Updated Practice Guidelines for the Use of Clozapine in Adult Individuals with Intellectual Disabilities
Jose de Leon

University of Kentucky Mental Health Research Center, Lexington, KY, USA and the Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain.

(Revised on September 11, 2014)

Reviewers of the first draft. The following authors, listed in alphabetical order by last name, reviewed the first version of these updated clozapine guidelines and provided suggestions:

Manuel Arrojo-Romero, Psychiatry Department (EOXI de Santiago), Gallegan Health System (Servicio Gallego de Salud), Santiago de Compostela, Spain.

Trino Baptista, Department of Physiology, Los Andes University Medical School, Mérida, Venezuela.

Pierre Baumann, Département de Psychiatrie (DP-CHUV), Université de Lausanne, Prilly-Lausanne, Switzerland.

Miquel Bernardo, Programa Esquizofrènia Clínic, Hospital Clínic de Barcelona, Departamento de Psiquiatría y Psicobiología Clínica, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain

Peter F. Buckley, Medical College of Georgia, Georgia Regents University, Augusta, GA, United States.

Dan Cohen, Community Mental Health, Mental Health Organization North-Holland North, Heerhugowaard, The Netherlands.

Guillaume Fond, INSERM U955 Eq 15, AP-HP, GHU Mondor, DHU Pe-Psy, Université Paris-Est Créteil, Fondation FondaMental, Fondation de Coopération Scientifique en Santé Mentale, Creteil, France.

Ana Gonzalez-Pinto, Department of Psychiatry. Hospital Universitario de Alava (Santiago). EHU/UPV University. CIBERSAM. Kronikgune. Spain.

Brian Greenlee, Neuropsychiatry and General Psychiatry, Lexington, KY, USA.

Christoph Hiemke, Department of Psychiatry and Psychotherapy University Medical Center Mainz, Germany.

Taro Kishi, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Hsien-Yuan Lane, Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan

Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.

Marion Leboyer, Psychiatry Department, University Paris Est Créteil, INSERM U955, FondaMental Foundation, Creteil, France.

Seung-Tae Lee, Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Carlos López-Jaramillo, Research Group in Psychiatry (GIPSI), Department of Psychiatry, Faculty of Medicine, University of Antioquia. Director Mood Disorders Program, San Vicente Fundation Univesrity Hospital, Medellín, Colombia.

Philip B. Mitchell, School of Psychiatry, University of New South Wales; and Black Dog Institute, Sydney, Australia.

Amy O’Neill, Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY, USA.

Jesus Perez, Department of Psychiatry, University of Cambridge, UK, and  CAMEO Early Intervention in Psychosis Services, Cambridgeshire and Peterborough NHS Foundation Trust, UK.

Irena Popovic, Specialized Hospital for Psychiatric Disorders,“GornjaToponica”, Niš, Serbia.

Thomas J. Raedler, Department of Psychiatry, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

Gary Remington, Department of Psychiatry, University of Toronto; Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Luis Salvador-Carulla, Centre for Disability Research and Policy, Faculty of Health Sciences, University of Sydney, Australia.

Flavian Stefan Radulescu, University of Medicine and Pharmacy Carol Davila, Faculty of Pharmacy, Department of Biopharmaceutics, Bucharest-020956, Romania.

Yi‐Lang Tang, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.

Victor A. Voicu, Romanian Academy, University of Medicine and Pharmacy Carol Davila, Faculty of Medicine, Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Bucharest, Romania.

Chuan‐Yue Wang, Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing,  Anding Hospital, Capital Medical University, China; and  Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders, Capital Medical University, Ministry of Science and Technology, China.

Abstract

This is an update of the 2005 practice guideline for the use of clozapine in adults with intellectual disabilities. It was developed by using drug prescribing information and reviewing the available literature on relevant neuropsychiatric disorders in populations without intellectual disabilities because of the dearth of available literature on the population with intellectual disabilities. This guideline includes indications (treatment-resistant schizophrenia, reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder, self- or hetero-aggressive behavior, polydipsia and other off-label uses); contraindications; assessments prior to and during treatment; dosing, with particular focus on dosing modifications required by drug-drug interactions, personal characteristics or genetic variants; and adverse drug reactions. This update includes advances in pharmacokinetics and therapeutic drug monitoring with recommendations for lower doses in East Asians and a new recommendation for increasing safety by means of very slow titration. The procedures contained in this guideline may not fully account for all of the possible risks of treatment in this population because of the limited studies available; thus, periodic updating as new information becomes available will be necessary.  Nevertheless, we believe that this guideline provides a useful resource for clinicians who treat adult individuals with intellectual disabilities. A clozapine drug utilization review that summarizes this guideline is included.

1. Introduction

            This guideline is a 2014 update of the clozapine guideline for adults with intellectual disabilities (IDs) published in 2006 (Sabaawi et al., 2006). Clozapine is a second-generation antipsychotic medication that was approved in Europe and then initially studied in the US in the 1970s (Simpson & Varga, 1974; 1975), but the development of agranulocytosis cases in Finland led to the discontinuation of the US studies (Kang & Simpson, 2010).  A subsequent US study in the 1980s (Kane et al., 1988) which focused on treatment-refractory schizophrenia patients led to clozapine’s marketing in the US in 1989 under restricted conditions meant to avoid agranulocytosis.  Its trade name was Clozaril, which was later owned by Novartis Pharmaceutical Corporation (2011). It is currently available in the US in generic forms, including orally disintegrating tablets (Jazz Pharmaceuticals, Inc., 2010).  Use of any clozapine product requires contacting the Clozapine National Registry (CNR).

            According to schizophrenia meta-analyses, clozapine is the most efficacious of the antipsychotics. From the time of its discovery, animal models indicated that clozapine was different than chlorpromazine and its congeners because it did not cause catalepsy, which is a predictor of extrapyramidal symptoms (EPS) in humans (Meltzer, 2012).  Later, it was found that clozapine is a D₂ antagonist, but its low affinity and loose binding to brain D₂ receptors may explain its low potential for causing EPS and hyperprolactinemia. A recent meta-analysis of brain imaging studies of D₂ receptor occupancy verified that clozapine (and quetiapine) are different than other antipsychotics (Yilmaz et al., 2012). Clozapine also has clinically relevant antagonism at (1) H₁ receptors, which may partially explain its sedating and weight-increasing properties; (2) muscarinic receptors, which may explain its propensity to cause constipation and other antimuscarinic adverse drug reactions (ADRs); and (3) α₁ receptors, which may explain its propensity to cause orthostatic hypotension and sexual ADRs. Other potential ADRs include hyperglycemia, hyperlipidemia and dose-related seizure risk. The most important and potentially lethal ADRs are agranulocytosis and myocarditis. Balancing potential benefits and risk, Meltzer (2012) comments that clozapine is underprescribed in the US, having only a 4.4% market share in the US in 2008, although it may be indicated for 35-40% of patients.  There is need for better teaching psychiatric residents in the appropriate use of clozapine to increase it use (Freudenreich et al., 2013).

            Clozapine is metabolized by several metabolic enzymes, but the literature describes cytochrome P450 1A2 (CYP1A2) as the main metabolic pathway. Inducers, such as some antiepileptic drugs (AEDs) and smoking, increase clozapine metabolism. Inhibitors such as fluvoxamine and caffeine can decrease clozapine metabolism. Clozapine therapeutic drug monitoring (TDM) indicates general agreement that 350 ng/ml is the lowest serum concentration associated with the possibility of a response. Based on randomized clinical trials (RCTs) and TDM studies, most patients in the US and Europe probably require  doses of at least 300 mg/day to reach this concentration  with average female non-smokers requiring 300 mg/day and average male smokers requiring 600 mg/day.  Although it has not been well-studied and well-reflected in clozapine review articles, East Asians (particularly from China) and probably individuals with no CYP2C19, called poor metabolizers (PMs), may require half of the clozapine dose to achive similar plasma clozapine concentrations compared with US Caucasians. This guideline uses the concentration-to-dose ratio (C/D) and TDM to guide dosing and increase safety during the prescription of clozapine in adults with IDs.  There is limited published information on clozapine pharmacokinetics in adults with IDs but, according to pharmacological knowledge, pharmacokinetics should not be influenced by ID and pharmacokinetic parameters should be similar in patients with schizophrenia and those with IDs once confounding factors such as age, gender, smoking, race and co-medication are taken into account.     

            There is very limited information on the use of clozapine in adults with IDs. A PubMed search (footnote a in Table 1) identified 12 articles (Pary, 1994; Sajatovic et al., 1994; Cohen & Underwood, 1994; Rubin & Langa, 1995; Holzer et al., 1996; Buzan et al., 1998; Antonacci & de Groot, 2000; Gobbi & Pulvirenti, 2001; Hammock et al., 2001; Thalayasingam et al., 2004; Gladston & Clarke, 2005; Beherec et al., 2011).  Singh et al. (2010) conducted a comprehensive review of clozapine in adults with IDs and helped us (footnote b in Table 1) identify six more studies (Vyncke, 1974; Hammock et al., 1995; Schroeder et al., 1995; Williams et al., 1995; Kamal & Kelly, 1999; Thuresson & Farnstrand, 1999).  Another antipsychotic review (Deb et al., 2007) helped us (footnote c in Table 1) to identify one more clozapine article in adults with IDs (Boachie & McGinnity, 1997). 

            To conclude this introduction, in the absence of expert consensus guidance and well-controlled comparison clozapine RCTs, we present a set of guidelines to inform initiation, dosing and monitoring of use in adults. Appendix 1 contains the clozapine drug utilization review that summarizes this guideline.

2. Indications for Use

            After deciding that the patient meets the indications listed below, it is fundamental to assess the probability of cooperation with clozapine treatment. The adult individual with ID needs to be willing to cooperate with treatment and periodic venipuncture.  In addition, the individual (and/or guardian) must be willing to sign the consent form.

2.1. Treatment-Resistant Schizophrenia

            Clozapine is approved by the Food & Drug Administration (FDA) for use in individuals with schizophrenia who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable ADRs from those drugs (Novartis Pharmaceutical Corporation, 2011). The literature (Singer & Law, 1974; Kane et al., 1988; Baldessarini & Frankenburg, 1991; Conley & Buchanan, 1997) has traditionally described clozapine as more efficacious than first-generation antipsychotic agents and the other second-generation antipsychotic agents. Furthermore, RCT meta-analyses (Wahlbeck et al., 1999; Essali et al., 2009; Leucht et al., 2009; Asenjo Lobos et al., 2010; Klemp et al., 2011) and a recent review of effectiveness trials (Attard & Taylor, 2012) supported the greater efficacy of clozapine among antipsychotics. All schizophrenia guidelines including those of (1) the Schizophrenia Patient Outcomes Research Team (Buchanan et al., 2010), (2) the American Psychiatric Association (2004), and  (3) in the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) (2009) support clozapine’s unique efficacy for refractory schizophrenia.

            The literature describes clozapine’s ability to help achieve a treatment response characterized, not only by symptom reduction, but also by improvement in certain aspects of cognitive functioning, social functioning and quality of life; decreased need for hospitalization; and enhanced compliance with treatment (Grace et al., 1996; Meltzer, 1992; Meltzer et al., 1990; Meltzer, 2012). However, in a recent meta-analysis of second-generation antipsychotic RCTs, Asenjo Lobos et al. (2010) found that data on clozapine’s superiority in other important outcomes such as cognitive functioning, quality of life, reduced deaths or service use is largely missing at present. As a matter of fact, a meta-analysis focused on long-term memory indicated marginally significant superiority in overall long-term memory for risperidone and olanzapine compared to clozapine, which reached significance for verbal long-term memory (Thornton et al., 2006). In a recent review, Hill and Freudenreich (2013) commented that although there is no clear data supporting an association between clozapine and greater quality of life, the patient may subjectively feel better after switching to clozapine.

            Thus, clozapine is indicated when the individual has a current DSM-5 diagnosis of schizophrenia eand has failed to tolerate or respond adequately to two prior antipsychotic trials. The prescriber must document in the chart that clozapine is being used for treatment-refractory psychosis and that the individual has failed to tolerate or respond adequately to other antipsychotics.  If possible, it is better to describe the duration and dosing of each antipsychotic trial.  In cases when it is known that another antipsychotic agent has been tried but precise history is absent, the psychiatrist needs to consult with the individual and/or guardian about the merits of repeating another trial of the same antipsychotic. Meltzer (2012) estimates that approximately 30% of schizophrenia patients meet the criteria for treatment resistance.

            The lower panel of Table 1 provides a summary of the use of clozapine to treat psychosis in adults with IDs. There are four articles describing case reports (Pary, 1994; Sajatovic et al.,1994; Rubin & Langa, 1995; Gladston & Clarke, 2005) and two retrospective reviews (Antonacci & de Groot, 2000; Thalayasingam et al., 2004).

            Clinicians frequently use another antipsychotic to augment clozapine response in patients with treatment-refractory schizophrenia and suboptimal clozapine response. Meta-analyses and reviews of the RTCs provide only weak support for augmentation with antipsychotics strategy (Barbui et al., 2009; Cipriani et al., 2009; Sommer et al., 2012a; Taylor et al., 2012). Other drugs (Porcelli et al., 2012; Sommer et al., 2012a) including lamotrigine (Tiihonen et al., 2009a) and topiramate (Hahn et al., 2010; Muscatello et al., 2011) have also been used to augment clozapine. The available information suggests that clozapine augmentation with agonists at the N-methyl-D-aspartate (NMDA)-glycine site and glycine transporter-1 inhibitors may not be effective (Lane et al., 2006). There are some studies on clozapine-augmentation with electroconvulsive therapy (Flamarique et al., 2012) and limited information in other techniques including transcranial magnetical stimulation (TMS) (Sommer et al., 2012b), or transcranial direct current stimulation (Andrade, 2013).  Physicians considering augmentation of a partial response to clozapine with other antipsychotics or other psychiatric drugs, in patients with IDs and schizophrenia, should be aware of the limited literature support for this strategy in adult patients with no IDs.

2.2. Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or

       Schizoaffective Disorder

            Clozapine is approved by the FDA for reduction of recurrent suicidal behavior in schizophrenia or schizoaffective disorder. A randomized, international two-year follow-up study found a reduction in suicidal behavior among individuals with schizophrenia (Barclay, 2003; Meltzer et al., 2003). Large epidemiological studies also support an association between clozapine treatment and reduction in suicide (Walker et al., 1997; Tiihonen et al., 2009b). The Schizophrenia PORT recommends that a trial of clozapine should be considered for people with schizophrenia who exhibit marked and persistent suicidal thoughts or behaviors (Buchanan, et al., 2010). Meltzer (2012) estimates that approximately 10% of schizophrenia patients survive a serious suicide attempt and are clozapine candidates.

Suicide risk in adults with IDs is not well understood and rarely investigated. In a set of classic meta-analyses, mental retardation and dementia were the only mental disorders without an increased death risk by suicide, but epilepsy increased death risk by suicide approximately five-fold (Harris & Barraclough, 1997). A recent review of the limited published information reported that data on suicidal behavior in adults with IDs is very limited and that suicidal ideation and attempts do occur in adults with mild to moderate IDs, but are extremely rare in adults with severe to profound IDs (Merrick et al., 2006).

2.3. Self- or Hetero-Aggressive Behavior

            The clozapine indication of aggressive behavior in schizophrenia is well established. The Schizophrenia PORT recommends that a trial of clozapine should be considered for people with schizophrenia who present with persistent symptoms of hostility and/or display persistent violent behaviors (Buchanan, et al., 2010). In a systematic review of the literature, Frogley et al. (2012) found that (1) clozapine's anti-aggressive effect was most commonly explored in patients with schizophrenia, (2) there was less evidence available for other psychiatric disorders, including borderline personality disorder, autism spectrum disorders, post-traumatic stress disorder, bipolar disorder and learning disability; and (3) there was mixed evidence to address the question of whether or not clozapine was any more effective than other antipsychotics.

            The use of clozapine among individuals with IDs is becoming increasingly accepted due to efficacy and safety profiles similar to those reported among individuals without IDs.  The upper panel of Table 1 provides a summary of the use of clozapine to treat behaviors in adults with IDs. There are six articles describing case reports (Cohen & Underwood, 1994; Rubin & Langa, 1995; Williams et al., 1995; Holzer et al., 1996;  Kamal & Kelly, 1999; Gobbi & Pulvirenti, 2001), case studies using single- (Hammock et al., 2001) or double-blind designs with placebo (Hammock et al., 1995; Schroeder et al. 1995) and five retrospective reviews (Vyncke, 1974; Boachie & McGinnity, 1997;  Buzan et al., 1998; Thuresson & Farnstrand, 1999; Beherec et al., 2011). 

