FDA looks at link between medications, depression Los Angeles Times April 14, 2008

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http://www.latimes.com/features/health/la-he-psycheffects14apr14,0,3637015.story From

the Los Angeles Times HEALTH FDA

looks at link between medications, depression Federal

regulators warn that an array of drugs could play a role in spurring thoughts

of suicide or other psychiatric symptoms. By Healy

Los Angeles Times Staff Writer

April 14, 2008

As symptoms of depression go, there is none much clearer than having thoughts

of suicide.

But a spate of recent announcements from federal health officials suggests a

surprising new interpretation of suicidal fantasies and the depression they are

thought to signal: Sometimes, sadness, anxiety and self-destructive thoughts

are not symptoms but side effects -- of medicine.

In this year alone, federal regulators have warned that a surprising array of

drugs could play a role in spurring thoughts of self-destruction. Medicines

that treat epilepsy, asthma and influenza are now under suspicion, as is one

that helps smokers kick the tobacco habit.

The FDA stresses that it has established no direct causal link between these

medications and suicidal thoughts in patients taking them. But in all the

cases, regulators acknowledge they had one of two indicators of potential

trouble.

In some cases, a review of a drug's early clinical trials turned up increased

rates of suicidal thinking among subjects taking the medicine. In others, the

tip-off came when the FDA observed an uptick of reports that patients taking a

medication for some other condition developed symptoms of depression.

As a result, FDA officials and medical researchers now are scouring their data

for clear signs that these drugs increase the risk of dangerous psychiatric

symptoms. Moving forward, the agency will require developers of many new drugs

to test for psychiatric side effects that could tip the balance between a new

medicine's risks and benefits.

"We're trying to develop systematic strategies for looking . . . in a more

rigorous way" for links between drugs and unintended psychiatric effects,

said Dr. Laughren, director of the FDA's division of psychiatry

products. "The difficulty is that we have such a primitive understanding

of human behavior on a biological level . . . it is hard to predict which

compounds are going to have psychiatric effects."

FDA warnings

The recent rash of advisories comes just four years after the FDA first

suggested a connection. Prompted by reports that suggested children taking

antidepressants were more likely, not less, to commit suicide, the agency in

2004 warned that antidepressants might actually increase the risk of suicidal

fantasies and behaviors among children. That link is now in doubt, after recent

studies showed a rise in youth suicide even as antidepressant use in that

population has plummeted.

But the experience of coping with the anguished families of young suicide

victims who took antidepressants has had a lasting effect on mental health

professionals, researchers and federal regulators. If early-warning systems

detect even a hint of psychiatric danger with a medication's use, government

officials are inclined to alert first, study later.

"When they see a signal, even if they don't understand the genesis of that

signal, that's a reasonable time to warn," said Dr. Ward, a member

of the FDA's pediatric advisory committee and professor of pediatric medicine

and pharmacology at the University of Utah .

As it moves forward, the FDA hopes to detect such signals -- and warn patients

and physicians -- before a drug

enters wide use. One of the first drugs that will require testing for

psychiatric side effects before it can be FDA-approved in the

U.S. is

rimonabant, an anti-obesity drug already used in some 20 other countries. After

early clinical trials suggested patients taking the drug had increased rates of

depression and anxiety, an FDA advisory panel voted last June to recommend a

delay in market approval pending further study.

The FDA has asked rimonabant's maker, the French pharmaceutical firm

Sanofi-Aventis, to use a new yardstick to detect and measure suicidal side

effects. Scientists have long known that many drugs used to treat symptoms

below the neck enter the brain also and that the receptors and chemicals on

which they work in organs such as the heart, blood vessels or liver are present

in the brain as well, although they may have different functions there. That

these drugs might have an incidental effect on mood, then, "shouldn't be

terribly surprising," Laughren said.

Abnormal behavior

Still, some of the bizarre reports prompting advisories were wholly unexpected.

In Japan ,

where antiviral medicines such as Tamiflu and Relenza are widely used to

shorten the duration and ease the symptoms of influenza, last year's flu season

raised serious alarms.

In the span of several months, two 14-year-old patients taking Tamiflu -- a boy

and a girl -- fell to their deaths from high-rise apartment buildings in

suspected suicides, and two 12-year-olds on the medication were injured after

falling from buildings. Delirium, hallucinations and psychotic behavior caused

one child taking the drug to bolt into traffic to his death.

In all, an FDA advisory panel was told last November, there have been 25 deaths

and 365 cases of abnormal behavior in children and young adults under 21 who

took Tamiflu since it was approved for use in 1999. Although regulators

underscored that hallucinations and bizarre behavior can be a consequence of

the high fevers and brain inflammation that can come with influenza, they

acknowledged they could not, without further scrutiny, rule out a link to

Tamiflu.

"It came as a surprise to everyone," Ward said. "First the

antidepressants raised people's concerns, and then they started to find these

unusual suicidal behaviors with Tamiflu. It caused people to ask, 'Whoa, what

is happening here?' "

Last month, the FDA notified physicians of the Japanese incidents (while also

noting that "the contribution of Tamiflu to these events has not been

established") and urged close monitoring of young patients with influenza,

who might be taking an antiviral medication. In early April, GlaxoKline,

maker of the antiviral medication Relenza, voluntarily issued a similar

notification to physicians.

On March 27, the FDA went on to announce it was investigating a "possible

association between the use of Singulair," a pill used to treat asthma and

allergies, and changes in mood and behavior, including suicidal thinking and

suicide attempts. That warning came after the FDA's adverse-event monitoring

system saw an uptick in reports about patients taking Singulair experiencing

symptoms of depression, including thoughts of self-destruction. Although this

monitoring system relies on voluntary reports from patients and physicians and

does not establish causal connections between a drug and a reported

"event," it is a key early detector of untoward side effects once a

drug enters wide use.

Reports to the FDA also prompted a warning to healthcare professionals on Feb.

1 about Chantix, an anti-smoking drug approved in May 2006. As the medication

gained a foothold among U.S. smokers wishing to quit, patients began telling physicians and the FDA of

peculiar behavior, agitation, depressed mood and suicidal thoughts and actions.

By January, the FDA had concluded "it appears increasingly likely that

there may be an association between Chantix and serious neuropsychiatric

symptoms" and urged physicians to weigh that possibility when prescribing

the drug, and to carefully monitor patients who take it.

One recent warning emerged not from spontaneous reports by patients and

doctors, but from an internal FDA effort. Last year, after studies had shown an

increase in suicidal thoughts and behavior among people taking certain drugs

for epilepsy, the FDA conducted a broad review of clinical trials conducted on

11 anti-convulsive drugs.

The result was a Jan. 31 alert informing physicians of an established link

between the 11 drugs and suicidal thinking and actions. As a group, patients

taking any of the 11 medications were twice as likely to experience suicidal

thoughts and actions as those who took a dummy pill. The heightened risk of

self-destructive symptoms was evident as early as one week into treatment and

continued throughout the 24 weeks of study.

Mind-body connection

Though such reports of psychiatric side effects defy prediction, researchers

said that growing understanding of the connection between mind and body should

lead the way to better guesses at which drugs may unexpectedly darken a

patient's mood, and why.

"With every passing day, we've learned so much that there's a strong

connection" between physical and mental health, said Dr. Husseini Manji,

director of the Anxiety and Mood Disorders Program at the National Institute of

Mental Health. "When you're depressed, a lot of things in your body don't

work well. But conversely, both medical illnesses and certain medications can

markedly make you depressed."

melissa.healy@...

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