Rationale and design of a randomized factorial clinical trial of pharmacogenetic and adherence optimization strategies to promote tobacco cessation among persons with HIV.

BACKGROUND: Tobacco use is approximately three times more common in people living with HIV (PLWH) than the general population. Moreover, current behavioral and pharmacological smoking cessation interventions are less effective for PLWH, highlighting a need for novel ways to optimize tobacco cessation treatments in this group. Prior research indicates that personalized treatment based on the nicotine metabolite ratio (NMR), a biomarker of nicotine metabolism, and augmenting smoking cessation medication adherence may improve cessation treatment for PLWH. METHODS: In this 2 × 2 factorial design trial, 488 smokers with HIV receive 12 weeks of smoking cessation medication along with randomization to 1) tailor the smoking cessation drug to their metabolism or not, and 2) provide additional counseling on smoking cessation medication adherence or not. Those randomized to the pharmacogenetic optimization arm receive varenicline or the nicotine patch based on their NMR (varenicline for fast metabolizers and the nicotine patch for slow metabolizers) and those in the control arm receive varenicline. Those randomized to the experimental adherence counseling arm receive Managed Problem Solving (MAPS) targeting their smoking cessation medication and those in the control arm receive standard counseling. CONCLUSION: PLWH on suppressive antiretroviral therapy who smoke lose more life-years due to tobacco use than to their HIV infection, and have lower response rates to current evidence-based treatments for smoking cessation. Both the NMR tailoring and MAPS interventions have the potential to optimize treatments for tobacco use among this population. If effective, this trial may demonstrate ways to further improve long-term health outcomes for PLWH.

Comparing the effectiveness of home visiting paraprofessionals and mental health professionals delivering a postpartum depression preventive intervention: a cluster-randomized non-inferiority clinical trial.

To determine whether pregnant women receiving the Mothers and Babies group-based intervention exhibited greater depressive symptom reductions and fewer new cases of major depression than women receiving usual community-based services, and to examine whether groups run by paraprofessional home visitors and mental health professionals yielded similar depressive symptom reductions and prevention of major depression. Using a cluster-randomized design, 37 home visiting programs were randomized to usual home visiting, Mothers and Babies delivered via home visiting paraprofessionals, or Mothers and Babies delivered via mental health professionals. Baseline assessments were conducted prenatally with follow-up extending to 24 weeks postpartum. Eligibility criteria were ≥ 16 years old, ≤ 33 gestation upon referral, and Spanish/English speaking. Depressive symptoms at 24 weeks postpartum was the primary outcome. Eight hundred seventy-four women were enrolled. Neither intervention arm was superior to usual care in decreasing depressive symptoms across the sample (p = 0.401 home visiting paraprofessional vs. control; p = 0.430 mental health professional vs. control). Post hoc analyses suggest a positive intervention effect for women exhibiting mild depressive symptoms at baseline. We have evidence of non-inferiority, as the model-estimated mean difference in depressive symptoms between intervention arms (0.01 points, 95% CI: -0.79, 0.78) did not surpass our pre-specified margin of non-inferiority of two points. Although we did not find statistically significant differences between intervention and control arms, non-inferiority analyses found paraprofessional home visitors generated similar reductions in depressive symptoms as mental health professionals. Additionally, Mothers and Babies appears to reduce depressive symptoms among women with mild depressive symptoms when delivered by mental health professionals. This trial is registered on ClinicalTrials.gov (initial post: December 1, 2016; identifier: NCT02979444).

Comparing Fidelity Outcomes of Paraprofessional and Professional Delivery of a Perinatal Depression Preventive Intervention.

Mothers and Babies (MB), a perinatal depression preventive intervention, has proven effective in decreasing depressive symptoms and preventing onset of major depression. An ongoing cluster-randomized trial is comparing the effectiveness of the six-session MB group intervention led by paraprofessionals versus mental health professionals. Twenty percent of all audio-recorded intervention sessions were randomly selected for fidelity checks. Analyses assessed mean facilitator adherence and competency overall, by study arm, and by session; and, examined site, facilitator, and client-specific effects. There were no significant differences found between study arms. Findings show paraprofessionals can deliver MB with similar fidelity as mental health professionals.

Four maternal characteristics determine the 12-month course of chronic severe postpartum depressive symptoms.

