Genetics Play a Role in Social Anxiety Disorder, Study Finds

The serotonin transporter gene “SLC6A4” is linked to social anxiety disorder.

Researchers at the Institute of Human Genetics at the University of Bonn in Germany recently discovered that a specific serotonin transporter gene called “SLC6A4” is strongly correlated with someone's odds of suffering from social anxiety disorder (SAD). The initial findings of this research were published online ahead of print March 9 in the journal Psychiatric Genetics.

Social anxiety disorder (or social phobia) is a common and heritable psychiatric disorder that is driven by a combination of genetic and environmental factors. Until now, genetic studies on SAD have been rare. According to the researchers, "This is the largest association study so far into social phobia."
For this study the German’s researcher genotyped 321 patients with SAD and 804 controls without social phobia. Then, they carried out a single-marker analysis to identify a quantitative association between SAD and avoidance behaviors. Their results provide evidence that the serotonin transporter gene SLC6A4 is frequently correlated with anxiety-related traits.

Notably, selective-serotonin reuptake inhibitors (SSRIs) are often prescribed to treat depression and anxiety disorders. SSRIs are believed to target the serotonin transporter gene SLC6A4.



People with social anxiety tend to avoid larger groups and situations in which they fearbeing judged by others. SAD is marked by symptoms such as increased heart rate, sweaty palms, shakiness, shortness of breath, etc.

The physiological discomfort of social anxiety reinforces avoidance behaviors and a withdrawal from face-to-face social contact. The fear of social encounters can lead to isolation and loneliness that snowballs. Unfortunately, people with social anxiety who rely excessively on social media to maintain a sense of connectedness may actually exacerbate their feelings of perceived social isolation, according to a recent study by researchers at the University of Pittsburgh, School of Medicine.

In 1948, when Maurice M. Rapport first isolated the chemical serotonin (5-hydroxytryptamine, 5-HT) in the human body and brain, serotonin was initially classified as a “serum agent that affected vascular tone.” Today, serotonin is commonly viewed as a neurotransmitter that helps to maintain mood balance.

Although there is a strong link between serotonin, depression, and social anxiety disorders; scientists remain uncertain about which comes first in terms of driving the correlation vs. causation dynamic between serotonin and psychiatric disorders. For example: Do low levels of serotonin contribute to social anxiety or does social phobia trigger a decrease in serotonin levels?

Interestingly, a 2015 study, "Serotonin Synthesis and Reuptake in Social Anxiety Disorder,“ published in JAMA Psychiatry reported that Individuals with social phobia have too much serotonin—not too little.

Surprisingly, the researchers found that the more serotonin someone with SAD self-produced, the more anxious he or she became in social situations. This raises doubt about the common assumption that selective serotonin reuptake inhibitor (SSRIs) help to lower social anxiety by keeping more serotonin in circulation.
In a statement, co-author Andreas Frick, a doctoral student at Uppsala University Department of Psychology said,



"Not only did individuals with social phobia make more serotonin than people without such a disorder, they also pump back more serotonin. We were able to show this in another group of patients using a different tracer which itself measures the pump mechanism.
We believe that this is an attempt to compensate for the excess serotonin active in transmitting signals. Serotonin can increase anxiety and not decrease it as was previously often assumed."

Taken together, all of this new research marks a significant leap forward when it comes to identifying changes in the brain's chemical messengers in people who suffer from social anxiety disorders. That said, much more research is needed to fully understand the enigmatic and complex workings of serotonin and transporter gene SLC6A4.

"There is still a great deal to be done in terms of researching the genetic causes of this illness," Andreas Forstner from the Institute of Human Genetics at the University of Bonn concluded.

If you would like to get involved in the genetic research on social anxiety disorder, Forstner and colleagues are encouraging the general public to participate in their research online by visiting their website: Social Phobia Research. The more people that get involved in the study of social anxiety disorder, serotonin, and SLC6A4, the more precisely the researchers will be able to decode these complex mechanisms.
References: Psychology Today
Andreas J. Forstner, Stefanie Rambau, Nina Friedrich, Kerstin U. Ludwig, Anne C. Böhmer, Elisabeth Mangold, Anna Maaser, Timo Hess, Alexandra Kleiman, Antje Bittner, Markus M. Nöthen, Jessica Becker, Franziska Geiser, Johannes Schumacher, Rupert Conrad.

