Sunday, April 04, 2004

Antidepressants and Suicide Risk
Latest Reliable Information

This post contains the latest information about the possibility that antidepressant medication could increase suicide risk.  At the end, I discuss the process that people go through when personally weighing risks and benefits of medication.  I also make some recommendations for people who are facing a choice about whether to take such a risk.

Note that this is not intended to be a comprehensive treatment of the subject.  I would have to write a book to do that. 

For background, see the previous CC posts: 1  2  3  4.  Briefly, the concern here is that there have been reports about a possible link between the use of antidepressant medication, and the emergence of new suicidal thoughts, impulses, or actions.  I haven't seen a convenient name for this, so I am going to refer to it as antidepressant treatment-emergent or exacerbation of suicidality (ATEES).  This is meant to exclude  suicidality that occurred prior to initiating treatment, but would include  any significant worsening of pre-existing suicidality.  Proposed mechanisms for this include: patient was too depressed to be suicidal or to act on suicidal thoughts before Rx, but has more energy after Rx and can think and act more effectively once on medication; patient develops motoric restlessness (akathisia) that leads to suicidality; suicidality emerges as a result of the illness worsening, before any medication effect can occur (typically it takes 2 to 6 weeks for an antidepressant to start working); patient looses hope when treatment does not work fast enough; or other, unspecified reasons. 

Medical data:  This month's issue of Current Psychiatry contains the latest information on the risk of suicide in children taking antidepressants.  It includes a summary of an analysis by the ACNP of all the published clinical trials, plus the previously-unpublished trials that started the recent media blitz.  By pooling the data from all the studies, they generated the following:

Independent findings: In January, an American College of Neuropsychopharmacology (ACNP) report concluded that SSRIs do not increase suicidal thoughts or suicide attempts in youth (Table 1). An ACNP task force examined the use of SSRIs in more than 2,000 children and adolescents, including all published clinical trial data, unpublished data from several pharmaceutical companies, and data reported to Britain's MHRA. An executive summary is available on the ACNP's Web site (see Related resources).

Here is a copy of the summary table:

Risk table

Notice that this information is not really conclusive.  We see that in some cases, there remains a significant possibility of risk.  The lack of statistical significance does not mean that there is no correlation between the medication and suicide risk.  It means that the correlation is too weak to draw any meaningful conclusion.  For example, looking at paroxetine (Paxil, Pexeva) there were 14 cases in the medication group and 7 in the placebo group.  The P value of 0.4 means that there is a 40% chance that this difference is due to random factors, and is not a true medication effect; it also means that there is a 60% chance that there is a real medication effect.  The fact that the correlations are weak is not a big surprise.  Even though the studies include over 2000 people, the risk of suicide for the general population is only 0.01%.  Thus, you would need a much larger sample to expect to see any meaningful correlation.

Having said that, there is some degree of reassurance here.  Although there are not enough data to say for sure that there is no elevation of risk, it is reasonable to say that if there is an elevation of risk, it probably is small. 

Personally, I think that there are some cases of ATEES that are real, and that some of them are caused directly by the medication.  I think that the number is too small to prove a cause-effect relationship in most studies.  A couple of months ago, a psychiatrist wrote in the NYT a personal account  of her antidepressant experience (Thanks to InDC Journal  for the link).  Although she does not report having developed suicidality, she clearly had enough discomfort that she could have become suicidal.  There also are personal accounts in the discussion  on Dean's World. 

Recent Editorial:  Andrew Solomon, an author who has written about his personal struggle with depression, wrote an editorial  in the NYT.  I like the fact that he discloses information that could bias his presentation.  (Thanks to Book of Joe  for the link) Excerpts follow:

It is probably the case that antidepressants both cause and prevent deaths. But it is also clearly the case that they prevent more deaths than they cause. The danger is that in seeking to prevent antidepressant-related suicide, we will increase depression-related suicide.

