--Demitri and Janice Papolos
It's hard to believe that
just about a year ago this site went live on the World Wide Web. We want to
thank all of you who've visited and provided important feedback. Your responses
to the July newsletter on night-terrors, in particular, indicated that many
children are suffering from these parasomnias and helped us assemble invaluable
data. You've enriched our knowledge
base about children with early-onset bipolar disorder.
Your comments on the site also allow
us to note emerging trends in prescribing practices. One of the most recent
we've spotted is the treatment of bipolar disorder in children and adolescents
without mood stabilizers, but rather with one of the newer, "atypical"
antipsychotic drugs such as olanzapine (Zyprexa), quetiapine (Seroquel), or
risperidone (Risperdal), often as a stand-alone therapy. In other words, the
only medication prescribed is one of these three newer antipsychotic drugs,
whose properties include antimanic effects, and so-far, unproved mood-stabilization.
Is this wise? Is this effective?
Are the risks involved less than those of the mood stabilizers (lithium and
several anticonvulsants)? What are the possible long-term effects? Why is this
apparent shift in prescribing practice appearing now?
We spent some time reviewing the
literature and interviewing some outstanding researchers and clinicians in the
field because there's a lot to examine here. First, however, we need to consider
the antipsychotic drugs in general, and their traditional role in psychiatry
and in the treatment of bipolar disorder.
Some History
The original antipsychotic drugs
were phenothiazines, originally used for their sedating and putative stress-limiting
effects before general anesthesia for surgery. Parisian military surgeon Henri
Laborit noticed that patients who were given chlorpromazine became remarkably
calm, but remained awake. These impressions soon spread to other physicians,
including the psychiatrist, Pierre Deniker. By 1952, Dr. Deniker and Dr. Jean
Delay completed their first clinical trials with chlorpromazine (Thorazine and
others), finding first that it was very effective in mania, and later that it
diminished delusional thoughts and hallucinations in schizophrenia. Before long
it was being used all over the world as a treatment for psychotic illness and,
often, also for mania.
Other commonly-prescribed standard
antipsychotic drugs include other phenothiazines, such as fluphenazine (Prolixin),
perphenazine (Trilafon), thioridazine (Mellaril), and trifluoperazine (Stelazine),
and other types of chemical agents, such as haloperidol (Haldol), pimozide (Orap),
and molindone (Moban). While they all have side effects, doctors and patients
and family members are concerned about the side effects that involve movement
or posture--the so-called extrapyramidal side effects (EPS) that encourage use
of the older term "neuroleptic" for these agents. These include early
and later muscle contractions (dystonia), slowed movements (akinesia, or parkinsonism),
restlessness with severe anxiety (akathisia), and later-emerging tardive dyskinesia
(TD). Let us explain these briefly.
Dystonic reactions are involuntary
muscle contractions that cause bizarre and uncontrolled movements of the face,
neck, tongue, and back and an uncontrolled rolling of the eyes, sometimes with
life-threatening compromise of the muscles required for breathing. It is quickly
counteracted by antihistamines including diphenhydramine (Benadryl) or anticholinergic-antiparkinson
drugs such as benztropine (Cogentin) or trihexyphenidyl (Artane).
Akinesia, or drug-induced parkinsonism,
resembles Parkinson's disease, with variable tremor and slowed movements characterized
by stiffness and diminished spontaneity of gestures, physical movement and speech.
It is also counteracted by the anticholinergic-antiparkinsonism drugs.
Akathisia is a feeling of restlessness
and an inability to sit still, as well as a subjective sensation of discomfort
usually described as anxiety and often mistaken for agitation due to primary
psychiatric illness, rather than a drug side effect. This very common condition
is often overlooked or misunderstood, and can be difficult to treat. Sometimes,
the use of the antihypertension beta-blocker propranolol (Inderal) or a benzodiazepine
sedative may help.
These movement disorders are usually
dealt with by lowering the dose of the antipsychotic medication, adding an antiparkinson
drug, or switching to another class of antipsychotics. Generally, the more potent
(fewer mg/day doses), older antipsychotic drugs are more likely to induce such
reactions, whereas the less potent agents more commonly produce excessive sedation
and low blood pressure. Antipsychotic agents including clozapine and the newer
atypical agents reviewed here, are less likely to have such effects. Indeed,
that is the main reason t hey are considered "atypical" antipsychotics.
