Mood Disorders Research Research Articles

Restraint Urged in Adding Antidepressant to Mood Stabilizer

Restraint Urged in Adding Antidepressant to Mood Stabilizer

Public-Academic Partnerships: The Continuous Improvement for Veterans in Care: Mood Disorders (CIVIC-MD) Study, a VA-Academic Partnership

The Department of Veterans Affairs (VA) provides an ideal opportunity to conduct mental health services research among vulnerable populations, given its extensive data sources, disproportionate number of vulnerable patients (older, often with comorbidities), and quality improvement mission. Although VA facilities are often affiliated with universities, successful VA-academic research partnerships are sometimes elusive. The Continuous Improvement for Veterans in Care: Mood Disorders (CIVIC-MD) study was a partnership with a VA facility that had not been engaged in mood disorders research. This column describes how the partnership formed, key elements of its success, and challenges and opportunities to inform future research partnerships.

NARSAD Honors Breakthroughs in Mental Illness Research

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessNARSAD Honors Breakthroughs in Mental Illness ResearchJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:16 Nov 2007https://doi.org/10.1176/pn.42.22.0014aNARSAD is the world's leading mental health research charity. Since its inception 20 years ago, it has awarded more than 3,200 research grants totaling more than $219 million to scientists working in the United States and 26 other countries.At its annual fundraising gala last month, NARSAD awarded annual prizes for achievement in mental health research. These awards went to the following scientists:♦ The Lieber Prize for Outstanding Achievement in Schizophrenia Research was awarded to Eve Johnstone, M.D., a professor of psychiatry at the University of Edinburgh in Scotland. For more than three decades she has used advanced brain-imaging methods to elucidate structural and functional changes associated with schizophrenia. According to William Bunney Jr., M.D., chair of NARSAD's Lieber Prize Selection Committee, “She initiated the most replicated finding in the literature on psychosis—enlargement of the lateral ventricles in the brain.”♦ The Falcone Prize for Outstanding Achievement in Mood Disorders Research went to Helen Mayberg, M.D., a professor of psychiatry at Emory University. For more than 20 years she has used functional neuroimaging to examine neural mechanisms implicated in the onset of depression. She also hypothesized, on the basis of the information she had collected, that the anterior cingulate cortex was pivotal in regulating depressed mood and proceeded to stimulate this region electrically. Thus, deep brain stimulation for treatment-resistant depression was born. “A number of the most treatment-resistant patients who received this treatment have shown remarkable antidepressant responses,” Robert Post, M.D., chair of NARSAD's Falcone Prize Selection Committee, commented.♦ The Ruane Prize for Outstanding Achievement in Child and Adolescent Psychiatric Research was given to James Leckman, M.D., a professor of child psychiatry at Yale University. His research has focused on autism, obsessive-compulsive disorder, and Tourette's disorder. His main research interest is the interaction between genes and environment in obsessive-compulsive disorder and Tourette's. “He has also organized one of the premier clinical and research training programs in child psychiatry, which will guarantee excellent clinical research for our next generation,” Judith Rapoport, M.D., chair of the Ruane Prize Selection Committee, said.♦ The Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience was given to Huda Akil, Ph.D., a professor of psychiatry and neuroscience at the University of Michigan. Akil has made valuable contributions to understanding the neurobiology of emotions, including pain, anxiety, and depression. Early on, she and her colleagues provided the first physiological evidence for the role of endorphins in the brain and showed that endorphins are activated by stress and inhibit pain.♦ The Sidney R. Baer Jr. Prize for Schizophrenia Research went to Jeremy Hall, M.D., Ph.D., a research council fellow at the University of Edinburgh in Scotland. Hall has been studying genetic factors influencing cognitive function in major mental disorders. His work integrates neuroimaging and neuropsychology with genetics. ▪ ISSUES NewArchived

