Wednesday, October 01, 2003

Feeling Good About Antidepressants

Better Than Prozac: Creating the Next Generation of Psychiatric Drugs

By: J. Raymond DePaulo, Jr., M.D.


At its best, Better Than Prozac is like a conversation with a genuine expert about the psychiatric medications used to treat clinical depression and other disorders of mental life. Although it describes our current medicines and how they were discovered over the past 50 years, at the heart of the book is a vision of how better medicines can be developed with the use of emerging knowledge of genes and their actions in the brain.

Samuel Barondes, M.D., professor of psychiatry and neuroscience at the University of California at San Francisco, is a distinguished neuroscientist, psychiatrist, and scholar with some four decades of clinical and research experience. He has been chairman of the renowned department of psychiatry at his institution and is director of a large research institute. He is also author of Mood Genes: Hunting for Origins of Mania and Depression (W. H. Freeman and Company, 1998). In Better Than Prozac, he makes real to us the benefits and failings of today’s psychotropic drugs through the stories of patients, including his own. The stories are unusually effective because they are not before-and-after testimonials but biographical sketches of people who have used psychotropic medications wisely but nevertheless paid a price for the improvement they experienced. Their decisions to try medications reveal their determination not to give in to their illnesses, and they are understandably grateful for the progress, but they also hope for even better answers. Barondes himself is optimistic, but not unrealistically so, about the prospects for radical progress.

For readers who think that taking a drug is not the most intuitive strategy for improving one’s lot in life, Barondes clarifies when medications might be worth trying (when a patient has clear indications of clinical depression, bipolar disorder, or a similar condition). He presents the benefits of taking psychotropic medications, as well as the drawbacks (side effects), and a few of the predicaments that have resulted from changes in the patterns of patients’ thoughts and reactions to life.

For one patient whose story he tells, the decision to try Prozac presented a distinctly modern dilemma. Barondes did not view this patient, a young woman, as an ideal candidate for an antidepressant. He worried that the Food and Drug Administration-approved guidelines for prescribing it were met, in this instance, only marginally. As a result, the patient was in the position of coaxing her risk-averse physician to let her try Prozac. She reassured him that she was aware of the risks and skeptical of going back to psychotherapy as her sole recourse. She had become aware through years of recurrences of her depression that it was a physical ailment, not a normal response to life’s ups and downs. She also happened to be a philosophy major with considerable facility in arguing persuasively for what amounted to an empirical trial with a single patient—herself.

The good news from that trial was that Prozac has been of considerable benefit to her, but it is not a cure for her depression, and the benefits come at a cost. She suffers one of the few common side effects of this group of drugs—a palpable decline in her libido at just the time she would welcome it back. Yet she will not willingly go back to her more severe depressive state, so she takes Prozac and accepts for now the lessening of life’s carnal pleasures. She leaves Barondes in no doubt, however, that she wants us psychiatrists to find a better Prozac and to do so now.


Barondes would like his readers to understand, by the end of this small volume, that, although we owe our current psychotropic medications largely to “happy accident” observations, later confirmed by double-blind placebo-controlled trials, we most likely will owe future medications to systematic genetic and molecular research. The stories of discovery start in the 1950s, with antihistamines (the cold capsules and allergy medicines of a prior era). The first of two rather monumental happy accidents occurred in the process of modifying an antihistamine compound in hopes of reducing its side effects. The modification was a failure, but the experiment was a runaway success. Some of the patients who tried the modified antihistamine happened to have schizophrenia as well as stuffy noses and discovered that on this new “cold medication” they could no longer hear the voices of their tormenters, or not as clearly as before. Thus were born the original neuroleptic, or antipsychotic, medicines, thorazine being the first.

A few years later, a second happy accident occurred when a modified version of the new antipsychotic drug was developed. This chemistry experiment failed even more miserably than the first one. The modified antipsychotic drug failed to help with hallucinations; in fact, it made several of the schizophrenic patients quite agitated. Fortunately, the doctor in charge of the patients was an astute observer. If the new compound agitated schizophrenic patients, might it conceivably stimulate his lethargic depressed patients in a helpful way? He tried it. Most of the depressed patients improved rather dramatically in their energy, optimism, and ability to function. He wrote a paper summarizing his experience using the new compound with several hundred depressed patients, and the world greeted its first tricyclic antidepressant, imipramine.