            Singh et al. (2010) completed a comprehensive review of the use of clozapine in IDs. They found that, of the 13 studies that met criteria for inclusion in this review, none of them met all the design requirements set forth in a prior risperidone review by Singh et al. (2005). Although many studies reported significant improvements in behavioral symptomatology, all relied on global impression scales. Only three of the studies they reviewed employed a rating scale, although such scales are more precise and provide a more detailed picture about behaviors of concern and provide the clinician with data regarding any antecedents and consequences of the individual’s behavior or response to medication.  Finally, 8 of the 13 studies reported that data was collected via subjective staff report. Overall, they found that the research on the use of clozapine to manage behavior among individuals with ID is inconclusive at best. They thought that some of the research they reviewed indicates that clozapine is indeed an effective treatment for individuals with IDs who engage in maladaptive behavior but, without meeting at least some of the methodological criteria set forth previously, it is difficult to say that with any degree of certainty. They urged clinicians who decide to prescribe psychotropic medication for behavioral uses to be highly cautious and carefully monitor behavioral, cognitive, and social responses as well as ADRs.

            Due to this limited data, clozapine should only be used to treat severe, persistent, self-injurious behavior (SIB) or aggressive behavior in individuals with IDs when there is evidence that (1) a behavioral treatment, as part of a formal training program, was adequately implemented and found to be ineffective; and (2) less toxic pharmacological interventions, including other antipsychotics, have been tried and the response considered unsatisfactory.

2.4. Polydipsia

            Although the studies are limited, clozapine appears to be the best treatment for the polydipsia associated with severe mental illness (Canuso & Goldman, 1999; de Leon et al., 1995; Verghese et al., 1996a; Goldman, 2010).  Typically, polydipsia is associated with schizophrenia, but it can be found in 5% of hospitalized individuals with mental retardation (Bremner & Regan, 1991; Deb et al., 1994; Hayfron-Benjamin et al., 1996).   In individuals with schizophrenia, the polydipsia response to clozapine appears to be independent from the antipsychotic response (Verghese et al., 1996a).  Polydipsia can be complicated by hyponatremia, which can be potentially lethal (de Leon et al., 1994a). In addition, case reports suggest that individuals with autism with complicated polydipsia may respond to a low dose of clozapine (<300 mg/day) (de Leon, 2003a; Ruktanonchai & de Leon, 2004).

            Due to this limited data, clozapine should only be used to treat polydipsia when there is evidence that (1) there are complications, particularly symptoms of hyponatremia and (2) a behavioral treatment to restrict water according to diurnal weight variations (Goldman & Luchins, 1987; de Leon et al., 1994a) was adequately implemented and found to be ineffective or impossible, particularly when it could not be implemented due to lack of patient cooperation.

2.5. Other Off-Label Uses

            In addition to its proven efficacy among individuals with schizophrenia, some studies suggest that clozapine treatment may be effective in individuals with schizoaffective and psychotic mood disorders (McElroy, 1991; Zarate et al., 1995) and non-psychotic rapid cycling bipolar disorder (Suppes et al., 1994). However, the current evidence supporting the use of clozapine for mania (Tohen & Vieta, 2009), bipolar disorder (Nielsen et al., 2012; Poon et al., 2012) or treatment-resistant depression (Wright et al., 2013) is limited. There are also RCTs supporting the use of clozapine for non-responsive first psychotic episodes (Freudenreich & McEvoy, 2012; Zhang et al., 2013) but this is currently an off-label indication. In China, Tang et al. (2008) described that about 25-60% of all treated patients with schizophrenia receive clozapine, which is preferred by some psychiatris as a first-line treatment for schizophrenia.

Clozapine has been consistently recommended in the literature for treating severe cases of tardive dyskinesia, particularly with a dystonic component (Simpson et al., 1978; Larach et al., 1997; Simpson, 2000; Conus et al., 2002; Pierre, 2005). In a recent tardive dyskinesia review, van Harten and Tenback (2011) recommended clozapine as a reasonable option (second in order among six options) when antipsychotics cannot be discontinued. Sajatovic et al. (1994) commented that the low risk of drug-induced tardive dyskinesia during clozapine treatment may be particularly beneficial for individuals with IDs who may have greater risk for tardive dyskinesia.

            Clozapine has been recommended for Parkinson’s disease with drug-induced and other concomitant psychosis (Friedman & Lannon, 1989; The Parkinson’s Study Group, 1999). Moreover, recent evidence-based reviews on the treatment of Parkinson’s disease indicate that clozapine (1) is efficacious in dyskinesia but, due to safety issues, it is considered to be only as “possibly useful” in clinical practice (Fox et al., 2011), and (2) is efficacious for psychosis (Goldman et al., 2011; Seppi et al., 2011). 

            Clozapine benefits have also been described as helpful in individuals with brain injury (Michals et al., 1993) and co-morbid schizophrenia and substance use disorder (Green et al., 1999; Kelly et al., 2012). If clozapine is prescribed for any of these other off-label uses, a comprehensive and detailed explanatory note should be included in the chart to justify its use.

3. Absolute Contraindications for Use

            The individual does not have any of the following major contraindications to clozapine use: (1)  hypersensitivity to clozapine or any other of the components of the drug,  (2) myeloproliferative disorder, (3) uncontrolled epilepsy, (4) paralytic ileus, (5) history of clozapine-induced agranulocytosis or severe granulocytopenia, (6) severe central nervous system (CNS) depression or comatose states, and (7) concurrent use of other drugs suppressing bone marrow function, (8) history of clozapine-induced myocarditis, (9) hepatic failure or progressive hepatic disease; (10) severe renal impairment, and 11) severe cardiac disease (Novartis Pharmaceutical Corporation, 2011; American Pharmacist Association, 2012).

4. Relative Contraindications for Use (Unless Benefit Outweighs Risk with Documentation)

            These guidelines provide a long list of relative contraindications: (1) pregnancy or breast feeding, (2) seizure disorder or history of seizure disorder, (3) association  with antimuscarinic activity (increased heart rate and sinus tachycardia risk, decreased gastric motility, decreased intestinal peristalsis and risk of constipation, decreased sweating and risk of heat stroke, proneness to urinary retention and/or preexisting benign prostate hyperplasia, combination with other antimuscarinic drugs, and narrow angle glaucoma),  (4) risk of orthostatic hypotension, (5) hypertension, (6) metabolic syndrome, (7) QTc prolongation and risk of sudden death,  (8) geriatric age (≥ 65 years),  (9) dementia, (10) treatment with drugs known to potentially suppress bone marrow function, (11) neutropenia, (12) benzodiazepine treatment, and (13) phenylketonuria with orally disintegrating tablets.  This long list of relative contraindications is not an attempt to discourage the prescription of clozapine in adults with IDs but an encouragement to closely monitor when any of these relative contraindications are present and to seek their resolution, when possible, before starting clozapine treatment.   

4.1. Pregnancy or Breast Feeding

            Clozapine is considered with caution in female individuals who have potential to become pregnant (category B) or are breast feeding.  According to the FDA, Category B means (1) animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women or (2) animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

            Clozapine, due to its metabolic risk, is associated with increased risk of gestational diabetes (Bodén et al., 2012). As clozapine has high antimuscarinic activity, it can cause delayed intestinal peristalsis in the newborn (Moreno-Bruna et al., 2012) and decreased fetal heart rate variability (Yogev et al., 2002)

            Breast-feeding is not recommended for mothers taking clozapine since clozapine appears to be eliminated in the milk (Barnas et al., 1994; Gentile, 2008).

4.2. Seizure Disorder or History of Seizure Disorder

            Due to its potential to decrease seizure threshold activity, clozapine is considered with caution if the individual has any of the following: (1) active seizure disorder; (2) history of a seizure disorder that required AEDs to achieve control, or (3) use of other drugs known to lower seizure threshold.

            Adult patients with IDs frequently have epilepsy with prevalences ranging from 16 to 26% (Bowley & Kerr, 2000; Forsgren et al., 1990; McDermott, et al. 2005; McGrother, et al. 2006; Morgan et al., 2003).  Therefore, in adults with IDs who have potential for seizures, the chart should document: (1) the risk-benefit, and (2) consideration of the need for a consultation with an expert in seizure disorders. The risk-benefit analysis should comment that other second-generation antipsychotics probably have less risk of decreasing seizure threshold than clozapine (de Leon et al., 2012).

4.3. Association with Antimuscarinic Activity

                Clozapine has high antimuscarinic activity (Raedler, 2007). Therefore, other clozapine relative contraindications are due to its potential antimuscarinic activity.  Clozapine should be used with caution in individuals with: (1) increased heart rate and sinus tachycardia risk, (2) decreased gastric motility and delayed gastric emptying, (3) decreased intestinal peristalsis with risk of constipation, (4) decreased sweating and risk of heat stroke, (5) proneness to urinary retention and/or preexisting benign prostate hyperplasia; (6) combination with other antimuscarinic drugs, and (7) narrow angle glaucoma (de Leon, 2011).

            Therefore, any relative contraindication due to its potential antimuscarinic activity requires documentation of the risk-benefit of clozapine versus other antipsychotics with less risk. The only other second-generation antipsychotic with high antimuscarinic activity in usual doses is olanzapine.  Quetiapine, in high doses, may also have clinically relevant antimuscarinic activity (de Leon, 2011).

4.3.1 Increased Heart Rate and Sinus Tachycardia Risk

Clozapine can cause tachycardia, and should be used cautiously in patients with tachycardia or those in whom increased heart rate is not recommended. Sinus tachycardia can also be associated with stimulant and related drugs (amphetamines, methylphenidate, atomoxetine, and rarely with modafinil), and some calcium channel blockers from the dihydropyridine family (amlodipine, felodipine, isradipine, and nifedipine) (Hoffman, 2006).  Thus, combining any of these drugs with clozapine increases tachycardia risk.   

4.3.2. Decreased Gastric Motility

An oral antidiabetic, pramlintide, can decrease gastric motility. It is better to discontinue pramlintide before starting clozapine. Much caution should be used when combining pramlintide with drugs with potent antimuscarinic activity such as clozapine; they may have additive effects in delaying gastric emptying (American Pharmacist Association, 2012).

4.3.3. Decreased Intestinal Peristalsis and Risk of Constipation 

As clozapine frequently causes constipation, clozapine should be used cautiously in patients with constipation and/or decreased intestinal motility.  Multiple medications can contribute to constipation by means of different mechanisms, including antacids containing aluminum or calcium, calcium channel blockers, calcium supplements, cholestyramine and colestipol, clonidine, diuretics, iron supplements, levodopa, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and vinca alkaloids (Arce et al., 2002; Bouras & Tangalos, 2009; Jacobs & Pamies, 2001; Spinzi, 2007). Thus, combining any of these drugs with clozapine increases constipation risk.

4.3.4. Decreased Sweating and Risk of Heat Stroke   

Antimuscarinic drugs such clozapine can definitively cause anhydrosis by parasympathicomimetically inhibiting sweat secretion, thus contributing to hyperthermia and heat stroke risk. There is more definitive risk if the patient is taking other drugs that may potentiate antimuscarinic effects, including other antipsychotics and carbonic anhydrase inhibitors (acetazolamide, topiramate and zonisamide). Antipsychotics including clozapine can interfere with heat regulation. Carbonic anhydrase inhibitors can inhibit sweating and have also been associated with heat stroke (Nolla-Salas et al., 2007; Shimizu et al., 1997). The risk is clear when patients are exposed to heat and/or strenuous exercise (Martin-Latry et al., 2007; Stadnyk & Glezos, 1983). Fatal heat stroke occurs mainly in the elderly (Peters, 1989). The co-administration of clozapine with drugs with antimuscarinic activity, other antipsychotics or carbon anhydrase inhibitors and exposure to hot weather or strenuous exercise should be accompanied by particular vigilance for hyperthermia and heat stroke.

4.3.5. Proneness to Urinary Retention and/or Preexisting Benign Prostate Hyperplasia

Clozapine, as with other antimuscarinic drugs, can interfere with detrusor muscle contraction; clozapine should be used cautiously in patients prone to urinary retention and/or with benign prostate hyperplasia. 

4.3.6. Combination with Other Antimuscarinic Drugs

            Clozapine may have additive antimuscarinic effects when combined with other antimuscarinic drugs (de Leon, 2011). Many drugs may have antimuscarinic activity, but there is definitive information that clinically relevant antimuscarinic activity is present for some antidepressants (amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, protryptiline, and trimipramine), some antipsychotics  (chlorpromazine and thioridazine), some antiemetics (meclizine, promethazine and prochlorperazine), some drugs for peptic ulcer (hyoscyamine and propantheline), some muscle relaxants (cyclobenzaprine, and orphenadrine), cyproheptadine, some bronchodilators (tiotropium), some antiarrhythmics (disopyramide), some drugs for dizziness (scopolamine), drugs for overactive bladders (darifenacin, fesoterodine, flavoxate, oxybutynin, oxybutynin transdermal system, solifenacin, tolterodine, and trospium), and some first-generation oral antihistamines (clemastine, dimenhydrinate, and diphenhydramine). Due to potentially increased risk for cognitive impairment and peripheral antimuscarinic ADRs, much caution should be used when combining clozapine with any of these drugs with antimuscarinic activity (de Leon, 2011).

            Lower risks are present for other drugs with possible antimuscarinic activity including some antidepressants (amoxapine, desipramine, maprotiline, mirtazapine, and paroxetine), some antipsychotics (loxapine, olanzapine, and quetiapine), ipratropium, some first-generation antihistamines (brompheniramine, carbinoxamine, chlorpheniramine, and hydroxyzine), some second-generation oral antihistamines (cetirizine, desloratidine, levocitirizine, and loratidine), some H₂ antagonists (cimetidine and ranitidine) and temazepam. Due to the potential for added cognitive impairment and peripheral antimuscarinic ADRs, much caution should be used when combining clozapine with any of these drugs with possible antimuscarinic activity (de Leon, 2011). 

4.3.7. Narrow Angle Glaucoma

            Clozapine, as other antimuscarinic drugs, can worsen narrow angle glaucoma; clozapine should be used cautiously in patients with narrow angle glaucoma.

4.4. Risk of Orthostatic Hypotension

            Clozapine has major risk of causing orthostatic hypotension and should be slowly titrated to avoid this. Clinicians should use clozapine cautiously in individuals: (1) predisposed to hypotension, (2) taking medication with potential to induce hypotension, including some antihypertensives, or (3) with underlying heart disease. Individuals with ID may have more difficulty expressing symptoms related to hypotension such as presyncope or lightheadedness so additional effort is required to monitor these complications more directly, such as obtaining orthostatic blood pressure changes.

4.5. Hypertension

            Another relative contraindication specific to clozapine is hypertension or history of hypertension.  First- or other second-generation antipsychotics do not appear to worsen hypertension directly in the average patient (de Leon & Diaz, 2007), but it is always possible that if they cause obesity they may secondarily contribute to hypertension and, in rare individuals, directly increase blood pressure (Villanueva et al., 2006).

            The number of patients who develop hypertension during clozapine treatment is usually small, <5% (Safferman et al., 1991), and may occur more frequently in patients with prior history of hypertension or borderline blood pressure baseline readings (Villanueva et al., 2006). Therefore hypertension or history of hypertension is a relative contraindication for clozapine and requires documentation of the risk-benefit of clozapine versus other antipsychotics.

4.6. Metabolic Syndrome

            Prior guidelines for other second-generation antipsychotics (de Leon et al., 2009a) consider as relative contraindications the presence of the metabolic syndrome or its components or high risk for them. The same relative contraindications apply to clozapine. The list includes (1) obesity, abdominal obesity, or personal history of high body mass index [BMI]; (2) diabetes mellitus, glucose intolerance, hyperglycemia, family history of diabetes; (3) hypertriglyceridemia or hypercholesterolemia (currently or historically) and (4) concomitant use of medications known to cause elevated blood glucose (e.g., steroids, niacin, thiazide diuretics).

            Clozapine is probably one of the antipsychotics with more risk for causing metabolic syndrome (Allison et al., 1999; de Leon & Diaz, 2007; Rummel-Kluge et al., 2010). Therefore, any of these signs or risks of metabolic syndrome are a relative contraindication for clozapine and require documentation of the risk-benefit of clozapine versus other antipsychotics with less risk. 

            Two additional issues need to be considered when writing the risk-benefit note: co-medication and baseline BMI. First, other medications may also influence weight gain (e.g., lithium, valproate, mirtazapine or paroxetine may be associated with weight gain), while bupropion and topiramate may be associated with weight loss (de Leon, 2008). Second, for individuals with low BMI, clinicians should be aware that paradoxically these individuals may be at greater risk for very high weight gain with clozapine (de Leon et al., 2007) while obese patients have less risk of gaining weight (de Leon et al., 2007; Pons et al., 2013).

