A multicomponent positive psychology intervention for euthymic patients with bipolar disorder to improve mental well-being and personal recovery: A pragmatic randomized controlled trial.

OBJECTIVE: Mental well-being and personal recovery are important treatment targets for patients with bipolar disorder (BD). The goal of this study was to evaluate the effectiveness of an 8-week group multicomponent positive psychology intervention (PPI) for euthymic patients with BD as an adjunct to treatment as usual (TAU) compared to TAU alone. METHODS: Patients with BD were randomized to receive TAU (n = 43) or the PPI in addition to TAU (n = 54). The primary outcome was well being measured with the Mental Health Continuum-Short Form. Personal recovery was measured with the Questionnaire about the Process of Recovery. Data were collected at baseline, mid-treatment, post-treatment and 6- and 12-month follow-up. Life chart interviews were conducted at 12 months to retrospectively assess recurrence of depression and mania. RESULTS: Significant group-by-time interaction effects for well-being and personal recovery were found favouring the PPI. At post-treatment, between-group differences were significant for well-being (d = 0.77) and personal recovery (d = 0.76). Between-group effects for well-being were still significant at 6-month follow-up (d = 0.72). Effects on well-being and personal recovery within the intervention group were sustained until 12-month follow-up. Survival analyses showed no significant differences in time to recurrence. CONCLUSIONS: The multicomponent PPI evaluated in this study is effective in improving mental well-being and personal recovery in euthymic patients with BD and would therefore be a valuable addition to the current treatment of euthymic BD patients. The fact that the study was carried out in a pragmatic RCT demonstrates that this intervention can be applied in a real-world clinical setting.

A Feasibility Study of the Addition of STEPPS in Outpatients With Bipolar Disorder and Comorbid Borderline Personality Features: Promises and Pitfalls.

Background: Pharmacotherapy is a cornerstone in bipolar disorder (BD) treatment whereas borderline personality disorder (BPD) is treated primarily with psychotherapy. Given the overlap in symptomatology, patients with BD may benefit from psychotherapy designed for BPD. Aims: This paper reports the findings of a non-controlled open feasibility study of STEPPS training in patients with BD and borderline personality features (BPF). Methods: Outpatients with BD were screened for BPD, and if positive interviewed with SCID-II. Patients with at least three BPF, always including impulsivity and anger burst, were included in the intervention study. Severity of BD and BPD and quality of life were assessed. Descriptive statistics were performed. Results: Of 111 patients with BD 49.5% also screened positive on BPD according to PDQ-4+, and 52.3% of these had BPD according to SCID-II. Very few participants entered the intervention study, and only nine patients completed STEPPS. Descriptive statistics showed improvement on all outcome variables post treatment, but no longer at 6-month follow up. We reflect on the potential reasons for the failed inclusion. Conclusion: Features of BPD were highly prevalent in patients with BD. Still, recruiting patients for a psychological treatment originally designed for BPD proved to be difficult. Feedback of participants suggests that the association of STEPPS with "borderline" had an aversive effect, which may have caused limited inclusion for screening and subsequent drop-out for the treatment. Therefore, STEPPS should be adapted for BD to be an acceptable treatment option. Clinical Trial Registration: www.ClinicalTrials.gov/3856, identifier: NTR4016.

Psychometric properties and utility of the Responses to Positive Affect questionnaire (RPA) in a sample of people with bipolar disorder.

OBJECTIVES: To evaluate the psychometric properties of the Responses to Positive Affect (RPA) questionnaire in a sample of persons with bipolar disorder (BD). METHOD: Cross-sectional survey study with 107 persons with BD. The original 3-factor model of the RPA was compared with a 2-factor model. Construct validity was determined with measures of well-being, personal recovery, social role participation, and psychopathology and incremental validity was evaluated. RESULTS: The fit of the 3-factor model was acceptable for most fit indices. Subscores of the RPA revealed a significant relationship with aspects of well-being, personal recovery, and psychopathology. Dampening and self-focused positive rumination explained additional variance in personal recovery above and beyond well-being. CONCLUSIONS: The RPA is an internally consistent and valid tool to assess positive emotion regulation processes in persons with BD. Specifically, the processes of dampening and emotion-focused positive rumination seem to play an important role in BD.

Measuring personal recovery in people with bipolar disorder and exploring its relationship with well-being and social role participation.

