the Dangers of Prozac, Zoloft, Paxil, and Other Antidepressants With
Safe, Effective Alternatives
Simon & Schuster
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
"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
"A medication side effect?" said Maura, dumbfounded.
"Yes. It looks like a tic disorder called tardive dyskinesia."
"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
"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?"
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
"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
"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
"And the other half?"
"Sometimes they get a little better."
"But they're permanent?"
"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
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
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
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
"Stress exacerbates these tics, for reasons that are not clear," I
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
Leslie's Amotivational Syndrome: A Case of Fatigue and
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
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
These were lively statements and ideas, not what one would expect
to hear from someone profoundly depressed. "Why don't you just do it?"
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
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
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
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
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
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
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
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
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,
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
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
"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
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
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
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
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
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
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
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
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
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
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
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
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
"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
"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
"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
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
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
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
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.
(C) 2000 Joseph Glenmullen All rights reserved. ISBN: