The lead article in this month's issue of
Harvard
Mental Health Letter
May
9, 2005
"What
are the real risks of antidepressants?"
Since
the late 1980s, America and the world have been enjoying the
benefits of the selective serotonin reuptake inhibitors (SSRIs).
These antidepressants: < fluoxetine (Prozac), sertraline
(Zoloft), paroxetine (Paxil),
fluvoxamine
(Luvox), citalopram (Celexa), and escitalopram(Lexapro) >
are among the world¹s most widely prescribed medications. They
are remarkably safe and effective. The range of their uses has
expanded from depression to anxiety, obsessive-compulsive
disorder, eating disorders, and many other psychiatric conditions.
The
number of patients who suffer destructive outcomes may be small,
but no medical treatment is without risk. In recent years, the
side effects of these drugs, from sexual dysfunction to suicidal
behavior, have received more attention. Drug makers have been
instructed to add warnings about the most serious dangers,
particularly the risk of suicide. So the public and professionals
are weighing risks and benefits anew. All clinicians and patients
should be aware of potential problems, questions, and concerns. We
review those issues here and try to put them in perspective.
Physical
symptoms. Some patients taking SSRIs develop insomnia, skin
rashes, headaches, joint and muscle pain, stomach upset, nausea,
or diarrhea. These problems are usually temporary or mild or both.
A more serious potential
problem
is reduced blood clotting capacity because of a decreased
concentration of the neurotransmitter serotonin in platelets.
Patients are at increased risk for stomach or uterine bleeding,
and are more likely to require a blood transfusion during or after
surgery. This risk is about the same as the risk of bleeding with
NSAIDs (aspirin, ibuprofen, naproxen). If patients use SSRIs and
NSAIDs at the same time, the risk more than doubles, so they must
be combined with care.
Involuntary
movements. These include tics, muscle spasms, dyskinesia
(repetitive muscle movements), parkinsonism (rigid and trembling
limbs, a shuffling gait, loss of fine motor control), and
akathisia (compulsive restlessness), any of which may be
accompanied by severe anxiety. Though rare, these symptoms are
more likely in the elderly and in patients taking fluoxetine and
citalopram, the SSRIs that remain longest in the body. Treatments
include the anti-anxiety drug diazepam (Valium), the beta-blocker
propranolol (Inderal), and antiparkinsonian drugs such as
benztropine
(Cogentin).
It may also help to switch to a different kind of antidepressant.
Sexual
effects. For many patients, SSRIs diminish sexual interest,
desire, performance, satisfaction, or all four. In men, SSRIs can
delay or inhibit ejaculation, and in women, delay or prevent
orgasm. They may also hinder
lubrication
of the vagina, erection of the penis, and engorgement of the
clitoris. And many users of SSRIs who can function physically lose
interest in sex.
Lowering
the dose may help, although the patient may lose the drug¹s
benefit. Another solution is adding or substituting bupropion (Wellbutrin),
which works by a different mechanism and does not generally cause
sexual side effects.
Sildenafil
(Viagra) or tadalafil (Cialis), taken an hour before sex, helps
maintain an erection in men by increasing blood flow to the penis.
The main potential side effects are headaches, flushing, upset
stomach, and
heartburn.
Used by a person taking nitrates for angina, these drugs could
cause a dangerous fall in blood pressure. They have not clearly
shown benefits for women in controlled trials. Drug interactions.
SSRIs are broken down in the liver by a group of enzymes known as
the cytochrome P450 system. By engaging these enzymes, SSRIs may
bump out another drug that requires the same breakdown process,
thus increasing its blood level and prolonging its action. The
danger is greatest with fluoxetine and paroxetine. Physicians who
prescribe SSRIs must know about other drugs a patient is taking so
that the dose can be adjusted.
If an
SSRI is taken along with another drug that enhances serotonin
activity, a rare condition called the serotonin syndrome may
develop < racing heart, sweating, high fever, high blood
pressure, and sometimes delirium. In particular, SSRIs should not
be mixed with certain other medications, especially the herbal
remedy St. John¹s wort, monoamine oxidase inhibitors such as
phenelzine (Nardil), and clomipramine (Anafranil). The serotonin
syndrome has also been reported when an SSRI is combined with
lithium, the standard treatment for bipolar disorder.
The
elderly. SSRIs are safer than tricyclic antidepressants for older
people because they do not disturb heart rhythms and rarely cause
dizziness that results in falls. But liver function is less
efficient in older people, so there is a greater risk of drug
interactions involving the cytochrome P450 system. For that
reason, older people do best with rapidly metabolized drugs like
sertraline.