BACKGROUND: Postpartum depression is a heterogeneous disorder in phenotype and etiology. Characterizing the longitudinal course of depressive symptoms over the first year after birth and identifying variables that predict distinct symptom trajectories will expedite efficient mental health treatment planning. The purpose was to determine 12-month trajectories of postpartum depressive symptoms, identify characteristics that predict the trajectories, and provide a computational algorithm that predicts trajectory membership. METHODS: A prospective cohort of women delivering at an academic medical center (2006-2011) was recruited from an urban women's hospital in Pittsburgh, PA. Women with a postpartum depressive disorder (n = 507) participated and completed symptom severity assessments at 4-8 weeks (intake), 3 months, 6 months, and 12 months. Women were predominantly Caucasian (71.8%), married (53.3%), and college educated (38.7%). Clinician interviews of depressive symptom severity, medical and psychiatric history, assessment of function, obstetric experience, and infant status were conducted. RESULTS: Analyses resulted in identification of three distinct trajectories of depressive symptoms: (1) gradual remission (50.4%), (2) partial improvement (41.8%), and (3) chronic severe (7.8%). Key predictive characteristics of the chronic severe versus gradual remission and partial improvement trajectories included parity, education, and baseline global functioning and depression severity. We were able to predict trajectory membership with 72.8% accuracy from these characteristics. CONCLUSIONS: Four maternal characteristics predicted membership in the chronic severe versus gradual remission and partial improvement trajectories with 72.8% accuracy. The trajectory groups comprise clinically relevant subgroups with the potential for tailored treatments to reduce the disease burden of postpartum depression.

Generating an efficient version of the Edinburgh Postnatal Depression Scale in an urban obstetrical population.

BACKGROUND: Postpartum depression incurs significant burden and suffering. METHODS: We investigated the latent structure of the most commonly used screening measure, the Edinburgh Postnatal Depression Scale (EPDS) in women (N=15,172) and tested its predictive validity for the diagnosis of depression as determined with a structured clinical interview. Exploratory and confirmatory factor analyses, Receiver Operating Characteristic curves, and logistic regression analyses were conducted. RESULTS: A seven-item one factor scale (items 1, 2, 6, 7, 8, 9, 10) emerged with a Goodness of Index Fit Index (GFI) =.96, relative to the ten-item two factor version of the EPDS (GFI =.94). The seven-item EPDS achieved good sensitivity and specificity in predicting the 10-item EPDS, with a cut point score of 4 on the seven item EPDS to predict a 10-item EPDS score of 10 or more (sensitivity =95%, specificity =91%). The seven and 10-item EPDS showed a similar ability to predict a diagnoses of depression (area under the ROC curve=.795 for the 10-item, .770 for the seven-item EPDS). Logistic regression analyses showed similar predictive ability between the seven- and 10-item scales in predicting scores higher than 18 on the clinical interview LIMITATIONS: The sample represents women from one Midwest medical center and the EPDS was measured via phone. CONCLUSION: The seven-item one factor version of the EPDS is an efficient and effective measure of depression severity on par with the two factor 10-item version of the EPDS.

Twice the negativity bias and half the positivity offset: Evaluative responses to emotional information in depression.

BACKGROUND AND OBJECTIVES: Humans have the dual capacity to assign a slightly pleasant valence to neutral stimuli (the positivity offset) to encourage approach behaviors, as well as to assign a higher negative valence to unpleasant images relative to the positive valence to equally arousing and extreme pleasant images (the negativity bias) to facilitate defensive strategies. We conducted an experimental psychopathology study to examine the extent to which the negativity bias and the positivity offset differ in participants with and without major depression.. METHOD: Forty-one depressed and thirty-six healthy participants were evaluated using a structured clinical interview for DSM-IV Axis I disorders, questionnaires, and a computerized task designed to measure implicit affective responses to unpleasant, neutral, and pleasant stimuli. RESULTS: The negativity bias was significantly higher and the positivity offset was significantly lower in depressed relative to healthy participants.. LIMITATIONS: Entry criteria enrolling medication-free participants with minimal DSM-IV comorbidity may limit generalizability of the findings. CONCLUSIONS: This study advances our understanding of the positive and negative valence systems in depression, highlighting the irregularities in the positive valence system..

The negativity bias predicts response rate to Behavioral Activation for depression.

