The

n e w e ng l a n d j o u r na l

From the Pulmonary and Critical Care and Sleep Medicine

Divisions, Brigham and Womens Hospital and Harvard Medical
School both in Boston.
1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insu-

lin therapy in critically ill patients. N Engl J Med 2001;345:

1359-67.
2. Angus DC, Abraham E. Intensive insulin therapy in critical
illness. Am J Respir Crit Care Med 2005;172:1358-9.
3. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-61.
4. Brown RT, Polinsky RJ, Lee GK, Deeter JA. Insulin-induced
hypotension and neurogenic orthostatic hypotension. Neurology 1986;36:1402-6.
5. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001;17:107-24.
6. Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004;350:2272-9.

of

m e dic i n e

7. Pillar G, Schuscheim G, Weiss R, et al. Interactions between

hypoglycemia and sleep architecture in children with type 1 diabetes mellitus. J Pediatr 2003;142:163-8.
8. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellisant E. A 3-level prognostic classification in septic shock based
on cortisol levels and cortisol response to corticotropin. JAMA
2000;283:1038-45.
9. Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.
10. Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit
Care Med 2003;31:1226-34.
11. Simpson F, Doig G. Parenteral versus enteral nutrition in the
critically ill patient: a meta-analysis of trials using the intentionto-treat principle. Intensive Care Med 2005;31:12-23.
12. Ibrahim E, Mehringer L, Prentice D, et al. Early versus late
enteral feeding of mechanically ventilated patients: results from
a clinical trial. JPEN J Parenter Enteral Nutr 2002;26:174-81.
Copyright 2006 Massachusetts Medical Society.

The Choice of Drugs for Schizophrenia

John M. Davis, M.D.
Schizophrenia is a serious chronic illness that
requires lifelong medication. In some patients,
the illness is refractory to even highly effective
medications such as clozapine, and these patients
desperately need more effective treatment regimens. Less dopamine is blocked with clozapine
than with other antipsychotic medications, and
adding more potent dopamine-blocking drugs,
such as risperidone, to clozapine may achieve better efficacy. Three randomized, controlled trials
examined the strategy of adding risperidone to
clozapine for patients whose illness is refractory
to treatment with clozapine alone. In this issue
of the Journal, Honer et al.1 report the results of
a trial supported by the Stanley Medical Research
Institute that addresses this question. This studys
investigators did not find any beneficial effects
of risperidone augmentation and found a slight
worsening in working memory among patients
treated with risperidone. In contrast, two previous trials,2,3 which were industry-funded, showed
a clear benefit for risperidone augmentation.
What are the explanations for these contradictory results?
Although all three trials appeared to be well
designed, they had important differences. Honer
and colleagues used an average of 2.8 mg per
day of risperidone, and the investigators involved
in the other two trials with positive findings
used substantially higher doses (4.3 to 5.1 mg
per day). The dose used in the Honer study may

518

n engl j med 354;5

have been too low to achieve efficacy. Previous

studies showed that 2 mg per day of risperidone
yielded 50 percent of the benefit found with 4 mg
or more per day.4 In addition, the two trials that
showed positive results included patients with
less severe schizophrenia (i.e., with lower scores
on the Positive and Negative Syndrome Rating
Scale) than in the Honer study. The Honer trial
may have focused on patients who were too sick
for augmentation to make a difference. Nonetheless, the Honer trial was carefully conducted, and
its negative findings introduce palpable doubt
about the efficacy of augmentation therapy in refractory schizophrenia. Given the contradictory
results among these studies, more industry-funded and independently funded trials are needed.
Like these trials of augmentation therapy, previous trials assessing the primary antipsychotic
agents for patients with schizophrenia also had
inconsistent results. A meta-analysis, which included mostly industry-funded randomized, controlled trials, showed that the second-generation
(i.e., atypical) antipsychotic drugs clozapine, olanzapine, risperidone, and amisulpride were more
effective than first-generation (typical) antipsychotic agents.4-7 Clozapine was the most effective
of the second-generation antipsychotic medications, and some second-generation agents (quetiapine, sertindole, and aripiprazole) were not
more effective than placebo.4-7 The large Clinical
Antipsychotic Trials of Intervention Effectiveness

