Treatment with Antipsychotic Medication
an Update
Table of Contents
Antipsychotic medications have been available since the mid-1950s when chlorpromazine (Thorazine)
was discovered by the French surgeon Henri Laborit while searching for a drug to reduce surgical shock.
This accidental discovery led to the development of other medications, including haloperidol, which
were highly effective in reducing psychotic symptoms in patients with schizophrenia. These medications
made significant improvements in the lives of individuals but brought with them a host of intolerable side
effects, primarily in the form of movement disorders.
Beginning in the 1990s, a new group of antipsychotic medications became available with the promise of
providing superior symptom relief with fewer movement disorder side effects. Because of their different
pharmacological profile, these medications were dubbed 2nd generation or "atypical" and the older antidopamine
type drugs were called 1st generation or "typical" antipsychotics. It was believed that treatment adherence,
which had been a frequent problem with the typicals, would improve with the atypical medications.
Atypical antipsychotic medications, including clozapine*, risperidone, olanzapine, quietiapine, sertindole, ziprasidone,
aripiprazole, and paliperidone, are now among the first line treatment for patients with schizophrenia and are effective in
treating psychotic symptoms. These medications have been shown to be effective in controlled clinical trials but are costly when
compared to the older medications. In addition, in some cases, these medications bring with them serious metabolic side effects,
including substantial weight gain, increased lipids (cholesterol and triglycerides), and increased risk for diabetes, all of which are
associated with disability and premature death. Given these issues, many have questioned whether when all factors are considered,
atypical antipsychotics are indeed superior to older medication.
The CATIE Study, Phase 1
To address this question, the National Institute of Mental Health (NIMH) conducted a
three phase Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study,
beginning in 2001 and ending in 2004, to find out how four atypical medications and
one typical medication work in "real-world" situations. The CATIE study was designed
to find out how individuals with or without co-morbid medical and substance abuse disorders
tolerated the medication over a long period of time, 18 months. They measured
time to discontinuation of medication and cause for discontinuation. Reasons could include failure of the medication to reduce
symptoms, intolerable side effects, or other issues such as inconvenience of taking the medication or lack of belief that medications
are necessary. This study differed from previous trials in that it was longer in duration and the patient population better represent a typical clinical population who often
have been ill for many years and have other medical or substance
abuse conditions. In this study, participants had been chronically
ill with schizophrenia for an average of 14 years and they often
had other mental disorders, substance abuse, or medical conditions.
This study also provided a protocol for allowing patients
to switch to different medications. This would provide valuable
information for clinicians since switching medications is a common
occurrence in clinical settings.
| Key Findings |
- Patients not satisfied with medications
- Older medications more comparable to newer medications than expected
- Clozapine was most effective
- Clozapine underused
- Metabolic side effects of newer antipsychotics reconfirmed
|
The results of Phase I were surprising. Overall, 74 percent
(3 out of 4) of participants discontinued their first study medication
before the end of 18 months. Furthermore, there was little
difference between the older "typical" antipsychotic medication
and the newer "atypical" medication in discontinuation rates.
The results showed that 1) Most participants discontinued the
first study medication on their own meaning that they were not
advised to stop taking the medication by their doctors because of
side effects or lack of efficacy; 2) Patients randomized to olanzapine
stayed on the study medication longer; and 3) Perphenazine
and the atypical antipsychotics were similarly effective in relieving
psychotic symptoms. These findings generated a flurry of
discussion and further analysis within the psychiatric community.
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The CATIE Study, Phase 2
Patients who stopped taking an atypical antipsychotic for any
reason were eligible to participate in Phase 2. If they were
receiving inadequate symptom control they were randomly
assigned to receive one of four medications: clozapine, olanzapine,
quetiapine, or risperidone. We will call this group 1. If they
stopped taking their Phase 1 medication because of intolerable
side effects or because they told their doctors they wanted to
change medications, but didn't want to take clozapine, they took
part in a different Phase 2 trial which did not include clozapine.
We will call this group 2. Group 2 patients either received
ziprasidone, the newest of the atypical medications at the time or
one of the other three Phase 1 atypical antipsychotic medications
(olanzapine, quetiapine, or risperidone).
The results of group 1 indicated that clozapine was the most
effective for relieving psychotic symptoms and was well tolerated.
Forty-four percent of patients who changed to clozapine
stayed on it for the rest of the 18-month study, compared with 18 percent of patients who changed to the other
medications. On average, patients stayed on clozapine for 10
months, while patients on the other medications stayed on them
for only 3 months. In group 2, patients remained on risperidone
and olanzapine longer (7 and 6 months respectively) than quetiapine
or ziprasidone. Overall results of Phase II of the CATIE
study suggest that clozapine is the most effective medication for
treatment resistant schizophrenia and that olanzapine and
risperidone are superior to quetiapine and ziprasidone in how
well they manage symptoms and how they are tolerated for long
term use.