4.7. QTc Prolongation and Risk of Sudden Death

            Clozapine has been associated with QTc prolongations and therefore potential for sudden death. Thus, relative contraindications include: (1) history of sudden death in the family,  (2) personal history of syncope, (3) electrolyte abnormalities, particularly severe hypokalimeia  that may contribute to QTc prolongation, (4) concomitant use of drugs that have demonstrated QTc prolongation as one of their pharmacodynamic effects and have shown this effect (e.g., dofetilide, sotalol, quinidine, mesoridazine, thioridazine, chlorpromazine, haloperidol, droperidol, pimozide, citalopram in doses > 40 mg/day, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, or tacrolimus), and (5) cardiovascular disease including recent acute myocardial infarct, uncompensated heart failure or clinically significant cardiac arrhythmia.

            Therefore, risk for QTc prolongation requires documentation of the risk-benefit of clozapine versus other antipsychotics. Among second-generation antipsychotics, ziprasidone and possibly iloperidone have higher risk of QTc prolongation than clozapine. Other second-generation antipsychotics probably have similar low risk of QTc prolongation except for aripiprazole, which is considered to have very limited risk of QTc prolongation (de Leon et al., 2012).

4.8. Geriatric age

Geriatric patients are particularly prone to sedation, cognitive impairment, delirium or hallucinations when taking antimuscarinic medication such as clozapine. Although the effect of aging in muscarinic neurotransmission has not been well studied, elderly patients may be more sensitive to the blockade of cholinergic and histaminic receptors, and there may be decreased brain cholinergic activity with aging (Peters, 1989; Trifiro & Spina, 2011). Another factor that can contribute to antimuscarinic ADRs is that the blood-brain barrier may be more permeable in the elderly (Cancelli et al., 2009).

Male geriatric patients are also particularly prone to urinary retention (Section 4.3.5). Geriatric patients of both genders are particularly prone to orthostatic hypotension (Section 4.4). 

4.9. Dementia

            Clozapine should not be used in demented patients for several reasons, including the following:  (1) the need of weekly WBCs; (2) high risk of orthostatic hypotension; (3) all antipsychotics include in their prescribing information a warning about the increased risk of mortality associated with their use in individuals with dementia (Section 7.3.5); (4) clozapine is a very potent blocker for brain muscarinic receptors and  blockade of brain M₁ and M₂ has been associated with impairment in memory and learning (de Leon, 2011); and (5) neuropathological and brain imaging studies (Sunderland et al., 1987) show a decrease in brain muscarinic receptors in Alzheimer disease.

4.10. Treatment with Drugs Known to Potentially Suppress Bone Marrow Function

            Drugs actively suppressing bone marrow function are absolute contraindications. If the individual is taking drugs known to potentially suppress bone marrow function (e.g., carbamazepine, captopril, propylthiouracil, penicillamine, sulfonamides and antineoplastic agents), careful consideration should be given to discontinuing these drugs before clozapine is started.  In these situations, the psychiatrist must discuss the case with the primary care physician and/or specialist and document this in the chart. 

4.11. Neutropenia

            The US prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends a white blood cell count (WBC) ≥ 3500/mm³ and an absolute neutrophil count (ANC) ≥ 2000/mm³ to start clozapine. 

            Benign ethnic neutropenia has been defined as “the occurrence of neutropenia, defined by normative data in white populations, in individuals of other ethnic groups who are otherwise healthy and who do not have repeated or severe infections” (Haddy et al., 1999). Rajagopal (2005) estimated that about 25% to 50% of Africans and some ethnic groups in the Middle East, including Yemenite Jews and Jordanians, have benign ethnic neutropenia.The Clozaril Patient Monitoring System used by clinicians in the United Kingdom and Ireland has different ranges for patients with benign ethnic neutropenia: 1) normal WBC monitoring is recommended when ANC ≥ 1500/mm,³  2) increased monitoring is recomemended with ANC > 1000/mm³ and < 1500/mm,³ and 3) stopping clozapine is recommended with ANC < 1000/mm³ (Blackman, 2008).

            In the US, Kelly et al. (2007) proposed that US African-Americans may be prone to benign ethnic neutropenia. Meltzer (2012) has proposed that in the US between 4–8% of Af­rican Americans and people of Middle Eastern origin have chronically low WBC (e.g., 2,500–3,500), with ANC of 1,300–1,700.  These individuals are not at any greater risk for agranulocytosis than are those with typical WBC of 4,500–8,000. Clinicians need to be aware of this to avoid denying them a clozapine trial (Rajagopal, 2005; Kelly et al., 2007; Meltzer, 2012).  In the US, cases of lithium use in benign ethnic neutropenia has been published (Nykiel et al., 2010).

            Rechallenge with clozapine after prior clozapine-induced neutropenia is a complex issue (Bogers et al., 2012). The literature describes patients who have been successfully rechallenged with clozapine after developing neutropenia during prior clozapine treatment. Some of them were treated with lithium at lithium levels around 0.4 mEq/L and/or granulocyte colony-stimulating factor (Conus et al., 2001; Manu et al., 2012), which can increase ANC. Rajagopal et al., (2007) described an adult with ID who was successfully rechallenged with clozapine after neutropenia using lithium and short-term treatments with granulocyte colony-stimulating factor.

            Clinicians who are dealing with patients with low ANC before or after starting clozapine should also know that a few patients with circadian rhythm variations have been described in the literature as having low ANC in the morning and normal values in the afternoon (Ahokas & Elonen, 1999; Esposito et al., 2003)

4.12. Benzodiazepine Treatment

            When possible, benzodiazepines should be stopped one week before starting clozapine and (Section 6.5.2), if needed, restarted one week after clozapine has been started.  If the benzodiazepines cannot be stopped, appropriate measures should be taken to monitor for the very rare risk of collapse or respiratory arrest during the first few days of clozapine treatment (Benzodiazepines subsection in Section 6.5.2).

4.13. Phenylketonuria with Orally DisintegratingTablets 

            Clozapine orally disintegrating tablets have phenylalanine (Jazz Pharmaceuticals, Inc., 2010) and this should be taken into account in patients with phenylketonuria. 

5. Assessment during Treatment

5.1. Before Initiating

5.1.1. Informed Consent

            Obtain informed consent prior to treatment initiation and document it in the chart.  The individual and /or guardian shall be informed of at least the following by the prescribing physician: (1) risk of agranulocytosis and the need for weekly blood tests during the first six months and every other week thereafter; (2) results of blood tests will be shared with the pharmacist and CNR, and the drug will not be supplied if the blood is not obtained; (3) myocarditis risk, (4) seizure risk, (4) other ADRs that may be relevant for that patient, (5) the risk of stopping clozapine suddenly, and (6) in females, caution regarding pregnancy and breast feeding.

5.1.2. Contacting CNR

            Contact CNR for individual and physician registration and to verify that the individual did not develop clozapine-related agranulocytosis or leucopenia in the past.  Treatment can be initiated only after an authorization number has been assigned by CNR.

5.1.3. Chart Documentation

            Chart documentation (prior to treatment) should include: (1) weight, height and BMI, (2) waist circumference, (3) personal history of diabetes mellitus and hyperlipidemia, and (4) family history of diabetes mellitus.

5.2. Initial Workup

5.2.1. Required Initial Workup

The patient’s initial workup should include:  (1) glycosylated hemoglobin level (Hgb A1C), (2) fasting serum glucose, (3) lipid panel, (4) electrolytes, (5) liver function tests, (6) tardive dyskinesia rating (e.g., Dyskinesia Identification System: Condensed User Scale, DISCUS, Sprague et al., 1984), and (7) EKG.

5.2.2. Optional Initial Workup to Help Diagnosing Myocarditis

            Australian researchers have been pioneers in diagnosing clozapine-induced myocarditis (Kilian et al., 1999). Cohen et al., (2012a) have described clozapine-induced myocarditis as much more frequent in Australia than in other countries. Recently, in order to decrease myocarditis risk in outpatients started on clozapine, Ronaldson et al. (2011) have proposed measuring at baseline: C - reactive protein (CRP), echocardiogram and troponin.  The purpose is to compare these measurements with changes occurring during the first weeks of clozapine treatment. 

            This guideline proposes that when clozapine is used in adult inpatients with IDs, a very conservative titration be used, which should substantially decrease the risk of myocarditis. Clinicians should consider whether or not to add CRP level to the baseline as an option. It appears reasonable to have a baseline CRP level since CRP elevations have been associated with clozapine-induced fever (Section 7.2.3) and myocarditis (Section 7.3.2). Troponin, and particularly an echocardiogram, appears excessive in the context of a very slow titration. Clinicians are encouraged to review the most updated literature to make decisions regarding preventing the risk of clozapine-induced myocarditis.  

5.2.3. Pharmacogenetic Testing for Clozapine

            Many pharmacognetic studies have been completed in patients taking clozapine (Arranz & de Leon, 2007; Raja, 2011). A Bristish study proposed that genetic pharmacodynamic variations can predict who may or may not respond to clozapine (Arranz et al., 2000). There were successive attempts to develop a test to predict clozapine response in the United Kingdom but very limited information exists about its usefulness in the clinical environment (de Leon et al., 2008).  Therefore, none of the available commercial tests for predicting clozapine response are recommended by this guideline.

            There is some information in the literature that pharmacokinetic genes may be helpful in predicting dosing, particularly in East Asians (Sections 6.7.1 and 6.7.2), but it is too early for clinical recommendations.  There are also preliminary studies on pharmacodynamic genetic variations associated with clozapine-induced weight gain (Lett et al., 2012).

5.2.4. HLA Testing and Risk for Clozapine-induced Agranulocytosis

            The  observation that Ashkenazi Jews may have greater risk of clozapine-induced agranulocytosis led to a possible HLA-B38 marker (Lieberman et al., 1990) and to further studies.  A pharmacogenetic company finally tried to market a test to prevent clozapine-induced agranulocytosis but the test was withdrawn from the market (de Leon et al., 2008). More recently, this company published a study of candidate genes associated with clozapine-induced agranulocytosis in two independent cohorts recruited in the US, Russia and South Africa (Athanasiou et al., 2011).  After refinement analyses of sequence variants in HLA-DQB1, a single nucleotide polymorphism (SNP), 6672G>C, was found to have an odds of clozapine-induced agranulocytosis 16.9 times greater in patients who carry this marker compared to those who do not.  This marker identifies a subset of patients with an exceptionally high risk of clozapine-induced agranulocytosis, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. The clinical utility of this marker is not established (Athanasiou et al., 2011).

5.3. Clozapine Adverse Reactions Scale for Nurses

5.3.1. Description

            The Clozapine Adverse Reactions Scale for Nurses (Appendix 2) has four sections: A through D.

Section A.  This section requires observing and asking about (1) symptoms/signs of infection, (2) salivation, (3) drowsiness/sedation, (4) falling, (5) leg folding or knee buckling, (6) dizziness, (7) constipation, (8) urinary incontinence, and (9) other.

Section B. This section requires recording the oral temperature. If the oral temperature is > 99.8, it should be repeated in 15 minutes.  The physician needs to consider the possibility of infection or benign hyperthermia (i.e., low grade fever with no cause).  The presence of fever is a red flag due to the possibility of agranulocytosis or myocarditis.  Special attention must be given to the possibility of severe respiratory infection which may increase clozapine levels (Section 6.7.6.).  The clinician must remember that agranulocytosis is rare (<1%), particularly after six months of treatment.   Moreover, it can easily be ruled out by drawing blood counts.

Section C. This section focuses on blood pressure and pulse. It serves three purposes, as it assesses (1) orthostatic hypotension, (2) pulse abnormalities, and (3) hypertension.

            Regarding orthostatic hypotension, this scale requires recording pulse and blood pressure after the patient has been seated for 3 minutes and has been standing for 2 minutes.  This is far from ideal for diagnosing orthostatic changes but appears a reasonable compromise for patients with IDs. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology (1996) states, “Orthostatic hypotension is a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.  An acceptable alternative to standing is the demonstration of a similar drop in blood pressure within 3 minutes, using a tilt table in the head-up position, at an angle of at least 60 degrees.”  The criteria of ≥ 20 mm Hg of systolic blood pressure or ≥ 10 mm of diastolic blood pressure is used in this guideline.  For patients with ID who receive medication at a nurse’s station, lying down or using a tilt table is not a practical alternative for measuring orthostatic changes. As a practical alternative for standardizing procedures and following prior experience in an RCT trial (Simpson et al., 1999) and in clinical practice (de Leon, et al., 2009a), measuring orthostatic changes after sitting for 3 minutes and standing for 2 minutes appears to be a reasonable alternative.  Although the 1996 definition of orthostatic changes is the most widely accepted, some authors have been critical. Wieling and Schatz (2009) commented that (1) the criteria of ≥ 20 mm Hg of systolic blood pressure or ≥ 10 mm of diastolic blood pressure is appropriate for normotensive individuals, but it may be too low for hypertensive individuals; and (2) sometimes a patient has symptoms within the first 30 seconds. For patients with IDs, measuring blood pressure twice within 30 seconds and again within the 3-minute limit appears too difficult from the practical point of view. As the patient is being observed for 2 minutes standing by the staff, any symptom associated with early (<30 seconds) orthostatic changes would be observed.  According to Braam et al., (2009), the prevalence of orthostatic change is higher going from supine to standing than from sitting to standing. As indicated above, supine position does not appear to be a good alternative for measuring blood pressure in ID patients who are going to receive their medications. Fedorowski and Melander (2009) stressed the importance of repetition of measures to identify real autonomic impairment. In that sense, this guideline based on prior experience (Simpson et al., 1999; de Leon et al., 2009a) recommends repeating abnormal measures in 15 minutes. The definition of orthostatic changes used in this guideline may need to be changed in the future, as proposals for modifying the 1996 definition are generally accepted. Recently, Freeman et al. (2011) have proposed modifying it by adding that in patients with supine hypertension, a reduction in systolic blood pressure of 30 mm Hg may be more appropriate. Currently, it is not clear how this modification will be accepted by the medical community.

            Clozapine can also induce tachycardia, whether or not associated with orthostatic changes (Section 7.1.3). Thus, this scale considers that a pulse in beats per minute (bpm) >120/min or < 60/min is considered abnormal while seated or standing and needs to be repeated in 15 minutes. Individuals with persistent tachycardia must be assessed for the risk of myocarditis.

            Clozapine can also induce hypertension (Section 7.2.9). Thus, this scale considers blood pressure < 90 or > 150 mm Hg of systolic blood pressure or < 60 or > 150 mm Hg of diastolic blood pressure are motive for concern, particularly after their presence a second time 15 minutes later.

Section D.  This section focuses on abnormal values after repetition. If any of the values normalize in the second measure, that clozapine dose may be given. If any recorded item lies outside the parameters given below and continues to be abnormal after 15 minutes, the physician should be called to assess the abnormal values before clozapine dose administration.  The parameters are: (1) oral temperature > 99.8, (2) systolic blood pressure < 90 mm or above 150 mm Hg; (3) diastolic blood pressure < 60 mm or > 100 mm Hg, (3) drop  > 20 mm of systolic or > 10 mm Hg diastolic pressure between sitting and standing, and (4) pulse > 120 bpm or < than 60 bpm. 

5.3.2. Use after Clozapine Initiation

            The Clozapine Adverse Reactions Scale for Nurses needs to be administered at the initial phase of the treatment every time a clozapine dose is given.  As clozapine is typically given twice a day, in the early morning and at night, the scale may be administered twice a day during the initial phase. As each clozapine titration needs to be personalized, a minimum 3-week scle use appears reasonable. Once most of the upward titration has been completed and the patient is on a stable dose, the Clozapine Adverse Reactions Scale for Nurses may be discontinued or at least discontinue Sections C and D. Sections A and B reflect ADRs that can be present during clozapine treatment and may be easily missed in adults with IDs. After the dose is relatively stable, if there is need to increase the clozapine dose, restarting the monitoring of orthostatic changes for one week may be a good idea. In summary, this guideline recommends a 3-week minimum use of the Clozapine Adverse Reactions Scale for Nurses but further uses are recommended when needed. Careful monitoring and delayed titration allows individuals to develop tolerance to orthostatic changes and tachycardia. Thus, in most cases, changes disappear over time.

5.3.3. Use before Clozapine Initiation

            In our experience, a modified version of the Clozapine Adverse Reactions Scale for Nurses can be administered before starting the clozapine treatment in order to get baseline data for comparison with clozapine treatment and to get the patient and staff used to the routine for clozapine titration.

