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1.  Treatment of depression in cancer patients 
Current Oncology  2007;14(5):180-188.
Question
What is the efficacy of pharmacologic and non-pharmacologic treatments for major depression and other depressive disorders in cancer populations?
Perspectives
Depression occurs at an increased rate in medically ill populations, including patients with cancer. In the general population, depression has been shown to be responsive to structured forms of psychotherapy and to pharmacologic interventions. The Supportive Care Guidelines Group conducted a systematic review of the evidence for the effectiveness of those therapies in patients with depression and cancer and developed the present clinical practice guideline based on that review and on expert consensus.
Outcomes
Outcomes of interest included symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life.
Methodology
Clinical recommendations were developed by the Supportive Care Guidelines Group based on a systematic review of the published literature through June 2005, feedback obtained from Ontario health care providers on the draft recommendations, the Report Approval Panel (rap) of Cancer Care Ontario’s Program in Evidence-Based Care, and expert consensus.
Results
The systematic review of the literature included eleven trials (seven of pharmacologic agents and four of non-pharmacologic interventions). Feedback received from 44 responding health care providers and the rap on the draft recommendations was addressed and documented in the guideline.
Among providers, 82% agreed with the draft recommendations as stated, 68% agreed that the report should be approved as a practice guideline, and 73% indicated that they would be likely to use the guideline in their own practice.
Practice Guideline
These recommendations apply to adult cancer patients with a diagnosis of major depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. The guideline is intended both for oncology health professionals and for mental health professionals engaged in the treatment of cancer patients. Expert consensus was central to the development of the guideline recommendations because of limited evidence in cancer patients.
Recommendations
Treatment of pain and other reversible physical symptoms should be instituted before or with initiation of specific antidepressant treatment.
Antidepressant medications should be considered for the treatment of moderate-to-severe major depression in cancer patients. Current evidence does not support the relative superiority of one pharmacologic treatment over another, nor the superiority of pharmacologic treatment over psychosocial interventions. The choice of an antidepressant should be informed by individual medication and patient factors: the side effect profiles of the medication, tolerability of treatment (including the potential for interaction with other current medications), response to prior treatment, and patient preference.
Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacologic interventions. Psychosocial treatment approaches that may be of value include those that provide information and support and those that address any combination of emotional, cognitive, and behavioural factors.
Qualifying Statements
Referral to a mental health specialist is appropriate when the diagnosis of depression is unclear, when the syndrome is severe, when patients do not respond to treatment, or when other complicating factors that may affect the choice of treatment are present.
Although care has been taken in the preparation of the information contained in this guideline, any person seeking to apply or to consult the guideline is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician.
PMCID: PMC2002483  PMID: 17938701
Practice guideline; depression; treatment; cancer
2.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments 
PLoS Medicine  2013;10(7):e1001489.
Background
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.
Methods and Findings
We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria—most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.
Conclusions
By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development process for new drugs is lengthy and complex. It begins in the laboratory, where scientists investigate the causes of diseases and identify potential new treatments. Next, promising interventions undergo preclinical research in cells and in animals (in vivo animal experiments) to test whether the intervention has the expected effect and to support the generalization (extension) of this treatment–effect relationship to patients. Drugs that pass these tests then enter clinical trials, where their safety and efficacy is tested in selected groups of patients under strictly controlled conditions. Finally, the government bodies responsible for drug approval review the results of the clinical trials, and successful drugs receive a marketing license, usually a decade or more after the initial laboratory work. Notably, only 11% of agents that enter clinical testing (investigational drugs) are ultimately licensed.
Why Was This Study Done?
The frequent failure of investigational drugs during clinical translation is potentially harmful to trial participants. Moreover, the costs of these failures are passed onto healthcare systems in the form of higher drug prices. It would be good, therefore, to reduce the attrition rate of investigational drugs. One possible explanation for the dismal success rate of clinical translation is that preclinical research, the key resource for justifying clinical development, is flawed. To address this possibility, several groups of preclinical researchers have issued guidelines intended to improve the design and execution of in vivo animal studies. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the authors identify the experimental practices that are commonly recommended in these guidelines and organize these recommendations according to the type of threat to validity (internal, construct, or external) that they address. Internal threats to validity are factors that confound reliable inferences about treatment–effect relationships in preclinical research. For example, experimenter expectation may bias outcome assessment. Construct threats to validity arise when researchers mischaracterize the relationship between an experimental system and the clinical disease it is intended to represent. For example, researchers may use an animal model for a complex multifaceted clinical disease that only includes one characteristic of the disease. External threats to validity are unseen factors that frustrate the transfer of treatment–effect relationships from animal models to patients.
What Did the Researchers Do and Find?
The researchers identified 26 preclinical guidelines that met their predefined eligibility criteria. Twelve guidelines addressed preclinical research for neurological and cerebrovascular drug development; other disorders covered by guidelines included cardiac and circulatory disorders, sepsis, pain, and arthritis. Together, the guidelines offered 55 different recommendations for the design and execution of preclinical in vivo animal studies. Nineteen recommendations addressed threats to internal validity. The most commonly included recommendations of this type called for the use of power calculations to ensure that sample sizes are large enough to yield statistically meaningful results, random allocation of animals to treatment groups, and “blinding” of researchers who assess outcomes to treatment allocation. Among the 25 recommendations that addressed threats to construct validity, the most commonly included recommendations called for characterization of the properties of the animal model before experimentation and matching of the animal model to the human manifestation of the disease. Finally, six recommendations addressed threats to external validity. The most commonly included of these recommendations suggested that preclinical research should be replicated in different models of the same disease and in different species, and should also be replicated independently.
What Do These Findings Mean?
This systematic review identifies a range of investigational recommendations that preclinical researchers believe address threats to the validity of preclinical efficacy studies. Many of these recommendations are not widely implemented in preclinical research at present. Whether the failure to implement them explains the frequent discordance between the results on drug safety and efficacy obtained in preclinical research and in clinical trials is currently unclear. These findings provide a starting point, however, for the improvement of existing preclinical research guidelines for specific diseases, and for the development of similar guidelines for other diseases. They also provide an evidence-based platform for the analysis of preclinical evidence and for the study and evaluation of preclinical research practice. These findings should, therefore, be considered by investigators, institutional review bodies, journals, and funding agents when designing, evaluating, and sponsoring translational research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001489.
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals; its Patient Network provides a step-by-step description of the drug development process that includes information on preclinical research
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides information about all aspects of the scientific evaluation and approval of new medicines in the UK; its My Medicine: From Laboratory to Pharmacy Shelf web pages describe the drug development process from scientific discovery, through preclinical and clinical research, to licensing and ongoing monitoring
The STREAM website provides ongoing information about policy, ethics, and practices used in clinical translation of new drugs
The CAMARADES collaboration offers a “supporting framework for groups involved in the systematic review of animal studies” in stroke and other neurological diseases
doi:10.1371/journal.pmed.1001489
PMCID: PMC3720257  PMID: 23935460
3.  Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy 
Several organizations worldwide have developed procedure-based guidelines and/or position statements regarding various aspects of quality and safety indicators, and credentialing for endoscopy. Although important, they do not specifically address patient needs or provide a framework for their adoption in the context of endoscopy services. The consensus guidelines reported in this article, however, aimed to identify processes and indicators relevant to the provision of high-quality endoscopy services that will support ongoing quality improvement across many jurisdictions, specifically in the areas of ethics, facility standards and policies, quality assurance, training and education, reporting standards and patient perceptions.
BACKGROUND:
Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy.
OBJECTIVE:
To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery.
METHODS:
A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants.
RESULTS:
Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), quality assurance (statements 10 to 13: 94% to 100%), training, education, competency and privileges (statements 14 to 19: 97% to 100%), endoscopy reporting standards (statements 20 and 21: 97% to 100%) and patient perceptions (statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified.
DISCUSSION:
The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services.
CONCLUSIONS:
The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.
PMCID: PMC3275402  PMID: 22308578
Digestive system; Endoscopy; Guideline; Health care; Quality assurance
4.  Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes 
PLoS Medicine  2013;10(3):e1001403.
In a systematic review and meta-analysis, Glen Spielmans and colleagues find that adjunctive atypical antipsychotic medications are associated with small-to-moderate improvements in depressive symptoms in patients with depression, but there is little evidence for improvement on measures of quality of life, and these medications are linked to adverse events such as weight gain.
Background
Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk–benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression.
Methods and Findings
We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48–2.73), OFC (OR, 1.42; 95% CI, 1.01–2.0), quetiapine (OR, 1.79; 95% CI, 1.33–2.42), and risperidone (OR, 2.37; 95% CI, 1.31–4.30).
The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58–2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87–1.93), quetiapine (OR, 1.53, 95% CI, 1.17–2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16–2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery–Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49).
Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events.
Conclusions
Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Everyone feels miserable occasionally. But for people who are clinically depressed, feelings of sadness and hopelessness and physical symptoms such as sleeping badly can last for months or years and can make them feel life is no longer worth living. Depression affects one in six people at some time during their life. Clinicians diagnose depression by asking their patients a series of questions about their feelings and symptoms. The answer to each question is given a score, and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. Treatment of depression often involves talking treatments (psychotherapy) such as cognitive behavioral therapy, which helps people change negative ways of thinking and behaving and antidepressant drugs, most commonly “selective serotonin reuptake inhibitors” such as fluoxetine and paroxetine.
Why Was This Study Done?