Tardive Dyskinesia
Perhaps the most publicized side-effect
of antipsychotic drugs is tardive dyskinesia, the "late appearing"
disorder characterized by abnormal movements. It can present with involuntary
facial grimacing, lip-smacking, chewing and sucking movements, cheek puffing,
and worm-like movements of the tongue, as well as quick movements of the fingers,
toes, arms and legs, or dystonic, writhing postures. Tardive dyskinesia tends
to wax and wane spontaneously, and in young patients, often remits spontaneously,
particularly if the offending agent is stopped.
Before the approved use of lithium
for manic-depressive illness (US, 1970), antipsychotic drugs were the only medications
that could control acute mania, and they were also widely employed to suppress
re-emerging manic symptoms, and had value for at least the psychotic symptoms
sometimes associated with depressed phases of bipolar disorder. Even after lithium
and the anticonvulsant antimanic agents became available, standard antipsychotics
continued to be widely used in the management of bipolar disorder patients.
Nearly all adult patients with bipolar disorder have had some exposure to a
traditional antipsychotic agent at some time. This usage is of particular concern
due to evidence that persons with mood disorder may be at even greater risk
for tardive dyskinesia than patients with schizophrenia or other chronic psychotic
disorders.
The Newer "Atypical"
Antipsychotics
In 1990, a new kind of antipsychotic--clozapine
(Clozaril)--came onto the US clinical market. This old drug had been known since
the 1960s, but was in and out of favor due to its strong association with potentially
lethal suppression of the production of white blood cells by the bone marrow
(agranulocytosis). However, demonstration of its superior effectiveness over
standard antipsychotic drugs led to its late acceptance in the United States.
Clozapine remains unique in its demonstrated clinical superiority, as well as
its atypical lack of risk of EPS. It strongly stimulated development of other
drugs with some similar properties, but greater safety. Among its applications
include use for the management of patients with otherwise intractable forms
of schizoaffective and even bipolar disorder, though formal research supporting
this use remains sparse.
The first of this new generation
of atypical antipsychotic agents was risperidone (Risperdal). It was followed
more recently by olanzapine (Zyprexa), and quetiapine (Seroquel), and still
others, notably ziprasidone (Zeldox), remain in advanced stages of clinical
development. These newer antipsychotic medicines are considered "atypical"
because they have relatively lower risks of acute EPS and TD, though not as
low as with clozapine. They also share with clozapine interactions with a wider
range of chemical messenger systems in the brain. They are not yet proved to
be superior clinically. However, studies to test this hopeful prediction are
ongoing.
Because the risk of TD and other
movement disorders is less with these newer medicines, they are commonly prescribed
in conjunction with a mood stabilizer such as lithium, carbamazepine (Tegretol)
or divalproex (Depakote), sometimes with both classes of drugs used on a long-term
basis. Nevertheless, it is important to emphasize that this practice remains
entirely empirical and clinical, and has not yet been tested in appropriate
research studies.
Clinical experience with childhood
bipolar disorder patients suggests that the atypical antipsychotic agents may
accomplish things and target symptoms that mood stabilizers don't. The atypicals
may benefit children who have prolonged rage attacks, psychotic symptoms, mixed-irritable
moods, and possibly very rapid cycling of mood--all of which are relatively
commonly associated with early-onset bipolar disorder and may require different
forms of treatment than are usual in adults.
"In many ways," says Mark
Sandrolini, M.D., Medical Chief of Outpatient Child Psychiatry at Rush-Presbyterian
St. Luke's Medical Center in Chicago, " the use of the term 'antipsychotic'
is a misnomer. These drugs not only work against psychosis and mania, but they
reduce hostility, and rage as well as anxiety and agitation."
The popularity of the newer atypical
antipsychotics for childhood bipolar disorder patients is growing rapidly, and
we have now heard of a number of cases where these drugs are prescribed alone,
as the major, or only treatment offered. Usually, this practice involves drugs
other than clozapine, since its potentially severe toxic effects and need for
regular blood sampling to monitor white blood cell counts make it clinically
less appealing than the simpler alternatives--Seroquel, Risperdal and Zyprexa.
If studies of combinations of atypical antipsychotics with antimanic-mood stabilizing
agents are limited, those involving monotherapy with an antipsychotic agent
in children are practically nonexistent.
One mother whose son's treatment
strategy called for Zyprexa as a monotherapy for his newly-diagnosed bipolar
disorder wrote us and asked: "Is my child being used as a guinea pig?"
