[Show abstract][Hide abstract] ABSTRACT: Background
Each year 5,000–6,000 individuals receive orthotopic liver transplant (OLT) in the United States, and of these, nearly 18% have alcoholic liver disease (ALD). Relapse to alcohol occurs in over 40% of patients with OLT for ALD.
We sought to: identify factors that predict relapse to alcohol or medication non-adherence post-OLT in patients with ALD, and review what randomized clinical interventions have addressed these factors post-OLT. Our hypothesis was that there would be factors before and after OLT that predict relapse to alcohol post-OLT, and that these, if targeted, might improve sobriety and associated outcomes of adherence with medications and appointments.
We performed a review (focused on articles published since 2004) with PubMed and MEDLINE searches using the following search terms: liver transplantation, recidivism, alcohol relapse and predictors of alcohol relapse. We supplemented the online searches with manual reviews of article reference lists and selected relevant articles for further review by author consensus.
In largely Caucasian populations, prospective studies document that shorter length of pretransplant sobriety is a significant predictor of time to first drink and to binge use. Presence of psychiatric co-morbidity, high score on standardized high-risk alcohol relapse scale, and diagnosis of DSM-IV alcohol dependence are predictive of post-transplantation alcohol relapse. Pre-transplant alcohol use history variables (e.g., positive family history of alcoholism) reliably discriminate between complete abstainers and those who drink, while medical and psychosocial characteristics early post-liver transplant (e.g., more bodily pain) maximally discriminate patterns of alcohol use. Alcoholic individuals with early onset, rapidly accelerating, moderate use and early onset, continuously increasing heavy use have over double the prevalence of steatohepatitis or rejection on biopsy and graft failure, and more frequent mortality resulting from recurrent alcoholic liver disease as compared to late onset (i.e., peak of heaviest drinking at 6 years post-transplantation) alcohol users. Fortunately, pre-transplant screening combined with a structured pre-transplant management program and 12-step program attendance reduced recidivism. No randomized clinical trials (RCTs) have been performed that target pre-transplant risk factors in individuals with ALD before, or after, OLT to improve post-OLT outcomes.
Recent research findings suggest that screening can reveal individuals vulnerable to alcohol relapse, and targeted intervention can prevent their relapse to alcohol. Based on existing addiction treatments (e.g., relapse prevention plan construction), RCTs tailored to the post-OLT patient should be conducted to improve survival and quality of life in these patients.
[Show abstract][Hide abstract] ABSTRACT: Background
Effective depression treatment does not reliably reduce glycosylated hemoglobin (HbA1c) in depressed patients with type 2 diabetes, possibly in part due to deficits in functional capacity, i.e. performance of certain everyday living skills, essential for effective diabetes self-management. We sought to determine: a) the magnitude of deficits in functional capacity among urban, African American (AA) patients with type 2 diabetes, and b) whether these deficits were associated with poorer glycemic control.
At their initial visit to an inner-city diabetes clinic, 172 AA patients with type 2 diabetes were assessed with a variety of instruments, including the Mini International Neuropsychiatric Interview (MINI) and the UCSD Performance Skills Assessment-Brief (UPSA-B). They then entered a comprehensive diabetes management intervention, whose success was indexed by HbA1c levels at up to four reassessments over a one-year period. A mixed-effects model repeated-measures method was used to predict HbA1c.
The prevalence of depression was 19%; the mean UPSA-B score was 81 +/- 17. After multivariate adjustment, increased HbA1c levels over time were predicted by the presence of major depression (B = .911, p = .002) and decreasing (worse) scores on the UPSA-B (B = -.016, p=.027), respectively. Further adjustment for increasing the dosage of oral or insulin during the treatment eliminated the association between the UPSA score and HbA1c level (B = -.010, p =.115).
Depression, as well as deficits in functional capacity, predicted reduced effectiveness of a diabetes self-management intervention. Future studies will determine whether interventions targeted at both improve glycemic control.
