Progress Report 2008: Psychiatric, Behavioral, and Addictive Disorders
The 2008 Progress Report on Brain Research


February, 2008

Mental health research in 2007 focused on gaining further understanding of the origins of certain disorders and on finding effective treatments. Many scientists maintained an emphasis on the underlying role of genetics in psychiatric disorders but moved toward more targeted study of what role genes play in management and treatment. In addition, neurobiological studies have broadened in scope by examining neural circuits, or connections between distinct parts of the brain, instead of individual regions, to understand how interrupted or misplaced signals may affect mental health.

Recent findings in depression research have led to better understanding of neural circuitry problems that may underlie the disorder, as well as potential non-drug treatments to alleviate these problems. Research into bipolar disorder has yielded a probable genetic indicator as well as the disorder’s first mouse model for further study. Finally, studies looking at both schizophrenia and alcoholism have identified new prospective drug treatments.

Depression

The hippocampus, integrally related to the system responsible for human emotion—the limbic system—has long been associated with memory and spatial processing. On the heels of findings that the hippocampus projects to brain areas implicated in depression and that antidepressant-stimulated hippocampal neurogenesis is associated with positive behavioral responses to the drugs, this region also has become an area of interest in the study of depression.

In a Science report published August 10, Karl Deisseroth and interdisciplinary colleagues at Stanford University identified a neurophysiological circuit connecting the hippocampus, including the dentate gyrus, to depression.1 This circuit may be of interest for future interventions.

The researchers subjected one group of rats to stressful situations, such as sleep deprivation, hostile lighting, and loud noises, while a control group lived in a relatively stress-free environment. In addition, some of the stressed rats were given antidepressant medication.

After several weeks, both groups of rats were observed after being submerged in water. The stressed rats that were not given anti-depressants swam less vigorously than the non-stressed and the medicated rats, which the researchers say represents a feeling of hopelessness.

The scientists then used a high-speed imaging technique called voltage-sensitive dye imaging to measure the electrical activity in the rats’ hippocampal area, in particular as it projected to the dentate gyrus. They found that the signals successfully conducted across the circuit in the non-stressed and medicated rats but were interrupted in the stressed ones, eventually leading activity in the circuit to die out.

These findings suggest that there may be no single cause for depression but that a single life event, such as a family member’s death or a stressful work situation, might cause a problem in the circuit, leading to the pervasive symptoms of depression. The authors also suggest the circuit as a prospective site for treatment therapies.

Other neural circuits in the limbic system have been associated with depression. These circuits often include brain areas such as the prefrontal cortex, amygdale, and subgenual cingulate cortex—areas associated with emotional processing, production of the neurotransmitters involved in sad emotions, and response to antidepressant drugs.

In a September Nature Neuroscience review by Kerry J. Ressler and Helen S. Mayberg of Emory University’s Department of Psychiatry and Behavioral Sciences, the authors argue that progress made in identifying and understanding the actions of depression-associated neural circuits, and in pinpointing specific areas within these circuits where their dysregulation is associated with behavioral symptoms, now makes the use of promising non-drug therapies feasible.2 Finding effective alternatives to currently available antidepressant medications is critically important for people with intractable depression who do not respond to these medications.

Foremost among these non-drug approaches is deep brain stimulation (see also Movement Disorders, page 27, and Neuroethics, page 43). Clinical studies of deep brain stimulation for treating intractable depression were based on Mayberg’s initial imaging studies, using positron emission tomography, that identified the subgenual cingulate cortex (Cg25) as an area associated with severe depression. Deep brain stimulation alters communication within and among brain circuits in this region via high-frequency stimulation to implanted electrodes.