Atypical antipsychotic medications (for example, aripiprazole, olanzapine/fluoxetine combination [OFC], quetiapine, and risperidone) are also widely prescribed for the treatment of depression. These drugs, which were developed to treat mental illnesses that are characterized by a loss of contact with reality, are used as adjunctive therapy for depression. That is, they are used in addition to antidepressant drugs. Clinicians wrote nearly four million prescriptions for adjunctive treatment of depression with atypical antipsychotic medications in 2007–2008 in the US alone. However, it is not known whether the benefits of using these drugs to treat depression outweigh their side effects, which include weight gain, sedation, and akathisia (a feeling of inner restlessness resulting in an urge to move, which may or may not be accompanied by increased movement). Here, the researchers undertake a systematic review and meta-analysis of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 14 short-term randomized controlled trials (duration 4–12 weeks) that compared adjunctive antipsychotic medications (aripiprazole, OFC, quetiapine, or risperidone) to placebo (dummy drug) in the treatment of depression that had not responded to antidepressant medication alone. All four drugs had statistically significant effects (effects unlikely to have happened by chance) on remission, which was most commonly defined as a score of less than eight at the study end point on the Montgomery–Asberg Depression Rating Scale. The researchers calculated the number of patients that would have to be treated for one patient to achieve remission (number needed to treat, or NNT). For OFC, the NNT was 19; for all the other drugs it was nine. All the drugs except OFC also significantly improved response rates (defined as a 50% improvement in depression rating score). However, the medications provided little or no benefit in terms of functioning and quality of life, except for risperidone, which had a small-to-moderate effect on quality of life. Finally, treatment with atypical antipsychotic medications was linked to several adverse effects, including weight gain (all four drugs) and akathisia (aripiprazole).
What Do These Findings Mean?
These results suggest that atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms. However, clinicians should interpret this conclusion cautiously for several reasons. First, adjunctive treatment with atypical antipsychotics provided only small-to-moderate benefits. Moreover, shortcomings in study design and data reporting methods may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Second, this study provides little evidence that adjunctive treatment with atypical antipsychotics improves patients' quality of life or reduces their functional impairment. Finally, this study highlights abundant evidence of potential treatment-related harm. This evaluation of the safety and efficacy of adjunctive treatments for clinical depression provides critical insights that should help clinicians better understand the risk–benefit profiles of this approach to the treatment of major depressive disorder.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001403.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); it has a webpage on mental health medications that includes information about atypical antipsychotics
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
The UK charity Mind provides information on depression and on antipsychotic drugs; Mind also includes personal stories about depression on its website
MedlinePlus provides links to other resources about depression (in English and Spanish)
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
doi:10.1371/journal.pmed.1001403
PMCID: PMC3595214  PMID: 23554581
5.  A Review of the Effectiveness of Antidepressant Medications for Depressed Nursing Home Residents 
Background
Antidepressant medications are the most common psychopharmacologic therapy used to treat depressed nursing home (NH) residents. Despite a significant increase in the rate of antidepressant prescribing over the past several decades, little is known about the effectiveness of these agents in the NH population.
Objective
To conduct a systematic review of the literature to examine and compare the effectiveness of antidepressant medications for treating major depressive symptoms in elderly NH residents.
Methods
The following databases were searched with searches completed prior to January 2011 and no language restriction: MEDLINE, Embase, PsycINFO, CINHAL, CENTRAL, LILACS, ClinicalTrials.gov, International Standard Randomized Controlled Trial Number Register, and the WHO International Clinical Trial Registry Platform. Additional studies were identified from citations in evidence-based guidelines and reviews as well as book chapters on geriatric depression and pharmacotherapy from several clinical references. Studies were included if they described a clinical trial that assessed the effectiveness of any currently-marketed antidepressant for adults aged 65 years or older, who resided in the NH, and were diagnosed by DSM criteria and/or standardized validated screening instruments with Major Depressive Disorder, minor depression, dysthymic disorder, or Depression in Alzheimer’s disease.
Results
A total of eleven studies, including four randomized and seven non-randomized open-label trials, met all inclusion and exclusion criteria. It was not feasible to conduct a meta-analysis because the studies were heterogeneous in terms of study design, operational definitions of depression, participant characteristics, pharmacologic interventions, and outcome measures. Of the four randomized trials, two had a control group and did not demonstrate a statistically-significant benefit for antidepressant pharmacotherapy over placebo. While six of the seven non-randomized studies identified a response to an antidepressant, their results must be interpreted with caution as they lacked a comparison group.
Conclusions
The limited amount of evidence from randomized and non-randomized open-label trials suggests that depressed NH residents have a modest response to antidepressant medications. Further research using rigorous study designs are needed to examine the effectiveness and safety of antidepressants in depressed NH residents, and to determine the various facility, provider, and patient factors associated with response to treatment.
doi:10.1016/j.jamda.2011.08.009
PMCID: PMC3340502  PMID: 22019084
Antidepressants; nursing homes; depression; effectiveness
6.  Effectiveness of cognitive behavioural therapy augmentation in major depression treatment (ECAM study): study protocol for a randomised clinical trial 
BMJ Open  2014;4(10):e006359.
Introduction
Major depression is a serious mental disorder that causes substantial distress and impairment in individuals and places an enormous burden on society. Although antidepressant treatment is the most common therapy provided in routine practice, there is little evidence to guide second-line therapy for patients who have failed to respond to antidepressants. The aim of this paper is to describe the study protocol for a randomised controlled trial that measures the clinical effectiveness of cognitive behavioural therapy (CBT) as an augmentation strategy to treat patients with non-psychotic major depression identified as suboptimal responders to usual depression care.
Methods and analysis
The current study is a 16-week assessor-blinded randomised, parallel-groups superiority trial with 12-month follow-up at an outpatient clinic as part of usual depression care. Patients aged 20–65 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Major Depressive Disorder who have experienced at least one failed trial of antidepressants as part of usual depression care, will be randomly assigned to receive CBT plus treatment as usual, or treatment as usual alone. The primary outcome is the change in clinician-rated 17-item GRID-Hamilton Depression Rating Scale (GRID-HAMD) score at 16 weeks, and secondary outcomes include severity and change in scores of subjective depression symptoms, proportion of responders and remitters, safety and quality of life. The primary population will be the intention-to-treat patients.
Ethics and dissemination
All protocols and the informed consent form comply with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethics review committees at the Keio University School of Medicine and the Sakuragaoka Memorial Hospital approved the study protocol. The results of the study will be disseminated at several research conferences and as published articles in peer-reviewed journals. The study will be implemented and reported in line with the CONSORT statement.
Trial registration number
UMIN Clinical Trials Registry: UMIN000001218.
doi:10.1136/bmjopen-2014-006359
PMCID: PMC4208050  PMID: 25335963
major depressive disorder; cognitive behavior therapy; randomized controlled trial; clinical protocols
7.  Depression screening and mental health outcomes in children and adolescents: a systematic review protocol 
Systematic Reviews  2012;1:58.
Background
Depression is an important cause of disability among children and adolescents. Depression screening is one possible method for managing depression, and screening programs have been initiated in some school and medical settings. However, in 2005, the Canadian Task Force on Preventive Health Care and the United Kingdom National Institute of Clinical Excellence did not recommend depression screening among children and adolescents. By contrast, in 2009, the United States Preventive Services Task Force recommended that all adolescents, but not younger children, be screened for depression in medical settings with integrated depression management services, although no trials of screening were identified. The objectives of this systematic review are to evaluate in children and adolescents the accuracy of depression screening tools; depression treatment efficacy; whether depression screening improves depression outcomes; and potential harms related to depression interventions and screening.
Methods/design
Data sources will include the bibliographic databases MEDLINE, Cochrane CENTRAL, PsycINFO, EMBASE, LILACS and Web of Science, supplemented by reference harvesting of eligible articles, relevant systematic reviews, relevant guidelines and recommendations, and selected journals, and by searches for unpublished studies. Eligible studies will report data for children and adolescents aged 6 to 18 years. Eligible diagnostic accuracy studies must compare a depression screening tool to a validated diagnostic interview for major depressive disorder and report diagnostic accuracy data. Eligible treatment studies must be randomized controlled trials of pharmacological, psychotherapeutic, or other depression treatments commonly available for children and adolescents in pediatric, primary-care, and family medicine settings. Eligible screening studies must be randomized controlled trials that compare depression outcomes between children or adolescents who underwent depression screening versus those who did not. Studies of harms will include randomized controlled trials and observational studies that evaluate harms from depression screening or treatment. Two investigators will independently review titles and abstracts, followed by full article review. Disagreements will be resolved by consensus. Two investigators will independently extract the data, with discrepancies resolved via consensus.
Discussion
The proposed systematic review will determine whether there is sufficient evidence of benefits in excess of harms and costs to support screening for depression in childhood and adolescence.
doi:10.1186/2046-4053-1-58
PMCID: PMC3563607  PMID: 23176742
Adolescents; Children; Depression; Screening
8.  A Review of Antidepressant Therapy in Primary Care: Current Practices and Future Directions 
Objective: To provide general practitioners with a comparison of major depressive disorder treatments received in primary care and psychiatric clinic settings, a focus on treatment outcomes related to currently prescribed antidepressants, and a review of new and emerging therapeutic strategies.
Data Sources: English-language evidence-based guidelines and peer-reviewed literature published between January 1, 2005, and December 31, 2011, were identified using PubMed, MEDLINE, and EMBASE. All searches contained the terms major depressive disorder and unipolar depression, and excluded the terms bipolar disorder/manic depressive disorder. The following search terms were also included: naturalistic study, antidepressant, relapse, recurrence, residual symptoms, response, remission, sequential medication trials, and treatment-resistant depression.
Study Selection: Meta-analyses, systematic reviews, and practice guidelines were included. Bibliographies were used to identify additional articles of interest.
Data Extraction: Abstracts and articles were screened for relevance to primary care practice. Population-based studies and those involving patients treated in primary care were used whenever possible.
Data Synthesis: Achieving remission from a major depressive episode is important to improve functional outcomes and to reduce relapse and recurrence. Despite the availability of numerous antidepressants, as many as 50% of patients require treatment modifications beyond first-line therapy. Among remitters, 90% report residual symptoms that may interfere with function. Patients treated in primary care often have chronic depression (symptom duration ≥ 24 months at presentation) and medical comorbidities. These are clinical predictors of worse outcomes and require individualized attention when treatment is initiated. Antidepressants differ in efficacy, tolerability, and side effects—factors that may affect adherence to treatment.
Conclusions: Major depressive disorder is highly prevalent in primary care and is among the most common causes of loss of disability-adjusted life-years worldwide. There are few differences in clinical profiles between depressed patients in primary care and those in specialist clinics, although differences in symptoms and comorbid conditions among individual depressed patients present a challenge for the physician providing individualized treatment. The goal of treatment is remission with good functional and psychosocial outcomes. Physicians in primary care should have expertise in working with a number of current antidepressant approaches and an awareness of new and emerging treatments.
doi:10.4088/PCC.12r01420
PMCID: PMC3733527  PMID: 23930234
9.  Depression Screening and Patient Outcomes in Cancer: A Systematic Review 
PLoS ONE  2011;6(11):e27181.
