We’ve Come a Long Way – Or Have We?

Contemporary antidepressants promise greater effectiveness over their predecessors. But do they really deliver?

With antidepressants playing a pivotal role in the treatment of depression, the challenges faced by clinicians are increasing. For this reason, a working knowledge of the different types of antidepressants, their side effects, and their benefits can help clinicians monitor 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.

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. But remission of depressive symptoms is much tougher to accomplish and may span an 8- to 12-week period. Achieving remission is critical, however, 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. Clients who do not improve on antidepressants – or even get worse – would likely benefit from a diagnostic re-assessment for bipolar.

A recent major study of antidepressants shows both successes and challenges. Called the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), it is the largest independently funded clinical trial for depression. The study’s primary objective was to develop a series of evidence-based steps for guiding prescribers in making sequenced treatment choices to enhance the odds of response rates and subsequent remission. The six-year study included approximately 3,000 clients. The initial results, published in 2006, find that about 30 percent of depressed clients 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 percent to 50 percent respond. But even after achieving full remission, relapse rates are high: Only 43 percent of subjects realized sustainable recovery. Also, given quality care, there is no difference in outcome whether the client was treated by a psychiatrist or a primary care physician. The bottom line: The pharmacological treatment of depression is downright challenging!

Improving Options?

In 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, Prozac was hailed as a breakthrough drug for the treatment of depression. Two years later, it was the most widely prescribed medication in the United States – and on the cover of Newsweek.

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 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. But while all antidepressants have similar efficacy, 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.

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 the cyclics are considered very effective medications, they 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. Also, the use of cyclics among the elderly contributed to memory loss and confusion, often leading to falls in this population group.

Similarly, while the monoamine oxidase inhibitors Parnate and Nardil are considered quite clinically effective, they 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. By contemporary treatment standards, the cyclics and the MAOIs are no longer in vogue.

Another category of antidepressants, Selective Serotonin Reuptake Inhibitors (SSRIs), are indeed popular – they include Prozac. 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. Side effects may include 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.

Another group, 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 150 mg or higher. At doses of less than 150 mg, 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 225 mg 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.

Enter Pristiq

Manufactured by the Wyeth Corp., this drug received FDA approval in March 2008. It too is in the SNRI antidepressant category.

Wyeth developed Pristiq at the same time it faced the loss of patent protection on its top-selling antidepressant, Effexor XR. In 2007, sales of Effexor XR hovered around $3.8 billion, according to a March 2008 article in the New York Times. But Wyeth’s patent on Effexor XR will end in 2010, when the drug goes fully generic.

Wyeth says Pristiq has several distinct advantages over Effexor XR. One is that patients can begin taking Pristiq at the therapeutic dose of 50 mg, 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. The most commonly reported side effect of Pristiq is nausea. Also, blood pressure needs to be monitored.

But several analysts are skeptical. They say Pristiq 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. They also point out that Pristiq is a primary active metabolite of Effexor. In other words, Pristiq is the chemical compound that results after Effexor is taken, metabolized and processed by the body. It’s worth noting that Wyeth is also seeking FDA approval for the use of Pristiq in decreasing menopause-related hot flashes.

The “Others”

A group of atypical antidepressants don’t fit neatly into any one antidepressant family. The most noteworthy drug in this category is Wellbutrin. It exerts no effect on serotonin and has only a modest effect on the neurotransmitter norepinephrine. Instead, 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 150 mg twice daily is recommended to help people abstain from smoking and avoid subsequent weight gain.

Aplenzin (bupropion hydrobromide) was approved by the FDA) in April 2008. Sanofi-aventis U.S., markets the product in the United States and Puerto Rico. The Aplenzin (bupropion hydrobromide) 522 mg dose is the only FDA-approved single-tablet, once daily treatment equivalent to 450 mg of Wellbutrin (bupropion HCl) therapy.

Oleptro ( trazodone extended-release), approved by the FDA in February 2010, is a long-acting offspring of the popular immediate-release antidepressant trazodone. Oleptro (trazodone extended-release) sports a combination rapid and sustained-release technology that claims to maintain blood levels within therapeutic range for 24 hours, potentially reducing the incidence and severity of side effects while maintaining efficacy in the treatment of major depressive disorder in adults.

Available in Europe but not yet in the U.S., Valdoxan (agomelatine) is the first melatonergic antidepressant. The drug activates specific melatonin receptors (MT-1, MT-2) in the brain. Valdoxan (agomelatine) claims to improve sleep disruption without affecting daytime vigilance by exerting specific actions on the regulation of circadian rhythms. The recommended starting dose is 25mg, once daily.

The big Pharma company Novartis owns the rights to market Valdoxan (agomelatine) in the United States, but lists the drug as scheduled for submission to the FDA for possible approval no earlier than 2012.
Another atypical, 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.

Antidepressants and Suicide Risk

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, however, that this increases the risk of completed suicide. (There were no suicides among the 4,000+ children in any of these studies.) On the other hand, the number of completed suicides has fallen during the last 10 years, and this just happens to coincide with rising usage of antidepressants in this population group.


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, www.pesi.com. To learn more about Joe’s programs or to contribute a question for Joe to answer in a future article, visit his website at www.thepharmatherapist.com, or e-mail him at joe@thepharmatherapist.com.