General Interest > Feed Your Head
Lincoln's Melancholy
Anonymous:
The new england journal of medicine
n engl j med 353;12
http://www.nejm.org september 22, 2005 1286
editorials
The Choice of Antipsychotic Drugs for Schizophrenia
Robert Freedman, M.D.
Since the discovery of the effects of chlorpromazine in the 1950s, treatment of schizophrenia has relied on antipsychotic drugs that target dopamine D2 receptors.
The effectiveness of these agents in reducing
the intensity of patients? delusions and hallucinations permitted outpatient treatment instead of lifelong institutionalization in state mental hospitals.
The many antipsychotic drugs introduced during
the next decade were increasingly potent, as medicinal chemists improved the drugs? affinity for the D2 receptor. However, the efficacy of the drugs was similar, since all had the same mechanism of action. (1)
A troubling problem was that the blockade of
dopaminergic neurotransmission in the basal ganglia caused parkinsonian syndromes. A long-lasting movement disorder, tardive dyskinesia, also occurred with prolonged treatment. More fundamentally, the early promise that these drugs might dramatically improve patients? psychosocial and cognitive disabilities was only partially fulfilled. (2)
Although many mental hospitals were closed, mental
health centers were filled with outpatients who
could not live successfully in their communities.
By the early 1970s, the European experience with
one drug, clozapine, suggested that it might be significantly more effective than other antipsychotic drugs and that it did not cause movement disorder to the same degree as the others. Clozapine indeed proved to be more effective at reducing symptoms than other neuroleptic agents. (3)
However, the potential of clozapine to cause toxic side effects, including agranulocytosis, has limited its prescription to about 10 percent of persons with schizophrenia. Clozapine was labeled an atypical antipsychotic agent because it caused less movement disorder than other antipsychotics.
The mechanism of action of clozapine differs in many ways from that of other dopamine D2 receptor antagonists; the most popular hypothesis is that it has weaker D2 antagonism and stronger antagonism at serotonin 5-hydroxytryptamine receptors. (4)
Pharmaceutical companies, acting on this hypothesis, have developed new drugs, attempting to capture the enhanced therapeutic effect of clozapine without its toxicity. The resultant second generation of drugs now accounts for the majority of antipsychotic drugs prescribed
for all psychiatric uses, including schizophrenia.
Concerns have emerged about this new generation
of drugs. First, although clozapine was introduced
after studies indicated that it had more
efficacy than first-generation drugs, the other new antipsychotic agents were marketed after studies showed efficacy that was only comparable to that of older drugs. Thus, the issue of whether they, like clozapine, were truly more effective remained largely unanswered. Second, although the newer drugs fulfilled their promise of causing less movement disorder, new problematic side effects ? severe weight gain, often accompanied by type 2 diabetes mellitus and hypercholesterolemia ? emerged. (5,6)
Weight gain had occurred with the older drugs, although it was generally less substantial. Third, the cost of newer medications caused payers to question their purported value. Therefore, the National Institute of Mental Health undertook a multisite, double-blind comparison between an older drug, perphenazine, and a series of the newer drugs; clozapine was omitted because it had already been observed to have superior efficacy.
The results of this work, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), are reported in this issue of the
Journal. (7)
What to measure in such a trial is itself problematic. Schizophrenia is a chronic disability of mental and social function, with superimposed
episodes of exacerbated psychotic symptoms. In
addition to hallucinations and delusions, affected
patients have characteristic neuropsychological difficulties, including problems in paying attention, learning new information, and recognizing social cues, such as the emotional meaning of facial expressions.
Their social isolation, loss of sense of
pleasure, inability to make decisions, and poor selfcare forms a third symptom complex. Patients who carry the diagnosis of schizophrenia vary markedly in these various aspects of their illness. Efficacy is therefore difficult to measure. The time to discontinuation of medication for any reason ? a side effect, poor efficacy, or the patient?s decision about adherence ? was the principal outcome variable in CATIE. Its advantage as a primary measure is that it is relatively definable and less subject to the vicissitudes
of patients? descriptions of their symptoms
and the perception of these symptoms by others,
even those trained in assessing them. CATIE used a
single scale, the Positive and Negative Syndrome
Scale (PANSS), to rate patients? symptoms as a secondary outcome. Side effects were recognized as
an important issue in the design of CATIE.
