The new england journal of medicine

editorials

The Choice of Antipsychotic Drugs for Schizophrenia

Robert Freedman, M.D.

Since the discovery of the effects of chlorpromazine tagonism and stronger antagonism at serotonin
in the 1950s, treatment of schizophrenia has relied 5-hydroxytryptamine2A receptors.4 Pharmaceutical
on antipsychotic drugs that target dopamine D2 re- companies, acting on this hypothesis, have devel-
ceptors. The effectiveness of these agents in reduc- oped new drugs, attempting to capture the enhanced
ing the intensity of patients’ delusions and halluci- therapeutic effect of clozapine without its toxicity.
nations permitted outpatient treatment instead of The resultant second generation of drugs now ac-
lifelong institutionalization in state mental hospi- counts for the majority of antipsychotic drugs pre-
tals. The many antipsychotic drugs introduced dur- scribed for all psychiatric uses, including schizo-
ing the next decade were increasingly potent, as me- phrenia.
dicinal chemists improved the drugs’ affinity for the Concerns have emerged about this new gener-
D2 receptor. However, the efficacy of the drugs was ation of drugs. First, although clozapine was in-
similar, since all had the same mechanism of ac- troduced after studies indicated that it had more
tion.1 A troubling problem was that the blockade of efficacy than first-generation drugs, the other new
dopaminergic neurotransmission in the basal gan- antipsychotic agents were marketed after studies
glia caused parkinsonian syndromes. A long-last- showed efficacy that was only comparable to that
ing movement disorder, tardive dyskinesia, also of older drugs. Thus, the issue of whether they, like
occurred with prolonged treatment. More funda- clozapine, were truly more effective remained large-
mentally, the early promise that these drugs might ly unanswered. Second, although the newer drugs
dramatically improve patients’ psychosocial and fulfilled their promise of causing less movement
cognitive disabilities was only partially fulfilled.2 Al- disorder, new problematic side effects — severe
though many mental hospitals were closed, men- weight gain, often accompanied by type 2 diabetes
tal health centers were filled with outpatients who mellitus and hypercholesterolemia — emerged.5,6
could not live successfully in their communities. Weight gain had occurred with the older drugs, al-
By the early 1970s, the European experience with though it was generally less substantial. Third, the
one drug, clozapine, suggested that it might be sig- cost of newer medications caused payers to ques-
nificantly more effective than other antipsychotic tion their purported value. Therefore, the National
drugs and that it did not cause movement disor- Institute of Mental Health undertook a multisite,
der to the same degree as the others. Clozapine in- double-blind comparison between an older drug,
deed proved to be more effective at reducing symp- perphenazine, and a series of the newer drugs; clo-
toms than other neuroleptic agents.3 However, the zapine was omitted because it had already been ob-
potential of clozapine to cause toxic side effects, in- served to have superior efficacy. The results of this
cluding agranulocytosis, has limited its prescrip- work, the Clinical Antipsychotic Trials of Interven-
tion to about 10 percent of persons with schizophre- tion Effectiveness (CATIE), are reported in this is-
nia. Clozapine was labeled an atypical antipsychotic sue of the Journal.7
agent because it caused less movement disorder What to measure in such a trial is itself prob-
than other antipsychotics. The mechanism of action lematic. Schizophrenia is a chronic disability of
of clozapine differs in many ways from that of oth- mental and social function, with superimposed
er dopamine D2 receptor antagonists; the most episodes of exacerbated psychotic symptoms. In
popular hypothesis is that it has weaker D2 an- addition to hallucinations and delusions, affected

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 editorials

patients have characteristic neuropsychological dif- her doctor face difficult choices. Two drugs, olan-
ficulties, including problems in paying attention, zapine and clozapine, appear to be more effective
learning new information, and recognizing social than other agents. However, both drugs induce a
cues, such as the emotional meaning of facial ex- significantly greater number of serious side effects.
pressions. Their social isolation, loss of sense of Even the most feared side effect of first-generation
pleasure, inability to make decisions, and poor self- drugs, tardive dyskinesia, seems less troubling than
care forms a third symptom complex. Patients who potentially fatal metabolic problems. Does the ap-
carry the diagnosis of schizophrenia vary marked- parently moderate increase in the efficacy of olan-
ly in these various aspects of their illness. Efficacy zapine and clozapine justify the use of these agents
is therefore difficult to measure. The time to dis- for treating patients? The answer to this question
continuation of medication for any reason — a side is a matter of clinical judgment and informed pa-
effect, poor efficacy, or the patient’s decision about tient preference. Most clinicians offer patients sev-
adherence — was the principal outcome variable in eral possibilities over the course of their illness.
CATIE. Its advantage as a primary measure is that Few clinicians offer patients first-generation
it is relatively definable and less subject to the vicis- drugs initially because the immediate problems with
situdes of patients’ descriptions of their symptoms movement disorder are associated with poor ad-
and the perception of these symptoms by others, herence. The relative absence of side effects with ris-
even those trained in assessing them. CATIE used a peridone, quetiapine, and ziprasidone make them
single scale, the Positive and Negative Syndrome frequent choices for initial treatment for many pa-
Scale (PANSS), to rate patients’ symptoms as a sec- tients. However, over the duration of the illness, it is
ondary outcome. Side effects were recognized as striking that olanzapine and clozapine often result
an important issue in the design of CATIE. in an increase in cognition that can lead to alter-
The results could be viewed as discouraging. ations in its course, although in some patients these
No drug provided the majority of patients a treat- improvements occur with other drugs as well.9,10
ment that lasted the full 18 months of the study. With these agents, patients resume vocational and
Thus, treating schizophrenia, even with new-gen- social interests that seemed irretrievably lost early
eration drugs, is only partially effective and is asso- in the course of their illness. Heavy cigarette smok-
ciated with problematic side effects. Only 36 per- ing often remits during treatment with olanzapine
cent of the patients receiving the most effective and clozapine, indicating decreased reliance on the
drug, olanzapine, completed the trial. Twenty-five effects of nicotine.11 Because metabolic problems
percent of those receiving perphenazine complet- are likely to occur, dietary and exercise counseling
ed the trial. Patients receiving other second-gen- should be introduced before the initiation of treat-
eration antipsychotic drugs — quetiapine, risperi- ment with these two drugs.
done, and ziprasidone — did no better than those Although no one postulates that the biologic ef-
receiving perphenazine. Thus, there was a small im- fects of clozapine and olanzapine are permanent,
provement with olanzapine as compared with the the positive effects often persist when, because of
first-generation drug perphenazine, but this advan- metabolic effects, treatment is switched to other
tage was not observed with the other second-gen- second-generation or even first-generation drugs.
eration drugs. This difference was reflected in the CATIE does not capture all these clinical points,
other clinical measurements, including PANSS rat- but it provides data consistent with these clinical
ings. The greater efficacy of olanzapine, as com- observations. It would thus seem reasonable to try
pared with that of these other drugs, is consistent olanzapine and clozapine in any patient with schizo-
with the results of a recent meta-analysis.8 How- phrenia who has not had a full clinical remission of
ever, olanzapine was also associated with notable the illness, which includes the reversal of cognitive
metabolic effects. Thirty percent of the patients re- and psychosocial disabilities. However, it is also
ceiving olanzapine gained more than 7 percent of prudent to switch treatment from these drugs to
their body weight during the trials, as compared one of the others if a metabolic syndrome is threat-
with 7 to 16 percent of those receiving the other ening the patient’s general health.
drugs. There were comparable problems revealed The problem of which antipsychotic agents to
in measured blood glucose, cholesterol, triglycer- use is particularly poignant for patients with child-
ide, and glycosylated hemoglobin levels. hood-onset schizophrenia. These young patients,
Thus, the patient with schizophrenia and his or who are often initially referred to pediatricians for

