Evidence-Based Reviews

Clozapine for schizophrenia: Life-threatening or life-saving treatment?

Current Psychiatry. 2009 December;8(12):56-63

References

1. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620-627 [online-only data supplement available with the article at ].

2. Schulte PFJ. Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. Ann Pharmacother. 2006;40:683-688.

3. Citrome L, Volavka J. Optimal dosing of atypical antipsychotics in adults: a review of the current evidence. Harvard Rev Psychiatry. 2002;10:280-291.

4. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1-56.

5. Citrome L, Jaffe A, Martello D, et al. Did CATIE influence antipsychotic use? Psychiatr Serv. 2008;59(5):476.-

6. Krakowski MI, Czobor P, Citrome L, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2006;63(6):622-629.

7. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.Erratum in: Arch Gen Psychiatry. 2003;60(7):735.

8. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-610.

9. Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419.

10. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553-564.

11. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41.

12. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166(2):152-163.

13. Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-naïve first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. 2003;28(5):995-1003.

14. Opgen-Rhein C, Dettling M. Clozapine-induced agranulocytosis and its genetic determinants. Pharmacogenomics. 2008;9(8):1101-1111.

15. Krakowski M, Czobor P, Citrome L. Weight gain, metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol. Schizophr Res. 2009;110(1-3):95-102.

16. Citrome L, Vreeland B. Schizophrenia, obesity, and antipsychotic medications: what can we do? Postgrad Med. 2008;120(2):18-33.

17. Annamraju S, Sheitman B, Saik S, et al. Early recognition of clozapine-induced myocarditis. J Clin Psychopharmacol. 2007;27(5):479-483.

18. Citrome L. Adjunctive lithium and anticonvulsants for the treatment of schizophrenia: what is the evidence? Expert Rev Neurother. 2009;9(1):55-71.

19. Mathewson KA, Lindenmayer JP. Clozapine and granulocyte colony-stimulating factor: potential for long-term combination treatment for clozapine-induced neutropenia. J Clin Psycho pharmacol. 2007;27(6):714-715.

Potential for longer life?

The population-based, cohort study from Finland demonstrated that—contrary to popular belief—the introduction of atypical antipsychotics during the 1990s did not adversely affect mortality of patients with schizophrenia, at least in Finland.¹

Clinical Point

Frequent visits for blood monitoring can be used to foster patient engagement with treatment and promote a therapeutic alliance

Researchers used nationwide case registers from 1996 to 2006 to compare cause-specific mortality in 66,881 patients vs Finland’s population (5.2 million) and to link these data with antipsychotic use. In those 11 years, the utilization rate for atypical antipsychotics increased from 13% to 64% of all antipsychotic treatments. Concurrently, the 25-year gap in life expectancy that existed between patients with schizophrenia and the general population narrowed to 22.5 years.

This study made specific drug comparisons and used perphenazine as the reference drug. The lowest risk for mortality was observed with clozapine, which showed a 26% relative advantage compared with perphenazine. Clozapine’s advantage was statistically significant when compared with all other antipsychotics tested.

The authors suggested provocatively that restrictions on clozapine use as a second- or third-line agent should be reassessed. A few caveats, however, might affect how one interprets this study or applies its findings to clinical practice:

The main comparisons were for patients receiving outpatient antipsychotic monotherapy. No information was available about antipsychotics used during inhospital treatment.
Only the most frequently used atypical antipsychotics (clozapine, olanzapine, oral risperidone, and quetiapine) or the most frequently prescribed first-generation antipsychotics (oral perphenazine, thioridazine, and oral haloperidol) were assessed individually.
Data about patients’ marital status, diagnoses of substance abuse, socioeconomic status, and other social variables were not available.
Not all antipsychotics were available throughout the study (quetiapine was the newest and available for the shortest time).
The study population consisted of patients of all ages, including those under 20 and over 70 years of age. Although the number of deaths and mortality rates increased with age, causes of mortality may differ when younger and older persons are compared. A data supplement to the study—available at www.thelancet.com—contains information about odds ratios by age and other factors.

Perhaps the study’s most valuable (and reassuring) finding was that long-term antipsychotic treatment of patients with schizophrenia is associated with lower mortality when compared with no antipsychotic treatment.

Recommendation. Consider clozapine earlier than as a “last resort” in the disease course of patients with schizophrenia. At the very least, routinely present clozapine to patients and their families as a possible treatment option.

Antiaggressive properties

Case series and retrospective studies have provided insights into clozapine’s antiaggressive properties, but the strongest evidence comes from a 12-week, double-blind, randomized trial that specifically enrolled patients with violent behavior.⁶ Clozapine, olanzapine, and haloperidol were directly compared in the treatment of assaults and other aggressive behaviors by physically assaultive in patients with schizophrenia and schizoaffective disorder:

The Modified Overt Aggression Scale (MOAS) physical aggression score measured the number and severity of assaults.
The Positive and Negative Syndrome Scale (PANSS) was used to assess psychiatric symptoms.

Clinical Point

Offer clozapine as an option for patients with persistent aggressive behavior; another antipsychotic might not be ‘good enough’

Clozapine was shown to be more effective than olanzapine and olanzapine was more effective than haloperidol in reducing the number and severity of physical assaults and in reducing overall aggression. Clozapine’s anti aggressive property was specific and not related to the PANSS outcomes or sedation.

Recommendation. Offer clozapine as an option for patients with schizophrenia or schizoaffective disorder and persistent aggressive behavior. Another antipsychotic might not be “good enough.”

Reduced risk of suicidality

The International Suicide Prevention Trial (InterSePT) was a multicenter, randomized, 2-year clinical study that compared the risk for suicidal behavior in patients treated with clozapine vs olanzapine.⁷ Enrolled were 980 patients with schizophrenia or schizoaffective disorder who were considered at high risk for suicide because of past suicide attempts or current suicidal ideation. Approximately one-quarter had not responded adequately to previous treatment.

All patients were seen weekly for 6 months, then biweekly for 18 months. The weekly or biweekly contact required to monitor for clozapine-associated agranulocytosis was matched with a similar visit schedule for olanzapine-treated patients, during which clinicians obtained vital signs. Primary endpoints included suicide attempts (including death), hospitalization to prevent suicide, and a rating of “much worsening of suicidality” from baseline. Blinded raters, including an independent suicide monitoring board, determined when patients achieved endpoint criteria.

Patients receiving clozapine showed significantly less suicidal behavior than those treated with olanzapine (a 24% relative advantage in the hazard ratio for suicide attempts or hospitalizations to prevent suicide). Fewer patients in the clozapine group: