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Found 5 results

  1. Obesity linked to worse outcomes of pain, fatigue, depression in women with lupus November 13, 2017 SAN DIEGO — Among women with systemic lupus erythematosus, obesity appears to be independently linked to worse patient-reported outcomes, suggesting that weight loss may improve outcomes for this population, according to findings presented at the American College of Rheumatology Annual Meeting. “The research that I am presenting at this conference was inspired by previous work that showed that patients with lupus experienced big deferments in patient-reported outcomes, or PROs,” Sarah L. Patterson, MD, a fellow in rheumatology at the University of California, San Francisco, and an author of the study, said in her presentation. “It's also been noted that these deferments in PROs are not fully explained by the severity of their lupus disease or by sociodemographic factors such as poverty. So, we therefore wanted to know whether body composition and, specifically, excess adipose tissue contributes to the worse health-related quality of life and greater symptom burden that we see in this particular patient population.” In the study, Patterson and colleagues identified a sample of 148 patients with SLE (65% white, 14% Asian and 13% African-American; mean age, 48 ± 12.3 years) from the Arthritis Body Composition and Disability (ABCD) study. Eligible participants were women aged at least 18 years who had a diagnosis of SLE that could be corroborated by medical record review. The researchers calculated BMI and fat mass index (FMI). FMI measures total fat mass adjusted for height and was evaluated in the study using whole dual-energy X-ray absorptiometry. Obesity was defined using two designations: FMI of at least 13 kg/m2 and BMI of at least 30 kg/m2. The following four validated patient-reported outcomes were included as dependent variables: disease activity via Systemic Lupus Activity Questionnaire, depressive symptoms via Center for Epidemiologic Studies Depression Scale, pain assessed by SF-36 pain subscale and fatigue measured by SF-36 vitality subscale. Multivariable linear regression was used to analyze correlations of obesity with patient-reported outcomes , adjusted for possible confounding factor (age, race, education, income, smoking status, disease duration, disease damage and prednisone use). Adjusted means for each outcome were then calculated based on the multivariable regression. Of the patients in the sample, 17% had poverty-level income; 86% had education beyond high school; the mean duration of disease was 16 ± 9 years; and 45% were being treated with glucocorticoids. Based on the FMI definition of obesity, 32% of patients met the criteria for obesity, whereas 30% were deemed obese by the BMI definition. The multivariate regression model found that FMI-defined obesity was correlated with worse scores on each patient-reported outcome (greater disease activity, higher levels of depression, more pain and more fatigue). In the analyses that used the traditional BMI of at least 30 kg/m2 criteria, the same correlations were seen between obesity and each of the patient-reported outcomes. “These findings have important clinical implications. The PROs that we measured, particularly pain and fatigue, are known to have profound effects on quality of life, and remain a major area of unmet need in people with lupus,” Patterson said. “In other words, there are many patients with lupus who are treated with aggressive immunomodulatory therapy and these symptoms of pain and fatigue persist. The relationship that we observed between excess fat and worse outcomes really underscores the need for lifestyle interventions for lupus patients who are overweight.” – by Jennifer Byrne Reference: Patterson SL, et al. Abstract #2263. Presented at: American College of Rheumatology Annual Meeting; Nov. 4-8, 2017; San Diego. Disclosures: The authors report no relevant financial disclosures. https://www.healio.com/rheumatology/lupus/news/online/{88b88835-9c84-4880-a058-1e4d1d926aa6}/obesity-linked-to-worse-outcomes-of-pain-fatigue-depression-in-women-with-lupus?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405
  2. Nocturnal Hot Flashes, Sleep Disturbance Independently Contribute to Depression By Will Boggs MD October 19, 2016 NEW YORK (Reuters Health) - Nocturnal hot flashes and sleep disturbance independently contributed to depression in women with artificially-induced estrogen deprivation, researchers report. During perimenopause and after bilateral oophorectomy, women are at increased risk for developing major depressive episodes and depressive symptoms. Hot flashes and sleep disturbance have both been linked to depressive symptoms during this transition, but the nature of the relationship remains unclear. Dr. Hadine Joffe from Brigham and Women's Hospital and Harvard Medical School in Boston and colleagues used leuprolide to induce hypoestrogenism and ovarian suppression in 29 healthy premenopausal women in an effort to dissect the specific impact of nighttime hot flashes from sleep disturbance and daytime hot flashes on mood. After four weeks on leuprolide, the average Montgomery-Asberg Depression Rating Scale (MADRS) score was 4.1, where significant depressive symptoms are associated with scores of 15 or higher, according to the September 28th online report in The Journal of Clinical Endocrinology & Metabolism. MADRS scores increased by at least 5 points from baseline in 24% of women and remained unchanged in 38%. Only one woman had post-leuprolide scores above 15. Twenty women (69%) developed hot flashes beginning an average 11.1 days after leuprolide initiation. There was no consistent pattern of daytime versus nighttime hot flashes. Ovarian suppression also had inconsistent effects on objective and subjective sleep parameters. The number of nighttime hot flashes reported was significantly associated with mood deterioration after adjustment for changes in sleep parameters. Similarly, several sleep parameters were independently associated with mood worsening. "In summary, this experimental investigation of estradiol suppression and induced hot flashes (HFs) provides strong evidence indicating that the development of mild depressive symptoms varies in relation to both the number of perceived nighttime HFs and the amount of objective and subjective sleep disruption that develops," the researchers conclude. "These results suggest that both sleep disruption and perceived nighttime HFs play a role in the generation of depressive symptoms related to surgical and natural menopause." "Women reporting nighttime HFs and sleep interruption should be screened for mood disturbance, and treatment of those with menopause-related depressive symptoms should encompass therapies that improve sleep interruption as well as nocturnal HFs," they add. "Future study directions include a focused approach on women with histories of mood disorders to determine the impact of these findings on women at particular risk for menopause-related mood disturbance." Dr. Nanette Santoro from University of Colorado School of Medicine, Aurora, Colorado, who recently reviewed menopausal symptoms and their management, told Reuters Health by email, "I think the main point of this paper, and Dr. Joffe's work in general, is that it's important to focus on the sleep issues in women who are menopausal and who are suffering from depressive symptoms or depression. Of course, the depression needs to be treated-but ways to improve sleep should also be considered. These need not be complicated, and they need not be pharmacological - methods like cognitive behavioral therapy may help." Dr. Carrie J. Gibson from San Francisco VA Medical Center and University of California San Francisco, who has investigated various aspects of hot flashes and menopause, told Reuters Health by email, "These findings underscore the importance of examining nighttime hot flashes or night sweats separately from daytime hot flashes whenever possible, adding to growing evidence that these symptoms are not equivalent or interchangeable in their relationships with mood and health concerns." "Interventions targeting both sleep disturbance and nighttime hot flashes may be beneficial in improving mild depressive symptoms in postmenopausal women," she said. "Mood symptoms may not be affected by interventions targeting daytime hot flashes." "It is often difficult to tease apart the impact of aging vs. menopause on health; the ability to separate age-related and estrogen withdrawal-related changes to sleep in this model is a valuable contribution to our understanding of these issues," Dr. Gibson added. Dr. Juan R. Ordonana from Universidad de Murcia, Spain recently reported on the prevalence of poor sleep quality in adults. He told Reuters Health by email, "The main message that emerges from this work is that menopause is a risk period for poor sleep quality and that sleep problems can be predicted, helping us to identify women that could benefit from an early intervention. Therefore, interventions must be proactive and start previous to the onset of the problem." "Interventions such as sleep hygiene and stimulus control can help prevent possible disturbances of sleep," he explained. "In addition, comorbidity should be taken into account, since there is a close relationship between mood disorders, such as depression, and sleep problems. Intervention towards sleep problems without confronting concomitant disorders is likely to fail. Conversely, a successful treatment of the comorbidity may be helpful in the improvement of sleep quality." Dr. Joffe did not respond to a request for comments. SOURCE: http://bit.ly/2e5XJCL J Clin Endocrinol Metab 2016. http://www.medscape.com/viewarticle/870444?src=wnl_edit_tpal
