PTSD: Anti-anxiety Drug Calms Fears by Altering Brain Chemistry

An advance in understanding the brain’s fear circuitry has been revealed by a research team. They say it may hold particular promise for people at risk for anxiety disorders, including those suffering post-traumatic stress disorder (PTSD). Findings are reported in the journal Molecular Psychiatry.

“What is most compelling is our ability to translate first from mice to human neurobiology and then all the way out to human behaviour,” says Ahmad Hariri, a neurobiologist at Duke University. “That kind of translation is going to define the future of psychiatry and neuroscience.”

Read the original study DOI: 10.1038/mp.2012.72

 

The common thread in their studies is a gene encoding an enzyme called fatty acid amide hydrolase, or FAAH.

The enzyme breaks down a natural endo-cannabinoid chemical in the brain that acts in essentially the same way that Cannabis, aka marijuana, does (hence the name endo-cannabinoid).

Earlier studies had suggested that blocking the FAAH enzyme could decrease fear and anxiety by increasing endo-cannabinoids, which is consistent with the decreased anxiety some experience after smoking marijuana.

In 2009, Hariri’s lab found that a common variant in the human FAAH gene leads to decreased enzyme function with affects on the brain’s circuitry for processing fear and anxiety.

In the new study, Andrew Holmes’ group at the National Institute on Alcoholism and Alcohol Abuse tested the effects of a drug that blocks FAAH activity in fear-prone mice that had also been trained to be fearful through experiences in which they were delivered foot shocks.

Tests for the ability of those mice to get over their bad experiences found that the drug allowed a faster recovery from fear thanks to higher brain endo-cannabinoid levels.

More specifically, the researchers showed that those drug effects traced to the amygdala, a small area of the brain that serves as a critical hub for fear processing and learning.

To test for the human relevance of the findings, Hariri’s group went back to the genetic variant they had studied earlier in a group of middle-aged adults.

They showed study participants a series of pictures depicting threatening faces while they monitored the activity of their amygdalas using functional magnetic resonance imaging (fMRI) scans. They then looked for how the genetic variant affected this activity.

While the activity of the amygdala in all participants decreased over repeated exposures to the pictures. But people who carried the version of the FAAH gene associated with lower enzyme function and higher endo-cannabinoid levels showed a greater decrease in activity.

Hariri says that suggests that those individuals may be better able to control and regulate their fear response.

Further confirmation came from an analysis led by Duke’s Avshalom Caspi and Terrie Moffitt of 1,000 individuals in the Dunedin Study, who have been under careful observation since their birth in the 1970s in New Zealand.

Consistent with the mouse and brain imaging studies, those New Zealanders carrying the lower-expressing version of the FAAH gene were found to be more likely to keep their cool under stress.

“This study in mice reveals how a drug that boosts one of the brain’s naturally occurring endo-cannaboids enables fear extinction, a process that forms the basis of exposure therapy for PTSD,” Holmes says.

“It also shows how human gene variation in the same chemical pathways modulates the amygdala’s processing of threats and predicts how well people cope with stress.”

Studies are now needed to further explore both the connections between FAAH variation and PTSD risk as well as the potential of FAAH inhibition as a novel therapy for fear-related disorders, the researchers say.

More news from Duke University: http://today.duke.edu/

Antidepressants in water trigger Autism genes in fish

Low levels of antidepressants and other psychoactive drugs in water supplies can trigger the expression of genes associated with autism, in fish at least.

The use of antidepressants has increased dramatically over the past 25 years, says Michael Thomas of Idaho State University in Pocatello. 

Around 80 per cent of each drug passes straight through the human body without being broken down, and so they are present in waste water. In most communities, water purification systems cannot filter out these pharmaceuticals. 

"They just fly right through," says Thomas, which means they ultimately find their way into the water supply.

The concentration of these drugs in drinking water is very low – at most, they are present at levels several orders of magnitude lower than the prescription doses. 

But since the drugs are specifically designed to act on the nervous system, Thomas hypothesised that even a small dose could affect a developing fetus.

