Outcomes of hyperbolic tapering of antidepressants.

Background: In patients attempting to discontinue their antidepressant medication, there have been no prospective studies on patterns of withdrawal as a function of the rate of antidepressant reduction during the tapering trajectory, and moderators thereof. Objective: To investigate withdrawal as a function of gradual dose reduction. Design: Prospective cohort study. Methods: The sampling frame consisted of 3956 individuals in the Netherlands who received an antidepressant tapering strip between 19 May 2019 and 22 March 2022 in routine clinical practice. Of these, 608 patients, majorly with previous unsuccessful attempts to stop, provided daily ratings of withdrawal in the context of reducing their antidepressant medications (mostly venlafaxine or paroxetine), using hyperbolic tapering strips offering daily tiny reductions in dose. Results: Withdrawal in daily-step hyperbolic tapering trajectories was limited, and inverse to the rate of taper. Female sex, younger age, presence of one or more risk factors and faster rate of reduction over shorter tapering trajectories were associated with more withdrawal and differential course over time. Thus, sex and age differences were less marked early in the course of the trajectory, whereas differences associated with risk factors and shorter trajectories tended to peak early in the trajectory. There was evidence that tapering in weekly larger steps (mean per-week dose reduction: 33.4% of previous dose), in comparison with daily tiny steps (mean per-day dose reduction: 4.5% of previous dose or 25.3% per week), was associated with more withdrawal in trajectories of 1, 2 or 3 months, particularly for paroxetine and the group of other (non-paroxetine, non-venlafaxine) antidepressants. Conclusion: Antidepressant hyperbolic tapering is associated with limited, rate-dependent withdrawal that is inverse to the rate of taper. The demonstration of multiple demographic, risk and complex temporal moderators in time series of withdrawal data indicates that antidepressant tapering in clinical practice requires a personalised process of shared decision making over the entire course of the tapering period.

Successful use of tapering strips for hyperbolic reduction of antidepressant dose: a cohort study.

BACKGROUND: Tapering strips facilitate antidepressant discontinuation, allowing for personalised titration of discontinuation to the intensity of withdrawal. A tapering strip consists of antidepressant or other medication, packaged in a 28-day roll of daily pouches, each with the same or slightly lower dose than the one before. Previous studies demonstrated 70% real-world effectiveness of tapering strips. Here, we present a third, questionnaire-based retrospective cohort study in a large sample. METHODS: Patients whose doctor had prescribed tapering strips between October 2015 and December 2018 were sent a questionnaire for participation after completion of tapering between December 2015 and January 2020. Of 1240 individuals who returned a questionnaire (response rate: 59%), 987 (80%) used an antidepressant, of whom 824 (83%) had wished to discontinue their antidepressant. RESULTS: The sample was demographically representative of antidepressant users in the Netherlands. Less than 40% of participants had heard of tapering strips through their clinicians - Internet was the most frequent source. Of the 824 individuals, 341 (41%) had used strips for tapering venlafaxine, 206 (25%) for paroxetine and 277 (34%) for other antidepressants. Median duration of antidepressant use was 5-10 years, and most (71%) had tried to come off without tapering strips at least once. Most patients (72%) were able to discontinue their antidepressant, using a median of two strips to taper over a median period of 56 days. Females and individuals with (1) more severe experience of withdrawal during the use of tapering strips, (2) more years of use of antidepressant medication and (3) more previous attempts at discontinuation were less likely to be able to discontinue their antidepressant medication with tapering strips. CONCLUSION: The results of this study validate, for the third time, the observation that tapering strips can address the problem of antidepressant withdrawal symptoms in individuals attempting to discontinue antidepressants.

Outcome of antidepressant drug discontinuation with taperingstrips after 1-5 years.

BACKGROUND: Stopping antidepressants is often difficult due to withdrawal. Taperingstrips were developed to facilitate antidepressant discontinuation according to the recently described Horowitz-Taylor method, allowing for personalised titration of discontinuation to the intensity of withdrawal. A taperingstrip consists of antidepressant or other medication, packaged in a 28-day roll of small daily pouches, each with the same or slightly lower dose than the one before it. We previously reported that the short-term success rate of antidepressant taperingstrips was 71%. Here, we examine longer-term outcome after 1-5 years. METHODS: Patients whose doctor had ordered taperingstrips between January 2015 and December 2019 were sent a questionnaire for participation in anonymised research in January 2020. Of 1012, 483 participated, of whom 408 (85%) had attempted antidepressant tapering. RESULTS: Of the 408 patients included, 192 (47%) had used strips for tapering venlafaxine, 142 (35%) for paroxetine and 74 (18%) for other antidepressants. Median length of antidepressant use was 4 years, and most (61%) had tried to come off without taperingstrips at least once. After 1-5 years, 270 patients (66%) remained off antidepressants after tapering their antidepressant, 6 (2%) had successfully reduced their medication, 87 (21%) had restarted due to (self-reported) relapse, 35 had restarted for another indication (9%), and 10 (3%) reported another outcome. People with more severe experience of withdrawal prior to tapering, and people who had been on antidepressants for a shorter period of time, were more likely to remain off medication after 1-5 years. CONCLUSION: The previously reported 71% short-term success rate of taperingstrips in the most severely affected group, was matched by a 68% rate after 1-5 years. The evidence-based approach of personal tapering to counter withdrawal, as used for drugs causing withdrawal, for example, benzodiazepines, may represent a simple solution for an important antidepressant-related public health problem, without extra costs.

How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication.

Coming off psychotropic drugs can cause physical as well as mental withdrawal, resulting in failed withdrawal attempts and unnecessary long-term drug use. The first reports about withdrawal appeared in the 1950s, but although patients have been complaining about psychotropic withdrawal problems for decades, the first tentative acknowledgement by psychiatry only came in 1997 with the introduction of the 'antidepressant-discontinuation syndrome'. It was not until 2019 that the UK Royal College of Psychiatrists, for the first time, acknowledged that withdrawal can be severe and persistent. Given the lack of a systematic professional response, over the years, patients who were experiencing withdrawal started to work out practical ways to safely come off medications themselves. This resulted in an experience-based knowledge base about withdrawal which ultimately, in The Netherlands, gave rise to the development of person-specific tapering medication (so-called tapering strips). Tapering medication enables doctors, for the first time, to flexibly prescribe and adapt the medication required for responsible and person-specific tapering, based on shared decision making and in full agreement with recommendations in existing guidelines. Looking back, it is obvious that the simple practical solution of tapering strips could have been introduced much earlier, and that the traditional academic strategy of comparisons from randomised trials is not the logical first step to help individual patients. While randomised controlled trials (RCTs) are the gold standard for evaluating interventions, they are unable to accommodate the heterogeneity of individual responses. Thus, a more individualised approach, building on RCT knowledge, is required. We propose a roadmap for a more productive way forward, in which patients and academic psychiatry work together to improve the recognition and person-specific management of psychotropic drug withdrawal.

The experience sampling method as an mHealth tool to support self-monitoring, self-insight, and personalized health care in clinical practice.

BACKGROUND: The experience sampling method (ESM) builds an intensive time series of experiences and contexts in the flow of daily life, typically consisting of around 70 reports, collected at 8-10 random time points per day over a period of up to 10 days. METHODS: With the advent of widespread smartphone use, ESM can be used in routine clinical practice. Multiple examples of ESM data collections across different patient groups and settings are shown and discussed, varying from an ESM evaluation of a 6-week randomized trial of mindfulness, to a twin study on emotion dynamics in daily life. RESULTS: Research shows that ESM-based self-monitoring and feedback can enhance resilience by strengthening the capacity to use natural rewards. Personalized trajectories of starting or stopping medication can be more easily initiated and predicted if sensitive feedback data are available in real time. In addition, personalized trajectories of symptoms, cognitive abilities, symptoms impacting on other symptoms, the capacity of the dynamic system of mental health to "bounce back" from disturbance, and patterns of environmental reactivity yield uniquely personal data to support shared decision making and prediction in clinical practice. Finally, ESM makes it possible to develop insight into previous implicit patterns of thought, experience, and behavior, particularly if rapid personalized feedback is available. CONCLUSIONS: ESM enhances clinical practice and research. It is empowering, providing co-ownership of the process of diagnosis, treatment evaluation, and routine outcome measurement. Blended care, based on a mix of face-to-face and ESM-based outside-the-office treatment, may reduce costs and improve outcomes.