People die from chemotherapy, but because we recognize that cancer is often fatal, we accept the risks of treatment. We tend to be less aware of the mortal nature of depression. Some 700,000 American adults attempt suicide every year; someone succeeds in committing suicide in the United States every 17 minutes. Four percent to 10 percent of people who suffer from major depression commit suicide. Untreated depression is lethal.

The solution is not to stop using the drugs, but to identify the populations in which their use could lead to suicide. There is no simple test to pinpoint those at risk. The best defense is to monitor people who are taking antidepressants — which we should do anyway. Sadly, medication has often replaced close personal attention; the best possible consequence of the labeling change would be a return to sustained scrutiny of depressed patients. (Full disclosure: my father is the chief executive of a pharmaceutical company that manufactures antidepressants.)

Here, he makes an important point: medication can have paradoxical effects, meaning that it is possible for medication to do the opposite of what it is supposed to do.  This phenomenon, by the way, is not limited to psychotropic medication.  But because the brain is the most complex organ, it presents the most opportunities for unexpected results when you tinker with it. 

In addition, antidepressants may actually escalate depression in a small number of people. When we muck around with brain chemistry, we see strange and subtle effects. The emotional brain is idiosyncratic. Experiences that make one person happy — the birth of a child, the first day of spring — may drive another to despair. If events can have such diffuse consequences, so can medications. Most psychoactive drugs provoke paradoxical responses in a limited number of people: stimulants prove sedating, and sedatives make them tense. Anything that is strong enough to bring someone back from the brink of suicide is strong enough to push him there. Serotonin, the neurotransmitter affected by most of the antidepressants on the F.D.A. list, is not a simple happiness compound.

There are cases of people who are given a heart medication who immediately have more heart problems; people given a drug to lower blood pressure who get higher blood pressure, and people given antibiotics who develop a more serious infection as a result of the antibiotic.  His final comment is a good one:

As a society, we are overmedicated and undermedicated. Many people with severe depression go untreated, and have barren, miserable lives because of it, while others commit suicide. Only 15 percent of people with major depression get appropriate treatment. Meanwhile, people with an inflated idea of how happy we should be, who want to medicate away their personalities, take risks seeking pharmaceutical remedies to human foibles.

Both problems are authentic, but undermedication is the more dangerous. What emerges clearly from the new F.D.A. warning is that people should act with caution on both fronts. Avoid medications if they can't help; take them if they can, but then pay attention to what happens.

Yes, definitely: "pay attention to what happens".   Experience always trumps theory.  If what happens doesn't fit your theory, you should change your theory; don't  discount your observation of what happened.   Not all observations are accurate, but all observations should be taken seriously. 

News Outlets:  I am not going to cite most of the newspaper articles on the subject, because there is not much there beyond what you can read in this and my previous posts on the subject.  This article  at CNN is fairly typical.  This Reuters article  reports that prescriptions for antidepressants are being filled increasingly often for children.  (Wings of Madness  also picked up on this, although they have the wrong link in their post.)

Express Scripts, which keeps statistics on drug use, said the number of prescriptions written for antidepressants is growing by about 10 percent a year in children and adolescents.

The study looked at a random sample of 2 million children covered by commercial insurance between 1998 and 2002. Among children under age 5, the number of girls being prescribed an antidepressant doubled and the number of boys went up by 64 percent, the group reported.

Writing in the April issue of Psychiatric Services, Express Scripts said antidepressant use for all children under 18 increased from 1.6 percent in 1998 to 2.4 percent in 2002.

"A number of factors acting together or independently may have led to escalated use of antidepressants among children and adolescents," Tom Delate, director of research at Express Scripts, said in a statement.

"These factors include increasing rates of depression in successive age groups, a growing awareness of and screening for depression by pediatricians and assumptions that the effectiveness experienced by adults using antidepressant medications will translate to children and adolescents."

It will be interesting to see if this trend continues, now that there is an FDA warning pertaining specifically to the use of antidepressants in children.  I hope that there is greater caution employed now, when antidepressants are given to children.  Greater caution might not lead to less prescribing, though.