Neuroimaging Approaches in Mood Disorders: Technique and Clinical Implications

Clinical research in mood disorders increasingly involves advanced neuroimaging techniques. The encompassing aim of this review is to provide the mental health care practitioner with a pragmatic understanding of neuroimaging approaches and their possible clinical application. We conducted a literature search of English-language articles using the search terms, major depressive disorder and bipolar disorder, cross-referenced with available neuroimaging technologies and analytical approaches, The search was supplemented with a manual review of relevant references. We organize the review by reviewing frequently asked questions on the topic of neuroimaging by mental health-care providers. Magnetic resonance (MR) approaches provide information on white and gray matter pathology (segmentation), cellular metabolism (MRS), oxygen consumption (BOLD), and neurocircuitry (DTI). Radionuclide-based neuroimaging methodologies provide quantitative estimates of brain glucose metabolism, regional blood flow, and ligand-receptor/transporter binding. Clinical implications of neuroimaging methodologies are reviewed. Advances in neuroimaging technology have refined models of disease pathophysiology in mood disorders and the mechanistic basis of antidepressant action. Multivariate analysis of functional and structural neuroimaging data, longitudinal analysis in the depressed and remitted states, and inclusion of representative patients with medical and psychiatric comorbidities will enhance the clinical translation of future research findings.

Pharmacogenomics in Psychiatry

Pharmacogenomics may provide us with the means to expedite treatment for patients with various psychiatric disorders. Treatment is presently hampered by individual variation in medication response that often results in an extended trial-and-error process of treatment until the optimal medication is found. This can extend the time until treatment optimization to months or years. Much of this variation may be genetically based. This review discusses current pharmacogenomics research in mood disorders and in schizophrenia. Although the field is in an early stage, results already suggest that DNA tests will one day be of clinical value in the optimal selection of medications for mood and thought disorders.

Lithium Treatment Reduces Suicide Risk in Recurrent Major Depressive Disorder

Evidence that clinical treatment reduces suicide risk in major depressive disorder (MDD) is limited and inconsistent. Since lithium shows major antisuicidal effects in bipolar disorders and in heterogeneous mood disorder samples, we evaluated evidence of antisuicidal effects of lithium in patients with recurrent MDD. We searched MEDLINE (January 1966 to April 2006; search terms: lithium, suicide, affective disorder, depression, major depression, and mood disorder) for studies reporting suicides or suicide attempts during treatment with and without lithium in recurrent MDD patients, and we added data for 78 new subjects, provided from the Lucio Bini Mood Disorders Research Center in Sardinia, Italy. Suicide rates were pooled and analyzed by use of incidence-rate ratios (IRRs) and meta-analytic methods. Eight studies involved 329 MDD patients and exposure for 4.56 years (1149 person-years) with, and 6.27 years (1285 person-years) without, lithium. Overall risk of suicides and suicide attempts was 88.5% lower with vs. without lithium: 0.17%/y versus 1.48%/y (IRR = 8.71; 95% CI: 2.10 to 77.2, p = .0005); for completed suicides (85% risk reduction), IRR = 6.77 (95% CI: 1.29 to 66.8, p = .01). Meta-analysis by risk difference and risk ratio supported these findings, and sensitivity analysis yielded similar results with studies omitted serially. This is the first meta-analysis suggesting antisuicidal effects of lithium in recurrent MDD, similar in magnitude to that found in bipolar disorders.

Neuromodulation

<p>This issue of <cite>Psychiatric Annals</cite> considers the growing field of therapeutic neuromodulation most recently exemplified by vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS) for major depression. In this context, Dr. Demitrack considers the role of these device-based therapies in an overall strategy to manage depression. Dr. Richelson explores the neurobiology related to their antidepressant effects. Dr. Sampson and colleagues then describe the clinical role of TMS for major depression, while Drs. Rado and Janicak review the application of VNS to treat more resistant depressive disorders.</p> <h4>ABOUT THE GUEST EDITORS</h4> <p>Philip Gregory Janicak, MD, is Professor of Psychiatry and Medical Director, Psychiatric Clinical Research Center, Rush University Medical Center, Chicago, IL.</p> <p>In addition to his private practice, Dr. Janicak serves as a consultant for the VA Chicago Health Care System, West Side Division, Chicago, IL. He is also an member of the <cite>Psychiatric Annals</cite> editoral board.</p> <p>Dr. Janicak received his undergraduate degree from Loyola University of Chicago, and his medical degree from Loyola University of Chicago, Stritch School of Medicine. He completed his residency in Psychiatry at Foster G. McGaw Hospital, Maywood, IL. </p> <p>Mark A. Demitrack, MD is Vice President and Chief Medical Officer of Neuronetics, in Malvern, PA. Dr. Demitrack has more than 20 years of experience in both academic and industry settings in clinical research of mood disorders and related conditions. </p> <p>Prior to joining Neuronetics, Dr. Demitrack was Assistant Vice President for Global Medical Affairs in Neuroscience at Wyeth Pharmceuticals. Dr. Demitrack also served as Medical Director of the New Antidepressant Team at Lilly Research Laboratories, where he led the registration clinical development program for the novel antidepressant, duloxetine (Cymbalta). </p> <p>Prior to his tenure in private industry, Dr. Demitrack was a faculty member of the Department of Psychiatry at the University of Michigan Medical School, where he was Director of the Michigan Eating Disorders Program and received federal grant funding in clinical research activities studying the neuroendocrinology of eating disorders, chronic fatigue syndrome and fibromyalgia. Dr. Demitrack received his undergraduate degree at Columbia University, and his medical degree from the Robert Wood Johnson Medical School in New Jersey. He pursued his residency training at the University of California-San Francisco and completed a research fellowship at the National Institute of Mental Health.</p>

