A Mega-analysis Of Genome-wide Association Studies For Major Depressive Disorder

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10−8), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083–53 822 102, minimum P=5.9 × 10−9 at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status

The Epidemiology Of Psychiatric Disorders: Past, Present, And Future Generations

This paper briefly reviews the history of psychiatric epidemiology and the future direction. Five generations of studies are described, beginning in 1885 with a community study in Worchester. The second generation studies began after World War II and emphasized social epidemiology. The third generation incorporated the development of structured diagnostic assessments and led to the Epidemiologic Catchment Area study at five sites in the USA and to a number of epidemiological studies throughout the world using similar methods. The fourth generation included the new comorbidity survey, a national probability sample in the USA, which used an instrument capable ofbridging DSM-III and ICD classification. The fifth generation began with the development of methods for apsychiatric epidemiological study of children. Future epidemiological studies need to include assessment of family psychiatry history as a risk factor, and promising biological markers. There needs to be regular monitoring to obtain accurate estimates of temporal changes in rates of psychiatric disorder

Applied Public Mental Health: Bridging The Gap Between Evidence And Clinical Practice

Wahlbeck describes a public mental health approach at a population level. His proposal is far reaching, including not only the reduction of mental illness or specific psychiatric disorders, but the promotion of mental wellbeing, positive mental health and happiness. The targets vary widely, including parenting, education, housing, employment, justice, etc. The interventions include relaxation, meditation, mindfulness training, job stress management, cognitive behavioral therapy, biofeedback, exercise, health education, social networking, etc. The strategies include health promotion, improvement of mental health services, reduction of stigma, fight for human rights, etc. The author concludes that challenges remain in identifying risk, protective and resilience factors for mental health problems across the lifespan, and developing effective and evidence-based public mental health interventions. One cannot disagree with the mandate. However, the breadth is overwhelming. Many of the actions described require partnerships well beyond public health, psychiatry or even medicine, and fall in the domain of social policy, government, and the will of the people in a functioning democracy. The actions impinge upon social values and the limits of governmental reach, which vary considerably by culture or country. Consider the public health problems of violence, which are often related to firearms. Prevention may engage issues such as enforcement of gun control legislation, raising minimum age requirements for gun ownership, reforming gun licensing, and imposing restrictions on gun purchases. Identifying the risk factors and health education alone may be insufficient. Safe food practices, immunization, public health education, and improved sanitation have been successful over the past century in increasing life expectancy and improving quality of life. Parallel public health initiatives for mental wellness will require a similar mobilization of government and business efforts based on known risks. Although social change itself may improve mental health, there will need to be a confluence of the common good for this to happen. Even then, there is little guarantee that programs will be effective or resources sufficient to sustain them

Psychotherapy: A Paradox

An editorial appeared in the September 27, 2012, issue of Nature entitled “Therapy Deficit: Studies to Enhance Psychological Treatments Are Scandalously Under-Supported”. Out of character for a leading basic science journal, it argued for the active consideration of psychotherapy for treatment and research, and it emphasized the funding disparities between psychotherapy and medication. The editorial did not describe the psychotherapy paradox. While psychotherapy is fading from consciousness and practice in some developed countries, it is being enthusiastically embraced in developing countries hurt by HIV, natural disasters, wars, or political strife. For example, World Vision, one of the largest international philanthropies, funded two clinical trials of interpersonal psychotherapy for the treatment of depression in Uganda, a country devastated by HIV and civil war. The treatment’s positive results in reducing depression and sustaining the effects were widely disseminated. Another clinical trial was completed in Goa, India, using the initial phase of interpersonal psychotherapy to treat depression in primary care, and the results were the subject of a recent editorial that questioned whether psychiatrists were needed. Verdeli and I responded strongly that psychiatrists were critical for overall quality control, patient evaluation, diagnosis, and program supervision. In fact, most of these global programs are led by psychiatrists

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from London to design a study to test the relative effi cacy of a tricyclic antidepressant alone and both with and without psychotherapy as maintenance treatment of ambulatory nonbipolar depression. The evidence for the effi cacy of tricyclic antidepressants for reducing the acute symptoms of depression was strong, yet the main treatment for depression at the time was psychodynamic psychotherapy. The few studies testing psychotherapy were behavioral treatments and were limited in scope and sample size. A manual for cognitive therapy (CT) was under development by Dr. Aaron Beck. At the time, it was clear that many patients with acute depression relapsed after termination of tricyclic antidepressant treatment. It was unclear how long psychopharmacologic treatment should continue and whether psychotherapy had a role in the prevention of relapse. Some psychotherapists thought medication would make patients less interested in psychotherapy, whereas some psychopharmacologists felt psychotherapy would undo the positive effects of medication by having patients talk about upsetting material. Dr. Klerman, then head of the Connecticut Mental Health Center and on the faculty at Yale School of Medicine, felt that a clinical trial of maintenance tricyclic antidepressants should, as much as possible, mimic clinical practice. Be

Outsourced Psychiatry: Experts Still Relevant

The News Focus story on global mental health, “Who needs psychiatrists?” (G. Miller, 16 March, p. 1294), implied that the answer is “no one.” This is not the case. It is true that clinical trials have demonstrated the efficacy of talking therapies for depression, anxiety, and other common mental disorders, when delivered by nonpsychiatrist health workers trained by professionals. Severely ill individuals (such as those with refractory depression, bipolar disorder, or schizophrenia) require medication, which can be administered safely by nurses, family doctors, and even health workers supervised by medical personnel. Investing in community health workers as mental health gatekeepers is the safest national strategy for sustainable mental health programs, for the reasons mentioned in the News Focus story as well as an additional one: Community health workers are not as susceptible to “brain drain”—the emigration of skilled workers for better working conditions—as health professionals

The Role Of Religiosity In Families At High-risk For Depression

Background. — About 40 years ago we began a study of the offspring of depressed (high-risk) and not depressed (low-risk) parents, matched for age and gender, from the same community. We interviewed all of their biological children, blind to the clinical status of the parents. Over the years, we returned to re-interview the families at baseline, 2, 10, 20, 25, 30, and 35 years. As the years went by and the sample grew up, we also interviewed the third generation, the grandchildren. As technology became available, we included measures of electrophysiology and magnetic resonance imaging in order to better understand the mechanisms of risk. At the 10-year follow up, we included measures of religion and spirituality — namely, personal religious/spiritual importance and frequency of religious service attendance. We included these measures in all subsequent waves including a more extensive follow up of religious beliefs at the 35-year follow up

Depression In Women: Implications For Health Care Research

Epidemiologic data from around the world demonstrate that major depression is approximately twice as common in women than men and that its first onset peaks during the childbearing years. Progress has been made in understanding the epidemiology of depression and in developing effective treatments. Much remains to be learned about the basic pathogenesis of depression and the specific treatment needs of depressed women and their offspring, especially during the reproductive years

Re: “guidelines For The Evaluation And Treatment Of Perimenopausal Depression: Summary And Recommendations” By Maki Et Al. (j Women’s Health 2019; 28:117–134)

This is a letter from Dr. Myrna M. Weissman and Dr. John C. Markowitz to Dr. Maki and Members of the Committee on Guidelines for the Evaluation and Treatment of Perimenopausal Depression

A Brain-based Endophenotype For Major Depressive Disorder

We have identified a brain-based endophenotype for major depressive disorder (MDD) that includes thinning of the cortex of the lateral aspect of the right hemisphere and the medial aspect of the left, as well as bilateral hypoplasia of frontal and parietal white matter. The endophenotype status of these abnormalities is supported by their presence in a multi-generational cohort of persons who themselves do not have MDD but who are at increased familial risk for developing the illness. Those who have the endophenotype but who are not ill nevertheless still suffer from inattention and poor visual memory for social stimuli in direct proportion to the magnitude of cortical thinning and white matter hypoplasia within the endophenotype. Identification of this endophenotype and its cognitive correlates provides targets for devising new preventive and therapeutic interventions for MDD