The relevance of personal recovery receives increasing attention in mental health care and is also important for people with bipolar disorder (BD). There is a need for reliable and valid instruments measuring personal recovery. Therefore, the current study evaluated the psychometric properties of a Dutch translation of the Questionnaire about the Process of Recovery (QPR) in a sample of people with BD and explored the relationship with constructs of well-being, social role participation, and psychopathology. A cross-sectional survey study was conducted in which 102 people diagnosed with BD completed the QPR. Factor structure of the QPR was evaluated by conducting confirmatory factor analyses (CFA), and internal consistency was assessed by calculating reliability coefficients. Convergent validation measures assessed well-being, social role participation, and symptomatology. Incremental validity was determined by evaluating the ability of the QPR to explain variance in symptomatology above and beyond well-being. Findings of the CFA supported a unidimensional factor structure, and internal consistency estimates were excellent. Scores of the QPR showed strong correlations with convergent measures, but were only weakly associated with manic symptomatology. Moreover, personal recovery explained additional variance in symptoms of depression and anxiety above and beyond well-being, indicating incremental validity. The QPR appears to be a reliable and valid tool to assess personal recovery in people with BD. Our findings underline the importance of personal recovery in the context of treatment of BD. Personal recovery demonstrates a substantial overlap with well-being.

B-positive: a randomized controlled trial of a multicomponent positive psychology intervention for euthymic patients with bipolar disorder - study protocol and intervention development.

BACKGROUND: Bipolar disorder (BD) is characterized by recurrent (hypo)manic and depressive episodes, alternating with euthymic states in which patients are relatively symptom free. Besides clinical recovery, it is important to also strive for improvement of mental well-being and personal recovery. One prominent field focussing on the improvement of well-being is positive psychology. However, studies assessing the effects of positive psychology or personal recovery interventions for people with BD are scarce and have used weak methodological designs. The study described in this protocol article aims to assess the effectiveness of a multicomponent positive psychology intervention ("Living well with bipolar disorder") adjusted for people with BD in the euthymic phase to improve well-being and personal recovery. METHOD: The study concerns a pragmatic randomized multicenter trial. The principle objective of the study is to assess whether the positive psychology intervention offered to BD patients in remission in addition to usual care (CAU) is more effective than CAU. The study will include 112 participants randomized to either the experimental condition receiving the intervention in addition to CAU or the control condition receiving CAU. The study population are patients with BD I or II in the euthymic phase. The inclusion criteria are 1) diagnosis of BD I or BD II, 2) between the ages of 18-65, 3) four or more supportive sessions in the last year, and 4) only residual depressive or manic symptoms. Patients are excluded if they are in a depressive or manic episode, have current addiction problems or have optimal levels of well-being. Measurements take place at baseline, post-intervention and follow-up 6 and 12 months from baseline. Outcomes of measures include positive well-being, personal recovery, psychopathology, self-compassion, positive relationships, dampening of positive affect and relapse. DISCUSSION: The outlined study will be the first RCT examining the effects of a multicomponent positive psychology intervention for patients with bipolar disorder. Several limitations, including generalizability of the results and possible attrition issues, are discussed in advance. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register ( NTR6729 ) on 12 October 2017.

Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.

Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.

Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial.

BACKGROUND & AIMS: Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PCLD). The resulting hepatomegaly compromises quality of life. Somatostatin analogues reduce PLD volume by approximately 5% when given for 6-12 months. A pilot trial in 16 ADPKD patients demonstrated that sirolimus, an mTOR inhibitor, reduced PLD volume by 26%. The aim of this study was to assess the PLD volume reducing effect of everolimus and octreotide relative to octreotide monotherapy. METHODS: We designed a randomized controlled trial that compared 48 weeks of everolimus 2.5 mg daily, combined with octreotide 40 mg intramuscularly every 4 weeks, to octreotide monotherapy. We included PCLD and ADPKD patients. Exclusion criteria were MDRD-GFR <60 ml/min/1.73 m(2) and liver volume <2500 ml. Primary outcome was change in liver volume measured with CT-volumetry. RESULTS: We randomized 44 PLD patients (29 PCLD, 15 ADPKD, 89% female) to treatment with octreotide (n=23) or octreotide-everolimus (n=21). Liver volume decreased by 3.5% (p<0.01) in the monotherapy arm, compared to 3.8% with combination therapy (p<0.01). The difference between treatment arms was not significant (p=0.73). CONCLUSIONS: Adding everolimus to octreotide in PLD does not increase the liver volume reducing effect of octreotide.

Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. METHODS/DESIGN: This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. DISCUSSION: We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. TRIAL REGISTRATION NUMBER: Clinical trials.gov NCT01354405.

Complications arising in simple and polycystic liver cysts.

Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.

Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE): study protocol for a randomized controlled trial.

BACKGROUND: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. METHODS/DESIGN: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. DISCUSSION: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01157858.

Congenital fibrocystic liver diseases.

Fibrocystic diseases affecting the liver and often also other organs like the kidneys are a clinically and genetically heterogeneous group of disorders that may present in utero or remain clinically silent into late adulthood. During recent years, substantial progress has been made in unravelling the aetiology with primary cilia playing a central pathogenic role in many if not all of these diseases. The fibrocystogenic process shares some common features including proliferation and dilatation of epithelial bile ducts with concomitant abnormal apoptosis, fluid secretion and extracellular matrix deposition. In this review, we summarise clinical and diagnostic aspects, mechanisms of hepatic cystogenesis, and recent knowledge on potential therapies for these conditions.