In the more than quarter century since the arrival of Prozac, the drug that Newsweek’s cover once declared the “breakthrough drug for depression,” we’ve seen the landscape of the mental health field transformed by the extraordinary growth of the psychopharmacology industry. Combined sales of antidepressants and antipsychotics in the United States accounted for less than $500 million in 1987, but annual sales today exceed $29 billion. Currently, 1 in 8 people regularly takes psychotropic medications, 10 percent of the entire population over the age of 6 use some kind of antidepressant, and antipsychotics have replaced cholesterol-lowering agents as the top-selling prescription drugs. While the number of people in psychotherapy has declined over the past decade, the multibillion-dollar advertising offensive waged by the drug companies year after year has succeeded in convincing the media and the general population that many psychological problems are primarily the result of chemical imbalances within the brain.
Amid the many controversies surrounding the influence of the drug companies on the quality of mental health care, one important fact about the medications brought to market over the past 25 years has received little attention—few represented any real advance in the science of psychopharmacology or any real expansion of our understanding of how to regulate the nervous system with chemicals. Almost all of the so-called “new” drugs have targeted the same mechanisms of action as those already in use, with only slight modifications in potency, receptor selectivity, metabolism, rate of absorption, or other pharmacokinetic properties. Most of the new psychotropic medications approved in recent years have been me-too drugs, chemical cousins of medications already on the market, introduced to compete against another company’s medication within an existing chemical class of drugs, or to replace a company’s own drug that was about to lose its patent protection to generic equivalents. Yet almost none of these meds has proven to offer distinct advantages over existing, usually less expensive, agents.
Here, as in other aspects of the development of pharmacological approaches to mental health treatment, it’s important to acknowledge the role that business considerations, rather than scientific discovery or genuine improvements in treatment outcomes, play in determining what new medications come on the market and become available to clinicians. For the pharmaceutical industry, developing a me-too drug is less time-consuming and more profitable than developing a completely novel chemical entity aimed at a new target mechanism of action. When a drug designed to treat any given condition is profitable, the company that sells it has no incentive to put forth a competitor. However, when a drug is close to losing patent protection, the company has a great incentive to move patients taking it over to a newer agent, rather than lose them to the cheaper generic equivalent. For example, just before Celexa was to become available as a generic, its manufacturer launched Lexapro, which contains only the more pharmacologically active half of Celexa.
The economic reality for the pharmaceutical company is that once a drug loses its patent protection, generic versions of it begin to be sold by other companies for a tiny fraction of the cost of the branded product. When that happens, companies stop advertising that medication, new indications are no longer sought out, and—given that the overwhelming majority of drug trials are industry funded—no more clinical trials are conducted. The drug, in effect, is put out to pasture.
Sometimes, however, an old drug proves to have therapeutic potency for a condition other than the one it was originally designed to target. A striking example is the discovery that a blood-pressure medication called prazosin can reduce the nightmares, hyperarousal, and avoidance symptoms frequently associated with post-traumatic stress disorder (PTSD). But most people haven’t heard about this new clinically valuable use of the drug—and for a good reason. Prazosin is inexpensive and already available generically, so a multimillion-dollar advertising campaign won’t be launching on its behalf anytime soon.
After the seeming boom times of the past couple of decades, nearly every major company in the psychopharmacology industry has either significantly decreased or abandoned its psychiatric drug-discovery efforts. The industry has concluded that this area of research is economically too risky. From 1975 to 2005, the average cost to develop a new drug increased from $100 million to $1.3 billion (in adjusted dollars), with the cost for psychiatric drugs even higher. At the same time, the risk for failure continues to be steep. Nearly 80 percent of drugs fail to advance beyond Phase III, the last and most expensive preapproval phase of clinical human trials, because of lack of efficacy or safety concerns. Accordingly, the drug companies have chosen to allocate their resources in areas like cancer treatment and immunology, which they consider better business investments with fewer downsides.
So what lies ahead for psychopharmacology? Where might the new advances come from? How will all our growing understanding of the brain and the nervous system and other kinds of scientific discoveries get translated into the development of more effective medications with fewer side effects? Will previously unrecognized forces for innovation lead to newer and better treatments? It’s always difficult to predict developments in any field, especially one as shaped by economic factors as psychopharmacology, but progress is likely to come in three broad areas: pharmacogenomic medicine, vaccination, and mind-altering drugs.
Certainly not all efforts by the pharmaceutical industry have been directed to the low-hanging fruit of me-too drugs. Although most of today’s psychotropic medications are targeted at neurotransmitters like the monoamines—serotonin, norepinephrine, and dopamine—which are involved in a range of activities within the nervous system, there’s much scientific interest in newer, finer-tuned targets, which might lead to new classes of psychotropic medications with more robust efficacy and fewer side effects. Thus, some researchers are looking beyond the traditional monoamine targets to neuropeptides like Substance P and its neurokinin receptor, which appear to be involved in regulating stress and anxiety response.
Another target of some research activity is glutamate, an excitatory neurotransmitter that’s often disrupted in patients with depression. This kind of advanced research represents a more precise approach to drug-discovery efforts, as most of the medications currently on the market were first discovered serendipitously when someone noticed that a certain substance happened to affect certain symptoms. In fact, the psychiatric medications in use today work exclusively by treating symptoms, rather than modifying diseases or changing nervous system functioning in any fundamental way.