5.4. WBC with Differential

.           This section of the guideline provides a simplified summary of the US prescribing information (Novartis Pharmaceutical Corporation, 2011). Other countries provide more flexibility. After 6 months on clozapine, The Netherlands Clozapine Collaboration group permits lowering the WBC frequency to four times a year for mentally competent and adequately informed patients (Cohen & Moden, 2013).  In other countries researchers have also proposed reducing WBC frequency after the period of greatest risk, the first 6 months (Pons et al., 2012).

            The United Kingdom and Ireland allow for lower ANC limits in benign ethnic neutropenia (Section 4.11.).  Several authors have recommended modifying the ANC limits in the US for patients with benign ethnic neutropenia (Mallinger & Lamberti, 2006; Kelly et al., 2007; Meltzer, 2012). 

5.4.1. Initiation

            The prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends a WBC ≥ 3500 mm³ and an ANC ≥ 2000 mm³ to start clozapine (Section 4.11).  

5.4.2. Frequency

            When all results for WBC ≥ 3500 mm³ and ANC ≥ 2000 mm³,  the WBC with differential will be measured (1) weekly for the first 6 months; (2) every two weeks for months 7 to 12; and (3) every four weeks after month 12 and following.

5.4.3. Abnormal Values

Immature Forms Present. Repeat WBC and ANC.

Substantial Drop in WBC or ANC. If there is a single drop or cumulative drop within 3 weeks of WBC ≥ 3000/mm³ and ANC ≥ 1500/ mm³, you need to (1) repeat WBC and ANC. For WBC between 3000-3500/mm³ and ANC >2000/mm³, monitor WBC with differential twice weekly. According to the prescribing information (Novartis Pharmaceutical Corporation, 2011), an analysis of WBC data from CNR suggests that patients who have an initial episode of moderate leukopenia (3000/mm³ > WBC ≥ 2000/mm³) are at an increased risk of subsequent episodes of agranulocytosis.

Mild Leukopenia (WBC Between 3000-3500/mm³) and/or Mild Granulocytopenia (ANC between 1500-2000/mm³).  Monitor WBC with differential twice weekly until WBC ≥ 3500/mm³ and ANC ≥ 2000/mm³ and then return to the previous frequency.

Moderate Leukopenia (WBC Between 2000-3000/mm³) and/or Moderate Granulocytopenia (ANC between 1000-1500/mm³). (1) Stop clozapine. (2) Monitor WBC with differential daily until WBC > 3000/mm³ and ANC > 1500/mm³ and then return to the previous frequency. (3) Monitor WBC with differential twice weekly until WBC > 3500/mm³ and ANC > 2000/mm³ and then return to the previous frequency. (4) Rechallenge may be given when WBC > 3500/mm³ and ANC > 2000/mm³. (5)  If rechallenge is used, monitor WBC with differential weekly for 1 year until returning to the usual schedule.

Severe Leukopenia (WBC Between <2000/mm³) and/or Severe Granulocytopenia (ANC < 1000/mm³). (1) Stop clozapine and do not rechallenge the patient. (2) Monitor until normal and for ≥ 4 weeks from the day of discontinuation as follows: (a) Daily WBC with differential until WBC > 3000/mm³ and ANC > 1500/mm³ and then (b) twice-weekly WBC with differential until WBC > 3500/mm³ and ANC > 2000/ mm³.

Agranulocytosis (ANC ≤ 500/mm³). (1) Stop clozapine and do not rechallenge the patient. (2) Monitor until normal and for ≥ 4 weeks from the day of discontinuation as follows: (a) Daily WBC with differential until WBC > 3000/mm³ and ANC > 1500/mm³ and then (b) twice-weekly WBC with differential until WBC > 3500/mm³ and ANC > 2000/mm³, and (c) weekly after WBC > 3500/mm³.

Greater Relevance of ANC. Besides following the prescribing information closely, one should remember that clozapine can destroy granulocytes but spare other leukocytes.  Therefore, ANC is a better measure than WBC for monitoring the risk of agranulocytosis.  The ANC varies greatly from individual to individual; a few individuals with very high ANC may have more room to drop to the ANC levels described by the prescribing information.  Thus, one should be alert to ANC drops unusual for a given individual but which may not reach the prescribing information thresholds.  An example would be if most of an individual’s ANCs over several months ranged between 5000-7000/mm³ with a few ANCs in the range of 3200-4600/mm³.  If the ANC drops to 2000/mm³ it is still above the guideline, but this ANC (2000/mm³) is clearly unusual for this individual.  It must also be remembered that viral infections sometimes cause temporal neutropenia.

Chronic low ANC with no further decreases of ANC. Section 4.1.1 describes: (1) some rare patients who may have circadian variations with low ANC only in the morning (Ahokas, 1999; Esposito et al., 2003), and (2) people with African or Middle Eastern ancestry who may have naturally low ANC (called benign ethnic neutropenia) and the recommendations provided in the United Kingdom and Ireland. 

5.4. Monthly Monitoring for the First Year  

            Monthly monitoring for the first year should include weight. Weight gain should prompt dietary interventions and nutritional consultation unless these were already in place.

5.5. Once after 1 Month on Clozapine and Quarterly Monitoring During the First Year

After 1 month on clozapine, the patient should be monitored with (1) fasting serum glucose, and (2) lipid panel.  Then quarterly (months 3, 6, 9 and 12) monitoring should include (1) fasting serum and/or hemoglobin A1C, and (2) lipid panel. Be alert to the possibility of diabetic ketoacidosis even in the absence of weight gain. A prior set of guidelines for other second-generation antipsychotics (de Leon, et al., 2009a) only recommended these metabolic tests semiannually. Earlier testing is recommended for clozapine to avoid diabetic ketoacidosis, which frequently occurs within the first 3 months (Section 7.3.9).  The Netherlands Clozapine Collaboration Group (2009) recommended 1) clozapine fasting glucose at 1, 2, 3, and 6 months and then annually and 2) if there are problems with fasting glucose to substitute HBA1C and non-fasting glucose levels.

5.6. Annual Monitoring

            The annual monitoring should include (1) waist circumference and review of the metabolic syndrome situation including (a) fasting serum and/or hemoglobin A1C, and (b) lipid panel, unless it was done as part of the last quarterly assessment of the first year; (2) EKG; (3) asking for changes in libido and erectile and ejaculatory function in males when it is appropriate; (4) consideration of any antimuscarinic ADRs, particularly constipation; and (5) a tardive dyskinesia rating (DISCUS).  

5.7. TDM

            Due to our limited knowledge of clozapine metabolism and the assumption that in most circumstances and most patients, norclozapine is the main clozapine metabolite (Section 6.5), it is not surprising that most TDM studies have focused on plasma clozapine and norclozapine concentrations. There is general agreement that among antipsychotic TDMs, clozapine TDM is the best studied (Mitchell, 2001; Baumann et al., 2004; Hiemke et al., 2011).

            When planning to use and/or interpret clozapine TDM results in adults with IDs, several principles need to be considered: (1) standardization, (2) parent versus metabolite concentrations, (3) therapeutic window, (4) normal variations, (5) the relationship between clozapine dose and concentrations in the US; (6) the relationship between clozapine dose and concentrations in East Asian individuals; and (7) the lack of clozapine TDM studies in adults with IDs.   

5.7.1. Standardization

            All of the clozapine C studies used trough steady-state concentrations.  Trough means that concentrations are drawn in the early morning before the morning dose is administered and approximately 12 hours after the last dose.  A steady-state concentration is usually estimated to require 5-7 half-lives (Bauer, 2006; Glauser & Pippenger, 2000). The elimination half-life of clozapine is estimated to be 12 hours with a range of 6-33 hours (Baldessarini & Frankenburg, 1991).  The rounded average for clozapine half-life is 24 hours (de Leon et al., 1996).  Thus, a good rule of thumb is to wait at least one week after the last clozapine dose change and after any important changes in major factors that influence the levels (e.g., smoking, caffeine intake, and the concomitant use of inhibitor or inducer drugs).  One needs to be sure of compliance with treatment during the week prior to obtaining levels.  When an abnormally low clozapine level is observed, one should first suspect noncompliance, which is common, and second, rapid metabolism. If a clozapine level is inconsistent with prior measures or clinical observations, it should be repeated (Oo et al., 2006). If one finds an unexpected high plasma clozapine concentration, measuring CRP levels (Section 6.7.6) to rule out undetected inflammatory process may be a good idea (Pfuhlmann et al., 2009).

5.7.2. Parent versus Metabolite Concentrations

Most clozapine TDM studies also measure norclozapine concentrations, the primary metabolite of clozapine.  Some in vitro studies suggest that norclozapine may bind to brain receptors, but there is no clinical evidence that norclozapine contributes to therapeutic activity, and limited information suggests that it may contribute to clozapine’s antimuscarinic ADRs (de Leon et al., 2003b).   Thus, although norclozapine levels do not predict therapeutic response, they may assist in monitoring clozapine metabolism for pharmacologists, since the addition of serum clozapine and norclozapine concentrations reflects clozapine metabolism better than serum clozapine concentrations alone (de Leon & Diaz, 2003),

            The total plasma clozapine concentration, calculated by adding plasma clozapine and norclozapine concentrations, may be a better indicator of overall clozapine metabolism than plasma clozapine concentration alone.  This total concentration is influenced by inducers and inhibitors in a way that is consistent with known pharmacological mechanisms (de Leon & Diaz, 2003; Diaz et al., 2008). Obviously, a better total clozapine concentration for reflecting clozapine metabolism would also include the plasma concentrations of all metabolites including clozapine-N-oxide.   However, the majority of commercial laboratories do not measure this metabolite, which in the majority of circumstances may be a minor metabolic pathway (Section 6.5).  

            This guideline does not recommend the use of total clozapine plasma concentrations (obtained by adding clozapine and norclozapine concentrations) unless the prescribers have a thorough understanding of clozapine metabolism.  Similarly, the norclozapine/clozapine ratio has occasionally been used in the literature, but this ratio: 1) is not a good measure of CYP1A2 activity (Doude van Troostwijk et al., 2003) and 2) has very high within-subject variability, even under the same clozapine dose (Raedler et al., 2008).  CYP1A2 contributes to the simultaneous formation and destruction of norclozapine while other CYPs and renal elimination contribute to norclozapine elimination (Olesen & Linnet, 2001; Ozdemir et al., 2002; Dailly et al., 2002).  Using a norclozapine/dose ratio makes little sense from a pharamacological point of view because it is difficult to quantitatively predict how increments or reductions in CYP1A2 activity influence this ratio.

5.7.3. Therapeutic Window

            The width of the therapeutic window determines the clinical significance of changes in plasma levels.  The lower limit of the window is the lowest level that is associated with therapeutic efficacy.  The upper limit is the level above which toxicity occurs.  Compared to other second-generation antipsychotics, clozapine has a much narrower therapeutic index (de Leon et al., 2005).

            Several controlled studies of plasma clozapine concentrations have been conducted in individuals with schizophrenia who are treatment-refractory.  Most studies recommend plasma clozapine therapeutic concentrations higher than 350 ng/ml (Hasegawa et al., 1993; Kronig et al., 1995; Perry et al., 1991; VenderZwaag et al., 1996), with a maximum of 420 ng/ml (Potkin et al., 1994). As a matter of fact, the Schizophrenia PORT provides two TDM recommendations (Buchanan et al., 2010): (1) If a person treated with clozapine has failed to demonstrate an adequate response, then a clozapine level should be obtained to ascertain whether the clozapine level is above 350 ng/ml. (2) If the blood level is less than 350 ng/ml, then the dosage should be increased, to the extent that side effects are tolerated, to achieve a blood level above 350 ng/ml.

Clozapine levels higher than 1,000 ng/ml have been associated with toxicity, including seizure risk and severe sedation (Simpson & Cooper, 1978).

5.7.4. Normal Variations

Clinicians frequently fail to understand that interpretation of a single clozapine level must be cautiously considered, and that a pattern change after several levels is more easily interpreted.  As a matter of fact, laboratory, technical and natural variations can cause some day-to-day variations in clozapine levels, even after assuming stability of all possible confounding factors such as timing of collection, dose and schedule, and DDIs.  There is limited information on normal variations of clozapine levels seen in the naturalistic setting (de Leon & Diaz, 2003; Kurz et al., 1998), which is probably lower than in well-controlled studies (Diaz et al., 2005).  Great variability in clozapine plasma concentrations may be a sign of poor compliance and carry the risk of exacerbations (Stieffenhofer et al., 2011). Based on this information, it seems reasonable to suggest that only a change by a factor of two is probably meaningful from the clinicians’ perspective (de Leon, 2004b; de Leon et al., 2005). This means that if an individual has a clozapine level of 500 ng/ml, the next one under the same stable conditions should not be > 1000 ng/ml or < 250 ng/ml.  However, a change from 500 ng/ml to 400 ng/ml is probably not very relevant.

5.7.5. Relationship between Clozapine Dose and Concentration in the US

            In typical doses, clozapine appears to have a linear relationship between typical doses and concentrations (first-order kinetics), particularly within the same individual (Choc et al., 1987).  Pharmacologists use a simple formula, the C/D ratio, to represent this relationship (de Leon, 2004b; de Leon et al., 2005; Diaz et al., 2008). Plasma clozapine concentrations exceeding 350 ng/ml are described as therapeutic, with most individuals requiring a dose of 300-600 mg/day to reach these levels. 

            Based on a US double-blind clozapine study (Simpson et al., 1999) and on a large Italian sample combining TDM and DDI studies (Diaz et al., 2008), a mathematical model for predicting clozapine concentration based on dosage has been developed (Diaz et al., 2007; Diaz et al., 2012a; Diaz et al., 2012b).   Assuming that an individual needs a dose of 300 mg/day to reach a level of 350 ng/ml provides a C/D of 1.2 (350/300).  Conversely, assuming that each individual needs a dose of 600 mg/day, this provides a C/D of 0.6 (350/600).   Based on these studies and models, the average US individual taking clozapine has a C/D of 0.6-1.2. The C/D of 1.2 appears typical of an average US female non-smoker who needs a D of 300/mg of clozapine to reach a therapeutic concentration. The C/D of 0.6 appears typical of an average US male smoker who needs a D of 600/mg of clozapine to reach a therapeutic concentration.  US female smokers and male non-smokers typically have C/D in the middle between 0.6-1.2. There is not as much research in European Caucasians concerning C/D ratio but, until there is more information, the limited available information suggests that C/D ranges between 0.6-1.2 in most patients appear reasonable. 

5.7.6. Relationship between Clozapine Dose and Concentrations in East Asians

             The studies in individuals with Chinese ancestry clearly suggest that average subjects from these populations have much lower capacity to metabolize clozapine than US Caucasians (Chang et al., 1997; Chong et al., 1997; Ng et al., 2005).  The average C/D ratio was 1.6 in 162 Chinese from Taiwan (Chang et al., 1997), which was clearly higher than five Caucasian studies that had C/D ratios ranging from 0.89-1.05.  In a Chinese study by Tang et al. (2007a), the C/D ratio was 1.65 for females, 1.33 for male non-smokers and 1.27 for male smokers. A C/D ratio of 2.9 was found in 14 Chinese patients in Singapore (Chong et al., 1997). Ng et al. (2005) compared 20 Asians from Singapore (13 Chinese, 4 Indians and 3 Malayans) and 20 Caucasians; the respective C/D ratios were 2.4 and 0.96. It is also possible that Koreans may metabolize faster than US Caucasians but this has not been well studied. In a recent study (Lee et al., 2009), the clozapine C/D ratio ranged from 1.4 in smokers to 2.2 in females. Although these studies do not provide C/D ratios stratified by gender and smoking status, they suggest that East Asians, particularly those of Chinese ethnicity, have average lower clozapine metabolic capacity than Caucasians; it may be half or lower, meaning that, on average, East Asians may require approximately half the dosage used for Caucasians (Sections 6.4 and 6.7.2). A recent Japanase study did not assess clozapine TDM (Kishi et al., 2013).