  3. Depression Linked to Hormonal Contraceptives http://www.medscape.com/viewarticle/869464?src=wnl_edit_tpal&uac=60604BR Megan Brooks September 29, 2016 Women who use oral hormonal contraceptives are at increased risk of developing depression, and adolescents seem most vulnerable, results of a large study suggest. "Women should generally be informed about this potential side effect with use of hormonal contraception, so they can react appropriately in case of mood changes or even depression development. Likewise, doctors who prescribe hormonal contraception should be aware of this potential risk," Øjvind Lidegaard, MD, Department of Gynecology, Rigshospitalet, Copenhagen, and Faculty of Health Sciences, University of Copenhagen, told Medscape Medical News. The study was published online September 28 in JAMA Psychiatry. Mood Changes Mood changes are a known reason for stopping hormonal contraceptives, but few studies have quantified the effect of low-dose hormonal contraception on the risk for depression, the researchers note. To investigate, they used Danish registry data for more than 1 million women and adolescents (aged 15 to 34 years) with no prior history of depression or other psychiatric diagnosis at baseline. The women were followed from 2000 through 2013; the average follow-up was 6.4 years. During follow-up, 55.5% of participants were current or recent users of hormonal contraception. There were 133,178 first prescriptions for antidepressants and 23,077 first diagnoses of depression. During follow-up, compared with nonusers, women and adolescents who used hormonal contraception were more likely to be prescribed an antidepressant for the first time. The risk varied by type of hormonal contraception. Table. Risk for First Use of Antidepressant by Hormonal Contraception Type of Contraception Relative Risk 95% CI Combined oral contraceptive pills 1.2 1.22 - 1.25 Progestin-only pills 1.3 1.27 - 1.40 Patch (norgestrolmin) 2.0 1.76 - 2.18 Vaginal ring (etonogestrel) 1.6 1.55 - 1.69 Levonorgestrel intrauterine system 1.4 1.31 - 1.42 95% CI, 95% confidence interval. The relative risks for a first diagnosis of depression were similar or slightly lower, the investigators report. They also found that after 6 months of starting hormonal contraceptives, the relative risk peaked at 1.4 (95% CI, 1.34 - 1.46) for first use of antidepressants and 1.5 (95% CI, 1.36 - 1.64) for diagnosis of depression. In age-stratified analyses, the relative risks for first antidepressant use generally decreased with increasing age. Patients aged 15 to 19 years seem most vulnerable to mood changes. In this group, the relative risk for first use of an antidepressant was 1.8 (95% CI, 1.75 - 1.84) with combined oral contraceptives and 2.2 (95% CI, 1.99 - 2.52) with progestin-only pills. For adolescents using nonoral birth control products, the risk for first use of an antidepressant was threefold higher than for nonusers. "Noteworthy" Research Dr Lidegaard told Medscape Medical News, "This is the first study ever conducted which has followed a large cohort of previously mentally healthy women starting on hormonal contraception...and then followed these women for 13 years for their eventual start on antidepressant therapy or getting a depression diagnosis, as compared with age-matched women not starting on hormonal contraception. At the same time, the study controls for important potential confounders. Women with previous mental disease were excluded, as were pregnant women." The findings support the theory of progesterone involvement in the etiology of depression, because progestin dominates combined and progestin-only contraceptives, the investigators say. Reached for comment, Keely Cheslack-Postava, PhD, associate research scientist, Department of Psychiatry, Columbia University Medical Center in New York City, described the study as "thorough and well-conducted, making use of nationwide registry data. "The study is noteworthy for its careful attention to the relationship in timing between use of hormonal contraceptives vs depression diagnosis or treatment. "On the other hand, it should be noted that previous studies do present conflicting evidence about the relationship between hormonal contraception and women's mental health. One aspect that needs further study is the distinction between diagnosed depression vs depressive symptoms that may or may not come to medical attention," she added. The study was supported by the Department of Gynecology, Rigshospitalet, University of Copenhagen, and by a grant from the Lundbeck Foundation. Dr Lidegaard has received received honoraria for talks on pharmacoepidemiologic issues within the past 3 years from Exeltis. JAMA Psychiatry. Published online September 28, 2016. Abstract Medscape Medical News © 2016 WebMD, LLC
  4. Therapy, Antidepressants Similarly Effective for Depression Marcia Frellick February 09, 2016 Cognitive behavioral therapy (CBT) is as effective for treating depression as antidepressants, and given its relative lack of potential harms, should be strongly considered as the first-line treatment, according to a new guideline issued by the American College of Physicians (ACP). The guideline is based on a systematic review of randomized controlled trials from 1990 through September 2015 comparing the benefits of second-generation antidepressants (SGAs) and nonpharmacologic interventions such as psychotherapies, complementary and alternative medicines (including acupuncture and St John's wort [Hypericum perforatum]), and exercise. The guideline was published online February 9 in the Annals of Internal Medicine. Physicians may be surprised to learn CBT is as effective as antidepressants, Amir Qaseem, MD, PhD, MHA, the ACP's vice president of clinical policy and lead author of the guideline, told Medscape Medical News. They are often more likely to recommend antidepressants first because prescribing medication does not require finding a provider and lining up services and meetings, as CBT does, and because the scope of what is involved with therapy may be unclear to primary care physicians, he said. But the trade-off may be the potential for more adverse effects. "[SGAs] tend to have more harms," he explained, including headaches, insomnia, constipation, diarrhea, sexual dysfunction, dizziness, and drowsiness. The guidelines also note that harms associated with SGAs are probably underrepresented in the trials studied. Problems With St John's Wort Another important message in the guideline is regarding the potential problems with the popular herbal therapy St John's wort, sold over the counter at drug stores and in health food stores. Patients increasingly are asking about the herb as a natural treatment for depression, said Dr Qaseem. Although the guideline shows low-quality evidence that St John's wort may be as effective as SGAs for treating major depressive disorder, and moderate-quality evidence showed that St John's wort was better tolerated than SGAs, the committee cannot recommend it as a treatment, he said. The first problem is that because it is not regulated by the US Food and Drug Administration, amounts of the active ingredient differ by the bottle, making comparison with amounts tested in clinical trials difficult, he explained. "We don't know the standards of purity and potency in the US at all," he said. The second problem is that St John's wort also is known to interfere with the efficacy of other treatments, including oral birth control, and drugs for HIV and transplant rejection. Adverse effects associated with it may include gastrointestinal symptoms, skin reactions, fatigue, dizziness, headache, and dry mouth, and it is contraindicated in patients taking monoamine oxidase inhibitors or selective serotonin re-uptake inhibitors. Dr Qaseem said it is important for physicians and patients to discuss the options and decide on a first-line therapy together. Guidelines in Line With American Psychiatric Association Advice The guidelines are in line with American Psychiatric Association guidelines on major depressive disorder from 2010, which also showed that CBT and SGAs are similarly effective, said Laura Fochtmann, MD, MBI, professor of psychiatry, pharmacological sciences, and biomedical informatics at Stony Brook University School of Medicine in New York. She told Medscape Medical News there are several factors that should be considered when physicians talk with their patients about which to choose: whether there is a trained CBT provider in the patient's vicinity, whether the patient is covered by insurance for the service and whether the available provider accepts the insurance, whether the patient can get appointments in evening hours, and what the patient prefers. "There are all sorts of barriers to psychotherapies that aren't present with medications," she said. "It is sometimes seen as an easier option to take medication." She noted that this may have led to the prevalence of medication over therapy, "even though we've known for quite a while that they were equally efficacious." Costs between the two are hard to estimate even for physicians, she said, as insurance coverage varies significantly. The new ACP guideline draws nonpsychiatric clinicians' attention to the importance of recognizing and identifying depression when patients present with depressive symptoms in primary care, said Dr Fochtmann. Physicians can help educate patients that this is a treatable