DBS May Offer Best Hope for Treatment-Resistant Depression

Deborah Brauser

December 20, 2011

December 20, 2011 — Although treatment given in several sequential steps is commonly needed to achieve remission in patients with major depressive disorder (MDD), deep brain stimulation (DBS) may hold promise for future success, according to a review published online December 20 in the Lancet.

The investigators present developments over the last 5 years in the diagnosis, neurobiology, and treatment of MDD. Their review included assessing studies of psychotherapies, antidepressants, and new compounds, as well as treatment-related issues such as suicide risks and safety during pregnancy.

"Increased data for imaging and genetics… provide potential biomarkers for the assessment of treatment outcomes," write lead author David J. Kupfer, MD, from the University of Pittsburgh Medical Center and Western Psychiatric Institute and Clinic in Pennsylvania, and colleagues.

"If a description of precise subgroups based on such data was to emerge, short-term and long-term benefits of treatment might be improved," they add.

Dr. Kupfer, who is also chair of the American Psychiatric Association's Task Force for the upcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and colleagues note that "clear advances have been made" in MDD treatments, but none are currently considered to be "fully satisfactory."

Psychotherapy and Pharmacotherapy

According to the researchers, mean health scores for chronic diseases such as angina, arthritis, asthma, and diabetes are significantly worse when these diseases occur in patients with MDD.

"A crucial implication is that primary care providers should not ignore the presence of depression when patients have a chronic physical disorder," the investigators write.

They note that research continues to suggest that both depression-specific psychotherapy and pharmacotherapy are effective in treating MDD, either alone or in combination.

Several large studies published in the United States and Europe have also shown success with the use of interpersonal psychotherapy and cognitive behavioral therapy. Nontraditional forms of cognitive therapy, such as therapy conducted via the telephone or the Internet, have also proved to be successful and cost-effective in primary care offices.

Nevertheless, the use of antidepressants in the treatment of MDD continues to grow; they became the most commonly prescribed drug type in both general practice and hospital outpatient settings in 2005, write the investigators.

However, low rates of their use persist in racial and ethnic minorities.

STAR*D's Successive Steps

The authors also bring up the widely discussed sequenced treatment alternatives to relieve depression (STAR*D) study, "the largest depression study ever done outside the pharmaceutical industry."

In that study, up to 4 successive treatment steps were used, beginning with the prescribing of citalopram and then switching to or augmenting citalopram therapy with other medication or with cognitive therapy.

"Remission rates in steps one to four were disappointing at 36.8%, 30.6%, 13.7%, and 13.0%, respectively, with a cumulative remission rate of 67%," write Dr. Kupfer and colleagues.

They note that these rates were lower than expected, suggesting that "in actual practice, most patients need several sequential treatment steps to achieve remission."

"Because the switch to a different treatment is dependent on the patient's response to the first treatment, reassessment of design and methodological approaches is needed."

For psychotic depression, the researchers write that electroconvulsive therapy has been effective, and that antipsychotics and antidepressants are being used more frequently. They note that 2 recent studies have shown that combining the medications were more effective than treating with an antidepressant alone.

As for new strategies, they write that ademetionine augmentation and agomelatine have shown some benefits for patients with MDD, and repeated doses of intravenous ketamine have been effective for treatment-resistant depression.

SSRIs Lower Suicide Risk?

The investigators write that there is currently strong debate on a possible association between selective serotonin reuptake inhibitors (SSRIs) and the risk of suicidal ideation and behavior.

Although some studies have shown no increased risk, others have shown a reduced risk of suicide attempts in adults after starting treatment with an SSRI, particularly in men and especially with sertraline.

"Despite these findings, caution is needed against strong conclusions being made on the basis of limited ecological analyses," write the researchers.

During their discussion of SSRI use and safety risks during pregnancy, the investigators note that paroxetine could cause major fetal malformations, especially cardiac defects. SSRI use during late pregnancy has also been associated with persistent pulmonary hypertension in newborns.

In addition, babies were more likely to be born preterm after continuous exposure to SSRIs throughout gestation compared with babies with little or no exposure.

Therefore, guidelines "suggest that SSRIs should be used with caution during pregnancy and that paroxetine be avoided," write the authors.

The Promise of DBS

The investigators conclude their article with a discussion of the "promising" use of DBS for treatment-resistant depression, even though it is not yet approved by the US Food and Drug Administration (FDA) or the European Medicines Agency.

"Work has shown the antidepressant effect of deep brain stimulation when used within the subgenual cingulate white matter (Cg25WM), the nucleus accumbens, the subcollosal cingulated gyrus, and the ventral capsule or ventral striatum."

Nevertheless, they note that the risk of suicide should be monitored.

The FDA has approved transcranial magnetic stimulation for MDD, but repetitive use may be less effective than electroconvulsive therapy. In addition, although it has been found to be generally safe and well-tolerated, a rare side effect has been seizures.

"Although new reports about treatment response in multisite studies have emerged in the past 5 years, treatment advances are somewhat lagging because of an inability to undertake adequate studies with the appropriate predictors of response," write the investigators.

The review was supported by grants from the National Institute of Mental Health. Dr. Kupfer and 1 of the other 2 study authors have disclosed no relevant financial relationships. Co-investigator Ellen Frank, PhD, serves on an advisory board for Servier.

Lancet. Published online December 20, 2011. Abstract

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