5.7.7. Lack of TDM studies in adults with IDs

            No good published information addresses the meaning of monitoring plasma clozapine levels in individuals with IDs.  However, using plasma levels and taking into account DDIs, caffeine use (Section 6.5.1), smoking status (Section 6.7.3) and individual metabolic differences appears to be good practice. This guideline recommends: (1) measuring plasma clozapine concentration at least once after reaching clozapine target dose, and (2) using a plasma clozapine concentration at target dose of ≥ 350 ng/ml. Two optional TDM recommendations are provided: (1) measuring plasma clozapine concentration to determine target clozapine dose after reaching steady state on (a) 300 mg/day for standard US subjects, or (b) 150 mg/day in East Asians, known CYP2C19 PMs, individuals taking relevant inhibitors of clozapine metabolism, or geriatric patients, and (2) repeating a plasma clozapine concentration which was inconsistent with prior measures or clinical observations (Oo et al., 2006). If one finds an unexpectedly high plasma clozapine concentration, measuring CRP levels to rule out an undetected inflammatory process may be a good idea (Pfuhlmann et al., 2009). Similarly, when intrepreting clozapine TDM in adults with IDs, clinicians pay attention to co-medication and caffeine intake.

5.8. Warning Signs and Symptoms for Daily Caretakers

The following may frequently occur, particularly when initiating or increasing clozapine doses:  (1) dizziness or falling, (2) drooling, (3) sedation or sleepiness, (4) constipation, (5) urinary retention, or (6) leg folding or seizures. After several months the patient may have significant weight gain

The following may rarely occur, but when present may indicate potentially lethal ADRs: (1) symptoms/signs of infection (e.g., sore throat or cough, mouth ulcers; chills; rectal soreness/itching; vaginal soreness/itching; urinary frequency/burning) or fever, and (2) heart symptoms including tachycardia, palpitations or unexplained fatigue.

            Caretakers, patients and families should be informed that: (1) undiagnosed and untreated clozapine-induced constipation (Section 7.3.7) or diabetes mellitus (Section 7.3.9) can become lethal.

 (2) severe respiratory infections and other severe infections or inflammations may be associated with clozapine toxicity even in the presence of doses of clozapine that were well-tolerated for months or years (Section 6.7.6), and (3) keeping stable caffeine intake (Caffeine subsection in Section 6.5.1) and stable smoking intensity (Section 6.7.3) is important for avoiding fluctuations in clozapine metabolism. Plans for smoking cessation needs to be reported to clozapine prescriber (Section 6.7.3).

6. Dosage

            The clozapine dosing recommendations provided in the prescribing information (Novartis Pharmaceutical Corporation, 2011) are generated by the dose response of the “average subject” in double-blind studies, where most co-prescriptions are forbidden.  Therefore, these recommendations may not be appropriate for many real-world individuals who cannot be considered “average”.  Examples include individuals lacking or having too much activity of the enzyme responsible for clozapine metabolism, and/or individuals taking other medications that significantly influence metabolism.

6.1. Addition to Currently Prescribed Antipsychotics

            Ideally, one would like to discontinue other antipsychotic medications or titrate down when clozapine is titrated up.  Individuals with IDs requiring clozapine treatment are probably very difficult to treat and it may not be prudent to discontinue the other antipsychotic before determining if clozapine is going to be tolerated or will work.  It appears reasonable to avoid adding clozapine to more than one antipsychotic, and, if the antipsychotic is a phenothiazine or olanzapine, which have potential for competing with clozapine metabolism (Other Antipsychotics subsection in Section 6.5.1), one should consider starting with a lower initial dose of 12.5 mg and a slower titration.  If the baseline medication is a long-acting antipsychotic intramuscular preparation, the prescriber should consider the convenience of changing from the long-acting formulation to the oral preparation to simplify the process of switching to clozapine.  

6.2. Administration Pattern

            The clozapine prescribing information (Novartis Pharmaceutical Corporation, 2011) describes the possibility of administration three times a day (tid). Based on experience with a RCT (Simpson et al., 1999) and clinical experience, a twice-a-day administration combined with The Clozapine Adverse Reactions Scale for Nurses appears safer and simpler than the tid administration.

            Based on experience with a RCT (Simpson et al., 1999) and clinical experience, it may be better administered with a larger dose at night and a smaller dose in the morning (e.g., 66% of the dose at night and 33% in the early morning).  Clozapine sedative and orthostatic changes are greater with the first few doses and tolerance usually develops in a few weeks. The first week’s dosing may be associated with greater risk of sedation and orthostatic changes. Administering the largest dosage at night would be associated with the highest peak occurring when the patient is sleeping. Therefore, the highest risk for sedation and orthostatic changes would occur when the patient is sleeping. To avoid orthostatic changes at night, orthostatic changes should be monitored closely and the patient may be reminded to get up slowly from the bed in the middle of the night, particularly within the first two weeks.

            The chart should document that consideration of ADRs was used to determine the best administration pattern in each patient.

            According to Tang et al (2008), the average daily clozapine dose in China is between 200 and 400 mg. This is much lower than US recommended dosages. This information, plus the pharmacokinetic information (section 5.7.6), indicates that it safer to recommend lower dosages and slower titration in East Asains and other non-standard patients (section 6.4). Until there is more definitive information, this guideline recommends dividing titration and target doses by half.   

6.3. Initial Dose, Titration, and Maximum Recommended Dose in Standard US Patients

6.3.1. Initial Dosage in Standard US Patients

            The prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends that treatment begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily. Based on experience with a RCT (Simpson et al., 1999) and clinical experience, a starting dose of 25 mg is safe in most standard US individuals. The next section (6.4) describes the individuals who are considered non-standard and may require halving the doses for the initial dose and for the titration dose.

6.3.2. Slow Titration in Standard US Patients

            The prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 weeks.  

            Based on experience with a RCT (Simpson et al., 1999) and clinical experience, we suggest a slower titration using an easier way of remembering the dosage. The targets for the standard patient at the end of weeks 1, 2, and 3 are 100 mg/day (25 mg in the morning and 75 mg at night), 200 mg/day (50 mg in the morning and 150 mg at night) and 300 mg/day (100 mg in morning and 200 mg at night). 

            In week 1, we recommend a first dose of 25 mg at night and the use of 25 mg increments, keeping approximately 2/3 at night and scheduling the increment to avoid major increases when there is less supervision (weekends).     

            During weeks 2 and 3 most standard patients tolerate increases of 50 mg/day. Thus, two increases of 50 mg/day are recommended during week 2 and two increases of 50 mg/day are recommended during week 3. These increases will allow going from 100 mg/day in week 1 to 200 mg/day in week 2 and to 300 mg/day in week 3.  Avoid these 50 mg/day increases when there is less supervision (weekends).    

            To minimize the occurrence and risk of serious ADRs associated with clozapine treatment, the initiation of therapy must be undertaken cautiously and slowly. This dose titration is recommended when ADRs are not present during the use of the Clozapine Adverse Reactions Scale for Nurses. If they are present, the titration should be slower.

6.3.3. Initial Target Dose and TDM in Standard US Patients

            There is no published information to support the idea of using clozapine TDM in individuals with IDs but it should make clozapine use safer in these patients to challenge the prescriber to focus on pharmacokinetic issues, and particularly the relationship between serum concentration and clozapine dosage. Clozapine TDM costs are small compared with the safety they provide and the possibility of minimizing doses with consecutive long-term savings. Thus, the inconvenience and cost of using TDM appears justified because it reduces risk and because clozapine TDM is probably one of the best established TDMs in psychiatry (Hiemke et al., 2011). Moreover, the prescriber should be aware (1) that the relationship between plasma concentration and clozapine dose is almost linear within in the same individual, and  (2) that individuals have constant C/D ratios, unless inducers or inhibitors are added or discontinued.  Statistical random-effects linear models of steady-state clozapine concentration have shown that this relationship between concentration and dose can be used for drug dosage individualization (Diaz et al., 2007; Diaz et al., 2012a; Diaz et al., 2012b).

            According to US data, a clozapine dose of 300 mg/day may be therapeutic in some individuals but not in others.  Thus, TDM is recommended one week after reaching this dose to determine any further need for dose increases.  If the individual is taking another antipsychotic, this may be the time to consider down titration and discontinuation in a few days.  If the other antipsychotic has been discontinued, it may be better to delay TDM for one week after discontinuation or draw blood levels twice (before and after antipsychotic discontinuation).

            The linear relation of C/D should be used to estimate the target clozapine dose.  If in doubt, another blood level can be drawn when the target dose is reached. After reaching 300 mg/day with sub-therapeutic blood levels and no clinical response, the dose can be increased by 50 mg/day according to tolerance, observing for two to three days before the next dose increase.  When prescribing doses higher than 300 mg/day, one should remember that rounded doses (400, 500 and 600) are easier to administer for months and years. It is simpler to administer one 100 mg tablet than two or three 25 mg tablets.  For example, a dose of 400 mg/day is easier to administer than a dose of 375 mg/day in tablets.

6.3.4. Maximum Recommended Dose in Standard US Patients

            In the US, the prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends doses up to 900 mg/day in adults.  The literature describes rare cases which have required higher clozapine doses to reach therapeutic levels and are possibly explained by genetic factors (Bender & Eap, 1998) or taking inducers (Riesselman et al., 2013).

6.4. Initial Dose, Titration, and Maximum Recommended Dose in Non-Standard Patients

         In the US, the prescribing information (Novartis Pharmaceutical Corporation, 2011) does not describe specific conditions under which to start a lower initial dose of 12.5 mg of clozapine. Based on pharmacokinetic principles and the linear relationship between concentrations and doses, it appears reasonable to recommend halving the dosage in individuals with expected reduced clozapine metabolism such as: (1) East Asians (Sections 5.7.6 and 6.7.2); (2) those known to be CYP2C19 PMs (Section 6.7.1); (3) those taking inhibitors (Other Powerful Inhibitors of Clozapine Metabolism subsection in Section 6.5.1); and (4) in anyone who may tolerate clozapine more poorly, such as geriatric patients (Section 6.7.9).  Use the following schedule:  (1) initial dose of 12.5 mg instead of the standard 25 mg,  (2) titration doses (end of week 1, 50 mg/day; end of week 2, 100 mg/day; and end of week 3, 150 mg/day) rather than the standard at end of week 1, 100 mg/day; end of week 2, 200 mg/day; and end of week 3, 300 mg/day;  and (3) target dose followed but TDM after one week (150 mg/day) rather than the standard (300 mg/day).

            In individuals with expected reduced clozapine metabolism such as (1) East Asians (Sections 5.7.6 and 6.7.2), (2) in individuals known to be CYP2C19 PMs (Section 6.7.1), (3) those taking inhibitors (Other Powerful Inhibitors of Clozapine Metabolism subsection in Section 6.5.1), and (4) geriatric patients (Section 6.7.9), it is recommended that clozapine TDM be measured before increasing clozapine doses ≥ 450 mg/day. This may be the maximum dose that the individual can tolerate. 

6.5. Dosing Modifications Associated with DDIs

            The pharmaceutical company that developed clozapine has published very limited information on clozapine metabolism (Fischer et al., 1992); most of our knowledge is limited to the N-desmethylation of clozapine to norclozapine.  In a Caucasian study, Bertilsson et al. (1994) proposed that approximately 70% of clozapine metabolism is explained by the cytochrome P450 1A2 (CYP1A2).  The usual current description is that in normal Caucasians, clozapine is metabolized to norclozapine (or desmethylclozapine) mainly by CYP1A2 with lesser roles for CYP2C19, CYP3A4, CYP2D6 (Spina & de Leon, 2007). There is limited information on the metabolism to clozapine-N-oxide, which is partially accounted for by flavin-containing monooxygenase (FMO) (Fang et al., 1998) and to the glucuronides by the UDP glucuronosyltransferases (UGTs) (de Leon, 2003b).

            A neglected issue in the literature is that CYP2C19 may have a greater role in clozapine metabolism than previously thought. In vitro (Olesen & Linnet, 2001) and clinical (Jaquenoud Sirot et al., 2009) studies have indicated that CYP2C19 activity may be relevant for clozapine metabolism. Jaquenoud Sirot et al. (2009) reported that CYP2C19 PMs had 2.3-fold higher plasma clozapine concentrations than patients with other CYP2C19 genotypes (Section 6.7.1). The lower metabolic capacity of East Asians (see Sections 5.7.6 and 6.7.2) may be explained by their lower CYP2C19 activity. 

            The conversion of clozapine to clozapine-N-oxide, a minor metabolic pathway when compared with norclozapine, is probably mainly explained by CYP3A4 and FMO3 (Fang et al., 1998), and is reversible (Chang et al. 1998).

            The lack of clozapine metabolism studies in nontypical situations, such as different races, or co-prescription of powerful inhibitors or inducers, is a problem not only with clozapine but with all drugs (de Leon et al., 2009b).      

6.5.1. Pharmacokinetic DDIs 

AED Inducers. Four “old” AEDs, carbamazepine, phenobarbital, primidone and phenytoin, are powerful clozapine metabolism inducers (Miller, 1991; Facciolà et al., 1998; Lane et al., 1998; de Leon, 2004b).  In the US (Novartis Pharmaceutical Corporation, 2011), co-prescription of carbamazepine is not recommended in patients taking clozapine due to its potential to cause agranulocytosis (Section 4.10). These AED inducers reduce the clozapine C/D ratio. Based on a literature review, de Leon et al. (2012) estimated that the addition of phenobarbital, primidone or phenytoin requires increasing the clozapine dose by two to four times. These AED inducers should not be prescribed without clozapine TDM.  The inductive effects of these drugs may typically take two to three weeks to disappear after discontinuation.  Therefore, if an individual is taking phenytoin and clozapine, physicians discontinuing phenytoin should expect a slow increase in clozapine levels over a period of two to three weeks by a factor of two to four (de Leon, 2004b).  

Other Inducers. Rifampin and omeprazole are CYP1A2 inducers (de Leon et al., 2005). Although there is not as much data as with AED inducers, rifampin may be as potent as they are and require massive increases in clozapine dosing. Rifampin should be avoided in clozapine patients or, if it is prescribed, it should be done using much caution and TDM. Omeprazole appears to be less potent and may require multiplying the clozapine dose by 1.5 or increasing the dose by 50%, particularly in non-smokers (de Leon et al., 2005). Some foods induce CYP1A2, particularly charbroiled food and cruciferous vegetables (e.g., broccoli, brussels sprouts and other plants belonging to the Cruciferae or Brassicaceae family), and may mildly reduce clozapine levels, but the clinical significance is unlikely to be relevant (Vistisen et al., 1991). A recent phenotyping study in the general population found that high broccoli and char-grilled meat consumption significantly lower CYP1A2 activity but effects were small (Perera et al., 2012).

Valproate.  Traditionally, valproate was considered the AED of choice in patients taking clozapine since prior literature indicated small increases or decreases of clozapine concentration after adding valproate (de Leon, 2004b). Unfortunately, more information has been accumulated, indicating that valproate may be an inducer in some situations (Riesselman et al., 2013).  A recent TDM study indicated that valproate may be an inducer of clozapine metabolism in smokers (Diaz et al., 2008). Based on this clozapine study (Diaz et al., 2008) and a prospective study on olanzapine (Spina et al., 2009), a drug that has metabolism similar to clozapine, it is also possible that valproate may also be a competitive inhibitor of clozapine metabolism, particularly in non-smokers.  The limited information suggests valproate inductive or inhibitory effects on clozapine metabolism are usually small, but rare cases of important effects exist. Riesselman et al. (2013) described a patient taking up to 1300 mg/day of clozapine who had a very high metabolic capacity demonstrated by a clozapine C/D ratio of 0.35. Until more definitive information on valproate-clozapine DDI exists, clinicians need to be aware that in some cases this DDI may be clinically relevant; when in doubt, clozapine TDM should be used.

Other AEDs. AEDs with mild inducing properties such as oxcarbazepine, rufinamide and topiramate may be mild inducers of clozapine metabolism but have not been well studied. In low doses, topiramate (Migliardi et al., 2007) had no obvious effects on clozapine metabolism in a prospective study. Lamotrigine does not appear to have pharmacokinetic DDI with clozapine and may be a good choice to combine with clozapine (Muzyk et al., 2010). Gabapentin, lacosamide, levetiracetam, pregabalin, retigabine, tiagabine and zonisamide are probably free of pharmacokinetic DDI with clozapine (de Leon et al., 2012). 

Fluvoxamine. It is a powerful inhibitor of clozapine metabolism (Hiemke et al., 1994; Spina & de Leon, 2007). This is not surprising since fluvoxamine is a strong CYP1A2 inhibitor, but other CYP inhibition may be relevant since fluvoxamine is also a strong inhibitor for CYP2C19, a moderate inhibitor for CYP2C9 and CYP3A4, and a weak inhibitor for CYP2D6 (Spina et al., 2008). Fluvoxamine inhibitory effects may vary from individual to individual, but clozapine concentrations may increase up to five to ten times in Caucasians (de Leon et al., 2005; Spina & de Leon, 2007).  This increase may be smaller in Chinese patients (Chang et al., 1999; Lu et al., 2000; 2002; Lin et al., 2006). Thus, fluvoxamine should not be prescribed with clozapine unless TDM is used and much precaution with dosing is observed.

