Are New Classes of Antidepressants Really More Effective?

doctorsIn 1990, the year when Prozac became the first drug ever to be featured on the cover of a major U.S. news magazine, a turning point in psychopharmaceutical history was established. Introduced in 1988, it was hailed as a breakthrough drug for the treatment of depression. Two years later it was the most widely prescribed medication in this country.

Prozac may have emerged as a 20th century star, but the oldest class of antidepressants, the cyclics such as Tofranil and Elavil, dates back to the early 1950s. All of the antidepressants are used to treat a range of disorders besides depression. They have proven efficacy and effectiveness in the management of anxiety, bulimia, chronic pain, obsessive compulsive disorder, panic, and as adjuncts to mood stabilizers in bipolar disorder. All of the antidepressants have similar efficacy, and most of them have different side effects. Therefore it makes sense for many clients to choose their own initial antidepressant based on what side effects they are willing to accept.

At least 50 percent of clients who will respond to antidepressants begin to demonstrate improvement within the first few days to a week of treatment. Remission of depressive symptoms is much tougher to accomplish and may span over an 8-12 week period. Achieving remission is critical because clients who do improve but continue to experience residual symptoms of depression are twice as likely to relapse, worsening their disability and increasing the risk of suicide. Antidepressants should be used prudently in the management of depressive symptoms associated with bipolar disorder, so clients who do not improve on antidepressants or even get worse would likely benefit from a diagnostic re-assessment for bipolar.

Major Study Shows Successes and Challenges

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) is the largest independently funded clinical trial for depression. The study’s primary objective was to develop a series of evidence-based steps intent on guiding prescribers in making sequenced treatment choices to enhance the odds of response rates and subsequent remission. The six year study included approximately 3000 clients. Initial results, published in 2006, provided the following information: expect about 30 percent of depressed clients to achieve remission on their first antidepressant trial with competent care. With subsequent trials, expect a total remission rate of about 60 percent; however with treatment dropouts considered, only 40-50 percent respond. But even after achieving full remission, relapse rates are high in that only 43 percent of subjects realized sustainable recovery. Also, with quality care, there is no difference in outcome whether the client was treated by a psychiatrist versus a primary care physician. The bottom line: treating depression is not easy!

Have Antidepressant Options Improved Over Time?

Cyclics Broke New Ground but Caused Cardiac and Memory Complications. The cyclic antidepressants, also referred to as tricyclics, are among the oldest group of antidepressants dating from the 1950s. Tofranil, Elavil and Anafranil for example, were the preferred treatments from the 1950s to the late 1980s. Although considered very effective medications, the cyclics are fraught with side effects that render them intolerable for many clients. Cardiac conduction problems purportedly led to six sudden deaths when used in children and adolescents. Their use in the elderly contributed to memory loss and confusion, often leading to falls in this population group.

MAOIs Caused Food and Drug Interactions. The Monoamine oxidase inhibitors Parnate and Nardil are considered quite clinically effective, but fell flat due to their numerous and potentially serious drug-drug and drug-food interactions. In 2006, a monoamine oxidase inhibitor transdermal delivery system (patch) called Emsam became available. Particularly at lower doses, this delivery system is associated with fewer of the drug-drug and drug-food side effects when compared to the oral administration of the MAOIs. So it is safe to say, by contemporary treatment standards, the cyclics and the MAOIs are no longer vogue.

Popular SSRIs Offer Ease of Use but Increase Discontinuation Concerns. The Selective Serotonin Reuptake Inhibitors (SSRIs) are indeed popular – one of the most famous, Prozac, ending up on the cover of Newsweek magazine. Other SSRIs include Zoloft, Paxil, Celexa, Luvox and Lexapro. These antidepressants work by selectively enhancing the actions of the neurotransmitter serotonin. Advantages of the SSRIs include few anticholinergic effects (less dry mouth, blurred vision, constipation, urinary retention and confusion), safety in overdose, easy dosing (usually once daily) and few cardiac side effects. The side effects of the SSRIs include some sexual dysfunction, initial anxiety, agitation and sleeplessness, and a discontinuation syndrome – shock-like sensations, brain “zaps,” tremor, nausea, irritability and flushing, particularly if stopped abruptly.

Cymbalta and Other SNRIs Add an Extra “Punch” Beyond SSRIs. The Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are considered dual-action antidepressants in that they enhance the actions of serotonin and norepinephrine. In this group are Effexor, Cymbalta and Pristiq. The model drug in this category is Effexor. In 1994, it was marketed as “Prozac with a punch.” The “punch” refers to Effexor’s probable activating effects on norepinephrine at doses of 150mg. or higher. At doses of less than 150mg., Effexor behaves like the SSRIs. Effexor has no anticholinergic side effects and is not sedating. It may raise blood pressure especially at daily doses of 225mg. or higher, may cause anxiety and sexual side effects similar to the SSRIs, and is possibly fatal in overdose. Cymbalta became available in 2004. This medication has dual indications for the treatment of depression and diabetic neuropathic pain. It is also demonstrating promising results in the management of chronic pain and stress urinary incontinence. Side effects are similar to the SSRIs, most frequently clients report nausea, dizziness, sleeplessness and changes in appetite. Hepatotoxicity (hepatitis, jaundice) have also been noted.