condition and that there are effective treatment options. "I think in that way, it's an important recommendation," she said. ACP's recommendations are based on a systematic evidence review by the Agency for Healthcare Research and Quality. Financial support for this guideline comes exclusively from the ACP operating budget. Three coauthors were recused from voting on this guideline and from chairing during the discussion of the guideline for indirect financial or direct intellectual conflicts. Dr Fochtmann has a contract with the American Psychiatric Association to write practice guidelines. http://www.medscape.com/viewarticle/858707?src=wnl_edit_tpal&uac=60604BR Ann Intern Med. Published online February 9, 2016. Full text Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of PhysiciansNonpharmacologic Versus Pharmacologic Treatment of Adults With MDD Clinical Guidelines February Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of PhysiciansNonpharmacologic Versus Pharmacologic Treatment of Adults With MDD ONLINE FIRST Amir Qaseem, MD, PhD, MHA; Michael J. Barry, MD; Devan Kansagara, MD, MCR, for the Clinical Guidelines Committee of the American College of Physicians [] Article, Author, and Disclosure Information Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness of treatment with second-generation antidepressants versus nonpharmacologic treatments for major depressive disorder in adults. Methods: This guideline is based on a systematic review of published, English-language, randomized, controlled trials from 1990 through September 2015 identified using several databases and through hand searches of references of relevant studies. Interventions evaluated include psychotherapies, complementary and alternative medicines (including acupuncture, ω-3 fatty acids, S-adenosyl--methionine, St. John's wort [Hypericum perforatum]), exercise, and second-generation antidepressants. Evaluated outcomes included response, remission, functional capacity, quality of life, reduction of suicidality or hospitalizations, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with major depressive disorder. This guideline grades the evidence and recommendations using ACP's clinical practice guidelines grading system. Recommendation: ACP recommends that clinicians select between either cognitive behavioral therapy or second-generation antidepressants to treat patients with major depressive disorder after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient (Grade: strong recommendation, moderate-quality evidence). Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world, resulting in significant costs to society and health care systems (1). The estimated economic burden associated with depression was $83.1 billion in 2000 and is probably higher today (2). Depressive disorders include major depressive disorder (MDD); dysthymia; and subsyndromal depression, including minor depression. Major depressive disorder is the most prevalent depressive disorder, with an estimated lifetime prevalence of 16% in the United States (3). An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD (4). The American Psychiatric Association (5) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms, including significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation nearly every day, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, indecisiveness or decreased ability to concentrate, and recurrent thoughts of death or suicide, that last for at least 2 weeks and affect normal functioning. Dysthymia is less severe, but symptoms last for 2 or more years. In contrast, subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses. The treatment of depression can be characterized by 3 phases (Figure 1): acute (6 to 12 weeks), continuation (4 to 9 months), and maintenance (≥1 year) (7). Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode, whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new, distinct episode. Response to treatment (typically defined as ≥50% reduction in measured severity) can be quantified using various tools, such as the Patient Health Questionnaire-9 (PHQ-9) (7) or the Hamilton Depression Rating Scale (HAM-D) (8). Grahic Jump Location Figure 1. Phases of treatment of major depression. Adapted from reference (6). TX = treatment. Grahic Jump Location Various treatment approaches can be used to manage MDD, such as psychotherapy, complementary and alternative medicine (CAM), exercise, and pharmacotherapy. The psychological interventions used to treat depression include acceptance and commitment therapy, cognitive therapy, cognitive behavioral therapy (CBT), interpersonal therapy, and psychodynamic therapies (Table 1). The CAM treatments include acupuncture, meditation, ω-3 fatty acids,S-adenosyl--methionine (SAMe), St. John's wort, and yoga. Exercise includes a broad range of activities that can be done for varying durations, in classes, individually, or in informal groups. For pharmacologic therapy, the scope of this guideline is limited to second-generation antidepressants (SGAs) (selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and selective serotonin norepinephrine reuptake inhibitors). First-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy. Table Jump PlaceholderTable 1. Common Psychological Interventions to Treat Depression The purpose of this guideline from the American College of Physicians (ACP) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs (including serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, bupropion, mirtazapine, nefazodone, and trazodone), alone or in combination, for MDD. The target audience for this guideline includes all clinicians, and the target patient population includes all adults with MDD. These recommendations are based on a background evidence article (9) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality (AHRQ) (6). Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ's RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center (6). Additional methodological details can be found in theAppendix, accompanying background evidence article (9), and full report (6). Reviewers searched several databases for studies published in English, German, or Italian from 1 January 1990 through September 2015. Studies on efficacy were limited to randomized, controlled trials and systematic reviews and meta-analyses, although evidence on harms included observational studies. Reviewers combined data when possible using meta-analysis and assessed the risk of bias and quality of studies according to established methods. The study population included adult outpatients (aged ≥18 years) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA. The review evaluated the following classes of interventions: depression-focused psychotherapy, CAM, exercise, and SGAs. Outcomes assessed included benefits in response (often defined as ≥50% improvement in HAM-D scores), remission (often defined as a HAM-D score ≤7), speed of response, speed of remission, relapse, quality of life, functional capacity (as assessed by various scales), reduction of suicidality, or reduction of hospitalization. Harms assessed included overall adverse events, withdrawals because of adverse events, serious adverse events, and specific adverse events. Quality of life, functional status, suicidality, and hospitalizations were rarely reported. Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process, which has been described (10). The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report (9) when reporting the evidence and graded the recommendations using ACP's guideline grading system (Table 2). Table Jump PlaceholderTable 2. The American College of Physicians' Guideline Grading System* Peer Review The AHRQ evidence review was sent to invited peer reviewers and posted on the AHRQ Web site for public comments. The guideline was peer-reviewed through the journal and was posted online for comments from ACP Governors and Regents. Refer to Appendix Table 1 and the accompanying systematic review (9) for additional details of the evidence. Table Jump PlaceholderAppendix Table 1. First-Line Treatment for MDD: SGAs Versus Nonpharmacologic Therapies* Table Jump PlaceholderAppendix Table 1–Continued Table Jump PlaceholderAppendix Table 1–Continued SGA Versus Psychological Interventions SGA Versus CBT Monotherapy. Moderate-quality evidence from 5 trials (11–15) showed no difference in response when comparing SGAs (fluoxetine, fluvoxamine, paroxetine, or sertraline) with CBT in patients with MDD after 8 to 52 weeks of treatment. Low-quality evidence from 3 trials (11, 14, 15) showed no difference between remission rates (fluoxetine, fluvoxamine, and paroxetine) and functional capacity (14) (fluvoxamine and paroxetine) for SGAs compared with CBT. Combination Therapy. Low-quality evidence from 2 trials (14, 16) showed no difference in response or remission when comparing monotherapy using SGAs (escitalopram, fluvoxamine, or paroxetine) with combination therapy using SGAs plus CBT (problem-solving therapy or telephone-based CBT) in patients with MDD after 12 to 52 weeks of treatment. Low-quality evidence from 2 trials (14, 16) assessed function, and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy, although clinically important differences on these measures are uncertain. SGA Versus Interpersonal Therapy Monotherapy. Low-quality evidence showed no difference in response (1 trial; escitalopram) (17) or remission (2 trials; citalopram, escitalopram, or sertraline) (17, 18) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment. Combination Therapy. Low-quality evidence from 1 trial (19) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy (with nefazodone) in patients with MDD after 12 weeks of treatment. SGA Versus Psychodynamic Therapies Monotherapy. Low-quality evidence from 1 trial (20) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment. Low-quality evidence from 2 trials (20, 21) showed few differences in functional capacity between the treatments. Combination Therapy. Low-quality evidence from 1 trial (21) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy. SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy. Low-quality evidence from 2 trials (22, 23) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment. Combination Therapy. Low-quality evidence from 2 trials (24, 25) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs (fluoxetine or paroxetine) in patients with MDD after 6 weeks of treatment. However, low-quality evidence from 1 trial (24) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy. SGA Versus ω-3 Fatty Acids Monotherapy. Low-quality evidence from network meta-analysis showed that SGAs (fluoxetine) were associated with a greater response than ω-3 fatty acids in patients with MDD. SGA Versus SAMe Monotherapy. Low-quality evidence from network meta-analysis showed no difference in response between treatment with escitalopram and SAMe in patients with MDD after 12 weeks of treatment. SGA Versus St. John's Wort Monotherapy. Low-quality evidence from 9 trials (26–34) showed no difference in response or remission (26, 27, 33–35) when comparing treatment using SGAs with St. John's wort in patients with MDD after 4 to 12 weeks of treatment. Levels of SGAs used in the comparative effectiveness studies with St. John's wort were capped at levels lower than usual dosing ranges in comparative studies. Thus, this evidence is rated as low quality. SGA Versus Yoga The evidence is insufficient to compare SGAs with meditation or yoga because there were no eligible trials. SGA Versus Exercise Monotherapy. Low-quality evidence from network meta-analysis showed no difference in response for SGAs versus exercise. Moderate-quality evidence from 2 trials (36,37) showed no difference in remission for sertraline compared with exercise in patients with MDD after 16 weeks of treatment. Combination Therapy. Low-quality evidence from 1 trial (38, 39) showed no difference in remission for treatment with sertraline compared with combination therapy of sertraline and exercise in patients with MDD after 16 weeks of treatment. Refer to Appendix Table 2 and the accompanying systematic review (9) for additional details of the evidence. Table Jump PlaceholderAppendix Table 2. Second-Line Treatment in Patients With MDD Who Failed Initial Treatment With SGAs: Switching or Augmenting Strategies* Switching to Other SGAs Moderate-quality evidence from 1 trial (40) showed no difference in response when switching from 1 SGA to another (bupropion vs. sertraline or venlafaxine and sertraline vs. venlafaxine). Low-quality evidence from 1 trial (40) showed no difference in remission (bupropion vs. sertraline or venlafaxine and sertraline vs. venlafaxine) or depression severity (venlafaxine vs. citalopram) when switching from 1 SGA to another. Low-quality evidence showed no difference in risk for overall adverse events, discontinuation due to serious adverse events, overall discontinuation rates, or suicidal thoughts associated with switching to venlafaxine versus switching to citalopram (40, 41). Switching From an SGA to a Different SGA Versus Switching to Cognitive Therapy Low-quality evidence from 1 trial (42) showed no difference in response or remission when switching from 1 SGA to another (sertraline, bupropion, or venlafaxine) compared with switching to cognitive therapy. Low-quality evidence also showed no difference in discontinuation due to adverse events when switching from 1 SGA (citalopram) to another (sertraline, bupropion, or venlafaxine) compared with switching to cognitive therapy (42). Augmenting With Another SGA Low-quality evidence from 1 trial (43) showed no difference in response or remission for augmentation of citalopram treatment with bupropion compared with augmentation with buspirone. However, augmenting with bupropion decreases depression severity more than augmentation with buspirone (43). Low-quality evidence showed no difference in suicidal ideas and behavior or serious adverse events, and moderate-quality evidence showed that discontinuation due to adverse events was lower with bupropion than with buspirone (43). Augmenting With Another SGA Versus Augmenting With Cognitive Therapy Low-quality evidence from 1 trial (43) showed no difference in response, remission, or depression severity for augmentation of citalopram treatment with another SGA (bupropion or buspirone) versus augmentation with cognitive therapy. Low-quality evidence showed no difference between augmenting with bupropion or buspirone for serious adverse events or discontinuation due to adverse events (43). SGA Versus Psychological Interventions SGA Versus CBT Monotherapy. Moderate-quality evidence from 4 trials (12, 14, 15, 26) showed no difference in overall discontinuation rates between SGAs (fluoxetine, fluvoxamine, or paroxetine) and CBT at 8 to 14 weeks of follow-up. Low-quality evidence from 1 trial (44) showed increased discontinuation of treatment (sertraline, paroxetine, or venlafaxine) at 24-week follow-up compared with CBT. Low-quality evidence from 3 trials (12, 14, 15) showed a non–statistically significant increase in discontinuation due to adverse events with SGAs compared with CBT at 8 to 14 weeks of follow-up. Combination Therapy Low-quality evidence from 2 trials (14, 16) showed no difference in overall discontinuation rates for treatment with escitalopram versus a combination of escitalopram and telephone-based CBT. Low-quality evidence showed a non–statistically significant increase in discontinuation due to adverse events with SGAs compared with CBT (14, 16). SGA Versus Interpersonal Therapy Monotherapy The evidence is insufficient to determine the comparative risk of treatment with SGAs versus interpersonal therapy. Combination Therapy Low-quality evidence from 1 trial (19) showed no difference in overall discontinuation rates for treatment with nefazodone versus a combination of nefazodone and interpersonal therapy. SGA Versus Third-Wave CBT Low-quality evidence from 2 trials (15, 45) showed that overall discontinuation rates and discontinuation due to adverse events were higher in patients treated with SGAs than with third-wave CBT. SGA Versus Psychodynamic Therapies Monotherapy Low-quality evidence from 1 trial showed no difference between SGAs and psychodynamic therapy for suicidality at 96 weeks of follow-up (21) or overall discontinuation rates at 8 to 16 weeks (20, 46, 47), 48 weeks (20), or 96 weeks (21) of follow-up. Combination Therapy Low-quality evidence from 1 trial (21) showed that overall discontinuation rates were lower for patients treated with fluoxetine than for those treated with fluoxetine combined with psychodynamic therapy. Low-quality evidence from 1 trial (21) showed a non–statistically significant increase in suicidality when comparing SGAs with a combination of SGAs and psychodynamic therapy after 96 weeks of follow-up. SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy Moderate-quality evidence from a systematic review of 21 trials (48) showed that the overall risk for adverse events is higher with SGAs than with acupuncture. Combination Therapy Low-quality evidence from 1 trial showed no difference in risk for overall adverse events (49), and low-quality evidence from 2 trials showed no difference in overall discontinuation rates (24, 25) or discontinuation due to adverse events (24, 49) for SGA monotherapy versus a combination of SGA plus acupuncture. SGA Versus ω-3 Fatty Acids Monotherapy Low-quality evidence from 1 trial (50) showed no difference in overall discontinuation rates of treatment using SGAs compared with ω-3 fatty acids. Combination Therapy Low-quality evidence from 2 trials (51, 52) showed no difference in overall discontinuation rates for SGA monotherapy compared with combination therapy of SGAs plus ω-3 fatty acids. SGA Versus SAMe Monotherapy Low-quality evidence from 1 trial (52) showed no difference in overall discontinuation rates between treatment with SGAs or SAMe. SGA Versus St. John's Wort Monotherapy Moderate-quality evidence from 9 trials (25–29, 31–33, 53) showed increased risks for discontinuation and discontinuation due to adverse events with SGAs compared with St. John's wort. Moderate-quality evidence from 8 trials (27,29–34, 54) also showed a non–statistically significant increase in the risk for overall adverse events with SGAs compared with St. John's wort. Low-quality evidence from 4 trials (27, 30, 31, 34) showed no difference in serious adverse events with SGAs compared with St. John's wort. SGA Versus Yoga The evidence is insufficient to compare SGAs with meditation or yoga because there were no eligible trials. SGA Versus Exercise Monotherapy. Low-quality evidence from 2 trials (36, 38) showed that sertraline was associated with an increased risk for discontinuation due to adverse effects compared with exercise, although both had similar overall discontinuation rates. Combination Therapy. Low-quality evidence from 1 trial (38) showed no difference in overall discontinuation rates or discontinuation due to adverse events for sertraline monotherapy compared with combination therapy of sertraline plus exercise. The evidence is inconclusive about whether MDD severity is a predictor of the risk for harms, serious