No preview · Article · May 2014 · Journal of Psychiatric Research
[Show abstract][Hide abstract] ABSTRACT: Abstract The prevalence of depressive symptoms in patients with cancer exceeds that observed in the general population and depression is associated with a poorer prognosis in cancer patients. The increased prevalence is not solely explained by the psychosocial stress associated with the diagnosis. Pro-inflammatory cytokines, which induce sickness behaviour with symptoms overlapping those of clinical depression, are validated biomarkers of increased inflammation in patients with cancer. A growing literature reveals that chronic inflammatory processes associated with stress may also underlie depression symptoms in general, and in patients with cancer in particular. Therapeutic modalities, which are frequently poorly tolerated, are used in the treatment of cancer. These interventions are associated with inflammatory reactions, which may help to explain their toxicity. There is evidence that antidepressants can effectively treat symptoms of depression in cancer patients though the database is meager. Novel agents with anti-inflammatory properties may be effective alternatives for patients with treatment-resistant depression who exhibit evidence of increased inflammation.
Full-text · Article · Feb 2014 · International Review of Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Context: Major depressive disorder (MDD) can be challenging to diagnose in patients with congestive heart failure, who often suffer from fatigue, insomnia, weight changes, and other neurovegetative symptoms that overlap with those of depression. Pathophysiologic mechanisms (eg, inflammation, autonomic nervous system dysfunction, cardiac arrhythmias, and altered platelet function) connect depression and congestive heart failure. Objective: We sought to review the prevalence, diagnosis, neurobiology, and treatment of depression associated with congestive heart failure. Data Sources: A search of all English-language articles between January 2003 and January 2013 was conducted using the search terms congestive heart failure and depression. Study Selection: We found 1,498 article abstracts and 19 articles (meta-analyses, systematic reviews, and original research articles) that were selected for inclusion, as they contained information about our focus on diagnosis, treatment, and pathophysiology of depression associated with congestive heart failure. The search was augmented with manual review of reference lists of articles from the initial search. Articles selected for review were determined by author consensus. Data Extraction: The prevalence, diagnosis, neurobiology, and treatment of depression associated with congestive heart failure were reviewed. Particular attention was paid to the safety, efficacy, and tolerability of antidepressant medications commonly used to treat depression and how their side-effect profiles impact the pathophysiology of congestive heart failure. Drug-drug interactions between antidepressant medications and medications used to treat congestive heart failure were examined. Results: MDD is highly prevalent in patients with congestive heart failure. Moreover, the prevalence and severity of depression correlate with the degree of cardiac dysfunction and development of congestive heart failure. Depression increases the risk of congestive heart failure, particularly in those patients with coronary artery disease , and is associated with a poorer quality of life, increased use of health care resources, more frequent adverse clinical events and hospitalizations, and twice the risk of mortality. Conclusions: At present, limited empirical data exist with regard to treatment of depression in the increasingly large population of patients with congestive heart failure. Evidence reveals that both psychotherapeutic treatment (eg, cognitive-behavioral therapy) and pharmacologic treatment (eg, use of the selective serotonin reuptake inhibitor sertraline) are safe and effective in reducing depression severity in patients with cardiovascular disease. Collaborative care programs featuring interventions that work to improve adherence to medical and psychiatric treatments improve both cardiovascular disease and depression outcomes. Depression rating scales such as the 9-item Patient Health Questionnaire should be used to monitor therapeutic efficacy.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To evaluate whether veterans with posttraumatic stress disorder (PTSD) or depression have differences in dry eye symptoms and signs compared to a population without these conditions.
Male patients aged ≥50 years with normal eyelid, conjunctival, and corneal anatomy were recruited from the Miami Veterans Affairs Eye Clinic (N = 248). We compared dry eye symptoms (determined by the Dry Eye Questionnaire 5 [DEQ5] score) to tear film indicators obtained by clinical examination (i.e., tear osmolarity, corneal staining, tear breakup time, Schirmer's, meibomian gland quality, orifice plugging, lid vascularity) between patients with PTSD or depression and those without these conditions. Student's t-tests, χ(2) analyses, and linear and logistic regressions were used to assess differences between the groups.
DEQ5 scores were higher in the PTSD (mean = 13.4; standard error [SE] = 1.1; n = 22) and depression (mean = 12.0; SE = 0.8; n = 40) groups compared to the group without these conditions (mean = 9.8; SE = 0.4; n = 186; P < 0.01 and P = 0.02, respectively). More patients in the PTSD and depression groups had severe dry eye symptoms, defined as a DEQ5 score ≥ 12 (77% and 63% vs. 41%; P < 0.01 and P = 0.02, respectively). No significant differences in tear film indicators were found among the three groups. Multivariable logistic regression indicated that a PTSD diagnosis (odds ratio [OR] = 4.08; 95% confidence interval [CI] = 1.10-15.14) and use of selective serotonin reuptake inhibitors (OR = 2.66; 95% CI = 1.01-7.00) were significantly associated with severe symptoms.
