Clozapine-induced seizures: prophylaxis or not?

Clozapine is associated with an elevated risk of seizures, especially with doses of 600 mg or greater. At such doses and with elevated serum levels, many psychiatrists consider adding a prophylactic antiepileptic, which was first recommended in the journal Neurology in 1991 (1). Caetano has reviewed available studies in an effort to determine if this is sound practice, and he concludes it is not (2). According to him, the risk of clozapine-induced seizures is greatest when the serum level is 1300 ng/ml or more, the equivalent of 4000 nmol/L. The evidence for this finding is skimpy, however, and consists of case reports: one from 1994, two from 1978, and one from 2001. To accurately determine the dose-response relationship between seizures and clozapine serum levels, prospective studies would be necessary.

Despite this shortcoming, Caetano’s recommendation against prophylaxis makes sense, at least if the serum level is not approaching 4000 nmol/L and the patient doesn’t have other risk factors such as coarse brain disease. The risk of pharmacokinetic interactions and additional adverse effects with anticonvulsants is high; for instance, phenytoin can decrease and lamotrigine can increase clozapine levels. He recommends other measures for managing seizure risk and what to do if a patient does have a seizure.


1. Devinsky O, Honigfeld G and Patin J. Clozapine-related seizures. Neurology. 1991;41:369–371. Abstract

2. Caetano D. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine. Australas Psychiatry. 2014;22:78-82. Abstract

Did DSM-5 throw out the subtype baby with the bathwater?

Many clinicians have suspected and some evidence indicates that patients with the disorganized subtype of schizophrenia, or hebephrenia, do not respond as well to non-clozapine antipsychotics as do other subtypes. Investigators examined this hypothesis in 93 consecutively admitted schizophrenia patients at one hospital in Brazil. They confirmed the diagnosis with the Structured Clinical Interview for DSM-IV, and classified patients as either paranoid or disorganized subtype based upon the predominance of hallucinations and delusions versus disorganized speech and behavior using relevant PANSS items. Only 8 patients, who had either catatonic or residual schizophrenia, were excluded. Treatment resistance was defined as failure of two different antipsychotics, and these patients were offered either clozapine or “combination therapy.”

The mean age of the patients was about 32 years and 56% were male. The demographic profiles did not differ between the 25 disorganized and the 60 paranoid patients; however, the disorganized patients had significantly earlier age of onset, more severe symptoms, and lower functioning as measured by the Global Assessment of Functioning scale. Among the disorganized cohort, 60% were treatment-resistant compared with 20% of the paranoid cohort (p < 0.001). The clozapine response rate, as measured by at least 40% reduction in the total PANSS score, was greater than 60% in both groups. Although DSM-5 has eliminated subtypes of schizophrenia, this study suggests that the disorganized-paranoid axis may retain prognostic and hence diagnostic significance. Another interpretation is merely that positive symptoms respond better to non-clozapine antipsychotics than do disorganized features, which may respond better to clozapine. The study did not have masked raters and the total number of patients is small, so replication is necessary. The Brazilian researchers nonetheless advocate for clozapine use earlier in the course of treatment for disorganized-type patients. If this were adopted widely, clinical subtyping would likely require a more careful approach to evaluation than is carried out in usual practice, such as the use of standardized rating instruments. Reference Ortiz BB, Araújo Filho GM, Araripe Neto AG, Medeiros D, Bressan RA. Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study. Rev Bras Psiquiatr. 2013;35(4):432-434. Full text

A study of clozapine discontinuation

In what they call the largest study to date of clozapine discontinuation, researchers examined a Veterans Administration cohort in the United States of 320 patients with schizophrenia or schizoaffective disorder, 91% male, who received clozapine. The Brief Psychiatric Rating Scale (BPRS) was used to assess symptoms. During 15 years of follow-up, 57% of patients had at least one discontinuation, which occurred most often between 3 and 6 months after treatment initiation.