Some thoughtful and experienced
clinicians are using this approach, and find that it can be quite helpful for
some young bipolar patients with bipoalr disorder. For example, this past May,
Dr. Raymond Behr, a highly respected clinical child psychiatrist at Albert Einstein
College of Medicine and the founder of the Child Psychopharmacology ListServ
for child psychiatrists, wrote about his success prescribing the atypical antipsychotics
in certain circumstances as a monotherapy. He also cited two recent, placebo-controlled
studies done by Dr. Mauricio Tohen and his team at Eli Lilly Laboratories, showing
that olanzapine (Zyprexa) proved superior to placebo in the short-term treatment
of adults with acute manic or mixed states. Similar work supports the antimanic
actions of risperidone (Risperdal) as well.
We called Dr. Tohen to find out
more detail. When we asked him what he meant when he stated that Zyprexa was
"mood stabilizing," he told us that their studies revealed that Zyprexa
not only worked on the manic and psychotic symptoms, but was also effective
on the depressive symptoms of mixed states or the depressive aspects of acute
mania. That statement may be a bit bewildering, but manic states are not just
a constant high with grandiose and activated thought, speech and behavior. Often
in adults, and very commonly in children, mania is interlaced with a rapidly
shifting mood (mood lability), irritability, sadness, sleeplessness, anxiety
and agitation. Dr. Tohen hastened to add that his study did not demonstrate
a therapeutic effect in acute depression, nor a long-term mood-stabilizing effect
on all phases of manic-depressive illness, though he indicated that such studies
are being mounted.
In 1995, Drs. Gianni Faedda and
Ross Baldessarini and their colleagues published an important review, entitled
"Pediatric-onset bipolar disorder: A neglected clinical and public health
problem." In it, they made a strong point that juvenile mania often includes
psychotic features and a good deal of agitation, aggression, possibly more so
than in adolescent or adult forms of the illness. They also emphasized evidence
of the tendency toward an admixture of manic and depressive-dysphoric-irritable
elements in kids--more than in adults--and a common lack of a clean episodic
course, or very rapid fluctuations of mood and behavior in bipolar kids.
Since agitation is a principal component
of mixed manic-depressive states, and the majority of children with bipolar
disorder have very rapid cycling as well as commonly mixed states, it should
come as no surprise that the atypical antipsychotic medications may prove to
have a special place in the treatment of pediatric bipolar disorder. Risperdal,
Zyprexa, and Seroquel can calm the agitation, anxiety, and rage and hostility,
as well as diminish psychotic symptoms such as hallucinations and delusions.
When we contacted Joseph Biederman,
M.D. at Harvard, an authority on pediatric bipolar disorder. He said: "It
is my opinion that the atypical antipsychotics are much more effective in the
treatment of pediatric mania than the mood stabilizers." (It should be
noted that Dr. Biederman sees pediatric mania as a chronically irritable state.)
So, there is some rhyme and reason
here, based on the nature of juvenile bipolar illness. In addition, the atypical
antipsychotic drugs are user-friendly to children and clinicians. They are easy
to administer, and, unlike the anticonvulsants, lithium, and clozapine, blood
drawing is rarely required to monitor blood concentrations and regular laboratory
testing is not required. Moreover, compliance with treatment is often a major
issue for children. Multiple pills are hard for young children to swallow, and
teenagers have a host of issues about taking any medicine. Any simplification
that can be gained by a monotherapy would be welcome.
But--ease aside--do these treatments
do the job and are there any negatives associated with them?
Some Negatives
As with lithium and with some anticonvulsants,
two words come to mind when discussing the down-side of atypical antipsychotics:
Weight gain. Not every child gains weight on these medicines, but many do, particularly
with Zyprexa. And when they do, it can be astonishing. The mother who e-mailed
us above about Zyprexa wrote: "He has put on eight pounds since Friday
and it's continuing." Since we received her e-mail on Tuesday, we wrote
back to make sure we were talking about a four-day period. "Yes,"
she shot back through cyberspace. That's two pounds a day, and climbing.
The atypical antipsychotics cause
more weight gain than most of the conventional antipsychotic medications. Dr.
Tohen told us that the weight-gain seems to be greater in children than in adults
and that the younger the age the higher the risk, but that it is unclear why.
In adults, there is some evidence that the weight-gain may not persist indefinitely,
and may diminish after a year. Since the weight-gain usually appears right away
in children, as it did in the little boy mentioned above, one can assume it
will continue and consider alternative treatments. It is unknown why people
gain weight (and so much of it) but it is hypothesized that the drugs' effects
on the part of the hypothalamus that regulate satiety may be the root cause.
Some clinicians will even mix olanzapine with risperidone and particularly with
quetiapine, in order to limit weight-gain, and there are promising observations
of a weight-limiting effect of the novel anticonvulsant topiramate (Topamax).
