What are the real risks of antidepressants?
the real risks of antidepressants?
(This article was first printed in the May
2005 issue of the Harvard Mental Health Letter.
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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 world’s
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 drug’s 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. John’s
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
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. “Discontinuation
syndrome” is a better description than “withdrawal
reaction,” a phrase associated with addiction.
The syndrome is usually (but not always) mild
and brief, peaking in the first week and quickly
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
mother’s 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
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
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 children’s growth or
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
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. It’s 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
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and Pediatric Depression — The Risk
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Serotonin Reuptake Inhibitors: Systematic
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Medical Journal (Feb. 19, 2005): Vol.
330, pp. 396–99.
Hallberg P, et al. “The
Use of Selective Serotonin Reuptake Inhibitors
during Pregnancy and Breast-Feeding: A
Review and Clinical Aspects,” Journal
of Clinical Psychopharmacology (Feb.
2005): Vol. 25, No. 1, pp. 59–73.
Whittington CJ, et al. “Selective
Serotonin Reuptake Inhibitors in Childhood
Depression: Systematic Review of Published
Versus Unpublished Data,” Lancet (April
24, 2004): Vol. 363, No. 9148, pp. 1341–45.
For more references, please see www.health.harvard.edu/mentalextra.