Translational Research in Late-Life Mood Disorders: Implications for Future Intervention and Prevention Research

Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.

Triggers for suicidal behavior in depressed older adolescents and young adults: Do alcohol use disorders make a difference?

Adolescent suicide is a major social and medical problem. Alcohol use disorders with comorbid major depression represent an especially high-risk profile for suicidal behavior, repeated suicidal behavior and completed suicide. We compared demographic and clinical characteristics, prevalence of interpersonal triggers and the number of triggers for suicidal behavior in depressed late adolescents and young adults with or without comorbid alcohol use disorders. 18-26-year-old subjects were recruited through advertising and referrals and participated in mood disorders research in a university hospital. Thirty-eight depressed suicide attempters without a history of any alcohol or substance abuse/dependence and 29 depressed suicide attempters with comorbid alcohol abuse or dependence participated in the study. Demographic and clinical parameters including parameters related to suicidal behavior were examined and recorded. There was no difference with regard to demographic parameters between the two groups. Depressed suicide attempters with comorbid alcohol use disorders had higher aggression and impulsivity scale scores and were more likely to be tobacco smokers compared to their counterparts without alcohol use disorders. Additionally, there was a trend towards higher lethality of suicide attempts in subjects with alcohol use disorders compared to the other group. We found no difference in the prevalence of interpersonal triggers or in the number of triggers for suicidal behavior between the two groups. It appears that among 18-26-year-old depressed suicide attempters, individuals with comorbid alcohol use disorders are more impaired with regard to aggressiveness and impulsivity compared to persons without comorbid alcohol abuse/dependence.

Suicidal risk in bipolar I disorder patients and adherence to long‐term lithium treatment

Among the well-established treatments for bipolar disorder (BPD), lithium continues to offer an unusually broad spectrum of benefits that may include reduction of suicidal risk. We examined the association of suicidal acts with adherence to long-term lithium maintenance treatment and other potential risk factors in 72 BP I patients followed prospectively for up to 10 years at a Mood Disorders Research Center in Spain. The observed rates of suicide were 0.143, and of attempts, 2.01%/year, with a 5.2-fold (95% CI: 1.5-18.6) greater risk among patients consistently rated poorly versus highly adherent to lithium prophylaxis (11.4/2.2 acts/100 person-years). Treatment non-adherence was associated with substance abuse, being unmarried, being male, and having more hypomanic-manic illness and hospitalizations. Suicidal risk was higher with prior attempts, more depression and hospitalization, familial mood disorders, and being single and younger, as well as treatment non-adherence, but with neither sex nor substance abuse. In multivariate analysis, suicidal risk was associated with previous suicidality > poor treatment adherence > more depressive episodes > younger age. The findings support growing evidence of lower risk of suicidal acts during closely monitored and highly adherent, long-term treatment with lithium and indicate that treatment adherence is a potentially modifiable factor contributing to antisuicidal benefits.

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

Does temperamental instability support a continuity between bipolar II disorder and major depressive disorder?