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editorials

(CATIE), sponsored by the National Institute of

Mental Health,8 showed olanzapine to be superior to the other second-generation agents (quetiapine, ziprasidone, and risperidone) and the firstgeneration agent (perphenazine) studied, in terms
of the primary end point, which was time to discontinuation. Many patients in the CATIE trial
received 3 mg per day of risperidone or 80 mg
per day of ziprasidone, doses that might have
been too low in this population,4 and patients
with tardive dyskinesia, whose disease was more
resistant to treatment, were not randomly assigned
to receive perphenazine.
In selecting therapy for patients with schizophrenia, consideration of medication side effects
and costs is important (Table 1). The highly effective second-generation agent clozapine causes
potentially lethal agranulocytosis in about 1 percent of patients, but the risk of death can be
virtually eliminated by requiring weekly evaluation of platelet counts and discontinuation of
the drug if these counts are abnormal. Many firstgeneration agents produce severe extrapyramidal
side effects as well as tardive dyskinesia. Halo-

peridol, a first-generation agent, causes a 10 percent increase in weight at the time of initial
treatment for schizophrenia,9 and patients who
are later treated with a second-generation atypical antipsychotic agent have an additional 5 to
10 percent weight gain. Typically, the weight gain
is rapid in the first month and plateaus after
several months. Early weight gain at three to six
weeks10,11 is highly predictive of total gain; continued weight gain may be avoided by intervening with a weight-control program or by switching medications. First-generation agents are much
less expensive than second-generation agents.
However, a generic form of the second-generation agent amisulpride is widely available outside
the United States, and generic risperidone will
be available shortly.
The early diagnosis and treatment of the first
episode of schizophrenia are important and may
prevent or delay more severe disease and the need
to consider augmentation therapy. We have known
for 30 years that a delay in initiating treatment
with antipsychotic medication may increase the
need for hospitalization over the subsequent five

Table 1. Efficacy, Side Effects, and Costs of Antipsychotic Medications.

Drug

Efficacy*

Extrapyramidal
Symptoms

Weight
Gain

Prolactin
Increase

Daily
Dose

30-Day
Cost

mg

Second-generation antipsychotic
agents
Clozapine

500

613

Olanzapine

20

684

Amisulpride

400

Risperidone

420

Aripiprazole

10

371

Quetiapine

400

492

Ziprasidone

120

438

10

35

First-generation antipsychotic
agents (e.g., haloperidol)

* Efficacy is rated on a scale of 1 to 4, with higher numbers indicating higher efficacy.

Side effects are rated on a scale of 0 to 4, with 0 indicating that the side effect is rarely observed and 4 indicating that
it is the most severe.
First-generation antipsychotic agents cause a gain in body weight of about 10 percent at the time of initial treatment
for schizophrenia. This column ranks weight gain after treatment with a second-generation antipsychotic medication
after the first episode of schizophrenia. Weight gain is highly variable among patients.
The daily dose is the lowest that is fully effective. The average is about 1.2 times as high as the lowest fully effective
dose, since some patients require a higher dose.
Cost is the average wholesale cost of an average dose for 30 days. Amisulpride is not sold in the United States.
Agranulocytosis can occur with clozapine.