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.

Understanding the Obsessive Compulsive Disorder: Conceptual Background and Brain Etiology

Patients suffering from obsessive–compulsive disorder (OCD) experience a combination of anxiety-producing obsessive thought patterns and related compulsive behaviors designed to reduce the distress associated with the obsessions.

Obsessions are recurrent thoughts, impulses, or images that are threatening because they are perceived as either unacceptable or leading to a dreaded outcome, and thus cause marked anxiety. Common obsessional ‘themes’ include contamination (thinking one has contacted dangerous germs or toxins), aggression (image or urge to drive into oncoming traffic or stab one’s spouse), accidental harm (fear that one has hit a pedestrian or doubting whether one turned off the stove), blasphemy (thinking one has offended God by doing a religious ritual incorrectly), and sexuality (intrusive images of having sex with a child or parent). Sometimes an obsession is vague, yet still evokes a looming sense of danger: a ‘bad feeling’ that occurs during an action, or the inexplicable sense that a behavior has not been done correctly. Multiple types of obsessions are found in most affected individuals and can change over time.



Compulsions include behaviors (e.g., hand washing, checking, ordering, or arranging things) and mental actions (e.g., praying, counting, repeating words silently) that are aimed at preventing or neutralizing the threat associated with the obsession, and thus temporarily reduce anxiety. This relief from the distress is highly reinforcing, resulting in the persistent use of compulsions. Compulsive behaviors are often repeated (checking the stove 15 times), or have to be performed according to rules that must be applied rigidly (a sterilization ritual for plates and silverware before meals).

Sometimes compulsions are ‘logically’ linked to the obsessions, as in the case of washing one’s hands in response to a contamination obsession, or driving back to a spot where one fears they may have hit someone. Done once, such behavior might seem reasonable; it is the repetitive, time-consuming, and rigid quality that distinguishes compulsions. Sometimes there is no ‘logical’ action to prevent the obsessional threat so, compulsions develop that are more akin to superstitious rituals. For example, going through doorways can often trigger an obsession (‘bad feeling’). Given no clear antidote to the vague threat, individuals may develop a ritualized compulsion aimed at neutralizing the obsession in some magical way. This might involve having to go through the door on the left side, touching both sides of the threshold 3 times, or passing through the doorway repeatedly until it is accomplished without any ‘bad thoughts.’



Individuals with OCD generally have some degree of insight that their symptoms are excessive or unreasonable. Nonetheless, the disorder is time-consuming, distressing, and severely impairing within the realms of both social and occupational functioning. It is also associated with increased risk of suicide. OCD has an estimated, lifetime prevalence in the general US population of 2–3%, and is equally common in both males and females. The age of onset follows a bimodal distribution: early onset (prepubescent, the majority of cases) and late onset (early 20s). Early-onset cases are more likely to be male, have a family history of OCD, greater symptom severity, and co-occurring tics, OCD spectrum (discussed in section Differential Diagnosis), and disruptive behavioral disorders (e.g., attention deficit hyperactivity disorder).

Differential Diagnosis
It is important to distinguish OCD from worry, intrusive thoughts, and compulsions seen in everyday life. OCD obsessions are experienced as unwanted and anxiety-producing, whereas worry functions more as a mental coping strategy that provides a sense of control and preparation for a perceived future threat. Intrusive thoughts (i.e., suddenly envisioning a family member falling off a cliff while hiking together) are common, but in OCD they occur at a higher frequency, and are experienced as having unusual importance, so are more distressing to the affected individual. Compulsive behaviors are also frequently seen in normal populations in the form of superstitious behavior and repetitive checking. The diagnosis of OCD is made only if they are time consuming or if they result in significant psychosocial impairment or distress.