Background The current categorical split of mood disorders in bipolar disorders and depressive disorders has recently been questioned. Two highly unstable personality features, i.e. the cyclothymic temperament (CT) and borderline personality disorder (BPD), have been found to be more common in bipolar II (BP-II) disorder than in major depressive disorder (MDD). According to Kraepelin, temperamental instability was the ‘foundation’ of his unitary view of mood disorders. Study aim The aim was to assess the distributions of the number of CT and borderline personality items between BP-II and MDD. Finding no bi-modal distribution (a ‘zone of rarity’) of these items would support a continuity between the two disorders. Methods Study setting: an outpatient psychiatry private practice. Interviewer: A senior clinical and mood disorder research psychiatrist. Patient population: A consecutive sample of 138 BP-II and 71 MDD remitted outpatients. Assessment instruments: The structured clinical interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV), the SCID-II Personality Questionnaire for self-assessing borderline personality traits (BPT) by patients, the TEMPS-A for self-assessing CT by patients. Interview methods: Patients were interviewed with the SCID-CV to diagnose BP-II and MDD, and then patients self-assessed the questions of the Personality Questionnaire relative to borderline personality, and the questions of the TEMPS-A relative to CT. As clinically significant distress or impairment of functioning is not assessed by the SCID-II Personality Questionnaire, a diagnosis of BPD could not be made, but BPT could be assessed (i.e. all BPD items but not the impairment criterion). The distribution of the number of CT and BPT items was studied by Kernel density estimate. Results CT and BPT items were significantly more common in BP-II versus MDD. The Kernel density estimate distributions of the number of CT and BPT items in the entire sample had a normal-like shape (i.e. no bi-modality). Conclusions The expected finding, on the basis of previous studies and of the present sample features, was a clustering of CT and BPT items on the BP-II side of the curves. Instead, no bi-modality was present in the distributions of the number of CT and BPT items in the entire sample, showing a normal-like shape. By using the bi-modality approach, a continuity between BP-II and MDD seems supported, questioning the current categorical splitting of BP-II and MDD based on classic diagnostic validators.

Discontinuing Antidepressants While Pregnant Poses Relapse Risk

Discontinuing Antidepressants While Pregnant Poses Relapse Risk

Mood Disorders: Clinical Management and Research Issues

This volume balances exciting promise with frustrating limitations as it seeks to survey the landscape of mood disorder research through many lenses. The book’s scope is ambitious, ranging from the expected discussions of medication and psychotherapy treatment, epidemiology, and genetics to a welcome and eclectic mix of chapters on brain stimulation, subthreshold disorders, sleep findings, novel drug targets, and clinical trial design.

Borderline personality–bipolar spectrum relationship

Background The relationship between borderline personality disorder (BPD) and bipolar disorders, especially bipolar-II disorder (BP-II), is unclear. Several reviews on the topic have come to opposite conclusions, i.e., that BPD is a bipolar spectrum disorder or instead that it is unrelated to bipolar disorders. Study aim was to find which items of BPD were related to BP-II, and which instead had no relationship with BP-II. Methods Study setting: An outpatient psychiatry private practice, more representative of mood disorders usually seen in clinical practice in Italy. Interviewer: A senior clinical and mood disorder research psychiatrist. Patient population: A consecutive sample of 138 BP-II and 71 major depressive disorder (MDD) remitted outpatients. Assessment instruments: The Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV) was used for diagnosing, the SCID-II Personality Questionnaire was used by patients to self-assess borderline personality traits. Interview methods: Patients were interviewed with the SCID-CV to diagnose BP-II and MDD. The questions of the Personality Questionnaire relative to borderline personality were self-assessed by patients. As clinically significant distress or impairment of functioning was not assessed by the questionnaire, a diagnosis of borderline personality disorder could not be made, but borderline personality traits (BPT) could be assessed (i.e., all DSM-IV BPD items but not the impairment criterion). Results BPT items were significantly more common in BP-II versus MDD. The best combination of sensitivity and specificity for predicting BP-II was found by using a cutoff number of BPT items ≥ 5: specificity was 71.4%, sensitivity was 45.9%. BPT (defined by ≥ 5 items) was present in 29.5% of MDD and in 46.3% of BP-II ( p = 0.019). Logistic regression of BP-II versus BPT items number found a significant association. Principal component factor analysis of BPT items found two orthogonal factors: “affective instability” including unstable mood, unstable interpersonal relationships, unstable self-image, chronic emptiness, and anger, and “impulsivity” including impulsivity, suicidal behavior, avoidance of abandonment, and paranoid ideation. “Affective instability” was associated with BP-II ( p = 0.010), but “impulsivity” was not associated with BP-II ( p = 0.193). Interitem correlation was low. There was no significant correlation between the two factors. Discussion Study findings suggest that DSM-IV BPD may mix two sets of unrelated items: an affective instability dimension related to BP-II, and an impulsivity dimension not related to BP-II, which may explain the opposite conclusions of several reviews. A subtyping of BPD according to these dimensions is supported by the study findings.