BACKGROUND AND OBJECTIVES: This treatment study investigated the extent to which asymmetric dimensions of affective responding, specifically the positivity offset and the negativity bias, at pretreatment altered the rate of response to Behavioral Activation treatment for depression. METHOD: Forty-one depressed participants were enrolled into 16 weekly sessions of BA. An additional 36 lifetime healthy participants were evaluated prospectively for 16 weeks to compare affective responding between healthy and remitted patients at post-treatment. All participants were assessed at Weeks 0, 8 and 16 using repeated measures, involving a structured clinical interview for DSM-IV Axis I disorders, questionnaires, and a computerized task designed to measure affective responses to unpleasant, neutral, and pleasant images. RESULTS: The negativity bias at pre-treatment predicted the rate of response to BA, while the positivity offset did not. LIMITATIONS: Only one treatment condition was used in this study and untreated depressed participants were not enrolled, limiting our ability to compare the effect of BA. CONCLUSIONS: Baseline negativity bias may serve as a signal for patients to engage in and benefit from the goal-directed BA strategies, thereby accelerating rate of response.

Differences in the neural correlates of affective responses in depressed and healthy women.

We aimed to characterize the extent to which there were differences in neural activation between female participants who were diagnosed with or without depression while viewing negative and neutral imagery. The study enrolled 105 medication-free, right-handed female participants between 17 and 63 years who met criteria for current Major Depressive Disorder (n=47) or no prior psychiatric diagnoses (n=58). All participants completed a clinical assessment and underwent a functional Magnetic Resonance Imaging (fMRI) scan while responding to an implicit affect task that required them to identify the location of ideographs embedded in one of four corners of each valenced image. When unpleasant (termed negative) stimuli were presented, depressed relative to healthy participants showed significantly decreased activation of the left amygdala and right Inferior Parietal Lobe (IPL). When activation was assessed during the negative versus neutral condition, depressed relative to healthy participants showed significantly increased activation in the Anterior Cingulate Cortex (ACC) and the left IPL. Notably, within-group analyses of healthy participants under the negative condition showed that depressive severity was positively correlated with activation in the left amygdala and left IPL. Our findings suggest that depression influences bottom-up and top-down processing of unpleasant information.

Reduced striatal activation in females with major depression during the processing of affective stimuli.

The extent to which affective reactivity and associated neural underpinnings are altered by depression remains equivocal. This study assessed striatal activation in fifty-one unmedicated female participants meeting DSM-IV criteria for Major Depressive Disorder (MDD) and 61 age-matched healthy females (HC) aged 17-63 years. Participants completed an affective reactivity functional magnetic resonance imaging task. Data were preprocessed using SPM8, and region-of-interest analyses were completed using MarsBaR to extract caudate, putamen, and nucleus accumbens (NAcc) activation. General linear repeated measure ANOVAs were used to assess group differences and correlational analyses were used to measure the association between activation, depression severity, and anhedonia. Main effects of hemisphere, valence, and group status were observed, with MDD participants demonstrating decreased striatal activation compared with HC. Across groups and valence types, the left hemisphere demonstrated greater activation than the right hemisphere in the putamen and nucleus accumbens, whereas the right hemisphere demonstrated greater activation than the left in the caudate. Additionally, unpleasant stimuli elicited greater activation than pleasant and neutral stimuli in the caudate and putamen, and unpleasant stimuli elicited greater activation than neutral stimuli in the NAcc. There were no significant associations between activation, depression severity, and anhedonia. Overall, depression was characterized by reduced affective reactivity in the striatum, regardless of stimuli valence, supporting the emotion context insensitivity model of depression.

Neural substrates of negativity bias in women with and without major depression.

BACKGROUND: The functional localization of negativity bias, an influential index of emotion information processing, has yet to be identified. METHOD: Depressed (n=47) and healthy participants (n=58) completed a clinical interview for DSM-IV Axis I disorders, symptom checklists, a behavioral task to measure negativity bias, and then viewed positive and negative images of social and nonsocial scenes during an event-related fMRI task. Two subsamples of participants with high (i.e., 75%; n=26) and low (i.e., 25%; n=26) negativity bias scores were as included in subsequent analyses to examine neural differences. RESULTS: Depressed participants with a higher, relative to lower, negative bias showed significantly greater neural activation in the left inferior frontal gyrus. CONCLUSION: High negativity bias evokes a distinctive pattern of brain activation in the frontal cortex of depressed participants. Increased activation occurred in the left inferior frontal gyrus, related to Brodmann area 44, which is associated with language and semantic processing, response inhibition, and cognitive reappraisal. This finding may reflect an abnormality in integrative emotional processing rather than processing of individual emotional dimensions in depressed participants with negativity bias.

Affective reactivity differences in pregnant and postpartum women.

