CHAPTER ONE

Prozac Backlash

Overcoming the Dangers of Prozac, Zoloft, Paxil, and Other Antidepressants With Safe, Effective Alternatives

By JOSEPH GLENMULLEN

Simon & Schuster

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The Awakened Giant's Wrath (Risking Brain Damage)





Maura: A Case of Disfiguring Tics

Late in her therapy, Maura took to lying back in the chair in my office, so relaxed she looked as if she drifted into a peaceful, tranquil state as we spoke. This involved a whole ritual for Maura: taking off her glasses and gently placing them on the small table beside the chair, leaning her head back into the soft headrest, closing her eyes, and relaxing her body, which seemed to melt down into the chair.

I would especially watch Maura's face at these times. A thirty-nine-year-old native of Ireland, Maura had milk-white skin and soft, delicate features framed by ringlets of auburn hair. As she continued to converse, reminiscing about her past, her face was a study in repose.

Unfortunately, this peace, hard won throughout a year of psychotherapy, was shattered by a chance observation on my part as I gazed at Maura's face. Suddenly I began to notice intense twitching all around her eyes. Her closed eyelids pressed more tightly shut. Waves of muscular contractions circled around her eyes. Bursts of this abnormal twitching punctuated periods of relative calm in which the muscles appeared to relax with just faint background activity.

How long had this twitching around Maura's eyes been present? I wondered. Was I just imagining that it was new? But I had been scrutinizing her resting face for months. Surely I would have noticed before. After I had observed the distinctive twitching for a number of weeks, I began to look for it when Maura was sitting upright with her eyes open and glasses on. Sure enough, the twitching was present at this time, too.

The image of Maura lying with her head as though on a pillow with twitches dancing around her eyes like fire came to haunt me because of what it portended. Maura had been in treatment with me for nearly a year. She originally had come for a second opinion about her medication, and had decided to stay on as a psychotherapy patient. The year before, her primary-care doctor had put her on Prozac for mild depression, because of her complaints of feelings of anxiety and tearfulness whenever she drove on highways. In two brief follow-up appointments, her doctor had doubled Maura's dose to 40 milligrams a day and given her a year's prescription for the drug. Primary-care doctors often see patients just once a year for an annual checkup. They frequently write year-long prescriptions for a host of drugs, from blood pressure medications to birth control pills. So when they prescribe serotonin boosters, writing a year's supply fits the routine for primary-care doctors even though this is not really appropriate to psychiatric drugs. At the end of the year, Maura consulted with me.

Maura grew up in war-torn Northern Ireland, in the small town of Ballymena. When she was eleven years old, she and her parents were innocent victims of a car bomb that exploded while they were driving to Belfast. Maura was badly injured, but she survived both the explosion and the trauma of witnessing the brutal death of both her parents. After living with an aunt for several years, Maura first came to the United States while in college. At the time that I met her, she was living in a Boston suburb with her American husband and their two daughters. As we pieced together her long-ignored, painful history, Maura realized that her depression began shortly before her elder daughter's tenth birthday. Like many parents, Maura would occasionally find herself daydreaming about what her life had been like at an age similar to her child's. As we talked, she realized her daughter was approaching the age Maura had been when her parents died. Her sudden sense of sadness and loss was worst while driving on highways, perhaps because it was a reminder of the fateful trip from her town into the city of Belfast. After several difficult months of reliving some of her traumatic memories and gaining a greater understanding of her symptoms, Maura gradually achieved the calm I was seeing when she leaned back in the chair. In anticipation of the well-earned end of therapy, we had decided to take Maura off Prozac and had lowered her dose from 40 to 20 milligrams.

"Have you noticed your eyes twitching lately?" I asked after observing the phenomenon for several weeks.

"No," said Maura, surprised.

I decided to write off the twitching as an anomaly, although now I wish I had made more of it. Not that this would have changed Maura's clinical course. A week later we stopped the Prozac. Prozac is a particularly long-lasting drug, lingering in the body for weeks. Two weeks after her last dose Maura called one day, frantic. "Something dreadful is happening to me," she said. "I need to see a neurologist. My lips are twitching and my tongue keeps darting out of my head." I told Maura that I would make time to see her, and to come to my office immediately. When she came, I was flabbergasted to see Maura's symptoms firsthand. Her lips now displayed twitching similar to that which I had observed around her eyes. But worst of all was the tongue-darting: fly-catcher-type movements in which her curled tongue darted in and out. The tongue-darting together with the twitching was disfiguring.

"Have I had a stroke? Do I have a tumor?" asked Maura, distraught.

"No," I said. "I don't think so. I believe this is a medication side effect."

"A medication side effect?" said Maura, dumbfounded.

"Yes. It looks like a tic disorder called tardive dyskinesia."

"Tar...what?"

"Tardive dyskinesia. It's a medication-induced tic disorder."

"But I'm not on any medication. I've just stopped the Prozac."

Could Prozac be causing Maura's tics? I wondered. I hadn't heard of Prozac causing these tics, but I had a lot of experience with them in association with major tranquilizers.

"I don't know why you're having these symptoms," I said, "but with other drugs they often worsen or emerge after patients stop taking them."

"What are you talking about?"

My mouth dry, feeling anxious and confused myself, I explained that tics are a well-known side effect of major tranquilizers. Not only do these earlier drugs cause tics, they can also suppress or mask them, as long as the patient is still on the drug. The tics emerge only after the medication is stopped.

"You're not taking any other medications, right?" I asked Maura.

"Right," she confirmed.

"Have you ever been prescribed any other psychiatric medications?"

"Never."

Since Maura had been on Prozac for two years and had not taken any other psychiatric medication, it seemed that Prozac was probably responsible for the tics.

"How can the drug be causing something when it's gone?" asked Maura.

"No one knows the exact process by which the tics come about," I said. "But we do know that they are caused by long-term exposure to certain drugs. Sometimes the tics become severe enough to overcome the drug suppressing them. But sometimes they only appear after the drug is gone. Removal of the drug brings out the tics."

In fact, with major tranquilizers the tics are a result of brain damage brought on by the medication, but in our initial conversation I avoided using these words with Maura, because she was already terribly upset.

"Will this go away?" asked Maura.

"There's a good chance it will."

"A good chance? What are the chances?"

"I don't know. I've never heard of this with Prozac."

"What are the chances with other kinds of drugs?"

"Major tranquilizers? In about half of those cases, the tics slowly go away."

"And the other half?"

"They stay."

"They're permanent?"

"Sometimes they get a little better."

"But they're permanent?"

"Yes."

"Can they get worse?"

"In some cases."

"Oh, my God. Is there any treatment?"

This is one of the most difficult questions to answer, because patients are so desperate to maintain some hope. In fact, no treatment has proven effective for these tics. Many treatments have been tried, without success. The results with one treatment, vitamin E, have been inconclusive. Some studies show that vitamin E improves the course of the tics while other studies show that it does not. Since the results are not conclusive, I suggested vitamin E to Maura without creating too high an expectation.

After Maura left my office, I was distracted for the rest of the day. I was certainly familiar with the kind of tics she had. In fact, I had seen much graver cases, but only in patients who had been treated with older drugs. Physicians always feel guilty when their treatments cause new, sometimes worse problems. I hadn't started Maura on Prozac but had maintained her on it for a year. Had Prozac really caused the tics? I asked myself.

At the first opportunity, in a break between appointments, I pulled out the Physician's Desk Reference, a large volume containing the manufacturers' information on every prescription drug. I turned to the information on Prozac and found the section on side effects occurring in the nervous system. Sure enough, "extrapyramidal syndrome" was listed as a neurological side effect. Extrapyramidal syndrome is the technical term for four closely related neurological side effects, including tics like Maura's.

Even more telling was an entry I found under "Postintroduction Reports." This section describes side effects that did not appear during the testing of a drug but only after its introduction to the market. Here I was taken aback to find what sounded like Maura's side effect. It was listed as a "dyskinesia," meaning abnormal movements, and described as a "buccal-lingual-masticatory syndrome with involuntary tongue protrusion," which took months to clear after the drug was stopped. This certainly sounded like the types of tics I was seeing with Maura. Buccal, lingual, and masticatory are technical terms for cheek, tongue, and chewing, respectively. Abnormal movements of the mouth, jaw, and tongue are the most common form of the tics.

Over the next month, Maura's tics worsened. The tongue-darting became more pronounced and more frequent. In addition, she developed chewing-the-cud type movements, indicating involvement of the jaw. I performed a neurologic screening test called the Abnormal Involuntary Movement Scale (AIMS test), used to assess and monitor the severity of medication-induced tics. For the AIMS test, Maura performed a series of exercises while sitting, standing, and walking. I rated a number of different measures of abnormal movements of the hands, arms, torso, pelvis, legs, gait, and mouth, all of which can become involved in the loss of motor control. So far, Maura had only facial tics, the most common form of this disorder. Other facial movements can include grimacing and snorting. Movements around the mouth are typically lip-smacking, blowing, kissing, or puckering.