Side Effects Beyond Weight Gain
While movement disorders (EPS and
TD) are less likely with the atypical than the older, standard neuroleptic-antipsychotics,
they do occur. Nevertheless, the specific risks of EPS and TD with the newer
drugs remain to be sorted out for children and adolescents. They appear to be
very low with both clozapine and quetiapine, and are substantially higher with
both olanzapine and risperidone, especially with higher doses of both drugs.
Risperidone has a broad dosing range, but is often useful, and safer, at remarkably
low doses, particularly in children. Risperidone and olanzapine might, therefore,
be considered "quantitatively atypical" drugs since their EPS risks
are not negligible, and are clearly greater than with clozapine.
Some clinicians recommend that parents
of children taking any antipsychotic medicine have a filled prescription of
an antiparkinson agent (such as Artane or Cogentin, or liquid Benadryl) in the
house to administer immediately. Movement disorders can be terribly distressing
and uncomfortable for a child and some of the movement disorders (particularly
acute dystonic reactions) can be reversed quickly (within a half hour). Some
physicians prescribe these drugs on a daily basis to prevent dystonic reactions
from occurring. Their benefit in preventing or treatment akathisia--the sense
of inner restlessness-- however, is much less convincing.
Other side effects reported are
sedation, nausea, constipation, blurring of vision, nasal congestion, and dry
mouth. We've heard parents complain of drooling and urinary incontinence from
risperidone (these symptoms are well-known to occur with clozapine). Also, there
is some anecdotal evidence and a few case reports in adults that rsiperidone
and olanzapine have been associated with the induction of manic or mixed states.
This may be because the atypical antipsychotics have an anti-serotonin (5-HT2)
receptor blocking effect and thus are mood elevating. (We have heard of an induction
of mania in children and a few adolescents, and it's something parents should
be aware of.)
Finally, there are a series of general
medical, metabolic problems that are being increasingly reported in association
with clozapine as well as the newer antipsychotics. These include new-onset,
type II (non-insulin dependent) diabetes mellitus, changes in lipid metabolism
and blood concentrations, sometimes severe and persistent elevations of prolactin
and other hormonal imbalances, and a range of adverse cardiovascular effects
that include low blood pressure and abnormal functioning of the heart. The long-term
implications of such adverse effects are not known, particularly for youngsters
who may need to remain on such medication for decades to come. Moreover, we
are just starting to be concerned about the potential individual and public
health implications of such effects, which threaten to be at least as problematic
as TD and EPS of the older drugs.
Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome is
now a rare, but life-threatening, adverse reaction to antipsychotic drugs that
is poorly understood. Most cases have been associated with use of relatively
high, or injected doses of the more potent older neuroleptic-antipsychotic agents.
The relative risks with the newer antipsychotic agents is not known, but a few
cases have been reported, particularly with risperidone, the atypical most nearly
like the older antipsychotics. The condition has been encountered in children
and adolescents, though it is more common among the elderly. They become severely
rigid and tremulous, can be very confused, and may have a high fever, unstable
heart rate and blood pressure, labored breathing, and a blood test for an enzyme
that is specifically released from over-stressed muscle tissue (creatine kinase)
may increase dramatically.
This syndrome constitutes a true
medical emergency. All antipsychotic medicines should be stopped immediately
at home, and the child taken immediately to a hospital emergency service. There,
cardiac monitoring, fever control, and fluid maintenance are usually administered,
and drugs with muscle-relaxing (especially dantrolene [Dantrium]) or dopamine-stimulating
effects (e.g., bromocriptine [Parlodel]) may be helpful. However, the primary
means of limiting fatalities from this potentially lethal form of catatonia
and fever is expert general supportive care.
Many people might ask: Who would
expose a child to something like this or tardive dyskinesia or the movement
disorders? Well, it all goes back to risk/benefit. The chances are that the
movement disorders and tardive dyskinesia or NMS may not appear, but certainly
psychosis, severe rage, profound anxiety, and mania are malignant for a child.
Untreated psychotic symptoms or mania gravely imperils a child.
Seroquel
When we handed in the manuscript
for our new book, The Bipolar Child, few doctors had experience with Seroquel
and in animal testing there was some association with cataracts and high-dose
Seroquel treatment in dogs. This problem was not found in monkey studies or
human trials, however, and while it's a good idea to have baseline and follow-up
eye examinations, cataracts do not now seem to be a major concern.