Hellen Mayberg - Spotlight
Earlier imaging studies associated too much activity in area Cg25, part of the subgenual cingulate cortex, with severe depression. Work in 2007 suggests that deep brain stimulation in area Cg25 has an antidepressant effect. These images show a reduction in blood flow to area Cg25 after deep brain stimulation, which involves the stimulation of an implanted electrode. (School of Engineering, Stanford University) 

The treatment was associated with antidepressant effects, a marked reduction in cerebral blood flow to area Cg25, and changes in multiple brain regions implicated in mood regulation and treatment response. Further clinical studies are under way in a larger number of patients to further establish the treatment’s safety and efficacy, to determine how brain circuitry in this region is involved in depression, and to determine how deep brain stimulation effectively intervenes in this circuitry.

Other potential alternatives to antidepressant medications include vagus nerve stimulation, electroconvulsive therapy, and repetitive transcranial magnetic stimulation. While electroconvulsive therapy has long been used to treat intractible depression and has regained acceptance in recent years, deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation all are being tested to determine their ability to interrupt and modify brain circuits that have been linked to depression and emotion regulation.

 

By using neuroimaging techniques such as positron emission tomography and functional magnetic resonance imaging before and after treatment, scientists are able to see changes in regional activation in the brain, showing the changes to the circuits involved. Improved understanding of the underlying neural circuitry may also make these therapies viable candidates to treat other psychiatric disorders, such as obsessive-compulsive disorder.

 

Although deep brain stimulation is now an accepted treatment for Parkinson’s disease patients who are no longer able to tolerate drug treatment with L-DOPA and shows promise in treating intractable depression, Ressler and Mayberg suggest that more research is needed, not only to better understand the long-term effects to patients but also to define optimal treatment conditions.

Bipolar Disorder

Previous studies have suggested that problems with the regulation of circadian rhythms, or the body’s internal clock, may play a pivotal role in bipolar disorder, a psychiatric condition sometimes also referred to as manic depression. In a study published in Proceedings of the National Academy of Sciences USA, Colleen McClung and colleagues created the first mutant mouse model of bipolar disorder by disrupting a gene called clock (circadian locomotor output cycles kaput) by inducing mutations to proteins that regulate the animal’s circadian rhythms.3

 

Clock is believed to produce a protein necessary to regulate the complex feedback loop governing circadian rhythms in the brain. McClung’s mutant, clock-free mice showed mania-type behaviors that mimic human bipolar symptoms. Those symptoms included hyperactivity and reduced sleep time as well as heightened response to novel stimuli and stimulants such as cocaine.

 

The clock mutant mouse is the first animal model of mania to be created, offering the potential for greater understanding of how circadian rhythms are neurally and genetically regulated and how dysregulation may lead to bipolar symptoms. Furthermore, the model presents researchers with a new direction in which to develop new and improved treatment options for bipolar patients.

 

 

Obsessive-Compulsive Disorder

In the past few years, research into obsessive-compulsive disorder (OCD) has consistently implicated the striatum, the input center of the basal ganglia system. Malfunctions in this system have been implicated in dysfunction of motor control, learning, and reward processing.

Guoping Feng and colleagues studied the role of a gene that is prevalent in the striatum. In a paper published in Nature, Feng’s team used gene knockout techniques to remove from mice the sapap3 gene, which is critical for the effective synaptic communication of neurons in the brain that use the neurotransmitter glutamate.4

 

The sapap3 mutant mice showed several OCD-like symptoms, including increased anxiety and excessive personal grooming to the point of hair loss. However, when the mice were treated with fluoxetine (Prozac), a drug commonly used to treat OCD, or when the sapap3 gene was directly reinserted into the striatum of the mutated mice, the symptoms abated.

 

These findings provide new insight into both the underlying neurobiological causes of obsessive-compulsive disorder and avenues for future treatment. Previous studies and treatments focused on the neurotransmitter serotonin, so this result, implicating glutamate, may inspire work on new drug therapies that target glutamate neurotransmission.

Schizophrenia

In 2005 and 2006, a group of independent studies showed that atypical, or second-generation, anti-psychotic medications were less effective than older drugs that often cause more side effects. In one study, led by Jeffrey Lieberman and published in 2005 in the New England Journal of Medicine, the exception was olanzapine, an atypical drug with which patients discontinued use at a lower rate than with its peers.5 However, patients experienced persistent weight gain and other metabolic side effects. The results of these studies caused widespread concern among psychiatrists and researchers about treatment options for schizophrenic patients.