By now Maura was avoiding social situations. When she did have to go out, she wore sunglasses and scarves in an attempt to hide the tics. Of course her husband was well aware of them and alarmed. Maura suffered from the strain of trying to hide the tics from her children in order not to frighten them.

During this time I began researching the side effects of serotonin boosters. Side effects such as Maura's can take months or years to develop and therefore are not picked up in the short, six-to-eight-week clinical studies required to win FDA approval for new psychiatric drugs. Since the FDA simply does not have the resources for a systematic program for monitoring late-appearing drug reactions, the agency is forced to rely on random, spontaneous reports from individual doctors. As a result, there is no central clearinghouse that makes thorough information on long-term side effects available, even to doctors. Instead, one has to comb through hundreds of often obscure medical journals tracking down spontaneous case reports.

I spent whole weekend days in the bowels of the Harvard Medical School Library poring through esoteric psychiatric journals. I was amazed to find reports estimating thousands of cases of four different side effects involving loss of motor control. The first is tics like Maura's. The second is neurologically driven agitation ranging from mild leg tapping to severe panic. The third is muscle spasms, which, when they are mild, can cause tension in the neck, shoulder, or jaw, but can lock body parts in bizarre positions when severe. The fourth is drug-induced parkinsonism, with symptoms similar to those seen in Parkinson's disease. In this chapter, I refer to this cluster of four, closely related syndromes — tics, agitation, muscle spasms, and parkinsonism — as the neurological side effects of the drugs. I found reports that they were occurring with all of the serotonin boosters: Prozac, Zoloft, Paxil, and Luvox. These neurological side effects represent abnormalities in the involuntary motor system, which is a large group of nerves found deep in the older part of the brain. Normally, these nerves influence automatic functions like eye-blinking, facial expression, and posture. When the brain attempts to compensate for the effects of a drug, it can lead to disorganized, chaotic activity in the involuntary motor system and loss of motor control — an example of Prozac backlash. In my experience, patients with any one of these side effects are at increased risk to develop the others, including tics.

One of the earliest published cases of tics associated with Prozac appeared in April 1992, in the journal Neuropsychiatry, Neuropsychology, and Behavioral Neurology. Dr. David Fishbain was the lead author in a team of five doctors at the University of Miami School of Medicine. The patient was a seventy-seven-year-old woman who was taking Prozac for depression and back pain. Prior to treatment with Prozac, she had no abnormal movements.

Forty milligrams a day of Prozac dramatically improved the patient's depression and pain syndrome. However, she developed severe facial tics — described as "bon-bon" (candy-sucking-like movements) and "fly-catch" involuntary tongue protrusion. The movements "were repeated on a regular basis at a frequency of about 2-4 times per minute." The Prozac was stopped immediately and both the bon-bon and fly-catcher tics improved significantly within four weeks and disappeared over the course of several months.

Less fortunate was a forty-three-year-old depressed woman who developed tics while taking Prozac. This case was reported in the October 1991 issue of the American Journal of Psychiatry by Drs. Cathy Budman and Ruth Bruun in New York. The patient's "tongue was observed to dart back and forth across her teeth, and it also rolled and curled laterally. There were sucking and blowing movements of her cheeks and intermittent clenching of her teeth. These movements kept her awake at night." This woman's tics subsided but did not fully clear even after the Prozac was stopped.

In the October 1993 issue of the Journal of Clinical Psychopharmacology, Drs. Dinesh Arya and E. Szabadi at the Queens Medical Center in Nottingham, England, reported a thirty-eight-year-old depressed woman who developed tics while taking Luvox. The patient's tics consisted of bouts of dramatic rapid eye-blinking occurring four or five times a minute. Her lips would protrude and twist to the left side in "peculiar, repetitive, involuntary movements." She also developed severe clenching of her teeth, which left the muscles of her gums and jaw in pain.

Another published case is of a twenty-nine-year-old man treated with Prozac for obsessive-compulsive disorder, reported in the February 1996 issue of the Journal of Clinical Psychiatry by Dr. Nat Sandler of Lexington, Kentucky. After more than a year on Prozac, the patient developed abnormal facial movements, especially around the mouth, including tongue-darting. The patient was aware of the movements but not incapacitated by them. However, Dr. Sandler reported, "Concern over gross thrusting of the tongue led to discontinuation of Prozac. Within two months...the tardive dyskinesia symptoms [tics] began to lessen; after six months, there were no signs of mouth movements." Warned Dr. Sandler, "Clinicians should consider the possibility of tardive dyskinesia [tics] occurring in patients taking Prozac."

Not all cases of tics associated with serotonin boosters have been facial. The large muscles of the trunk and limbs can become involved. Doctors Brian Fallon and Michael Liebowitz at the College of Physicians and Surgeons of Columbia University reported in the April 1991 issue of the Journal of Clinical Psychopharmacology on a thirty-eight-year-old woman with mild lupus who was started on 20 milligrams a day of Prozac for depression. On Prozac, the patient developed "truncal dyskinesia [tics]" characterized by "mild involuntary pelvic rocking." Fallon and Liebowitz reported that the "pelvic dyskinesia [tics]...persisted without much change until after the Prozac was stopped."

Even more "complex movement disorders" after long-term treatment with Prozac were reported by Drs. Kersi Bharucha and Kapil Sethi at the Medical College of Georgia in 1996 in the journal Movement Disorders. One patient was a seventy-two-year-old woman admitted to the hospital because of loss of motor control that emerged after two years of treatment with 20 milligrams a day of Prozac. The patient had "constant" movements of her upper lip and jaw that made it difficult for her to speak. She had muscle contractions in the neck, jaw, floor of the mouth, and shoulders. Irregular, jerking movements occurred in both arms and legs. And the patient had involuntary wiggling of her toes. When the Prozac was discontinued "the involuntary movements ceased completely." While some of the patient's tics, twitches, and jerking resembled what is traditionally seen with major tranquilizers, others did not. Bharucha and Sethi advocated the use of the term "complex movement disorders induced by Prozac" because of the combination of a number of different involuntary movements in this and other patients. Much more research is needed to characterize the different types of tics, twitches, and jerking seen with these drugs.

As I told Maura about these and the many other cases I was finding, she asked, "Why aren't patients told about such severe side effects? Why do most doctors not even know?" In a way, this book is my answer to Maura's question, an attempt to remedy the lack of public information on this phenomenon.

While Maura and I anxiously monitored her tics, waiting to see what would happen, she wanted to review why she was put on Prozac in the first place. Here she was like a trauma victim wanting to go over the scene of the crime, looking for clues to how things might have gone differently. In fact, Maura's original symptoms had been relatively mild. For about a month she felt down with sudden feelings of great sadness and loss. She had episodes of feeling particularly upset while driving on the highway. But she had none of the physical symptoms of moderate and severe depression: difficulty sleeping, change in her appetite, poor concentration, inability to function, or suicidality. I thought Prozac was too powerful a drug for her mild distress. When she first consulted with me, I had said this to Maura. She had been taking Prozac for a year, however, and she felt stable on it and did not want to change. Since I had not been aware of the serious side effects emerging with the drug, at the time I did not push too hard for her to stop it. In retrospect, it was awful to think Maura might not have needed Prozac in the first place, given the disfiguring side effect she was now experiencing.

Psychiatric syndromes have two parts: a psychological core and superficial physical symptoms. As we discovered, the core of Maura's difficulty was her parents' traumatic death during her childhood. Long dormant, this trauma was reawakened by her daughter's approaching the age Maura had been when her parents died. Since Maura was not aware of the true source of her upset, she developed symptoms, becoming distressed and tearful, which were a kind of code or flag raised over her distress. Psychotherapy consists of deciphering the code and bringing the flag, or symptoms, down in the process. By contrast, medications only suppress symptoms. They are like crutches or Band-Aids. By themselves, they are never a cure. As such, they should be used only as adjuncts to the real healing, aids used to buy time and protect the healing process. Since medications entail risks and dangers, they should be used only when truly necessary. The least invasive medication should always be chosen, and even then, medication should be used judiciously.

Unfortunately, primary-care doctors do not have the training or time to evaluate and treat the psychological core of psychiatric syndromes. But under managed care and in HMO settings, they are under pressure to treat the psychiatric conditions of their patients. They are trained to follow simple protocols, or algorithms, which look only at the superficial symptoms. Maura, for instance, was medicated according to a simple "If depressed, then Prozac" model. Primary-care clinicians are not trained to explore questions like How mild or severe are the symptoms? How often are they occurring? Why is it happening at this particular time in the patient's life? This more informed, thorough approach requires a specialist — a psychiatrist, psychologist, or social worker -- none of which were available to Maura until a year later, when she sought a second opinion from me on her own initiative.

At the two-month mark, Maura's AIMS test showed her tics had stabilized. They no longer appeared to be worsening.

"They seem to get worse when I'm stressed or anxious. I seem to chew and stick my tongue out more," said Maura, unconvinced they were stabilizing.

"Stress exacerbates these tics, for reasons that are not clear," I explained.

Relating a comment of her husband's, Maura added, "John says my tics disappear when I'm asleep."

"That, too, is characteristic."