There are a number of disorders that share the features of OCD, and are sometimes considered as ‘OCD spectrum disorders.’ Disorders such as body dysmorphic disorder, hypochondriasis, and hoarding and eating disorders include obsessive-like fears (that one has a serious illness or is fat), but the thoughts are not experienced themselves as highly intrusive and inappropriate. Derma-tillomania (skin picking) and trichotillomania (hair pulling) have repetitive behaviors that may bring some anxiety relief, but they are neither triggered by obsessions nor have the magical or ritualistic quality of OCD compulsions. Although impulse-control disorders such as kleptomania, pyromania, and pathological gambling also have recurrent thoughts and behaviors that are difficult to resist, the drive tends to be more pleasure-seeking than distress reducing.



Schizophrenia is often characterized by strongly held beliefs that are clearly false (delusions) as well as by stereotyped behaviors. Individuals with OCD, however, generally show considerable insight into their symptoms. In major depression, the depressed individual may have distressing, repetitive thoughts, but these are rarely resisted, and are often focused on a past incident rather than on a current or future threat. Although it has a similar name, obsessive–compulsive personality disorder is actually quite different from OCD. Obsessive–compulsive personality disorder does not involve obsessions or compulsions; rather, it is characterized by a pervasive pattern of maladaptive orderliness, perfectionism, and control.

Other disorders may mimic OCD. Tics and stereotyped movements are similar to compulsions in their appearance but not in their function. Generally, the cognitive elements involved in OCD compulsions are much more complex, whereas in tics and stereotypic movements, the individual does not report any specific reason for the behavior, but only a nonspecific tension that builds until the behavior is performed. Of note, Tourette’s syndrome and OCD are frequently co-occurring disorders, and individuals with Tourette’s should be routinely asked about the presence of obsessions and compulsions.



Etiology
There is converging evidence that OCD involves dysfunction of the corticostriatal-thalamic circuits, which help integrate cognitive and sensorimotor functions, and in particular initiate automatic, procedural behaviors. The high co-occurrence of OCD with Tourette’s – a disorder involving cortical and striatal pathways – is suggestive of a similar etiology. There are also data supporting an association between an autoimmune response to Group A β-hemolytic Streptococcus, affecting the striatal regions, and the acute emergence of OCD, often with tic symptoms (including Tourette’s). The term pediatric autoimmune neuropsychiatric disorder associated with Streptococcus refers to a group of children with this presumed immunological etiology. The role of serotonin in the corticostriatal-thalamic circuits is thought to be important, and several studies suggest that serotonin reuptake inhibitors may normalize activity in these pathways. Medications that boost serotonin activity reliably reduce OCD symptoms. Research also suggests that abnormalities in the glutamate and dopamine systems are involved in OCD as well.

The evidence for a genetic contribution is supported by the monozygotic twin studies showing a concordance rate from 63% to 87%, and first-degree relatives showing rates of OCD in the range of 10–22.5%. No candidate gene has been identified that can reliably account for the broad phenotype of OCD. Animal models of OCD, such as those found naturally in dogs or induced in laboratory mice identify the potential genes for further study.



From the standpoint of neuroimaging, OCD is one of the most investigated illnesses in the anxiety cluster. As of yet, it remains impossible to attribute causality to particular brain structures in the cognitions and clinical features of OCD. In animal models, abnormalities in the orbitofronto-striatal circuits are associated with an impaired ability to modify behavior in response to new information, for example: impaired inhibition of previously important, but now inappropriate response to stimuli. Humans with injuries to the striatum, or areas to which it projects, often develop obsessive –compulsive behaviors. Nevertheless, no consistent structural abnormality has been identified in patients meeting the criteria for OCD. This may suggest that the causative abnormalities are present at the level of a system or network, not at the level of isolated neuroanatomical structures, or because of a marked heterogeneity within the diagnosis. Illnesses with components of compulsive and impulsive behaviors, such as Tourette’s syndrome and trichotillomania, tend to occur in comorbidity with OCD, or cluster with OCD within families. Further research into these disorders of overlapping end phenotype may serve to illuminate the rest of the OCD picture as it relates to the brain structure.
Source: Vimen L. Beckner, University of California San Francisco, and San Francisco Group for Evidence-Based Psychotherapy, San Francisco, CA, USA.

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.

