Antidepressants and Depression

FDA has also directed Eli Lilly and Company, manufacturer of Strattera, to develop a Medication Guide for patients and caregivers.

FDA is advising health care providers and caregivers that children and adolescents being treated with Strattera should be closely monitored for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior, especially during the initial few months of therapy or when the dose is changed (either increased or decreased).

Patients and caregivers who have concerns or questions about these symptoms should contact their healthcare provider.

The actions follow a review and analysis of 12 clinical trials conducted in children with ADHD and one trial in children with enuresis (bedwetting) that identified an increased risk of suicidal thinking for Strattera.

There was one suicide attempt by a patient who received Strattera among the approximately 2,200 patients in the trial.

As part of a larger evaluation of psychiatric drugs and suicidality, FDA had requested that the manufacturer conduct a review of its database and clinical trials, which included more than 2200 patients -- 1350 patients receiving Strattera (atomoxetine) and 851 receiving a placebo.

The analysis showed that 0.4% of children treated with Strattera reported suicidal thinking compared to no cases in children treated with the placebo.

Strattera, manufactured by Eli Lilly, has been on the market since 2002 and has been used in more than two million patients.

Teen suicide is the third-leading cause of death for people in the U.S. between the ages of 15 and 24. Only homicide and accidents claim more lives.

The statistics from the U.S. Centers for Disease Control and Prevention also show as many as 20% of teens consider suicide at some point during the year.

But help may be available from an unexpected source.

In many instances, young people appear too reliant on digital communication, sending hundreds of texts and spending hours posting on social media sites. Some say it's not healthy. Now, mental health officials say what looks like a negative might actually turn out to be beneficial if it can be harnessed to provide a teen suicide early warning system.

After all, young people tend to be quite revealing when they send out a text or post something online. What if someone just paid closer attention?

Analyzing posts

A research team based at Ohio State University (OSU) began monitoring posts on MySpace. In one month they found 64 comments in which adolescents expressed a wish to die.

The researchers then conducted a follow-up survey of young adults and found that young people were highly likely to use text messages when they felt very depressed, reaching out to family and friends. They were least likely, the researchers found, to call a suicide-prevention hotline, which is probably the most common prevention strategy among existing suicide-prevention initiatives.

Obvious tool

Together, the data from the two studies told the researchers that an obvious tool was right in front of them. They conclude that teen suicide-prevention efforts should employ social networking and other types of technology.

“Obviously this is a place where adolescents are expressing their feelings,” said Scottye Cash, associate professor of social work at OSU and lead author of the studies. “It leads me to believe that we need to think about using social media as an intervention and as a way to connect with people.”

The team focused on MySpace and not Facebook because most Facebook profiles are private and not accessible. The challenge was finding expressions that met the test of a real suicide threat, not an easy task considering the age group.

“There’s a lot of drama and angst in teenagers so in a lot of cases, they might say something ‘will kill them’ but not really mean it. Teasing out that hyperbole was an intense process,” Cash said.

Song lyrics often a clue

Sometimes a post would reference a song lyric that was about suicide. According to Cash, the three most common phrases within the final sample were “kill myself,” referenced in 51.6 percent of the posts, “want to die,” mentioned 15.6 percent of the time, and “suicide,” mentioned 14.1 percent of the time.

Cash and her colleagues determined that 42 percent of the posts referred to problems with family or other relationships – including 15.6 percent that were about break-ups – and 6.3 percent were attributable to mental health problems or substance abuse.

A report by the National Institute of Mental Health, issued in 2004, determined that risk factors for suicide include depression and other mental disorders, and substance-abuse disorders. Sometimes these factors combined with other mental disorders. According to the report, more than 90 percent of people who die by suicide have these risk factors.

On top of the risk factors, mental health experts point to additional stressors, such as disciplinary problems, interpersonal losses, family violence, sexual orientation confusion, physical and sexual abuse and being the victim of bullying.

For decades, some physicians have suspected that patients' risk of suicidal thoughts and behavior increased when pediatric patients first begin taking antidepressants. Research indicates that there is no such association in adults.

In 2003, a report submitted to the Food and Drug Administration (FDA) suggested a link between the antidepressant paroxetine and suicidality in pediatric patients. The FDA then requested pediatric data from the manufacturers of eight other antidepressant drugs, the authors report.

Tarek A. Hammad, M.D., Ph.D., and colleagues at the FDA performed a meta-analysis of data from 23 short-term clinical trials received in response to the request, as well as one trial funded by the National Institute of Mental Health (NIMH). The 24 studies included 4,582 pediatric patients taking one of nine antidepressant medications for depression, anxiety or other psychiatric disorder.