By the third and fourth month Maura's tics were gradually improving. At the four-month mark, when I performed the AIMS test, the most dramatic of her tics, the chewing-the-cud and fly-catcher tongue-darting, were gone. By six months Maura's tics had largely cleared. She was left with permanent, subtle twitching around her mouth and eyes, but incorporated into her facial expression, these were not noticeable to the casual observer.

Maura only gradually regained her confidence in social situations. Losing the fear that a tic would suddenly act up in the middle of a conversation took months to achieve. Once she regained most of her former ease and was less self-conscious again, Maura no longer needed to be in treatment. She was finally able to stop therapy a few months after the ordeal of her tics.

Maura's case and my research confirming other, similar cases left me thoroughly sobered about the safety of these new serotonergic drugs, tics such as hers being the dread side effect of psychiatric medications because no effective treatment exists. With major tranquilizers, the earlier class of drugs associated with the tics, they develop silently, are often masked by the drugs that cause them, and can be permanent in as many as 50% of cases. In some cases, the tics lead to wide-based, lurching gaits; swinging and flailing of the arms; or twisting and writhing of the hands. Why some patients develop the tics more quickly than others is not fully understood. They may be caused by cumulative damage resulting from exposure to certain drugs, viral infections, central nervous system diseases, and the loss of brain cells that occurs with normal aging. Thus the elderly are more likely to develop tics quickly, as are people with prior exposure to drugs causing similar damage. When the tics began appearing with major tranquilizers, it was thought that only certain vulnerable populations like the elderly or medically ill would develop them. It is now recognized that anyone can develop them, including young, healthy patients. With long-term exposure to the drugs, the emergence of tics steadily increases over time. A study being conducted at the Yale University School of Medicine has estimated that 32% of patients develop persistent tics after 5 years on major tranquilizers, 57% by 15 years, and 68% by 25 years. In addition to patients who develop overt tics, many have tics that are suppressed by the drugs. When patients are taken off major tranquilizers specifically to look for tics previously not present, 34% of patients have tics unmasked by stopping the drugs. With tics associated with serotonin boosters, we do not know how many patients will ultimately develop them or what percentage might be permanent. Serotonin boosters are still relatively new and these side effects have not been studied systematically. But what we know from the side effects with major tranquilizers is cause for serious concern.

The research I had done in response to Maura's case had taught me that serotonin boosters cause not only the tics but three other, closely related neurological side effects. Having witnessed the first of these disorders, I now wondered if I would see the other three. From my earliest days as a doctor, I learned to expect that drugs that cause one of these side effects will often cause the others as well. In addition to tics, the other neurological side effects are muscle spasms, agitation, and drug-induced parkinsonism. Had I seen them already, I wondered, and mistaken them for something else? Might the "caffeinated" feeling so many people describe when starting serotonin boosters, in fact, be neurologically driven agitation in some instances? Later on, after being on the drugs weeks or months many patients develop "paradoxical fatigue." Most doctors consider this fatigue to result from the nervous system's being in chronic overdrive due to the drugs' stimulating effects. But might it be fatigue caused by drug-induced parkinsonism? How would one differentiate these symptoms from the patient's underlying depression? I was soon to find out.

Leslie's Amotivational Syndrome: A Case of Fatigue and Apathy

Leslie's internist asked me to see her in consultation. She explained that significant changes had occurred in Leslie's life in recent years. Leslie was in her mid-fifties, and all of her children were now grown and had left home. Struggling with the changes in her role, Leslie was having difficulty re-entering the job market. Over the course of three years, her internist had prescribed increasing doses of Prozac for her. Her dose was now at the maximum recommended, 80 milligrams per day. Concerned that her depression was still not better and possibly worsening, the doctor now wanted Leslie to have a psychiatric evaluation.

When I met Leslie in the waiting room, her burdened look did not strike me as unusual for a depressed person. Her handshake was limp. She was slow walking into the office. Was Leslie profoundly depressed? Was she showing me the worst of how she felt, wanting to be sure I got the picture of how bad things were? Were characterologic issues going to be prominent?

Once in the office, however, as we talked I gradually began to question whether Leslie was depressed. She was straightforward about missing her children and the role she played as a busy mother. But she seemed to have made peace with this. As she said, the children left gradually, giving her time to slowly adjust.

Leslie's job situation was more frustrating to her. She did not like interviewing for positions: "I hate trying to 'market my skills' in interviews," said Leslie. Surprisingly, she had specific ideas for a business of her own: "I love books. My friends who are librarians or book dealers tell me it's difficult to find people to restore old books — for example, to put new leather bindings on them. Even some new books have leather bindings in limited editions and, again, it's difficult to find people who can do the work. I'd like to take a course or two and invest in the equipment I'd need to set myself up in business. I'd love to do that kind of quality work. I'd also like to be responsible for my own financial fate and be able to make my own hours."

These were lively statements and ideas, not what one would expect to hear from someone profoundly depressed. "Why don't you just do it?" I asked.

Two things held Leslie back. Her husband had not been particularly supportive. He preferred her to get a more "regular, secure" job. But the bigger problem was her fatigue and indifference: "I'm slowed down. I don't get around like I used to. Although I have things I'd like to do, I feel unmotivated...apathetic. I don't know what's wrong."

"Is it your depression?"

"I don't feel depressed now. I might have been a few years ago, when my children started leaving. But I don't think I am now."

By this time, I agreed. But if Leslie was not depressed, what would explain her symptoms? Did she have some neurological condition? Was it a side effect of her medication? Could Leslie's lack of motivation and fatigue be due to parkinsonism, I wondered, sensitized to the possibility by Maura's case. Parkinsonism is a term used for drug-induced side effects that resemble the symptoms of Parkinson's disease in the elderly. Parkinsonism is generally considered reversible when the offending drug is stopped, while Parkinson's disease has an inevitably progressive course.

Parkinson's disease can make people feel profoundly fatigued and apathetic. Their facial expression, speech, walking, reaching motions, and all their movements make them look progressively as if they are in slower and slower motion. In severe cases, people are virtually immobilized, stuck in a frozen state of rigidity. Some patients develop a characteristic pill-rolling tremor in their fingers, which contrasts sharply with their prominent, overall inactivity.

As with Maura, Leslie's eyes provided the first clue to her real problem. In parkinsonism, diminished movement in the facial musculature renders the skin, or surface, of the face relatively flat and immobile. The eyes seem to move independently of facial expression. As I watched Leslie, I thought her eyes looked as though they were peering out from behind a mask, rather than a fully expressive face. Parkinsonism, I thought, would explain the incongruity between her mental agility and her slowed physical state. But I did not know Leslie's baseline as a point of comparison. Was this how she looked before the drug? Or was this a change?

As we continued to talk, I observed Leslie carefully. I noted that her slowness had a particular quality: When Leslie moved her body, she tended to do so en bloc, in a somewhat wooden manner. Again, this was subtle, the kind of observation one makes based on experience from having seen patients who developed parkinsonism on older drugs like major tranquilizers.

Finally, I asked Leslie if she would do a diagnostic test. "I'd like to see if you have any stiffness that might be a side effect of the Prozac," I explained. As we stood up, I asked Leslie to relax her arm. Holding her elbow in one hand and her wrist in the other, I slowly moved her arm about the elbow joint. Sure enough, I could feel the ratchet-like resistance to motion one finds in parkinsonism.

I told Leslie I thought her lack of motivation and fatigue were parkinsonism, a side effect of the Prozac. Leslie was quite shocked. She had an elderly uncle with Parkinson's disease. Any comparison with the ravages of his severe illness frightened her. I explained that her symptoms would probably clear up if we lowered or stopped her medication.

In the ensuing weeks, we gradually brought Leslie's dose down, ultimately stopping the medication altogether, since she did not become depressed again. Slowly, her energy and motivation returned. Her facial expression and general body movements became more fluid. Leslie was enormously relieved by her improvement. After she recovered from the shock that it was the medication that had been making her look depressed, Leslie began to pursue her plan for a business. She stayed in psychotherapy, using it for support in overriding her husband's, as well as her own, hesitations. Once he saw Leslie's energy and determination, her husband was actually quite helpful, working closely with her to find the right bookbinding equipment. While Leslie's venture did involve start-up costs, ultimately it was quite successful. She recently saw me in follow-up and told me she now has five people working for her.

As in Leslie's case, the distinction between worsening depression and parkinsonian side effects is often subtle. Making the correct assessment and intervention depends upon an awareness of the side effect and clinical experience. Unfortunately, her primary-care doctor had been unaware of this side effect occurring with serotonin boosters. Instead, the doctor clung to the idea that Leslie was suffering from the "empty nest" syndrome and thought her depression was worsening.

Numerous cases, small-scale studies, and articles on parkinsonian side effects in patients on serotonin boosters have been published. Writing in the November 1993 issue of Human Psychopharmacology, Dr. Michael Berk at the University of Witwatersrand Medical School in Johannesburg, South Africa, reported a twenty-six-year-old man with obsessive-compulsive disorder who developed parkinsonism after three months on Paxil, at a dose of 60 milligrams a day. The patient's parkinsonian symptoms included rigidity and excessive salivation. When his dose was reduced to 40 milligrams a day, the parkinsonian side effects cleared.