A noteworthy news report is from the BYU newspaper, NewsNet:

[...] [L]ocal experts say that because of many factors in a person's emotions, it is impossible to say for certain that antidepressants are the cause of suicide.

Suicide is a known associate to depression, but the cause of suicide is often difficult to distinguish, said Dr. Joseph Miner, director of the Utah County Health Center.

He said when people suffer from depression, there is a very high rate of suicide, whether or not the person is on medication.

"It is not a common enough problem or a definite enough problem that they do want the warning there because it has been recognized and suicide is a common part of depression and if you don't use the medication then you are more often more at risk," he said.

He said the purpose of the recent FDA warning is for the government to fulfill its responsibility to make sure the drugs are safe for the consumer.

"We see suicide in our county almost every week and the majority are young adults in their early to mid-20s," Miner said.

Additionally, he said the western United States has seen a significant higher rate of suicide.

"In general, the rate of mental illness is pretty consistent," Miner said. "Alcohol use is much less, many people treat their depression, since the culture in Utah county doesn't self-medicate with alcohol so readily; but, like they should, they go to a professional to get a prescription for the mental health problem."

He theorizes that Utah rates of antidepressant usage may be higher than the rest of the country because of a lack of self-medication, such as the use of drugs and alcohol to numb the senses.

Dr. Robert Crist, a psychologist with the BYU Health Center, said the newer antidepressants are much better than the old ones because they have fewer side effects. This is not the first time antidepressant use has been linked with suicide, he said.

"The major problem that we have today is that 80 percent of those who receive antidepressants receive them from doctors who don't specialize in psychiatry or psychology," he said.

Miner said it is complex and it is difficult to say which stage people are in and if medication is helping them. It is important that people get the right prescription, diagnosis and regular check-ups.

I cited this article because the author actually took the time to gather some information -- in this case, from local experts -- before blindly echoing a newsfeed.  The physician quoted in the article makes a point about not "self-medicating" with "drugs or alcohol to numb the senses."  Some critics of antidepressant medication argue that the antidepressants do exactly that: numb the senses.  But this is a fallacy that should be put to rest.  Antidepressants do not work by numbing anything.  Quite to the contrary, most persons treated with antidepressants experience a wider range of feelings, and have a more appropriate connection between their emotional states and what is going on around them, after they receive appropriate treatment.  There are a few individuals who get emotional numbness from antidepressants, but this is an unintended side effect; it is not an effect that is necessary for the medication to work.

Blogosphere:  Bitch Has Word has an amusing take on the subject:

Feeling Down?

Then don't take an antidepressant, unless you're serious about ending it all.

Patients on some popular antidepressants should be closely monitored for warning signs of suicide, the government warned Monday in asking the makers of 10 drugs to add the caution to their labels.

I guess patients on unpopular antidepressants don't have anything to worry about.

In other headlines, antifreeze now thought to cause frostbite; antiperspirants,
sweating; antibiotics, syphilis; antioxidants, aging; and antibellums, peace.

In addition to the bloggers I mentioned in my 3/27/2004  post there are a few more worth mentioning.  Mythusmage Opines  writes:

It's simplified sensationalism, with no consideration for all the facts. What was going on in the victim's life. What pressures did he have? What treatment was he receiving? Every case is unique and each suicide cannot be credited to a single common cause.

What is home life like? Does the patient have a support system in place? What is the patient's relationship with his family and friends? Does the patient have other medical problems? How old is the patient? Has the medication been effective in treating the depression? What other types of treatment is the patient in? Has the patient been hospitalized recently? For how long? What are conditions like at work? At home? What sort of experiences has the patient gone through recently? What other medications are they taking? What about their diet? What are they drinking?

[...] Paxil (which I now take) interacts with caffeine to raise anxiety levels in some people. Which means I can't drink Sunkist Orange Soda or Barque's Rootbeer (they both have added caffeine). Now note that by itself Paxil does not make my anxiety disorder worse, it's in combination with caffeine that the damage is done.