Patients with PTSD have ocular surface symptoms that are not solely explained by tear indicators. Identifying underlying conditions associated with ocular discomfort is essential to better understand the mechanisms behind ocular pain in dry eye syndrome.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, two weeks prior to, and during IL-2 treatment [720 000 units/kg q8 hrs X 5 days (1 cycle) every 3 weeks X 4 cycles]. Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms [Hamilton Depression Rating Scale (HDRS) score]. Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both groups [ESC (n=9), placebo (n=11)] exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Though ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, i.e., a maximal difference of ~3 points on the HDRS, which, though not statistically significant (in part due to small sample size), represents a clinically significant difference according to National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2- induced neurobehavioral changes.Neuropsychopharmacology accepted article preview online, 10 April 2013; doi:10.1038/npp.2013.85.
No preview · Article · Apr 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Decreased treatment adherence in patients with diabetes mellitus type 1 (type 1 DM) may reflect impairments in decision-making and underlying associated deficits in working memory and executive functioning. Other factors, including comorbid major depression, may also interfere with decision-making. The authors sought to review the clinically relevant characteristics of decision-making in type 1 DM by surveying the literature on decision-making by patients with type 1 DM. Deficiencies in decision-making in patients with type 1 DM or their caregivers contribute to treatment nonadherence and poorer metabolic control. Animal models of type 1 DM reveal deficits in hippocampal-dependent memory tasks, which are reversible with insulin. Neurocognitive studies of patients with type 1 DM reveal lowered performance on ability to apply knowledge to solve problems in a new situation and acquired scholarly knowledge, psychomotor efficiency, cognitive flexibility, visual perception, speed of information-processing, and sustained attention. Other factors that might contribute to poor decision-making in patients with type 1 DM, include "hypoglycemia unawareness" and comorbid major depression (given its increased prevalence in type 1 DM). Future studies utilizing novel treatment strategies to help patients with type 1 DM make better decisions about their disease may improve their glycemic control and quality of life, while minimizing the impact of end-organ disease.
Full-text · Article · Mar 2013 · The Journal of Neuropsychiatry and Clinical Neurosciences
[Show abstract][Hide abstract] ABSTRACT: Background:
Depression is common in patients with HIV/AIDS, and can have an impact on quality of life, as well as various health outcomes. This study was designed to observe the efficacy of standard treatment of depression in human immunodeficiency virus (HIV) (+) individuals in an urban psychiatric clinic.
This study consisted of a retrospective chart review of patients presenting for psychiatric services between January 1, 2008 and December 31, 2010. A total of 211 charts were examined for factors including diagnosis given at initial visit, health status, sociodemographic factors and comorbid illnesses, as well as treatment plan prescribed; of these, 132 patients were determined to be depressed at the initial evaluation (Beck Depression Inventory (BDI> 13) and to return for at least one follow-up visit.
Of the 132 depressed patients, 48 (36.4%) reached remission (BDI <13) at some point at follow-up, and an additional 12 (50.7%) achieved response (decrease in BDI of 50%). Remission correlated with having disability income and having a viral load that was not detectable.
Depression is common in HIV/AIDS, and is important to treat. Furthermore, individuals with depression and HIV/AIDS respond at rates similar to what is seen in other depressed populations.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Dry eye syndrome (DES) is a worldwide public health problem that negatively affects one's ability to work and function. It is the leading cause of visits to eye clinics, and DES medications account for approximately $1.9 billion annually in the US.
Methods: Male patients aged 50+ were recruited from the Miami VA eye clinic and received examination of tear film parameters (N=250) and completed a Dry Eye Questionnaire (DEQ5). PTSD and Depression ICD-9 codes and prescription medications were obtained from medical records. The main outcome measures were self-reported dry eye symptoms and clinical signs of DES; scores were compared across those with PTSD (n=22), depression (n=40), and a group with neither diagnosis (n=186). T-test, Chi-square, and logistic regression analyses were used to compare groups.