Other Powerful Inhibitors of Clozapine Metabolism. The fluroquinolones, particularly ciprofloxacin and norfloxacine, are powerful CYP1A2 inhibitors and are expected to increase clozapine levels (Raaska & Neuvonen, 2000; Brouwers et al., 2009).   Other fluroquinolones, including gatifloxacin, gemifloxacin, levofloxacin, moxifluxacin and trovafloxacin, do not appear to inhibit CYP1A2 and can be safely prescribed for individuals taking clozapine (de Leon et al., 2005).  Macrolides, such as erythromycin and clarithromycin, are very powerful inhibitors of CYP3A4, close monitoring is recommended when adding to clozapine (Hagg et al., 1999).  Cimetidine should be avoided in individuals taking clozapine (Szymanski et al., 1991). Although grapefruit juice does not appear to inhibit clozapine metabolism (Lane et al., 2001a;b), it should not be administered to individuals with IDs due to the high DDI risk with multiple drugs. Amiodarone can inhibit several CYPs and has potential to inhibit clozapine metabolism (Stevens et al., 2008). A few cases of clinically relevant increases in clozapine levels after adding oral contraceptives containing estrogens have been described (Gabbay et al., 2002; Sandson et al., 2007).

Caffeine. The metabolism of caffeine is highly dependent (> 90%) on CYP1A2 and caffeien can be a competitive inhibitor of CYP1A2 (White & de Leon, 1996; de Leon, 2004a).   See 6.7.4 section for recommendations.

Other Antidepressants. Fluoxetine and paroxetine are mild inhibitors of clozapine metabolism (Centorrino et al., 1994; Spina & de Leon, 2007; Diaz et al., 2008). Sertraline does not usually increase plasma concentrations in a relevant way (Spina & de Leon, 2007; Diaz et al., 2008), but it may occur when used in high doses (Pinninti & de Leon, 1997). Studies indicate that citalopram, duloxetine, escitalopram, mirtazapine, and venlafaxine do not usually influence plasma clozapine concentrations (Spina & de Leon, 2007; Spina et al., 2012). Although not studied, bupropion, desvenlafaxine, mirtazapine, and vilazadone, due to their pharmacokinetic profile, are not likely to have pharmacokinetic DDI with clozapine (Spina et al., 2012).

Other Antipsychotics. Other second-generation antipsychotics are not considered to be potent inducers or inhibitors (de Leon et al., 2005; Spina & de Leon, 2007). Therefore, they are not likely to have pharmacokinetic DDI with clozapine.  Olanzapine metabolism is mainly dependent on CYP1A2 and UGTs (de Leon et al., 2005).  As there is substantial overlap with clozapine metabolism, it is possible that olanzapine may mildly increase clozapine levels due to competitive inhibition. If olanzapine is co-prescribed with clozapine, careful monitoring is warranted and consideration of clozapine TDM is required if the combination is prescribed for the long term. Among the first-generation antipsychotics, perphenazine and other phenothiazines clearly have potential to increase clozapine levels (Cooke & de Leon, 1999).  Haloperidol is probably relatively free of pharmacokinetic interactions with clozapine, although it has not been systematically studied.

6.5.2.   Pharmacodynamic DDIs 

Sedating drugs.  When combined with other sedating drugs, including antiepileptics, benzodiazepines, opioids, sedating antihistamines and some antidepressants and some other antipsychotics, clozapine may have additive sedative effects.  

Other Antipsychotics. Although there is limited data supporting this practice, sometimes clinicians prescribe antipsychotics to augment clozapine response (last paragraph of Section 2.1).  One should consider that adding another antipsychotic to clozapine may have the additive effects of blocking brain receptors because many antipsychotics block the same brain dopaminergic, adrenergic, serotonergic, muscarinic and histaminic receptors as clozapine and also increase seizure risk. One should consider that adding another antipsychotic to clozapine may have the additive effects of blocking peripheral receptors because many antipsychotics block the same peripheral adrenergic, serotonergic, and muscarinic receptors as clozapine.  One should consider that adding another antipsychotic to clozapine may have the additive effects of peripheral ADRs, including QTc prolongation and hyperglycemia/hyperlipidemia. Several antipsychotics have been particularly associated with QTc prolongation including phenothiazines, haloperidol, ziprasidone and iloperidone (Ramos-Ríos et al., 2010; de Leon et al., 2012).  As QTc prolongation is usually considered a risk factor for sudden death associated with torsades de pointes, if one prescribes clozapine with any of these antipsychotics with higher risk of QTc prolongation, one should remember that clozapine would increase the risk of QTc prolongation.

            Adding clozapine to antipsychotics with the highest risk of metabolic syndrome (phenothiazines, olanzapine and quetiapine) may also increase the risk of weight gain, hyperglycemia and/or hyperlipidemia.  Some preliminary but interesting naturalistic studies and a RCT suggest that aripiprazole adjunctive therapy may decrease clozapine’s metabolic ADRs (Fan et al., 2013). Prescribers considering this strategy search are urged to review the more recent literature for other studies.

Benzodiazepines. A poorly understood benzodiazepine DDI with clozapine has been described in a few individuals during the first days of clozapine treatment, usually within 48 hours after the first clozapine dose. ADRs of this DDI may include lethargy, ataxia, loss of consciousness, and, rarely, respiratory arrest.  Similar ADRs have been described in patients only taking clozapine. Sassim and Grohmann (1988) first reported two cases; then they reviewed 959 patients taking clozapine. Four cases of severe cardiovascular and respiratory dysregulation were seen with the combination of clozapine-benzodiazepines at the beginning of the clozapine titration (Grohmann et al., 1989).  Finkel & Schwimmer (1991) reported seven cases of respiratory arrest after treating 12,000 individuals, but only two of these cases were associated with the combination of benzodiazepines and the first clozapine doses. Klimke & Kleiser (1994) reported that of 162 individuals treated with the combination of clozapine and benzodiazepines in a German hospital, one death by respiratory arrest occurred in an individual suffering from liver impairment. Faisal et al. (1997) reviewed company data and found (1) 6 US cases of respiratory depression/arrest in combination clozapine-benzodiazepine treatment in 15,311 clozapine patients, and (2) 10 European cases of cardiorespiratory arrest within the first 3 days (some taking benzodiazepines) in 63,000 patients. The occurrence of respiratory arrest during the co-administration of benzodiazepines and clozapine appears to be an idiosyncratic reaction that many individuals can tolerate, even in the first days of clozapine treatment, without ADRs.  However, it is safer to avoid benzodiazepines the week before starting clozapine and during the first week of dose titration (Section 4.12).

Tricyclic antidepressants (TCAs). TCAs should be avoided in patients taking clozapine because they may increase clozapine levels, have antimuscarinic activity and, more importantly, exacerbate the risk of cardiovascular toxicity due to their prolongation of the QTc interval.

 Lithium. Lithium is frequently associated with leukocytosis as it increases ANC (Manu et al., 2012). Thus, the ANC increase may obscure the development of agranulocytosis in an individual taking clozapine.

Other Antimuscarinic Drugs. Clozapine may have additive antimuscarinic effects when combined with other antimuscarinic drugs (de Leon, 2011). Many drugs may have antimuscarinic activity, but there is definitive information that clinically relevant antimuscarinic activity is present for some antidepressants (amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, protryptiline, and trimipramine), some antipsychotics  (chlorpromazine and thioridazine), some antiemetics (meclizine, promethazine and prochlorperazine), some drugs for peptic ulcer (hyoscyamine and propantheline), some muscle relaxants (cyclobenzaprine, and orphenadrine), cyproheptadine, some bronchodilators (tiotropium), some antiarrhythmics (disopyramide), some drugs for dizziness (scopolamine), drugs for overactive bladders (darifenacin, fesoterodine, flavoxate, oxybutynin, oxybutynin transdermal system, solifenacin, tolterodine, and trospium), and some first-generation oral antihistamines (clemastine, dimenhydrinate, and diphenhydramine). Due to potentially increased risk for cognitive impairment and peripheral antimuscarinic ADRs, much caution should be used when combining clozapine with any of these drugs having antimuscarinic activity (de Leon, 2011).

            Lower risks are present for other drugs with possible antimuscarinic activity, including some antidepressants (amoxapine, desipramine, maprotiline, mirtazapine, and paroxetine), some antipsychotics (loxapine, olanzapine, and quetiapine), ipratropium, some first-generation antihistamines (brompheniramine, carbinoxamine, chlorpheniramine, and hydroxyzine), some second-generation oral antihistamines (cetirizine, desloratidine, levocitirizine, and loratidine), some H₂ antagonists (cimetidine and ranitidine) and temazepam. Due to the potential for added cognitive impairment and peripheral antimuscarinic ADRs, much caution should be used when combining clozapine with any of these drugs having possible antimuscarinic activity (de Leon, 2011). 

Other Drugs with Potential to Impair Cognition.As decribed above, clozapine may impair cognition by its brain antimuscarinic activity. Drugs that may impair cogintion using other mechanisms may have additive effects. Topiramate may be a good example (Muscatello et al., 2011).

Other Drugs with Potential to Decrease Seizure Threshold. Clozapine may be the worst of the antipsychotics for reducing the seizure threshold (Alper et al., 2007; de Leon et al., 2012). Thus, clozapine can potentiate the risk of seizures when combined with other drugs that decrease seizure threshold (including many antidepressants and many antipsychotics; Alper et al. (2007) or when AEDs are discontinued during clozapine treatment.

Drugs That Can Cause Tachycardia. Sinus tachycardia can also be associated with stimulant and related drugs (amphetamines, methylphenidate, atomoxetine, and rarely with modafinil), and some calcium channel blockers from the dihydropyridine family (amlodipine, felodipine, isradipine, and nifedipine) (Hoffman, 2006).  Thus, combining any of these drugs with clozapine increases tachycardia risk (Section 4.3.1).  

Pramlintide. An oral antidiabetic, pramlintide, can decrease gastric motility. It is better to discontinue pramlintide before starting clozapine (Section 4.2.3). Much caution should be used when combining pramlintide with drugs having potent antimuscarinic activity such as clozapine; they may have additive effects in delaying gastric emptying.

Drugs That Can Contribute to Constipation. These include antacids containing aluminum or calcium, calcium channel blockers, calcium supplements, cholestyramine and colestipol, clonidine, diuretics, iron supplements, levodopa, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and vinca alkaloids (Arce et al., 2002; Bouras & Tangalos, 2009; Jacobs & Pamies, 2001; Spinzi, 2007). Thus, combining any of these drugs with clozapine increases constipation risk (Section 4.3.3).

Drugs That Can Increase Risk of Heat Stroke. Antimuscarinic drugs, other antipsychotics and carbon anhydrase inhibitors (acetazolamide, topiramate and zonisamide) can increase risk of heat stroke (Section 4.3.4). The risk is clear when patients are exposed to heat and/or strenuous exercise (Martin-Latry et al., 2007; Stadnyk & Glezos, 1983). Fatal heat stroke occurs mainly in the elderly (Peters, 1989). The co-administration of clozapine with drugs with antimuscarinic activity, other antipsychotics or carbon anhydrase inhibitors and exposure to hot weather or strenuous exercise should be accompanied by particular vigilance for hyperthermia and heat stroke.

Drugs That Can Increase Risk of Orthostatic Hypotension. The co-administration of any drugs that can cause orthostatic hypotension, including some antihypertensives, should be accompanied by particular vigilance for orthostatic hypotension.

Drugs That Influence the Metabolic Syndrome.         They include (1) any antipsychotic that may increase the risk of metabolic syndrome (co-prescription with aripiprazole may decrease it (Other Antipsychotics subsection, above), (2) medications known to cause elevated blood glucose (e.g., steroids, niacin, thiazide diuretics), or (3) medications that can cause weight gain (e.g., lithium, valproate, mirtazapine or paroxetine), The co-administration of any drugs should be accompanied by chart documentation of the DDI. Medications that can cause weight loss such as bupropion and topiramate may decrease risk of weight gain associated with clozapine. Small weight losses have been associated wih topiramate treatment in clozapine patients (Navarro et al., 2001; Hahn et al., 2010).

Drugs Known to Potentially Suppress Bone Marrow Function. If the individual is taking drugs known to potentially suppress bone marrow function (e.g., carbamazepine, captopril, propylthiouracil, penicillamine, sulfonamides and antineoplastic agents), careful consideration should be given to discontinuing these drugs before clozapine is started (Section 4.10). In the rare event that they are not discontinued, the chart should document why they are continued and what type of monitoring is being used.   

6.6. Dosing Modifications of Other Drugs

            Clozapine, as with other second-generation antipsychotics, is not considered to be a potent inducer or inhibitor (de Leon et al., 2005; Spina & de Leon, 2007). Therefore, it is not likely to have pharmacokinetic DDI with other drugs. However, in unusual polypharmacy situations where patients take drugs with a narrow therapeutic window, adding clozapine may be the straw that breaks the camel’s back through competitive inhibition of multiple drugs vying for particular metabolic enzymes. A case report suggesting that clozapine increased the concentration of a TCA has been described (Smith & Riskin, 1994).

6.7. Dosing Modifications Associated with Other Personal Characteristics

            The personal charcatristics that may be relevant in clozapine metabolism include (1) genetics, (2) East Asian ancestry, (3) smoking, (4) caffeine intake; (5) gender, (6) pregnancy, (7) major infections or inflammations, (8) hepatic impairment, (9) renal impairment, (10) geriatric age, and (11) weight.

6.7.1. Genetics

            Some CYPs, such as CYP2D6 and CYP2C19, are polymorphic with some alleles having no activity and others having increased activity. Thus, subjects lacking CYP2D6 or CYP2C19, due to the presence of two inactive alleles, are called poor metabolizers (PMs) and those having more activity than normal are called ultrarapid metabolizers (UMs).  There are no significant numbers of CYP1A2 PMs or UMs in the studied population (Gunes & Dahl, 2008; Zhou et al., 2010). Some CYP1A2 alleles may change the effects of inducers on CYP1A2, but the clinical relevance for clozapine of this change is still under debate (Kootstra-Ros et al., 2005; Gunes & Dahl, 2008).

            Some published cases indicate that some rare subjects metabolize clozapine poorly and need lower doses, possibly due to genetic variants (Allorge et al., 2003; Gunes & Dahl, 2008; Sani et al., 2010), or metabolize clozapine faster and need higher than recommended doses (Bender & Eap, 1998; Conley, 1998; Ozdemir et al., 2001; Eap et al., 2004; Bersani et al., 2011).

            Jaquenoud Sirot et al. (2009) completed a very important study that has not received enough attention in the literature. They described that CYP2C19 PMs had 2.3-fold higher plasma clozapine concentrations than patients with other CYP2C19 genotypes. This may explain the differences between Caucasians and East Asians (Sections 5.7.6 and 5.7.7). If this result is verified by other researchers, genotyping for CYP2C19 PM may be clinically relevant since these subjects may need half the usual clozapine dosage.

            As previously indicated (Section 6.5), FMO3 may contribute to transformation between clozapine and clozapine-N-Oxide. A study of FMO3 polymorphism in Caucasians found no clinically relevant effects on clozapine metabolism (Sachse et al., 1999).

6.7.2. East Asian Ancestry

            As Section 5.5.7 summarizes, the published information suggests that East Asians, particularly Chinese, have lower clozapine metabolic capacity. The lower capacity to metabolize clozapine may be explained by 1) lower CYP2C19 activity of many East Asians (de Leon et al., 2006), and 2) possibly lower average CYP1A2 activity. In a recent phenotyping CYP1A2 study in the general population, Perera et al. (2012) decribed lower median CYP1A2 activity in Indians and Sri Lankans (median 0.42, range 0.10-1.06 ) than in Caucasians (median 0.54, range 0.12-1.64).  Section 6.4 recommends halving the initial and maximum doses and the titration in individuals with East Asian ancestry.

6.7.3. Smoking

            Tobacco smoking is associated with schizophrenia all over the world (de Leon & Diaz, 2005) and in China as well, at least for male patients (Tang et al., 2007b).  Tobacco smoking by-products, particularly the polycyclic aromatic hydrocarbons, are metabolic inducers, and also induce clozapine metabolism.  It is believed that the polycyclic aromatic hydrocarbons induce CYP1A2 through an aryl hydrocarbon receptor (AHR) located in the cell nuclei. These compounds may also induce UGTs (de Leon, 2003b).