Loss
of effectiveness. Any antidepressant may lose its effect after
months or years, sometimes because the brain has become less
responsive to the drug (tolerance). Solutions include increasing
the dose and switching to another
antidepressant
with a different mechanism of action.
Discontinuation
symptoms. Symptoms that may occur on stopping an SSRI include
dizziness, loss of coordination, fatigue, tingling, burning,
blurred vision, insomnia, and vivid dreams. Less often, there may
be nausea or
diarrhea,
flu-like symptoms, irritability, anxiety, and crying spells. ³Discontinuation
syndrome² is a better description than ³withdrawal reaction,² a
phrase associated with addiction. The syndrome is usually (but not
always) mild and brief, peaking in the first week and quickly
fading. Although none of these drugs should be stopped abruptly,
paroxetine tends to produce the most intense discontinuation
symptoms. Here is a place where the longer-lasting drugs have an
advantage; some clinicians switch to fluoxetine before gradually
lowering the dose.
Antidepressants
before birth. Some (but not all) studies have found a higher than
average risk for low birth weight and premature delivery when
antidepressants are taken during pregnancy, especially in the last
three
months.
At birth, infants may suffer withdrawal symptoms, including
jitters, crying, irritability, shivering, and, rarely, seizures.
One study, correcting statistically for other factors including
the mother¹s depression, found more respiratory distress in
infants exposed to paroxetine in the last months of pregnancy. The
symptoms were most intense in the first
few
days and usually disappeared within a month.
Reports
of discontinuation symptoms are difficult to interpret because
they do not come from controlled experiments. Risks to the fetus
must be weighed against the considerable risks of depression to
both mother and child. More seriously depressed women are more
likely to need antidepressant drugs while pregnant, and depression
itself can affect the unborn child. In such situations, it may be
essential to prescribe antidepressants for pregnant women.
Breast-feeding. Similar cautions apply to nursing mothers. A
meta-analysis published in 2004 indicated that the quickly
eliminated drugs paroxetine and sertraline do not reach
significant levels in breast milk, but fluoxetine and citalopram
do.
Suicide.
The risk that antidepressants will incite violent or
self-destructive actions is the subject of renewed controversy.
Suicidal thoughts (although no suicides) in patients taking SSRIs
were first reported in 1990, shortly after the drugs were
introduced. An FDA committee rejected the association, and most
mental health professionals accepted that conclusion. But the
issue was never completely settled.
One
reason for concern is the increasing number of children and
adolescents receiving prescriptions for antidepressants. An
analysis of clinical trials in patients under age 18 found that
SSRIs raised the risk of suicidal thinking when compared with a
placebo. Many studies have followed, and although results vary,
there is a consistent trend. When compared with a placebo, all
antidepressants, including SSRIs, seem to double the risk of
suicidal thinking, from 1%2% to 2%4%, in both children and adults.
In October 2004, after much hesitation and pressure from parents
and Congress, the FDA issued a Black Box Warning for physicians
and pharmacists < its strongest available measure short of
withdrawing a drug from the market. The warning is placed on
package inserts for all antidepressants in common use. It mentions
the risk of suicidal thoughts, hostility, and agitation in both
children and adults, specifically citing statistical analyses of
clinical trials. The FDA has also issued a public advisory to
parents, physicians, and pharmacists, and it will develop an
information guide to be distributed with each new prescription.
Professional
organizations are also acting. The American Academy of Child and
Adolescent Psychiatry has established a committee to monitor
controlled trials, set standards, and promulgate guidelines for
the use of drugs in children. The Academy will also work with the
National Institute of Mental Health (NIMH) to publish a review of
these issues and a guide for investigators. The American Medical
Association is preparing an independent review of the evidence on
risks and benefits of antidepressants. Self-destructive feelings
and thoughts in patients taking SSRIs may be the result of anxiety
or akathisia. Sometimes a person with hidden bipolar disorder
receives an antidepressant and develops an irritable manic
reaction. Some patients may recover their energy and therefore
their ability to act before mood improves or hope returns. The
danger is greatest in the first few weeks of treatment. If a
patient begins to have suicidal thoughts
after
many months on an antidepressant, the drug is probably not to
blame. It's more likely to be caused by the underlying illness.
A bad
outcome can be avoided by regular follow-up and close monitoring.
