Discontinuing antidepressant medication after mindfulness-based cognitive therapy: a mixed-methods study exploring predictors and outcomes of different discontinuation trajectories, and its facilitators and barriers.

OBJECTIVES: This study aimed to explore predictors and outcomes associated with different trajectories of discontinuing antidepressant medication (ADM), in recurrently depressed individuals after participation in mindfulness-based cognitive therapy (MBCT). Facilitators and barriers of discontinuation were explored qualitatively. DESIGN: Mixed-methods study combining quantitative and qualitative data, drawn from a randomised controlled trial. SETTING: Twelve secondary and tertiary psychiatric outpatient clinics in the Netherlands. PARTICIPANTS: Recurrently depressed individuals (N=226) who had been using ADM for at least 6 months and in partial or full remission. Regardless of trial condition, we made post-hoc classifications of patients' actual discontinuation trajectories: full discontinuation (n=82), partial discontinuation (n=34) and no discontinuation (n=110) of ADM within 6 months after baseline. A subset of patients (n=15) and physicians (n=7) were interviewed to examine facilitators and barriers of discontinuation. INTERVENTIONS: All participants were offered MBCT, which consisted of eight weekly sessions in a group. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic and clinical predictors of successful discontinuation within 6 months, relapse risk within 15 months associated with different discontinuation trajectories, and barriers and facilitators of discontinuation. RESULTS: Of the 128 patients assigned to MBCT with discontinuation, only 68 (53%) fully discontinued ADM within 6 months, and 17 (13%) discontinued partially. Predictors of full discontinuation were female sex, being employed and lower levels of depression. Relapse risk was lower after no discontinuation (45%) or partial discontinuation (38%), compared with full discontinuation (66%) (p=0.02). Facilitators and barriers of discontinuation were clustered within five themes: (1) pre-existing beliefs about depression, medication and tapering; (2) current experience with ADM; (3) life circumstances; (4) clinical support and (5) mindfulness. CONCLUSIONS: Discontinuing antidepressants appears to be difficult, stressing the need to support patients and physicians in this process. MBCT may offer one of these forms of support. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT00928980); post-results.

Blood pressure-lowering interventions to prevent dementia: a systematic review and meta-analysis.

: Our objective was to study the preventive effect of lowering blood pressure (BP) by medication and/or lifestyle changes on incident all-cause dementia, Alzheimer's disease and vascular dementia. In this systematic review, we included randomized controlled trials with a BP-lowering intervention. Of the nine included trials, seven assessed the effect of antihypertensive medication and two of a lifestyle or combined intervention. In the intervention arm, 1041 out of 29 029 (3.6%) participants were diagnosed with dementia compared with 1090 out of 28 653 (3.8%) controls during a median follow-up of 3.9 years [range 2-10], resulting in a pooled risk ratio of 0.93 (95% confidence interval 0.84-1.02; I 16%). Three trials specified dementia subtypes, with no significant effect on Alzheimer's disease or vascular dementia. To conclude, lowering BP by medication and/or lifestyle changes did not lead to a significantly reduced risk of dementia. This appeared independent of dementia subtype.

Prefrontal activation may predict working-memory training gain in normal aging and mild cognitive impairment.

Cognitive training has been shown to result in improved behavioral performance in normal aging and mild cognitive impairment (MCI), yet little is known about the neural correlates of cognitive plasticity, or about individual differences in responsiveness to cognitive training. In this study, 21 healthy older adults and 14 patients with MCI received five weeks of adaptive computerized working-memory (WM) training. Before and after training, functional Near-Infrared Spectroscopy (fNIRS) was used to assess the hemodynamic response in left and right prefrontal cortex during performance of a verbal n-back task with varying levels of WM load. After training, healthy older adults demonstrated decreased prefrontal activation at high WM load, which may indicate increased processing efficiency. Although MCI patients showed improved behavioral performance at low WM load after training, no evidence was found for training-related changes in prefrontal activation. Whole-group analyses showed that a relatively strong hemodynamic response at low WM load was related to worse behavioral performance, while a relatively strong hemodynamic response at high WM load was related to higher training gain. Therefore, a 'youth-like' prefrontal activation pattern at older age may be associated with better behavioral outcome and cognitive plasticity.