Background
Several practice guidelines recommend screening for depression in cancer care, but no systematic reviews have examined whether there is evidence that depression screening benefits cancer patients. The objective was to evaluate the potential benefits of depression screening in cancer patients by assessing the (1) accuracy of depression screening tools; (2) effectiveness of depression treatment; and (3) effect of depression screening, either alone or in the context of comprehensive depression care, on depression outcomes.
Methods
Data sources were CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO and SCOPUS databases through January 24, 2011; manual journal searches; reference lists; citation tracking; trial registry reviews. Articles on cancer patients were included if they (1) compared a depression screening instrument to a valid criterion for major depressive disorder (MDD); (2) compared depression treatment with placebo or usual care in a randomized controlled trial (RCT); (3) assessed the effect of screening on depression outcomes in a RCT.
Results
There were 19 studies of screening accuracy, 1 MDD treatment RCT, but no RCTs that investigated effects of screening on depression outcomes. Screening accuracy studies generally had small sample sizes (median = 17 depression cases) and used exploratory methods to set sample-specific cutoff scores that varied substantially across studies. A nurse-delivered intervention for MDD reduced depressive symptoms moderately (effect size = 0.37).
Conclusions
The one treatment study reviewed reported modest improvement in depressive symptoms, but no evidence was found on whether or not depression screening in cancer patients, either alone or in the context of optimal depression care, improves depression outcomes compared to usual care. Depression screening in cancer should be evaluated in a RCT in which all patients identified as depressed, either through screening or via physician recognition and referral in a control group, have access to comprehensive depression care.
doi:10.1371/journal.pone.0027181
PMCID: PMC3215716  PMID: 22110613
10.  How Does Medical Device Regulation Perform in the United States and the European Union? A Systematic Review 
PLoS Medicine  2012;9(7):e1001276.
Aaron Kesselheim and colleagues conduct a systematic review to examine the strengths and weaknesses associated with approaches to medical device regulation in the US and EU.
Background
Policymakers and regulators in the United States (US) and the European Union (EU) are weighing reforms to their medical device approval and post-market surveillance systems. Data may be available that identify strengths and weakness of the approaches to medical device regulation in these settings.
Methods and Findings
We performed a systematic review to find empirical studies evaluating medical device regulation in the US or EU. We searched Medline using two nested categories that included medical devices and glossary terms attributable to the US Food and Drug Administration and the EU, following PRISMA guidelines for systematic reviews. We supplemented this search with a review of the US Government Accountability Office online database for reports on US Food and Drug Administration device regulation, consultations with local experts in the field, manual reference mining of selected articles, and Google searches using the same key terms used in the Medline search. We found studies of premarket evaluation and timing (n = 9), studies of device recalls (n = 8), and surveys of device manufacturers (n = 3). These studies provide evidence of quality problems in pre-market submissions in the US, provide conflicting views of device safety based largely on recall data, and relay perceptions of some industry leaders from self-surveys.
Conclusions
Few studies have quantitatively assessed medical device regulation in either the US or EU. Existing studies of US and EU device approval and post-market evaluation performance suggest that policy reforms are necessary for both systems, including improving classification of devices in the US and promoting transparency and post-market oversight in the EU. Assessment of regulatory performance in both settings is limited by lack of data on post-approval safety outcomes. Changes to these device approval and post-marketing systems must be accompanied by ongoing research to ensure that there is better assessment of what works in either setting.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Medical devices—health technologies that are not medicines, vaccines, or clinical procedures—cover a vast range of equipment from the simple to the more complex. Medical devices are essential for patient care, and in the past decade, new devices have offered improved treatment alternatives for many diseases and conditions, leading to substantial growth in the US$350 billion medical device industry. However, new medical devices also pose substantial risks to patients, as shown in recent high-profile product recalls involving breast implants and artificial hip implants.
Why Was This Study Done?
Concerns about the safety of new medical devices have led to calls for greater testing of the safety and effectiveness of new devices before they come on the market and for improved monitoring of their performance after new devices have been approved for use by a regulatory body. In this study, the researchers systematically reviewed evidence about the performance of medical device approval and post-market surveillance systems in two of the most important world markets for medical devices—the United States and the European Union.
What Did the Researchers Do and Find?
The researchers performed a keyword search in Medline (a database of published biomedical literature) for all relevant articles, and supplemented this search with a review of reports on Food and Drug Administration (FDA) device regulation in the US Government Accountability Office's online database. Then they consulted with both US and EU experts and also conducted Google searches to capture reports by management consultant firms. The researchers included only those studies that reported empirical data, either qualitative or quantitative, about the characteristics, performance metrics, or effectiveness of device evaluation or post-market oversight in the US or EU.
Using these methods the researchers identified nine studies that focused on pre-market evaluation and timing, eight studies of device recalls, and three surveys of device manufacturers. Because of the variable quality and lack of outcomes from these studies and reports, the researchers concluded that these studies offered only limited insights into either the US or EU systems. But the available evidence does suggest that in the US, the FDA could improve oversight of device approval, for example, by following up on its commitment to reclassify high-risk medical devices and improve post-market surveillance of devices that are approved on the basis of limited data. The researchers also suggest that using recalls to measure the safety record of individual devices or classes of devices is flawed, as particular devices may be over- or underrepresented in recall data depending on the frequency of their use, design complexity, and the clinical manifestations of malfunction. In the EU, apart from a few studies addressing the timing of approval, the researchers found almost no robust data on device regulation. Some case reports suggested substantial dangers to patients in the EU from devices approved on the basis of limited data, but the researchers could not systematically compare the quality of studies used for device approval or post-approval safety outcomes between the EU and US, mainly because of the lack of transparency among the EU regulators (Notified Bodies).
What Do These Findings Mean?
These findings show that few studies have quantitatively assessed medical device regulation in either the US or EU, but the existing studies examined in this review suggest that policy reforms are necessary for both device approval and post-market evaluation of performance, including improving classification of devices in the US and promoting transparency and postmarket oversight in the EU. However, assessment of regulatory performance in both the US and EU is limited by lack of data on post-approval safety outcomes. Any changes to medical device approval and post-marketing systems should be accompanied by ongoing research and evaluation to ensure that there is an improved assessment of what works in either setting.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001276.
This study is further discussed in a PLoS Medicine Perspective by Sanket Dhruva and Rita Redberg
The WHO website has a comprehensive topic section on medical devices
Information on medical devices is also available from the FDA and the European Commission
doi:10.1371/journal.pmed.1001276
PMCID: PMC3418047  PMID: 22912563
11.  Developing a national dissemination plan for collaborative care for depression: QUERI Series 
Background
Little is known about effective strategies for disseminating and implementing complex clinical innovations across large healthcare systems. This paper describes processes undertaken and tools developed by the U.S. Department of Veterans Affairs (VA) Mental Health Quality Enhancement Research Initiative (MH-QUERI) to guide its efforts to partner with clinical leaders to prepare for national dissemination and implementation of collaborative care for depression.
Methods
An evidence-based quality improvement (EBQI) process was used to develop an initial set of goals to prepare the VA for national dissemination and implementation of collaborative care. The resulting product of the EBQI process is referred to herein as a "National Dissemination Plan" (NDP). EBQI participants included: a) researchers with expertise on the collaborative care model for depression, clinical quality improvement, and implementation science, and b) VA clinical and administrative leaders with experience and expertise on how to adapt research evidence to organizational needs, resources and capacity. Based on EBQI participant feedback, drafts of the NDP were revised and refined over multiple iterations before a final version was approved by MH-QUERI leadership. 'Action Teams' were created to address each goal. A formative evaluation framework and related tools were developed to document processes, monitor progress, and identify and act upon barriers and facilitators in addressing NDP goals.
Results
The National Dissemination Plan suggests that effectively disseminating collaborative care for depression in the VA will likely require attention to: Guidelines and Quality Indicators (4 goals), Training in Clinical Processes and Evidence-based Quality Improvement (6 goals), Marketing (7 goals), and Informatics Support (1 goal). Action Teams are using the NDP as a blueprint for developing infrastructure to support system-wide adoption and sustained implementation of collaborative care for depression. To date, accomplishments include but are not limited to: conduct of a systematic review of the literature to update VA depression treatment guidelines to include the latest evidence on collaborative care for depression; training for clinical staff on TIDES (Translating Initiatives for Depression into Effective Solutions project) care; spread of TIDES care to new VA facilities; and integration of TIDES depression assessment tools into a planned update of software used in delivery of VA mental health services. Thus far, common barriers encountered by Action Teams in addressing NDP goals include: a) limited time to address goals due to competing tasks/priorities, b) frequent turnover of key organizational leaders/stakeholders, c) limited skills and training among team members for addressing NDP goals, and d) difficulty coordinating activities across Action Teams on related goals.
Conclusion
MH-QUERI has partnered with VA organizational leaders to develop a focused yet flexible plan to address key factors to prepare for national dissemination and implementation of collaborative care for depression. Early indications suggest that the plan is laying an important foundation that will enhance the likelihood of successful implementation and spread across the VA healthcare system.
doi:10.1186/1748-5908-3-59
PMCID: PMC2631596  PMID: 19117524
12.  Effect of Treatment of Obstructive Sleep Apnea on Depressive Symptoms: Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(11):e1001762.
In a meta-analysis of randomized controlled trials, Matthew James and colleagues investigate the effects of continuous positive airway pressure or mandibular advancement devices on depression.
Please see later in the article for the Editors' Summary
Background
Obstructive sleep apnea (OSA) is associated with increased morbidity and mortality, and decreased quality of life. Treatment with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is effective for many symptoms of OSA. However, it remains controversial whether treatment with CPAP or MAD also improves depressive symptoms.
Methods and Findings
We performed a systematic review and meta-analysis of randomized controlled trials that examined the effect of CPAP or MADs on depressive symptoms in patients with OSA. We searched Medline, EMBASE, the Cochrane Central Registry of Controlled Trials, and PsycINFO from the inception of the databases until August 15, 2014, for relevant articles.