Many authors have described cases where serotonin boosters dramatically worsened parkinsonian symptoms in patients with pre-existing Parkinson's disease. Patients with this disease have a particularly high incidence of depression and are therefore often prescribed antidepressants. Writing in the December 1994 issue of Neurology, a group of Spanish doctors headed by Dr. F. J. Jiménez-Jiménez at the University Hospital in Madrid described a thirty-five-year-old woman with early-onset Parkinson's disease who was put on 20 milligrams of Paxil. Stated Dr. Jiménez-Jiménez: "One month later, all her symptoms had worsened." The patient had developed flattening of her facial expression, rigidity, "difficulty in performing fine finger movements with both hands, short steps, loss of associated movements, and postural instability." These markedly worsened symptoms took two months to clear after the Paxil was stopped.

Much more needs to be learned about the effects of serotonin boosters on existing or incipient Parkinson's disease in elderly patients. In a piece entitled "Serotonin, Depression, and Parkinson's Disease" in the August 1993 issue of Neurology, the Dutch neurologist Jan Hesselink laments, "Unfortunately, methodologically sound studies evaluating the efficacy of serotonergic drugs" in depressed patients with Parkinson's disease "are virtually nonexistent so far."

Equally important may be cases of fatigue or indifference occurring in younger patients, in their twenties, thirties, or forties. Many people on Prozac-type drugs report a peculiar "bone-weary fatigue" in which they feel lethargic but not sleepy and, in fact, cannot fall asleep. They describe a "heaviness" in their bones, as though it is just too much to move. This fatigue can be quite severe and is relieved only by reducing the dose or stopping the drug. Other patients emphasize feeling indifferent on the medications. "All the same problems are present in my life but I just don't care anymore" is a frequent refrain. Some patients welcome this more "mellow" attitude toward life, although they may not be aware of the possibility that it entails serious risks. Other patients regard the change as more disturbing, saying that the drugs make them feel "blunted" or "flat" and not at all like their usual selves.

Because parkinsonism with these drugs has not been adequately studied, most doctors do not think of it as a possible cause of fatigue or indifference. But Principles of Neurology, the authoritative textbook by Adams and Victor, notes that fatigue and malaise are often the earliest symptoms of parkinsonism: "The fatigue of Parkinson's disease may precede the recognition of [more obvious] neurological signs by months or even years. It is probably a reaction to the subjective awareness of increasing disability occasioned by the akinesia [a disinclination to move]." Since fatigue or indifference are common with Prozac-type antidepressants, they may be particularly worrisome indications of how many people are suffering from mild parkinsonian side effects and therefore are vulnerable in the long term to developing tics.

With major tranquilizers, research has shown the development of parkinsonism, in particular, predicts the later emergence of tics. Psychopharmacologist Guy Chouinard of the Royal Victoria Hospital in Montreal followed ninety-eight patients on the drugs for ten years. He found that the presence of parkinsonism increased the risk of later developing tics. Chouinard presented this important study looking at risk factors for tics at the American Psychiatric Association's annual meeting in May 1990.

Ming and Cora: Cases of Muscle Spasms

Ming is a thirty-eight-year-old Chinese woman who lives in Singapore. Five months after starting Luvox, she developed severe tightening of the muscles in her jaw, resulting in involuntary clenching of her teeth. Ming's lockjaw became so severe that she had great difficulty chewing her food. Obviously, such a dramatic situation would be frightening. Ming's lockjaw improved when the Luvox was reduced from 100 to 50 milligrams but did not fully clear until the drug was stopped. Ming's case was reported by her psychiatrist, Siow Ann Chong, in the September 1995 issue of the Canadian Journal of Psychiatry.

Ming's clenched jaw was caused by muscle spasms, another of the four closely related, neurological side effects. Muscle spasms are prolonged contractions of muscles that lock body parts in abnormal positions lasting for minutes to hours. This is in contrast to tics, which are short bursts of repetitive activity.

Cora was a twenty-two-year-old college student in Gainesville, Florida, when she sought treatment for depression. Because she had only a partial response to Prozac, her dose was increased to 80 milligrams over the course of three months. Ten days after reaching the 80-milligram dose, Cora developed severe lockjaw and spasms of the muscles in her neck and tongue. The spasms were so frightening that Cora went to a hospital emergency room. There she was given Benadryl, which relaxed the muscles. Cora was sent home, but the spasms returned five hours later. She went back to the emergency room and was given a second dose of Benadryl.

Cora's psychiatrist stopped the Prozac, but three weeks later she was feeling depressed and asked to try the drug again. One week after being on just 20 milligrams of Prozac, Cora again developed severe lockjaw, neck tension, and tongue thickening. She again went to the hospital emergency room. This time, even though the Prozac was stopped, the spasms took three days to clear.

Cora's case was reported in the November 1990 issue of the Journal of Clinical Psychiatry by three doctors in Gainesville, Florida: Lawrence Reccoppa, Wendy Welch, and Michael Ware. Her case illustrates another important point: Even though a side effect may clear, the nervous system can be left more vulnerable in the future. One sees this dramatically if the patient is re-exposed to the drug and proves more sensitive to developing motor abnormalities. When Cora was re-exposed to Prozac, her reaction was more severe, with the muscle spasms occurring after only one week on 20 milligrams, whereas the first time she was on the drug for three months and up to a dose of 80 milligrams before developing spasms. Say Reccoppa, Welch, and Ware at the conclusion of Cora's case, "Clinicians should be aware of this serious...side effect, especially in light of the current widespread use of Prozac."

Some cases of muscle spasms can be even more dramatic and frightening. Spasms affecting the arms, legs, or torso can lock the body in bizarre, twisted postures. In the January 1994 issue of the American Journal of Psychiatry, Dr. Mahendra Dave, of Syracuse, New York, reported on a fifty-four-year-old woman who developed acute spasms in her legs and back a month after starting 20 milligrams of Prozac a day. The spasms caused bizarre posturing in which she tilted backward and to the right. When she tried to walk, the spasms caused her to drag her left foot. In addition to the bizarre posturing and foot-dragging, the patient developed a tremor in her lip called "rabbit syndrome" and spasms of the left eyelid that clamped her eye shut.

Instead of stopping Prozac, another medication (Cogentin) was added to suppress the side effects. On the drug combination, the spasms subsided over the course of three weeks. The use of additional drugs like Cogentin or Benadryl to treat muscle spasms is well known to doctors from their experience with the side effects in patients on major tranquilizers. Although many doctors suppress medication-induced movement disorders in this way, I worry that ongoing exposure to the offending drug will cause damage eventually leading to tics. My preference is always to take patients off the offending agent, whenever possible.

Much more common than these dramatic, published cases are milder instances in which patients complain of muscle tension in their shoulders, neck, or jaw. Often, patients have to be asked specifically about these side effects, because it does not occur to them that the muscle tension is related to the drug. The connection may become clear only when the drug is stopped and the pain disappears.

Mild to moderate spasms may affect as many as 10% of patients. This estimate comes from a clinical study of Luvox by the Italian psychiatrists V. Porro and S. Fiorenzoni. Of forty-one patients treated with Luvox, four complained of mild to moderate muscle spasms during the first week of treatment. Muscle spasms were the fifth most common side effect reported in the study published in the April 1988 issue of Current Therapeutic Research.

Ironically, one of the first patients ever put on Prozac in the earliest stages of testing the drug developed acute muscle spasms. Writing in the Journal of Neural Transmission in 1979, Herbert Meltzer, a psychiatrist at the University of Chicago, described the twenty-five-year-old depressed patient as having neck spasms so severe that they twisted his neck and rotated his head into an abnormal position. He also developed spasms in the muscles of his jaw. Eli Lilly had given Meltzer a grant to study the effects of Prozac and supplied the drug, which was not yet available to doctors. This was a decade before the pharmaceutical company began marketing Prozac for the general public. One wishes this patient had been an early warning sign to Lilly of the potential for serotonin boosters to cause not only muscle spasms but all four of these closely related neurological side effects.

Ron: A Case of Neurologically Driven Agitation

"I feel like I have coffee running into my veins," said Ron, as he crisscrossed the office, pacing compulsively. Ron was a forty-seven-year-old engineer, whom I had started on Paxil because of his severe depression. Since Ron had a large family to support and was concerned that his depression was threatening his job, using Paxil to jump-start him seemed reasonable. Whereas previously Ron had not been able to get out of bed because he was so depressed, now he could not sit still.

"I'm not feeling better," said Ron. "In fact, I'm feeling worse. I'm exhausted, but when I try to fall asleep I lie there tossing and turning with my legs kicking all night." In addition to the physical restlessness, he described the accompanying inner state: "My bones feel like tuning forks humming up and down my body." Ron paced ceaselessly, and looked as if he was going to crash into a table or a wall. "Believe me, I don't do any illegal drugs," he said. "I'm not withdrawing from anything. I don't know what's happening to me."

I asked Ron to sit in a chair so I could examine him.

"I can't sit down," Ron protested impatiently.