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 The new england journal of medicine

school problems, begin experiencing hallucina- 1. Creese I, Burt DR, Snyder SH. Dopamine receptor binding pre-
dicts clinical and pharmacological potencies of antischizophrenic
tions and delusions before the age of 13 years.12 drugs. Science 1976;192:481-3.
Olanzapine is frequently the medication that pro- 2. Green MF. What are the functional consequences of neuro-
vides optimal remission of their mental symptoms. cognitive deficits in schizophrenia? Am J Psychiatry 1996;153:
321-30.
A child who is less disturbed, despite the nearly 3. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treat-
inevitable massive weight gain, appears at least at ment-resistant schizophrenic: a double-blind comparison with
first to have a better outcome. However, as the obe- chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.
4. Meltzer HY. Clinical studies on the mechanism of action of clo-
sity continues to increase over a period of several zapine: the dopamine-serotonin hypothesis of schizophrenia. Psy-
years, affected children and families eventually ask chopharmacology (Berl) 1989;99:Suppl:S18-S27.
to switch to other drugs, to restore normal weight, 5. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck
R. Association of diabetes mellitus with use of atypical neurolep-
even at the cost of exacerbated psychosis. tics in the treatment of schizophrenia. Am J Psychiatry 2002;159:
Of course, new drugs that do not have metabol- 561-6.
ic side effects but that do confer the antipsychotic 6. Lindenmayer JP, Czobor P, Volavka J, et al. Changes in glucose
and cholesterol levels in patients with schizophrenia treated with
effects of clozapine and olanzapine would be desir- typical or atypical antipsychotics. Am J Psychiatry 2003;160:290-6.
able. Just as the second generation of drugs moved 7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of anti-
beyond D2 antagonism, aripiprazole — a partial psychotic drugs in patients with chronic schizophrenia. N Engl J Med
2005;353:1209-23.
agonist at dopamine D2 receptors that facilitates 8. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of
low levels of receptor activation while blocking second-generation antipsychotics. Arch Gen Psychiatry 2003;60:
higher levels — as well as other new drugs in devel- 553-64.
9. Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects
opment have mechanisms that move beyond the of clozapine, olanzapine, risperidone, and haloperidol in patients
dopamine D2–5-hydroxytryptamine2A hypothe- with chronic schizophrenia or schizoaffective disorder. Am J Psychi-
sis. How these drugs perform in comparison with atry 2002;159:1018-28.
10. Green MF, Marder SR, Glynn SM, et al. The neurocognitive ef-
olanzapine is still unknown. The value of CATIE is fects of low-dose haloperidol: a two-year comparison with risperi-
that it provides solid evidence to help clinicians and done. Biol Psychiatry 2002;51:972-8.
their patients make the difficult decisions needed 11. McEvoy JP, Freudenreich O, Wilson WH. Smoking and thera-
peutic response to clozapine in patients with schizophrenia. Biol
to optimize the treatment of schizophrenia with Psychiatry 1999;46:125-9.
the compounds currently available. 12. Schaeffer JL, Ross RG. Childhood-onset schizophrenia: pre-
morbid and prodromal diagnostic and treatment histories. J Am
From the Department of Psychiatry, University of Colorado Health Acad Child Adolesc Psychiatry 2002;41:538-45.
Sciences Center, and the Veterans Affairs Medical Center — both Copyright © 2005 Massachusetts Medical Society.
in Denver.

Immune Response as a Biomarker

for Cancer Detection and a Lot More
Olivera J. Finn, Ph.D.

In 2000, the American Cancer Society inaugurat- making these methods clinically applicable are not
ed a yearly report on guidelines for cancer detec- being developed fast enough. The only laboratory
tion. The latest update, published in 2005,1 is identi- test for cancer screening on the society’s list is the
cal to the previous versions in its recommendation test for prostate-specific antigen (PSA). The PSA
regarding screening techniques that have not level can be useful in monitoring disease progres-
changed in decades. An especially striking feature sion or recurrence, but as a screening test it can lead
of the recommendations is the continued absence to overdiagnosis and unnecessary biopsies.5,6 The
of any mention of laboratory tests that should be PSA problem speaks loudly to the need for better
readily available, considering the explosion of tests for prostate cancer and other cancers.
knowledge in cancer biology, molecular biology, The search for new biomarkers for use in the
genetics, and immunology. The scientific litera- diagnosis of cancer entails characterizing one or a
ture is full of articles heralding the potential of ge- few proteins produced by cancer cells and estab-
nomics,2 proteomics,3 metabolomics,4 and other lishing assays with high specificity and sensitivity
“omics” for the improvement of the diagnosis, for cancer or defining a cancer fingerprint on the
treatment, and prognosis of cancer, but ways of basis of a larger set of proteins, many of which are

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