In a random effects meta-analysis of 19 identified trials, CPAP treatment resulted in an improvement in depressive symptoms compared to control, but with significant heterogeneity between trials (Q statistic, p<0.001; I2 = 71.3%, 95% CI: 54%, 82%). CPAP treatment resulted in significantly greater improvement in depressive symptoms in the two trials with a higher burden of depression at baseline (meta-regression, p<0.001). The pooled standardized mean difference (SMD) in depressive symptoms with CPAP treatment in these two trial populations with baseline depression was 2.004 (95% CI: 1.387, 2.621), compared to 0.197 (95% CI: 0.059, 0.334) for 15 trials of populations without depression at baseline. Pooled estimates of the treatment effect of CPAP were greater in parallel arm trials than in crossover trials (meta-regression, p = 0.076). Random effects meta-analysis of five trials of MADs showed a significant improvement in depressive symptoms with MADs versus controls: SMD = 0.214 (95% CI: 0.026, 0.401) without significant heterogeneity (I2 = 0%, 95% CI: 0%, 79%). Studies were limited by the use of depressive symptom scales that have not been validated specifically in people with OSA.
Conclusions
CPAP and MADs may be useful components of treatment of depressive symptoms in individuals with OSA and depression. The efficacy of CPAP and MADs compared to standard therapies for depression is unknown.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is particularly common among middle-aged and elderly people, although most are unaware that they have the condition. It is characterized by the occurrence of numerous brief (ten seconds or so) breathing interruptions during sleep. These “apneas” occur when relaxation of the upper airway muscles decreases airflow, which lowers the level of oxygen in the blood. Consequently, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Mild to moderate OSA can also be treated using a mandibular advancement device (MAD), a “splint” that fits inside the mouth and pushes the jaw and tongue forward to increase the space at the back of the throat and reduce airway narrowing. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air into the airway through a facemask to keep it open.
Why Was This Study Done?
OSA is a serious condition that is associated with an increased risk of illness and death. Clinical depression (long-lasting, overwhelming feelings of sadness and hopelessness), for example, is common among people with OSA. The interaction between these frequently co-morbid (co-existing) conditions is complex. The sleep disruption and weight gain that are often associated with depression could cause or worsen OSA. Conversely, OSA could trigger depression by causing sleep disruption and by inducing cognitive changes (changes in thinking) by intermittently starving the brain of oxygen. If the latter scenario is correct, then treating OSA with CPAP or MADs might improve depressive symptoms. Several trials have investigated this possibility, but their results have been equivocal. Here, the researchers undertake a systematic review and meta-analysis of randomized controlled trials that have examined the effect of CPAP or MADs on depressive symptoms in patients with OSA to find out whether treating co-morbid OSA in patients with depression can help to treat depression. A randomized controlled trial compares the outcomes of individuals chosen to receive different interventions through the play of chance, a systematic review uses predefined criteria to identify all the research on a given topic, and meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 trials that investigated the effects of CPAP or MAD treatment in patients with OSA and that measured depressive symptoms before and after treatment. Meta-analysis of the results of 19 trials that provided information about the effect of CPAP on depressive symptoms indicated that CPAP improved depressive symptoms compared to the control intervention (usually sham CPAP) but revealed considerable heterogeneity (variability) between trials. Notably, CPAP treatment resulted in a greater improvement in depressive symptoms in trials in which there was a high prevalence of depression at baseline than in trials in which there was a low prevalence of depression at baseline. Moreover, the magnitude of this improvement in depressive symptoms in trials with a high prevalence of depression at baseline was large enough to be clinically relevant. Meta-analysis of five trials that provided information about the effect of MADs on depressive symptoms indicated that MADs also improved depressive symptoms compared to the control intervention (sham MAD).
What Do These Findings Mean?
These findings suggest that both CPAP and MAD treatment for OSA can result in modest improvements in depressive symptoms and that populations with high initial levels of depressive symptoms may reap the greatest benefits of CPAP treatment. These findings give no indication of the efficacy of CPAP and MADs compared to standard treatments for depression such as antidepressant medications. Moreover, their accuracy may be limited by methodological limitations within the trials included in the meta-analyses reported here. For example, the questionnaires used to measure depression in these trials were not validated for use in people with OSA. Further high-quality randomized controlled trials are therefore needed to confirm the findings of this systematic review and meta-analysis. For now, however, these findings suggest that the use of CPAP and MADs may help improve depressive symptoms among people with OSA.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001762.
The US National Heart, Lung, and Blood Institute has information (including several videos) about sleep apnea (in English and Spanish)
The UK National Health Service Choices website provides information and personal stories about obstructive sleep apnea and depression
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and healthcare professionals, including personal stories about the condition
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish)
The Anxiety and Depression Association of America provides information about sleep disorders
The MedlinePlus encyclopedia has a page on obstructive sleep apnea; MedlinePlus provides links to further information and advice about obstructive sleep apnea and about depression (in English and Spanish)
doi:10.1371/journal.pmed.1001762
PMCID: PMC4244041  PMID: 25423175
13.  The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists✩ 
General hospital psychiatry  2009;31(5):403-413.
Objective
To address the maternal and neonatal risks of both depression and antidepressant exposure and develop algorithms for periconceptional and antenatal management.
Method
Representatives from the American Psychiatric Association, the American College of Obstetricians and Gynecologists and a consulting developmental pediatrician collaborated to review English language articles on fetal and neonatal outcomes associated with depression and antidepressant treatment during childbearing. Articles were obtained from Medline searches and bibliographies. Search keywords included pregnancy, pregnancy complications, pregnancy outcomes, depressive disorder, depressive disorder/dt, abnormalities/drug-induced/epidemiology, abnormalities/drug-induced/et. Iterative draft manuscripts were reviewed until consensus was achieved.
Results
Both depressive symptoms and antidepressant exposure are associated with fetal growth changes and shorter gestations, but the majority of studies that evaluated antidepressant risks were unable to control for the possible effects of a depressive disorder. Short-term neonatal irritability and neurobehavioral changes are also linked with maternal depression and antidepressant treatment. Several studies report fetal malformations in association with first trimester antidepressant exposure but there is no specific pattern of defects for individual medications or class of agents. The association between paroxetine and cardiac defects is more often found in studies that included all malformations rather than clinically significant malformations. Late gestational use of selective serotonin reuptake inhibitor antidepressants is associated with transitory neonatal signs and a low risk for persistent pulmonary hypertension in the newborn. Psychotherapy alone is an appropriate treatment for some pregnant women; however, others prefer pharmacotherapy or may require pharmacological treatment.
Conclusions
Antidepressant use in pregnancy is well studied, but available research has not yet adequately controlled for other factors that may influence birth outcomes including maternal illness or problematic health behaviors that can adversely affect pregnancy.
doi:10.1016/j.genhosppsych.2009.04.003
PMCID: PMC3094693  PMID: 19703633
Depression; Pregnancy; Antidepressant agents
14.  The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists☆,☆☆ 
Obstetrics and gynecology  2009;114(3):703-713.
Objective
To address the maternal and neonatal risks of both depression and antidepressant exposure and develop algorithms for periconceptional and antenatal management.
Method
Representatives from the American Psychiatric Association, the American College of Obstetricians and Gynecologists and a consulting developmental pediatrician collaborated to review English language articles on fetal and neonatal outcomes associated with depression and antidepressant treatment during childbearing. Articles were obtained from Medline searches and bibliographies. Search keywords included pregnancy, pregnancy complications, pregnancy outcomes, depressive disorder, depressive disorder/dt, abnormalities/drug-induced/epidemiology, abnormalities/drug-induced/et. Iterative draft manuscripts were reviewed until consensus was achieved.
Results
Both depressive symptoms and antidepressant exposure are associated with fetal growth changes and shorter gestations, but the majority of studies that evaluated antidepressant risks were unable to control for the possible effects of a depressive disorder. Short-term neonatal irritability and neurobehavioral changes are also linked with maternal depression and antidepressant treatment. Several studies report fetal malformations in association with first trimester antidepressant exposure but there is no specific pattern of defects for individual medications or class of agents. The association between paroxetine and cardiac defects is more often found in studies that included all malformations rather than clinically significant malformations. Late gestational use of selective serotonin reuptake inhibitor antidepressants is associated with transitory neonatal signs and a low risk for persistent pulmonary hypertension in the newborn. Psychotherapy alone is an appropriate treatment for some pregnant women; however, others prefer pharmacotherapy or may require pharmacological treatment.
Conclusions
Antidepressant use in pregnancy is well studied, but available research has not yet adequately controlled for other factors that may influence birth outcomes including maternal illness or problematic health behaviors that can adversely affect pregnancy.
doi:10.1097/AOG.0b013e3181ba0632
PMCID: PMC3103063  PMID: 19701065
Depression; Pregnancy; Antidepressant agents
15.  Pharmacologic treatment of depression in the elderly 
Canadian Family Physician  2014;60(2):121-126.
Abstract
Objective
To discuss pharmacologic treatment of depression in the elderly, including choice of antidepressants, titration of dose, monitoring of response and side effects, and treatment of unresponsive cases.
Sources of information
The 2006 Canadian Coalition for Seniors’ Mental Health guideline on the assessment and treatment of depression was used as a primary source. To identify articles published since the guideline, MEDLINE was searched from 2007 to 2012 using the terms depression, treatment, drug therapy, and elderly.
Main message
The goal of treatment should be remission of symptoms. Improvement of symptoms can be monitored by identifying patient goals or by use of a clinical tool such as the Patient Health Questionnaire–9. Treatment should be considered in 3 phases: an acute treatment phase to achieve remission of symptoms, a continuation phase to prevent recurrence of the same episode of illness (relapse), and a maintenance (prophylaxis) phase to prevent future episodes (recurrence). Initial dosing should be half of the usual adult starting dose and be titrated regularly until the patient responds, until the maximum dose is reached, or until side effects limit further increases. Common side effects of medications include falls, nausea, dizziness, headaches, and, less commonly, hyponatremia and QT interval changes. Strategies for switching or augmenting antidepressants are discussed. Older patients should be treated for at least a year from when clinical improvement is noted, and those with recurrent depression or severe symptoms should continue treatment indefinitely. Treatment of specific situations such as severe depression or depression with psychosis is discussed, including the use of electroconvulsive therapy. Criteria for referral to geriatric psychiatry are provided; however, many family physicians do not have easy access to this resource or to other nonpharmacologic clinical strategies.