Results: The PTSD and depression groups had significantly higher self-reported dry eye symptoms compared to those without these diagnoses, but there were no significant differences in tear film parameters among groups. Logistic regression comparing those with severe self-reported dry eye symptoms versus those with less severe or no symptoms found antidepressant use (OR=2.34; 95% CI=1.15-4.78) and PTSD (OR=3.69; CI=1.18-11.53) to be significant predictors after controlling for demographic and health-related variables. There was a non-significant trend for those with depression to have higher symptoms (OR=1.99; CI=0.89-4.48).
Discussion: PTSD and antidepressant medications are associated with more severe self-reported dry eye symptoms. Evaluation of ocular health in veterans with PTSD or depression is warranted, particularly considering the potential impact of DES symptoms on physical and mental well-being.
[Show abstract][Hide abstract] ABSTRACT: Objective. As few, small studies have examined the impact of electroconvulsive therapy (ECT) upon the heart rate variability of patients with major depressive disorder (MDD), we sought to confirm whether ECT-associated improvement in depressive symptoms would be associated with increases in HRV linear and nonlinear parameters.
Methods. After providing consent, depressed study participants (n = 21) completed the Beck Depression Index (BDI), and 15-minute Holter monitor recordings, prior to their 1st and 6th ECT treatments. Holter recordings were analyzed for certain HRV indices: root mean square of successive differences (RMSSD), low-frequency component (LF)/high-frequency component (HF) and short-(SD1) versus long-term (SD2) HRV ratios.
Results. There were no significant differences in the HRV indices of RMSDD, LF/HF, and SD1/SD2 between the patients who responded, and those who did not, to ECT.
Conclusion. In the short term, there appear to be no significant improvement in HRV in ECT-treated patients whose depressive symptoms respond versus those who do not. Future studies will reveal whether diminished depressive symptoms with ECT are reliably associated with improved sympathetic/parasympathetic balance over the long-term, and whether acute changes in sympathetic/parasympathetic balance predict improved mental- and cardiac-related outcomes.
Full-text · Article · Aug 2012 · Cardiovascular Psychiatry and Neurology
[Show abstract][Hide abstract] ABSTRACT: In patients at high risk for recurrence of malignant melanoma, interferon-α (IFN-α), a stimulator of innate immunity, appears to induce distinct neurobehavioral symptom dimensions: a mood and anxiety syndrome, and a neurovegetative syndrome, of which the former is responsive to prophylactic administration of paroxetine. We sought to determine whether symptom dimensions (and treatment responsiveness) arise in patients with hepatitis C administered IFN-α and ribavirin. In a randomized, double-blind, 6-month study, 61 patients with hepatitis C eligible for therapy with IFN-α and ribavirin received the antidepressant paroxetine (n=28) or a placebo (n=33). Study medication began 2 weeks before IFN-α/ribavirin therapy. Neuropsychiatric assessments included the 10-item Montgomery-Asberg Depression Rating Scale (MADRS). The items of the MADRS were grouped into depression, anxiety, cognitive dysfunction, and neurovegetative symptom dimensions, and analyzed using a mixed model. By 2 weeks of IFN-α/ribavirin therapy, all four dimensions increased, with the symptom dimensions of anxiety and cognitive dysfunction fluctuating and worsening, respectively, in both groups over time. The depression symptom dimension was significantly lower in the paroxetine treatment group (p=0.04); severity of the neurovegetative symptom dimension was similar in both groups. Similar to patients with malignant melanoma receiving high-dose IFN-α, the depression symptom dimension is more responsive to paroxetine treatment in individuals undergoing concomitant IFN-α/ribavirin therapy. However, the anxiety, cognitive dysfunction, and neurovegetative symptom dimensions appear less responsive to prophylactic paroxetine administration. Different neurobiologic pathways may contribute to the responsiveness of IFN-α-induced symptom dimensions to antidepressant treatment, requiring relevant psychopharmacologic strategies.
Full-text · Article · Feb 2012 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Diabetes is a highly prevalent, chronic disease that requires ongoing, multi-specialty medical care combined with patient self-management, family support, and education to prevent or delay end-organ morbidity and mortality. There is clearly an increased prevalence of major depressive disorder, a relatively common and costly central nervous system syndrome, in diabetic patients. During the past two decades, multiple studies reveal that not only are depressive symptoms a risk factor for the development of type 2 diabetes, but they have also been shown to contribute to hyperglycemia, diabetic complications, functional disability and all-cause mortality among diabetic patients. This article reviews studies examining the relationship between depression and diabetes, neurochemical underpinnings of the two disorders, and the diagnosis and treatment of depression associated with diabetes. We examine the validity of rating scales used to diagnose depression in diabetic patients and review the literature on psychotherapeutic and psychopharmacologic management for these patients. The challenges of optimal depression screening and treatment in primary care settings of diabetic patients are currently under close scrutiny, especially regarding their potential impact related to improvements in diabetes-related outcomes and decreased health care costs, be it "depression" or "diabetes" relevant. Much of the current literature regarding the intertwined nature of diabetes and depression is cross-sectional in nature. Future research should focus on longitudinal, prospective studies to determine causal factors. What is clear from the research reviewed in this article is that depression and diabetes should be treated together rather than as isolated diseases. The mind/body dualism is a false dichotomy and a truly team-based approach is necessary to address both issues of depression and diabetes. Collaborative care and the "patient-centered medical home" have emerged as potentially effective interventions to improve quality of care and patient outcomes in patients with depression and medical illnesses such as diabetes.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: In order to improve the delivery of health services for chronic medical conditions in our methadone clinic, we added an onsite health screening and brief health counseling to the treatment plans for patients receiving methadone maintenance treatment at the Atlanta Veterans Affairs Medical Center (VAMC). We then conducted a follow up retrospective chart review to assess whether this intervention improved health outcome for those patients. METHODS: We reviewed the charts of one hundred and two patients who received treatment at Atlanta VAMC methadone clinic between 2002 and 2008. We sought to determine whether our increased health education and screening intervention was associated with improved: 1) Improved drug addiction outcome (as measured by comparing percentage of opiate and cocaine positive drug screens from admission to most recent). 2) Basic health screening, (as measured by the patient's compliance with primary care physicians (PCP) appointments and current smoking status). 3) Management of co-occurring medical conditions (as measured by levels of LDL cholesterol, hemoglobin A1c, and systolic blood pressure (SBP). 4) Presence of QTc prolongation (difference in QTc between baseline and most recent EKG). RESULTS: Illicit drug use (opiate and cocaine) markedly decreased in patients overall. The effect was more robust for those successfully "retained" (n=55, p<0.0001) in treatment, compared to those who "dropped out" (n=40, p=0.05) of treatment. Compliance with PCP appointments was high (82% and 88% before and after the onsite intervention, respectively) for "retained" patients. LDL cholesterol level was within normal range for all patients. A1c improved by 40% after the onsite intervention as reflected by the decreased percentage of patients with A1c > 7 % from before to after the intervention (90% vs. 50%, p=0.05). However, the prevalence of uncontrolled hypertension did not significantly improve after the onsite intervention (38% vs. 28%, p=0.34). As might be expected with MMT, the prevalence of QTc prolongation actually increased from 399 m sec. (+/- 92) to 439 msec. (+/- 22) after the onsite intervention (p=0.003). CONCLUSIONS: Our retrospective study supports the previous literature that methadone maintenance therapy is effective in reducing illicit drug use. Although patients with history of heroin dependence and in methadone maintenance treatment are at increased risk for chronic medical conditions like hepatitis C and diabetes, there are minimal federal guidelines for medical care, except than a physical exam upon admission, and basic screening for some infectious diseases e.g. HIV and Hepatitis C for those patients. Our study demonstrated the need for and potential benefit of enhancing the delivery of health promotion services for chronic medical conditions in methadone maintained patients. Improving management of hepatitis C, diabetes, hypertension, and other related conditions, in this high risk, difficult-to-treat, and underserved population may reduce their morbidity and premature mortality.
Full-text · Article · Sep 2010 · Journal of Addiction Medicine
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to compare the effectiveness of a combined 12-week home-based exercise (EX)/cognitive behavioral therapy (CBT) program (n=18) with CBT alone (n=19), EX alone (n=20), and with usual care (UC, n=17) in stable New York Heart Association Class II to III heart failure (HF) patients diagnosed with depression.
