Richard G. Petty, MD

An Important Change in the Warning on Antidepressant Medicines

If we could, we would only use natural medicines to treat depression.

Sadly it is not always possible to do that, and it doesn’t help when people with a demonstrable biochemical disturbance are told that their depression is all about internalized anger or an unwillingness to face some issue in their lives.

The trouble with those theories is that they often don’t take into account a tragic fact: depression can be fatal.

Not only because of the risk of suicide and other kinds of self-injury, but because depression is associated with many physical problems including chronic inflammation and carbohydrate intolerance.

Today the United States Food and Drug Administration (FDA) asked makers of all antidepressant drugs to change the existing "black box" labels on their products to warn about increased risk of suicidality (suicidal thinking and behavior) among young adults aged 18 to 24 in the first few weeks of treatment.

The FDA has also asked the pharmaceutical companies to revise the existing warning to show that there is no evidence that this risk exists for adults over 24, and furthermore, for those aged 65 and older the scientific data suggests the suicidality risk is decreased.

The American Psychiatric Association (APA) said this:

"The FDA’s new labeling acknowledges, for the first time, that untreated depression puts people at risk for suicide."

They said that studies showed that the old label issued in 2004 was associated with a steep drop in use of antidepressants and was followed by an increase in the rate of suicide "reversing a decade-long decline in suicide deaths in the United States".

The FDA said the emphasis on the new labels should be that depression and other serious psychiatric illnesses are themselves the most important causes of suicide.

Director of FDA’s Center for Drug Evaluation and Research, Dr Steven Galson said that:

"Today’s actions represent FDA’s commitment to a high level of post-marketing evaluation of drug products."

"Depression and other psychiatric disorders can have significant consequences if not appropriately treated. Antidepressant medications benefit many patients, but it is important that doctors and patients are aware of the risks."

The FDA recommends that people who are currently taking antidepressants should not stop taking them as a result of hearing this news.

The warning revision applies to all antidepressants and comes in the wake of controlled trials that showed a reasonably consistent risk of suicidality across most of the antidepressant drug categories. The FDA said that the evidence does not support excluding any antidepressant medication from this update request.

This update request follows the labeling changes made in 2005 to warn of increased suicidality in children and adolescents taking antidepressants.

Since then, the FDA undertook a comprehensive review of 295 drug trials examining the risk of suicidality among adults taking antidepressants.

The trials included over 77,000 adult patients with major depressive disorder (MDD) and other psychiatric conditions.

The results was that in December last year, the FDA’s Psychopharmacologic Drugs Advisory Committee said labels should be changed to tell doctors about the increased risk of suicidality among younger adults taking antidepressants.

The Committee also said the labels should remind doctors that the disorders themselves present the greater risk, and that among older adults the antidepressants do not carry the suicidality risk and have an apparent beneficial effect.

The FDA is preparing drafts of patient guides and wording for the labels. The manufacturers have 30 days to submit their own versions for FDA review.

The drugs affected include:

— Anafranil (clomipramine)
— Asendin (amoxapine)
— Aventyl (nortriptyline)
— Celexa (citalopram hydrobromide)
— Cymbalta (duloxetine)
— Desyrel (trazodone hydrochloride)
— Elavil (amitriptyline)
— Effexor (venlafaxine hydrochloride)
— Emsam (selegiline)
— Etrafon (perphenazine/amitriptyline)
— Lexapro (escitalopram hydrobromide)
— Limbitrol (chlordiazepoxide/amitriptyline)
— Ludiomil (maprotiline)
— Luvox (fluvoxamine maleate)
— Marplan (isocarboxazid)
— Nardil (phenelzine sulfate)
— Norpramin (desipramine hydrochloride)
— Pamelor (nortriptyline)
— Parnate (tranylcypromine sulfate)
— Paxil (paroxetine hydrochloride)
— Pexeva (paroxetine mesylate)
— Prozac (fluoxetine hydrochloride)
— Remeron (mirtazapine)
— Sarafem (fluoxetine hydrochloride)
— Seroquel (quetiapine)
— Sinequan (doxepin)
— Surmontil (trimipramine)
— Symbyax (olanzapine/fluoxetine)
— Tofranil (imipramine)
— Tofranil-PM (imipramine pamoate)
— Triavil (perphenazine/amitriptyline)
— Vivactil (protriptyline)
— Wellbutrin (bupropion hydrochloride)
— Zoloft (sertraline hydrochloride)
— Zyban (bupropion hydrochloride)

The APA said:

quot;We believe the new label, which still contains important warning information, reminds physicians and patients that antidepressants save lives. Physicians and patients need all the facts in order to make appropriate, informed decisions about any proposed course of treatment."