Conclusion
The effectiveness of pharmacologic treatment of depression is not substantially affected by age. Identification of depression, choice of appropriate treatment, titration of medications, monitoring of side effects, and adequate duration of treatment will improve outcomes for older patients.
PMCID: PMC3922554  PMID: 24522673
16.  Association of FKBP51 with Priming of Autophagy Pathways and Mediation of Antidepressant Treatment Response: Evidence in Cells, Mice, and Humans 
PLoS Medicine  2014;11(11):e1001755.
Theo Rein and colleagues examine the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy.
Please see later in the article for the Editors' Summary
Background
FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, the underlying mechanisms remain elusive. The objective of this study was to elucidate the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy.
Methods and Findings
Established cell lines, primary neural cells, human blood cells of healthy individuals and patients with depression, and mice were treated with antidepressants. Mice were tested for several neuroendocrine and behavioral parameters. Protein interactions and autophagic pathway activity were mainly evaluated by co-immunoprecipitation and Western blots. We first show that the effects of acute antidepressant treatment on behavior are abolished in FKBP51 knockout (51KO) mice. Autophagic markers, such as the autophagy initiator Beclin1, were increased following acute antidepressant treatment in brains from wild-type, but not 51KO, animals. FKBP51 binds to Beclin1, changes decisive protein interactions and phosphorylation of Beclin1, and triggers autophagic pathways. Antidepressants and FKBP51 exhibited synergistic effects on these pathways. Using chronic social defeat as a depression-relevant stress model in combination with chronic paroxetine (PAR) treatment revealed that the stress response, as well as the effects of antidepressants on behavior and autophagic markers, depends on FKBP51. In human blood cells of healthy individuals, FKBP51 levels correlated with the potential of antidepressants to induce autophagic pathways.
Importantly, the clinical antidepressant response of patients with depression (n = 51) could be predicted by the antidepressant response of autophagic markers in patient-derived peripheral blood lymphocytes cultivated and treated ex vivo (Beclin1/amitriptyline: r = 0.572, p = 0.003; Beclin1/PAR: r = 0.569, p = 0.004; Beclin1/fluoxetine: r = 0.454, p = 0.026; pAkt/amitriptyline: r = −0.416, p = 0.006; pAkt/PAR: r = −0.355, p = 0.021; LC3B-II/PAR: r = 0.453, p = 0.02), as well as by the lymphocytic expression levels of FKBP51 (r = 0.631, p<0.0001), pAkt (r = −0.515, p = 0.003), and Beclin1 (r = 0.521, p = 0.002) at admission. Limitations of the study include the use of male mice only and the relatively low number of patients for protein analyses.
Conclusions
To our knowledge, these findings provide the first evidence for the molecular mechanism of FKBP51 in priming autophagic pathways; this process is linked to the potency of at least some antidepressants. These newly discovered functions of FKBP51 also provide novel predictive markers for treatment outcome, consistent with physiological and potential clinical relevance.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Everyone feels miserable sometimes, but about one in six people will have an episode of clinical depression during their lifetime. For people who are clinically depressed, overwhelming feelings of sadness, anxiety, and hopelessness can last for months or years. Affected individuals lose interest in activities they used to enjoy, they sometimes have physical symptoms such as disturbed sleep, and they may contemplate suicide. Clinicians diagnose depression and determine its severity using questionnaires (“depression rating scales”) that explore the patient's feelings and symptoms. Mild depression is often treated with talking therapies (psychotherapy) such as cognitive behavioral therapy, which helps people change negative ways of thinking. For more severe depression, patients are also usually prescribed an antidepressant, most commonly a “selective serotonin reuptake inhibitor” such as paroxetine or a tricyclic antidepressant such as amitriptyline.
Why Was This Study Done?
Unfortunately, antidepressants don't work for more than half of patients. Moreover, because it is unclear how antidepressants work, it is not possible to predict which patients will respond to which antidepressants. Thus, matching patient to drug can be a lengthy, sometimes unsuccessful, process. Here, the researchers use several approaches to test the hypothesis that a protein called FK506 binding protein 51 (FKBP51) is involved in the actions of antidepressants and to investigate whether the ability of both FKBP51 and antidepressants to regulate a process called autophagy underlies the impact of FKBP51 on antidepressant responses. FKBP51 is a regulator of stress physiology, which is connected to the development and treatment of depression; genetic studies have suggested a link between FKBP51 expression and the antidepressant response rate. Some antidepressants are known to alter the initial steps in the autophagy pathway, a multistep process that maintains the integrity of cells through regulated degradation and recycling of cellular components; however, the potential synergistic role of FKBP51 and antidepressants in regulating pathways of autophagy are unknown.
What Did the Researchers Do and Find?
The researchers first treated wild-type mice and FKBP51 knockout mice (genetically altered animals that make no FKBP51) with an acute dose of antidepressant and compared their behavior in a forced swim test, an assay that measures the action of antidepressants in mice by determining how long the mice struggle or float inertly when placed in deep water. As expected, acute antidepressant treatment increased the time that wild-type mice spent struggling. However, this effect of antidepressant treatment was greatly attenuated in the FKBP51 knockout mice. Moreover, the levels of several autophagy markers increased in the brains of wild-type mice following antidepressant treatment but not in the brains of FKBP51 knockout mice. Next, using “chronic social defeat stress” to model the “endophenotype” of depression (a combination of physiological, hormonal, and behavioral traits seen in people with depression) in mice, the researchers showed that the stress response and the effect of chronic antidepressants on behavior and on autophagic markers all depend on FKBP51. Using cell-based assays, the researchers showed that antidepressants and FKBP51 had synergistic (interactive) effects on the autophagic pathway and that, in human blood cells, FKBP51 levels correlated with the potential of antidepressants to induce autophagic pathways. Finally, the researchers report that the clinical response to antidepressant treatment in 51 patients with depression was associated with the response of autophagic markers in their peripheral blood lymphocytes to antidepressant treatment in test tubes, and that the expression levels of FKBP51 and autophagy markers in patient lymphocytes at admission were associated with subsequent clinical responses to antidepressants.
What Do These Findings Mean?
These findings suggest that the protein FKBP51 is required for the effects of both acute and chronic treatment with some antidepressants on behavior and on autophagic pathways in mice. These findings also reveal an association between antidepressant treatment responses in patients and both the expression levels of FKBP51 and autophagy markers in lymphocytes at admission and the response of autophagic markers to antidepressant treatment in patient lymphocytes. The accuracy of these findings is limited by the small number of clinical samples available for analysis, by the use of only male mice in the animal experiments, and by the inability of animal models of depression to fully replicate the human condition. Nevertheless, these findings identify the early stages of autophagy as potential targets for the development of new antidepressants and identify several potential biomarkers that might, after further clinical validation, help clinicians predict antidepressant efficacy in patients with depression.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001755.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish), including information on antidepressants
The UK National Health Service Choices website provides detailed information about depression and about antidepressants; it also provides personal stories about depression
The UK charity Mind provides information on depression, including some personal stories about depression
More personal stories about depression are available from healthtalk.org
MedlinePlus provides links to other resources about depression
Wikipedia has a page on autophagy (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The patients included in this study were all enrolled in the Munich Antidepressant Response Signature project, which aims to identify gene variants and biomarkers that predict treatment outcomes with antidepressants
doi:10.1371/journal.pmed.1001755
PMCID: PMC4227651  PMID: 25386878
17.  Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash 
OBJECTIVE
To provide an evidence-based clinical practice guideline for the chiropractic cervical treatment of adults with acute or chronic neck pain not due to whiplash. This is a considerable health concern considered to be a priority by stakeholders, and about which the scientific information was poorly organized.
OPTIONS
Cervical treatments: manipulation, mobilization, ischemic pressure, clinic- and home-based exercise, traction, education, low-power laser, massage, transcutaneous electrical nerve stimulation, pillows, pulsed electromagnetic therapy, and ultrasound.
OUTCOMES
The primary outcomes considered were improved (reduced and less intrusive) pain and improved (increased and easier) ranges of motion (ROM) of the adult cervical spine.
EVIDENCE
An “extraction” team recorded evidence from articles found by literature search teams using 4 separate literature searches, and rated it using a Table adapted from the Oxford Centre for Evidence-based Medicine. The searches were 1) Treatment; August, 2003, using MEDLINE, CINAHL, AMED, MANTIS, ICL, The Cochrane Library (includes CENTRAL), and EBSCO, identified 182 articles. 2) Risk management (adverse events); October, 2004, identified 230 articles and 2 texts. 3) Risk management (dissection); September, 2003, identified 79 articles. 4) Treatment update; a repeat of the treatment search for articles published between September, 2003 and November, 2004 inclusive identified 121 articles.
VALUES
To enable the search of the literature, the authors (Guidelines Development Committee [GDC]) regarded chiropractic treatment as including elements of “conservative” care in the search strategies, but not in the consideration of the range of chiropractic practice. Also, knowledge based only on clinical experience was considered less valid and reliable than good-caliber evidence, but where the caliber of the relevant evidence was low or it was non-existent, unpublished clinical experience was considered to be equivalent to, or better than the published evidence.
REPORTED BENEFITS, HARMS AND COSTS
The expected benefits from the recommendations include more rapid recovery from pain, impairment and disability (improved pain and ROM). The GDC identified evidence-based pain benefits from 10 unimodal treatments and more than 7 multimodal treatments. There were no pain benefits from magnets in necklaces, education or relaxation alone, occipital release alone, or head retraction-extension exercise combinations alone. The specificity of the studied treatments meant few studies could be generalized to more than a minority of patients.
Adverse events were not addressed in most studies, but where they were, there were none or they were minor. The theoretic harm of vertebral artery dissection (VAD) was not reported, but an analysis suggested that 1 VAD may occur subsequent to 1 million cervical manipulations.