A related area of investigation that may offer the most exciting prospects for the future is pharmacogenomics research, an approach that seeks to fine-tune medication choice to match a person’s genetic makeup. This approach focuses on the connection between a person’s genetic markers and the likelihood that they’ll respond to some drugs and not others. By identifying at the beginning of treatment what medications have the best chance of working, we can move past the scientifically imprecise trial-and-error and one-size-fits-all prescription practices of today. Using pharmacogenomics testing results to guide clinical decisions could also improve care and lower costs by reducing the time to therapeutic response and avoiding unnecessary and costly drug trials.
We haven’t developed any crystal balls to help us determine the perfect drug for a patient, but we’re beginning to identify genetic markers that can tell us whether a person is a slow or ultrarapid metabolizer of enzymes, and that can help us determine how different medications are likely to be broken down in that person’s body. This information can help us decide what drug might be best suited for a given individual’s treatment. Such testing is still new—and, for many, too costly or simply unavailable—but we may one day reach the point where a simple blood test could be used in the standard prescription process, rather than the often unsystematic and intuitive procedures in use today.
One of the greatest medical breakthroughs of the last century was the development of safe and reliable vaccines, which virtually eradicated diseases such as smallpox, polio, diphtheria, tetanus, measles, mumps, rubella, and chickenpox. Might there be a role for vaccines in mental health? Vaccine development has shown promise in the treatment of substance abuse. This approach is based on the established finding that the faster a substance can enter the body, cross the blood–brain barrier, and activate the target neurotransmitters, the higher its potential for becoming addictive. Researchers are studying whether giving patients a medication that primes their immune system could slow down the rapid access of that drug into the brain and therefore reduce that substance’s reinforcing properties. As a result, ingesting that substance would produce an antibody that would reduce the brain’s response. Currently, clinical trials looking at nicotine and cocaine vaccines are under way. In the nicotine vaccine studies, subjects with a larger antibody response were likelier to quit smoking, without even being counseled to do so, than those with a lower antibody response.
A somewhat controversial area of psychopharmacology is cosmetic psychiatry, a term that refers to the use of drugs to achieve a more enhanced or desirable state. One example is the use of the antidepressant Wellbutrin for its effects of increased energy, motivation, and sex drive. Another is using Provigil for its ability to augment alertness and its cognition-enhancing effects. This category of drugs also includes Ritalin and Adderall, initially prescribed for use in people with attention-deficit disorders, which are increasingly used to heighten productivity and improve concentration and cognitive performance. In our highly competitive, achievement-oriented society, it’s inevitable that interest in the clinical use of cognitive and other performance enhancers will increase.
With the medicinal use of marijuana already legalized in 22 states, we’re likely to have more and more open discussion of the therapeutic uses of other recreational and currently illicit drugs. Already there’s a growing discussion of whether marijuana has a valid medicinal use in alleviating psychiatric symptoms. Many patients with depression, anxiety, and bipolar disorder claim that the recreational use of marijuana improves their mood and reduces anxiety, but there’s still no data to support such claims. In fact, the Institute of Medicine, the American Medical Association, the American Society of Addiction Medicine, and other organizations, oppose the use of marijuana for medicinal purposes. Supportive data thus far are limited to its effects as an appetite stimulant, antiemetic, and antispasmodic. Its use for psychiatric symptoms needs to be further studied, especially with respect to comparative efficacy, long-term effect on cognition, and risk for dependence. Nevertheless, several states already list PTSD as a qualifying condition for the use of medical marijuana.
Since the 1970s, some psychotherapists have championed the use of MDMA—popularly known as ecstasy—as an adjunct to therapeutic treatment because they believe it enhances communication during therapy by reducing the psychological defenses of patients and increasing their ability to look inward. Most recently, two small studies examining the use of ecstasy-facilitated psychotherapy in patients with PTSD have shown promising results. However, more and larger studies will be necessary before this intervention can be considered clinically.
The past quarter century could well be described as a golden age for shareholders in the psychopharmacology industry, but the same can’t be said for the mental health field. Remarkably steep increases in the use of psychiatric drugs have seen no corresponding increases in the rate of recovery from mental illness and no declines in the prevalence of anxiety, depression, and suicide. At the moment, no breakthrough discoveries of new cures are likely to transform our expectations for improved treatment results on the horizon. Whatever the message of drug-company advertising, it’s still clear that psychotropic medications target symptoms but don’t cure diseases or speak to all the needs that bring people to therapy. Thus, psychopharmacology hasn’t made the psychotherapists of the world irrelevant, nor is it likely to anytime soon.
For some people, especially those in extreme states of distress, psychopharmacology does offer symptomatic relief that can increase their receptivity to all kinds of influences that can enhance their well-being, including psychotherapy. So it’s important that therapists remain as informed as they can about the latest advances in what mental health benefits medications provide, as well as their limitations. But therapists also need to be aware of a range of other approaches that are proven to help clients regulate their own nervous systems and navigate life’s challenges. These approaches include exercise, mindfulness techniques, and mind–body practices. For now, with no new generation of magical pills—or any other kind of magical solution—on the horizon, that kind of broad perspective would appear to be the knowledgeable practitioner’s wisest alternative.
Illustration © Art Valero / Illustration Source
Talia Puzantian, PharmD, BCPP, is a clinical psychopharmacology consultant in a private practice based in southern California and works with clients globally. She lectures in various continuous education programs to health professionals across the country, reviews for Pharmacotherapy, and writes for The Carlat Psychiatry Report.