Twenty-five years ago, Eli Lilly’s Prozac (fluoxetine) became the first selective serotonin reuptake inhibitor (SSRI) to hit the market, where it quickly gained popularity for the treatment of depression. Soon, the drug was earning more than a billion dollars in revenues—at a time when the average American’s income was around $25,000.
A quarter of a century later, treatments for depression are no more effective, but they are safer. Much has happened since the advent of fluoxetine, but as many as half of patients still do not receive relief in the idealized situations studied in clinical trials.
Why was fluoxetine so successful? According to John Markowitz, PharmD, Professor of Pharmacy at the University of Florida, “Its ease in dosing and lack of lethality in overdose made [fluoxetine] much more desirable compared to tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs] that dominated before Prozac.” SSRIs are safer than TCAs, but they do have underappreciated adverse effects.
C. Lindsay DeVane, PharmD, Professor of Psychiatry at the Medical University of South Carolina, noted that fluoxetine’s expanding indications and off-label uses for obsessive-compulsive disorder and anxiety disorders made brand-name Prozac as identifiable as Valium (diazepam—Roche). DeVane also attributed the drug’s widespread use and acceptability as factors in removing the stigma of depression.
On April 2, 2013, President Barack Obama announced the Brain Initiative—a project to map the function of the brain led by the National Institutes of Health (NIH), Defense Advanced Research Projects Agency (DARPA), and National Science Foundation. DARPA brought us the Internet, while NIH led the Human Genome Project. At the time, NIH Director Francis Collins, MD, PhD, made the analogy that while fixing the heart requires first understanding how that organ works, brain conditions are treated without knowing how the brain works. What really causes depression?
The neurotransmitters that should be targeted to treat depression are unknown. Brain problems are described as chemical imbalances, but targeting neurotransmitters might not be the best approach. Researchers initially hoped that promoting one chemical or inhibiting another would rebalance the brain, allowing psychiatrists to cure, for example, depression with a dose of serotonin or a mixture of other neurotransmitters. But as Markowitz told Pharmacy Today, “There is no evidence that depressed patients have low amounts of serotonin in their brains.”
As Obama said in his press conference announcing the Brain Initiative, “A brain contains almost 100 billion neurons making trillions of connections.” Collins likened understanding single neurons to listening only to the strings section and trying to figure out what the whole orchestra sounds like.
Perhaps the Brain Initiative will unlock the secrets of depression and other mental disorders. Markowitz theorized that just as congestive heart failure can be treated effectively with diuretics, which correct heart failure by affecting the kidney, similar indirect approaches targeting nonmonoamine neurochemicals may ultimately become the primary treatments for depression.
According to the American Psychiatric Association (APA) guidelines for the treatment of depression, different antidepressants are interchangeable for most patients. Response rates range from 50% to 75%. Health professionals choose antidepressants based on tolerability, safety, and cost, as well as patient preference and history of prior treatment, rather than relative effectiveness. Simultaneous conditions may also give an advantage for one drug or category over another.
During the last 25 years, many other antidepressants have entered the market. Multiple other SSRIs reached patients after fluoxetine, as well as serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine. Several other antidepressants are also available to patients; these include bupropion, mirtazapine, and nefazodone.
DeVane told Today that none of these drug classes display better efficacy than the others and that the same is true of the different SSRIs. Some patients find better results by switching to other antidepressants, he noted, but it is unclear why one drug sometimes works when others do not.
One of the latest trends in psychiatry has seen health professionals repurposing brand-name atypical antipsychotics for depression. In a recent meta-analysis published in PLOS Medicine, Glen Spielmans, PhD, and colleagues examined studies of atypical antipsychotics as adjunctive therapy for depression. Although these agents modestly lowered observer-rated symptoms, the authors questioned their value, noting that their “findings raise significant concerns regarding the impact of these medications in improving overall well-being.”
According to Spielmans and colleagues, despite the “small” improvement in depression severity, there was no evidence that atypical antipsychotics improved quality of life for patients with depression; in fact, they were often associated with harm, including weight gain and restlessness. In addition, these drugs are expensive. Markowitz described expanded use of antipsychotics for nonpsychotic depression as “a bad idea.”
Some patients and health professionals turned to the dietary supplement St. John’s wort (Hypericum perforatum), which seemed to hold promise for the treatment of depression. The passage of the Dietary Supplement Health and Education Act of 1994 led to a boom in the use of St. John’s Wort and other products. In 2002, however, a study funded by the National Center for Complementary and Alternative Medicine, National Institute of Mental Health, and NIH published in JAMA questioned its effectiveness, finding “no evidence for a superior effect … relative to placebo.”