Costs were not analyzed in this guideline, but it is the understanding of the GDC that recommendations limiting ineffective care and promoting a more rapid return of patients to full functional capacity will reduce patient costs, as well as increase patient safety and satisfaction.
For simplicity, this version of the guideline includes primarily data synthesized across studies (evidence syntheses), whereas the technical and the interactive versions of this guideline (http://ccachiro.org/cpg) also include relevant data from individual studies (evidence extractions).
RECOMMENDATIONS
The GDC developed treatment, risk-management and research recommendations using the available evidence. Treatment recommendations addressing 13 treatment modalities revolved around a decision algorithm comprising diagnosis (or assessment leading to diagnosis), treatment and reassessment. Several specific variations of modalities of treatment were not recommended.
For adverse events not associated with a treatment modality, but that occur in the clinical setting, there was evidence to recommend reconsideration of treatment options or referral to the appropriate health services. For adverse events associated with a treatment modality, but not a known or observable risk factor, there was evidence to recommend heightened vigilance when a relevant treatment is planned or administered. For adverse events associated with a treatment modality and predicted by an observable risk factor, there was evidence to recommend absolute contraindications, and requirements for treatment modality modification or caution to minimize harm and maximize benefit. For managing the theoretic risk of dissection, there was evidence to recommend a systematic risk-management approach. For managing the theoretic risk of stroke, there was support to recommend minimal rotation in administering any modality of upper-cervical spine treatment, and to recommend caution in treating a patient with hyperhomocysteinemia, although the evidence was especially ambiguous in both of these areas.
Research recommendations addressed the poor caliber of many of the studies; the GDC concluded that the scientific base for chiropractic cervical treatment of neck pain was not of sufficient quality or scope to “cover” current chiropractic practice comprehensively, although this should not suggest other disciplines are more evidence-based.
VALIDATION
This guideline was authored by the 10 members of the GDC (Elizabeth Anderson-Peacock, Jean-Sébastien Blouin, Roland Bryans, Normand Danis, Andrea Furlan, Henri Marcoux, Brock Potter, Rick Ruegg, Janice Gross Stein, Eleanor White) based on the work of 3 literature search teams and an evidence extraction team, and in light of feedback from a commentator (Donald R Murphy), a 5-person review panel (Robert R Burton, Andrea Furlan, Richard Roy, Steven Silk, Roy Till), a 6-person Task Force (Grayden Bridge, H James Duncan, Wanda Lee MacPhee, Bruce Squires, Greg Stewart, Dean Wright), and 2 national profession-wide critiques of complete drafts. Two professional editors with extensive guidelines experience were contracted (Thor Eglington, Bruce P Squires). Key contributors to the guideline included individuals with specialties or expert knowledge in chiropractic, medicine, research processes, literature analysis processes, clinical practice guideline processes, protective association affairs, regulatory affairs, and the public interest. This guideline has been formally peer reviewed.
PMCID: PMC1839918  PMID: 17549134
chiropractic; guideline; evidence-based; neck pain
18.  Comparative Efficacy of Seven Psychotherapeutic Interventions for Patients with Depression: A Network Meta-Analysis 
PLoS Medicine  2013;10(5):e1001454.
Jürgen Barth and colleagues use network meta-analysis - a novel methodological approach - to reexamine the comparative efficacy of seven psychotherapeutic interventions for adults with depression.
Please see later in the article for the Editors' Summary
Background
Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression.
Methods and Findings
We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = −0.62 to d = −0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = −0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = −0.30, 95% credibility interval [CrI] [−0.54 to −0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [−0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [−0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions.
Conclusions
Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression is a very common condition. One in six people will experience depression at some time during their life. People who are depressed have recurrent feelings of sadness and hopelessness and might feel that life is no longer worth living. The condition can last for months and often includes physical symptoms such as headaches, sleeping problems, and weight gain or loss. Treatment of depression can include non-drug treatments (psychotherapy), antidepressant drugs, or a combination of the two. Especially for people with mild or intermediate depression, psychotherapy is often considered the preferred first option. Psychotherapy describes a range of different psychotherapies, and a number of established types of psychotherapies have all shown to work for at least some patients.
Why Was This Study Done?
While it is broadly accepted that psychotherapy can help people with depression, the question of which type of psychotherapy works best for most patients remains controversial. While many scientific studies have compared one psychotherapy with control conditions, there have been few studies that directly compared multiple treatments. Without such direct comparisons, it has been difficult to establish the respective merits of the different types of psychotherapy. Taking advantage of a recently developed method called “network meta-analysis,” the authors re-examine the evidence on seven different types of psychotherapy to see how well they have been shown to work and whether some work better than others.
What Did the Researchers Do and Find?
The researchers looked at seven different types of psychotherapy, which they defined as follows. “Interpersonal psychotherapy” is short and highly structured, using a manual to focus on interpersonal issues in depression. “Behavioral activation” raises the awareness of pleasant activities and seeks to increase positive interactions between the patient and his or her environment. “Cognitive behavioral therapy” focuses on a patient's current negative beliefs, evaluates how they affect current and future behavior, and attempts to restructure the beliefs and change the outlook. “Problem solving therapy” aims to define a patient's problems, propose multiple solutions for each problem, and then select, implement, and evaluate the best solution. “Psychodynamic therapy” focuses on past unresolved conflicts and relationships and the impact they have on a patient's current situation. In “social skills therapy,” patients are taught skills that help to build and maintain healthy relationships based on honesty and respect. “Supportive counseling” is a more general therapy that aims to get patients to talk about their experiences and emotions and to offer empathy without suggesting solutions or teaching new skills.
The researchers started with a systematic search of the medical literature for relevant studies. The search identified 198 articles that reported on such clinical trials. The trials included a total of 15,118 patients and compared one of the seven psychotherapies either with another one or with a common “control intervention”. In most cases, the control (no psychotherapy) was deferral of treatment by “wait-listing” patients or continuing “usual care.” With network meta-analysis they were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of several psychotherapies within the same trial (where those were available) with indirect comparisons across all trials (using no psychotherapy as a control intervention).
Based on the combined trial results, all seven psychotherapies tested were better than wait-listing or usual care, and the differences were moderate to large, meaning that the average person in the group that received therapy was better off than about half of the patients in the control group. When comparing the therapies with each other, the researchers saw small or no differences, meaning that none of them really stood out as much better or much worse than the others. They also found that the treatments worked equally well for different patient groups with depression (younger or older patients, or mothers who had depression after having given birth). Similarly, they saw no big differences when comparing individual with group therapy, or person-to-person with internet-based interactions between therapist and patient.
However, they did find that smaller and less rigorous studies generally found larger benefits of psychotherapies, and most of the studies included in the analysis were small. Only 36 of the studies had at least 50 patients who received the same treatment. When they restricted their analysis to those studies, the researchers still saw clear benefits of cognitive-behavioral therapy, interpersonal therapy, and problem-solving therapy, but not for the other four therapies.
What Do these Findings Mean?
Similar to earlier attempts to summarize and make sense of the many study results, this one finds benefits for all of the seven psychotherapies examined, and none of them stood as being much better than some or all others. The scientific support for being beneficial was stronger for some therapies, mostly because they had been tested more often and in larger studies.
Treatments with proven benefits still do not necessarily work for all patients, and which type of psychotherapy might work best for a particular patient likely depends on that individual. So overall this analysis suggests that patients with depression and their doctors should consider psychotherapies and explore which of the different types might be best suited for a particular patient.
The study also points to the need for further research. Whereas depression affects large numbers of people around the world, all of the trials identified were conducted in rich countries and Western societies. Trials in different settings are essential to inform treatment of patients worldwide. In addition, large high-quality studies should further explore the potential benefits of some of therapies for which less support currently exists. Where possible, future studies should compare psychotherapies with one another, because all of them have benefits, and it would not be ethical to withhold such beneficial treatment from patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001454.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); information on psychotherapy includes information on its most common forms
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
The UK nonprofit Mind provides information on depression, including an explanation of the most common psychotherapies in the UK
MedlinePlus provides links to other resources about depression (in English and Spanish)
The UK nonprofit healthtalkonline.org has a unique database of personal and patient experiences on depression
doi:10.1371/journal.pmed.1001454
PMCID: PMC3665892  PMID: 23723742
19.  Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis 
PLoS Medicine  2013;10(8):e1001498.
Background
Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care.
Methods and Findings
To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained.
Conclusions
Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
In the past, doctors tended to rely on their own experience to choose the best treatment for their patients. Faced with a patient with dementia (a brain disorder that affects short-term memory and the ability tocarry out normal daily activities), for example, a doctor would use his/her own experience to help decide whether the patient should remain at home or would be better cared for in a nursing home. Similarly, the doctor might have to decide whether antipsychotic drugs might be necessary to reduce behavioral or psychological symptoms such as restlessness or shouting. However, over the past two decades, numerous evidence-based clinical practice guidelines (CPGs) have been produced by governmental bodies and medical associations that aim to improve standards of clinical competence and professionalism in health care. During the development of each guideline, experts search the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluate the quality of that evidence, and then make recommendations based on the best evidence available.
Why Was This Study Done?
Currently, CPG development manuals do not address how to include ethical issues in CPGs. A health-care professional is ethical if he/she behaves in accordance with the accepted principles of right and wrong that govern the medical profession. More specifically, medical professionalism is based on a set of binding ethical principles—respect for patient autonomy, beneficence, non-malfeasance (the “do no harm” principle), and justice. In particular, CPG development manuals do not address disease-specific ethical issues (DSEIs), clinical ethical situations that are relevant to the management of a specific disease. So, for example, a DSEI that arises in dementia care is the conflict between the ethical principles of non-malfeasance and patient autonomy (freedom-to-move-at-will). Thus, healthcare professionals may have to decide to physically restrain a patient with dementia to prevent the patient doing harm to him- or herself or to someone else. Given the lack of guidance on how to address ethical issues in CPG development manuals, in this thematic text analysis, the researchers assess the representation of ethical issues in CPGs on general dementia care. Thematic text analysis uses a framework for the assessment of qualitative data (information that is word-based rather than number-based) that involves pinpointing, examining, and recording patterns (themes) among the available data.
