Publications by authors named "Christine E Ryan"

43 Publications

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors.

Blood Adv 2020 04;4(7):1458-1463

Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Opportunistic infections (OIs), such as Pneumocystis jirovecii pneumonia (PJP), have been reported in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and are an important cause of morbidity and mortality. Currently, there are no international consensus guidelines regarding the use of antimicrobial prophylaxis for OIs, and in particular PJP, in CLL patients treated with Bruton tyrosine kinase inhibitors (BTKi's). We evaluated the frequency of PJP in CLL patients at our institution who were treated with BTKi's, and assessed the impact of prophylaxis on reducing the risk of PJP. We identified 217 patients treated with BTKi's, consisting of 3 cohorts: 143 patients on either BTKi monotherapy with ibrutinib or acalabrutinib, 17 patients receiving ibrutinib combination therapy with umbralisib as part of a clinical trial, and 57 patients receiving ibrutinib in combination with standard chemotherapy, also as part of a clinical trial. Forty-one percent of patients on BTKi monotherapy received prophylaxis, which was given at the discretion of the treating physician. The prevalence of PJP in all patients not on prophylaxis was 3.4% (3 of 87), and, specifically in BTKi-monotherapy patients not on prophylaxis, the PJP prevalence was 2.4% (2 of 85). PJP prophylaxis was effective, as there were no cases of PJP in patients on prophylaxis (0 of 130). The relatively low prevalence of PJP in our study population suggests that routine prophylaxis may not be indicated in CLL patients on BTKi therapy.
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http://dx.doi.org/10.1182/bloodadvances.2020001678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160295PMC
April 2020

BCL-2 Inhibitors, Present and Future.

Cancer J 2019 Nov/Dec;25(6):401-409

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

The members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic apoptotic pathway; dysregulation of this pathway leads to pathologic survival of cancer cells. B-cell leukemia/lymphoma-2 had long been viewed as a promising target for the treatment of several hematologic malignancies, specifically chronic lymphocytic leukemia (CLL), yet for many years the development of a drug to successfully target this protein remained elusive. The approval of the BCL-2 inhibitor venetoclax for relapsed/refractory del(17p) CLL in 2016 represented the culmination of decades of molecular and clinical research and has paved the way for new combination therapy regimens in CLL, including the venetoclax + rituximab regimen approved for relapsed/refractory CLL in 2018 and the venetoclax + obinutuzumab regimen approved for frontline CLL treatment in 2019. Here, we provide an overview of the mechanism of action of BCL-2 inhibition, the role of this approach in the current treatment paradigm of CLL, and an in-depth focus on the clinical trials in CLL involving venetoclax. Additionally, we review key areas of active research including the integration of minimal residual disease as a marker of clinical efficacy in current clinical trials as well as the emergence of venetoclax resistance mechanisms and potential strategies to overcome this resistance. Given the success of venetoclax in the clinical setting thus far, it is likely that BCL-2 inhibition will take on an increasingly important role in the treatment of CLL going forward.
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http://dx.doi.org/10.1097/PPO.0000000000000408DOI Listing
August 2020