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Discussion
There are important lessons to be learned from the results of this
study. First, the high discontinuation rate (74%) shows there is
a lot of dissatisfaction with the new medications and there is a
need for developing more effective and better tolerated treatments
for schizophrenia. Of the three measured causes for discontinuation
(lack of efficacy, intolerable side effects, and
patient decision) patient decision was the most frequent. This
group includes those who may lack insight into the necessity for
treatment because of cognitive deficits due to the disorder or
other reasons. Perhaps therapies that address other issues
involved in this disorder, including cognitive behavioral therapy,
might improve medication adherence. Second, we need better
training for clinicians on when and how to use clozapine. It
was again shown to be superior in effectiveness but continues to
be underused in typical clinical settings. There is progress in
identifying genetic factors that contribute to vulnerability to
clozapine-induced agranulocytosis which may eventually lead
to making the use of clozapine easier because it might eliminate
the need for close monitoring of individuals who are not genetically
disposed to agranulocytosis.
The perceived advantage of olanzapine in this study is controversial.
The dosage used in
the study was higher than the
usual dose in clinical practice
whereas the dosages of the
other study medications were
more in line with typical dosing.
This may have skewed the
results in favor of olanzapine./p>
Another analysis of the data
looking at whether patients
were switching or staying with
their old medicine found that
there was an advantage to "staying"
with current medication
and a disadvantage to "switching",
no matter which medication
was studied. If a person was randomly assigned to a medication
that they had been on prior to the study, they were more
likely to stay on it. This was the case with olanzapine where a
higher percentage of patients were on it prior to the study.
The adverse metabolic effects of atypical antipsychotics,
particularly olanzapine and clozapine were clearly observed and
pose a real dilemma for patients and clinicians. Weight, blood
pressure and lipids need to be closely monitored and patients
educated on nutrition and exercise as a way to counter potential
serious side effects of some of the newer medications. Our
MIRECC is conducting a study that will provide clinicians with
a protocol for monitoring their patients for signs of metabolic
side effects and then provide these patients with the opportunity
to participate in a wellness program. The goal is that these
patients will be better educated and able to take responsibility
for lowering their risk for cardio-vascular disease.
The current medications are effective for reducing psychotic
symptoms of schizophrenia but they are relatively ineffective
for improving the cognitive deficiencies associated with this
disorder. MIRECC director Stephen R. Marder, M.D., and
Michael F. Green, Ph.D. were co-principal investigators in the
NIMH-sponsored program, Measurement and Treatment
Research to Improve Cognition in Schizophrenia (MATRICS).
This program developed the MATRICS Consensus Cognitive
Battery, a brief battery of tests for measuring several areas of
cognition as well as guidelines for clinical trials for potential
cognitive-enhancing medications and new approaches for drug
discovery. These guidelines are being utilized in the Treatment
Units for Research on Neurocognition and Schizphrenia, another
NIMH-sponsored initiative headed by Stephen R. Marder,
M.D. for finding new medications to improve cognitive abilities
in individuals with schizophrenia.
One potential target for cognitive enhancing medication is
the glutamate system. Glutamate is a chemical in the brain that
is believed to play a role in learning and memory. Nicotine activates
the glutamate neurotransmitter system. There is a higher
prevalence of smokers among people with schizophrenia than in
the general population which may provide a clue for future drug
discovery. The challenge may be to find a medication with the
cognitive enhancing benefits of nicotine, without its harmful
side effects.
* Clozapine, the first atypical antipsychotic was first discovered in the
1950s, but not approved for use the US until 1989. It has not received
wide usage in the US because it can lead to a dangerous side effect,
agranulocytosis, an acute condition involving a dangerously low white
blood cell count. Clinicians are reluctant to prescribe clozapine for
that reason. Patients on clozapine must have their blood counts closely
monitored.
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A MIRECC Study Comparing Risperidone & Olanzapine
Investigators from the MIRECC including Stephen Marder,
M.D. and Shirley Glynn, Ph.D. recently reported on a study that
compared risperidone and olanzapine in 107 patients from Los
Angeles, California and Manchester, New Hampshire. This was
reported at the annual meeting of the American College of
Neuropsychopharmacology. Patients were stabilized individuals
with schizophrenia who were also participating in supported
employment. As in CATIE we measured how long patients
remained on their assigned medication without changing it for
reasons that included lack of efficacy, lack of tolerability or
other reasons. Using this measure, we found no difference
between risperidone and olanzapine. We also found that
patients in both groups showed improvement in positive and
negative symptoms, and we found no difference between the
two drugs. Patients in both groups were more likely to remain
on the medication to which they were assigned when compared
with CATIE patients. This may be because they were receiving
supported employment and they were more stable. Although
patients gained more weight on olanzapine than risperidone the
amount of weight gain was substantially less than the weight
gain on olanzapine in CATIE. In CATIE, patients gained an
average of 2 pounds each month on olanzapine. In our study,
olanzapine treated patients gained about 6 pounds over two
years. In addition, the elevations in triglycerides and cholesterol
were lower. This probably occurred because weight and
lipids were measured more frequently and patients were
removed from the study when these and other side effects
occurred. This suggests that careful monitoring of patients may
be an effective strategy for managing the metabolic side effects
of antipsychotics.
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