Since weight-gain is such a confounding
problem--particularly in children--the risks of medical complications beyond
movement disorders with most of the atypicals, may supersede the benefits of
some of these drugs, particularly when clinicians entertain the idea of their
use as a long-term monotherapy. For this reason, Seroquel may prove to be particularly
useful, since it appears to produces far less weight gain at lower dosage ranges
(50-150 mg ) than its cousins olanzapine and clozapine, and possibly less than
risperidone. It may even limit weight-gain when combined with small doses of
the other atypical antipsychotics.
When All is Said and Done
So, will the atypical antipsychotics
replace mood stabilizers as a first-line of treatment in children with bipolar
disorder? Not in our opinion, and not in the opinion of most everyone to whom
we spoke. It has yet to be proved that the atypical antipsychotics actually
stabilize mood over prolonged times, and prevent further episodes of bipolar
depression and mixed states as well as mania, and that they do so at least as
well as lithium and perhaps some anticonvulsants. In fact, lithium is unmatched
in research support for long-term clinical effectiveness against all phases
of manic-depressive illness and there is substantial evidence that lithium has
a strong and possibly unique effect against suicidal behavior. Lithium also
has been shown to prevent neuronal cell death and enhance neuronal growth, though
the clinical implications of these intriguing effects are not known.
It is clear that most antipsychotic
medications work very rapidly in acute mania. This advantage appears to include
the newer atypical antipsychotics, although they are limited in not being available
in injectable forms, and by their sometimes limited tolerability when administrated
in initially high doses. Their effects on rage and anxiety are impressive. A
new atypical antipsychotic is ziprasidone (Zeldox). It is likely to enter the
US clinical market soon, and it does not cause as much weight-gain as olanzapine
(Zyprexa).
Other potentially serious long-term
risks of the newer atypical antipsychotic drugs remain to be adequately evaluated.
In addition to sometimes massive weight-gain, these appear to include adverse
metabolic, hormonal, and cardiovascular effects. Even the risks of EPS and TD
with the newer drugs remain to be sorted out for children and adolescents.
In general, children tend to break
down and eliminate most drugs more rapidly and efficiently than adults and elderly
persons. That tends to protect them from drug side effects. However, there is
both laboratory and clinical evidence that children and younger animals are
more sensitive to antipsychotic drugs than adults, and require much smaller
doses. As the optimal dosing with the newer antipsychotic drugs is worked out,
it is wise to start with low doses in children. For example, daily doses of
Risperdal of 0.25 to 2.5 mg, 2.5-5 mg of Zyprexa, and less than 200 mg of Seroquel
may suffice. Hopefully, such doses may also limit side-effect risks.
Gianni Faedda, M.D. of the Lucio
Bini Center for mood disorders research in New York City wrote us the following
statement when we spoke to him about this newsletter. It seems appropriate to
end this discussion with his words:
"In children and adolescents,
Risperdal, Zyprexa, and Seroquel are useful in the acute and maintenance treatment
of bipolar disorder. Although I have used both Seroquel and Zyprexa in monotherapy
in selected cases, I am not willing to advocate their routine use as monotherapy,
as the available data remain inadequate to justify this practice.
I remain of the opinion that all
the effective mood stabilizers are antimanic agents (with the possible exception
of lamottrigine (Lamictal). Their mechanism of action is probably not unitary,
and some patients respond to one but not to the other.
Until their safety and efficacy
both in the acute and maintenance phases of treatment are proven, they should
be used as second-line agents or as add-ons, unless there are compelling reasons
(such as failure to respond to a combination of lithium and an anticonvulsant,
or inability to tolerate therapeutic doses of the mood stabilizers)."
Dr. Faedda went on to say something
else very important: "It should be emphasized that antidepressants can
cause a trial of a mood stabilizer to look as though it has failed because the
antidepressants can be very destabilizing for a child or adult with bipolar
disorder. Stimulants can do the same thing. Therefore, a gradual tapering of
antidepressants and stimulants and an assessment of response to mood-stabilizing
agents should precede the addition of antipsychotics--typical or atypical."
*************
We'll write again soon. Meantime, let us know how your children are responding
to any of the medications mentioned above. We'll keep asking the questions and
monitoring the research findings as they appear and report back what we find.
We send you our best,
Janice Papolos and Demitri Papolos, M.D.
The authors wish to thank Ross J. Baldessarini, M.D., one of the foremost
authorities on antipsychotic medications, for his invaluable contribution to
this newsletter.
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Demitri Papolos, M.D.
Copyright 1999-2000
http://www.bipolarchild.com
info@bipolarchild.com