Factors associated with an elevated likelihood of discontinuation were:
• African-American race
• Older age
• Lower disability award from the VA
• Smaller reduction in BPRS score

The top three causes of discontinuation were nonadherence (35%), adverse effects (28%), and administrative reasons (19%). The adverse effects related to discontinuation in order of frequency were:
• Hematologic, most often neutropenia
• Nervous system including sedation and seizures
• Cardiovascular including hypotension and tachycardia
• Autonomic including sialorrhea
• Weight gain

Agranulocytosis occurred in 3 patients, whereas lesser cases of granulocytopenia which still eliminated the possibility of rechallenge occurred in 4 patients; 3.3% of discontinuations therefore precluded restarting clozapine. One patient died of agranulocytosis; the only other clozapine-related death was in a patient with adynamic bowel and consequent aspiration.

The investigators looked at outcomes following discontinuation. Among 183 patients who stopped clozapine, only 16% restarted it and about half of those continued it. Among the approximately 170 patients who remained off clozapine and who received at least 3 months treatment with another antipsychotic, the mean BPRS score rose significantly from 39 to 52.

The limitations of the study include its naturalistic design and retrospective method.

The data confirm clinical impression that clozapine trials often do not succeed, and the chief challenges are managing adherence and adverse effects. Patients who can’t tolerate clozapine do poorly. We need more options for treatment-resistant psychosis.


Davis MC, Fuller MA, Strauss ME, Konicki PE, Jaskiw GE. Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients. Acta Psychiatr Scand. Published online 2 Dec 2013. Abstract

12-month trial of clozapine augmentation with aripiprazole or haloperidol

The latest trial for clozapine-resistant patients comes from Italy (1). The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a multicentre, randomized, 12-month trial of patients with schizophrenia and persistent positive symptoms despite at least six months of clozapine therapy at a minimum dose of 400 mg. Outcome measures included the Brief Psychiatric Rating Scale and, for subjective rating of adverse effects, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The primary outcome was treatment discontinuation, “a pragmatic and reliable estimate of treatment efficacy and tolerability” according to the authors.

Based on a power calculation, the investigators intended to recruit 194 participants but randomized 106 patients, about 65% men and with a mean age of 41 years. In addition to clozapine, patients received either haloperidol or aripirpazole for 12-months. Baseline demographics and BPRS scores did not significantly differ between the groups. The dose of adjunctive antipsychotic was adjusted according to clinical response, and the patients could receive any necessary additional medications including mood stabilizers and antidepressants. Although the investigators did not report the mean dose of adjunctive antipsychotics in this publication, they reported in 2011 that at month 3, the mean aripiprazole dose was 11.8 mg and the mean haloperidol dose was 2.8 mg (2).

During the study, 19 aripirpazole and 15 haloperidol patients withdrew, which was not significantly different. At 6 months, the mean BPRS score in the aripirpazole group had decreased by 8.8, and in the haloperidol group, by 8.1; the improvement persisted at 12 months. By 3 months the mean LUNERS score decreased significantly in the aripirpazole group but not in the haloperidol group, which indicated that patients taking aripirpazole reported a decrease in adverse effects whereas those taking haloperidol did not.
Both aripirpazole and haloperidol showed effectiveness in augmenting clozapine, but aripirpazole was better tolerated by self-report. Despite this apparent preference for aripirpazole, the groups had a comparable rate of treatment discontinuation: about a third of patients dropped out, most during the first 6 months of augmentation. The findings of the study are limited by lack of statistical power and of a placebo arm. The researchers claim, however, that CHAT is the longest non-industry-sponsored RCT of treatment-resistant schizophrenia.


1. Cipriani A, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33: 533-537. Abstract

2. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011;31: 266-273. Abstract

Famotidine for treatment-resistant schizophrenia

Psychiatrists regard the histamine-receptor antagonism of antipsychotics mostly as a nuisance given its relationship to sedation and weight gain. Some evidence, including research on animal models and preliminary human investigations, suggest that in fact it has a therapeutic role for schizophrenia. Recent research has found that clozapine is an inverse agonist at H2 receptors, meaning that it reduces H2 receptor activity below its baseline (1).