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519

editorials

years.12,13 Unfortunately, the pathologic changes medication as they tailor treatment to the indiassociated with schizophrenia (loss of brain tis- vidual patient.
No potential conflict of interest relevant to this article was resue and enlarged ventricles) progress despite treatported.
ment with antipsychotic agents. There is limited
evidence from randomized, controlled trials that From the Psychiatric Institute, University of Illinois at Chicago,
and the University of Maryland Psychiatric Research
olanzapine (and perhaps other second-generation Chicago,
Center, Baltimore.
agents) may slow this progression.14 Prompt di- 1. Honer WG, Thornton AE, Chen EYH, et al. Clozapine versus
agnosis and treatment of the first episode of clozapine and risperidone in patients with refractory schizoschizophrenia are important in preventing pro- phrenia. N Engl J Med 2006;354:472-82.
Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al.
gression, preserving family ties, and preventing A2. double-blind
controlled study of adjunctive treatment with
weight gain.
risperidone in schizophrenic patients partially responsive to cloOne important difference between augmen- zapine: efficacy and safety. J Clin Psychiatry 2005;66:63-72.
3. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augtation with a second medication and treatment mented
with risperidone in the treatment of schizophrenia:
with the primary antipsychotic agent is that a sec- a randomized, double-blind, placebo-controlled trial. Am J Psyond medication may be tried and stopped, but a chiatry 2005;162:130-6.
4. Davis JM, Chen N. Dose response and dose equivalence of
primary medication is typically needed for the antipsychotics.
J Clin Psychopharmacol 2004;24:192-208.
rest of the patients life. Patients who stop taking 5. Heres S, Davis JM, Maino K, Jetzinger E, Kissling W, Leucht
antipsychotic medications have a relapse rate of S. Why olanzapine beats risperidone, risperidone beats quetiaand quetiapine beats olanzapine again: an analysis of headabout 10 percent per month, until eventually al- pine
to-head studies on second-generation antipsychotics. Am J Psymost all patients have a relapse. In the trials of chiatry (in press).
augmentation therapy with the use of a variety of 6. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy
second-generation antipsychotics. Arch Gen Psychiatry 2003;
drugs (e.g., other antipsychotic agents, mood sta- of
60:553-64.
bilizers, or antidepressants), there have been hints 7. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulof efficacy but no definitive proof.15 The most pride, an unusual atypical antipsychotic: a meta-analysis of rancontrolled trials. Am J Psychiatry 2002;159:180-90.
important aspects of the decision to initiate a domized
8. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of
second drug or to change the primary drug are antipsychotic drugs in patients with chronic schizophrenia.
careful assessment of efficacy and the recogni- N Engl J Med 2005;353:1209-23.
tion that a drug is not helping and should be 9. Zipursky RB, Gu H, Green AI, et al. Clinical correlates of
weight gain in first episode patients treated with olanzapine and
discontinued.
haloperidol. Presented at the annual meeting of the American
I recommend striving for as complete a re- Psychiatric Association, San Francisco, May 1722, 2003 (poster).
mission as possible, remembering that the achiev- 10. Davis JM. A meta-analytic overview of second-generation
antipsychotic-induced long-term weight gain. Am J Psychiatry
able end point needs to be individualized and may (in press).
vary from minimal improvement to complete re- 11. Newcomer JW. Second-generation (atypical) antipsychotics
mission. In some cases, several second-genera- and metabolic effects: a comprehensive literature review. CNS
Drugs 2005;19:Suppl 1:1-93.
tion atypical agents must be tried before it is 12. Davis JM, Chang SS. Does psychotherapy alter the course of
clear that no further improvement is possible. schizophrenia? In: Brady JP, Brodie HKH, eds. Controversy in
Philadelphia: W.B. Saunders, 1978:595-620.
Although the side effects of medication are a psychiatry.
13. May PR, Tuma AH, Yale C, Potepan P, Dixon WJ. Schizophremajor concern, patients do not always have the nia a follow-up study of results of treatment. Arch Gen Psyside effects that worry clinicians, and patients chiatry 1976;33:481-6.
quality of life is improved tremendously when 14. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic
drug effects on brain morphology in first-episode psychosis.
symptoms of schizophrenia are controlled. In car- Arch Gen Psychiatry 2005;62:361-70.
ing for patients with refractory schizophrenia, 15. Remington G, Saha A, Chong SA, Shammi C. Augmentation
clinicians must balance efficacy, the prevention strategies in clozapine-resistant schizophrenia. CNS Drugs 2005;
19:843-72.
of disease progression, and the side effects of Copyright 2006 Massachusetts Medical Society.

520

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