abstract/contingent learning, working memory, language fluency and impulse control. RESULTS: Past attempters performed more poorly in attention, memory and working memory domains, but also in an estimate of pre-morbid intelligence. After correction for this estimate, tests that had previously distinguished past attempters - a computerized Stroop task and the Buschke Selective Reminding Test - remained significantly worse in attempters. In a secondary analysis, similar differences were found among those with the lowest levels of depression (Hamilton Depression Rating Scale score <10), suggesting that these deficits may be trait markers independent of current symptomatology. CONCLUSIONS: Deficits in interference processing and learning/memory constitute an enduring defect in information processing that may contribute to poor adaptation, other higher-order cognitive impairments and risk for suicidal behavior.

Life events: a complex role in the timing of suicidal behavior among depressed patients.

Suicidal behavior is often conceptualized as a response to overwhelming stress. Our model posits that given a propensity for acting on suicidal urges, stressors such as life events or major depressive episodes (MDEs) determine the timing of suicidal acts. Depressed patients (n=415) were assessed prospectively for suicide attempts and suicide, life events and MDE over 2 years. Longitudinal data were divided into 1-month intervals characterized by MDE (yes/no), suicidal behavior (yes/no) and life event scores. Marginal logistic regression models were fit, with suicidal behavior as the response variable and MDE and life event score in either the same or previous month, respectively, as time-varying covariates. Among 7843 person-months, 33% had MDE and 73% had life events. MDE increased the risk for suicidal behavior (odds ratio (OR)=4.83, P⩽0.0001). Life event scores were unrelated to the timing of suicidal behavior (OR=1.06 per 100 point increase, P=0.32), even during a MDE (OR=1.12, P=0.15). However, among those without borderline personality disorder (BPD), both health- and work-related life events were key precipitants, as was recurrent MDE, with a 13-fold effect. The relationship of life events to suicidal behavior among those with BPD was more complex. Recurrent MDE was a robust precipitant for suicidal behavior, regardless of BPD comorbidity. The specific nature of life events is key to understanding the timing of suicidal behavior. Given unanticipated results regarding the role of BPD and study limitations, these findings require replication. Of note, that MDE, a treatable risk factor, strongly predicts suicidal behaviors is cause for hope.

Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.

BACKGROUND: Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. METHOD: Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n = 72) were compared to medication-free depressed subjects with no history of suicidal behavior (n = 80) and healthy volunteers (n = 56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS: All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS: Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se.

Clinical features of depressed patients with or without a family history of alcoholism.

OBJECTIVE: To compare clinical features of depressed subjects without alcoholism but with a family history of alcoholism to a depressed group without alcoholism and without a family history of alcoholism. METHOD: Clinical and demographic data of 209 depressed subjects without a history of alcoholism in first-degree relatives and 73 depressed individuals with a history of alcoholism in first-degree relatives were compared. Subjects with a personal history of alcoholism were excluded. RESULTS: Depressed subjects with a family history of alcoholism have a significantly higher prevalence of reported childhood physical and sexual abuse and post-traumatic stress disorder (PTSD), make more suicide attempts, and have greater intent to die at the time of their most lethal suicide attempt, compared to depressed subjects without a family history of alcoholism. CONCLUSION: Depressed patients with a family history of alcoholism are at greater risk for suicidal behavior and PTSD and may require more careful management.

Proteoglycans in granulomatous lung diseases.

In nongranulomatous fibrotic lung conditions, we have recently shown that early collagen synthesis by myofibroblasts occurs in an extracellular matrix rich in the proteoglycan versican. We hypothesized that versican is associated with the process of collagen synthesis resulting from chronic inflammation. In this study, we examined the localization of proteoglycans and collagen in the granulomatous lung conditions, sarcoidosis, extrinsic allergic alveolitis (EAA) and tuberculosis (TB). Tissue from individuals with sarcoidosis (n=6), EAA (n=4) and TB (n=2) was examined for glycosaminoglycans and collagen using histochemistry, and for versican, decorin, biglycan, hyaluronan, type I procollagen and alpha-smooth muscle actin using immunohistochemistry. The results showed that in sarcoidosis, EAA and TB, the rim of connective tissue surrounding granulomas contained glycosaminoglycans and collagen, and that glycosaminoglycan staining corresponded to localization of versican. Versican-rich zones contained myofibroblasts that stained intracellularly for type I procollagen. Hyaluronan was found diffusely throughout the matrix. Decorin was localized intracellularly in the epithelioid cells of granulomas and some myofibroblasts. We conclude that the deposition of versican is specific to the early remodelling process in both granulomatous and nongranulomatous lung diseases. In both forms of lung fibrosis, regardless of the nature of the driving inflammatory process, collagen synthesis takes place in a versican-rich provisional matrix. These results suggest that versican may influence the progression of the repair process following many different types of lung injury.

Proteoglycan deposition in pulmonary fibrosis.

This study compares the deposition of proteoglycans in the extracellular matrix of the lung lesions of the adult respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) to those present in idiopathic pulmonary fibrosis (IPF). Tissue from individuals with ARDS (n = 7), BOOP (n = 5), IPF (n = 5), and control subjects (n = 5) was examined for glycosaminoglycans and collagen by histochemistry, and for hyaluronan, versican, decorin, biglycan, Types I and III collagen, type I procollagen and alpha-smooth muscle actin (alpha-SMA) using immunohistochemistry. The results showed that glycosaminoglycan deposition in the lesions of ARDS, BOOP, and IPF corresponded to the deposition of versican. Versican localized to the thickened interstitium in the fibroproliferative phase of ARDS, to the intraluminal buds in BOOP, and to early fibroblast foci in IPF. The versican-rich areas contained little mature collagen, but the myofibroblasts in these areas stained for type I procollagen, suggesting early collagen synthesis, and stained intracellularly for decorin. The localization of versican in ARDS, BOOP, and IPF suggests that this proteoglycan may influence early repair processes in the lung.