Or…Can Antidepressants Cause Suicide?
Fluoxetine, (Prozac) was the first SSRI (selective serotonin reuptake inhibitor) to be approved in the United States for use in depression. It was FDA approved for adults in 1987. Although it was not FDA approved for use in depressed children until early 2003, clinicians widely used this type of medication to treat children and adolescents with depression and anxiety.
Prior to the 1990s, antidepressants were used less frequently in children and adolescents. The available antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors had more side effects. These medications were also much more dangerous if there was an overdose. The tricyclic antidepressants (nortryptiline, amitryptiline desipramine and others) could effect heart rhythm. This cardiac effects were more common in children and adolescents. We had a much higher threshold for starting a child on an antidepressant. We would get frequent tests to check blood levels of the antidepressant. There were some studies that showed that tricyclics helped with AD/HD but we did not have good controlled studies showing that they helped with adolescents. We would also obtain frequent tests of heart rhythm, (EKGs) Tricyclics have other side effects, but since these medications are not often used in children, I will not enumerate them here.
In June 2003, the FDA (US Food and Drug Administration) issued a recommendation that paroxetine, (Paxil) not be used to treat children or adolescents with depression. Paroxetine is approved for the treatment of adults with obsessive-compulsive disorder, depression, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia. It is not approved for pediatric use but physicians have frequently used paroxetine for children and adolescents with depression and anxiety. (Physicians are permitted to use medications in ways not indicated on the FDA labeling if the physician feels that the medication is necessary.) In August 2003, Wyeth Pharmaceuticals sent a “Dear Doctor” letter warning that venlafaxine (Effexor and Effexor XR) was associated with an increased rate of hostility, and suicidal ideation in pediatric clinical trials.
After these warnings, the British Medicines and Healthcare Products Regulatory Agency (the British equivalent to the FDA) reviewed data on the efficacy of other SSRI (Selective Serotonin Reuptake Inhibitors–Prozac, Paxil, Zoloft and others.) They concluded that other than Prozac (fluoxetine) the data did not show proven efficacy. They also said that the data did support an increase in suicidal thinking and behavior in youth. The FDA reviewed published and unpublished data on the use of the SSRI and other antidepressant medications in children and adolescents. Based on their review of these studies, the FDA determined that further consumer warnings were warranted. (Since then other SSRI medications have been shown to be effective in children and adolescents.)
On October 15, 2004, the FDA (United States Food and Drug Administration) issued an advisory to raise the awareness of the public of the risk of increase suicidal behavior and thoughts in children treated with antidepressants. They required the manufacturers of antidepressants to place a black box warning on the drug labeling that is directed toward health practitioners. The black box is the strongest warning placed on a prescription medication. The FDA also has issued a requirement for a Patient Medication Guide be given out with each antidepressant prescription filled. The Med Guide is directed toward patient and their parents. The FDA also issued recommendations for close follow up of children and adolescents started on antidepressants.
What do these recent announcements mean? Do they apply to all medications in these classes? Why should these medications affect children differently from adults?
For many years, physicians who treated children had to work with partial information. Pharmaceutical companies often are the ones funding research on their medications. They have often insisted that that researchers sign confidentiality agreements. Researchers who signed such agreements cannot discuss their scientific findings unless the company agrees. Thus, the pharmaceutical companies could choose which studies are published and which data remains secret. There was some limitations on this secrecy—if deaths or serious medical problems occur during clinical studies, this was be revealed to the appropriate governmental agency. The FDA had access to the data from the trials. After the publicity about the unpublished drug trials, the pharmacuetical companies now have to be more open about negative findings.
When the FDA analyzed pooled data from all SSRI antidepressants, they found a significant increase in suicidal thoughts and actions (but not completed suicides) in children and adolescents. However, no individual drug except venlafaxine (Effexor) showed statistically significant increases in suicidal thinking and behavior.
The 2003 FDA Statement: The FDA (US Food and Drug Administration) issued a public statement October 27, 2003. I am including an excerpt. It can be read in its entirety at http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01256.html
“In the 20 placebo-controlled trials being considered for these 8 drugs (citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine), involving over 4100 pediatric patients, there have been no reports of completed suicides. However, FDA has not at this point been able to rule out an increased risk of suicidality for any of these drugs, including Paxil (paroxetine), which was the subject of a FDA Talk Paper on June 19, 2003.