Long Pauses in Cerebellar Interneurons in Anesthetized Animals.

Are long pauses in the firing of cerebellar interneurons (CINs) related to Purkinje cell (PC) pauses? If PC pauses affect the larger network, then we should find a close relationship between CIN pauses and those in PCs. We recorded activity of 241 cerebellar cortical neurons (206 CINs and 35 PCs) in three anesthetized cats. One fifth of the CINs and more than half of the PCs were identified as pausing. Pauses in CINs and PCs showed some differences: CIN mean pause length was shorter, and, after pauses, only CINs had sustained reduction in their firing rate (FR). Almost all pausing CINs fell into same cluster when we used different methods of clustering CINs by their spontaneous activity. The mean spontaneous firing rate of that cluster was approximately 53 Hz. We also examined cross-correlations in simultaneously recorded neurons. Of 39 cell pairs examined, 14 (35 %) had cross-correlations significantly different from those expected by chance. Almost half of the pairs with two CINs showed statistically significant negative correlations. In contrast, PC/CIN pairs did not often show significant effects in the cross-correlation (12/15 pairs). However, for both CIN/CIN and PC/CIN pairs, pauses in one unit tended to correspond to a reduction in the firing rate of the adjacent unit. In our view, our results support the possibility that previously reported PC bistability is part of a larger network response and not merely a biophysical property of PCs. Any functional role for PC bistability should probably be sought in the context of the broader network.

Silencing the majority of cerebellar granule cells uncovers their essential role in motor learning and consolidation.

Cerebellar granule cells (GCs) account for more than half of all neurons in the CNS of vertebrates. Theoretical work has suggested that the abundance of GCs is advantageous for sparse coding during memory formation. Here, we minimized the output of the majority of GCs by selectively eliminating their CaV2.1 (P/Q-type) Ca(2+) channels, which mediate the bulk of their neurotransmitter release. This resulted in reduced GC output to Purkinje cells (PCs) and stellate cells (SCs) as well as in impaired long-term plasticity at GC-PC synapses. As a consequence modulation amplitude and regularity of simple spike (SS) output were affected. Surprisingly, the overall motor performance was intact, whereas demanding motor learning and memory consolidation tasks were compromised. Our findings indicate that a minority of functionally intact GCs is sufficient for the maintenance of basic motor performance, whereas acquisition and stabilization of sophisticated memories require higher numbers of normal GCs controlling PC firing.

Apoptosis and NET formation in the pathogenesis of SLE.

Systemic Lupus Erythematosus is an autoimmune disease characterized by the formation of anti-nuclear autoantibodies, particularly anti-chromatin. Although the aetiology of the disease has not yet been fully elucidated, several mechanisms have been proposed to be involved. Due to an aberrant apoptosis or decreased removal of apoptotic cells, apoptotic blebs containing chromatin are released. During apoptosis, chromatin is modified that increases its immunogenicity. Myeloid dendritic cells (myDC) can take up apoptotic blebs and stimulate autoreactive T helper cells, and subsequently the formation of autoantibodies by autoreactive B cells. Immune complexes formed by anti-chromatin autoantibodies and modified chromatin deposit on basal membranes, and incite a local inflammation, but can also stimulate plasmacytoid dendritic cells to produce IFN-α. In addition to apoptotic blebs, neutrophil extracellular traps released by dying neutrophils, in a process called NETosis, may serve as a source of autoantigens as well. In this review, we describe the role of both apoptosis and NETosis in the pathogenesis of SLE, and show how both processes may interact with each other.