The United Kingdom's equivalent of the U.S. Food and Drug Administration
(FDA) issued sweeping warnings on the safety of selective serotonin reuptake
inhibitor antidepressants last month.
The warnings were issued in a report from the Medicines and Healthcare
Regulatory Products Agency's (MHRA) Committee on the Safety of Medicines
The CSM report, titled the "Expert Workgroup Report on SSRIs,"
confirmed that "SSRIs are effective medicines in the treatment of
depression and anxiety conditions, and the CSM has concluded that the balance
of risks and benefits of all SSRIs in adults remains positive in their
licensed indications." However, the work group believed that the MHRA
should give prescribers "clear advice" regarding "withdrawal
reactions, dose changes, and suicidal behaviors associated with the
In some sense, the new U.K. guidelines are "more balanced and
thoughtful than the FDA's black-box warnings on SSRIs," noted Darrel
Regier, M.D., M.P.H., executive director of the American Psychiatric Institute
for Research and Education and director of APA's Division of Research."
They start by recognizing that depression is a serious illness and that
suicidal ideation is a component of the illness."
The work group noted a series of "key findings" regarding the
use of SSRIs in adults. First, "careful and frequent monitoring by
health care professionals.. .is important in the early stages of treatment,
particularly if a patient experiences worsening of symptoms or new symptoms
after starting treatment."
The work group recommended that adult "patients should be monitored
around the time of dose changes for any new symptoms or worsening of
Moreover, "All SSRIs may be associated with withdrawal reactions on
stopping or reducing treatment." The report pointed out that paroxetine
(Paxil) and venlafaxine (Effexor) "seem to be associated with a greater
frequency of withdrawal reactions." Common symptoms of withdrawal
reactions include dizziness, numbness and tingling, gastrointestinal
disturbances (notably nausea and vomiting), headache, sweating, anxiety, and
sleeping difficulties. The work group strongly recommended that doses be
slowly tapered to minimize symptoms and risk.
In particular, the report noted "patients should be monitored for
signs of restlessness and agitation at the beginning of treatment" and
if they occur, "increasing the doses... may be detrimental."
With regard to the use of SSRIs in children and adolescents, the work group
continues to believe that "the balance of risks and benefits for the
treatment of depressive illness in under 18s is judged to be
unfavorable" for paroxetine, venlafaxine, sertaline (Zoloft), citalopram
(Celexa), escitalopram (Lexapro), and mirtazapine (Remeron).
"Only fluoxetine (Prozac) has been shown in clinical trials to be
effective in treating depressive illnesses in children and adolescents,
although it is possible that, in common with the other SSRIs, it is associated
with a small increased risk of self-harm and suicidal thoughts."
In addition to releasing the work group report, the CSM also"
considered the risks and benefits of [venlafaxine] because of concerns
about cardiotoxicity and toxicity in overdose."
The CSM strongly recommended that venlafaxine "be initiated [only] by
specialist mental health practitioners, including GPs with a special interest,
and there should be arrangements in place for continuing supervision of the
"This purported higher toxicity with overdoses [of venlafaxine] is
something most clinicians in the United States may not be aware of and is a
finding that should be confirmed by replication," observed APA's Regier."
If found to be true, it should be communicated clearly that lower
quantities of the medication should be prescribed early in the course of
However, Regier noted, the suggestion that prescription of venlafaxine be
limited to certain skilled individuals is "somewhat unusual." He
added, "Tricyclic antidepressants have no such restriction and arguably
have much higher risks of cardiac arrhythmias than venlafaxine."
The CSM further said that venlafaxine is contraindicated "in patients
with heart disease," such as heart failure, coronary artery disease,
electrocardiographic abnormalities, and patients with electrolyte imbalances
The U.S. labeling for venlafaxine has cautioned prescribers for years about
the use of the drug in patients with hypertension; however, the labeling does
not address electrocardiographic abnormalities.
In conjunction with the CSM's release of added warning language, the U.K.'s
National Institute for Clinical Excellence (NICE) issued guidelines for the
U.K. National Health Service on the treatment of patients with depression and
Notably, the depression guideline recommends that for "mild and
moderate depression, psychological treatments specifically focused on
depression (such as problem-solving therapy, cognitive-behavioral therapy, and
counseling) can be as effective as drug treatments and should be offered as
Specifically, the guideline states that "antidepressants should not
be used for the initial treatment of mild depression, because the risk-benefit
ratio is poor." Conversely, for depression that is moderate or severe,
the guidelines specifically note that an SSRI should be prescribed,"
because SSRIs are as effective as tricyclic antidepressants, and their
use is less likely to be discontinued because of side effects."
The depression guideline goes on to note that patients must be properly
informed about "discontinuation/withdrawal symptoms" and urges
that "for severe depression, psychological treatment should be used in
combination with antidepressant medication."
The new anxiety guideline recommends that patients be offered (in
descending order of long-term effectiveness) psychological therapy, such as
CBT; medication, such as an SSRI; and "self-help, such as bibliotherapy
(the use of written materials) based on CBT principles."
The anxiety guideline also notes that a strong therapeutic alliance often
greatly benefits patients with anxiety disorders and that access (including
support groups) to information is often a powerful support tool.
"The MHRA's Expert Workgroup Report on SSRIs" is posted
The NICE guideline on depression is posted at<www.nice.org.uk/page.aspx?o=235367>,
and the anxiety disorders guideline is posted at<www.nice.org.uk/page.aspx?o=235400>.▪