Mindfulness Meditation and Anxiety Disorders

Research evaluates the effects of meditation training on patients’ biological reaction to stress

Characterized by persistent and excessive worry, generalized anxiety disorder affects nearly seven million adults in the U.S

Those who are prone to anxiety tend to have greater difficulty managing and coping with stress, experts say, where chronic stress is shown to have physiologic effects including raising heart rate and blood pressure and increasing one's risk for heart attack and stroke. In an effort to find calm, research shows those struggling with anxiety may be well-served by turning to mindfulness meditation – a technique that involves focusing on the present and non-judgmentally paying attention to thoughts and feelings as they arise.

“If you think of anxiety – there are anxious thoughts and there are anxious feelings, and those go together,” says Judson Brewer, director of research for the Center for Mindfulness at the University of Massachusetts Medical School. “There are two ways that we can deal with them.”

One is our natural learned response that since anxiety feels bad, he says, we need to do something to make it feel better. “So we avoid it, we suppress it, we repress it – we do all these things to distract ourselves from the anxiety itself.” However, attempts to avoid uncomfortable thoughts and feelings may worsen anxiety. “The paradox here is that mindfulness helps us turn toward those and learn to change our relationship to the actual thoughts and the physical sensations, rather than try to change them in any way,” Brewer says. “By changing that relationship, we actually stop feeding those cyclical processes and they start to die off on their own.” By learning mindfulness-based stress reduction – an approach first developed at UMass that uses meditation to lower stress levels – research finds many people report reduced anxiety and stress levels.



Taking that a step further, a recent National Institutes of Health-funded study published in January in the journal Psychiatry Research also looked at the biological responses of patients with generalized anxiety disorder to stress, after they’d undergone MBSR. In the study, 70 participants were randomly assigned either to receive the mindfulness meditation training or to undergo stress management education – the study’s control group. “This was a sort of a wellness class where there was a series of lectures on different topics, like sleep improvement and exercise and nutrition,” says Dr. Elizabeth Hoge, an associate professor of psychiatry at Georgetown University Medical Center in Washington. Hoge conducted the research while she was a postdoctoral researcher at Massachusetts General Hospital.

Participants were asked to give an impromptu speech in front of an audience of testers – a typically stress-inducing experience – before and after the 8-week intervention, either the mindfulness meditation training or the stress management class. They were also asked to do mental arithmetic: “Start with the number 996 and subtract by seven all the way down to zero, which is really hard to do in front of an audience,” Hoge notes. “The testers had all the numbers in front of them on a clipboard and they were wearing white lab coats, and we videotaped and had microphones and photography flood lamps. [We] basically set up the laboratory stress test to be like the worst kind of speech challenge that a person can experience.”

Even so, blood testing revealed that study participants had significantly lower levels of the stress hormone ACTH and inflammatory reactions to stress (measured by looking at inflammatory proteins IL-6 and TNF-α) following mindfulness meditation training. That compared to the control group for whom biological stress responses actually increased somewhat the second time they underwent the social stress test.



The results offer biological data showing how mindfulness meditation training can affect the ability of a person with generalized anxiety disorder to be resilient in the face of stressful circumstances. “You can’t fake that,” Hoge says; nor could the results be explained by the placebo effect or a patient’s expectation that meditation would help, since their reactions were measured at a physiological level. “For people who have generalized anxiety disorder, our research provides evidence that this might be a reasonable treatment option,” she says.

Hoge says one of the reasons she was interested in pursuing the research was to look at alternatives to standard treatments for anxiety disorders, typically antidepressant medication and psychotherapy. “It’s hard for some people to get those treatments, either because of insurance, financial limitations and also the stigma that’s involved with coming to a psychiatric clinic for treatment," she says. "And a lot of people don’t want to go on medications.”

Though standard treatments work well for many patients, experts say it’s important to provide various options to match individual preference.

One question that remains is whether the stress levels – measured on a biological level – would be reduced over the long term by meditative techniques, says Dr. Madhav Goyal, an internist at NorthBay Healthcare in Vacaville, California, and an assistant professor of general internal medicine at Johns Hopkins University School of Medicine in Baltimore. Goyal has done research on meditation programs to address stress and improve well-being. “We know that people who are more stressed in general tend to be more susceptible to getting infections” among other health issues, Goyal says.



If meditation can treat anxiety disorder and help those with anxiety better cope with stress, it could also improve a person’s overall health in the long term. But more research is needed to determine the impact that meditation might have on chronic stress levels, Goyal says.