 

Another group of researchers, led by Sandeep Patil of Lilly Research Laboratories, tested a new drug called LY2140023, which moderates the neurotransmitter glutamate in the brain. In a paper in the September Nature Medicine, the researchers compared the new drug with olanzapine and a placebo for four weeks in 200 patients with schizophrenia.6

 

The group found that more than 25 percent of patients who took LY2140023 responded positively to treatment, without negative side effects. The results suggest that drugs that help the brain adapt to disrupted glutamate pathways may be a safe and useful treatment option in the future for those suffering from schizophrenia.

Alcoholism

Drugs have been used with mixed success in the treatment of alcoholism. A study by Lara Ray and Kent Hutchison that appeared in September in the Archives of General Psychiatry suggests that naltrexone, an opioid receptor antagonist and one of the drugs prescribed to combat alcoholism, is more successful in the treatment of individuals with a certain genotype than others.7

 

Ray and Hutchison found that people addicted to alcohol who had a certain type of a gene called OPRM1 not only reported greater feelings of intoxication after drinking but also had a reduced response to alcohol after taking naltrexone. These results provide an avenue for further study not only of genetic indicators in alcoholism but also of how those indicators may interact with treatment.

Future Directions in Study and Treatment

The completion of the International HapMap Project, a catalog of common human genetic variants, in 2005 has provided mental health researchers with a new opportunity to undertake whole-genome studies to identify genetic factors underlying complex psychiatric disorders. “Genome-wide association” studies in heart disease, diabetes, and certain cancers have yielded extensive new avenues for the discovery of disease development and treatment, and scientists are hopeful that comparable studies examining schizophrenia, bipolar disorder, and obsessive-compulsive disorder will yield similar success.

 

Thomas R. Insel, director of the National Institute of Mental Health, and Thomas Lehner of the institute’s Division of Neuroscience and Basic Behavioral Science argue in a May editorial in Biological Psychiatry that the potential for genome-wide association is high but that researchers need to consider the requirements to successfully carry out these analyses.8 Large sample sizes with well-defined characteristics are a must, which may be difficult for smaller research laboratories with a small pool of patients. Also, disorders with broad or contentious diagnostic criteria may present difficulties in narrowing down the genetic factors involved.

 

To combat these issues, the authors advocate the sharing of genomic databases. One such database is the NIMH’s bipolar disorder phenome database. Researchers at the institute compiled a database of validated variables for more than 5,000 people with bipolar disorder.9

 

The database is available to laboratories and research centers to identify genetic indicators and effects. As more such databases are assembled and made available for public use, a more sophisticated understanding of the role of genes in psychiatric disorders, as well as opportunities for new and more effective treatments, may be possible.

 

Notes

1. Airan RD, Meltzer LA, Madhuri R, Gong Y, Chen H, and Deisseroth K. Highspeed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 2007 317:819–823.

2. Ressler KJ and Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic. Nature Neuroscience 2007 10(9):1116–1123.

3. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon, Jr. WA, and McClung CA. Mania-like behavior induced by disruption of clock. Procedings of the National Association of Sciences USA 2007 104(15):6406–6411.

4. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding J-D, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, and Feng G. Cortio-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 2007 448:894–899.

5. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, and Hsiao JK. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005 353(12):1209–23.

6. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, and Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nature Medicine 2007 13(9):1102–1107.

7. Ray LA and Hutchison KE. Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response. Archives of General Psychiatry 2007 64(9):1069–1077.

8. Insel TR and Lehner T. A new era in psychiatric genetics? Biological Psychiatry 2007 61:1017–1018.

9. Potash JB, Toolan J, Steele J, Miller EB, Pearl J, Zandi PP, Schulze TG, Kassem L, Simpson SG, and Lopez V. The bipolar disorder phenome database: A resource for genetic studies. American Journal of Psychiatry 2007 164:1229–1237.

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