adverse events, or discontinuation of treatment. For demographic characteristics, no trials assessed the difference in benefits or harms between sexes or by race/ethnicity. For accompanying psychiatric symptoms, no trials assessed coexisting anxiety, insomnia, low energy, or somatization. Low-quality evidence from 1 trial (54) showed no difference in response rates, overall adverse events, or discontinuation due to adverse effects when comparing treatment using SGAs with St. John's wort in older adults (aged 60 to 80 years). For most comparisons studied, low-quality evidence showed no difference in effectiveness or adverse effects between first-line intervention using pharmacologic (SGAs) or nonpharmacologic (CAM or exercise monotherapies or combination therapies) treatments in patients with MDD. Moderate-quality evidence showed no difference in response or discontinuation of treatment when comparing SGAs with CBT. Patients are often treated for depression by primary care physicians who frequently prescribe SGAs (55, 56). A previous systematic review and the 2008 ACP guideline (57, 58) have shown similar safety and efficacy among the different SGAs. Most patients do not achieve remission after initial treatment with SGAs (59), in which case switching therapies or augmenting with additional interventions may be warranted. Table 3 summarizes the typical duration, dosages, and comparative adverse effects associated with SGAs (60). Table Jump PlaceholderTable 3. Durations and Dosages of SGAs Used in the Trials Reviewing the Comparative Efficacy and Effectiveness of MDD* Adverse effects commonly associated with SGAs include constipation, diarrhea, dizziness, headache, insomnia, nausea, sexual adverse events, and somnolence (58). Adverse effects associated with St. John's wort include gastrointestinal symptoms, dizziness or confusion, and fatigue or sedation. For second-line treatment after unsuccessful treatment with SGAs, low-quality evidence showed that strategies to switch to or augment with another drug or nonpharmacologic therapy are similarly effective. Most evidence came from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study (40,42, 43). Data on population subgroups were limited; however, in older persons, St. John's wort was equally effective and had similar rates of adverse events compared with SGAs (low-quality evidence). Evidence was insufficient to determine whether depression severity was a modulator of treatment efficacy or harms. Low-quality evidence showed that St. John's wort may be as effective as SGAs for treating MDD, and moderate-quality evidence showed that St. John's wort was better tolerated than SGAs. However, St. John's wort is not currently regulated by the U.S. Food and Drug Administration, and there is no current standard in place about the contents and potency of the medication. Therefore, patients in the United States may not be able to get a quality-controlled medication or reliably obtain preparations with similar effectiveness as those used in the included studies. Adverse effects associated with St. John's wort may include mild gastrointestinal symptoms, skin reactions, fatigue, sedation, restlessness, dizziness, headache, and dry mouth (61, 62). St. John's wort is associated with important drug–drug interactions and is known to induce cytochrome P450 isoenzyme 3A4 (63). It may reduce the bioavailability or efficacy of some drugs, such as oral contraceptives and immunosuppressants, and is contraindicated in patients receiving monoamine oxidase or serotonin reuptake inhibitors (64–66). Recommendation: ACP recommends that clinicians select between either cognitive behavioral therapy or second-generation antidepressants to treat patients with major depressive disorder after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient. (Grade: strong recommendation, moderate-quality evidence) Moderate-quality evidence shows that CBT and SGAs are similarly effective treatments for MDD. Moderate-quality evidence suggests that discontinuation rates are similar for CBT and SGAs, although discontinuation due to adverse events is non–statistically significantly increased with SGAs. However, harms associated with SGAs are probably underrepresented in the included trials. Thus, we conclude that CBT has no more—and probably fewer—adverse effects than SGAs. In addition, lower relapse rates have been reported with CBT than SGAs (11, 15). Although SGAs are often initially prescribed for patients with depression, CBT is a reasonable approach for initial treatment and should be strongly considered as an alternative treatment to SGAs where available. Further, there are reported differences among SGAs in mild (constipation, diarrhea, dizziness, headache, insomnia, nausea, and somnolence) to major (sexual dysfunction and suicidality) adverse effects. Bupropion is associated with a lower rate of sexual adverse events than fluoxetine and sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, and sertraline (57). Physicians and patients should discuss adverse event profiles before selecting a medication. Figure 2 summarizes the recommendations and clinical considerations. Grahic Jump Location Figure 2. Summary of the American College of Physicians guideline on nonpharmacologic versus pharmacologic treatment with second-generation antidepressants for adult patients with major depressive disorder. CBT = cognitive behavioral therapy; CYP 3A4 = cytochrome P450 isoenzyme 3A4; IT = interpersonal therapy; PSYD = psychodynamic therapy; SGA = second-generation antidepressant. Grahic Jump Location Evidence was insufficient to determine the comparative effectiveness of SGAs to third-wave CBT. Further, there was insufficient evidence to determine the comparative harms of SGAs versus monotherapy using interpersonal therapy or combination therapy with SGAs. For second-line therapy of switching or augmentation strategies, no studies directly compared SGAs with CAM or exercise. No studies directly compared switching versus augmentation strategies. Evidence was insufficient to determine whether the comparative effectiveness of SGAs to other treatments is a function of disease severity, and there were limited data on assessing the efficacy of treatments for MDD based on the subgroups of populations. In addition, there is insufficient evidence about the applicability of studies of St. John's wort to patients in the United States, especially about the purity and potency of St. John's wort preparations available in this country. Appendix: Detailed Methods The evidence review was conducted by the AHRQ's RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center. Details of the ACP guideline development process can be found in ACP's methods paper (10). Key Questions Addressed Key Question 1a: In adult patients with MDD who are attempting initial treatment, what is the effectiveness of SGA monotherapy compared with either nonpharmacologic monotherapy or combination therapy (involving nonpharmacologic treatments alone or in combination with an SGA)? Key Question 1b: Does comparative treatment effectiveness vary by MDD severity? Key Question 2a: In adult patients with MDD who did not achieve remission after an initial adequate trial with 1 SGA, what is the comparative effectiveness of second-line therapies? Key Question 2b: Does comparative treatment effectiveness vary by MDD severity? Key Question 3a: In adult patients with MDD, what are the comparative risks for harms of these treatment options for those attempting initial treatment or those who did not achieve remission after an initial adequate trial with an SGA? Key Question 3b: Do the comparative risks for treatment harms vary by MDD severity? Key Question 4: Do the benefits and risks for harms of these treatment options differ by subgroups of patients with MDD defined by common accompanying psychiatric symptoms (coexisting anxiety, insomnia, low energy, or somatization) or demographic characteristics (age, sex, race, or ethnicity)? The Clinical Guidelines Committee was particularly interested in comparative effectiveness of treatment according to MDD severity (key questions 1b, 2b, and 3b) because depression screening is becoming more widespread, which will tend to increase the proportion of patients being diagnosed with milder MDD. Search Strategy Reviewers searched MEDLINE (via PubMed), EMBASE, the Cochrane Library, AMED, PsycINFO, and CINAHL from 1 January 1990 through September 2015 for studies in English, German, or Italian. Studies on efficacy were limited to randomized, controlled trials and systematic reviews and meta-analyses, although evidence on harms included observational studies. For additional information, including inclusion and exclusion criteria, refer to the accompanying systematic review (9) and the full evidence report sponsored by AHRQ (6). Further, there were no limitations on study duration or length of follow-up. Meta-analysis and Network Meta-analysis Direct comparisons were made using meta-analytic techniques. Network meta-analysis was used when there was a lack of studies on direct comparisons. The reviewers used a hierarchical frequentist approach and random-effects models, including placebo- and active-controlled randomized, controlled trials that were homogenous in study populations and outcome assessments and were part of a connected network (67, 68). Quality Assessment The quality of studies was assessed using the AHRQ handbook (69). The risk of bias for studies was assessed using AHRQ guidance (70) and the Cochrane Risk of Bias tool (71). Tests for publication bias had low sensitivity because of the small number of