This change is not in any way an indictment of the medicines, it just acknowledges the reality that depression is dangerous.

Why is the risk apparently greater in younger people? It is thought that it has to do with the fact that the frontal lobes of the brain, that are involved in the control of emotions, have not yet fully formed.

Retinoic Acid and Suicide

Retinoic acid is an organic compound derived from Vitamin A, that is involved in the development of the brain and in normal visual function. It is because of the involvement in the formation of the brain that medicine containing retinoic acid like compounds must not be given to women who could become pregnant.

In recent years it has become clear that it is also involved in the function of the mature nervous system, and there have been suggestions that it may have a role in illnesses life Alzheimer’s disease and schizophrenia.

One of the big breakthroughs in skin care was the introduction, in 1982, of a form of retinoic acid – isoretinoin – for the treatment of severe acne. It is marketed as Accutane in the USA and Roaccutane in the United Kingdom. Since its introduction there have been claims that it has caused depression and suicide in some patients taking it. The package insert specifically mentions this possible association. The trouble has been trying to sort out whether people taking it for acne became depressed because of the acne, whether it was the drug, or whether it was a chance association. 13 million patients have taken it world-wide, so sadly some depression might occur by chance.

That it was the drug causing the problem was supported by reports of people developing depression within days of starting the medicine. But it’s always difficult to go from association to causality. After all, it has not been possible to prove that smoking causes lung cancer, though nobody doubts it, becuase the association between the two is so strong.

The Medicines and Healthcare products Regulatory Agency had received 1,588 reports of suspected adverse events experienced by people taking the drug up to this month. This included 25 people who died from suicide.

Now a paper in the journal Neuropsychopharmacology has added substantial support the the notion that the medicine may cause depression. The researchers gave a form of retinoic acid to adolescent mice. They found that while there was no change in the physical abilities of the mice, the rodents spent significantly more time immobile in a range of laboratory assessments designed to test their response to stress.

This was interpreted as a sign that the animals were exhibiting signs of depression.

It’s difficult to extrapolate from mice to humans, and this certainly does not nail down the problem. It also does not mean that people should stop their treatment: this medicine works. But it emphasizes the importance of doing what the package insert says: watching young people with acne who are on treatment for any signs of depression.

Cutting and Self-injury

There’s an extremely disturbing trend: ever-increasing numbers of young people who are cutting themselves. Once rare, and something usually seen only in people with serious psychiatric illness, many school children encourage and goad each other into doing it, and there are websites dedicated to cutting, on which young people compare notes and even give each other advice on how to conceal what they are doing, by cutting themselves in places like the lower back.

We have been offered a great many explanations for this worrying development, but not much in the way of evidence. We know that most people who cut themselves are female adolescents or young adults, and apart from the obvious physical dangers, there is evidence that this behavior may lead to a more serious psychological condition called Borderline Personality Disorder. This can be a serious problem that carries a high risk of suicide. It is also of some theoretical interest, because there seem to be genuine cultural differences in borderline personality disorder. An estimated 5.8 million to 8.7 million Americans, mostly women, suffer from it, but it is far less common in most of Western Europe and Australia. Research over the last decade has indicated that the condition is becoming more common in these regions. People with the borderline personality disorder have a wide spectrum of difficulties that are marked by emotional instability, difficulty in maintaining close relationships, eating disorders, impulsivity, chronic uncertainty about life goals and addictive behaviors such as using drugs and alcohol. They also have major impact on the medical system by being among the highest users of emergency and in-patient medical services. Glen Close’s character Alex Forrest in the movie Fatal Attraction, had some of the features that we might expect in some with borderline personality disorder.

Researchers from the University of Washington in Seattle have reported that adolescent girls who engage in cutting behavior have lower levels of the chemical transmitter serotonin in their blood. They also have reduced levels of activity in the parasympathetic nervous system as measured by what is called respiratory sinus arrhythmia, a measure of the ebb and flow of heart rate as we breath. Low levels of this measure are typically found in people who are anxious or depressed. The study included 23 girls aged 14 to 18, who engaged in what psychologists call “parasuicidal” behavior. Participants were included if they had engaged in three or more self-harming behaviors in the previous six months or five or more such behaviors in their lifetime. The comparison group consisted of an equal number of girls of the same ages who did not engage in this behavior.

In line with previous research, the adolescents in the parasuicide group reported far more incidents of self-harming behavior than did their parents.