No children committed suicide in any of the trials. Although the NIMH-funded trial was the only individual trial to show a significant increase in suicidality among children taking antidepressants, the analysis of all the trials together showed a higher risk of suicidal ideation and behavior for children taking the drugs compared with those who were not.

"When considering 100 treated patients, we might expect one to three patients to have an increase in suicidality beyond the risk that occurs with depression itself owing to short-term treatment with an antidepressant," the authors write.

The FDA now requires warnings regarding the risk of suicidality in children on antidepressant labeling and the distribution of a patient medication guide to patients, families and caregivers, the authors write.

"Although there remain differences of opinion in the clinical community about the strength of this signal for antidepressant druginduced suicidality in pediatric patients and the implications for clinical practice, it is important to be clear that the FDA has not contraindicated any of the antidepressant drugs for pediatric use," they conclude.

"The FDA recognizes that depression and other psychiatric disorders in pediatric patients can have significant consequences if not appropriately treated. The new warning language recognizes this need but advises close monitoring of patients as a way of managing the risk of suicidality."

Researchers at UC San Francisco (UCSF) and Baystate Medical Center in Massachusetts have found that that Prozac and other selective serotonin reuptake inhibitors (SSRIs) can cause all types of problems when taken close to surgery.

The researchers came to this conclusion after examining over 530,000 medical records of patients who underwent surgery in the U.S. between the years of 2006 and 2008.

The 2012 AGS Beers Criteria showed SSRIs were potentially harmful for some seniors because they caused fall and balance issues.

More evidence found

Andrew D. Auerbach, MD, MPH, a professor of medicine at UCSF and lead author of the research, said past studies showed small signs of SSRIs being potentially harmful.

“There have been small studies that suggested there was a problem, but it has never been well-proven,” said Auerbach. “With this huge data set, we feel confident in saying that SSRIs are associated with about a 10% increased risk for these adverse outcomes.”

Auerbach and his team said if taken around the time of a surgery, SSRIs could cause hospital readmission, bleeding, transfusion and death.

Furthermore, the research team said many patients taking SSRIs already have conditions that could cause surgeries to go wrong, like chronic pulmonary disease, rapid weight gain and depression, so they took that into consideration.

Some factors eliminated

Some of the patients reviewed in the study were prescribed SSRIs for the first time, which Auerbach thought might be a contributor to some surgeries going wrong. But after looking closer, he said that argument didn't hold up. 

To make sure SSRIs actually did increase the chances of bleeding, transfusions and death during surgeries, researchers looked at patients who were on the antidepressant and patients who were not. Afterwards, they still found the same higher risk.

Auerbach said further research needs to be done involving actual patients on SSRIs at the time of surgery. For this current study only past medical records were used.

“A prospective observational study, in which patients are randomly assigned to take SSRIs around the time of surgery is still needed,” he said.

Autism link?

Surgery patients aren’t the only ones who might face potential harm from taking SSRIs. A new report out of Sweden indicates the antidepressant could cause autism in newborn babies too.

‘In utero exposure to both selective serotonin reuptake inhibitors and nonselective monoamine reuptake inhibitors (tricyclic antidepressants) was associated with an increase risk of autism spectrum disorders, particularly without intellectual disability,” wrote the researchers.

After looking at the medical records of women during the early stages of pregnancy, researchers discovered the potential link between the antidepressant drug and autism.

The new evidence adds weight to concerns raised by a 2011 study in California, in which researchers also found that SSRI use in pregnancy was associated with increased risks of autism in the exposed children.  Furthermore, they showed that the association was with the SSRI use and not depression (that is, the depression-only group did not have an increased risk of autism.)  

Both studies found about a three-fold (or 300%) increased risk. 

“Future, larger studies, with access to both diagnostic and treatment data at multiple stages of pregnancy may help disentangle the role of maternal depression and the individual drugs used to treat it in the risk of autism spectrum disorder,” the Swedish researchers wrote.

What makes someone depressed? The question becomes more urgent as the number of cases of clinical depression increases.

The Centers for Disease Control and Prevention (CDC) estimates depression at some point affects about 9% of U.S. adults, leaving them with feelings of hopelessness, despondency, and sometimes guilt. The agency says major depression is the leading cause of disability for Americans between the ages of 15 and 44.

Researchers have turned out study after study trying to better understand the condition. At the University of Washington a recent study suggested stress is a major trigger.