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Authors:
Lauren A Eberly Aaron Richterman Anne G Beckett Bram Wispelwey Regan H Marsh Emily C Cleveland Manchanda Cindy Y Chang Robert J Glynn Katherine C Brooks Robert Boxer Rose Kakoza Jennifer Goldsmith Joseph Loscalzo Michelle Morse Eldrin F Lewis Samantha Abel Ayrenne Adams Joseph Anaya Erik H Andrews Benjamin Atkinson Viswatej Avutu Alexandra Bachorik Omar Badri Mariel Bailey Katie Baird Salina Bakshi Denis Balaban Kenneth Barshop Emily Baumrin Omar Bayomy Julia Beamesderfer Nora Becker David D Berg Adam N Berman Steven M Blum Alexander P Boardman Kaeleen Boden Robert A Bonacci Sarah Brown Kirsti Campbell Siobhan Case Emily Cetrone Alexandra Charrow David Chiang Devin Clark Aaron J Cohen Alissa Cooper Tomas Cordova C Nicholas Cuneo Alsina Alejandro de Feria Karen Deffenbacher Ersilia M DeFilippis Geneva DeGregorio Aaron J Deutsch Bradford Diephuis Sanjay Divakaran Peter Dorschner Nicholas Downing Caitlin Drescher Kristin M D'Silva Peter Dunbar David Duong Sarah Earp Christine Eckhardt Scott A Elman Ross England Kay Everett Natalie Fedotova Tamara Feingold-Link Mark Ferreira Herrick Fisher Patricia Foo Michael Foote Idalid Franco Thomas Gilliland Jacqueline Greb Katherine Greco Sungat Grewal Benjamin Grin Matthew E Growdon Brendan Guercio Cynthia K Hahn Brian Hasselfeld Erika J Haydu Zachary Hermes Gordon Hildick-Smith Zachary Holcomb Kathryn Holroyd Laura Horton George Huang Stanley Jablonski Douglas Jacobs Nina Jain Sohan Japa Richard Joseph Mariya Kalashnikova Neil Kalwani Daniel Kang Abraar Karan Joel T Katz Daniel Kellner Khameer Kidia June-Ho Kim Scott M Knowles Laura Kolbe Idil Kore Yiannis Koullias Ifedayo Kuye Joshua Lang Matthew Lawlor Melissa G Lechner Ken Lee Scott Lee Zachary Lee Neha Limaye Stephanie Lin-Beckford Marla Lipsyc Jessica Little Julia Loewenthal Ranjani Logaraj Diana M Lopez Daniel Loriaux Yi Lu Kevin Ma Nareh Marukian Wilfredo Matias Jared R Mayers Ian McConnell Michael McLaughlin Christina Meade Catherine Meador Anish Mehta Elizabeth Messenger Constantinos Michaelidis Jacob Mirsky Emilie Mitten Alisa Mueller Jyotsna Mullur Amir Munir Emily Murphy Ellen Nagami Abirami Natarajan Michelle Nsahlai Chijioke Nze Noreen Okwara Peter Olds Rafael Paez Michael Pardo Siddharth Patel Alec Petersen Laura Phelan Erica Pimenta Daniel Pipilas Molly Plovanich Denise Pong Brian W Powers Anita Rao Haiyan Ramirez Batlle Mattheus Ramsis Anna Reichardt Sheridan Reiger Michelle Rengarajan Stephanie Rico Benjamin N Rome Rachael Rosales Lisa Rotenstein Alexis Roy Sarah Royston Hallie Rozansky Meghan Rudder Christine E Ryan Sanjay Salgado Pablo Sanchez Jennifer Schulte Aswin Sekar Nicholas Semenkovich Evan Shannon Neil Shaw Andrew Ben Shorten William Shrauner Lauren Sinnenberg James W Smithy Gregory Snyder Anirudh Sreekrishnan Hans Stabenau Eleni Stavrou Andrew Stergachis Robert Stern Alexander Stone Shervin Tabrizi Sam Tanyos Cristina Thomas Haley Thun Kristine Torres-Lockhart An Tran Carolyn Treasure Frederick D Tsai Stephen Tsaur Evan Tschirhart Justin Tuwatananurak Ramkumar V Venkateswaran Anastasia Vishnevetsky Lindsay Wahl April Wall Frances Wallace Elisa Walsh Priscilla Wang Heather B Ward Lindsay N Warner Lachelle D Weeks Kipp Weiskopf Jordan Wengrod Jessica N Williams Marisa Winkler Jeffrey L Wong Devin Worster Aileen Wright Caroline Wunsch Jamila S Wynter Chase Yarbrough Wai-Ying Yau Daniel Yazdi Jennifer Yeh Maria A Yialamas Nicholas Yozamp Marina Zambrotta Rebecca Zon

Circ Heart Fail 2019 11 29;12(11):e006214. Epub 2019 Oct 29.

Division of Cardiovascular Medicine, and Department of Medicine (E.F..L.), Brigham and Women's Hospital, Boston, MA.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality.

Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.

Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183732PMC
November 2019

Large Morel-Lavallée lesion presenting as fungating mass with skin ulceration.

J Clin Orthop Trauma 2016 Oct-Dec;7(Suppl 1):103-105. Epub 2016 Jun 20.

Stanford University School of Medicine, Department of Medicine, USA.

A Morel-Lavallée lesion, a type of soft tissue degloving injury that has also been referred to as a chronic expanding hematoma, is a relatively rare condition that usually develops following traumatic injury. Here, we present a case of a 60-year-old male with a Morel-Lavallée lesion diagnosed over 5 years after a traumatic injury of the hip. He presented with a large fungating mass and overlying skin ulceration, which was highly suspicious for sarcoma. However, lack of other systemic findings and constitutional complaints, as well as negative imaging studies, did not support a diagnosis of malignancy. This information, combined with the history of remote trauma to the affected area, instead led us to suspect the alternative diagnosis of a Morel-Lavallée lesion. The diagnosis was later confirmed by pathology showing a chronic expanding hematoma. To our knowledge, a Morel-Lavallée lesion presenting as a fungating mass has not been previously described.
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http://dx.doi.org/10.1016/j.jcot.2016.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167448PMC
June 2016

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

Blood 2016 12 1;128(25):2899-2908. Epub 2016 Nov 1.

Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.
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http://dx.doi.org/10.1182/blood-2016-06-715284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179333PMC
December 2016

A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells.

MAbs 2015 ;7(5):946-56

a Department of Medicine; Division of Hematology, Cancer Institute; and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford , CA , USA.

Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.
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http://dx.doi.org/10.1080/19420862.2015.1062192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623422PMC
June 2016

Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages.

Proc Natl Acad Sci U S A 2015 Mar 16;112(13):4074-9. Epub 2015 Mar 16.

Departments of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, and

BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.
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http://dx.doi.org/10.1073/pnas.1413383112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386392PMC
March 2015

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans.

Blood 2015 May 12;125(20):3193-201. Epub 2015 Mar 12.

Division of Blood and Marrow Transplantation, Department of Medicine and.

Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HY-Ab was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant.
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http://dx.doi.org/10.1182/blood-2014-11-613323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432013PMC
May 2015

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer.

Breast Cancer Res Treat 2013 Jan 15;137(2):483-92. Epub 2012 Dec 15.

Section of Breast Oncology, Division of Oncology, Department of Medicine, Washington University School of Medicine, Campus Box 8056, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100-125 mg/m(2) IV days 1, 8, 15, 22) and UCN-01 (70 mg/m(2) IV day 2, 35 mg/m(2) day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1(S296) on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.
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http://dx.doi.org/10.1007/s10549-012-2378-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539064PMC
January 2013

Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.

J Clin Invest 2012 Apr 26;122(4):1541-52. Epub 2012 Mar 26.

Section of Breast Oncology, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.

Patients with triple-negative breast cancer (TNBC) - defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification - have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background results in apoptosis [corrected] in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.
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http://dx.doi.org/10.1172/JCI58765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314455PMC
April 2012

Impact of family functioning on quality of life in patients with psychogenic nonepileptic seizures versus epilepsy.

Epilepsia 2011 Feb 7;52(2):292-300. Epub 2011 Feb 7.

Department of Psychiatry, Rhode Island Hospital, Providence, Rhode Island 02903, USA.

Purpose: To evaluate different contributions of aspects of family functioning (FF) on health-related quality of life (HRQOL) in patients with psychogenic nonepileptic seizures (PNES) versus epileptic seizures (ES).

Methods: Forty-five participants with PNES and 32 with ES completed self-report measures of FF (Family Assessment Device; FAD), HRQOL (Quality of Life in Epilepsy-31), and depression (Beck Depression Inventory-II; BDI-II). The FAD is a self-report questionnaire that assesses FF along six dimensions and general functioning. Regression analyses were used to evaluate the contribution of FF to HRQOL above and beyond the effects of disease severity and depression.