A Finnish team has completed a four-week randomized, controlled, and double-masked trial of famotidine, a selective H2 antagonist now marketed as an over-the-counter remedy for heartburn (2). They recruited 30 patients with treatment-resistant schizophrenia, mean age about 51 years, who were on a variety of antipsychotics and had residual functional impairment; 11 of them were on clozapine. They assessed them with the Scale for Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANNS), and the CGI. The active-treatment group received 100 mg of famotidine twice daily; no significant adverse reactions occurred, but 3 subjects receiving placebo dropped out “for unclear reasons.”

In comparison with the placebo group, the famotidine group had a significant reduction in mean PANSS total score and PANSS general subscale score and in mean CGI. The mean total PANSS score decreased 11% in the famotidine group and 1% in the placebo group. The researchers acknowledged that their study was too brief and had too few subjects to adequately investigate famotidine, and they suggested a follow-up trial with at least 80 subjects for 8 to 10 weeks to test the potential of this well-tolerated medication in treatment-resistant patients.


1. Humbert-Claude M, Davenas E, Gbahou F, et al. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology. 2012;220:225-241.

2. Meskanen K, Ekelund H, Laitinen J et al. A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33:472-478.

Reduction in cortical thickness in treatment-resistant schizophrenia

Reduced grey-matter volume and cortical thickness are well documented in people with schizophrenia, but few studies have examined structural changes in treatment-resistant schizophrenia (TRS). In this study from Brazil, the researchers examined cortical thickness by means of MRI volumetrics in three groups: 61 patients with TRS, 67 patients with non-TRS, and 80 unaffected controls (1). The mean age of all subjects was about 34 years and two-thirds were men. The mean PANSS score of the TRS group was 63.4, significantly greater than the mean score of the non-TRS group which was 54.6. Of the TRS patients, 72% were receiving clozapine whereas the majority of non-TRS patients were receiving either olanzapine, quetiapine, or risperidone.

In comparison with the control group, the TRS group had significant reduction in cortical thickness in four regions of the right hemisphere, including the precentral, middle temporal, and lateral occipital gyri; and six regions of the left hemisphere, including the middle temporal, middle frontal, lateral orbitofrontal, and superior temporal gyri. In comparing the TRS and non-TRS groups, the investigators found a significant reduction in thickness of the left dorsolateral prefrontal cortex in the TRS patients, even when controlling for duration of illness and dose of medication.

The investigators cite existing research suggesting that dysfunction of the dorsolateral prefrontal cortex, which is associated with working memory in healthy subjects, may correlate with poor treatment response. For instance, a 2003 study found that greater cortical volume in this region predicts good response to clozapine (2). Studies that examine the dynamics of volume loss prospectively might help determine the correlates of regional cortical thinning in TRS.

1. Zugman A, Gadelha A, Assuncao I, et al. Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia. Schizophr Res. 30 May 2013. doi: 10.1016/j.schres.2013.05.002. [Epub ahead of print] Abstract

2. Molina V, Reig S, Sarramea F, et al. Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia. Psychiatry Res. 2003;124(3):153-161. Abstract

BDNF variant may predict treatment resistance

Among subjects in the CATIE trial of antipsychotic effectiveness, a large U.S. study of schizophrenia treatment, 74 genes were associated with treatment failure as defined by antipsychotic discontinuation (1). Some of the identified genes code for proteins relevant to schizophrenia research, including brain-derived neurotrophic factor (BDNF). The role of BDNF in the pathophysiology of psychosis was reviewed by Nurjono et al., who highlighted research showing correlation of serum BDNF and positive symptoms, and reduction of BDNF-related mRNA in the hippocampus and frontal lobe of schizophrenia patients (2). Furthermore, certain single-nucleotide polymorphisms (SNPs) of the BDNF gene, including Val66Met, correlate with aspects of the disease.