"I need you to try," I responded. "It's a test to see what's going on. I want you to sit as still as possible."

Ron had to hold himself down, his white-knuckled hands pulling against the arms of the chair. As he did, his feet displayed a telltale sign, tapping and dancing around the floor uncontrollably. This is a cardinal feature separating medication-induced agitation from psychologically driven anxiety. While patients who are anxious for psychological reasons may move around, they do not experience the same compulsive, relentless activity. Asked to sit still in a chair, an anxious patient might curl up in a ball, petrified but motionless. Ron could not do this. In medication-induced agitation, the patient cannot escape the urge to move, particularly to move the legs.

"Am I going crazy?" Ron asked desperately.

"Not at all," I reassured him. "This is a side effect of the medication."

Had I not known that Paxil can cause agitation, the fourth of the neurological side effects, I might have missed the correct diagnosis and instead thought Ron had developed an agitated depression. The distinction is crucial, because the appropriate intervention is the opposite. If Ron's depression was worsening, one would go up more quickly on the medication. But this would have made the agitation worse. Instead, knowing the agitation was medication-induced, I stopped the drug. Within days, his agitation cleared.

Ron was so "spooked" by the severe side effect that he refused to try another medication. While psychotherapy alone took a while longer to pull him out of the worst of his depression, he did fine without an antidepressant.

When severe, neurologically driven agitation can be quite dangerous, especially if the patient has not been warned about the side effect and confuses it with deterioration of his own emotional state. Some patients describe feeling as if their heads are "going to explode." Others compare the profoundly disturbing inner state to the feeling of fingernails scratching relentlessly up and down a blackboard. Some develop an "abject terror," which can precipitate psychosis and suicidality.

Agitation was the first of the neurological side effects associated with Prozac-type medications to come to the attention of professionals. In 1989 a team of four Harvard Medical School psychopharmacologists at McLean Hospital, led by Dr. Joseph Lipinski, published an article entitled "Prozac-Induced Akathisia [Agitation]: Clinical and Theoretical Implications" in the Journal of Clinical Psychiatry. Lipinski and his colleagues described five vivid cases. Within days of starting Prozac, one patient "reported severe anxiety and restlessness. She paced the floor throughout the day, found sleep at night difficult because of the restlessness, and constantly shifted her legs when seated." Two days after starting Prozac, another patient reported, "I couldn't keep my legs still....I would find myself bicycling in bed or just turning around and around. I was embarrassed because I kept my roommate awake."

In this early article, appearing within two years of Prozac's release, Lipinski said the agitation was "clinically indistinguishable" from that caused by major tranquilizers, well known to cause these neurological side effects. Declaring neurologically driven agitation a "common side effect of Prozac," he estimated it occurs in 10-25% of patients. Similar reports of agitation with Zoloft, Paxil, and Luvox appeared after these drugs were introduced.

In mild cases, patients may only experience foot-tapping and a vague sense of needing to keep busy. "I cleaned my house for days when I first went on Zoloft," said one patient. Said another, "I had a desk and six bookcases that I wanted to refinish for some time. Right after I went on Prozac I spent weeks compulsively sanding and finishing the furniture. At the time, I thought it was because my depression had lifted. Now I realize it was because I couldn't sit still."

Lipinski may be right that this agitation is a very common side effect of the serotonin antidepressants. Many patients describe feeling "caffeinated" in the early weeks on the drug. When Prozac was introduced, Eli Lilly researchers coined the euphemism "activating" for the stimulating effects of the drug. How often is this caffeinated effect in fact neurologically driven agitation?

Lipinski's early report might have served as more of a warning. Appearing in 1989, not long after Prozac was introduced, the report on Prozac-induced agitation might have raised concern that all four of the closely related neurological side effects would eventually appear. Unfortunately, this possibility was not adequately considered in the rush to prescribe the popular new medications.





While these four neurological side effects — parkinsonism, agitation, muscle spasms, and tics — are often discussed as separate, distinct side effects, patients can have more than one at a time. Indeed, the four may not be so distinct after all; they may just be different manifestations of the effects of certain drugs, toxins, or viral infections. Patients with Parkinson's disease caused by viral infections also evidence agitation, muscle spasms, and tics like those seen with the drugs. In his book Awakenings, neurologist Oliver Sacks vividly describes these postinfectious Parkinson's disease patients. Thus, certain viruses, toxins, and drugs may induce a syndrome of which parkinsonism, agitation, muscle spasms, and tics are just different manifestations.

The Serotonin-Dopamine Connection

These dangerous neurological side effects — parkinsonism, agitation, muscle spasms, and tics — are known to originate in a particular region deep in the brain, the involuntary motor system. We do not know exactly how serotonin boosters induce them, but they appear to represent Prozac backlash, the brain's reaction to intruding chemicals. When a drug boosts serotonin in the brain, the brain's chemical balance is upset. The result is artificially induced fluctuations not only of serotonin but also of the many other chemicals that act in concert with it.

Prozac backlash is the brain's attempt to reverse the effects of drugs in this class. Whenever the drugs step on the chemical gas pedal, the brain tries to slam on the brakes. The result is jerking, stop-and-go oscillations in brain activity that can go out of control. Writing about these kinds of medication-induced side effects, neurologist Oliver Sacks describes them as "sudden and catastrophic oscillations," random, erratic instabilities, which he says are best explained by chaos theory. Although Sacks was writing about the drug levodopa in patients with Parkinson's disease, he compared its side effects with those of major tranquilizers.

There are a number of scientific hypotheses for why this chaos comes about when serotonin is unnaturally boosted in the brain. The leading hypothesis is that boosting serotonin levels has repercussions on the levels of dopamine. Dopamine is a close chemical partner of serotonin. A large body of research over decades has implicated dopamine, not serotonin, in these disorders, regardless of whether they are caused by medications such as major tranquilizers or by diseases such as Parkinson's and Huntington's. As reports of these side effects occurring with the Prozac group have mounted, researchers have been puzzled by the question of how drugs that boost serotonin could cause side effects usually linked to dopamine. Scientists point to research showing a strong link between serotonin and dopamine in the involuntary motor system. Dutch psychiatrist Jan Hesselink wrote in the August 1993 issue of Neurology, "From preclinical studies already a decade old, we learned that the relation between the serotonergic and dopaminergic systems is an intimate one." Said Dr. Dinesh Arya in the December 1994 issue of the British Journal of Psychiatry, "Serotonin seems to modulate dopamine function." Thus, fluctuations in serotonin levels lead to fluctuations in dopamine levels, which in turn result in loss of motor control.

In particular, elevated serotonin levels trigger a compensatory drop in dopamine. The relationship between serotonin and dopamine can be visualized as a seesaw: When serotonin goes up, dopamine goes down. And it is dopamine suppression that has long been associated with this loss of motor control.

In a particularly relevant study published in the July 1988 issue of Biological Psychiatry, Dr. Marc Laruelle used one of the serotonin boosters (Paxil) with a radioactive tag on it to study what locations in the human brain are especially targeted by the drug. Laruelle found some of the highest concentrations of the drug's target cells in the involuntary motor system. Indeed, the highest concentration was found in the specific location (called the substantia nigra) known to be involved in Parkinson's disease.

Because of growing concern about these side effects, in recent years the serotonin-dopamine connection has become an area of active research. Neuroscientists have specifically designed experiments to test whether or not serotonin boosters are associated with a dopamine drop in the involuntary motor system. Dr. Junji Ichikawa at Case Western Reserve University School of Medicine measured dopamine levels in rats before and after administration of Prozac. In the August 1995 issue of the European Journal of Pharmacology, Ichikawa reported Prozac produced a 57% drop in dopamine in the involuntary motor system. By contrast, older antidepressants did not produce a drop in dopamine.

A team of neuroscientists headed by Dr. Stephen Dewey at the Brookhaven National Laboratory tested the newest serotonin booster, Celexa. Dewey used not only biochemical measurements but also brain scans to measure dopamine activity in rats and baboons. Writing in the January 1995 issue of the Journal of Neuroscience, Dewey reported that Celexa produced a 50% drop in dopamine, again demonstrating that while the drugs put serotonin up, they simultaneously put dopamine down.

Dr. A. DiRocco at the Mount Sinai Medical Center in New York found a dopamine drop in response to Zoloft. Writing in the February 1998 issue of the Journal of Neural Transmission, Di Rocco said that "motor activity is highly dependent on a balanced dopaminergic system" and that serotonin boosters appear to "specifically affect dopamine" levels in the involuntary motor system.

Thus, the Prozac group's much-touted "selectivity" for serotonin may, in fact, be a liability: Boosted beyond ordinary levels, elevated serotonin could trigger a dangerous backlash, a compensatory drop in dopamine, resulting in the drugs' most severe neurological side effects. This is like squeezing one end of a balloon only to have it pop out elsewhere. Of course, this kind of secondary, indirect effect on other neurotransmitters renders the drugs not "selective" at all. Indeed, we now know the Prozac group has effects on other neurotransmitters in addition to serotonin and dopamine.