In the immediate term, for individuals considering meditation to treat anxiety disorder, Brewer suggests MBSR, which has been well-studied in this regard. The Center for Mindfulness has a worldwide online directory of MBSR teachers certified by the UMass Center for
Mindfulness.

Ultimately, experts say, meditation may help those with anxiety gain a greater understanding of more troubling underlying emotions, such as sadness or anger, while improving their ability to cope with stress. “Instead of being drawn into these long worry bouts, people can have more freedom to deal with those thoughts in a way that’s more constructive,” Hoge says.
Writer: Michael O. Schroeder / Health.news.com

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.

New Breakthrough: The new Treatment strategies for Bipolar Disorder and Epilepsy

Summary: A new study looks at how a gene associated with bipolar disorder affects the balance between inhibition and excitation; revealing a link with epilepsy.

People with bipolar disorder suffer from excessive emotional highs and lows that can cycle uncontrollably, severely distorting their awareness of self and others, impairing social and work ability and causing high risk of suicide. Current treatments are only partly effective. Researchers at Baylor College of Medicine have used mouse models and advanced molecular mapping studies in both mouse and human to learn how a gene associated with bipolar disorder controls the balance between brain excitation and inhibition and shown for the first time that it also is linked to epilepsy.

The findings, appearing recently in the early online edition of Molecular Psychiatry, open new treatment strategies for both bipolar disorder and epilepsy.

“We became very interested in a gene called ‘ankyrin 3’, or ANK3, a decade ago when we discovered it coded for a partner of two other genes that are mutated in some people with epilepsy. Soon afterward, ANK3 was connected with bipolar disorder by genetic testing of thousands of psychiatric patient volunteers around the world,” said Dr. Edward C. Cooper, associate professor of neurology, molecular and human genetics, and neuroscience at Baylor. “Although there are important differences, we noted similarities between bipolar disorder and epilepsy: both cycle, both are risk factors for the other, and both are currently treated using many of the same drugs. Reasons behind these overlaps were mysterious, and the specific parts of the ANK3 gene linked with bipolar had no known function. We decided to take a much closer look at the human brain and mice with bipolar-like behavior. In our study we found that reduced expression of one type of ANK3 removes a brake on the output of brain neurons, leading to excesses in firing in circuits for emotions, memory and epilepsy.”



Proteins coded by ANK3. Blue: output cells. Yellow: nerve impulse trigger zones of output cells. White: Inhibitory neurons that hold back output. Red: trigger zones with a different type of ANK3 protein, lost in bipolar disorder and epilepsy. NeuroscienceNews.com image is credited to the researchers.

Within each ANK3 gene are bits of DNA containing information coding for several different proteins. The research team found that, in both mice and human, different ANK3-coded proteins were expressed on brain cells responsible for increasing output (excitation) and holding back output (inhibition). Working with Cooper, Baylor genetics graduate student Angel Lopez discovered that an ANK3 type found in lower amounts in bipolar disorder patients was selectively lost by inhibitory neurons, lowering their output. Activity of neighboring excitatory cells proved unaffected. So, what scientists call “excitation/inhibition” balance, was shifted in the direction of excessive excitation.

When Lopez and colleagues engineered mice to lose this inhibitory form of ANK3, they found that the imbalance caused both frequent epileptic seizures and an increased risk of sudden death across the lifespan.

“This showed us that imbalance in ANK3 function can result not only in excessive circuit sensitivity and output leading to bipolar
disorder, but also severe epilepsy,” Cooper said.

Although diagnosis and care for bipolar disorder and epilepsy often are viewed as distinctly psychiatric and neurological issues, respectively, the study highlights an example of common genetic and biological underpinnings at a frontier between medical disciplines. The results open the door to additional lab and clinical research and could lead to new treatment options for both conditions by targeting ANK3 and its molecular partners in the brain.



“Our work also provides an example of how conducting and participating in unbiased human genetic studies, such as those that implicated ANK3 in bipolar disorder, can illuminate unforeseen connections between disease categories and the benefits of research that crosses disciplinary borders” said Cooper.
Source: Neuroscience News, Baylor College of Medicine

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.