            Haslemo et al.  (2006) have estimated that a daily consumption of 7-12 cigarettes may be enough to cause maximal induction in average clozapine subjects. Since inducers require new enzyme synthesis for their effects, they usually take several weeks to reach maximum effects.  The effects may take a few weeks to disappear as well.  Case reports of clozapine toxicity, including seizures, after smoking cessation suggest smoking inductive effects take at least two to four weeks to disappear (McCarthy, 1994; Skogh, et al., 1994; Zullino et al., 2002; Bondolfi et al., 2005). 

            Smoking cessation in a typical smoker would probably cause clozapine levels to increase by a factor of approximately 1.5 or 50%, two to four weeks later.  Checking for ADRs and clozapine TDM may then be prudent since the 1.5 factor is a gross approximation (Meyer 2001a, de Leon, 2004a; Diaz et al., 2008). There is great interindividual variability in CYP1A2 inducibility due to smoking, which is only poorly explained by known CYP1A2 polymorphisms. It is suspected that regulatory pathways, including transcription factors and the AHR, may contribute to this variability. Although studies have not been published on clozapine, caffeine (Dobrinas et al., 2013) and olanzapine studies (Söderberg et al. 2013) indicate that genetic variations in these pathways may be clinically relevant.  It is not currently known whether these genetic variations will help clinicians in the future to understand interindividual differences.  As the next section indicates, smoking and smoking cessation influences on clozapine metabolism may be indirectly influenced by smoking effects on caffeine metabolism.

            In summary, stable smoking may not be an important factor in a stable smoking environment, but radical changes such as cessation or starting heavy smoking may influence clozapine levels in a clinically relevant way. The chart should document the effort to educate patient, staff and family that keeping smoking stable is important for avoiding fluctuations in clozapine metabolism and that smoking cessation on the part of the patient needs to be communicated to the clozapine prescriber.

6.7.4. Caffeine Intake

            Caffeine is the drug most frequently consumed around the world; most people in the US may have detectable plasma caffeine levels from consuming caffeinated beverages or some foods (de Leon et al., 2003a). Caffeine is highly dependent (>90%) on CYP1A2 for its metabolism.  As Section 6.5.1 describes, caffeine can competitively inhibit clozapine metabolism and cause clinically significant DDIs.

            When considering caffeine intake in clozapine patients, it is important to consider it in the context of smoking behavior.  Smoking is a powerful inducer of caffeine metabolism and additive brain pharamacodynamic effects between nicotine and caffeine are possible, leading to complex interactions between smoking and caffeine intake in schizophrenia patients (Gurpegui et al., 2004; 2006).                                    In the US, brewed coffee is estimated to contain 85mg/5 oz cup; instant coffee, 65 mg/5 oz cup; decaffeinated coffee, 3mg/5 oz cup; tea, 40 mg/5 oz cup; and caffeinated sodas including caffeinated colas, 40mg/12 oz can (or one-sixth of a 2-liter bottle) (de Leon et al., 2003a). In Europe and other countries, brewed coffee cups may have more caffeine (100-120 mg). Caffeinated over-the-counter medicines and some of the recently-introduced energy beverages may contain large quantities of caffeine. There are no data on what level of caffeine intake is safe for individuals taking clozapine. 

            Steady caffeine doses in a stabilized clozapine individual should not concern clinicians. However, it may be important to warn the individual to avoid “dramatic” changes (up or down) in caffeine intake.  Although no published study defines what a “dramatic” change is, caution has been recommended with increases or decreases of daily caffeine intake of > 1 cup of coffee (or 2 cans of caffeinated sodas) in non-smokers and > 3 cups (or 6 cans of caffeinated soda) in smokers.  For example, when a smoker taking clozapine increases caffeine intake by three cups of coffee (e.g., from 2 to 5 cups per day), clinicians should watch for increased side effects due to increased clozapine levels.  When a non-smoker taking clozapine decreases caffeine intake by two cans op caffeinated sodas (e.g., from 4 to 2 cans per day), clinicians should be alert to a possible loss of clozapine response due to decreased levels (de Leon, 2004a). The chart should document the effort to educate patient, staff and family that keeping stable caffeine intake is important for avoiding fluctuations in clozapine metabolism.

6.7.5. Gender

            It appears that gender may play a role in clozapine metabolism.  The limited available information suggests that an average US female non-smoker may require clozapine doses around 300 mg/day to reach therapeutic levels, while an average male heavy smoker may require high doses (around 600 mg/day) (de Leon et al., 2005). US male non-smokers and female smokers fall in between (Perry et al., 1998; Rostami-Hodjegan et al., 2004).  These average results may not apply to specific individuals, especially if other factors that may affect clozapine metabolism are not taken into account.  Studies in Chinese patients also suggest that females had lower clozapine metabolic capacity (Lane et al., 1999; Tang, et al., 2007a) but the studies need to control for smoking status better.

            It is possible that estrogens may contribute to decreases in clozapine metabolism seen in females. Certainly oral contraceptives appear to be inhibitors of clozapine metabolism (Gabbay et al., 2002; Sandson et al., 2007).

6.7.6. Pregnancy

            There are no well-controlled studies of clozapine metabolism during pregnancy.  The pharmacokinetic literature consistently reports (Anderson, 2005; Hodge & Tracy, 2007) that pregnancy is associated with a decrease of CYP1A2 and CYP2C19 activity. As indicated in the prior section, estrogens may be inhibitors of clozapine metabolism; plasma estrogen concentrations increase remarkably during pregnancy. Clinicians should expect a clinically relevant decrease in clozapine metabolism in the second and third trimesters with an increase in plasma clozapine concentrations. Therefore, clozapine TDM is recommended.

6.7.7. Major Infections or Inflammations

            Respiratory infections can inhibit CYP1A2 because cytokines released during infection decrease enzyme activity and synthesis (Abdel-Razzak et al., 1993).  Clinicians caring for individuals with IDs who are taking clozapine must be careful should the individual develop serious respiratory infections with fever, and pay special attention to signs of toxicity including severe sedation, myoclonus or even seizures.  If any of these signs and symptoms appears, the clozapine dose should be decreased at least by half, until the individual has recovered from the infection (de Leon & Diaz, 2003; de Leon, 2004c). Other serious infections, such as pyelonephritis or appendicitis (Haack et al., 2003) or even major inflammations (Haack et al., 2003), including those associated with ADRs (Egger et al., 2010), may also have similar effects in decreasing clozapine metabolism.

            If one finds an unexpectedly high serum clozapine concentration in a patient, it may be a good idea to measure CRP to rule out undetected inflammatory process (Pfuhlmann et al., 2009).

6.7.8. Hepatic Impairment

            There are no clozapine studies in patients with hepatic impairment. Clozapine should be used with caution in hepatically-impaired patients

6.7.9. Renal Impairment 

            There are no clozapine studies in patients with renal impairment. Clozapine should be used with caution in renally-impaired patients (Novartis Pharmaceutical Corporation, 2011). According to estimation in the average patient, radioisotope studies showed that almost 50% of clozapine was recovered in the urine with 0.5% unchanged in urine and 49% as metabolites (Sheehan et al., 2010).

6.7.10. Geriatric Age 

            Some studies indicate that greater age may be associated with slightly lower clozapine clearance (Diaz et al., 2008). This lower clearance is probably explained by the decrease in creatinine clearance with age.

6.7.11. Weight 

            Several TDM studies using large samples indicate that greater weight may be associated with a mild decrease in plasma clozapine concentrations (Haring et al. 1990; Rostami-Hodjegan et al., 2004; Bowskill et al., 2012; Couchman et al. 2013). Although this pharmacological finding has never been studied, it is probably explained by a greater volume of distribution and higher storage of clozapine and norclozapine in tissues associated with lower drug clearance. In summary, this is a relatively small effect of interest to pharmacologists rather than prescribers but it cannot be ruled out that in rare circumstances it may be relevant (e.g., in cases of extreme obesity or dramatic changes in weight within the same patient.)

6.8. Duration of Clozapine Trial

            Clozapine has a particularly complex risk-benefit profile, including potentially high risks and potential benefits.  Therefore, it is crucial to establish an appropriate duration of the clozapine trial needed to determine response in each patient; it should not be unnecessarily long in duration for patients who may not respond.  Clozapine is too toxic, too inconvenient and too expensive to be continued if there is no clear response. This guideline stresses the convenience of using TDM to establish in each patient that the trial has been of sufficient duration for him or her. In patients with discontinuation in the absence of ADRs, the chart should provide justification for the duration of the clozapine trial.

6.8.1.   Adult Individuals IDs with Treatment-Resistant Schizophrenia   

Three-Month Duration. There is no consensus as to the total time required to achieve an optimal response to clozapine treatment.  It has been reported that individuals who respond to clozapine typically show their response within eight weeks of a change in dosage (Conley, 1998). Safferman et al. (1991) recommended duration of ≥ 3 months for a clozapine trial. Meltzer (2012) reports that in some patients the improvement of positive symptoms may require up to six months and that some patients may show no advantage with clozapine for the first three months. Therefore, based on currently available information, it appears safe to recommend at least three months of continued treatment with a dose associated with clozapine levels of ≥ 350 ng/ml for individuals with treatment-resistant schizophrenia before determination of lack of response to clozapine treatment.    

Partial-response. For individuals who do not respond or only respond partially to clozapine, some published practice guidelines support continuing clozapine and augmenting treatment with another antipsychotic.  As indicated in the last paragraph of Section 2.1, the support of RCTs is rather limited. Agents with previous history of partial response in that specific patient may be preferred.  As mentioned earlier (subsection Other Antipsychotics in Section 6.5.1), clinicians should be careful with phenothiazines and olanzapine, which may increase serum clozapine concentrations.  In the case of partial response, it appears convenient to carefully review the most updated literature on RCTs (Porcelli et al.,  2012; Sommer et al., 2012a) and consider prior partial responses to psychiatric drugs in that specific patient. A careful discussion with the individual/guardian and chart documentation is required after any decision is made.

Lack of Response to Clozapine and Clozapine Augmentation. There are no controlled data to provide guidance for the use of any single antipsychotic or any combination of antipsychotics for individuals who do not respond adequately to clozapine and to clozapine augmentation.  However, published practice guidelines suggest discontinuation of clozapine and attempting one final trial of antipsychotic monotherapy, preferably with an agent with a history of partial response, before resorting to antipsychotic polypharmacy (Miller et al., 2004).

6.8.2. Adult Individuals with IDs with Risk of Recurrent Suicidal Behavior in Schizophrenia or

Schizoaffective Disorder      

            There is no literature to provide suggestions for the duration of the clozapine trial for preventing suicide in adults with IDs. The prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends a 2-year treatment to reduce suicide risk.

6.8.3.   Adult Individuals with IDs with Self- or Hetero-Aggressive Behavior

Three-Month Duration. There is not enough information to provide recommendations regarding the duration and dose for clozapine trials in these individuals.  Due to lack of information, it is reasonable to suggest at least a three-month trial of a dose associated with clozapine levels of at least 350 ng/ml.

Lack of Response. If individuals fail to respond satisfactorily, published practice guidelines (Expert Consensus Series, 2000) suggest the following: (1) discontinue clozapine and switch to a different second-generation antipsychotic, mood stabilizer or a selective serotonin reuptake inhibitor (SSRI) (if no response), or (2) continue clozapine and add a mood stabilizer or an SSRI (if partial response). Obviously, it is important to consider prior responses in that specific patient.

6.8.5. Adult Individuals with IDs and Polydipsia

            Unfortunately, patients with polydipsia tend to be very difficult to treat and there is very limited information based on RCTs even in patients without IDs. Careful follow-up using biological measures in individuals with schizophrenia and polydipsia suggests that clozapine’s positive effects on hyponatremia occur early, within two weeks, and with doses as low as 100 or 200 mg/day (de Leon et al., 1995), but that polydipsia may take up to 12 weeks to improve (Verghese et al., 1998).  Based on available information, it is reasonable to recommend clozapine doses of up to 300 mg/day for 3 months in standard US adult individuals with ID and complicated polydipsia in addition to a water restriction behavioral program using the target weight method.

6.9. Discontinuation

6.9.1. Clozapine Pharmacology and Discontinuation

            Clozapine is the antipsychotic most consistently associated with withdrawal symptoms after sudden discontinuation. Clozapine pharmacokinetic and pharmacodynamic properties explain this high risk of withdrawal symptoms.

Pharmacodynamics. Seeman and Tallerico (1998) suggested that clozapine may show a different profile with low D₂ blocking in in vivo studies due to low clozapine affinity for D₂, which would allow clozapine to be displaced by dopamine (it is estimated that 25-40% of D₂ receptors are occupied by endogenous dopamine) (Kapur & Seeman, 2001). Therefore, low affinity and fast dissociation from D₂ receptors would explain the atypicality among some antipsychotics, such as clozapine and quetiapine, which can be displaced by dopamine. In a very graphic way, these antipsychotics are described as using “hit-and-run” action toward the dopamine D₂ receptor, hitting this receptor with sufficient force (binding affinity) to result in AP effects, yet binding weakly enough to dissociate from the receptor (run) before causing EPS (Shayegan & Stahl, 2004). Clozapine actions at other brain receptors may also contribute to clozapine potential for withdrawal symptoms; in that sense cholinergic overdrive and gamma-aminobutyric acid (GABA) supersensitivity may also be contributing factors (Verghese et al., 1996b).

Pharmacokinetics. The elimination half-life of clozapine is estimated to be 12 hours with a range of 6-33 hours (Baldessarini & Frankenburg, 1991). According to the limited information available serum clozapine concentrations quickly decrease, and may be completely eliminated from the body after one week (de Leon et al., 1996). Thus, a rounded average clozapine half-life that can be easily remembered by clinicians is 24 hours (de Leon et al., 1996). 

6.9.2. Withdrawal Symptoms

            Sudden discontinuation of clozapine has been associated with withdrawal symptoms.  Some individuals have symptoms suggestive of a cholinergic rebound including nausea, vomiting, diarrhea, headache, agitation, confusion and diaphoresis.  These symptoms are probably explained by the antimuscarinic properties of clozapine and appear to respond to anticholinergic treatment. (de Leon et al., 1994b).  Other individuals appear to have worsening psychosis and/or abnormal movements (Stanilla et al., 1997) and, on rare occasions, catatonic symptoms (Wadekar & Syed, 2010) and severe anxiety have been described (Berecz et al., 2000).

6.9.3. Sudden Withdrawal Due to ADRs

            If clozapine has to be discontinued suddenly due to ADRs, consider adding another second-generation antipsychotic to cover withdrawal psychosis or withdrawal movements.  Olanzapine may be a particularly good choice (Tollefson et al., 1999). If there are signs of cholinergic rebound, anticholinergics should be added (e.g., 2-6 mg of benztropine mesylate or 5-15 mg/day of trihexphenidyl) and monitored closely, since higher doses may sometimes be needed (de Leon et al., 1994b).

6.9.4. Slow Withdrawal due to Lack of Response

            If clozapine is to be discontinued due to lack of therapeutic response, it should be tapered off slowly over a period of a few weeks.  At least two to three weeks appears reasonable for a planned discontinuation of a relatively high dose (e.g., 600 mg/day). 

6.9.5. WBCs after Discontinuation

            After the discontinuation of clozapine and in the absence of low ANC (1) repeat weekly WBC with differential for 4 weeks after discontinuation, or (2) until WBC ≥ 3500/mm³ and ANC ≥2000/mm³ (Novartis Pharmaceutical Corporation, 2011).

6.9.6. Treatment Interruption

            According to the prescribing information (Novartis Pharmaceutical Corporation, 2001), if clozapine treatment is interrupted for a period of ≥ 48 hours, the individual should be restarted with 12.5 mg (half of a 25 mg tablet) once or twice daily and titrated upward as if new to clozapine.  If the individual is doing very poorly and a faster schedule appears necessary to reach prior clozapine therapeutic doses, a consultation with a psychiatrist with sufficient clozapine experience may be required. In patients with a treatment interruption for a period of ≥ 48 hours, the chart should provide justification for how the clozapine dose was restarted.

7. ADRs

            These guidelines classify ADRs in a practical way: common (Section 7.1), relatively uncommon (Section 7.2), and potentially lethal (Section 7.3). There is also a section on the metabolic syndrome (Section 7.4). Common ADRs occurred in more than 10% of the patients in the RCTs, as described in the prescribing information. The other ADRs are classified as relatively uncommon unless they are potentially lethal, in which case they are described as such. Clinicians treating adults with IDs need to be aware that clozapine can cause potentially lethal ADRs.

7.1. Common ADRs

            The list of ADRs with frequency >10% in RCTs include (1) drowsiness (39-46%), (2) sialorrhea (31-48%), (3) tachycardia (25%), (4) dizziness (19-27%), (5) constipation (14-25%), (6) weight gain (4-31%), (7) insomnia (2-20%), and (8) nausea/vomiting (3-17%) (American Pharmacist Association, 2012).