What Did the Researchers Do and Find?
The researchers identified 12 national CPGs on dementia care by searching guideline databases and by contacting national psychiatric associations. They developed a framework for the assessment of the ethical content in these CPGs based on a previous systematic review of ethical issues in dementia care. Of the 31 DSEIs included by the researchers in their analysis, the proportion that were explicitly addressed by each CPG ranged from 22% (Switzerland) to 77% (USA); on average the CPGs explicitly addressed half of the DSEIs. Four DSEIs—adequate consideration of advanced directives in decision making, usage of GPS and other monitoring techniques, covert medication, and dealing with suicidal thinking—were not addressed in at least 11 of the CPGs. The inclusion of recommendations on how to deal with DSEIs ranged from 10% of DSEIs covered in the Swiss CPG to 71% covered in the US CPG. Overall, national guidelines differed substantially with respect to which ethical issues were included, whether ethical recommendations were included, whether justifications or citations were provided to support recommendations, and to what extent the ethical issues were clearly explained.
What Do These Findings Mean?
These findings show that national CPGs on dementia care already address clinical ethical issues but that the extent to which the spectrum of DSEIs is considered varies widely within and between CPGs. They also indicate that recommendations on how to deal with DSEIs often lack the evidence that health-care professionals use to justify their clinical decisions. The researchers suggest that this situation can and should be improved, although more research is needed to determine how ethical issues and recommendations should be addressed in dementia guidelines. A more systematic and transparent inclusion of DSEIs in CPGs for dementia (and for other conditions) would further support the concept of medical professionalism as a core element of CPGs, note the researchers, but is also important for patients and their relatives who might turn to national CPGs for information and guidance at a stressful time of life.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001498.
Wikipedia contains a page on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US National Guideline Clearinghouse provides information on national guidelines, including CPGs for dementia
The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
The American Medical Association provides information about medical ethics; the British Medical Association provides information on all aspects of ethics and includes an essential tool kit that introduces common ethical problems and practical ways to deal with them
The UK National Health Service Choices website provides information about dementia, including a personal story about dealing with dementia
MedlinePlus provides links to additional resources about dementia and about Alzheimers disease, a specific type of dementia (in English and Spanish)
The UK Nuffield Council on Bioethics provides the report Dementia: ethical issues and additional information on the public consultation on ethical issues in dementia care
doi:10.1371/journal.pmed.1001498
PMCID: PMC3742442  PMID: 23966839
20.  What are hospitals doing about clinical guidelines? 
Quality in Health Care  1997;6(4):187-191.
OBJECTIVES: To assess the attitudes of senior hospital staff towards clinical guidelines, and to ascertain the perceived extent and benefits of their local use; to identify those hospitals with current or planned future written strategies for the systematic development of clinical guidelines, and the staff responsible for leading them; and to establish the essential elements of existing strategies, and the methods used to ensure the proper development, dissemination, implementation, and evaluation of local guidelines. DESIGN: Cross sectional survey. PARTICIPANTS: Senior staff of 270 acute hospitals in the United Kingdom (response rate 202/270 (75%)) in 1995. RESULTS: 197/199 (99%) of respondents thought that clinical guidelines were a good idea, and 176/196 (90%) were aware of some guideline activity occurring within their hospitals. The most important benefits of local guideline activity were increased healthcare efficiency and effectiveness, greater consistency of treatment, and team building. 174/194 (90%) of respondents were in favour of the development of a readily accessible national repository of evidence-based clinical guidelines. 38/201 (19%) of respondents had a clinical guidelines strategy and a further 91/201 (45%) said that they had plans to develop one in the near future. The need to improve clinical outcomes was most often reported as the reason for developing a strategy. Medical directors most commonly had formal responsibility to lead the strategy, but someone without formal responsibility ran the operation in half the hospitals. Only 18/36 (50%) of strategies gave advice on the development of guidelines; and only a few strategies made explicit statements on which clinical services to target for guideline development, or the methods to be used for their validation and promotion. Some strategies lacked explicit statements on methods to monitor adherence, routine review, and update of guidelines. Internal literature searches (29/31 (94%)), the use of national guidelines (29/32 (91%)), local consensus conferences (28/32 (88%)), and peer group review (21/24 (88%)) were the most popular methods of validation used in hospitals with a strategy. Methods used to promote the dissemination, implementation, and evaluation of clinical guidelines included clinical audit (31/32 (97%)), peer review (25/30 (83%)), continuing education (23/29 (79%)), targeting of opinion leaders (17/26 (65%)), use of structured case notes (14/31 (45%)), patient mediated interventions (9/26 (35%)), and patient specific reminders (8/26 (31%)). CONCLUSIONS: Most senior hospital staff have a favourable attitude towards clinical guidelines. Most hospitals are undertaking some guideline activity, but few seem to be doing so within a locally agreed hospital wide strategy in which guideline development, dissemination, implementation, and evaluation are systematically considered. Many of the current methods used to validate guidelines locally are inadequate. Evidence-based clinical guidelines should be developed nationally, leaving hospitals to focus their energies on the local adaptation, dissemination, implementation, and evaluation of such guidelines. Only in this way will local guidelines achieve their full potential to improve clinical care and patient outcomes.
PMCID: PMC1055490  PMID: 10177032
21.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
Objective
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
Method
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
Results
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Conclusions
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
doi:10.1176/appi.ajp.2013.13020185
PMCID: PMC4091043  PMID: 24030475
22.  Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010 
PLoS Medicine  2013;10(11):e1001547.
In this paper, Ferrari and colleagues analyzed the burden of depressive disorders in GBD 2010 and identified depressive disorders as a leading cause of burden. The authors present severity proportions; burden by country, region, age, sex, and year; as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Please see later in the article for the Editors' Summary
Background
Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Methods and Findings
Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders.
Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and dysthymia for 1.4% (0.9%–2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and dysthymia for 0.5% (0.3%–0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs.
Conclusions
GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depressive disorders are common mental disorders that occur in people of all ages across all world regions. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—can make people feel that life is no longer worth living. People affected by depression lose interest in the activities they used to enjoy and can also be affected by physical symptoms such as disturbed sleep. Major depressive disorder (MDD, also known as clinical depression) is an episodic disorder with a chronic (long-term) outcome and increased risk of death. It involves at least one major depressive episode in which the affected individual experiences a depressed mood almost all day, every day for at least 2 weeks. Dysthymia is a milder, chronic form of depression that lasts for at least 2 years. People with dysthymia are often described as constantly unhappy. Both these subtypes of depression (and others such as that experienced in bipolar disorder) can be treated with antidepressant drugs and with talking therapies.
Why Was This Study Done?
Depressive disorders were a leading cause of disease burden in the 1990 and 2000 Global Burden of Disease (GBD) studies, collaborative scientific efforts that quantify the health loss attributable to diseases and injuries in terms of disability adjusted life years (DALYs; one DALY represents the loss of a healthy year of life). DALYs are calculated by adding together the years of life lived with a disability (YLD, a measure that includes a disability weight factor reflecting disease severity) and the years of life lost because of disorder-specific premature death. The GBD initiative aims to provide data that can be used to improve public-health policy. Thus, knowing that depressive disorders are a leading cause of disease burden worldwide has helped to prioritize depressive disorders in global public-health agendas. Here, the researchers analyze the burden of MDD and dysthymia in GBD 2010 by country, region, age, and sex, and calculate the burden of suicide and ischemic heart disease attributable to depressive disorders (depression is a risk factor for suicide and ischemic heart disease). GBD 2010 is broader in scope than previous GBD studies and quantifies the direct burden of 291 diseases and injuries and the burden attributable to 67 risk factors across 187 countries.
What Did the Researchers Do and Find?
The researchers collected data on the prevalence, incidence, remission rates, and duration of MDD and dysthymia and on the excess deaths caused by these disorders from published articles. They pooled these data using a statistical method called Bayesian meta-regression and calculated YLDs for MDD and dysthymia using disability weights collected in population surveys. MDD accounted for 8.2% of global YLDs in 2010, making it the second leading cause of YLDs. Dysthymia accounted for 1.4% of global YLDs. MDD and dysthymia were also leading causes of DALYs, accounting for 2.5% and 0.5% of global DALYs, respectively. The regional variation in the burden was greater for MDD than for dysthymia, the burden of depressive disorders was higher in women than men, the largest proportion of YLDs from depressive disorders occurred among adults of working age, and the global burden of depressive disorders increased by 37.5% between 1990 and 2010 because of population growth and ageing. Finally, MDD explained an additional 16 million DALYs and 4 million DALYs when it was considered as a risk factor for suicide and ischemic heart disease, respectively. This “attributable” burden increased the overall burden of depressive disorders to 3.8% of global DALYs.
What Do These Findings Mean?
These findings update and extend the information available from GBD 1990 and 2000 on the global burden of depressive disorders. They confirm that depressive disorders are a leading direct cause of the global disease burden and show that MDD also contributes to the burden allocated to suicide and ischemic heart disease. The estimates of the global burden of depressive disorders reported in GBD 2010 are likely to be more accurate than those in previous GBD studies but are limited by factors such as the sparseness of data on depressive disorders from developing countries and the validity of the disability weights used to calculate YLDs. Even so, these findings reinforce the importance of treating depressive disorders as a public-health priority and of implementing cost-effective interventions to reduce their ubiquitous burden.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001547.
The US National Institute of Mental Health provides information on all aspects of depression
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
MedlinePlus provides links to other resources about depression (in English and Spanish)
The World Health Organization provides information on depression and on the global burden of disease (in several languages)
Information about the Global Burden of Disease initiative is available
beyondblue provides many resources on depression
The Queensland Centre for Mental Health Research provides information on epidemiology and the global burden of disease specifically for mental disorders
doi:10.1371/journal.pmed.1001547
PMCID: PMC3818162  PMID: 24223526
23.  Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature 
PLoS Medicine  2011;8(5):e1000434.
A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.
