A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder

Background: Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD).Methods: Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment.Results The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group.Conclusions: These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD.

Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment

This paper introduces a simple futility design that allows a comparative clinical trial to be stopped due to lack of effect at any of a series of planned interim analyses. Stopping due to apparent benefit is not permitted. The design is for use when any positive claim should be based on the maximum sample size, for example to allow subgroup analyses or the evaluation of safety or secondary efficacy responses. A final frequentist analysis can be performed that is valid for the type of design employed. Here the design is described and its properties are presented. Its advantages and disadvantages relative to the use of stochastic curtailment are discussed. Copyright (C) 2003 John Wiley Sons, Ltd.

Threat interpretation in anxious children and their mothers: comparison with nonclinical children and the effects of treatment

Interpretation biases towards threat play a prominent role in cognitive theories of anxiety, and have been identified amongst highly anxious adults and children. Little is known, however, about the development of these cognitive biases although family processes have been implicated. The current study investigated the nature of threat interpretation of anxious children and their mothers through (i) comparison of a clinic and non-clinic population, (ii) analysis of individual differences; and (ill) pre- and post-treatment comparisons. Participants were 27 children with a primary anxiety disorder and 33 children from a non-clinic population and their mothers. Children and mothers completed self-report measures of anxiety and indicated their most likely interpretation of ambiguous scenarios. Clinic and non-clinical groups differed significantly on measures of threat interpretation. Furthermore, mothers' and children's threat interpretation correlated significantly. Following treatment for child anxiety, both children and their mothers reported a reduction in threat interpretation. (c) 2005 Elsevier Ltd. All rights reserved.

Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response

OBJECTIVE: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response. METHOD: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine. RESULTS: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms. CONCLUSIONS: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.

Likelihood estimate of treatment effects under selection bias

We consider methods for estimating causal effects of treatment in the situation where the individuals in the treatment and the control group are self selected, i.e., the selection mechanism is not randomized. In this case, simple comparison of treated and control outcomes will not generally yield valid estimates of casual effects. The propensity score method is frequently used for the evaluation of treatment effect. However, this method is based onsome strong assumptions, which are not directly testable. In this paper, we present an alternative modeling approachto draw causal inference by using share random-effect model and the computational algorithm to draw likelihood based inference with such a model. With small numerical studies and a real data analysis, we show that our approach gives not only more efficient estimates but it is also less sensitive to model misspecifications, which we consider, than the existing methods.

Comparison of treatment of incomplete abortion with misoprostol by physicians and midwives at district level in Uganda : a randomised controlled equivalence trial

BACKGROUND: Misoprostol is established for the treatment of incomplete abortion but has not been systematically assessed when provided by midwives at district level in a low-resource setting. We investigated the effectiveness and safety of midwives diagnosing and treating incomplete abortion with misoprostol, compared with physicians. METHODS: We did a multicentre randomised controlled equivalence trial at district level at six facilities in Uganda. Eligibility criteria were women with signs of incomplete abortion. We randomly allocated women with first-trimester incomplete abortion to clinical assessment and treatment with misoprostol either by a physician or a midwife. The randomisation (1:1) was done in blocks of 12 and was stratified for study site. Primary outcome was complete abortion not needing surgical intervention within 14-28 days after initial treatment. The study was not masked. Analysis of the primary outcome was done on the per-protocol population with a generalised linear-mixed effects model. The predefined equivalence range was -4% to 4%. The trial was registered at ClinicalTrials.gov, number NCT01844024. FINDINGS: From April 30, 2013, to July 21, 2014, 1108 women were assessed for eligibility. 1010 women were randomly assigned to each group (506 to midwife group and 504 to physician group). 955 women (472 in the midwife group and 483 in the physician group) were included in the per-protocol analysis. 452 (95·8%) of women in the midwife group had complete abortion and 467 (96·7%) in the physician group. The model-based risk difference for midwife versus physician group was -0·8% (95% CI -2·9 to 1·4), falling within the predefined equivalence range (-4% to 4%). The overall proportion of women with incomplete abortion was 3·8% (36/955), similarly distributed between the two groups (4·2% [20/472] in the midwife group, 3·3% [16/483] in the physician group). No serious adverse events were recorded. INTERPRETATION: Diagnosis and treatment of incomplete abortion with misoprostol by midwives is equally safe and effective as when provided by physicians, in a low-resource setting. Scaling up midwives' involvement in treatment of incomplete abortion with misoprostol at district level would increase access to safe post-abortion care. FUNDING: The Swedish Research Council, Karolinska Institutet, and Dalarna University.

Effectiveness of treatment programmes for depression among adults with mild/moderate intellectual disability

Background The current study describes the development and evaluation of group treatment programme for people with mild/moderate intellectual disability (ID).
Methods A total of 34 participants (16 males, 18 females) completed the treatment programme and 15 participants (six males, nine females) comprised a control group.
Results Compared to the control group, the intervention group showed an improvement in levels of depression, positive feelings about the self, and lower levels of automatic negative thoughts after the intervention. These changes were maintained at 3-month follow-up.
Conclusions These results demonstrate that intervention programmes are effective for the treatment of depression among people with ID.

Children with persistent conduct problems who dropout of treatment

Dropout of treatment is one of the key issues in outcome in a child and adolescent mental health service. We report two studies focusing on the treatment process and the dropout rate of children with persistent conduct problems presenting to a community mental health service, using a prospective design. The first study included 32 children and used a randomised controlled treatment design comparing a CBT approach with conjoint family therapy and an eclectic approach. The overall dropout rate was 36%. Dropout occurred significantly less frequently in the CBT group. The dropout group was associated with mothers who were younger and less educated, a poorer rating by the clinicians at the last meeting, parental dissatisfaction with the treatment service and perception that the treatment was less organised and having less behavioural tasks. In the second study we used a naturalistic follow-up design. Forty-six children were included. The overall dropout rate was 48%. Again, the children who defaulted were rated by clinicians as less likely to have improved and dropout was also  significantly associated with parental perception of a less organised treatment. In both studies dropout usually occurred after assessment and at the early phase of treatment.