studies. This guideline rates the evidence and recommendations using ACP's guideline grading system (Table 1). Population The population included adult outpatients (aged ≥18 years) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA. Interventions Evaluated The interventions evaluated are as follows: depression-focused psychotherapy; CAM, including acupuncture, meditation (for example, mindfulness-based stress reduction), ω-3 fatty acids, SAMe, St. John's wort (Hypericum perforatum), and yoga; exercise; and SGAs, including bupropion, citalopram, desvenlafaxine, duloxetine, fluoxetine, escitalopram, fluvoxamine, levomilnacipran, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, venlafaxine, vilazodone, and vortioxetine. Drugs evaluated for combination or augmentation therapies included atypical antipsychotics (aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone), psychostimulants (amphetamine–dextroamphetamine, armodafinil, dexmethylphenidate, dextroamphetamine, lisdexamfetamine, methylphenidate, and modafinil), buspirone, -thyroxine (T4), lithium, and pindolol triiodothyronine (T3). Comparators The SGAs were compared with monotherapy that involved nonpharmacologic interventions or combination therapies of SGAs and nonpharmacologic interventions. To assess second-line treatment, modifications of initial treatment with SGAs were compared with nonpharmacologic interventions; other pharmacologic interventions, including CAM; or combinations of nonpharmacologic and pharmacologic strategies as either switches to new treatment or augmentation of existing therapy. Outcomes Benefits assessed included response (often defined as ≥50% improvement in HAM-D scores), remission (often defined as a HAM-D score ≤7), speed of response, speed of remission, relapse, quality of life, functional capacity (as assessed by various scales), reduction of suicidality, or reduction of hospitalization. Quality of life, functional status, suicidality, and hospitalizations were rarely reported. Harms assessed included overall adverse events, withdrawals because of adverse events, serious adverse events, specific adverse events (including hyponatremia, seizures, suicidality, hepatotoxicity, weight gain, gastrointestinal symptoms, and sexual adverse events), withdrawals because of specific adverse events, or drug interactions. Target Audience The target audience for this guideline includes all clinicians, patients, health system leaders, and policymakers. Target Patient Population The target patient population includes all adults with MDD. Peer Review The AHRQ evidence review was sent to invited peer reviewers and posted on the AHRQ Web site for public comments. The guideline underwent a peer-review process through the journal and was posted online for comments from ACP Governors and Regents. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. 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  5. www.medscape.com http://www.medscape.com/viewarticle/818516?src=wnl_edit_tpal&uac=60604BR Are Severe Depressive Symptoms Associated With Infertility-related Distress in Individuals and Their Partners? Brennan D. Peterson, Camilla S. Sejbaek, Matthew Pirritano, Lone Schmidt Hum Reprod. 2014;29(1):76-82. Abstract and Introduction Abstract Study question Are severe depressive symptoms in women and men associated with individual and dyadic infertility-related stress in couples undergoing infertility treatment? Summary answer Severe depressive symptoms were significantly associated with increased infertility-related distress at both the individual and partner level. What is known already? An infertility diagnosis, the stress of medical treatments and a prior history of depression are risk factors for future depression in those undergoing fertility treatments. Studies examining the impact of severe depressive symptoms on infertility-related distress in couples are lacking. Study design, size, duration This cross-sectional study included 1406 couples who were consecutively referred patients undergoing fertility treatments in Denmark in the year 2000. A total of 1049 men and 1131 women were included in the study. Participants/materials, setting, methods Participants were consecutively referred patients undergoing a cycle of medically assisted reproduction treatment at five Danish public and private clinics specializing in treating fertility patients. Severe depressive symptoms were measured by the Mental Health Inventory 5 from the Short Form Health Survey 36. Infertility distress was measured by the COMPI Fertility Problem Stress Scales. Multilevel modelling using the actor–partner interdependence model was used to study the couple as the unit of analysis. Main results and the role of chance Severe depressive symptoms were reported in 11.6% of women and 4.3% of men, and were significantly associated with increased infertility-related distress at the individual and partner level. There was no significant interaction for gender indicating that men and women did not differ in how severe depressive symptoms were associated with infertility distress. Limitations, reason for caution Because of the cross-sectional study design, the study findings only show an association between severe depressive symptoms to individual and partner distress at a single point in time; however, nothing is known about causality. Wider implications of the findings This study adds to the growing body of literature using the couple as the unit of analysis to study the relationship between depression and infertility distress. Recommendations for medical and mental health professionals that underscore the potential risk factors for depressed men and women who are pursuing infertility treatments are provided. Additional studies using a longitudinal study design to track the impact of depression on distress over the course of the infertility treatment cycle would be valuable for increasing our understanding of the complex relationship that exists between these psychosocial factors. Study funding/competing interests Authors Brennan Peterson and Matthew Pirritano have no financial disclosures for this study. Camilla Sandal Sejbaek and Lone Schmidt have received research grants from the Danish Health Insurance Foundation (J. nr. 2008B105) and Merck Sharp & Dohme. The funders had no influence on the data collection, analyses or conclusions of the study. Introduction The experience of infertility is commonly linked with unexpected stressors that can impact one's personal life, social support networks and marital relationships (Newton et al., 1999). These stressors can cause significant disruption in one's life and be related to increased psychological distress in men and women (Wichman et al., 2011). One of the key types of distress reported in infertility patients is depression. An infertility diagnosis and the stress of medical treatment can put women at risk of depressive symptoms, particularly after treatment failure (Newton et al., 1990; Domar et al., 1992; Verhaak et al., 2007; Volgsten et al., 2010). On the other hand, women with depressive symptoms may be more likely to experience infertility due to depression's impact on the biological mechanisms that influence hormone production and ovulation (Lapane et al, 1995; Williams et al., 2007). Adding to the already complicated relationship that exists between these variables, a prior history of depression is a risk factor for future depression in women undergoing fertility treatments (Vahratian et al., 2011; Pasch et al., 2012). The majority of studies examining the relationship between depression and infertility have examined the impact of depression on pregnancy and live birth rates. While some studies have found that depression is linked with lower pregnancy rates in couples pursuing assisted reproductive technologies (ART) (Klonoff-Cohen, 2005), two recent meta-analyses have found that depression was not associated with a reduced chance of pregnancy outcome (Boivin et al., 2011; Matthiesen et al., 2011). However, a recent study using a national register-based cohort found that of the 42 880 Danish women participating in ART treatments, women with a depression diagnosis prior to fertility treatments participated in fewer ART cycles and had fewer ART live births when compared with the non-depressed group (Sejbaek et al., 2013). This supports a previous research finding that women with major depression reported the lowest live birth rate among study participants (Volgsten et al., 2010). For infertility patients who undergo ART, a prior depression history is the strongest risk factor for future depression (Vahratian et al., 2011; Pasch et al., 2012). Men and women with depression prior to infertility treatment likely have less physical, emotional and social resources to cope with the stress of infertility treatments and treatment failure, and thus may be considered an 'at risk' group. In a Swedish study of 545 couples undergoing in vitro fertilization (IVF), 10.9% of women and 5.1% of men had major depression at treatment initiation (Volgsten et al., 2008). In this study, major depression was measured by the Primary Care Evaluation of Mental Disorders (PRIME-MD) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). This is a substantial percentage of the patients seen for infertility treatments, and because we currently know very little about the association between pre-existing depressive symptoms and infertility-related distress in infertility patients, it is important to establish a baseline if such an association exists. In addition to our limited understanding of the association between severe depressive symptoms