Dorthea at Caveat Lector  writes: 

As I understand it, putting a seriously depressed person with existing suicidal ideation on anti-depressants can indeed increase the risk of a suicide attempt. The problem appears to be that the anti-depressant relieves the patient's mental and physical lethargy before the suicidal thoughts subside. A more motivated and energetic person, still with suicidal ideation, is more likely to plan and carry out a suicide attempt.

[...] There is definitely a finger to be pointed here. The appropriate place to point it, however, is for once not at the drugs. It's at our ludicrous health-care system that is happier to pay for drugs than for therapy, that allows GPs to prescribe drugs without even checking for suicidal ideation, and that allows people taking drugs to get by without anything even vaguely resembling appropriate follow-up and oversight.

Analysis: A lot has been said about the potential for suicidal thoughts or behaviors to emerge after starting an antidepressant, or for pre-existing suicidality to become worse.  This is a matter that is addressed most appropriately with a risk-benefit analysis.  However, this is not easy to do when the risks are not quantified and when there are strong emotional influences affecting one's judgment.  Furthermore, it is not common for people to be able to do a good risk-benefit analysis about a complex topic. 

When individuals weight relative risks and benefits, they often do so according to their personal value system.  This may lead to unexpected conclusions.  Some persons might say that they are not willing to accept any additional risk that might be posed by medication.  This is true even though the risk of not taking the medication may be greater.  Although this may seem illogical, it is fairly common for people to be more willing to accept risks that seem to be posed by random acts of nature than they are to accept risks imposed by their own actions.  Another way to put this is to say that it may be easier to accept a relatively large risk posed by inaction, than a smaller risk created by initiating some kind of action.  In other cases, people might be more willing to accept a risk that is natural (in some personal sense) than a risk that seems somehow unnatural.  Alternatively, other persons might be more willing to accept risks created by action, because they would rather do something than nothing.  In my experience, it is a minority of persons who go by a strict numerical balance of risk vs benefit.  Most persons weigh risk by attaching some kind of emotional weight to the various risks, rather than just looking at the numbers. 

In the case of medication, if the person gets a strong negative feeling when thinking about the medication, that person might put a greater weight on a small risk from medication than they would if they had no emotional reaction.  Similarly, if a person has a strong negative feeling when thinking about passively accepting their fate, they may place a smaller weight on the risks associated with taking some kind of action. 

Another factor that I see sometimes, as people decide whether or not to take medication, is the influence of personal endorsement.  We all know that if Michael Jordan endorses Nike shoes, people are more likely to buy Nike shoes.  This makes some kind of sense, as Michael Jordan ought to know something about shoes.  Buy what about Tiger Woods endorsing a Buick?  It still influences their behavior, even though Mr. Woods has no particular claim to automotive expertise.  Likewise, if a person is thinking about taking medication, and their best friend has already taken a similar medication, and it turned out OK, then they are more likely to go ahead and take the medication.  If, on the other hand, their friend vomited all over the place after taking the medication, they will be disinclined to take it themselves.  There is no rational basis for this, but it is a very powerful influence. 

Reading brief news reports and hearing personal anecdotes are both valid sources of information, but when it comes to making important desicions, sometimes a little knowledge is worse than none at all.  Therefore, there is a need for people to think at length about the choices facing them, and to be adequately informed. 

Recommendations:  I think that for persons facing a choice, if there is a risk either way they go, it is good for them to think first about the process  of deciding, before actually deciding which way to go.  Do you prefer action over inaction?  Passively encountered risk over actively created risk?  Known, quantified risks over unknown risks?  Consider if there might be some factors, such as a personal endorsement or TV advertisement, that might be influencing you as you make the choice.  Although it is not possible to neutralize such factors by sheer force of will, it does help to at least try to be objective.