One of the world's leading authorities on serotonin is Efrain Azmitia at New York University. Writing in the December 1991 issue of the Journal of Clinical Psychiatry, Dr. Azmitia called the serotonin system a "giant" neuronal system because of its far-reaching effects in the brain. Dr. Azmitia described drugs that externally manipulate the system as "awakening the sleeping giant." The backlash triggered in the brain, reactions like a compensatory drop in dopamine, can be thought of as the awakened giant's wrath.

Working out the full details of the serotonin-dopamine connection may take decades or more. Meanwhile, we are left with the clinical reality of these serious side effects, which in some cases are devastating. The unfortunate irony is that drugs heavily promoted as correcting unproven biochemical imbalances may, in fact, be causing imbalances and brain damage.

To a layperson it may seem surprising that despite reports estimating thousands of cases of such serious side effects, more patients are not advised of them. But only by searching through academic and professional journals one by one does a researcher find the information reported here. In our computer age, a more centralized source of information on side effects would benefit doctors and patients alike. At this time, because we lack a systematic program for monitoring long-term side effects and alerting doctors, many clinicians who prescribe serotonin boosters have not been made aware of the dangers.

The Story of Major Tranquilizers

Of all the earlier mood-altering drugs to have been approved and later heavily controlled or withdrawn from the market, the most pertinent here are major tranquilizers, because they induce the cluster of neurological side effects now emerging with serotonin boosters. The first of these drugs, Thorazine, was introduced in the early 1950s by Smith Kline French. Eventually, there were more than a dozen drugs in this class of agents. Major tranquilizers suppress dopamine directly, whereas the Prozac group are thought to do so indirectly, via their effect on serotonin.

In the 1950s, 1960s, and 1970s, major tranquilizers were immensely popular as treatments for the same everyday conditions for which serotonin boosters are now so popular, including mild depression, anxiety, nervousness, and insomnia. By 1965, Thorazine alone had been prescribed to 50 million patients in the United States. Eventually, an estimated 250 million people worldwide were exposed to major tranquilizers.

By the early 1960s, roughly ten years after Thorazine's introduction, numerous reports of tics, acute muscle spasms, parkinsonism, and agitation resulting from these drugs had been reported in medical journals. Since muscle spasms, agitation, and parkinsonism could all be relieved to some extent with additional drugs, the tics, for which no treatment worked, slowly emerged as the most serious in the cluster of closely related side effects.

By the twenty-year mark in 1973, 2,000 cases of the tics had been reported. Only at this point did some doctors begin sounding the alarm among professionals. They were vigorously opposed by drug proponents, however, who insisted the tics were rare, since there were only 2,000 cases out of the millions on the drug. Drug advocates alleged that only certain "vulnerable" populations like the elderly or those with pre-existing brain damage would get tics. Those concerned about the side effects countered that the reported cases represented only random, spontaneous ones and systematic studies might well show a much higher percentage of patients affected.

In a good, if unfortunate, example of the clash between opposing sides, at the twenty-year mark in 1973, psychiatrist George Crane published a rousing article in the journal Science in which he raised the alarm about the neurological side effects of major tranquilizers, especially permanent tics. Twenty years after Thorazine had been introduced, Crane lamented, "Many physicians are still unaware of this problem or seem to be completely unconcerned about it." Crane estimated that tics occurred in "at least 5% of patients exposed to drugs for several years...." He criticized the "indiscriminate and excessive use of potentially dangerous drugs" and called for more thoughtful treatment programs balancing drugs with psychological interventions.

In the same year, in the Archives of General Psychiatry, Daniel X. Freedman, a strong proponent of the increasing reliance on medication in psychiatry, blasted back at "uninformed alarmists" trying to raise concerns about the dangerous side effects of the drugs. Freedman excoriated psychiatrists like Crane, calling them "extremists among the consumer advocates."

Eventually, the drug proponents were proven profoundly wrong in their vitriol for patient advocates. By 1980, repeated systematic studies using neurological screening tests to look carefully for early, mild tics found them in an astounding 40% of patients treated with major tranquilizers, many of whom had been on the drugs for less than two years. In addition, landmark malpractice cases awarded patients huge settlements if they had not been adequately warned of the tics. Finally, the medical profession began to take these neurological side effects seriously, severely limiting the use of major tranquilizers to only the most serious conditions, such as schizophrenia. Only in 1985, because of intense pressure resulting from media coverage of the side effects, did the FDA finally require manufacturers to add a warning to the drugs' labels, alerting doctors and patients to these serious side effects. This was more than thirty years after the introduction of Thorazine and decades of indiscriminate use of the popular drugs. Originally, when they were prescribed to the general population, these drugs were simply called tranquilizers. As they fell from favor, however, they were renamed "major" tranquilizers to distinguish them from the Valium-type sedatives, which were called "minor" tranquilizers. As the original tranquilizers became discredited, Valium-type agents replaced them for conditions like anxiety and insomnia in the general population. Valium-type drugs do not cause the same neurological side effects as major tranquilizers, although they have other problems. Eventually, major tranquilizers were renamed again: Today they are officially called "antipsychotics" in an effort to distance the name "tranquilizer" from any association with these dread neurological side effects. But this kind of renaming confuses people, by veiling the history of a discredited class of drugs. Many doctors practicing today are unaware how popular and widely prescribed these drugs were in the 1950s, 1960s, and 1970s. I adhere to the name "major tranquilizers" because it is still used interchangeably with the name "antipsychotics" and serves as a reminder that these drugs were the Prozac of their day.

Experts now acknowledge that all patients on major tranquilizers — even young, healthy patients — can eventually develop tics. Most psychiatrists consider a key factor to be total, cumulative exposure to the drugs. Being on a low dose for a long enough time can eventually cause the same cumulative damage as being on a high dose for a short period of time. The June 1990 issue of Clinical Psychiatry News reported on psychiatrist Guy Chouinard's research on tics induced by major tranquilizers: "It appears that drug exposure of 15 years or more would lead to almost certain risk for tardive dyskinesia [tics]."

Now some of the world's best-informed psychopharmacologists are comparing serotonin boosters to major tranquilizers because of the similarities in their clinical uses and side effects. Ronald Pies, who is on the faculty of both Harvard and Tufts medical schools and the author of a textbook of psychopharmacology, wrote a special editorial in the December 1997 issue of the Journal of Clinical Psychopharmacology, entitled "Must We Now Consider SSRIs [Serotonin Boosters] Neuroleptics [Major Tranquilizers]?" In the editorial, Pies discussed the worrisome emergence of neurological side effects with serotonin boosters at some length. Although he concluded that Prozac-type drugs are not exactly like major tranquilizers, he cited research showing that they can be used to treat conditions formerly treated with major tranquilizers, indicating that they may, indeed, have "properties" of these earlier drugs.

Similarly, in a keynote address at an October 1998 Harvard Medical School conference on psychopharmacology, Ross Baldessarini, professor of psychiatry and neuroscience at Harvard, said, "The traditional view of drugs and particular classes as being simply antipsychotic [major tranquilizer], simply antidepressant...those boundaries are breaking down....You have to be thinking in a different way of how to categorize these" drugs.

In his 1997 book The Antidepressant Era, David Healy also comments on our emerging understanding of the overlap between serotonin boosters and major tranquilizers. Healy is a psychiatrist at the University of Wales College of Medicine and one of Europe's leading authorities on psychiatric drugs. Healy wrote that the effects of serotonin boosters "lie midway between the effects of classical antidepressants and classicial neuroleptics [major tranquilizers]."

Regarding tics associated with serotonin boosters, some doctors point to published cases in which the abnormal movements cleared when the drug was stopped and express the hope that this will be true for the majority of cases. Unfortunately, similar hopes and reassurances were once made on behalf of major tranquilizers. Even drug advocates acknowledge that the published cases reflect a fraction of the true incidence of any side effect. We simply have no idea of the frequency of tics with serotonin boosters or their likely time course. The largest databases on side effects are kept by pharmaceutical companies themselves. Most of the information the FDA has on side effects is forwarded to them by drug manufacturers. Eli Lilly acknowledged in a letter to one doctor who reported Prozac-induced tics that the "true incidence is difficult to determine....It is possible for an event [side effect] to be coded [i.e., recorded in Lilly's databases] as one of several related terms." In other words, a side effect may be logged in databases under a variety of different labels. But experts argue this can obscure the true frequency of side effects. The problems with the labyrinthine databases used by pharmaceutical companies to monitor side effects are discussed in detail in Chapter 4.

Do we this time want to ignore the early warning signs of these effects with serotonin boosters? Should the same pro-drug, authoritarian approach prevail for another decade or two, as it did with tranquilizers? Surely we know too much about these side effects to again take the cavalier attitude "let's see before alerting the public." Even if disfiguring tic disorders turn out to be infrequent, with tens of millions of people having been on serotonin boosters, hundreds of thousands could be affected. If they occur with anywhere near the frequency seen with major tranquilizers, millions would be affected.

Sharon, Jonathan, and Carl: Cases of Memory Problems

Sharon was a hairdresser in her mid-forties who owned her own busy salon with a dozen people working for her. Acutely aware of appearances and hygiene because of the business she was in, Sharon had always been embarrassed by her habit of biting her nails. Most of the women who worked for her and many of her clients had beautifully manicured nails, which Sharon was never able to achieve.