and infertility-related distress, we know very little about how depression is associated with infertility distress at the dyadic level. In other words, is there an association between an individual's severe depressive symptoms and a partner's levels of infertility-related distress? To address the lack of studies using the couple as the unit of analysis, researchers have begun to use a data analytic technique called the actor–partner interdependence model (APIM) (Kenny et al., 2006), to study how the stressors of infertility are related to individual and partner outcomes (Peterson et al., 2008, 2009, 2011; Benyamini et al., 2009). A small number of these studies have used depression as a study variable and have examined its relationship with coping (Berghuis and Stanton, 2002), marital conflict (Proulx et al., 2009) and the transmission of depressive symptoms between partners undergoing fertility treatments (Knoll et al., 2009). However, few studies have examined how depression is associated with infertility distress, and particularly how depressive symptoms are associated with both the individual's and partner's levels of distress. Because infertility is ultimately a shared stressor that exists between both members of the couple, more studies are needed to utilize dyadic analyses in order to provide a more complete picture of the infertility experience. The current study attempted to examine how severe depressive symptoms in women and men are associated with individual and dyadic infertility-related distress. The study asked the following research questions: (i) Prior to fertility treatments, do men and women with severe depressive symptoms experience higher levels of infertility distress when compared with men and women who do not report severe depressive symptoms? (ii) Are an individual's severe depressive symptoms associated with increased infertility-related distress in the individual and in their partner? Materials and Methods Procedure This study is part of The Copenhagen Multi-centre Psychosocial Infertility (COMPI) Research Programme (Schmidt, 2006), a prospective longitudinal cohort study of infertile couples in fertility treatment. Patients who were consecutively referred at one of the four public hospital-based tertiary fertility clinics and one private clinic between January 2000 and August 2001 received a questionnaire for each spouse before attending their first treatment. The study complied with the Helsinki II Declaration was assessed by the Scientific Ethical Committee of Copenhagen and Frederiksberg Municipalities (KF 01-107/99), and was approved by the Danish Data Protection Agency (J. nr. 1999-1200-233; 2001-41-1486; 2005-41-5694). Measures The 5-item Mental Health Inventory 5 (MHI-5) from the 36-item Short-Form Health Survey (SF-36), Medical Outcomes Study, was used to measure severe depressive symptoms (Bjorner et al., 1998a,b; Strand et al., 2003). Previous studies comparing MHI-5 with other (validated) mental health scales have shown MHI-5 to be a good measure of severe depressive symptoms (Berwick et al., 1991; Strand et al., 2003). The five items in the MHI-5 measure the mood of the participants in the past 4 weeks (e.g. felt so down in the dumps that nothing could cheer you up, felt downhearted and blue). The response key was a 6-point scale ranging from (1) all of the time to (6) none of the time. The scores for two of the items were reversed and the answers were summed up to a raw score ranging from 5 to 30 (Bjørner et al., 1997). The raw score was then transformed to a scale ranging from 0 to 100. The scale was dichotomized with a cut-off point at 52 and participants scoring ≤52 were categorized as having severe depressive symptoms. This cut-off point was chosen in agreement with previous studies comparing other scales measuring depressive symptoms to the MHI-5, and investigating different cut-off points for the MHI-5 (Holmes, 1998; Strand et al., 2003). Studies in other research fields also use a cut-off point at ≤52 (Rugulies et al., 2012). Therefore, choosing the same cut-off point as other studies makes it possible to compare results. The MHI-5 has been widely used in studies assessing mental health, as well as general health, and has had a Cronbach's alpha of 0.82 (Strand et al., 2003). Infertility-related distress was measured by the COMPI Fertility Problem Stress Scales, a 14-item instrument based on The Fertility Problem Stress Inventory (Abbey et al., 1991) and qualitative interviews of Danish infertile patients regarding the psychosocial consequences of infertility and fertility treatment (Schmidt, 1996). The measure includes questions regarding one's personal distress (six items, e.g. how much stress the individual felt in their life as a result of the childlessness), marital distress (four items, e.g. how much stress the childlessness placed on marriage and sexual relationship) and social distress (four items, e.g. how much stress the fertility problem placed on relationships with family, friends and workmates). The response key for 10 of the 14 items is based on a 4-point scale from (1) a great deal to (4) none at all, while four items are based on a 5-point scale from (1) strongly agree to (5) strongly disagree. An exploratory factor analysis produced a set of parsimonious factors (Schmidt et al., 2003). In the exploratory factor analysis, items with factor loadings >0.45 were assigned to the factor (personal, marital or social distress) for which they had the greatest loading. As mentioned above, the three domains were uncovered in accordance with Abbey et al. (1991) and the interviews conducted by Schmidt (1996). The range, mean and Cronbach alpha coefficients differed depending on the subscale: personal distress (range 0–20, mean 6.86, SD 4.48, Cronbach alpha 0.82); marital distress (range 0–14, mean 3.86, SD 3.16, alpha 0.73) and social distress (range 0–12, mean 1.87, SD 2.43, alpha 0.82) (Schmidt et al., 2003). Data Analysis This study was cross-sectional. Multilevel modelling using the APIM(Kenny et al., 2006; Kashy and Donnellan, 2008) was used to study the association between a partner's severe depressive symptoms and his or her partner's distress (personal, marital and social) (see Fig. 1). The APIM allows for the simultaneous estimation of actor effects (individual effects) and partner effects (the effects of another closely associated person) to shared stressors in dyads, thus providing a more complete picture of how severe depressive symptoms are related to distress in couples. Figure 1. General model of actor and partner effects of severe depressive symptoms on distress. Data were analysed with the couple as the unit of analysis. This was done by conducting multilevel analyses using the SAS 9.2® mixed procedure. A multilevel analysis involves more than one regression model calculated at different levels of a nested design. In the current set of analyses, level 1 was the individual level that was nested within level 2, the couple. Multilevel analyses estimate the model independently at each of these levels. The design of the analysis is very similar to a multiple regression with one dependent variable and a set of predictors, or independent variables. Analyses provide unstandardized estimates of path coefficients for actor and partner effects. The analyses were cross-sectional with severe depressive symptoms (dichotomous) as the independent variable, and personal, marital and social distress as the dependent variables. Three analyses were conducted, one for each of the three types of distress. Because previous research has found infertility diagnosis (i.e. male or female factor infertility) to be related to other psychosocial consequences of infertility (Peronace et al., 2007), infertility diagnosis based on five categories [i.e. male factor, female factor, both male–female factor, other causes (not specified), unknown] was therefore tested as a covariate in the analyses. However, no statistical association between infertility diagnosis and severe depressive symptoms and personal and marital distress was found, so it was not included in the final analyses. Results In total, 2812 fertility patients (1406 couples) received a baseline questionnaire for each partner and 80.0% ( n = 2250) participated. Couples who had a child together prior to inclusion in COMPI and participants without a severe depressive symptoms score were excluded from the analyses. Thus, 1049 men and 1131 women were included in the overall study. At baseline the mean age of women was 31.9 years (SD = 3.6 years) while their male partners mean age was 34.3 years (SD = 5.1 years). Couples had been together for an average of 7.7 years (SD = 3.7) and had been infertile for ~4.2 years (SD = 2.3). Nearly 60% had been in fertility treatment prior to inclusion in the COMPI Research Programme. As shown in , 11.6% of women in the sample reported severe depressive symptoms compared with 4.3% of men (χ 2 = 39.0, P < 0.001). Women with severe depressive symptoms had significantly higher distress levels for all three measures compared with women with no severe depressive symptoms. The same relationship was also found for men (see ). Women reported significantly higher levels of personal distress ( t = −15.9, P < 0.001) and social distress ( t = −7.73, P < 0.001) when compared with men. However, no difference was found between women and men with respect to marital distress. Severe depressive symptoms were significantly associated with increased personal, marital and social distress in both men and women (i.e. significant actor effects). There were no interaction effects with gender, indicating