Key Findings: Mean Family General Functioning fell in the unhealthy range in participants with ES or PNES. On further analysis, male participants in each group endorsed unhealthy levels of FF compared to female participants. Patients with PNES reported poorer HRQOL and greater depressive symptoms compared to ES participants; there were no gender differences in HRQOL. Regression analyses indicated that the FAD Roles subscale predicted reduced HRQOL in patients with PNES after controlling for illness duration, seizure frequency, and depression. After controlling for the same factors, Communication and Affective Involvement subscales scores predicted HRQOL in ES participants.

Significance: Family dysfunction was reported in both ES and PNES participants, but greater family dysfunction was experienced by male participants in both groups. Aspects of FF predicted HRQOL in patients with PNES and ES differentially. FF may be an important treatment target to enhance coping in these groups, although the treatments may need to target different aspects of FF in PNES versus ES.
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http://dx.doi.org/10.1111/j.1528-1167.2010.02765.xDOI Listing
February 2011

A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.

Cancer Chemother Pharmacol 2011 Jun 8;67(6):1225-37. Epub 2010 Aug 8.

Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA.

Purpose: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.

Experimental Design: Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.

Results: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).

Conclusion: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
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http://dx.doi.org/10.1007/s00280-010-1410-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102212PMC
June 2011

An adjunctive Management of Depression Program for difficult-to-treat depressed patients and their families.

Depress Anxiety 2010 ;27(1):27-34

Department of Psychiatry and Human Behavior, The Warren Alpert School of Medicine at Brown University and Rhode Island Hospital, Providence, Rhode Island, USA.

Background: The goal of this open-label feasibility trial was to test a short-term, adjunctive intervention, the Management of Depression (MoD) Program, to determine if patients with difficult-to-treat forms of depression and their family members could learn to cope more effectively with their illness.

Methods: Nineteen patients meeting The Diagnostic and Statistical Manual IV criteria for major depressive disorder, dysthymia, or chronic/recurrent depression and their family members participated in an open-label study testing the efficacy of the MoD Program. The intervention consisted of nine sessions over 16 weeks, followed by an 8-month maintenance phase. Outcome measures focused on quality of life, psychological and family functioning, and level of depression.

Results: Fourteen patients and their family members improved significantly in psychosocial and family functioning, and depression severity (all P-values <.05) by the end of the 16-week intervention. There was also significant improvement in quality of life, psychosocial and family functioning, and depression scores (all P-values<.05) for the 10 patients who completed the maintenance phase.

Conclusion: The MoD Program is a useful adjunctive intervention that helped patients and their family members deal more effectively with their persisting depression. The disease management approach improved the patient's perceived quality of life and functioning, reduced depressive symptoms, and improved perception of their family's functioning.
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http://dx.doi.org/10.1002/da.20640DOI Listing
March 2010

Family focused therapy shortens recovery time from depression but not mania in adolescents with bipolar disorder.

Evid Based Ment Health 2009 May;12(2):48

Rhode Island Hospital/Brown University, Providence, Rhode Island, USA.

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http://dx.doi.org/10.1136/ebmh.12.2.48DOI Listing
May 2009

Cognitive behavioral therapy for psychogenic nonepileptic seizures.

Epilepsy Behav 2009 Apr 20;14(4):591-6. Epub 2009 Feb 20.

Department of Psychiatry and Human Behavior, Rhode Island Hospital, Brown Medical School, Providence, RI 02903, USA.