When Sharon complained about her nail-biting to her primary-care doctor, he suggested Zoloft for the "obsessive" habit. Although surprised by the recommendation, Sharon was game to try. Indeed, she was quite surprised when the drug stopped her nail-biting within a few weeks, by which time her dose had been raised to 100 milligrams a day.

Sharon's enthusiasm for the drug changed abruptly when she developed serious memory problems: "I just suddenly forget all kinds of things. One night my husband and I were going to a party at the home of our best friends. I had picked him up after work and was driving. It was dark out and raining heavily, so I was concentrating on the road, hyperfocused on the immediate traffic around me. Suddenly, my mind went blank while I was stopped at an intersection. I couldn't remember where we were going! When my husband told me, I had to ask him for directions! I didn't know where our friends lived, even though I'd been there hundreds of times. Both my husband and I were so unnerved, I pulled over to the side of the road and he took over driving."

When the memory lapses began happening "constantly," Sharon went back to her primary-care doctor. Concerned about the severity of the problem, he referred her to a neurologist. Sharon had a complete neurological workup, which found nothing to explain the dramatic memory lapses. The neurologist concluded the problem must be Zoloft. When her doctor lowered Sharon's Zoloft dose to 50 milligrams, her memory problems improved significantly but did not go away completely. At that point, she consulted me for a second opinion.

Like a great many clinicians, I felt nail-biting was too trivial a reason to be on such a powerful drug, and I advised Sharon to stop altogether. When she went off Zoloft, her memory lapses cleared.

Most patients who complain of memory problems have much more subtle difficulties. Jonathan was in his late twenties and a medical student when I started him on Prozac because he was severely depressed. He responded well to the drug and within a month was no longer depressed.

A short while later, however, Jonathan developed subtle but distinct memory problems. "I have trouble finding the word for something, like a person's name," he said. "I know that I know the name, but I can't retrieve it. I can't bring it up from my memory. Or someone's phone number. A close friend whose phone number I have always known, yet suddenly I can't recall it. This is definitely new. I never had these kinds of problems before. People have always commented that my memory was like a steel trap. It's just not the same anymore."

Yet another difficulty was that Jonathan would forget the "context" in which he learned something: "I've always remembered things in a lot of detail. Now I remember some things without any context. I might remember that a good friend and his wife have separated and are getting a divorce. But I can't remember when I learned it, who told me, where we were at the time, and what else we were talking about. I might have learned it just a few days before, but for the life of me, I can't recall the context."

Being a student whose performance depended on his memory, Jonathan was disturbed by this side effect. He talked to a friend who experienced the same problem on Prozac. Said Jonathan, "If someone told me, 'You've lost five miles an hour on your fast ball,' I'd say: 'Well, it doesn't matter. I don't pitch anymore.' But I feel like I've lost five miles an hour of my mind, and that's a serious problem."

His memory problems motivated Jonathan to get off Prozac even faster than we originally planned. Within a month of stopping the drug, his memory was back to normal.

Some patients have memory problems because of their depression. But Sharon was on Zoloft because of nail-biting, and Jonathan's difficulties started after he was no longer feeling depressed on Prozac.

Memory problems can be more dramatic in the elderly. Carl was a seventy-three-year-old man whom I put on 20 milligrams a day of Prozac for depression. Carl was in excellent physical health. Indeed, he still worked three days a week in the family business, a jewelry manufacturing company, which two of his sons now ran. He worked in the customer service office, overseeing the processing of orders.

Three weeks after starting Prozac, Carl reported, "I'm feeling less depressed but I'm having severe trouble with my memory." When I asked Carl to describe an example, he responded, "At work last week I couldn't close out the new orders. It's a procedure I've done weekly for years. You have to know how to categorize and break down the different types of orders so all the totals come out accurately. I just stared at the blank pages and didn't know what to do. I was so embarrassed I actually considered fudging the report, hoping someone would catch the problem and fix it. But I realized that if it wasn't picked up, it could lead to much worse difficulties. So I went quietly to one of my sons and explained I couldn't remember how to do this task. We were both worried I'd had a stroke or something until we thought of the drug." When he went off Prozac, Carl's memory problems cleared.

In still another example, Lauren Slater, a teacher of creative writing and a practicing psychologist in Boston, says in her 1998 memoir Prozac Diary, "I am fearful of the as-yet-undiscovered side effects....Lately I have become especially concerned about Prozac and memory. I used to be able to read a paragraph and recite back its phrases in near-perfect order. I never before needed an appointment book....I am not so old [in her mid-thirties] that I should frequently forget the names of towns I've lived in, streets I've roamed, dishes I have always savored. People I have loved. Gaps in my cognition are appearing, places where the denim is worn so thin the skin shows through."

Major tranquilizers have long been suspected of causing cognitive deficits and impairment in intellectual functioning. These concerns surfaced only after the drugs had been on the market for decades and their use had become limited to schizophrenics. Unfortunately, the concerns have not been adequately investigated and we are not equipped to recognize the signs of these drug effects.

Silent Brain Damage

A final, serious concern with these neurological side effects is silent brain damage occurring in patients who do not develop overt symptoms. We still do not fully understand how tics reflecting permanent brain damage develop with major tranquilizers. But when one looks at the symptoms, the best model to explain them is that the appearance of noticeable tics is merely the final stage in a process of slow, progressive damage. Even in patients who do not develop tics, significant damage may have occurred. One sees this dramatically in patients restarted on a drug who quickly develop tics or other side effects not present during the previous course of the medication. Prior exposure left them with significant injury, which then predisposes them to rapid development of the side effects with just a little additional damage from the re-exposure.

As we age, everyone is vulnerable to developing a variety of neurological conditions such as Parkinson's disease, senile tics, gait abnormalities, stooped posture, and loss of cognitive functioning. These arise from a lifetime of cumulative damage to the brain from many causes: drugs, environmental toxins, viruses, and the loss of brain tissue that accompanies the normal aging process. Will silent damage caused by a serotonin booster accelerate the aging process and make some people more prone to develop neurological symptoms later in life? In some instances, Parkinson's disease is caused by viral infections. In one form of postinfectious Parkinson's disease seen after World War I, some patients did not develop symptoms until twenty-five years after the original exposure to the viral toxin. Their symptoms are thought to have developed because of a variety of factors, including the cumulative effect of the original damage plus the loss of nerve cells and additional damage that accompany aging.

In the case of Parkinson's disease, we know the group of cells in the brain that are destroyed. The cells are believed to be weak links in neural circuitry particularly vulnerable to damage. Autopsy studies have shown that by age sixty individuals who do not have Parkinson's disease have lost about 40% of cells in this region as a result of normal aging. By contrast, patients with Parkinson's disease have lost 80% or more of the cells in this region. If normal aging claims 40% of the cells and patients with Parkinson's disease have lost 80%, this normally leaves a comfortable reserve of 40% offering protection against the disease.

We know a great deal about Parkinson's disease because this is such a well-studied entity, but this model of a comfortable reserve that can be eroded may well apply to other areas of the brain and symptoms that are less well understood. What if being on a serotonin booster for a decade damages a quarter or a third of the cells in a particular region of the brain? This might not be sufficient to produce symptoms in a young patient, but would dangerously narrow the margin of safety later in life. Will someone who has been on a serotonin booster for a decade in her twenties be prone to prematurely develop neurological conditions — senile tics, gait disturbances, memory loss, personality changes, or dementia — because of silent damage sustained years earlier while on the drug?

The best-known diseases of the involuntary motor system, Parkinson's and Huntington's disease, can cause dramatic personality changes and severe dementia as they progress. We now know that the involuntary motor system is crucial not only to motor behavior but to motivation and information processing of all kinds as well, because it is in constant communication with the cerebral cortex, the site of higher cognitive functioning. This is why damage to these deep brain structures can eventually destroy personality, intellect, cognition, and memory. Indeed, some experts believe there is considerable overlap between the dementia seen in diseases of the involuntary motor system and the dementia seen in Alzheimer's disease.

Recently a physician colleague of mine had to travel to California to put his mother in a nursing home because severe memory loss made it impossible for her to continue living independently. In addition to disabling memory deficits, his mother's personality had changed profoundly in the years immediately preceding the move to the nursing home. Whereas all her life she had been a strong-willed, independent woman who ran her own business, now she was a timid, docile shadow of her former self. "For all intents and purposes my mother is gone," said the colleague. "She's semi-living. What's left is not the woman I knew." The changes were all the more tragic because otherwise his mother was in good physical health.

During the trip, my colleague and his wife visited his mother's neurologist, who showed them a CAT scan of her brain. The scan showed significant loss of brain cells, thinning of the tissue, and resulting expansion of the fluid-filled cavities in the brain. While the scan explained his mother's symptoms, what puzzled the doctors was that the tissue loss was so advanced for someone her age. Her brain scan looked like that of someone ten to fifteen years older.

As they left the hospital, my colleague's wife asked, "What could have caused this to happen? Your mother wasn't an alcoholic. She hasn't had any strokes. She didn't smoke. What can it be?"