The findings of low serotonin and low parasympathetic activity support the idea that the inability to regulate emotions and impulsivity can trigger self-harming behavior. The primary problem is an inability to manage their emotions: the people who cut themselves have excessively strong emotional reactions and they have extreme difficulty in controlling those emotions. Their self-harming behavior may serve to distract them from these emotions.

A characteristic feature of borderline personality disorder is not just self-injurious behavior but also stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with the condition. The increasing incidence of the condition in Europe is attracting many European investigators and colleagues from Mannheim in Germany have recently traced the neurological circuits involved in this stress-induced reduced pain perception.

There is good evidence that people who cut themselves are more likely to have been victims of sexual abuse or violence as children, though that obviously does not mean that every person who harms themselves has had something bad happen to them in childhood. Sadly the research has become more complex because of the numbers of people who have been given false memories of abuse by well-meaning psychologists.

Treating people who cut themselves, whether or not they have borderline personality disorder can be very challenging. The first thing is to treat any underlying mood or anxiety disorder. A combination of medications and psychotherapy is normally used, with people making claims for the value of different types of therapy. Many therapists also say that they have helped people who cut themselves with tapping therapies, acupuncture, homeopathy and qigong. I’ve not been able to find any credible research evidence to support the use of those therapies, though I’ve also seen some success stories.

We also have the puzzle about why cutting and borderline personality disorder seems to have been less common in other parts of the world and are now increasing. There is research to show that it’s not just a matter of recognition or of calling the illness something else in Europe. I have a friend who is a senior academic at an Ivy League University, and an expert on borderline personality disorder. During a sabbatical in Scotland some 15 years ago, he could not find a single case. This matters, because if we can identify what’s changed, we may have some clues about treatment. There are hundreds of candidates, including environmental stress, diet and toxins.

There’s an important new study in which 13 children with autism showed marked improvement in some of their challenging behaviors when they were given 1.5gms of omega-3 fatty acids each day. This was only a six week study, but it needs to be replicated using larger numbers. It is also important to be alert to the possibility that some makes of omega-3 fatty acids on the market contain mercury. The one that we have found best so far has been OmegaBrite. It will also be useful to see if dietary supplementation will help self-injurious behavior in other types of people.

Here is a list of some of the better information sites about self-harm.

The key to success with helping complex problems, as I point out in great detail in Healing, Meaning and Purpose, is a comprehensive approach:

Combinations are Key

Bipolar Disorder, Insomnia and Suicide

For many years now, I have advised on the treatment of many well-known people with all sorts of problems and illnesses. I always admire people who reveal that they have suffered from a problem in the hope of helping other sufferers.

The actor Stephen Fry has recently described his struggles with bipolar disorder and why he suddenly abandoned a play in London after developing stage fright. You may have seen him playing Jeeves to Hugh Laurie’s Wooster, or in the Blackadder shows.

Stephen was once described as a man with a “Brain the size of Kent.” He said that he became so knowledgeable because of terrible insomnia, which kept him up nights: he used the time to read enormous numbers of books. He also described a suicide attempt and a very serious plan to kill himself.

Though I’ve not examined Stephen, I can now explain several things to you:
1.    Bipolar disorder is not uncommon, and is rather more common in highly creative people. That being said, we must not romanticize an illness that carries a substantial mortality. The illness is frequently misdiagnosed, and when it is, there is an ever-present risk of suicide, as well as a host of other medical problems.
2.    Anxiety disorders occur in 80-90% of people struggling with bipolar disorder, and stage fright is one of these anxiety states
3.    Stephen may not have had insomnia as much as a reduced need for sleep, which is a classic symptom of one type of bipolar disorder. People with insomnia cannot sleep and usually go through the day feeling un-rested. People with a reduced need for sleep not only stay awake, but don’t get tired until they have been up for days at a time. Doing something like reading lots of books at night is another classic symptom.

Stephen Fry has just made a documentary for the BBC in which he talks about bipolar disorder with Carrie Fisher, Richard Dreyfuss and Robbie Williams.

They all deserve our gratitude for speaking out, telling their stories, and hopefully helping alleviate some of the stigma of mental illness, and helping more people get the diagnosis and treatment that they need.

Thank you Stephen!

P.S. There has recently been a rumor going round that your humble reporter was the model for Hugh Laurie’s Golden Globe award-winning portrayal of Dr. Gregory House. I don’t know where it started, but there’s absolutely no truth in this vile calumny. I’m never irritable or curmudgeonly…

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