Contrast this model of discovery with the paradigm that Barondes predicts will guide scientists seeking the next generation of medications. This is the paradigm called “molecular biology,” and it depends largely upon genetics research. James Watson and Francis Crick’s discovery in 1953 of the double-helix structure of DNA, our genetic material, and the later development of methods for identifying all genes within our DNA and observing how they direct the chemistry of our cells, have made molecular biology of brain functioning possible. The knowledge that Barondes expects will guide psychiatry includes knowledge of which genes (and their structural variations) make some of us vulnerable to depression and which genes regulate how humans respond to different medications. Call it progress, call it a paradigm shift; it is, in truth, a new epoch not so much of discovering cause and effect as of deliberately engineering it.

Barondes readily acknowledges that finding and proving how genes cause depression is, and will be, quite a challenge. Fortunately, we do not have to know all of this to start making improvements. With enough information about genes and the molecular biology of the brain, we will be able to try our hand at making our bodies produce greater or lesser quantities of particular proteins in order to change the chemistry of our cells. We will hope and expect that some of these changes will be very helpful to patients with disorders such as depression and schizophrenia. So are we back to happy accidents? Not quite. A simple example of how this can work is provided by diabetes mellitus. Children who develop diabetes lack the ability of particular cells in the pancreas to make insulin. To treat these children, we used to extract insulin from pigs and simply inject the child in the morning and sometimes at other times during the day. This treatment does not cure the child’s diabetes and is not a perfect way to manage it, but it has enabled these children to live and thrive into adulthood. Doing something similar could make an enormous difference in the lives of patients with depression or schizophrenia.

But let us go a step farther. The problem with injecting insulin is that it does not supply the insulin in the precise amount or at the precise times that a healthy pancreas would supply it to regulate glucose sugar perfectly. Knowledge of the stages of cell development has led to stem cell research, and one of the most promising applications of this research is giving children with diabetes some of these immature cells that have the capacity to find their way to the pancreas and turn into the pancreatic cells that make insulin normally. This process could be a giant step closer to getting the insulin in the right amounts at the right times. Progress will depend also on our ability to predict what adverse effects could result from these molecular manipulations and to develop strategies to minimize those effects. If we apply this kind of thinking to psychiatric medications, it might turn out that for a person with minimal ability to metabolize a new drug, we might need to give small doses of the drug in order to prevent toxicity. For persons with an excessive quantity of enzymes fueling their metabolism of a particular drug, we might need to give very large doses of the drug to get any benefit. The key will be to know how fast patients will metabolize the new drug before we give the first dose, not after.

Better Than Prozac succeeds on two important counts. Happy accidents did in fact occur and led to the discovery of valuable medications for schizophrenia, depression, and other illnesses; the molecular method for devising new medications has already worked in some areas of medicine—notably in cancer. To treat cancer, we have four categories of rational therapies: surgery (to remove some or all of the cancer), cytotoxic chemotherapy and radiation therapy (to destroy rapidly dividing cells such as cancer cells while causing relatively little harm to most healthy and more slowly dividing cells), hormonal therapies (to regulate the growth cues for cancer cells such as breast and prostate cancer cells that often have hormone receptors on their cell surfaces), and immune therapies that make the body more active in rejecting cancer cells as aliens. All of these strategies, with the exception of surgery, depend on some degree of genetic and molecular knowledge gleaned in the 30-year “War on Cancer.” A very high probability exists that this new paradigm for drug design will work for psychiatric conditions, as well. The major disorder described in this book, clinical depression, is now known to have genetic as well as environmental causes, so it is likely that drugs targeted to the action of some genes could have positive effects on the illness.


Are there other books to compare this one to?
Are criticisms possible? Are they important?
And do I wish I had written this book?
The short answers to the four questions are
Yes, Yes, Maybe, and You bet I do.

There are certainly many books about treatments for depression. They are mostly of three types: “How-to-do-it” manuals that detail benefits and side effects; books advocating a particular treatment for all depression, usually arguing from testimonials; and polemical volumes that argue against all or particular groups of medications. Better Than Prozac is none of these; it is about the changing nature of drug development for psychiatric disorders made possible by advances in molecular biology.

In its conversational style, Better Than Prozac resembles the popular book of exactly a decade ago, Listening to Prozac, by Peter Kramer. Both books use patient stories to bring the good and bad effects of treatment to life. Both authors are good observers and depict their patients in ways that symptom-rating scales and statistical analyses cannot hope to do.