Reactions to emotional cues, termed affective reactivity, promote adaptation and survival. Shifts in affective reactivity during pregnancy and postpartum may invoke altered responses to environmental and biological changes. The development and testing of affective reactivity tasks, with published normative ratings for use in studies of affective reactivity, has been based on responses provided by healthy college students. A comparison of the healthy norms with ratings provided by peripartum women has yet to be conducted, despite its value in highlighting critical differences in affective reactivity during peripartum phases. This study compared arousal ratings of unpleasant, neutral, pleasant, and threat stimuli from the International Affective Picture System (IAPS; Lang, P.J., Bradley, M.M., Cuthbert, B.N. 2008. International Affective Picture System (IAPS): Affective Ratings of Pictures and Instruction Manual (Technical Report A-8). University of Florida, Gainseville, FL.) between three samples: (a) women measured during pregnancy and again at postpartum, (b) age-matched nonpregnant women, and (c) college-aged women from the normative sample used to test the stimuli. Using mixed-design GLMs, results showed that the pregnant and postpartum women and the age-matched women showed suppressed arousal relative to the college-age women. Additionally, postpartum women showed increased arousal to unpleasant/threat images compared to other types of images. The data suggest that future research on peripartum women should include affective reactivity tasks based on norms reflective of this specific population.

Resting-state functional connectivity in women with Major Depressive Disorder.

OBJECTIVE: Limited research has focused on whole-brain functional connectivity in a well-characterized sample of subjects with current Major Depressive Disorder (MDD). We aimed to investigate resting-state functional connectivity and the extent to which this is correlated with depression severity in unmedicated depressed subjects without comorbidities. METHODS: We utilized Independent Component Analysis (ICA) to investigate whole-brain functional connectivity in a sample of healthy controls (n = 26) and unmedicated subjects diagnosed only with current MDD (n = 20). Correlations were calculated between network connectivity strength and depression severity. RESULTS: Depressed subjects demonstrated significantly decreased connectivity in the right frontoparietal (p = 0.03), left frontoparietal (p = 0.01), and language (p = 0.02) networks compared to healthy control subjects. CONCLUSION: We found abnormal resting-state functional connectivity not previously reported in MDD. Decreased connectivity in the frontoparietal and language networks may represent depression-related difficulties in attention, cognitive control, goal-directed cognition, and language. Findings from this study may further elucidate functional connectivity as a diagnostic marker of depression severity.

The negativity bias: conceptualization, quantification, and individual differences.

There is an extensive literature on the negativity bias, including its conceptualization, measurement, temporal stability (individual differences), and neural and genetic associations. Hibbing et al. posit that the difference across individuals in the negativity bias is a key factor in determining political predisposition. The measures and paradigms developed in this literature provide a means of testing this hypothesis.

Empathy, depressive symptoms, and social functioning among individuals with schizophrenia.

Empathy deficits have been associated with schizophrenia and depression. We compared whether individuals with schizophrenia with and without co-occurring depressive symptoms differed on self-reported and performance-based measures of empathy and social functioning. We also examined the relationships among depressive symptoms, empathy, clinical symptoms, and social functioning. Twenty-eight individuals with schizophrenia and depressive symptoms, 32 individuals with schizophrenia without depressive symptoms, and 44 control subjects were compared on assessments of depressive symptoms, empathy, global neurocognition, clinical symptoms, and social functioning. Both groups of individuals with schizophrenia scored higher than controls on the Interpersonal Reactivity Index personal distress subscale. Individuals with schizophrenia and co-occurring depressive symptoms scored significantly higher than individuals with schizophrenia without depressive symptoms on the personal distress subscale. Personal distress and depressive symptoms were significantly correlated among individuals with schizophrenia and co-occurring depressive symptoms, while both measures negatively correlated with social functioning. Emotional empathy was related to clinical symptoms in both groups of individuals with schizophrenia. Personal distress partially mediated the relationship between co-occurring depressive symptoms and social functioning. Personal distress may be an important implication for social functioning among individuals with schizophrenia and co-occurring depressive symptoms, and should be examined further as a potential treatment target.

Frontal alpha EEG asymmetry before and after behavioral activation treatment for depression.

BACKGROUND: Mid-frontal and mid-lateral (F3/F4 and F7/F8) EEG asymmetry has been associated with motivation and affect. We examined alpha EEG asymmetry in depressed and healthy participants before and after Behavioral Activation treatment for depression; examined the association between alpha EEG asymmetry and motivational systems and affect; and evaluated the utility of alpha EEG asymmetry in predicting remission. METHODS: Depressed (n=37) and healthy participants (n=35) were assessed before and after treatment using a clinical interview, a task to measure baseline EEG, and questionnaires of behavioral activation and inhibition, avoidance, and affect. RESULTS: Alpha EEG asymmetry was significantly higher in depressed than healthy participants at pre-treatment, positively correlated with negative affect and behavioral inhibition, and inversely correlated with lower behavioral activation sensitivity. CONCLUSIONS: Heightened alpha EEG asymmetry in depressed participants was significantly associated with increased behavioral inhibition and negative emotion and was independent of clinical remission.

