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Dec 24, 2009

Part 1—Questions Remain about Whether Antidepressants Really Work

Significant side effects continue to plague currently available drugs, and efficacy is only seen in the most severely depressed patients.

  • Antidepressants have provided huge profits for pharmaceutical companies. Drug sales reached almost $11 billion in 2008, with Wyeth’s Effexor representing almost 36% of the market at about $3.93 billion. According to IMS Health, 164 million antidepressant prescriptions were written in 2008, an increase of 4 million over 2007.

    Other major players include GlaxoSmithKline (Paxil and Wellbutrin; $1.17 billion), Forest Laboratories (Lexapro, $2.29 billion), and Eli Lilly (Cymbalta; $2.697 billion). Several major therapies in the antipsychotic market have patent expiration dates before 2014, including Cymbalta (June 11, 2013) and Lexapro (March 14, 2012). When these therapeutics lose patent exclusivity, generics will offer psychiatrists cheaper medications to prescribe, substantially decreasing the market share enjoyed by the big brands. This has created a scramble for newer drugs to fill the money void that will be created by their diminishing returns.

    GEN is running a two-part series covering the antidepressant segment. In this first part, we analyze how currently available antidepressants work and whether this is enough. In Part 2, which will run on Wednesday, December 30, we’ll take a look at what’s coming down the pipeline.

    Currently Available Treatments

    The most popular drugs used to treat depression are either serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Wellbutrin, however, acts differently, affecting dopamine reuptake as well. SSRIs and related drugs work by preventing the presynaptic neuron reuptake of serotonin, thereby maintaining higher levels of neurotransmitters in the synapse between neurons. The resulting increase in communication between and among neurons is said to result in improved mood elevation.

    Antidepressants are often the first treatment choice for adults with moderate or severe depression—not because they cure depression, but because they can help patients achieve remission, according to the Mayo Clinic. SSRIs offer physicians and patients relatively safer therapeutic alternatives for depression compared to older tricyclic antidepressants (TCAs) that also work by inhibiting the reabsorption of serotonin and norepinephrine by brain cells (and, to a lesser extent, that of dopamine).

    SSRIs, the first of which was Prozac marketed in 1987, were developed as more selective agents that would inhibit serotonin reuptake without affecting other neurotransmitters that are affected by TCAs, including histamine, acetylcholine, and alpha-1 adrenergic receptors.

    The Hype Surrounding Antidepressants

    Despite their profitability and popularity, though, questions about how many people SSRIs really help and concerns about their significant side effects won’t go away. Some studies say that more than half the people who take antidepressants never get relief. Drug-placebo efficacy differences increase as a function of baseline severity but are relatively small even for severely depressed patients, according to a study conducted by Irving Kirsch, Ph.D., a professor of psychology at the University of Hull, U.K., and professor emeritus at the University of Connecticut.

    Additionally, the relationship between initial severity and antidepressant efficacy is often attributable to decreased responsiveness to placebo among very severely depressed patients rather than to increased responsiveness to medication. “There seems little reason to prescribe antidepressant medication to any but the most severely depressed patients,” Dr. Kirsch commented in his paper titled “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration,” which appeared in PLoS Medicine in February 2008.

    In another 2008 report published in The New England Journal of Medicine, Erick H. Turner, M.D., of Portland VA Medical Center and his colleagues said that the effectiveness of a dozen popular antidepressants had been exaggerated by selective publication of favorable results. According to published literature, it appeared that 94% of trials conducted were positive. By contrast, when Dr. Turner’s team included unpublished data submitted to the FDA, 51% of trials had positive results.

    The researchers found that a total of 37 studies viewed by the FDA as having positive results were published, and one study viewed as positive was not published. On the other hand, three studies viewed by the FDA as having negative or questionable results were published, 22 negative studies were not published at all, and 11 were published in a way that, in the authors’ opinion, conveyed a positive outcome. The selective data publication presented doctors and patients with a less-than-accurate picture of how such drugs actually work, the authors concluded.

    The currently available antidepressants have a range of adverse effects including nausea, sleep disturbance, fatigue, anxiety, sexual dysfunction in men, and suicidality. As with many medications that may be required chronically by otherwise healthy people, the side-effect tolerance level is lower than for medications for critically ill individuals. The resulting increase in FDA scrutiny makes it harder to get these drugs to market. Another drawback is that most typical antidepressants have a delayed onset of action (2–6 weeks) and are usually administered for anywhere from months to years.

    Now pharma companies are mixing stronger medicines, or at least different ones, with antidepressants as adjunctive therapies. On December 4, AstraZeneca got the nod from the FDA for a label extension for once-daily Seroquel, which is approved for management of schizophrenia, bipolar I mania, bipolar I depression, bipolar II depression, and used off-label for a variety of other purposes including insomnia and anxiety disorders. For AstraZeneca, Seroquel 2008 revenues were up 11% over 2007 to $4.452 billion. U.S. sales were $3.02 billion, a 5% increase over 2007.

    The latest sanction includes the use of Seroquel as an adjunctive treatment to antidepressants in adults with major depressive disorder. The agency also required that AstraZeneca implement a Risk Evaluation and Mitigation Strategy through a medication guide and periodic assessments that will include a survey of patients' understanding of the potential risks of the drug.

    Basic research over the past several years, however, is changing the perception of what antidepressants should target and revealing newer molecular targets. Part 2 of this article will discuss perception-altering studies and some novel antidepressant targets under development.

     


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