"The only thing I can think of," he responded, "is that for the past thirty years she's taken every popular psychiatric drug to come along." The majority of them were major tranquilizers and antidepressants, most recently Prozac and Zoloft. The colleague related the story to me because he had seen patients with dramatic memory loss on serotonin boosters. As a physician, he is concerned that psychiatric drugs can cause silent injury to the brain over many years in ways we do not yet understand.

Patients Have a Right to Know

Many patients looking for information on these side effects have to turn to chat rooms on the Internet, support groups in cyberspace for people on the drugs, because so little official information is available. In this Internet correspondence, people post notices or questions to which others can then respond. A number of patients have brought me representative printouts from chat rooms with names like alt.support.depression, alt.support.anxiety-panic, and alt.support.ocd at Web sites with names like www.dejanews.com. Reading the Internet correspondence, I was struck by the similarities between what people are reporting on the Web and what I have seen in my office.





Asked one person, "Anyone on SSRIs [serotonin boosters] get real bad, i.e., terminal leg twitching? Anyone know anything about this?"

Responded another, "There is some research (I've seen it posted here a couple of times) that SSRIs lead to a dopamine drop, which is the current theory for how they cause these side effects."

"In the past, I've occasionally experienced an eyelid twitch or tic, but it seems that the condition has increased considerably since taking the Luvox," said a third correspondent. "Has anybody else experienced this?"

"I find I get a 'flutter' or 'twitch' under my eyelid. I used to get this occasionally if I was tired, but since taking Zoloft, I find I am getting this much more often, even after what seems like a good night's sleep. It's not a blink, just a twitching feeling around the eyelids (sometimes top, sometimes bottom). It seems to happen quite randomly during the day and I'm not sure if it is visible to others. So the proverbial question, 'Am I nuts' or has anyone else had this side effect with Zoloft?"

"Oh, my goodness, yes! I had that happen to me all the time on Zoloft and thought maybe it was my imagination! It's weird, hey? I often wondered if other people could tell, but I don't think they can. So no you aren't nuts, unless I am too."

"I'm curious about the muscle twitches I've had on Paxil. Actually, I'd call them spasms. My stomach muscles will twitch so badly that it'll wake me up at night. Has anybody else experienced these spasms?"

"Yup. Sounds familiar, and otherwise normal, for SSRIs."

"When I was on Effexor, I got this weird side effect: While I was falling asleep or when my body was relaxed, like when I was lying down watching TV, I would get twitching in my legs and head/neck, like involuntary movements. Now that I've decreased my dose from 225 milligrams per day to 150, it doesn't happen nearly as often but does happen on occasion. Am I the only one who's had this weird effect?"

"I started Paxil a couple weeks ago. I've been getting occasional muscle twitches, usually in my legs. Actually, I don't know if 'twitches' really defines it very well. What happens is a muscle will all of a sudden tighten up with a jerk, causing an involuntary movement. Is this muscle-twitch stuff a big deal? Or is it just one of those miscellaneous 'perks' that comes from using antidepressants? If it's relevant I'm on Buspar as well. But this stuff started with the Paxil so I think that's what's causing it."





Reading this entry, I thought, Combinations of Buspar and a serotonin booster may be worrisome, since both have been implicated in involuntary movement disorders. Also worrisome are combinations of serotonin boosters and major tranquilizers. And increasingly, patients are prescribed two serotonergic drugs simultaneously in what psychopharmacologists call "drug cocktails," again, compounding the risks.

Still another person responded to the above entry:





"I've never eaten Paxil but I got lots of twitches from Zoloft and from Wellbutrin. My doctor was a little surprised at my twitches, but not completely. I spoke to a couple of doctors about it including a Parkinson's disease researcher. I just had to get off those drugs because the twitches eventually caused me too much anxiety."





Patients should not have to turn to the Internet in hopes of finding information that ought to be readily available from their doctors. Unfortunately, the history of delayed reaction to these side effects with major tranquilizers appears to be repeating itself with serotonin boosters. In spite of reports estimating thousands of cases of neurological side effects, the reaction is again slow, marked by hesitancy to inform the public. The spontaneous reports by clinicians are considered to represent a small fraction of the total number of cases, which only more systematic monitoring would expose. In recent years some psychiatrists have tried to call professional attention to the problem. In the February 1995 Canadian Journal of Psychiatry, Dr. Paul Hoaken wrote an "alert" on involuntary motor disorders with serotonin antidepressants. In the October 1996 Journal of Clinical Psychiatry, Dr. Raphael Leo wrote a review article called "Movement Disorders Associated with the Serotonin Selective Reuptake Inhibitors" [SSRIs, i.e., serotonin boosters], in which he said, "This article addresses a previously underrecognized but clinically significant consequence of SSRI use, namely, the development of movement disorders. These disorders can be uncomfortable for patients, influence compliance, and contribute to significant psychosocial and occupational impairments." In the January 1997 Psychiatric Times, psychopharmacologist Frank Ayd said of the published reports of antidepressant-induced tics, "In most instances, TD [tardive dyskinesia]-like symptoms [tics] did not improve with Prozac discontinuation."

Concerns have been raised over whether any one or two of the serotonin boosters are more likely to cause these side effects than the others. In February 1993, the British Committee on the Safety of Medicines, the equivalent of our Food and Drug Administration, raised concerns in their newsletter, Current Problems in Pharmacovigilance, that some neurological side effects seemed to occur "more frequently with Paxil" than with other serotonin boosters. In test tubes, Paxil is one of the most potent of the serotonin boosters. The following month, however, Vivien Choo in the British medical journal Lancet examined the database of the Drug Safety Research Unit in Southampton, England, and concluded that this was not the case. Reported Choo in the Lancet, "Comparison with PEM [prescription event monitoring — i.e., side-effect monitoring] data on two other SSRIs, Luvox and Prozac, show that the reactions are not commoner with Paxil than with these two drugs...." Choo concluded that "the reactions seem to be a class effect," meaning they occur with all the drugs in the Prozac group.

Significantly, there is beginning to be some official recognition of the problem: In the most recent edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM IV), the mental health professional's diagnostic bible, a specific category was added recognizing these antidepressant-induced movement disorders. Most recently, psychopharmacologist Ronald Pies (cited earlier for his comparing serotonin boosters to major tranquilizers) published an article in the January 1999 issue of the Psychiatric Times in which he advocated that patients on serotonin boosters should be informed of these potentially dangerous side effects and evaluated for whether or not they are experiencing any of them. But not all physicians agree with the approach of Dr. Pies. Shortly after his article was published, I attended a Harvard conference at which another leading psychopharmacologist gave a talk on serotonin boosters. This psychopharmacologist said Pies was "crazy" to suggest informing patients. He protested, "You can't tell patients whom you're giving something that's supposed to help them that it may poison them." He insisted, "We have to put the best face on our treatments."

A colleague in the next seat commented under his breath, "Would he have said the same about Thalidomide [the psychiatric drug that later proved to cause severe birth defects], morphine, and amphetamines when these were popular prescription drugs in their day?" Should doctors not have voiced their concerns to patients taking these drugs as serious side effects began to emerge? Or should they have remained silent and ridden the enthusiasm for the popular medications for as long as it lasted?

While doctors debate what people should be told, many patients with early, mild cases of the neurological side effects of serotonin boosters may go undetected. Instead of diagnosing them early, patients will continue to be exposed to the drugs when this could have been prevented, just as happened with major tranquilizers. Especially in managed care settings, little or no effort is made to periodically reassess whether a patient's dosage can be reduced or the drug stopped. Instead, the drugs are thoughtlessly prescribed year after year. Often the dose needed to maintain the effects of these drugs once they are working is much lower than the dose required for start-up. In my experience consulting to patients who have been treated with these drugs, about 75% are able to dramatically reduce their dose or eliminate the drug altogether.

In light of these neurological side effects, we should especially question how freely these drugs are being prescribed to children. When major tranquilizers were in vogue, they were readily prescribed to children for mild anxiety, insomnia, or hyperactivity. The drugs are no longer used in this way on children because they cause tics. Current estimates are that serotonin boosters are being prescribed to over half a million children in this country, with pediatric use of the drugs one of the fastest-growing "markets." This in spite of repeated studies showing antidepressants are no more effective in children and adolescents than placebos. Should we not be protecting children, with their developing nervous systems, from drugs with potentially serious side effects?

With reports estimating thousands of cases of these serious side effects occurring with serotonin boosters and research documenting the drugs' effects on dopamine as the likely cause, we have strong evidence the drugs are doing something worrisome in the involuntary motor system deep in the brain. How many people on a serotonin booster are silently developing tic disorders? How many others are incurring silent brain damage that could accelerate the aging process, even if they do not develop overt symptoms? Drug advocates and advertisements that portray serotonin boosters as having only trivial, transient side effects are terribly misleading. We need more systematic, long-term monitoring of patients who have developed these side effects and more thorough research on how the drugs cause them. But while we are waiting for definitive answers that could take years, even decades, patients should know about these conditions sooner rather than later in order to make informed choices.