Early childhood depression alters brain development

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"The brains of children who suffer clinical depression as preschoolers develop abnormally, compared with the brains of preschoolers unaffected by the disorder, according to new research at Washington University School of Medicine in St. Louis. Their gray matter -- tissue that connects brain cells and carries signals between those cells and is involved in seeing, hearing, memory, decision-making and emotion -- is lower in volume and thinner in the cortex, a part of the brain important in the processing of emotions. The new study is published Dec. 16 in JAMA Psychiatry. "What is noteworthy about these findings is that we are able to see how a life experience -- such as an episode of depression -- can change the brain's anatomy," said first author Joan L. Luby, MD, whose research established that children as young as 3 can experience depression. "Traditionally, we have thought about the brain as an organ that develops in a predetermined way, but our research is showing that actual experience -- including negative moods, exposure to poverty, and a lack of parental support and nurturing -- have a material impact on brain growth and development." The findings may help explain why children and others who are depressed have difficulty regulating their moods and emotions. The research builds on earlier work by Luby's group that detailed other differences in the brains of depressed children. Luby, the Samuel and Mae S. Ludwig Professor of Child Psychiatry, and her team studied 193 children, 90 of whom had been diagnosed with depression as preschoolers. They performed clinical evaluations on the children several times as they aged. The researchers also conducted MRI scans at three points in time as each child got older. The first scans were performed when the kids were ages 6 to 8, and the final scans were taken when they were ages 12 to 15. A total of 116 children in the study received all three brain scans. "If we had only scanned them at one age or stage, we wouldn't know whether these effects simply were present from birth or reflected an actual change in brain development," said co-investigator Deanna M. Barch, PhD, head of Washington University's Department of Psychological and Brain Sciences in Arts & Sciences. "By scanning them multiple times, we were able to see that the changes reflect an actual difference in brain maturation that emerges over the course of development." The gray matter is made up mainly of neurons, along with axons that extend from brain cells to carry signals. The gray matter processes information, and as children get older, they develop more of it. Beginning around puberty, the amount of gray matter begins to decline as communication between neurons gets more efficient and redundant processes are eliminated. "Gray matter development follows an inverted U-shaped curve," Luby said. "As children develop normally, they get more and more gray matter until puberty, but then a process called pruning begins, and unnecessary cells die off. But our study showed a much steeper drop-off, possibly due to pruning, in the kids who had been depressed than in healthy children." Further, the steepness of the drop-off in the volume and thickness of the brain tissue correlated with the severity of depression: The more depressed a child was, the more severe the loss in volume and thickness. The researchers determined that having depression was a key factor in gray matter development. In scans of children whose parents had suffered from depression -- meaning the kids would be at higher risk -- gray matter appeared normal unless the kids had suffered from depression, too. Interestingly, the differences in gray matter volume and thickness typically were more pronounced than differences in other parts of the brain linked to emotions. Luby explained that because gray matter is involved in emotion processing, it is possible some of the structures involved in emotion, such as the brain's amygdala, may function normally, but when the amygdala sends signals to the cortex -- where gray matter is thinner -- the cortex may be unable to regulate those signals properly. Luby and Barch are planning to conduct brain scans on even younger children to learn whether depression may cause pruning in the brain's gray matter to begin earlier than normal, changing the course of brain development as a child grows. "A next important step will involve determining whether early intervention might shift the trajectory of brain development for these kids so that they revert to more typical and healthy development," said Barch, also the Gregory B. Couch Professor of Psychiatry. Luby said that is the main challenge facing those who treat kids with depression. "The experience of early childhood depression is not only uncomfortable for the child during those early years," she said. "It also appears to have long-lasting effects on brain development and to make that child vulnerable to future problems. If we can intervene, however, the benefits might be just as long-lasting." ### Funding from the National Institute of Mental Health and the National Institutes of Health Blueprint of the National Institutes of Health (NIH), grant numbers R01 MH66031, R01 MH084840, R01 MH090786, R01 MH098454-S, U54 MH091657, 2R01 MH064769-06A1, PA-07-070 NIMH R01 5K01MH090515-04 and T32 MH100019. Luby JL, Belden AC, Jackson JL, Lessov-Schlaggar CN, Harms MP, Tillman R, Botteron K, Whalen D, Barch DM. Early childhood depression and alterations in the trajectory of gray matter maturation in middle childhood and early adolescence?. JAMA Psychiatry, published online Dec. 16, 2015. http://jamapsychiatry.com doi:10.1001/jamapsychiatry.2015.2356 Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare." For more information on depression and other mental health related topics,please visit Aspira Continuing Education Online Courses

Ketamine Cousin Rapidly Lifts Depression Without Side Effects

Neurons in a subsection of the adult rat hippocampus are stained with a monoclonal antibody (yellow) that enhances learning and memory. A portion of this antibody is where GLYX-13 came from. Source: Dr. Joseph Moskal, Ph.D., Northwestern University GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a study funded by the National Institute of Mental Health (NIMH) that was published last month in Neuropsychopharmacology. Background Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide. Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect—--the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior. “Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.” Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program. While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules. Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine. Results of the Study GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats. Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons. These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents. Significance NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants. What’s Next GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism. “One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.” Alcoholism and Drug Abuse Counselors Continuing Education Reference Burgdorf J, Zhang X-l, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects. Neuropsychopharmacology, April 2013. 38:729–742.