Treatment trials for psychogenic nonepileptic seizures (PNES) are few, despite the high prevalence and disabling nature of the disorder. We evaluated the effect of cognitive behavioral therapy (CBT) on reduction of PNES. Secondary measures included psychiatric symptom scales and psychosocial variables. We conducted a prospective clinical trial assessing the frequency of PNES in outpatients treated using a CBT for PNES manual. Subjects diagnosed with video/EEG-confirmed PNES were treated with CBT for PNES conducted in 12 weekly sessions. Seizure calendars were charted prospectively. Twenty-one subjects enrolled, and 17 (81%) completed the CBT intervention. Eleven of the 17 completers reported no seizures by their final CBT session. Mean scores on scales of depression, anxiety, somatic symptoms, quality of life, and psychosocial functioning showed improvement from baseline to final session. CBT for PNES reduced the number of PNES and improved psychiatric symptoms, psychosocial functioning, and quality of life.
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http://dx.doi.org/10.1016/j.yebeh.2009.02.016DOI Listing
April 2009

Preventing recurrence of bipolar I mood episodes and hospitalizations: family psychotherapy plus pharmacotherapy versus pharmacotherapy alone.

Bipolar Disord 2008 Nov;10(7):798-805

Department of Psychiatry and Human Behavior, Brown University, Rhode Island Hospital, Providence, RI 02903-4970, USA.

Objectives: This study compared the efficacy of three treatment conditions in preventing recurrence of bipolar I mood episodes and hospitalization for such episodes: individual family therapy plus pharmacotherapy, multifamily group therapy plus pharmacotherapy, and pharmacotherapy alone.

Methods: Patients with bipolar I disorder were enrolled if they met criteria for an active mood episode and were living with or in regular contact with relatives or significant others. Subjects were randomly assigned to individual family therapy plus pharmacotherapy, multifamily group therapy plus pharmacotherapy, or pharmacotherapy alone, which were provided on an outpatient basis. Individual family therapy involved one therapist meeting with a single patient and the patient's family members, with the content of each session and number of sessions determined by the therapist and family. Multifamily group psychotherapy involved two therapists meeting together for six sessions with multiple patients and their respective family members, with the content of each session preset. All subjects were prescribed a mood stabilizer, and other medications were used as needed. Subjects were assessed monthly for up to 28 months. Following recovery from the index mood episode, subjects were assessed for recurrence of a mood episode and for hospitalization for such episodes.

Results: Of a total of 92 subjects that were enrolled in the study, 53 (58%) recovered from their intake mood episode. The analyses in this report focus upon these 53 subjects, 42 (79%) of whom entered the study during an episode of mania. Of the 53 subjects who recovered from their intake mood episode, the proportion of subjects within each treatment group who suffered a recurrence by month 28 did not differ significantly between the three treatment conditions. However, only 5% of the subjects receiving adjunctive multifamily group therapy required hospitalization, compared to 31% of the subjects receiving adjunctive individual family therapy and 38% of those receiving pharmacotherapy alone, a significant difference. Time to recurrence and time to hospitalization did not differ significantly between the three treatment groups.

Conclusion: For patients with bipolar I disorder, adjunctive multifamily group therapy may confer significant advantages in preventing hospitalization for a mood episode.
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http://dx.doi.org/10.1111/j.1399-5618.2008.00624.xDOI Listing
November 2008

Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379.

Mol Cell Biol 2008 Oct 21;28(19):5874-85. Epub 2008 Jul 21.

Department of Cell Biology and Physiology, Washington University School of Medicine, Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, USA.

The Chk2 protein kinase protects genome integrity by promoting cell cycle arrest or apoptosis in response to DNA double-strand breaks, and Chk2 mutations are found in both familial and sporadic cancers. Exposure of cells to ionizing radiation (IR) or radiomimetic drugs induces Chk2 phosphorylation by ATM, followed by Chk2 oligomerization, auto-/transphosphorylation, and activation. Here we demonstrate that Chk2 is ubiquitinated upon activation and that this requires Chk2 kinase activity. Serine 379 (S379) was identified as a novel IR-inducible autophosphorylation site required for ubiquitination of Chk2 by a Cullin 1-containing E3 ligase complex. Importantly, S379 was required for Chk2 to induce apoptosis in cells with DNA double-strand breaks. Thus, auto-/transphosphorylation of S379 is required for Chk2 ubiquitination and effector function.
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http://dx.doi.org/10.1128/MCB.00821-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547006PMC
October 2008

A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression.

J Psychiatr Res 2009 Jan 30;43(3):205-14. Epub 2008 Jun 30.

Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, RI, United States.

Objective: Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.

Method: Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.

Results: Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.

Conclusion: Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
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http://dx.doi.org/10.1016/j.jpsychires.2008.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685867PMC
January 2009

Family treatment for bipolar disorder: family impairment by treatment interactions.

J Clin Psychiatry 2008 May;69(5):732-40

Department of Psychiatry and Human Behavior, Brown University, Butler Hospital, Providence, RI 02906, USA.

Objective: There is a clear need for psychosocial treatments to supplement pharmacotherapy for bipolar disorder. In this study, the efficacy of 2 forms of adjunctive family intervention were compared to pharmacotherapy alone. In addition to evaluating overall differences between treatments, a chief goal was to examine whether family impairment levels moderated the effects of family intervention on outcome.

Method: Ninety-two patients diagnosed with bipolar I disorder (according to DSM-III-R) were randomly assigned to receive (1) pharmaco-therapy alone, (2) family therapy + pharmacotherapy, or (3) multi-family psychoeducational group + pharmacotherapy. Treatments and assessments continued for up to 28 months. Primary outcome measures were number of episodes per year and percentage of time symptomatic throughout the entire follow-up period. The study was conducted from September 1992 through March 1999.

Results: No significant main effects were found for treatment condition. Thus, for the total sample, the addition of a family intervention did not improve outcome. However, there were significant treatment condition by family impairment interactions (p < .05). In patients from families with high levels of impairment, the addition of a family intervention (family therapy or psycho-educational group) resulted in a significantly improved course of illness, particularly the number of depressive episodes (p < .01) and proportion of time spent in a depressive episode (p < .01). These effects were relatively large (Cohen d = 0.7-1.0), with patients receiving either family intervention having roughly half the number of depressive episodes and amount of time spent depressed as those receiving pharmaco-therapy alone. In contrast, for patients from low-impairment families, the addition of a family intervention did not improve course of illness.

Conclusions: Our findings build on previous literature suggesting the importance of treatment matching within the mood disorders and suggest that the utility of adding family interventions for bipolar patients and their families may depend upon the family's level of impairment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862220PMC
http://dx.doi.org/10.4088/jcp.v69n0506DOI Listing
May 2008

STAR*D: have we learned the right lessons?

Am J Psychiatry 2008 Jan;165(1):133; author reply 133-4

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http://dx.doi.org/10.1176/appi.ajp.2007.07081375DOI Listing
January 2008

Methodological issues in conducting treatment trials for psychological nonepileptic seizures.

J Neuropsychiatry Clin Neurosci 2007 ;19(4):391-8

Department of Neurology, Comprehensive Epilipsy Program, Brown Medical School, Providence, Rhode Island, USA.

A randomized, placebo-controlled trial has yet to be completed in patients with psychological nonepileptic seizures (NES). Treatment publications for NES are limited to class III trials and class IV reports. Little is written on the methodology of treatment trials in NES. The authors describe the procedures and limitations of such a trial to inform future NES treatment trials, based on their prospective, open-label pharmacological, feasibility trial. The authors review the recruitment, enrollment, completion of surveys, compliance, and follow-up of patients with NES. The majority of patients who enrolled, readily completed surveys and took the medication during the trial. Twelve patients were screened, eight enrolled, and six completed the trial. The authors discuss the use of outcomes and the various symptoms scales in the trial. A comprehensive neuropsychiatric initial assessment and assessing cognitive, emotional, behavioral, and psychosocial measures are important for monitoring the outcomes in NES treatment RCTs.
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http://dx.doi.org/10.1176/jnp.2007.19.4.391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777885PMC
January 2008

Family functioning in bipolar I disorder.

J Fam Psychol 2006 Dec;20(4):701-4

Department of Psychiatry and Human Behavior, Brown University and Psychosocial Research Program, Butler Hospital, Providence, RI, USA.