Depressive symptom severity [Hamilton Rating Scale for Depression (HAM-D)], physical function [6-min walk test (6MWT)], and health-related quality of life (HRQOL) (Minnesota Living with Heart Failure Questionnaire) were evaluated at baseline (T1), after the 12-week intervention/control (T2), and following a 3-month telephone follow-up (T3). A repeated measures analysis of variance was used to determine group differences. Depression severity was dichotomized as minor (HAM-D, 11-14) and moderate-to-major depression (HAM-D, >/=15), and group intervention and control responses were also evaluated on that basis.
The greatest reduction in HAM-D scores over time occurred in the EX/CBT group (-10.4) followed by CBT (-9.6), EX (-7.3), and UC (-6.2), but none were statistically significant. The combined group showed a significant increase in 6-min walk distance at 24 weeks (F=13.5, P<.001). Among all groups with moderate-to-major depression, only those in CBT/EX had sustained lower HAM-D scores at 12 and 24 weeks, 6MWT distances were significantly greater at 12 (P=.018) and 24 (P=.013) weeks, and the greatest improvement in HRQOL also occurred.
Interventions designed to improve both physical and psychological symptoms may provide the best method for optimizing functioning and enhancing HRQOL in patients with HF.
No preview · Article · Aug 2010 · Journal of psychosomatic research
[Show abstract][Hide abstract] ABSTRACT: Depression is associated with increased morbidity and mortality in patients with coronary heart disease (CHD). Increased platelet activation has been proposed as a potential mechanism by which depression may lead to adverse cardiovascular outcomes. In this cross-sectional study, we measured platelet activation in 104 patients with stable CHD, including 58 with a current episode of major depression and 46 without past or current major depression. Participants were instructed not to take aspirin for 7 days prior to the study appointment. Platelet activation was measured by plasma concentrations of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG), and by 24-h urinary concentrations of 11-dehydro-thromboxane B(2) (TBXB2). We observed no differences in the mean levels of PF4, B-TG or TBXB2 in patients with and without major depression. Results were unchanged after adjustment for age, smoking, use of aspirin, and use of any psychotropic medication. We found no evidence of an association between major depression and platelet activation as measured by plasma concentrations of PF4 and beta-TG, or urinary TBXB2 in 104 outpatients with stable CHD. These findings do not support a role for platelet activation in the association between depression and cardiovascular disease among patients with stable CHD.
Full-text · Article · Feb 2010 · Psychiatry Research
[Show abstract][Hide abstract] ABSTRACT: Variations of the corticotropin-releasing hormone receptor 1 (CRHR1) gene appear to moderate the development of depression after childhood trauma. Depression more frequently affects women than men. We examined sex differences in the effects of the CRHR1 gene on the relationship between childhood trauma and adult depression. We recruited 1,063 subjects from the waiting rooms of a public urban hospital. Childhood trauma exposure and symptoms of depression were assessed using dimensional rating scales. Subjects were genotyped for rs110402 within the CRHR1 gene. An independent sample of 78 subjects underwent clinical assessment, genotyping, and a dexamethasone/CRH test. The age range at recruitment was 18-77 years and 18-45, for the two studies respectively. In the hospital sample, the protective effect of the rs110402 A-allele against developing depression after childhood trauma was observed in men (N = 424), but not in women (N = 635). In the second sample, the rs110402 A-allele was associated with decreased cortisol response in the dexamethasone/CRH test only in men. In A-allele carriers with childhood trauma exposure women exhibited increased cortisol response compared men; there were no sex differences in A-allele carriers without trauma exposure. This effect may, however, not be related to gender differences per se, but to differences in the type of experienced abuse between men and women. CRHR x environment interactions in the hospital sample were observed with exposure to physical, but not sexual or emotional abuse. Physical abuse was the most common type of abuse in men in this cohort, while sexual abuse was most commonly suffered by women. Our results suggest that the CRHR1 gene may only moderate the effects of specific types of childhood trauma on depression. Gender differences in environmental exposures could thus be reflected in sex-specific CRHR1 x child abuse interactions.
Full-text · Article · Nov 2009 · Frontiers in Behavioral Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine.
Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy.
Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together.
We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha.
Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival.
This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.