Are criticisms possible? Yes. Are they important? For the most part, no. The title, Better Than Prozac, is less lively than the book. Having chosen it, however, Barondes probably should have taken note of the flurry of books that also have used Prozac in the titles and too often have frightened patients into stopping medications or inspired lawyers to defend clients accused of murder or to sue drug companies for the murders or suicides enacted by individuals taking a selective serotonin reuptake inhibitor (SSRI). Prozac, an antidepressant known to chemists as fluoxetine, was the original “American Blockbuster” antidepressant. Although not the first drug of the SSRI type, it was the first marketed in the United States and an enormous commercial success, earning an annual income of $2 billion for Eli Lilly and Company until its patent expired two years ago. Because of its market success and memorable name, it has been part of the title line for more than 20 books written for the general public. This is the most book titles earned by brain-active drugs since the discovery of morphine. 

The public should read Better Than Prozac because it is informative, lively, and accurate in its accounts of how antidepressants and other psychotropic drugs are used and why better ones are needed. Yes, Prozac is an effective antidepressant, helping 50 to 70 percent of patients, but it may surprise many readers that it is no more effective than the first antidepressant, imipramine, discovered in the 1950s. Instead, its virtues are its relatively benign side effects (lack of sexual responsiveness and sexual interest are most common) and, perhaps most important for its huge sales, the ease in prescribing and using it (one pill a day for almost all patients). Barondes makes it clear that science offers us powerful reasons, rooted in molecular biology, for optimism that soon we will have better, perhaps far better, treatments for many psychiatric disorders.  


From Better Than Prozac: Creating the Next Generation of Psychiatric Drugs, by Samuel H.Barondes. © 2003 by Samuel H. Barondes.Reprinted with permission of Oxford University Press.

The idea of chemical imbalance in the brain had come to Clara’s attention from extensive coverage of this topic in magazines and newspapers. Having read many articles about the behavioral effects of brain chemicals such as dopamine, norepinephrine, and serotonin, Clara was fascinated by the proposal that different balances of these and other chemicals might make people more or less confident or self-critical. The articles also heralded the arrival of new medications that could manipulate brain chemicals with scientific precision, thereby alleviating many forms of mental distress. For example, if someone had a deficiency of brain serotonin, it could be fixed by a medication that raised the level of serotonin to normal. Although Clara recognized that such claims might not be completely accurate, she longed for the relief that they promised— relief she had found hard to achieve by way of self-reflection and cognitive therapy.

It was, in fact, through the popular press that Clara first laid her eyes on the green-andivory pill call Prozac (fluoxetine), a great big zeppelin of a pill floating in welcoming clouds on the cover of a 1990 issue of Newsweek, along with the headline “A Breakthrough Drug for Depression.” Several years later she gobbled up Peter Kramer’s Listening to Prozac, which called attention to the widespread practice of prescribing this and other medications for people with levels of mental distress that seemed mild compared to her own. Although not everyone who wrote for the public was in favor of the burgeoning use of these new medications, it was hard to ignore the outpouring of testimonials.

Clara told me that she was particularly struck by Time magazine’s description of Susan Smith, “a [44-year-old] self-described workaholic [who] needs a little chemical help to be a supermom: she has been taking the antidepressant Prozac for five years.” In the October 11, 1993, article from Time, which Clara gave me, the author Anastasia Toufexis, went on to explain: “Smith never had manic-depression or any other severe form of mental illness. But before Prozac, she suffered from sharp mood swings, usually coinciding with her menstrual periods. ‘I would become highly emotional and sometimes very angry, and I really wasn’t sure why I was angry,’ she recalls. Charles [her husband] will never forget the time she threw her wedding ring at him during a spat. Now, says Susan, ‘the lows aren’t as low as they were. I’m more comfortable with myself.’ And she has no qualms about her long-term relationship with a psychoactive pill: ‘If there’s a drug that makes you feel better, you use it.’ ”

It was this article in Time that had persuaded Clara to think seriously about taking medications. The carefully folded article, which she had pulled from her briefcase, showed a photo of Susan Smith in a position of tranquil repose. Now that Clara had had her taste of psychopharmacology with a successful response to the sedative effect of amitriptyline, she said that she was ready for the next experiment. But an increased dose of amitriptyline was not appealing to her because the very same sedative effect that she was already using to good advantage at bedtime would make her sleepy throughout the day. Following the example of Susan Smith, Clara wanted to find out if she, too, would benefit from that new wonder drug, Prozac.  

About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Helen Mayberg, M.D., Icahn School of Medicine at Mount Sinai 
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine
Charles Zorumski, M.D., Washington University School of Medicine

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