Mood disorders and their treatment: alterations in the regulation of receptor‐G protein coupling

AbstractBiochemical research in mood disorders has focused, along the cascade of events involved in signal transduction, from studies at the level monoamine neurotransmitters and their receptors to mechanisms beyond receptors. Growing evidence suggests that G proteins may be involved in the pathophysiology and treatment of mood disorders: (1) lithium, other antibipolar and antidepressant treatments affect G protein levels, function, and mRNA levels; (2) differential alterations exist in G proteins measures in peripheral blood elements of patients with mood disorders; (3) alterations in G proteins levels exist in postmortem tissues of patients with mood disorders; and (4) candidate G protein–encoding genes as susceptibility loci for bipolar mood disorder and depression were detected. G protein signal transduction is regulated at a proximal point: following phosphorylation by G protein–coupled receptor kinases, receptors bind to arrestins, uncoupling the receptors from G proteins; at a distal regulatory point, regulators of G protein signaling proteins act primarily as GTPase‐activating proteins. Both regulatory points have been recently found to be involved in the pathophysiology and treatment of mental disorders. It is to be hoped that an admixture of genomics, proteomics, multi‐marker, large‐scale automated measures, together with the “old” biochemical approaches, will enable the development of an objective biological differential diagnostic system for major mental disorders that will also enable monitoring and predicting response to treatments. Drug Dev. Res. 65:147–155, 2005. © 2005 Wiley‐Liss, Inc.

Autism Spectrum Traits in Children with Mood and Anxiety Disorders

The autism spectrum disorders (ASDs) can present with symptoms commonly found in mood and anxiety disorders. The Social Communication Questionnaire (SCQ), Children's Communication Checklist (CCC-2), and the Social Reciprocity Scale (SRS) were used to screen children in a mood disorders research clinic setting for symptoms of ASD. Ninety-three patients (mean age, 12.7 +/- 2.8 years; percent male, 63%) completed at least one scale, and 50 children completed all three. The prevalence of those screening positive for a possible ASD on one instrument was 62% and on all three measures was 8%. Fifty-seven percent (n = 21/37; odds ratio, 4.59 [95% confidence interval (CI) = 1.40-15.11]) of those scoring in the "ASD-likely" range on the SRS scored in that range on the CCC-2. Only 16% (n = 6/37; odds ratio, not significant (NS)) of those scoring in the ASD-likely range on the SRS, and 14% (n = 5/37; odds ratio, NS) of those scoring in the ASD-likely range on the CCC-2, scored similarly on the SCQ. These results demonstrate a need to develop valid and reliable instruments to screen for ASDs in children presenting outside of ASD clinics.

Do Word-Processing Problems Cause Social Anxiety?

Do Word-Processing Problems Cause Social Anxiety?

Teoría y tratamiento de la depresión: ¿Hacia su integración?

Recent research has changed our view on depression in important ways. The National Institute of Mental Health (NIMH) Strategic Plan for Mood Disorders Research (NIMH, 2003) is currently the most ambitious attempt to give a new impetus to research on mood disorders, and to develop more encompassing theories that will ultimately lead to more effective treatment strategies. However, in our view, this strategic plan fails to address several important issues and recent developments in research on depression. In this article, several important points of divergence are outlined with special reference to a conference on the integration of theories and treatment strategies on depression held in Kortenberg (Belgium) on March 14, 2003.

Needed: Clinical Research in Mood Disorders

Mood disorders are among the leading causes of morbidity and disability worldwide. They are also associated with increased risk of mortality due to physical complications. Much research has been carried out to map susceptibility genes and to understand the pathophysiology of the illness. Yet, progress has been slow. This is partly explained by the obvious complexity of brain function and mood regulation; however, another reason for the lack of progress may be clinical. This month’s “In Review” section is dedicated mainly to clinical research in mood disorders. Not surprisingly, many of the issues addressed by these reviews have been studied before and have produced controversial findings. As the papers in this issue demonstrate, large samples and careful scrutiny of relevant factors are needed to arrive at unequivocal conclusions. This issue also allows us to introduce the work of the International Group for the Study of Lithium-Treated Patients (IGSLI; http://www.igsli.org): all 5 papers are from the IGSLI centres. The group, established in 1988, has collaborated over the past 15 years on several large-scale projects, such as studies of mortality among patients treated with lithium and molecular genetic studies of responders to lithium.