Thomas's group created a cocktail of the anti-epileptic drug carbamazepine and two selective serotonin uptake inhibitor (SSRI) antidepressants, fluoxetine and venlafaxine, at this low concentration. 

They exposed fathead minnows (Pimephales promelas) to the drugs for 18 days, then analysed the genes that were being expressed in the fishes' brains.

Although the researchers had expected the drugs might activate genes involved in all kinds of neurological disorders, only 324 genes associated with autism in humans appeared to be significantly altered. Most of these genes are involved in early brain development and wiring.

The finding fits with previous research which had found that pregnant women who take SSRIs are slightly more likely to have autistic children. (Archives of General Psychiatry, DOI: 10.1001/archgenpsychiatry.2011.73).

To test whether these changes actually altered the fish's behaviour, the researchers did an experiment in which they startled the fish. Fish exposed to the drugs tended to panic and behave differently from a control group of fish.

Thomas emphasises that the research is very preliminary – there's no need for pregnant women to worry about their drinking water yet, he says. The researchers next plan to study whether the drugs have a similar effect in mammals. 

They are testing this by lacing the drinking water of pregnant mice with the low-concentration cocktail. 

They are also studying water supplies in areas around the country where there are particularly high concentrations of drugs to determine whether the fish – and people – in these areas have autism-like gene expression patterns.

Journal reference: PLoS One, DOI: 10.1371/journal.pone.0032917

Antidepressants During Pregnancy: What Are the Risks?

What is a woman struggling with depression supposed to do when she becomes pregnant?

A study published on Monday in the Archives of General Psychiatry tackles the tough decision of deciding to keep taking the medication, or risk harming the fetus.

Roughly six percent of pregnant women are taking antidepressants. The struggle to live with depression or risk your baby's health has plagued women for quite some time.

The latest study included 7,696 pregnant women. Five hundred and seventy of the women suffering from depression were not on medication, and 99 women with depression "were being treated with selective serotonin reuptake inhibitors (SSRIs), a common class of antidepressants."

What this study found is that women going untreated for depression gave birth to babies that had a reduction in total body growth.

This affected the fetal head growth as well. Those women taking prenatal SSRI also had babies that suffered from a reduced growth of the fetal head, but the overall growth of the body during pregnancy was not affected.

What are the risks for the fetus during pregnancy with antidepressants? Mothers taking antidepressants could have preterm babies, who face higher health risks like respiratory and gastrointestinal disorders.

Not only could these children be born preterm, but according to the authors of the study, reduced fetal head-growth can lead to behavioural problems and psychiatric disorders later on.

However, the risks for the mother may outweigh the risks of the pregnancy, if she discontinues antidepressant medication.

Dr. Sudeepta Varma, clinical assistant professor of psychiatry at NYU Langone School of Medicine reported "If we are talking about a woman who can't take care of her health as a result of battling with moderate to severe depression, she faces risks to herself as well as the baby that are associated with untreated depression during pregnancy."

According to Varma, "if you don't take care of the mom, there may be no baby to speak of."

These findings however are inconclusive according to the authors of the study. "More long-term drug safety studies are needed before evidence-based recommendations can be derived," concluded the authors.

Anti-Depressants Increase Blood Pressure in Newborns

Antidepressant use in expecting mothers can cause their babies to develop pulmonary hypertension, a condition that increases blood pressure in the lungs, according to a study published Thursday in the British Medical Journal.

Babies born from mothers who took the most prescribed type of antidepressants, serotonin reuptake inhibitors (SSRI) during pregnancy were twice as likely to develop pulmonary hypertension compared with mothers who did not take the medications.

The study could impact about 1.5 percent of pregnant women in the U.S. - the percentage of expecting mothers who take the antidepressants more commonly known by their brand names of Zoloft, Paxil, and Celexa and Lexapro.

Researchers reviewed records from 6 million births from 1996 to 2007 in Nordic countries and found the risk of pulmonary hypertension doubled in infants whose mothers took SSIs.

Experts said that the risk remained low.