Spatial affect learning restricted in major depression relative to anxiety disorders and healthy controls.

Detecting and learning the location of unpleasant or pleasant scenarios, or spatial affect learning, is an essential skill that safeguards well-being (Crawford & Cacioppo, 2002). Potentially altered by psychiatric illness, this skill has yet to be measured in adults with and without major depressive disorder (MDD) and anxiety disorders (AD). This study enrolled 199 adults diagnosed with MDD and AD (n=53), MDD (n=47), AD (n=54), and no disorders (n=45). Measures included clinical interviews, self-reports, and a validated spatial affect task using affective pictures (IAPS; Lang, Bradley, & Cuthbert, 2005). Participants with MDD showed impaired spatial affect learning of negative stimuli and irrelevant learning of pleasant pictures compared with non-depressed adults. Adults with MDD may use a "GOOD is UP" heuristic reflected by their impaired learning of the opposite correlation (i.e., "BAD is UP") and performance in the pleasant version of the task.

Affective information processing in pregnancy and postpartum with and without major depression.

Adults with clinical depression exhibit systematic errors in their recognition and interpretation of affective stimuli. This study investigated the extent to which depression and phases of pregnancy and postpartum influence affective processing of positive and negative information, and the extent to which affective information processing in pregnancy predicts depressive symptoms in postpartum. Data were collected from 80 unmedicated women, diagnosed with major depressive disorder (MDD) or with no psychiatric disorder and between ages 18 and 44 years, during 32-36 weeks of pregnancy and during 6-8 weeks postpartum. All completed a Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) Axis I review, symptom reports, and a computer task measuring affective information processing. Significant group differences were found in which postpartum women with major depression were less responsive to negative stimuli, with lower ratings of intensity and reactions to negative pictorial stimuli, compared with postpartum healthy women. Also, lower ratings of the intensity and reactions to negative stimuli during pregnancy among depressed women predicted postpartum depression severity, even after controlling for depressive severity and affect ratings in pregnancy. Blunted affective reactivity to negative stimuli is a characteristic of depression that was observed among depressed women during pregnancy and postpartum in our study.

Exploring sudden gains in behavioral activation therapy for Major Depressive Disorder.

Understanding the onset and course of sudden gains in treatment provides clinical information to the patient and clinician, and encourages clinicians to strive for these sudden clinical gains with their patients. This study characterizes the occurrence of sudden gains with Behavioral Activation (BA; Martell, Addis, & Jacobson, 2001), and the extent to which pre-treatment dysfunctional depressive thinking predicts sudden gains during treatment. We enrolled a sample of adults (n = 42) between ages 18-65 diagnosed with primary Major Depressive Disorder. All participants completed a 16-week course of BA, with clinical and self-report assessments at pre-, mid- and post-treatment. Results indicated that sudden gain and non-sudden gain participants showed differential improvement across treatment. No significant effects emerged for the dysfunctional cognitive style as a predictor of sudden gain status. Sudden gains may result from interaction of non-specific factors with the BA techniques implemented during early phases of therapy.

Pilot study of Internet-based early intervention for combat-related mental distress.

This article evaluates an Internet-based early intervention combining online cognitive-behavioral therapy (CBT) with electronic peer-to-peer support intended to promote mental health and well-being among combat veterans. We conducted a phase 1 clinical trial of 50 Iraq and Afghanistan veterans using a pre and post single-arm design. We evaluated feasibility and changes in mental health symptoms (depression and posttraumatic stress disorder [PTSD]), functional status, and attitudes toward treatment seeking at baseline and weeks 4, 8, and 12. A diverse group of veterans was enrolled (26% ethnic minority, 90% male, 66% with income <$30,000/year, 88% with no prior treatment for depression). Participants completed a mean of 4 of 6 lessons (standard deviation = 2.54). From baseline to week 12, there were significant declines in the Center for Epidemiologic Studies-Depression scale score (effect size [ES] = 0.41) and PTSD Checklist-Military version score (ES = 0.53). There were significant improvements in willingness to accept diagnosis (ES = 1.08) and perceived social norms and stigma regarding friends (ES = 1.51). Although lack of a control group is a limitation, the Internet-based program combining CBT-based coping skills training and peer-to-peer support demonstrated potential feasibility and evidenced benefit in symptom remediation for depression and PTSD.