FDA emphasizes that, for the 7 drugs evaluated in pediatric major depressive disorder (MDD), data reviewed by FDA were adequate to establish effectiveness in MDD for only one of these drugs, Prozac (fluoxetine). Failure to show effectiveness in any particular study in pediatric MDD, however, is not definitive evidence that the drug is not effective since trials may fail for many reasons. FDA recognizes that pediatric MDD is a serious condition for which there are few established treatment options, and that clinicians often must make choices among treatments available for adult MDD. FDA emphasizes that these drugs must be used with caution. “
Suicide rates and the rate of antidepressant use: A study published in the Archives of General Psychiatry October 2003 showed an inverse relationship between regional change in the use of antidepressants in individuals ages 10-19 and the incidence of completed suicide. In other words, if the area showed an increase in the use of antidepressants there was a decrease in the incidence of completed suicides. The study did not find this correlation with the tricyclic antidepressants, but these are now used much less frequently in this age group. Actual completed suicides are much rarer than suicidal ideation and suicide attempts. Thus, this data is hopeful, but but is not a direct measure of the effect of antidepressants on suicidal acts.
The TADS Study: In August 2004, JAMA (The Journal of the American Medical Association) published a large, multi-site controlled study comparing the effectiveness of fluoxetine (Prozac), cognitive behavioral psychotherapy and placebo in the treatment of adolescents with Major Depression. The study commonly called TADS (Treatment of Adolescents with Depression Study) was sponsored by the National Institute of Mental Health. The study involved 439 adolescents with moderate to severe depression. The teens were randomly assigned to receive medication alone, placebo pills alone, cognitive behavioral therapy alone or a combination of medication and cognitive behavioral therapy. Individuals who received a combination of psychotherapy and medication achieved the best overall results. Those on medication alone or psychotherapy alone did not do significantly better than placebo. However the adolescents on medication alone did do significantly better than those who received psychotherapy alone. The rates of improvement were 34.8% for placebo, 43.2% for therapy alone, 60.6% for medication alone and 71% for the combination of medication and psychotherapy. Although a number of adolescents started the study with suicidal thoughts, there was a significant reduction in the incidence of such thoughts with treatment. The reduction was most marked in the adolescents who received a combination of medication and therapy. This is probably the best controlled study of the effects of an antidepressant and therapy on adolescents.
Should you take your child off medication?
How do we interpret this data? Although fluoxetine (Prozac) and escitalopram (Lexapro) are the only SSRI medications which have met FDA criteria for treatment of youth, many clinicians have seen good results from other antidepressants in their clinical practices. Fluvoxamine, (Luvox) has FDA approva for treatment of obsessive compulsive Disorder but not depression in youth.
No one should suddenly stop medication without first consulting his or her physician. Paxil and Effexor and some other SSRI medications can cause uncomfortable withdrawal effects. Stopping the medication might cause a recurrence of the depression or anxiety. It is important for the physician to discuss the potential risks and benefits of antidepressants with parents and with older children and adolescents. This cannot be done in a 10 minute session. The child should have time alone with the physician to discuss how he is doing and how he feels about medication. He or she should have some understanding about what the medication is supposed to do and how to tell if it is working. He should be asked about suicidal ideation, as well as symptoms of irritability and agitation. The physician should discuss the potential side effects with the parent in more detail. The parent and child should understand the various options for treatment of depression.
Why might these medications cause agitation or suicidal ideation? We cannot be sure. There are several possibilities:
Akathesia: SSRIs, Effexor and other psychiatric medications may sometimes cause a feeling that one cannot keep still physically or mentally. This unpleasant feeling most often occurs when the medication is first started or when the dose is increased. Children may be more vulnerable to this effect. This can be minimized by starting the medication slowly and telling the family to call if it is a problem.
Mania: Children who become depressed before puberty have a higher than average chance of developing bipolar disorder. The first episode of this condition may be a depression. An antidepressant medication may precipitate the mania or cause rapid mood cycling. It is important to get a complete family history before starting antidepressants. If there is a family history suggestive of mania or bipolar disorder, one should proceed cautiously with antidepressants.
External improvement preceding internal improvements. I warn patients about the “cruel irony of antidepressants.” Other people may notice that they show more energy, sleep better, and get more things done. However the individual is still trapped in his depressed mode of thought. If a person is depressed but gets more energy, he may get up the nerve to do something self-destructive. One should monitor the person closely during this period. It also helps to tell them that improvement in the external symptoms is the harbinger of later improvement in internal depressive thoughts.
Handing a depressed adolescent a bottle of pills. Parents should not teach their children about responsibility by asking them to take charge of their medications. Cleaning one’s room or walking the dog is a much better way to teach accountability. I encourage parents to use pill boxes and to keep all medications in a secure place. Physicians should frequently review how medications are administered and where they are kept.
