As was the case in 2005, mental health research in 2006 continued its concentration on the role of genes in mental disorders and the effects of the interaction of those genes with environmental factors. However, 2006 brought with it a new focus on clinical and genetic investigations of treatments for those disorders.
Research in schizophrenia examined the clinical effectiveness of newer antipsychotic drugs in comparison with their predecessors. Genetic studies in depression focused on possible predictors of antidepressant treatment outcomes, evidence of whether antidepressant treatment is linked to suicide, and how treatment of depressed mothers affects the likelihood of depressive symptoms and diagnoses in their children.
Antipsychotic medications have long been the primary treatment for patients with schizophrenia. Unfortunately, many traditional drugs come with a host of disagreeable side effects related to the inhibition of the neurotransmitter dopamine. As a result many psychiatrists are now prescribing second-generation or “atypical” antipsychotics that are less likely to block dopamine transmission in brain areas not directly affected by the disorder. But is this new class of therapeutic agents more effective and tolerated better by patients than the first-generation therapies?
Most are not, according to work in 2005 and 2006 by Jeffrey Lieberman and colleagues. Research published in 2005 revealed no difference in effectiveness between the first- and second- generation antipsychotics.1 In terms of tolerability, olanzapine, a second-generation drug, showed a slightly lesser rate of discontinuation by patients of their medication compared to other drugs, but it was associated with unpleasant weight gain and metabolic side effects.
Lieberman’s group continued their work in 2006, publishing two papers in the American Journal of Psychiatry that examined antipsychotic treatment in more detail. The group found that chronic schizophrenic patients were more likely to continue treatment if they were taking olanzapine and risperidone rather than other atypical antipsychotics.2
|Differences in antipsychotic drugs: Researcher Jeffrey Lieberman has compared the effectiveness of first- and second- generation antipsychotics and has found that the newer generation actually is less effective on the whole. (Photograph courtesy of Jeffrey Lieberman) |
Correspondingly, in patients who did not respond to previous atypical antipsychotic medication at all, the investigators looked at the effectiveness of clozapine, a “last-resort” medication with strong side effects for treatment-resistant patients. They found that these patients responded better to clozapine than to a second atypical antipsychotic.3
In an independent study across the Atlantic, Peter Jones at Cambridge and his team of researchers also studied the effectiveness of second-generation antipsychotic medications in treating chronic schizophrenia. Participants were randomly prescribed either a first- or a second-generation antipsychotic drug and were evaluated for one year by a clinician who did not know which medication they had been assigned.
Symptoms, adverse effects, and quality of life were measured and compared. Jones’s team expected to find that the atypical drugs were more effective than their predecessors but, in fact, they found the opposite to be true. Patients responded better and scored higher on quality-of-life scales when taking the first-generation drugs.4
As might be expected, this finding, coupled with Lieberman’s research, has caused some consternation among psychiatrists. Together, these results suggest that atypical antipsychotic drugs generally should be tried primarily if patients are resistant to first-generation antipsychotic medications.
Research on the elusive causes of schizophrenia continues to focus on the role of dopaminergic neurons. Early research implicated excessive dopamine transmission in the disorder’s behavioral symptoms. But Michael O’Donovan, Michael Owen, and their collaborators studied the abnormal function of brain cells called glia as another possible precursor to the disorder, based on prior postmortem and neuroimaging evidence of both structural and volume differences in brain white matter (the neural connections) between patients with schizophrenia and healthy controls. Glial cells interact with neurons to produce myelin, a fatty insulator that helps facilitate transmission of electrical signals from one brain cell to another.The group’s findings, published in Proceedings of the National Academy of Sciences, indicate that variation in a gene called OLIG2, which regulates the creation of myelin, makes carriers vulnerable to schizophrenia. This finding suggests that further research into the genes governing glial function on the production of myelin may provide important insights into the complex processes involved in schizophrenia.5
Violence and Aggression
Researchers have attempted to pinpoint underlying causes of violence and aggression in humans for hundreds of years. Though the socio-environmental side of the equation has been explored in depth, underlying genetic components have been more difficult and controversial to study.
To date, the most substantiated genetic link associated with violent behavior involves monoamine oxidase A (MAOA), an enzyme directly involved in the metabolic breakdown of the neurotransmitter serotonin. In a paper published in Proceedings of the National Academy of Sciences, Andreas Meyer-Lindenberg and colleagues reported the results of a study that used voxel-based morphometry, a computer-based neuroanatomical method that measures differences in concentrations of brain tissue, and functional magnetic resonance imaging to study the role of MAOA. They found that people with no history of a violent psychiatric disorder, but who had a gene variation that lowered MAOA enzyme expression, showed significant structural and functional brain differences compared to people with higher MAOA expression.
People with reduced MAOA expression showed not only reduced volume of gray matter in the cingulate gyrus, amygdala, and anterior cingulate cortex but also increased activation of the amygdala and limbic regions—areas implicated in emotional processing—when asked to distinguish angry faces from fearful ones.