A recent British study found over-achievers are more at risk of depression, becaise they become addicted to the Internet. Companies fail to notice the depression, the researchers conclude, because the sufferers are all successful.

Since many of the cases of depression have appeared in the wake of the financial crisis, some researchers looked for – and found – a link to long-term unemployment. Nearly 1 in 5 Americans who have been unemployed for a year or more say they currently have or are being treated for depression.

Physical illness

Here's a new theory. Major depressive disorder (MDD) is actually an infectious disease and not always caused by external influences.

Turhan Canli, a psychology professor at Stony Brook University, suggests that major depression may result from parasitic, bacterial, or viral infection. He thinks depression needs to be reclassified from a mental illness to a physical one while research continues into its causes.

“Future research should conduct a concerted effort search of parasites, bacteria, or viruses that may play a causal role in the etiology of MDD,” he said.

Canli offers 3 arguments why reconceptualizing MDD as an infectious disease may pay off.

For starters, patients with MDD exhibit physical symptoms like a loss of energy. Beyond that, inflammatory biomarkers associated with depression also suggest an illness-related origin.

Viruses can alter behavior

Canli says there is plenty of evidence that parasites, bacteria and viruses that infect humans can alter their emotional behavior. Finally, he cites the concept of the human body as an ecosystem for microorganisms and the role of genetics.

There's enough there, says Canli, to justify large-scale studies with depressed patients to see if there actually is a causal relationship between infectious disease and depression. A Northwestern University study, published in September, just might provide some ammunition.

Researchers developed a blood test that measures the levels of 9 RNA blood markers which seem to be different in patients diagnosed with clinical depression, suggesting some kind of physical link.

Depression symptoms

The CDC says symptoms of depression can range from a sad mood and diminished interest in activities to dramatic weight gain or loss, fatigue and excessive and unjustified feelings of guilt.

The condition also poses a substantial burden to the sufferer and friends and family. Interpersonal relationships are particularly likely to suffer when someone is depressed and the CDC says data suggest that few families or networks of friends are likely to remain unaffected.

When major depression goes unrecognized and untreated the results can turn tragic. Consequences can range from ruined marriages to damaged careers to suicide.

The CDC says this disorder is still misconstrued as a sign of weakness rather than being recognized as an illness.

Emptiness. It is a word that many people with depression are familiar with. It is characterized by a distinct feeling of being lacking – lacking in feeling, lacking in motivation, lacking essential internal components that can make you feel “normal.” Ironically, researchers have found that it is an excess of a certain protein in the brain that may be a major factor in the development of depression in individuals.

The protein in question is called fibroblast growth factor 9, or FGF9 for short. When researching the protein, scientists found that people with major depression had 32% more of this protein in certain parts of their brain.

Testing the theory

Researchers from many organizations and universities, including the University of Michigan Medical School and the Pritzker Neuropsychiatric Disorders Research Consortium, developed their theory on FGF9 after years of studying brain tissue samples. They found that, along with increased levels of FGF9, the section of the brain called the hippocampus was smaller in brain samples of depressed individuals. They theorize that this is the result of FGF9 blocking cell growth and development in the brain.

In order to get a firm grasp on what FGF9 does to the brain, researchers used rats to see how changing the levels of the protein in their brains modified behavior. First, they exposed the rats to increased social stress for a week-long period. They found that FGF9 levels did increase, and the subjects became more socially withdrawn.

Next, the researchers injected FGF9 into the brains of an experimental rat group; the control group was given a placebo. The rats that received the real injection became much more anxious and less motivated to move around. These symptoms only worsened with more injections.

Finally, the researchers created a virus that would interfere with FGF9 production in the brain. They injected it into an experimental group of rats and found that FGF9 levels decreased by 30%. These rats became much less anxious as a result.

Better treatment

If we take a cue from the last experiment mentioned, then we can begin to see what some of the benefits of this research could be. It has already gone a long way in proving that depression is a physical illness, which has been debated in the medical community for many years.

“Fixing depression is not easy, because it’s a disorder at the level of the circuits that connect brain cells, and many regions of the brain are involved,” said Elyse Aurbach, co-author of the paper. “Still, this is the first time FGF9 has been identified as related to depression, and found to be active in a critical area of the brain for the disorder. We and others need to study it further to determine what is going on. It’s very exciting.”

