FDA looks at meds and depression

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FDA looks at link between medications, depression

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

spurring thoughts of suicide or other psychiatric symptoms.

By Melissa 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. Thomas 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. Robert

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, GlaxoSmithKline, 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