Using the 74 candidate genes from CATIE as a point of departure, Zhang et al. compared SNP frequency in 89 patients on clozapine, who represented a treatment-resistant cohort, to SNP frequency in 190 patients not on clozapine (3). The mean age of subjects was 38.8 years and all were Caucasian. The only SNPs significantly associated with clozapine therapy were located on the BDNF gene. The minor alleles of three BDNF SNPs showed a dose-response such that homozygotes had the greatest likelihood of clozapine therapy and heterozygotes had an intermediate likelihood compared with major allele homozygotes, who had the lowest likelihood of clozapine therapy.

The minor allele of the Val66Met polymorphism results in BDNF with methionine instead of valine at codon 66. In prior research in patients with schizophrenia, the met allele was associated with reduced frontal gray matter, larger lateral ventricles, and impaired short-term episodic memory. Men with schizophrenia who were homozygous for the met allele developed psychosis earlier than heterozygotes or major-allele homozygotes (2).

Studies in Asians and Caucasians found that the BDNF met allele is not associated with increased risk for schizophrenia (1). However, in the presence of schizophrenia, available research indicates that the met allele is associated with a more severe and possibly treatment-resistant form of the disease. Zhang et al. suggest that the mechanism may be related to reduced synaptic plasticity and hippocampal dysfunction, phenotypic expressions of the met allele in healthy humans. Further research in people with schizophrenia who are met carriers may help elucidate the origins of treatment resistance and the pharmacogenetics of clozapine.


1. Nurjono M, Lee J, Chong SA. A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci. 2012;10:61-70. Full text

2. Need AC, Keefe RS, Ge D, et al. Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur J Hum Genet. 2009;17:946–957. Full text

3. Zhang JP, Lencz T, Geisler S, Derosse P, Bromet EJ, Malhotra AK. Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res. 2013 Feb 19. doi:pii: S0920-9964(13)00058-3. 10.1016/j.schres.2013.01.020 [Epub ahead of print]. Abstract

Pimozide is ineffective for clozapine augmentation

Partial or non-response to clozapine is a challenging clinical situation. For these patients, who are considered refractory or ultra-resistant, we have limited options. Available evidence for augmenting clozapine is discouraging, but even negative trial results are valuable as a guide for what not to do. Exposing patients to ineffective treatments increases both costs and risk of adverse effects.

Pimozide, a potent D2 receptor antagonist, was found to be effective in a 1997 open-label clinical trial in partial clozapine responders. In a 2011 double-blind, placebo-controlled, 12-week trial in patients with partial or non-response to clozapine, pimozide at a mean dose of 6.5 mg daily was ineffective (1). A different U.S. group just published another randomized, double-blind, placebo-controlled trial of pimozide at 4 mg daily in patients with partial clozapine response (2). Using the BPRS, the Schedule for the Assessment of Negative Symptoms, and evaluations of verbal memory, working memory and executive function, the investigators found no significant differences between the groups at 12 weeks, although both showed improvement in the BPRS over time.

With two negative trials, it seems that pimozide as a clozapine augmentation agent can be put to rest. In fact, the entire strategy of adding first-generation D2 antagonists to clozapine for partial or non-repsonse is dubious.


1. Friedman JI, Lindenmayer JP, Alcantara F, et al. Pimozide augmentation of clozapine in patients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology. 2011;36:1289-1295. Full text

2. Gunduz-Bruce H, Oliver S, Gueorguieva R, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res. 2013;143:344-347. Abstract

Clinical Neurosciences Conference 2013

Treatment resistant schizophrenia (TRS) is a clinical challenge for mental health professionals, patients and families. Dr. Herbert Meltzer, Professor of Psychiatry at Northwestern Feinberg School of Medicine in Evanston, Illinois, spoke about his research on this disorder at the Clinical Neurosciences 2013 conference in Vancouver on March 8, 2013. Dr. Meltzer was an investigator in the 1988 pivotal U.S. clozapine trial. He emphasized that clozapine remains the best treatment and is greatly underutilized in North America. He shared data of a 15-year follow-up of clozapine-treated patients indicating that their reduction in psychosis and functional gains persisted and in some cases continued to improve. The one domain in which the outcomes were worse was cognition as measured by the Wisconsin Card Sort test.