As Aurbach says, there is still much research to be done on FGF9 before any sort of antidepressant can be developed. But when antidepressants can be developed, they would be much safer. Because the new medication would work at inhibiting FGF9 levels, instead of decreasing levels of something else in the brain, the risk of side effects would be greatly reduced. This thought will no doubt spur researchers on and keep them cautiously optimistic. 

Overcoming depression can be a major challenge for people who experience it every day. There are currently over 120 million people who suffer from it worldwide, and the existing therapies and prescriptions do not work for everyone. Luckily, recent research has found that elevating the levels of a signaling molecule in the brain can alter a person’s response to stress. This discovery could provide a new approach to treating depression.

The study was conducted by researchers from the UT Southwestern Medical Center. They found that mice changed their stress-induced behaviors when cyclic adenosine monophosphate (cAMP) levels in their brains were increased. This is extremely relevant to depression because other studies have showed that depressed people often have impaired cAMP signaling in their brains. Most antidepressants work by attempting to turn this signaling system on.

“This is the first step in the development of a treatment for patients with major depressive disorder using this new strategy,” said Dr. James Bibb, who is the lead author the study and a professor of psychiatry, neurology, and neurotherapeutics at UT Southwestern.

Changing responses to stressors

The cAMP levels in the brain correlate with feelings of pleasure, motivation, and reward. They are controlled by a variety of other molecules, which include an enzyme called phosphodiesterase-4 (PDE4). By disrupting PDE4 levels in the brain, scientists found that cAMP levels were able to elevate higher within the mice, which changed their behavioral responses to different stressors.

The researchers have already developed a drug-like peptide that they hope can selectively block PDE4 function. If successful, it could provide a new way for people with depressive disorders to deal with their condition and the stressors that cause it.  

“These exciting findings could help us develop very novel treatments to reduce stress response and prevent or treat depression effectively in the future," said Dr. Madhukar Trivedi, who is the Director of the Center of Depression Research and Clinical Care. The full study has been published in the journal Nature Neuroscience.

Those who suffer from depression or anxiety may find that getting through each day is a daily struggle. Working up the drive to perform even the simplest tasks might take large amounts of energy, and naturally it would be easy to develop a negative outlook on the world.

Now, a new study suggests that lack of sleep may be behind the negative emotional responses that many anxious and depressed people feel. Researchers at the University of Illinois at Chicago (UIC) point out that anxiety and depression often lead to sleeping problems that may affect an area of the brain that regulates how we react to the world around us.

"Our research indicates sleep might play an important role in the ability to regulate negative emotions in people who suffer from anxiety or depression,” said lead researcher Heide Klumpp, assistant professor of psychiatry at UIC.

Reappraisal difficulty

The study assessed 78 participants between the ages of 18 and 65 who had been diagnosed with an anxiety disorder and/or a major depressive disorder. Using a device called an actigraph, the researchers measured participants awake time in bed over a six-day period to evaluate sleep efficiency. Before the evaluation, participants were also asked to complete a questionnaire gauging their sleep over the past month and to take part an emotion-regulation task involving reappraisal.

Reappraisal is an exercise where participants are asked to look at an image – in this case a scene of violence such as a war or accident photo – and try to look at it in a more positive way. For example, an image of a woman with a bruised face might be seen as an actress wearing makeup for a role rather than a survivor of violence.

"Reappraisal is something that requires significant mental energy. In people with depression or anxiety, reappraisal can be even more difficult, because these disorders are characterized by chronic negativity or negative rumination, which makes seeing the good in things difficult," explains Klumpp.

Less sleep stresses the brain

The questionnaire revealed that three out of four participants met the criteria for significant sleep disturbance, while the actigraph showed that most the group suffered from insomnia. When comparing data on all the tasks, the researchers found that those who reported poorer sleep on the questionnaire had less brain activity in a particular area of the brain during the reappraisal task. However, those who had more awake time in bed and lower sleep efficiency according to the actigraph had higher brain activity during the reappraisal task, indicating that their brains had to work harder to carry out the task.

"Because the questionnaire and actigraph measure different aspects of the sleep experience, it is not surprising that brain activity also differed between these measures. The questionnaire asks about sleep over the previous month, and answers can be impacted by current mood. Plus, respondents may not be able to accurately remember how they slept a month ago. The actigraph objectively measures current sleep, so the results from both measurements may not match," explains Klumpp.

The researchers say that their findings indicate that sleep plays an important role when it comes to regulating negative emotions, and that those who suffer from anxiety and depression could be at a disadvantage because their conditions tend to inhibit sleep.

The full study has been published in Depression and Anxiety.