that the association between depression and distress did not differ between men and women. There were also significant partner effects for men and women in that an individual's severe depressive symptoms were associated with higher levels of personal and marital distress in one's partner. However, for social distress only a female partner effect was found, showing that a male's severe depressive symptoms were significantly associated with a female partner's social distress. None of the interaction effects between partner effects and gender were significant, indicating that the association between severe depressive symptoms and effects on the partner's distress did not differ between males and females. Discussion This study adds to the growing body of literature that examines the dyadic impact of a partner's response to infertility (Berghuis and Stanton, 2002; Benyamini et al., 2009; Knoll et al, 2009; Peterson et al., 2009, 2011) by providing support that severe depressive symptoms are significantly associated with personal, marital and social infertility-related distress at the individual and partner level. Although there are studies that have examined the dyadic impact of depression in couples pursuing infertility treatments (Berghuis and Stanton, 2002; Knoll et al., 2009), to our knowledge, this is the first study to demonstrate that severe depressive symptoms are significantly associated with individual and partner infertility distress. The current study used severe depressive symptoms as the independent variable in the study analysis. Although we cannot draw predictive conclusions relative to severe depressive symptoms and infertility-related distress, the purpose of the current study was to examine if such an association exists so that baseline data can lay the groundwork for future longitudinal studies. In our sample, 11.6% of women and 4.3% of men reported severe depressive symptoms; these rates compared favourably with a large sample of infertility patients reporting depression in Sweden (10.9% women, 5.1%, men) (Volgsten et al., 2008). The fact that two studies found such high rates of depressive symptoms in men and women prior to pursuing infertility treatments illustrates the significance of studying the possible association between severe depressive symptoms and infertility-related distress. Furthermore, it is possible that these rates even underrepresent the actual percentage of depressed men and women experiencing infertility, as researchers have found that depression can act as a barrier to seeking out medical advice for infertility (Herbert et al., 2010). It has been well documented that infertility is commonly linked with depression, particularly in women (Domar et al, 1992), and that an infertility diagnosis and the subsequent stress of treatments have been linked with increased infertility distress (Newton et al., 1999; Greil et al., 2010). In the current study, women reported higher levels of infertility distress when compared with men, a finding supported by a wide body of literature (Newton et al., 1999; Greil et al., 2010). In addition, a significantly higher percentage of women reported severe depressive symptoms when compared with men. This is consistent with depression rates in the general population where women are two to three times as likely to be depressed as men (Kessler, 2003). It is noteworthy that the current study used a sample of men and women that included people who reported severe depressive symptoms. A meta-analysis of 28 studies examining the relationship between depression and women experiencing polycystic ovary syndrome found that over 50% of the studies reported depression scores in the non-clinical range, while the remaining studies were in the mild depression range (Veltman-Verhulst et al., 2012). Using a sample of couples with severe depressive symptoms helps give voice to an understudied and at-risk population of women and men. Furthermore, the current study answered calls of previous researchers to use multilevel models that enhance our understanding of the dyadic impact of an individual's severe depressive symptoms on one's partner (Lund et al., 2009). The finding of the current study that an individual's severe depressive symptoms are related to increased infertility-related distress in the partner supports this call, and underscores the importance of conceptualizing infertility as a couples-level stressor. A large number of studies examining the relationship between depression and infertility have done so by examining the impact of depression on pregnancy outcomes. While it is encouraging that recent meta-analyses and studies have found that depression prior to infertility treatment does not influence pregnancy rates, a finding that can reduce the amount of self-blame a woman may feel following unsuccessful treatment (Boivin et al., 2011; Matthiesen et al., 2011; Pasch et al., 2012), the findings from this study underscore possible risk factors for depressed men and women pursuing infertility treatments. It has been shown that higher depression in women prior to IVF treatment was associated with higher depression following IVF treatment (Pasch et al., 2012). This finding may be explained in part because men and women, who are depressed prior to treatments, are likely experiencing greater amounts of infertility distress compared with non-depressed couples. Because this distress increases at both the individual and partner level, and because depressed individuals have fewer emotional resources to cope with this distress, this group may be at particular risk of future depression following treatment failure. The findings from the current study may have implications for medical and mental health professionals (Peterson et al., 2012). Pasch et al. (2012) recommended that psychological interventions be focused on helping couples cope with the stress of infertility and treatment failure, as opposed to using psychological treatments to reduce stress in an attempt to become pregnant. This may be particularly true for men and women entering treatment with severe depressive symptoms, as their levels of infertility stress may be higher than those without depressive symptoms. The findings from this study must be interpreted in the context of the study's limitations. First, due to the cross-sectional study design, we cannot make conclusions that depressive symptoms cause increased infertility distress in individuals or partners, or that infertility distress causes an increase in an individual's or partner's depressive symptoms. These findings only represent the association between severe depressive symptoms and infertility distress, and therefore cannot be used to infer any causality or directionality of this relationship. Second, the COMPI scales used in this study have not yet been validated in large-scale psychometric studies. The fertility problem stress scales were adopted from an existing scale (Abbey et al., 1991) and further developed based on findings from in-depth detailed qualitative research and interviews with Danish fertility patients (Schmidt, 1996). Explanatory factor analyses showed infertility-specific distress in three different domains (personal, marital, social) (Schmidt et al., 2003), and the infertility-specific scales are being used in several other studies in different countries, with a cross-cultural validation study currently being carried out. Third, the multilevel analyses are unadjusted, although the findings show that the couples are intertwined and that the dyadic analyses add information about couples and their influence on each other. Fourth, the MHI-5 was developed to assess mental health in general and was not designed to assess severe depressive symptoms. However, a study comparing clinical diagnosis with MHI-5 found good agreement for mood disorders and the MHI-5 (Rumpf et al., 2001), which indicates that it is plausible to use the MHI-5 as a proxy for severe depressive symptoms. Finally, the cut-point of the MHI-5 could have been higher (e.g. 56 or 60), hence identifying more individuals with severe depressive symptoms. However, because the MHI-5 is not a clinical instrument, the lowest cut-point identified was used. This is also in accordance with other studies (Holmes, 1998; Strand et al., 2003; Rugulies et al., 2012) that found ≤52 as the best cut-point. Given these limitations, additional studies using a longitudinal study design to track the impact of depression on distress over the course of the infertility treatment cycle would be valuable in increasing our understanding of the complex relationship that exists between these variables. References Abbey A, Andrews FM, Halman JL. Gender's role in responses to infertility. 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Acknowledgements The Infertility Cohort is part of The Copenhagen Multi-centre Psychosocial Infertility (COMPI) Research Programme initiated by Dr Lone Schmidt, University of Copenhagen, 2000. The programme is a collaboration between the public Fertility Clinics at: Horsens (former Braedstrup) Hospital; Herlev University Hospital; The Juliane Marie Centre, Rigshospitalet and the Odense University Hospital. Authors' roles All authors contributed substantially to the concept and the design of the study. L.S. obtained the data. C.S.S. and M.P. performed the data analysis. B.D.P. drafted the article. All authors contributed to the data interpretation, critical and substantial revisions of the paper and final approval of the manuscript. Hum Reprod. 2014;29(1):76-82. © 2014 Oxford University Press
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