5 Most Common Mental Illnesses Share the Same Genes

From Autism to Depression: Largest Genetic Study Shows Mental Disorders Share Genetic Kinks --Associated Press Mental Illnesses Share Common DNA Roots, Study Finds --nbcnews.com An NIMH-funded study published online today in Lancet reveals that the five most common disorders—autism, attention deficit hyperactivity disorder, bipolar disease, schizophrenia, and major depression—all share similar genetic components. “These disorders that we thought of as quite different may not have such sharp boundaries,” said Dr. Jordan W. Smoller of Massachusetts General Hospital, one of the lead study authors. The results suggest that a rethink in how these disorders are defined might be in order. Rather than focusing on symptoms, which can be attributed to one or more disorder, physicians could one day start to rely on specific gene mutations or biologic pathways to make a formal diagnosis Aspira Continuing Education Online Courses And it also could lead to better treatments, said Dr. Bruce Cuthbert, director of the NIMH’s Division of Adult Translational Research and Treatment Development. “We are finally starting to make inroads where we have actual physiological mechanisms that we can target,” he said. “We can really start to understand the biology instead of having to guess at it.” Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-wide Analysis. Lancet, published online February 28, 2013.

Depression, Major Depression, and Depressive Disorders CEUs

Depression, Major Depression, and Depressive Disorders CEUs
Click here for full text
© 2009 by Aspira Continuing Education. All rights reserved. No part of this material
may be transmitted or reproduced in any form, or by any means, mechanical or
electronic without written permission of Aspira Continuing Education.
Course Objectives: This course is designed to help you:
1. Identify and diagnose Depressive Disorder
2. Become familiar with the historical framework concerning the inclusion
of Depressive Disorder in contemporary mental health and the DSM
3. Identify Depressive Disorder symptoms and related behaviors
4. Become familiar with common causes
5. Learn and apply widely accepted theoretical treatment approaches such
as Cognitive Behavioral Therapy
6. Access relevant resources
Table of Contents:
1. Definition and Types
2. History
3. Symptoms and the DSM-IV-TR
4. Causes
5. Treatment
6. Resources
7. References
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1. Definition and Types
Depressive disorders and symptoms may vary and can include:
o Major depressive episode
o Atypical depression, a cyclical sub-type of major depression
where sleep, feeding and perception of pleasure are normal but
there is a feeling of lethargy
o Melancholic depression a sub-type of major depression
characterized by an inability to feel pleasure combined with
physical agitation, insomnia, or decreased appetite
o Psychotic depression, a sub-type of major depression combined
with psychotic or delusional perceptions
o Depressive Disorder Not Otherwise Specified
 Depression (mood)
 Postpartum depression, a depressive episode occurring within a year
of childbirth
 Dysthymic disorder , a long-term low-grade depressive condition
 Adjustment disorder with depressed mood, previously known as
"reactive depression"
 Seasonal affective disorder (SAD), a depressed mood related to the
seasons
 Depression is the fourth stage of the Kübler-Ross model (commonly
known as the "stages of dying")
(American Psychiatric Association (2000a). Diagnostic and statistical
manual of mental disorders, Fourth Edition, Text Revision: DSM-IV-TR.
Washington, DC: American Psychiatric Publishing, Inc.)
Major depressive disorder is also known as clinical depression or major
depression. It is a diagnosis contained in the Diagnostic and Statistical
Manual of Mental Disorders by the American Psychiatric Association.
Major depression is a serious illness that affects a person's relationships,
family, work or school life, sleeping and eating habits, social activities, and
general health. Those who suffer from a major depressive episode usually
exhibit a very low mood pervading all aspects of life and an inability to
experience pleasure in previously enjoyable activities. Other symptoms may
include the preoccupation with, or ruminating over, thoughts and feelings of
worthlessness, inappropriate guilt or regret, helplessness, hopelessness, and
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self hatred. Other symptoms include poor concentration and memory,
withdrawal from social situations and activities, reduced sex drive, and
thoughts of death or suicide. Insomnia is common: in the typical pattern, a
person wakes very early and is unable to get back to sleep. Hypersomnia, or
oversleeping, is less common. Appetite often decreases, with resulting
weight loss, although increased appetite and weight gain occasionally occur.
The person may report multiple physical symptoms such as fatigue,
headaches, or digestive problems; physical complaints are the most common
presenting problem in developing countries according to the World Health
Organization's criteria of depression. Family and friends may notice that the
person's behavior is either agitated or lethargic. Older depressed persons
may have cognitive symptoms of recent onset, such as forgetfulness, and a
more noticeable slowing of movements. In severe cases, depressed people
may have symptoms of psychosis such as delusions or, less commonly,
hallucinations, usually of an unpleasant nature (American Psychiatric
Association, 2000a. Diagnostic and statistical manual of mental disorders,
Fourth Edition, Text Revision: DSM-IV-TR. Washington, DC: American
Psychiatric Publishing, Inc).