|Gene linked to violence: Group data from two types of magnetic resonance scans show that in people with a gene variation linked to aggression, the volume and activity of a region called the anterior cingulate cortex, shown in dark gray, are reduced. The region helps regulate emotional and aggressive responses. (Image courtesy of Andreas Meyer-Lindenberg and Joshua Buckholtz, NIMH/IRP) |
The study also revealed a sex component: male participants exhibited enhanced activity of the amygdala and hippocampus, compared with females, during an emotional memory task. The researchers note that although multiple factors contribute to violent behavior, these findings suggest a possible biological predisposition for impulsive violence, especially in males with this particular gene variation.6
Genes were also the focus of research on anxiety-related disorders in 2006. Using mouse models, Carrolee Barlow’s group at the Salk Institute identified 17 genes with expression patterns associated with typical anxiety disorder symptoms. Their paper, published in Nature, also discusses two genes involved with oxidative stress metabolism, the increased production of oxidants that result in the degeneration of neurons, as potential causes for anxiety-related disorders. By transferring these genes into cells through viruses, Barlow’s team found that when the genes were over expressed in mice, anxiety-like behavior increased.7
In a similar vein, a group led by David Goldman examined genes that are associated with one specific anxiety disorder: obsessive compulsive disorder, or OCD. His group found that HTT, a serotonin transporter gene, is implicated in OCD. In a paper published in the American Journal of Human Genetics, they discuss the finding that HTTLPR, previously thought to have only two genetic variants, actually has three. Multiple genotyping methods revealed a previously unknown variation of this gene, which could lead to new understanding of the neurobiology of OCD.8 The bases for these alterations of behavior have been difficult to discern. Perhaps these newer genetic approaches will provide more definitive information.
There continues to be interest in the use of deep brain stimulation for the treatment of those with depression resistant to the usual medications. Further studies by Helen Mayberg and colleagues at Emory University may help reveal whether this treatment is effective in a broader range of patients.9
Among other approaches were studies of genetic factors that may influence the response to more conventional antidepressant treatments. Researchers led by Francis McMahon examined the genetic basis of individual variations in antidepressant treatment outcomes. By studying the DNA of 1,953 patients with major depressive disorder being treated with citalopram, a common antidepressant, they demonstrated a significant association between favorable treatment outcome and the A variant of a gene responsible for serotonin reception, HTR2A. The results of the study are reported in the American Journal of Human Genetics.10
Furthermore, this A variation was found to occur six times more frequently in Caucasian patients than in African-American patients, who correspondingly showed poorer response to citalopram treatment. The findings provide a compelling case for the role of this gene in antidepressant action, and may help to explain racial differences in responses to antidepressant treatments.Elsewhere, Myrna Weissman and colleagues illustrated an interesting phenomenon involving depression in children. It has long been known that children of depressed parents are at high risk for developing a depressive disorder of their own. Weissman’s group reported in the Journal of the American Medical Association that when mothers were successfully treated with medication for depression over three months, their children showed a reduction in depressive and other symptoms and diagnoses.
Conversely, children of mothers who remained depressed suffered from an increased rate of symptoms. This suggests that environmental effects can also affect the psychopathology of this high-risk group of children.11
Researchers led by Mark Olfson looked at a different facet of antidepressant treatment: its relationship to suicide attempts and deaths in adults and children. The results of their matched case-control study, published in the Archives of General Psychiatry, revealed that although antidepressant treatment was not associated with either suicide attempts or deaths in adults, it was significantly associated with both suicide attempts and deaths in children and adolescents. This finding suggests at a minimum that drug treatment in younger patients needs to be closely supervised by clinicians, and parents.12
|Depression treatment: Stress from chronic social defeat causes a drop in a protein called brain-derived neurotrophic factor, center, research in mice has shown. Treatment with an antidepressant, bottom, brought BDNF levels back up. (Illustration by Farley Bookout) |
The neurobiology of stress-induced depression was the focus of Eric Nestler’s research group. In a study in Nature Neuroscience, mice were subjected to chronic social defeat stress, a frequent precursor to depressive disorders, followed by the chronic administration of imipramine, an antidepressant. Nestler’s group found that this defeat stress generated a decrease in a protein called brain-derived neurotrophic factor (BDNF) in the hippocampus as well as increased modifications to specific proteins associated with gene transcription, called histone methylation.The antidepressant agent reversed this effect, as did an infusion of BDNF itself. The findings suggest that histone methylation and the neurobiological processes related to it may provide a new area of therapeutic interest for depression treatment.13
Meanwhile, Michel Lazdunski and his collaborators identified a different area of interest for future antidepressant development. Writing in Nature Neuroscience, Lazdunski’s group reported their discovery that a background potassium channel regulated by serotonin, TREK-1, was implicated in depression resistance in mice. Those without the TREK-1 channel showed a resistance to depression under stress, suggesting that this channel may be a viable target for new drug interventions for depression.14
Does increased dopamine release underlie the craving for drugs? Researchers led by Nora Volkow delved deeper into why drug-related cues can produce persistent conditioned responses in former addicts and found that the answer may be yes.
Previous brain imaging studies have associated those responses with activation in specific limbic structures. Using positron-emission tomography, Volkow’s group demonstrated a conditioned dopamine release in the dorsal striatum of former cocaine addicts when they were shown a cocaine-related video.
These results, published in the Journal of Neuoscience, suggest that therapies designed to restrain dopamine increases may assist in the treatment of addiction.15
Finally, functional brain imaging studies have demonstrated that several brain regions, including the prefrontal cortex and the amygdala, are activated during drug-associated cues. These areas are linked to another area of the brain, the ventral tegmental area, or VTA. Synaptic changes in the VTA may provide researchers clues into the neurobiological causes of drug addiction, withdrawal, and relapse.
Mu-Ming Poo and colleagues examined the dopaminergic neurons in the VTA of rats after cocaine withdrawal and reported their findings in Nature Neuroscience. They found heightened brain-derived neurotrophic factor (BDNF) in those cells of the rats. During withdrawal, the dopaminergic neurons in the VTA may be primed by this increased BDNF expression, starting a chain of events that could elicit a craving for the drug when a person is exposed to reminders of past drug use.16