Is Pristiq a Real Improvement Over Effexor XR? The newest entry into the antidepressant market is Pristiq (desvenlafaxine). Pristiq (desvenlafaxine) is in the SNRI category of antidepressants and is manufactured by the Wyeth Corporation. This drug received FDA approval in March, 2008. Faced with the fact that Wyeth is losing patent protection for its top-selling antidepressant Effexor XR, the company needed a brand product that would potentially replace some of the revenue loss when Effexor XR goes generic in 2010. Sales of Effexor XR in 2007 hovered around 3.8 billion dollars (New York Times, March, 2008). Wyeth claims that Pristiq has distinct advantages over Effexor XR. Among them are that patients can begin taking Pristiq at the therapeutic dose of 50 milligrams thereby circumventing the “start low, go slow” gradual increases associated with determining the appropriate dose for a client. Another advantage of Pristiq, according to Dr. Philip Ninan, a Wyeth vice president for neuroscience, is that Pristiq is unlikely to interact with other medications metabolized by the liver. But several analysts are skeptical of Pristiq, claiming that it has not set itself apart from other antidepressants on the market, and that its release appeared primarily to have the drug serve as a “patent extender” for Effexor XR. This is because Pristiq is a primary active metabolite of Effexor, meaning Pristiq is the chemical compound that results after Effexor is taken, metabolized and processed by the body. Interestingly, Wyeth is also seeking FDA approval for the use of Pristiq in decreasing menopausal related hot flashes. The most commonly reported side effect of Pristiq is nausea. Also, blood pressure needs to be monitored.

The “Others” – Wellbutrin, Zyban, and Remeron. The atypical antidepressants don’t fit neatly into an antidepressant family as the others do. The most noteworthy drug in this category is Wellbutrin. Wellbutrin exerts no effect on serotonin and has only a modest effect on the neurotransmitter norepinephrine. This medication’s effectiveness as an antidepressant is likely linked to its action on the chemical dopamine. Wellbutrin is referred to as a dopamine and norepinephrine reuptake inhibitor (DNRI). Some studies suggest that Wellbutrin does not destabilize the moods of bipolar patients, resulting in fewer of them tipping into mania or rapid cycling. The most frequently reported side effects of Wellbutrin are anxiety and insomnia. It is less likely than the SSRIs and SNRIs to cause weight gain and is associated with few, if any sexual side effects. Zyban is a slow-release form of Wellbutrin that has been approved by the FDA as a treatment for smoking cessation. A dosage of 150mg. twice daily is recommended to help people abstain from smoking and avoid subsequent weight gain. Remeron works indirectly on the norepinephrine and serotonin neurotransmitter systems. It seems to help with the anxiety and sleep problems common to depression. With Remeron, however, weight gain due to an increase in appetite is very common. In rare instances, Remeron can decrease white blood cell counts in susceptible clients.

The Real Facts about Antidepressants and Suicide

Since 2004, all antidepressants on the U.S. drug market have carried an FDA “black box” warning on the packaging. This label states that there is a possible risk of suicide when used by children and adolescents. We are left with a considerable amount of uncertainty regarding the use of antidepressants, especially in young people under 18. There seems to be evidence that suicidal ideation may emerge during the early phases of treatment with antidepressants. There is no evidence though that this increases the risk of completed suicide. (No suicides in 4000+ children in any of these studies). Interestingly, completed suicides have fallen during the last 10 years and this just happens to coincide with rising usage of antidepressants in this population group.

For Social Workers

With antidepressants playing an increasingly pivotal role in the treatment of depression, the challenges faced by social workers are increasing. Non-medical clinicians are the majority providers of mental health services in the United States, so a working knowledge of the different types of antidepressants, their side effects, and their benefits can help social workers monitor such issues as compliance and other medication-related challenges. Ideally, medication prescribers and non-prescribers alike will work together to implement treatment strategies geared specifically toward improving client outcomes. Stay tuned for more information and analysis in future articles regarding the parameters associated with psychotropic medication selection.


Joe Wegmann is a licensed clinical social worker and a clinical pharmacist with over 30 years of experience in counseling and medication treatment of depression and anxiety. Joe’s new book, Psychopharmacology: Straight Talk on Mental Health Medications is available at To learn more about Joe’s programs or to contribute a question for Joe to answer in a future article, visit his website at, or e-mail him at