Identification of the Mhc region as an asthma susceptibility locus in recombinant congenic mice.

Mouse models of allergic asthma are characterized by airway hyperreactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locus on chromosome 17 mediates a strong effect on Th2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrow down this number of candidate genes, we performed genome-wide transcriptional profiling on lung tissue from C.lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C.lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1.

Patients can diagnose too: How continuous self-assessment aids diagnosis of, and recovery from, depression.

BACKGROUND: A dichotomous ICD-10 or DSM-IV diagnosis of depression does not fully capture its natural phenotype: a dimensional continuum of environmentally reactive fluctuations in mood. Therefore, ICD and DSM labels of depression, although useful from a service perspective, fail to help patients directly. This paper will show, using the author's experiences as an example, that patients with mood disorders can "diagnose" the natural phenotype, in the sense that systematic recording of painful fluctuations in environmentally reactive moods by the patient him- or herself may: (i) not only provide an accurate assessment of depression, but (ii) result in a process of conscious awareness of aberrant responses to the environment - a first step on the way to recovery. METHOD: The author developed a rudimentary but useable method to diagnose his dynamic mood fluctuations over the years. The continuous assessment method allowed him to systematically score his mood and activities every day, enabling him to study and analyse in detail the course and context of mood symptoms over time. RESULTS: With time, this initial strategy evolved into a new, more informed, more empowered diagnosis of his problems and ultimately contributed to a more resilient mind set with regard to mood changes and ways of active rather than avoidant coping with them. CONCLUSIONS: Many people with mood problems receive a DSM label but are not taught to engage in diagnosing what depression is: a dynamic pattern of environmentally reactive mood responses. Continuous diagnostic self-assessment strategies may help patients to learn, adjust and cope with their emotional vulnerabilities expressed as dimensional and reactive variation in mood. Patients can be empowered to diagnose experiences as a means to understand the sources and consequences of continuous mood variation over time.

Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo.

Antigen-presenting cells are localized in essentially every tissue, where they operate at the interface of innate and acquired immunity by capturing pathogens and presenting pathogen-derived peptides to T cells. C-type lectins are important pathogen recognition receptors and the C-type lectin, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), is unique in that, in addition to pathogen capture, it regulates adhesion processes such as DC trafficking and T-cell synapse formation. We have isolated a murine homologue of DC-SIGN that is identical to the previously reported murine homologue mSIGNR1. mSIGNR1 is more closely related to the human DC-SIGN homologue L-SIGN than to DC-SIGN itself because mSIGNR1 is specifically expressed by liver sinusoidal endothelial cells, similar to L-SIGN, and not by DCs. Moreover, mSIGNR1 is also expressed by medullary and subcapsular macrophages in lymph nodes and by marginal zone macrophages (MZMs) in the spleen. Strikingly, these MZMs are in direct contact with the bloodstream and efficiently capture specific polysaccharide antigens present on the surface of encapsulated bacteria. We have investigated the in vivo function of mSIGNR1 on MZMs in spleen. We demonstrate here that mSIGNR1 functions in vivo as a pathogen recognition receptor on MZMs that capture blood-borne antigens, which are rapidly internalized and targeted to lysosomes for processing. Moreover, the antigen capture is completely blocked in vivo by the blocking mSIGNR1-specific antibodies. Thus, mSIGNR1, a murine homologue of DC-SIGN, is important in the defense against pathogens and this study will facilitate further investigations into the in vivo function of DC-SIGN and its homologues.

Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers.

Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.