British Regulators Urge Physicians To Be Cautious in Prescribing SSRIs

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 (CSM).

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 medications.”

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 disease.”

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 patient.”

“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 treatment.”

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 or hypertension.

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 anxiety.

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 treatment options.”

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 online at<www.mhra.gov.uk/news/2004/SSRIfinal.pdf>. 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>.▪