When I see someone who is considering taking an antidepressant, but who is ambivalent, I usually advise them to think about it carefully.  Then if they decide to do it, they should really do it, and do it right.  If they remain ambivalent, but go ahead anyway, there is a fair chance that they will take the medication for a short time, then stop.  What does this accomplish?  It exposes them to risk, with no chance of benefit.  In other words, they end up maximizing risk while minimizing benefit.  Obviously, that is the exact opposite of what we are trying to accomplish. 

Usually, we want to minimize risk and maximize benefit.

There is a concept in psychopharmacology: the adequate trial.   An adequate trial of medication is defined as taking the right dose for the right amount of time in order to have a good idea of what the drug does and does not do.  Typically, it takes six weeks at the maximum dose in order to complete an adequate trial of an antidepressant.   This is not always perfectly clear-cut, because it is not always clear what the maximum dose is. 

When a person starts an antidepressant medication, it should be started with the intent of completing an adequate trial.  Notice that this does not mean that the person should keep taking the medication no matter what adverse effects occur.  There is another concept: dose-limiting adverse effects.  If a person develops intolerable adverse effects at or below whatever dose is required to achieve a therapeutic benefit, then that drug is not useful for that person. (Unless the adverse effects can be counteracted, which sometimes is possible.)  If dose-limiting adverse effects occur, then an adequate trial has been achieved.  Even though the trial might have been short, it was sufficient to establish the usefulness of that medication, for that person, at that time. 

In routine practice, though, it often happens that people get adverse effects that would be intolerable over a long period of time, but which can be tolerated for short periods of time.  It this kind of situation, it is necessary to make a judgment about how likely it is that the adverse effect may go away.  Some, such as headaches, usually do either diminish of disappear within a few weeks.  Others, such as sexual dysfunction, tend to persist.  It is not well established how likely suicidal thoughts and impulses are to diminish over time.  If ATEES is due to akathisia, it can be treated with a beta-blocker or something else.  If it is due to the underlying illness, then it should go away when the illness is brought under control. 

Sometimes suicide risk requires a stay in a hospital to manage.  Often, though, it can be managed without resorting to hospitalization.   Working out a safety plan that includes: regular contact with supportive people, frequent clinic visits, and a list of emergency numbers, often will enable a person to feel safe and stay safe in the early phase of treatment.  If medication is part of the treatment, it is a good idea to put the medication and dosage schedule on the safety plan.  It also is a good idea to be sure to take the medication exactly as prescribed, and to always get all your medications at the same pharmacy.  Avoiding use of alcohol and illegal drugs is essential. 

One thing I saw in most of the personal accounts posted on the 'net is that people with depression think they should be asked specifically about suicidality.  They also want to know what to do if these thoughts or impulses occur.  Many clinicians routinely will work out a safety plan with their clients.  If they don't offer this, just ask.  Perhaps you should not have to ask, but ask anyway.

Conclusion:  The issue of antidepressant use, and the risk of suicide associated with such use, presents an interesting study in the interface between hard science and social science.  Psychopharmacologists tend to look just at the chemistry and the symptomatology of the illness.  Although many try to attend to the psychological and sociological implications of what they do, these things can be overlooked.  Spirited, but serious public discussion of these issues can contribute to the establishment of a broad framework for understanding all the implications of psychopharmacology: not just the medicinal aspects, but also the effects of the prescribing of medication on the patient's psychological state, the family and group dynamics affecting the individual, and the social and cultural effects of the use of psychotropic medication. 

For Further Discussion:  One think I learned in researching this topic, is that there still is a lot of doubt out there about the effectiveness of antidepressant medication.  Much of this comes from the fact that 1) published studies are difficult to interpret accurately, for technical reasons, 2) published studies do not accurately represent what happens in the course of routine treatment, and 3) there is a lot of misunderstanding about what the treatment is supposed to accomplish.  Another issue I run across often, is the question of the appropriateness of using antidepressant medication for anything other than classic Major Depressive Disorder.  These are things I would like to address separately.