In a sample of 62 patients with Bipolar I disorder, the authors used a repeated measures longitudinal design to examine whether global family functioning was associated with the presence of a concurrent bipolar episode as well as whether global family functioning was associated with the presence of manic and depressive episodes in the following 3 months. Participants were recruited for a randomized clinical trial examining the efficacy of family treatments combined with pharmacotherapy for bipolar disorder. Global family functioning was repeatedly measured with both clinician-rated and patient-rated assessment instruments over the 28-month study period. Results indicated that mood episodes were associated with concurrent global family functioning within individuals, but global family functioning was not associated with episode status in the subsequent 3 months. The repeated measures nature of these results suggests that global family functioning and bipolar episodes may fluctuate in concert with each other but that global family functioning is not associated with subsequent change in episode status.
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http://dx.doi.org/10.1037/0893-3200.20.4.701DOI Listing
December 2006

Family functioning and mood disorders: a comparison between patients with major depressive disorder and bipolar I disorder.

J Consult Clin Psychol 2006 Dec;74(6):1192-1202

Department of Psychiatry and Human Behavior.

Within a sample of patients with major depressive disorder (MDD; n = 121) and bipolar affective disorder (BPAD; n = 69), the authors examined (a) diagnostic differences in family functioning at acute episode, (b) diagnostic differences in family functioning at episode recovery, (c) within-group changes in family functioning from acute episode to recovery, and (d) whether within-group changes from acute episode to recovery varied by diagnosis. Using a multidimensional model, the authors evaluated interviewer, patient, and family ratings. Overall, patients with MDD and BPAD evidenced similar levels of family impairment at acute episode and recovery. Generally, patients in both groups experienced improvement in family functioning over time, yet mean scores at recovery continued to range from fair to poor. Although certain specific differences emerged, diagnostic groups appeared to be more similar than different in level and pattern of family functioning.
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http://dx.doi.org/10.1037/0022-006X.74.6.1192DOI Listing
December 2006

Realistic expectations and a disease management model for depressed patients with persistent symptoms.

J Clin Psychiatry 2006 Sep;67(9):1412-21

Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA.

Objective: To describe the efficacy of currently available treatments for depression in achieving remission and to highlight additional strategies for those patients who continue to experience persistent depressive symptoms in spite of optimal treatment.

Data Sources: The authors reviewed the literature (electronic and hand searches) on the efficacy of current pharmacologic and psychotherapeutic antidepressant treatments and the utility of a chronic disease management model. A search of PubMed was conducted for English-language articles published from 1980 to 2005 using the keywords depression treatments, outcome, course of illness, and treatment resistant depression.

Data Synthesis: Current treatments for depression leave a significant minority (20%-40%) of patients with persistent depressive symptoms. A disease management model that may be useful for major depressive disorder is described.

Conclusions: The goal of treating depression to achieve remission, although ideal, is currently unattainable for many patients. The long-term care of patients with persisting depressive symptoms may be well served by adding a disease management component to the overall treatment strategy. Doing so may help to improve coping, interpersonal functioning, and quality of life.
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http://dx.doi.org/10.4088/jcp.v67n0912DOI Listing
September 2006

Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit.

Mol Cell Biol 2006 Oct 5;26(20):7529-38. Epub 2006 Aug 5.

Department of Cell Biology and Physiology & Howard Hughes Medical Institute, Washington University School of Medicine, Box 8228, 660 South Euclid Ave., St. Louis, MO 63110, USA.

In higher eukaryotic organisms, the checkpoint kinase 1 (Chk1) contributes essential functions to both cell cycle and checkpoint control. Chk1 executes these functions, in part, by targeting the Cdc25A protein phosphatase for ubiquitin-mediated proteolysis. In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. Here, we report that inhibition of Chk1 kinase activity paradoxically leads to the accumulation of S317- and S345-phosphorylated Chk1 in vivo and that ATR catalyzes Chk1 phosphorylation under these conditions. We demonstrate that Chk1 phosphorylation by ATR is antagonized by protein phosphatase 2A (PP2A). Importantly, dephosphorylation of Chk1 by PP2A is regulated, in part, by the kinase activity of Chk1. We propose that the ATR-Chk1-PP2A regulatory circuit functions to keep Chk1 in a low-activity state during an unperturbed cell division cycle but at the same time keeps Chk1 primed to respond rapidly in the event that cells encounter genotoxic stress.
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http://dx.doi.org/10.1128/MCB.00447-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636880PMC
October 2006

Family functioning in the caregivers of patients with dementia: one-year follow-up.