St. John’s wort also burst perceptions that dietary supplements do not cause harm, even if they are ineffective. The supplement inhibits cytochrome P450 (CYP)3A4, which can render ineffective a number of drugs, including antiretrovirals for patients with HIV, immunosuppressants used after organ transplants, oral contraceptives, and other widely used medications.
Established guidelines help patients and health professionals manage antidepressant adverse effects. Some of these tips are practical, such as taking SSRIs with food or in divided doses to mitigate nausea. Other recommendations include taking SSRIs in the morning to deal with activation and exercising to manage weight gain—which may have an independent beneficial effect on depression.
Other adverse effects are more difficult to manage. Adding another drug, such as a beta blocker or benzodiazepine, to treat antidepressant adverse effects like restlessness can lead to other problems caused by polypharmacy. Switching to another drug may be a better strategy than adding medications to manage adverse effects.
Adverse effects caused by cessation of antidepressants is referred to as discontinuation syndrome instead of withdrawal because these drugs are not abused. Because of the widespread use of SSRIs, pharmacists and other health professionals must have a good understanding of this condition. Patients using antidepressants should have their dosages gradually reduced to avoid discontinuation symptoms. APA guidelines recommend a slow taper. Patients can also change to a brief course of fluoxetine before tapering.
Symptoms of discontinuation syndrome include flu-like symptoms such as nausea, headache, light-headedness, chills, and body aches and neurological symptoms such as paresthesia, insomnia, and electric shock–like phenomena. These symptoms typically resolve without specific treatment in 1 or 2 weeks but can lead to a misdiagnosis of another medical problem if a health care provider is not aware of a patient’s medication history or is unfamiliar with discontinuation syndrome. Because of the longer half-life of fluoxetine, patients who use this drug are less likely to experience severe discontinuation symptoms, while paroxetine is more likely to cause these adverse effects.
A potentially fatal drug reaction linked to SSRI use, serotonin syndrome is often difficult to diagnose. Symptoms include abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy, mental status changes, tremor and myoclonus, rhabdomyolysis, renal failure, and cardiovascular shock. Patients can experience serotonin syndrome from an antidepressant alone, but the condition usually occurs when patients use an antidepressant in combination with other drugs associated with serotonin release.
Make sure that patients do not use an MAOI concomitantly with an SSRI, as these two drugs carry a serious risk for serotonin syndrome. Other drugs, such as linezolid, tramadol, or a triptan, can also trigger this condition. Health professionals should be able to recognize serotonin syndrome and promptly stop use of the responsible agents; most cases are self-limiting.
Helen Fisher, PhD, a Rutgers University anthropologist, has theorized that SSRIs hinder normal relationships and love. By increasing serotonin and decreasing dopamine levels in the brain, Fisher argued, SSRIs blunt feelings of elation and love and may prevent patients from falling and staying in love.
SSRIs are also linked to sexual dysfunction, including decreased libido, decreased arousal, and anorgasmia. These adverse effects may be more common than originally thought, and serotonin may be the culprit. Sexual dysfunction in patients using antidepressants may be drug-induced or a symptom of depression, however. A lower dose may alleviate these effects but could also lead to decreased efficacy. Patients can try an alternative antidepressant, like bupropion, or antiserotonin agents, but the latter can contribute to polypharmacy.
Suicide is a possible outcome of untreated or undertreated depression, while suicidal ideation is thinking about killing oneself—and a possible adverse effect of SSRIs. Thoughts of suicide and the act itself are inseparable. It can be difficult to differentiate between depression and its treatment as the cause of these outcomes in some cases. Suicidal ideation and behavior can be caused by antidepressants, but can also result from lack of appropriate therapy.
Researchers have theorized that antidepressants may lead to suicidal behavior by giving patients the energy to act on their thoughts. Thus, health professionals should focus on this potential effect during the early phases of treatment, particularly for high-risk groups like adolescents and young adults.
David Angaran, MS, FCCP, FASHP, University of Florida Professor and founder of the school’s Medication Therapy Management (MTM) Communication and Care Center, commented that “sexual dysfunction will not kill you; suicide will.” As a result, the university’s MTM program focuses on monitoring suicidal ideation when antidepressants are started.
While treatments for depression can be effective, many patients do not receive relief. This represents a serious public health issue, because the National Institute of Mental Health has estimated that one in six people will experience depression in his or her lifetime.
Current therapies have limitations that may be difficult to recognize, like discontinuation and serotonin syndromes. Unfortunately, there are few novel therapies on the horizon. “New therapies will likely be much different than the existing treatments,” DeVane noted. “New receptor targets like nicotine receptors are being investigated to see if they have clinical utility.” It may be innovative efforts like the Brain Initiative that offer patients greater relief with fewer adverse effects in another 25 years.