For TRS patients who cannot tolerate clozapine, we need more options. Dr. Meltzer has recently investigated high-dose second-generation antipsychotics such as olanzapine, risperidone, and lurasidone. In a 2008 trial of high-dose olanzapine (mean dose 34 mg daily) compared with clozapine (mean dose 564 mg daily) in TRS, he found no difference between the treatments at 6 months, although olanzapine caused more weight gain. This may seem like a long time to wait, but full clozapine response may take as long or longer.

He has also examined high-dose risperidone for TRS in the form of risperidone microsphere depot injections, 100 mg every 2 weeks, compared with a more conventional dose of 50 mg every 2 weeks for 6 months. He found no difference between the doses, which had less robust outcomes than clozapine, but he added that the serum levels of risperidone were not higher than in oral dosing. Dr. Meltzer said that were he to investigate further, he would consider testing 150 mg of risperidone microspheres every 2 weeks.

In other presentations, Dr. Ofer Agid discussed the algorithm for first-episode schizophrenia that he and his team devised at the Centre for Addiction and Mental Health in Toronto. Drs. Debbie Thompson and Joing Wu presented their experience and data from the Fraser Health Psychosis Treatment Optimization Program. Dr. Bill MacEwan, who organizes the annual conference, discussed findings from the Vancouver Hotel Study, and Andrea Jones described distinguishing characteristics of substance-induced psychosis in polysubstance users.

The speaker who perhaps most captivated the audience was Erin Hawkes, a woman living with schizophrenia who discussed her experience as a patient in B.C. hospitals. She has courageously spoken and written about being psychotic, refusing medication, and being restrained and injected. Although she now accepts her diagnosis and treatment, what she underwent was at times degrading and traumatizing. She reminded the audience that small acts of kindness and a gentle approach can make a difference when someone is in great distress and turmoil.

A Canadian cohort of patients with treatment-resistant schizophrenia

Researchers at the Centre for Addiction and Mental Health in Toronto characterized a cohort of people with schizophrenia who had enrolled in a genetics study. In this convenience sample of 478 subjects, 156 were considered treatment resistant (TR) according to American Psychiatric Association guidelines. The APA guidelines define treatment resistance as “little or no symptomatic response to multiple (at least two) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range).”

The investigators found no correlation between treatment resistance and sex; family history of psychosis; schizophrenia subtype; cannabis, alcohol or drug use; or number of cigarettes consumed daily. However, the TR patients had been ill for a mean of 21 years compared with 15 years for the non-TR group (P < .001). Among patients identified as having white European ancestry, 37% were TR, whereas 18% of nonwhites were TR (P =.03). Several treatment factors were significantly correlated with treatment resistance. In the TR group, 33% were on clozapine compared with 13.3% in the non-TR group, and 25% of TR patients were on more than one antipsychotic, double the rate in the non TR group. Ten percent of the TR patients were on clozapine and at least one other antipsychotic. Furthermore, the TR patients had a mean of 3 failed medication trials, whereas the non-TR patients had a mean of 0.5 failed trials. This nonrandom sample is not necessarily representative of all TR patients, so the significance of the lower rate among non-white patients is unclear. The study corroborates previous research indicating that treatment resistance occurs in chronic patients, and that polypharmacy is used possibly at the expense of clozapine. References Teo C, Borlido C, Kennedy JL, De Luca V. The role of ethnicity in treatment refractory schizophrenia. Compr Psychiatry. 2013;54(2):167-172. Link to abstract.

Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(Suppl):1-56.