Bull Menninger Clin 2006 ;70(3):222-31

Psychiatry and Human Behavior (Clinical), Brown University Medical School, Butler Hospital, Providence, Rhode Island 02906, USA.

Caregivers for relatives with dementia can maintain their quality of life without specific intervention. It is unclear which variables are protective and which variables are aggravating for the caregiver. To assess the impact of family functioning on caregiver burden over time, the authors had caregivers of out patients with dementia complete self-report questionnaires at recruitment and at 1 year. At recruitment, 63% of caregivers were female, with a mean age of 62 years. Mean patient age was 73 years. The average number of caregiving years was 3.1. Caregivers were more likely to be spouses (61%). After 1-year, caregivers who stayed in the study reported no change in burden, reward, quality of life, or overall family functioning, although the patient's activities of daily living and level of disability were perceived to have significantly deteriorated. Caregivers who reported poor family functioning at initial assessment had higher ratings of strain and burden.
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http://dx.doi.org/10.1521/bumc.2006.70.3.222DOI Listing
October 2006

Psychoeducation for caregivers of patients with chronic mood disorders.

Bull Menninger Clin 2005 ;69(4):331-40

Brown University Medical School, Butler Hospital, Providence, Rhode Island 02906, USA.

Caregivers of patients with mood disorders report high levels of caregiver burden and poor family functioning. This study assessed the impact of educating caregivers about their symptoms and about community resources. Depressive symptoms were reported by 74% of caregivers, but only 37% of these caregivers accepted a referral and only 6% followed through. Similarly, of those with poor family functioning, 44% were offered a referral, 22% accepted, but only 5% followed through. Overall, 82% reported that the psychoeducational packet was useful.
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http://dx.doi.org/10.1521/bumc.2005.69.4.331DOI Listing
June 2006

Treatment matching in the posthospital care of depressed patients.

Am J Psychiatry 2005 Nov;162(11):2131-8

Psychosocial Research Program, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA.

Objective: This study assessed the efficacy of 1) matching patients to treatments and 2) adding additional family therapy or cognitive therapy in a group of recently discharged patients with major depression.

Method: Patients with major depression were recruited during a psychiatric hospitalization. After discharge, they were randomly assigned to one of four treatment conditions that were either "matched" or "mismatched" to their pattern of cognitive distortion and family impairment. The four treatment conditions were 1) pharmacotherapy alone; 2) combined pharmacotherapy and cognitive therapy; 3) combined pharmacotherapy and family therapy; and 4) combined pharmacotherapy, cognitive therapy, and family therapy. Randomly assigned treatment continued for 24 weeks on an outpatient basis.

Results: Among patients with at least moderate depressive symptoms at hospital discharge, low rates of remission (16%) and improvement (29%) were obtained. Matched treatment led to a significantly greater proportion of patients who improved and greater reductions over time in interviewer-rated depressive symptoms than mismatched treatment. However, matched treatment did not produce greater change in self-reported depression or interviewer-rated suicidal ideation. Treatment that included a family therapy component also led to a greater proportion of patients who improved and to significant reductions in interviewer-rated depression and suicidal ideation than treatment without family therapy.

Conclusions: These results suggest that 1) current treatments are not very efficacious in the aftercare of hospitalized depressed patients, 2) treatment matching moderately improves outcome for patients who are symptomatic at hospital discharge, and 3) inclusion of family therapy improves the outcome of posthospital care for depressed patients.
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http://dx.doi.org/10.1176/appi.ajp.162.11.2131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1899157PMC
November 2005