The results could be viewed as discouraging.
No drug provided the majority of patients a treatment that lasted the full 18 months of the study.
Thus, treating schizophrenia, even with new-generation drugs, is only partially effective and is associated with problematic side effects.
Only 36 percent of the patients receiving the most effective drug, olanzapine, completed the trial.
Twenty-five percent of those receiving perphenazine completed the trial. Patients receiving other second-generation antipsychotic drugs ? quetiapine, risperidone, and ziprasidone ? did no better than those receiving perphenazine.
Thus, there was a small improvement with olanzapine as compared with the first-generation drug perphenazine, but this advantage was not observed with the other second-generation drugs.
This difference was reflected in the other clinical measurements, including PANSS ratings.
The greater efficacy of olanzapine, as compared
with that of these other drugs, is consistent
with the results of a recent meta-analysis. 8
However, olanzapine was also associated with notable metabolic effects. Thirty percent of the patients receiving olanzapine gained more than 7 percent of their body weight during the trials, as compared with 7 to 16 percent of those receiving the other drugs. There were comparable problems revealed in measured blood glucose, cholesterol, triglyceride, and glycosylated hemoglobin levels.
Thus, the patient with schizophrenia and his or
her doctor face difficult choices. Two drugs, olanzapine and clozapine, appear to be more effective than other agents.
However, both drugs induce a significantly greater number of serious side effects.
Even the most feared side effect of first-generation drugs, tardive dyskinesia, seems less troubling than potentially fatal metabolic problems.
Does the apparently moderate increase in the efficacy of olanzapine and clozapine justify the use of these agents for treating patients?
The answer to this question is a matter of clinical judgment and informed patient
preference.
Most clinicians offer patients several
possibilities over the course of their illness.
Few clinicians offer patients first-generation
drugs initially because the immediate problems with movement disorder are associated with poor adherence.
The relative absence of side effects with risperidone, quetiapine, and ziprasidone make them
frequent choices for initial treatment for many patients.
However, over the duration of the illness, it is
striking that olanzapine and clozapine often result in an increase in cognition that can lead to alterations in its course, although in some patients these improvements occur with other drugs as well. (9,10)
With these agents, patients resume vocational and
social interests that seemed irretrievably lost early in the course of their illness. Heavy cigarette smoking often remits during treatment with olanzapine and clozapine, indicating decreased reliance on the effects of nicotine. (11)
Because metabolic problems are likely to occur, dietary and exercise counseling should be introduced before the initiation of treatment
with these two drugs.
Although no one postulates that the biologic effects of clozapine and olanzapine are permanent,
the positive effects often persist when, because of metabolic effects, treatment is switched to other second-generation or even first-generation drugs.
CATIE does not capture all these clinical points,
but it provides data consistent with these clinical observations.
It would thus seem reasonable to try
olanzapine and clozapine in any patient with schizophrenia who has not had a full clinical remission of the illness, which includes the reversal of cognitive and psychosocial disabilities.
However, it is also prudent to switch treatment from these drugs to one of the others if a metabolic syndrome is threatening the patient?s general health.
The problem of which antipsychotic agents to
use is particularly poignant for patients with childhood-onset schizophrenia. These young patients, who are often initially referred to pediatricians for school problems, begin experiencing hallucinations
and delusions before the age of 13 years. (12)
Olanzapine is frequently the medication that provides optimal remission of their mental symptoms.
A child who is less disturbed, despite the nearly
inevitable massive weight gain, appears at least at first to have a better outcome. However, as the obesity continues to increase over a period of several years, affected children and families eventually ask to switch to other drugs, to restore normal weight, even at the cost of exacerbated psychosis.
Of course, new drugs that do not have metabolic
side effects but that do confer the antipsychotic
effects of clozapine and olanzapine would be desirable.
Just as the second generation of drugs moved
beyond D2 antagonism, aripiprazole ? a partial
agonist at dopamine D2 receptors that facilitates
low levels of receptor activation while blocking
higher levels ? as well as other new drugs in development have mechanisms that move beyond the
dopamine D2?5-hydroxytryptamine (2A)
hypothesis.
How these drugs perform in comparison with
olanzapine is still unknown. The value of CATIE is
that it provides solid evidence to help clinicians and their patients make the difficult decisions needed to optimize the treatment of schizophrenia with the compounds currently available.
From the Department of Psychiatry, University of Colorado Health Sciences Center, and the Veterans Affairs Medical Center ? both in Denver.
1.
Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic
drugs. Science 1976;192:481-3.
2.
Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia?
Am J Psychiatry 1996;153: 321-30.
3.
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment- resistant schizophrenic: a double-blind comparison with
chlorpromazine.
Arch Gen Psychiatry 1988;45:789-96.
4.
Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia.
Psychopharmacology (Berl) 1989;99:Suppl:S18-S27.
5.
Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159: 561-6.
6.
Lindenmayer JP, Czobor P, Volavka J, et al. Changes in glucose and cholesterol levels in patients with schizophrenia treated with
typical or atypical antipsychotics. Am J Psychiatry 2003;160:290-6.
7.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med
2005;353:1209-23.
8.
Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics.
Arch Gen Psychiatry 2003;60: 553-64.
9.
Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients
with chronic schizophrenia or schizoaffective disorder.
Am J Psychiatry 2002;159:1018-28.
10.
Green MF, Marder SR, Glynn SM, et al. The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone.
Biol Psychiatry 2002;51:972-8.
11.
McEvoy JP, Freudenreich O, Wilson WH. Smoking and therapeutic response to clozapine in patients with schizophrenia.
Biol Psychiatry 1999;46:125-9.
12.
Schaeffer JL, Ross RG. Childhood-onset schizophrenia: premorbid and prodromal diagnostic and treatment histories.
J Am Acad Child Adolesc Psychiatry 2002;41:538-45.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from http://www.nejm.org at UC SHARED JOURNAL COLLECTION on September 20, 2005.
Anonymous:
MINDFREEDOM NEWS ALERT - 20 September 2005
http://www.MindFreedom.org - please forward
Below is an article from the front page
of today's _Washington Post_ about a new
federal study that "challenges widespread
assumptions" about one of psychiatry's
most frequently-used drugs, the neuroleptics,
also known as "antipsychotics."
The _Post_ quotes David Oaks, Director,
MindFreedom International. AT BOTTOM is
MindFreedom's full public statement.
Article link posted here for Fornits,
instead of full article for brevity for
those who have already read article:
http://www.washingtonpost.com/wp-dyn/co ... 67_pf.html
Statement by David Oaks, Director
MindFreedom International
I have heard zealots lobby for a massive
increase in involuntary psychiatric
drugging by claiming that the newer
neuroleptics are far more effective and
that the side effect nightmare that
plagued older neuroleptics had been
solved.
But this new federal study shows that
many of our members who have been
desperately trying to say "no" to forced
neuroleptics have had a better grip on
reality than the medical community.
The drug industry hype about miracle
wonder pills turns out, once more, to be
fraud. The drug industry has seriously
mis-informed the public, the medical
community, government decision-makers,
families and patients. This fraud has
caused serious suffering among a very
marginalized group. The bizarrely high
costs of these drugs threaten to bankrupt
many state and local health care systems.
The New England Journal of Medicine
official editorial warns that patients
face "difficult choices" about drugs that
can potentially cause "fatal metabolic
problems" and therefore the answer is
"informed patient preference." But when the
rubber hits the road, patients and their
families are routinely lied to about
efficacy and hazards of these drugs, and
far too many patients are forced and
coerced to take neuroleptics, including
with court orders on an outpatient basis
in their own homes.
And of course, families in crisis are seldom
offered humane and safe alternatives to
psychiatric drugs.
I have personally experienced
forced neuroleptics and the experience
can feel overwhelmingly horrible, a
profound intrusion of our basic human
rights, like a wrecking ball to the mind.
That qualitative experience doesn't tend
to get out in these studies.
The controversy here is beyond being pro
or con drugs. Some of our members willingly
choose to take prescribed psychiatric drugs.
The issue is really about freedom. And the
drug corporation domination threatens basic
human rights in our society.
The big picture is what we at MindFreedom
call the take-over of the mental health
system by the drug industry, which
impacts research, conferences, medical
associations and choice of treatments.
While it's good to see a study focus on
efficacy and side-effect problems such as
weight gain and diabetes, the biggest
story that the public hasn't heard yet is
that taking long-term high-dosage
neuroleptic is associated with actual
structural damage to the higher level
parts of the brain. These brain changes
can make it very difficult to quit
neuroleptics by creating dependence.
It would also be good to see far more
studies about non-drug alternatives that
have been shown to be effective, safer
and more sustainable, especially ten,
twenty or thirty years down the road. A
core recommendation of President Bush's
New Freedom Commission was more study of
the long-term effects of psychiatric
drugs but we haven't seen that happen yet.
A drug-based approach to psychiatric
problems is also poised to globalize as
never before. There ought to be open,
honest and public debate about these
questions to prevent that from happening.
It's time for democracy to get informed
and hands-on with the mental health
system.
After thirty years of watching the
psychiatric drug industry I've come to
see it as a traveling medical show.
Whenever their current approach is
finally debunked they already have a load
of new drugs waiting in the pipeline. We
expect to see a number of new
neuroleptics produced in the next few
years and the public's skepticism ought
to be on high alert.
- end statement -
http://www.mindfreedom.org/
Anonymous:
Well, the answer according to those that
bask medications and chose not to read
the editorial to the research study ...
Bring back the asylum's, remove the MI
from the streets and any housing they may
have.
Those that are working, get them off the
damn harmful meds and back in the hospital
fully symptomatic where they belong.
---
The truth, prior to medications we needed the mentally ill in those mental institutions.
After medications the number of inpatient
patients was slashed about 95% ...
They are now outpatients ...
Are these medication really that bad if they
got them out of a permanent hospital stay?
Deborah:
Let's see....
Permanent hospital stay
OR
Potentially fatal metabolic problems... Weight gain... Diabetes... Structural damage to the higher level parts of the brain... Drug dependence... Involuntary muscle movements...
not to mention the Bizarrely high
costs of these drugs.
Sounds like a toss up to me.... And a real bitch if you ended up in a permanent hospital stay AND forced to take the drugs.
But wait... wasn't there a THIRD option?
YES!!!
Humane and safe non-drug alternatives that
have been shown to be effective, safer
and more sustainable.
Whew... anon would have us believe that it's either 'freedom' via drugs or a lifetime pass to the asylum.
Anonymous:
--- Quote ---On 2005-09-21 16:43:00, Deborah wrote:
"
Let's see....
Permanent hospital stay
OR
Potentially fatal metabolic problems... Weight gain... Diabetes... Structural damage to the higher level parts of the brain... Drug dependence... Involuntary muscle movements...
not to mention the Bizarrely high
costs of these drugs.
Sounds like a toss up to me.... And a real bitch if you ended up in a permanent hospital stay AND forced to take the drugs.
But wait... wasn't there a THIRD option?
YES!!!
Humane and safe non-drug alternatives that
have been shown to be effective, safer
and more sustainable.
Whew... anon would have us believe that it's either 'freedom' via drugs or a lifetime pass to the asylum."
--- End quote ---
Anon is quoting the real facts.
There where asylums, now there is a fraction
of them left.
Deborah would have us believe that all those
on medication are going to have these horrible
complications. Meds have been around since the
50's so where are all these victims of medications?
You do research all the time, correct, just
how many have been harmed?
Regarding the safe and human treatments.
Where are they?
Have they been studied for efficacy?
People have a choice to flock to these
treatment centers, where are they?
Why are not psychiatric patients demanding
these treatments that you so fondly speak of?
Patients can simply stop taking medications
if they wish, the study said what, 85% of
those with schizophrenic disorders do not
take meds. If this world is really rounding
up people and forcing them to take medication
then why are they not interested in rounding
up these 85%.
In your research just how many people in
just the US are "forced" to take medications?
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