Withdrawal: Both paroxetine (Paxil) and venlafaxine (Effexor) have relatively short durations of action and uncomfortable withdrawal effects. Withdrawal from these medications can be associated with nausea, agitation, mood changes, anxiety, irritability and other symptoms. Some individuals can experience these if they miss a couple of doses. Children who move from one parent’s home to another may not always get their medication consistently. Longer-acting medications such as fluoxetine (Prozac) do not have such prominent withdrawal symptoms.
Are Herbal Remedies Safer? Some families may conclude that herbal medications are safer. This may be a false hope. Supplements or “natural” medications are not regulated by the FDA. There is no guarantee that the supplement contains a standard amount of the active compounds. The supplements do not undergo the same rigorous testing as do prescription medications. Most importantly, if you simply buy these pills at a health food store, your physician is not monitoring the treatment. No one is checking to make sure that the herbal compounds are not interfering with each other or exacerbating existing medical conditions. Some supplements may be helpful. However I believe that any pill strong enough to be effective is also strong enough to cause side effects.
Psychotherapy can be an effective treatment for depression or anxiety in children or adults. Even here the family must act as informed consumers. There are different forms of therapy. Therapists may have different levels of experience. If you elect to treat the depression with therapy alone, make sure that you schedule periodic reviews of progress. If the therapist cannot prescribe medication, make sure that the therapist has an ongoing relationship with a child and adolescent psychiatrist. That way, you can get a speedy referral if your child’s condition worsens. Ideally the same person would prescribe medication and do the psychotherapy. If your child is seeing separate clinicians for therapy and medication, make sure that there is coordination between them. Do not assume that your child’s non-physician therapist is giving the physician regular updates. Sometimes the clinicians need to actually talk to each other in real time. In other circumstances, the members of the treatment team can communicate by email or by leaving messages on each other’s voice mails.
Group therapy is an underutilized treatment. Children and teens can encourage each other. Those who are further along in their recovery can encourage those new to treatment.
Are other medications safe for children? Fluoxetine (Prozac) is FDA approved for the treatment of depression in children aged 8 and up. Sertraline (Zoloft) Fluvoxamine (Luvox) are approved for children who have Obsessive-Compulsive Disorder. Escitalopram (Lexapro) is approved for the treatment of depression in those aged 12 and up. Bupropion (Wellbutrin, Wellbutrin SR and Wellbutrin XL) affects norepinephrine and is not approved for children. Still it may be useful for some depressed children and adolescents. Other SSRI medications may also be useful and have been regularly used by clinicians. These medications might have the potential causing agitation or akathesia in sensitive individuals. The clinician should inform the family and follow the situation carefully.
Many well designed, controlled studies show that antidepressants are effective for adults. The FDA made it clear that the recent British data did not apply to adults. However, far fewer controlled studies show clear positive effect in pediatric depression. This may be partly due to the fact that fewer medication studies are done on children. When pediatric medication studies are done, there may be a selection bias. Parents may be more reluctant to enroll their child in a clinical study where the child might receive an experimental drug or a placebo. Children are suggestible and show a greater response to placebo. The brain of a child may be different form the brain of an adult and may respond differently to medications. Children may experience depression and mood swings differently from adults. Children may metabolize certain medications faster than adults. Finally a child’s understanding of depression and its treatment may be different from that of an adult.
Before Prozac and the other SSRI antidepressants, we were much more cautious about prescribing medications for depressed and anxious children and adolescents. A child had to be much more depressed to merit pharmacological treatment. The newer antidepressants such as the SSRI medications and bupropion, are less toxic and are have fewer medical risks.
How should we treat depressed children and teens? I do not think that we should stop using medication to treat depressed children and adolescents. The TADS study in particular suggests that an antidepressant can be an important part of the treatment of depression. However, we should take the recent data seriously. I am more cautious about starting medication with a child than with an adult. When I complete an evaluation of a depressed child or adolescent, I like to discuss the full range of treatment options with the parents and the child. In many cases, we may opt for a trial of individual, group of family psychotherapy before starting medication. Some children and adolescents improve without medication. However, if the depression is severe, one may consider starting medication and therapy at the same time. I am reluctant to treat a depressed child or adolescent with medication in the absence of other therapeutic interventions. It is particularly important to follow the child closely in the early stages of treatment. It is a good idea to schedule frequent sessions even if the patient and family do not complain of side effects. It is important to determine whether irritability is a symptom of the depression or a medication side effect. If the patient later starts to appear apathetic, one must determine whether the apathy caused by the depression or is the result of too much medication.
We should not throw the baby out with the bath water. Depression can be a dangerous and debilitating disorder for children or adults. Antidepressants, when used properly, can save lives. Medications can be a powerful and effective tool in our armamentarium. We should use them carefully.
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