Background
Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Methods and Findings
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
Conclusions
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Bipolar disorder (manic depression) is a serious, long-term mental illness that affects about 1% of adults at some time during their life. It usually develops in late adolescence or early adulthood and affects men and women from all backgrounds. People with bipolar disorder experience wild mood swings that interfere with daily life and damage relationships. During “manic” episodes, which can last several months if untreated, they may feel euphoric (“high”), energetic, or irritable. They may be full of ambitious plans, feel creative, and spend money recklessly. They can also have psychotic symptoms—they may see or hear things that are not there. During depressive episodes, affected individuals may feel helpless, worthless, and suicidal. Treatments for bipolar disorder include drugs to stabilize mood swings (for example, lithium and anticonvulsant medications), antidepressants to treat depressive episodes, and antipsychotic drugs to treat manic episodes. Psychotherapy can also help and patients can be taught to recognize the signs of approaching manic or depressive episodes and the triggers for these episodes.
Why Was This Study Done?
Treatment of bipolar disorder is divided into three phases: acute treatment lasting about 2 months to achieve remission, continuance treatment lasting from months 2 through 6 to prevent relapse, and long-term maintenance treatment to prevent recurrence. Second-generation (atypical) antipsychotics are widely used for acute treatment of manic episodes but are also used for maintenance treatment. For example, the atypical antipsychotic aripiprazole, which gained US approval for this indication in 2005, is now a popular choice among clinicians for treating bipolar disorder. But how much evidence is there to support aripiprazole's use in the maintenance treatment of bipolar disorder? Here, the researchers systematically search the published literature for double-blind randomized controlled trials of aripiprazole for this indication, critically analyze the quality of these trials, and undertake a citation search to investigate how the results of these trials have been disseminated in the scientific literature. In double-blind randomized controlled trials, patients are randomly assigned to receive a test drug or a control (generally, placebo), and the effects of these drugs compared; patients in the trial, and physicians administering treatments, would not know who is receiving the test drug or control until the trial is completed.
What Did the Researchers Do and Find?
The researchers' search for reports of double-blind randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder using predefined criteria identified only two publications, both describing a single trial—the Keck trial. Critical review of this trial identified four issues that limit its interpretation for supporting aripiprazole as a maintenance therapy: the trial was too short to demonstrate maintenance efficacy; all the trial participants had responded well to aripiprazole as an acute treatment so the generalizability of the trial's results was limited; the trial design meant that some of the apparent beneficial treatment results could have reflected the adverse effects of abrupt medication discontinuation in the control group; and the trial had a low completion rate. The researchers' citation search identified 80 publications that cited the Keck trial in discussions of the use of aripiprazole for maintenance treatment of bipolar disorder. Only a quarter of these papers presented any numerical data from the trial, only a third mentioned any of the reported adverse events, and only four papers mentioned the trial's limitations.
What Do These Findings Mean?
This evaluation of the evidence base supporting the use of aripiprazole for the maintenance treatment of bipolar disorder shows that the justification for this practice relies on the results of one published trial. Moreover, the methodology and reporting of this trial mean that its results cannot easily be generalized to inform the treatment of most patients with bipolar disorder. Worryingly, the researchers' citation search indicates that the Keck trial has been cited uncritically in the ensuing scientific literature. Although the unique features of bipolar disorder make it hard to undertake controlled studies of treatment options, the researchers express concern that “the publication and apparently uncritical acceptance of this trial may be diverting patients away from more effective treatments”.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000434.
The US National Institute of Mental Health has detailed information on bipolar disorder, including an Easy to Read booklet (in English and Spanish)
The UK National Health Service Choices website provides information on all aspects of bipolar disorder
The UK charity Mind has information on bipolar disorder and provides links to other useful organizations
MedlinePlus has links to further information on bipolar disorder (in English and Spanish)
doi:10.1371/journal.pmed.1000434
PMCID: PMC3086871  PMID: 21559324
24.  Does Evidence Support the American Heart Association's Recommendation to Screen Patients for Depression in Cardiovascular Care? An Updated Systematic Review 
PLoS ONE  2013;8(1):e52654.
Objectives
To systematically review evidence on depression screening in coronary heart disease (CHD) by assessing the (1) accuracy of screening tools; (2) effectiveness of treatment; and (3) effect of screening on depression outcomes.
Background
A 2008 American Heart Association (AHA) Science Advisory recommended routine depression screening in CHD.
Methods
CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO and SCOPUS databases searched through December 2, 2011; manual journal searches; reference lists; citation tracking; trial registries. Included articles (1) compared a depression screening instrument to a depression diagnosis; (2) compared depression treatment to placebo or usual care in a randomized controlled trial (RCT); or (3) assessed the effect of screening on depression outcomes in a RCT.
Results
There were few examples of screening tools with good sensitivity and specificity using a priori-defined cutoffs in more than one patient sample among 15 screening accuracy studies. Depression treatment with antidepressants or psychotherapy generated modest symptom reductions among post-myocardial infarction (post-MI) and stable CHD patients (N = 6; effect size = 0.20–0.38), but antidepressants did not improve symptoms more than placebo in 2 heart failure (HF) trials. Depression treatment did not improve cardiac outcomes. No RCTs investigated the effects of screening on depression outcomes.
Conclusions
There is evidence that treatment of depression results in modest improvement in depressive symptoms in post-MI and stable CHD patients, although not in HF patients. There is still no evidence that routine screening for depression improves depression or cardiac outcomes. The AHA Science Advisory on depression screening should be revised to reflect this lack of evidence.
doi:10.1371/journal.pone.0052654
PMCID: PMC3538724  PMID: 23308116
25.  Acupuncture and Counselling for Depression in Primary Care: A Randomised Controlled Trial 
PLoS Medicine  2013;10(9):e1001518.
In a randomized controlled trial, Hugh MacPherson and colleagues investigate the effectiveness of acupuncture and counseling compared with usual care alone for the treatment of depression symptoms in primary care settings.
Please see later in the article for the Editors' Summary
Background
Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care.
Methods and Findings
In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2∶2∶1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat.
PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (−2.46, 95% CI −3.72 to −1.21) and counselling (−1.73, 95% CI −3.00 to −0.45), and over 12 months for acupuncture (−1.55, 95% CI −2.41 to −0.70) and counselling (−1.50, 95% CI −2.43 to −0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported.
Conclusions
In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone.
Trial Registration
Controlled-Trials.com ISRCTN63787732
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression–overwhelming sadness and hopelessness–is responsible for a substantial proportion of the global disease burden and is a major cause of suicide. It affects more than 350 million people worldwide and about one in six people will have an episode of depression during their lifetime. Depression is different from everyday mood fluctuations. For people who are clinically depressed, feelings of severe sadness, anxiety, hopelessness, and worthlessness can last for months and years. Affected individuals lose interest in activities they used to enjoy and sometimes have physical symptoms such as disturbed sleep. Clinicians can diagnose depression and determine its severity by asking patients to complete a questionnaire (for example, the Beck Depression Inventory [BDI-II] or the Patient Health Questionnaire 9 [PHQ-9]) about their feelings and symptoms. The answer to each question is given a score and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. Antidepressant drugs are usually the front-line treatment for depression in primary care.
Why Was This Study Done?
Unfortunately, antidepressants don't work for more than half of patients. Moreover, many patients would like to be offered non-pharmacological treatment options for depression such as acupuncture–a therapy originating from China in which fine needles are inserted into the skin at specific points of the body–and counseling–a “talking therapy” that provides patients with a safe, non-judgmental place to express feelings and emotions and that helps them recognize their capacity for growth and fulfillment. However, it is unclear whether either of these treatments is effective in depression. In this pragmatic randomized controlled trial, the researchers investigate the clinical effectiveness of acupuncture or counseling in patients with depression compared to usual care in primary care in northern England. A randomized controlled trial compares outcomes in groups of patients who are assigned to different interventions through the play of chance. A pragmatic trial asks whether the intervention works under real-life conditions. Patient selection reflects routine practice and some aspects of the intervention are left to the discretion of clinician, By contrast, an explanatory trial asks whether an intervention works under ideal conditions and involves a strict protocol for patient selection and treatment.
What Did the Researchers Do and Find?
The researchers recruited 755 patients who had consulted their primary health care provider about depression within the past 5 years and who had a score of more than 20 on the BDI-II–a score that is defined as moderate-to-severe depression on this depression rating scale–at the start of the study. Patients were randomized to receive up to 12 weekly sessions of acupuncture plus usual care (302 patients), up to 12 weekly sessions of counseling plus usual care (302 patients), or usual care alone (151 patients). Both the acupuncture protocol and the counseling protocols allowed for some individualization of treatment. Usual care, including antidepressants, was available according to need and monitored in all three groups. Compared to usual care alone, there was a significant reduction (a reduction unlikely to have occurred by chance) in the average PHQ-9 scores at both 3 and 6 months for both the acupuncture and counseling interventions. The difference between the mean PHQ-9 score for acupuncture and counseling was not significant. At 9 months and 12 months, because of improvements in the PHQ-9 scores in the usual care group, acupuncture and counseling were no longer significantly better than usual care.
What Do These Findings Mean?
These findings suggest that, compared to usual care alone, both acupuncture and counseling when provided alongside usual care provided significant benefits at 3 months in primary care to patients with recurring depression. Because this trial was a pragmatic trial, these findings cannot indicate which aspects of acupuncture and counseling are likely to be most or least beneficial. Nevertheless they do provide an estimate of the overall effects of these complex interventions, an estimate that is of most interest to patients, practitioners, and health care providers. Moreover, because this trial only considers the effect of these interventions on patients with moderate-to-severe depression as classified by the BDI-II; it provides no information about the effectiveness of acupuncture or counseling compared to usual care for patients with mild depression. Importantly, however, these findings suggest that further research into optimal treatment regimens for the treatment of depression with acupuncture and counseling is merited.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001518.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish)
The UK National Health Service Choices website provides detailed information about depression, including personal stories about depression, and information on counseling and acupuncture
The UK charity Mind provides information on depression, on talking treatments, and on complementary and alternative therapies including acupuncture; Mind also includes personal stories about depression on its website
More personal stories about depression are available from Healthtalkonline
MedlinePlus provides links to other resources about depression and about acupuncture (in English and Spanish)
doi:10.1371/journal.pmed.1001518
PMCID: PMC3782410  PMID: 24086114

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