Substance use treatment
A growing body of literature suggests that clozapine may reduce cravings for alcohol and illicit drugs because of its unique receptor profile. Much of the data has been collected in dual diagnosis patients taking clozapine primarily to treat schizophrenia or schizoaffective disorder. Patients in 1 study showed a comparable response to clozapine therapy whether they had a history of substance abuse or not. The authors opined that their results demonstrated a more generalizable decrease in cravings and recommended further study.25
In a naturalistic study of 151 dual diagnosis patients with schizophrenia, alcohol use rates decreased significantly among those who received clozapine for psychiatric symptoms. After 3 years, 79% of patients treated with clozapine were in remission from alcohol use, compared with 33.7% of patients treated with other antipsychotics.26
Other studies have reported decreased alcohol and illicit drug use in patients with schizophrenia and concomitant substance use.27,28 Animal studies have displayed similar results, showing decreased alcohol intake with clozapine.29,30
Compelling results have been shown in patients with schizophrenia and Cannabis use disorder. A small randomized trial compared clozapine with other antipsychotics in individuals with schizophrenia and Cannabis use disorder. Clozapine was associated with significantly decreased Cannabis use, independent of overall symptom response or level of functioning.31 An animal study demonstrated an attenuated development of conditioned place preference (classical conditioning) to cocaine. The authors suggested that clozapine should be considered as a future pharmacotherapy to treat cocaine use.32
The literature does not support prescribing clozapine solely for alcohol or illicit drug use, but clozapine merits consideration in patients with schizophrenia and comorbid substance use. This approach may be most beneficial in controlled environments, such as inpatient or residential facilities.
Suicidality
The 2-year International Suicide Prevention Trial (InterSePT) was the first to support clozapine’s efficacy in reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.33 InterSePT data were in line with earlier observations, including improvement in reported depression and hopelessness in patients with primary psychotic disorders.34,35 Clozapine’s action at serotonin receptors (in addition to dopamine receptors) may explain the benefits, based on the suspected link between suicide risk and serotonin.34,36
Most published reports regarding clozapine for suicidality involve patients with schizophrenia or schizoaffective disorder. We found only 1 published case report describing clozapine’s use for recurrent suicidality in a patient with bipolar disorder. The authors described a dramatic reduction in suicidal ideation, suicide attempts, and hospitalizations after other attempted interventions—including electroconvulsive therapy—had been ineffective.37
Aggression
In the absence of FDA-approved treatments for long-term management of aggression, many clinicians prescribe atypical antipsychotics. With the exception of clozapine, the demonstrated benefits of these medications for reducing aggression are equivocal. Clozapine is thought to be superior among atypical antipsychotics for addressing aggression because of its unique and broad combination of dopaminergic and serotonergic activity. Its effects on the D1-dopamine receptor likely target aggression, and its effects on the serotonin 2A receptor (5-HT2A) likely target the impulsivity commonly associated with aggression.38,39
Clozapine has been shown to reduce long-term aggression in patients with psychotic disorders.40-44 Most reports involve individuals with schizophrenia or schizoaffective disorder because this population is most commonly treated with clozapine. However, clozapine’s anti-aggressive benefits appear not to be solely related to sedation or improvement in psychosis.42,45
What is known about clozapine’s mechanism suggests that its anti-aggressive benefits would extend beyond patients with schizophrenia and schizoaffective disorder. In a case series of 7 nonpsychotic patients with antisocial personality disorder and psychopathic traits, all displayed benefits with clozapine—particularly in domains of impulsive behavioral dyscontrol and anger.46
Self-injurious behaviors (SIB) and aggression in 2 patients with profound mental retardation were reduced significantly after treatment was switched from risperidone to clozapine.47 In a similar case, SIB and aggression improved in a man with cognitive impairment.48 The case of Mr. C recounts our experience with using clozapine in a patient with cognitive impairment.
CASE REPORT
Daily assaults keep patient hospitalized
Mr. C, age 19 at the end of treatment, had moderate intellectual disability and an extensive history of violence. He grew up in group homes and long-term psychiatric facilities. Immediately after turning 18, he was transferred from an adolescent facility to an adult psychiatric hospital.
Our treatment team tried various combinations of benzodiazepines, mood stabilizers, and antipsychotics, but Mr. C consistently assaulted 1 or 2 peers daily without clear provocation. Eventually we started him on clozapine, which we titrated to an effective dose (based on a therapeutic serum level). We also added a therapeutic dosage of lithium to address his residual aggression. With the regimen of clozapine and lithium, Mr. C’s assaultive behavior improved dramatically. After going more than 1 year without assaulting a peer, he was placed in the community.