Patients should be warned that there is a slight chance they will
feel worse for a while, and they should let their prescribing
clinicians know immediately if they begin to feel worse or develop
new symptoms, especially after changing the medication or the
dose. Weighing the risks for children. Those who think
antidepressants and other psychiatric drugs are being prescribed
too freely for children and adolescents may feel vindicated by
these developments. They doubt that we know enough about the
long-term effects of antidepressants and other drugs on children¹s
growth or developing brains.
As of
early 2005, only fluoxetine is FDA-approved for major depression
in patients under age 18. Fluoxetine, fluvoxamine, and sertraline
are approved for childhood obsessive-compulsive disorder. In a
clinical trial, paroxetine was found effective for social anxiety
disorder in children. But the difference between drug and placebo
is moderate, and psychotherapy is generally equally effective. The
NIMH is also sponsoring a study of antidepressants and
psychotherapy in adolescents who have attempted suicide. The
warnings and regulations have influenced professional judgments.
The number of antidepressant prescriptions for children, which
rose rapidly throughout the 1990s, has begun to fall almost as
precipitously. According to a company that processes prescriptions
for HMOs and employers, child and adolescent antidepressant use
dropped 16% in the last three months of 2004. Overall,
pediatricians and general practitioners write about a third of
antidepressant prescriptions for children and adolescents. It¹s
expected that many of them will stop prescribing these drugs and
instead refer patients with suspected depression to mental health
professionals. One optimistic view is that this change will result
in closer monitoring. And in the future SSRIs may be prescribed
mostly for children and adolescents with persistent or severe
symptoms that are not responding to psychotherapy. The other side.
The practical significance of the findings on suicidal thinking is
still uncertain. The lifetime suicide rate of people with major
depression is 15%, and depression can also be lethal in other
ways; for example, a history of major depression doubles the risk
of heart disease. And it has been estimated that only 25% of cases
of major depression receive adequate treatment of any kind, either
drugs or psychotherapy. The adolescent suicide rate declined
nearly 15% in the United States between 1985 and 1999, while use
of SSRIs in that age group was rising by nearly
70%.
Only 20% of adolescents who commit suicide have ever taken an
antidepressant drug. Ironically, the most worrisome potential side
effects of SSRIs < loss of libido and suicidal thinking <
are also common symptoms
of
depression. Another irony is that SSRIs have largely replaced the
older tricyclic antidepressants partly because they cannot be used
to commit suicide.
Some
will always think that drugs are overused, others that they are
not used enough. Decisions about SSRIs engage professional
loyalties < psychologists naturally tend to be more skeptical
about drugs than psychiatrists < as well as economic interests,
including concern about the rising costs of health care. There are
larger issues, too < whether the
current
popularity of drug treatment means that psychotherapy is being
neglected and depression understood too exclusively as a
biochemical problem.
Research
in genetics, pharmacology, and neuroscience may eventually reduce
uncertainty and anxiety by helping us choose which antidepressant
will have the greatest benefits with the fewest side effects for a
given patient.
Meanwhile,
the period of adjustment we have been going through in the early
2000s should help bring judgments on the risks and benefits of
antidepressants into better balance.
Resources
Information
on antidepressant research findings, guidelines, and regulations
is
available on the Web.
U.S.
Food and Drug Administration
www.fda.gov/cder/drug/antidepressants/default.htm
National
Institute of Mental Health
www.nimh.nih.gov/healthinformation/antidepressant_child.cfm
American
Academy of Child and Adolescent Psychiatry
www.aacap.org/announcements/psychiatricmeds.htm
References
Brent
DA. ³Antidepressants and Pediatric Depression < The Risk of
Doing
Nothing,²
New England Journal of Medicine (Oct. 14, 2004): Vol. 351, No. 16,
pp.
15981601.
Fergusson
D, et al. ³Association between Suicide Attempts and Selective
Serotonin
Reuptake Inhibitors: Systematic Review of Randomized Controlled
Trials,²
British Medical Journal (Feb. 19, 2005): Vol. 330, pp. 39699.
Hallberg
P, et al. ³The Use of Selective Serotonin Reuptake Inhibitors
during
Pregnancy and Breast-Feeding: A Review and Clinical Aspects,²
Journal
of
Clinical Psychopharmacology (Feb. 2005): Vol. 25, No. 1, pp. 5973.
Whittington
CJ, et al. ³Selective Serotonin Reuptake Inhibitors in Childhood
Depression:
Systematic Review of Published Versus Unpublished Data,² Lancet
(April
24, 2004): Vol. 363, No. 9148, pp. 134145.