            Drowsiness is described in Section 7.1.1 on sedation. Sialorrhea is described in Section 7.1.2 on hypersalivation. Tachycardia and dizziness are described in Section 7.1.3 on orthostatic hypotension and tachycardia.  Constipation is described in Section 7.1.4. Weight gain is described in Section 7.4.1 on the metabolic syndrome.  Insomnia is not mentioned in a subsection since this symptom is not frequent in second-generation antipsychotic RCTs and its associated pharmacological mechanisms are poorly understood (de Leon et al., 2012). Nausea and vomiting are included in Section 7.1.5 entitled Upper Gastrointestinal (GI) Symptoms.

7.1.1. Sedation

            Sedation is probably the most common ADR during clozapine treatment (Miller, 2000; Novartis Pharmaceutical Corporation, 2011).   Clozapine high affinity for H₁ receptors and its blocking action at these brain receptors probably explain clozapine-induced sedation (Richelson, 1999; de Leon et al., 2012). In a recent meta-analysis of second-generation antipsychotic RCTs, Asenjo Lobos et al. (2010) reported that clozapine produces significantly more sedation than olanzapine, quetiapine and risperidone.

Sedation is usually mild, tends to occur during the initial phase of treatment and is transient (Miller, 2000).  Some individuals develop some tolerance to sedation; for others, sedation becomes a persistent ADR.  The risk of sedation is decreased by giving higher doses at night, slower titration, and dose reduction.  Iqbal et al. (2003) state that in severe cases, pharmacological management with stimulants should be considered, but this should be done with much caution due to the risk of worsening psychosis. Using TDM to determine the minimum dose that provides therapeutic concentrations and the lowest possible sedation appears to be a much safer intervention.

7.1.2. Hypersalivation

            Hypersalivation may be the second most common ADR during clozapine treatment. In a recent meta-analysis of second-generation antipsychotic RCTs, Asenjo Lobos et al. (2010) described clozapine as the producer of significantly more hypersalivation than olanzapine, quetiapine and risperidone.

            Clozapine-induced hypersalivation typically occurs at night.  A recent review reported that clozapine increases salivation during sleep and at rest and decreases it during meals (Ekström et al., 2010). Most antimuscarinic drugs cause dry mouth; however, clozapine frequently causes hypersalivation.  Clozapine-induced hypersalivation is frequently explained by the mixed profile of antagonism for some muscarinic receptor subtypes and agonism for others. It is believed that clozapine may be a partial agonist at M₁ and M₃ receptors, and its metabolite, norclozapine, is definitively an allosteric agonist of M₁ (Sur et al., 2003; Davies et al., 2005). Some tolerance may develop but frequently hypersalivation can persist after several years of treatment (Safferman et al., 1991).

            The easiest intervention for clozapine-induced hypersalivation is recommending that the patient sleep with a towel on the pillowcase to prevent soaking the pillow at night.  If there is no development of tolerance to hypersalivation, using TDM to determine the minimum dose providing therapeutic concentrations and the lowest possible hypersalivation appears to be a good idea.

            There are no definitive studies for recommending the best pharmacological treatment for clozapine-induced sialorrhea (Reinstein et al., 1999; Sockalingam et al., 2007; Syed et al., 2008). However, there are some recent double-blind RCTs of (1) glycopyrrolate versus biperiden showing positive results from both drugs, but a better ADR profile for glycopyrrolate (Liang et al., 2010); (2) botulinum toxin by injection versus placebo, with positive results for botulinum toxin (Steinlechner et al., 2010), and (3) ipatropium versus placebo, with negative results for ipatropium (Sockalingam et al., 2009). Case reports indicate that oral anticholinergics such as benztropine may be effective for treating clozapine-induced hypersalivation (Rogers & Shramko, 2000). Case reports also indicate that other alternatives with less risk of cognitive impairment than benztropine may be effective including:  (1) botulinum toxin injections (Kahl et al., 2004); (2) anticholinergics with lower brain entrance than benztropine such as atropine eye drops administered intraorally (Antonello & Tessier, 1999), glycopyrrolate (Robb et al., 2008), ipatropium sprays (Calderon et al., 2000; Tessier & Antonello, 2001; Townsend & Baier, 2004), or scopolamine patches (Gaftanyuk & Trestman, 2004); or (3) α₂ agonists such as clonidine (Grabowski, 1992; Praharaj et al., 2005) or guanfacine (Webber et al., 2004).

7.1.3. Orthostatic Hypotension and Tachycardia

            Clozapine’s propensity to cause orthostatic hypotension can be explained by its α₁ receptor antagonistic properties (Richelson, 1999; de Leon et al., 2012). Orthostatic hypotension is usually transient and occurs during initial treatment.  Tolerance develops in most cases. The prevalence and severity of orthostatic hypotension are related to the pace and magnitude of dose titration (Miller, 2000). These guidelines recommend slow titration (Section 6.3.2) and the use of the Clozapine Adverse Reactions Scale for Nurses (Section 5.3) to avoid orthostatic hypotension.

            Tachycardia is a rather common side effect of clozapine treatment, occurring in about 25% of cases (Miller, 2000).  Tachycardia can be explained as a response to orthostatic hypotension but may be associated with other pharmacological mechanisms including its elevation of plasma norepinephrine (Miller, 2000) and its antimuscarinic activity at the heart, particularly at M₂ receptors (de Leon, 2011).

Tachycardia may be transient and related to dose titration or persistent. In the presence of tachycardia, it is important to rule out (1) orthostatic hypotension, (2) myocarditis, and (3) high clozapine concentrations.  

            Recently, Freeman et al. (2011), in their modification of the orthostatic hypotension consensus guidelines, proposed the existence of a postural tachycardia syndrome (POTS) characterized by a sustained heart rate increment of ≥ 30 bpm within 10 minutes of standing. The standing heart rate for all subjects is often ≥ 120 bpm. These criteria may not be applicable for individuals with low resting heart rates. For individuals aged 12–19 years the required increment is ≥ 40 bpm. There is no data using this recent POTS definition on clozapine patients, but the definition is provided in case there is need of using it in a clozapine patient who developed tachycardia. Future versions of this clozapine guideline will need to consider the inclusion of this definition.

            Orthostatic changes and tachycardia can be avoided by careful monitoring and delaying titration to allow the individual to develop tolerance. Rising slowly after being seated or lying down and increasing fluid and salt intake are advised. Support stockings and tilting the head of the bed at night may be needed.  Some review articles (Iqbal et al., 2003) describe pharmacological management with fludrocortisone or ephedrine for orthostatic hypotension and propranolol for tachycardia. However, orthostatic hypotension and/or tachycardia disappear over time; conservative interventions such as lowering total dose according to TDM or lowering the relevant divided dose to ensure lower peaks should be tried first.

7.1.4. Constipation

Clozapine antimuscarinic activity in the GI system, particularly at M₃ colon receptors (de Leon, 2011), explains its propensity to cause constipation. Lowest clozapine dose possible, high fiber diet, adequate fluid intake and exercise minimize the risk of constipation. Fiber supplements, stool softeners, laxatives, stimulant cathartics or enemas may be needed, depending on the severity of the condition (Iqbal et al., 2003).  The Netherlands clozapine guideline recommends preventive prescription of a laxative and regular (weekly) inquiry about any constipation during titration (Netherlands Clozapine Collaboration Group, 2009).

7.1.5. Upper GI Symptoms

            Dopamine blockers usually have an antinausea effect; therefore it is not well understood how some antipsychotics, including clozapine, can cause nausea or vomiting (de Leon et al., 2012). All antipsychotics may interfere with swallowing, cause esophageal dysmotility and contribute to aspiration. Clinicians should be careful using any antipsychotic, including clozapine, in patients with dysphagia (de Leon et al., 2012). As a matter of fact, clozapine may be particularly prone to cause upper GI symptoms including gastroesophageal reflux, since clozapine prescription tends to be associated with greater prescription of antacids (John et al., 1995; Taylor et al., 2010).

7.2. Relatively Uncommon ADRs

            The relatively uncommon ADRs include (1) seizures, (2) EPS, (3) fever, (4) hypothermia;         (5) delirium, (6) obsessive-compulsive (OC) symptoms,  (7) hyperprolactinemia, (8) sexual ADRs, (9) urinary incontinence, (10) hypertension, (11) effusions and polyserositis, (12) eosinophilia, (13) abnormal liver tests, and (14) creatine kinase (CK) elevations. 

7.2.1. Seizures

            Reviews suggest that clozapine may be the worst among the antipsychotics for reducing the seizure threshold (Alper et al., 2007; de Leon et al., 2012). In a recent meta-analysis of second-generation antipsychotic RCTs, Asenjo Lobos et al. (2010) described clozapine as producing significantly more seizures than olanzapine and risperidone. The mechanisms behind this decrease in seizure threshold are not well understood but include D₂, H₁ and α₁ receptor blockade, actions by neurosteroids or by pharmacological kindling (Torta & Monaco, 2002).  

            According to the prescribing information (Novartis Pharmaceutical Corporation, 2011), clozapine-induced seizures (1) have a cumulative incidence at one year of approximately 5%, and (2) are dose-related.  Devinsky et al. (1991) reviewed the first 1248 patients treated with clozapine in the US between 1972 and 1988. They described a prevalence of 2.8% (41/1418) of generalized tonic-clonic seizures and predicted a cumulative 10% risk of seizures after 3.8 years. The prevalence was dose-related with 4.4% in doses ≥ 600 mg/day, 2.7% in doses of 300-600 mg/day and 1% in doses < 300 mg/day. They also stated that rapid upward titration may increase seizure risk. After a larger review including 5,629 clozapine patients, but limited to the first 6 months after marketing, Pacia and Devinsky (1994) found a prevalence of 1.3% (71/5629) of generalized tonic-clonic seizures. They clarified that seizures tended to occur at low doses (< 300 mg/d) during the titration phase, and at high doses ≥ 600 mg/day. Patients with a history of seizures or epilepsy were more likely to have seizures soon after initiation of therapy, on low doses.

            Myoclonic seizures without loss of consciousness or with progression to tonic-clonic seizures may also occur. Myoclonic jerks may be dose-related and usually manifest as orofacial movements (Bak et al., 1995), knee buckling or leg folding (Antelo et al., 1994). These movements frequently represent myoclonic seizures and some cases have been followed by grand mal seizures (Gouzoulis et al., 1993).  Although there are no good studies, myoclonic jerks appear to be dose-related. If seizures or myoclonic jerks are present, clozapine dose reduction, adding or increasing AED dosages, clozapine discontinuation and/or consultation with an epileptologist may be required. When AEDs are prescribed, careful consideration of DDIs is required (AED Inducers subsection in Section 6.5.1). If an AED is added, Toth and Frankenburg (1994) recommended valproate and Wong and Delva (2007) recommended lamotrigine or valproate. Valproate may have more risk of DDI (Valproate subsection in Section 6.5.1) and has recently been associated with increased myocarditis risk in Australian studies (Section 7.3.2).  

            The prescribing information (Novartis Pharmaceutical Corporation, 2011) warns that (1) caution should be used in administering clozapine to patients having a history of seizures or other predisposing factors, and (2) patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others, (e.g., the operation of complex machinery, driving an automobile, swimming, climbing, etc.).

            The interpretation of electroencephalogram (EEG) findings in individuals taking clozapine is confounded by the occurrence of frequent abnormalities in patients taking clozapine (Günther et al., 1993); they may be dose-related (Freudenreich et al., 1997). 

7.2.2. EPS

Clozapine is a D₂ antagonist but has low affinity and loose binding to brain D₂ receptors, which may explain its low potential for causing EPS (Seeman & Tallerico, 1998; Shayegan & Stahl, 2004). A recent meta-analysis verified the clinical experience that clozapine has a better profile for EPS than other second-generation antipsychotics (Rummel-Kluge et al., 2012), including (1) significantly less use of anticholinergics than risperidone, and (2) lower scores on akathisia and EPS (not reaching significance). Asenjo Lobos et al. (2010), in a recent meta-analysis of second-generation antipsychotic RCTs, indicated that clozapine produces significantly fewer EPS than risperidone. Weiden (2007) points out that clozapine may be different than other second-generation antipsychotics (except quetiapine) in that higher doses do not cause more EPS. 

Acute dystonic reactions during clozapine treatment are usually not described in studies (Raja & Azzoni, 2001), but the literature describes very rare cases of acute dystonic reactions associated with clozapine treatment (Kastrup et al., 1994; Elliott et al., 2000).

According to the prescribing information, akathisia is rare in patients taking clozapine, with a prevalence of 3% in a study of 842 patients (Novartis Pharmaceutical Corporation, 2011). Other studies also indicate a low prevalence of akathisia (Chengappa et al., 1994).

            Tardive dyskinesia rarely occurs with clozapine (de Leon et al., 1991; Li et al., 2009), but rare cases of clozapine-induced exacerbations of tardive dyskinesia have been published (Raguraman & Vijaysagar, 2007).  A recent meta-analysis indicated that chlorpromazine has significantly more risk of causing tardive dyskinesia than clozapine (Hartling et al., 2012). On the other hand, there is evidence that tardive dyskinesia may improve after a switch to clozapine (Spivak et al., 1997; Pierre, 2005), and clozapine has been consistently recommended for treating tardive dyskinesia, particularly in cases with tardive dystonia (Larach et al., 1997; Simpson, 2000; Pierre, 2005; van Harten & Tenback, 2011).  

7.2.3. Fever

            The presence of fever and/or infection may be indicative of the presence of agranulocytosis.  However, most cases of fever in clozapine-receiving individuals are unrelated infections.  If the individual has fever and no cause is found, it may be a clozapine-induced benign hyperthermia. According to Røge et al., (2012) clozapine-induced hyperthermia is probably explained by an increase in cytokines.  Lowe et al. (2007) described clozapine-induced fever as usually occurring within 10-15 days after treatment initiation, as lasting 2 to 4 days, and as perhaps being present in up to 50% of the patients. Safferman et al. (1991) described it as present in up to 5% of individuals, usually within the first three weeks of treatment with minor increases of 1 or 2 degrees F and as resolving spontaneously with continuation of treatment. Kohen et al. (2009) indicated that clozapine-induced fever may be associated with increases in CRP. From the practical point of view, if fever is present, it is important to rule out agranulocytosis and neuroleptic malignant syndrome (NMS). Antipyretic agents such as acetaminophen can be used (Lowe et al., 2007).

            Chung et al. (2008) proposed that in Chinese patients, clozapine-induced hyperthermia may be associated with rapid titration, defined as > 50 mg/week.  Section 6.4 recommends clozapine increases ≤ 50 mg/week in East Asians.

7.2.4. Hypothermia

            Rarely, clozapine has been associated with severe hypothermia that may be explained by 5-HT_2A receptor blockade and possibly α₂ blockade (van Marum et al., 2007). Safferman et al. (1991) estimate that up to 87% of clozapine patients may have mild hypothermia.

7.2.5. Delirium

Clozapine, due to its antimuscarinic activity, has been implicated in the development of delirium or confusion in the elderly or in individuals with cognitive deficits, particularly when taking other antimuscarinic medication (Young et al., 1998). In a study of 139 inpatients, Centorrino at al. (2003) found a 10% incidence of delirium. Associated factors included (1) co-treatment with other centrally acting antimuscarinic agents, (2) poor clinical outcome, (3) older age, and (4) longer hospitalization. Dose reduction and slowing the rate of titration may be needed if delirium occurs (Young et al., 1998). Centorrino et al. (2003) recommended extreme caution when other antimuscarinic drugs are used in elderly patients taking clozapine.

7.2.6. Emergence of OC Symptoms

            Case reports and small studies indicate that adding clozapine can exacerbate OC symptoms when OC disorder is pre-existing, or even start them (Ongür & Goff, 2005). On the other hand, some case reports and small studies indicate clozapine can improve OC symptoms in schizophrenia patients unless they were present before the schizophrenia illness started (Reznik et al., 2004).  Obviously this is a complex area, and although there are no definitive prospective studies, the literature clearly suggests that clozapine can occasionally exacerbate and initiate OC symptoms and that this ADR may not be present with other antipsychotics (Scheltema Beduin et al., 2012; Schirmbeck & Zink, 2012). The link between clozapine and OC symptoms is reinforced by the association between the severity of OC symptoms and higher clozapine doses and concentrations (Schirmbeck & Zink, 2012). SSRIs have been used to treat OC symptoms associated with clozapine treatment (Andrade, 2012); particular attention to DDIs is needed (Section 6.5.1).

7.2.7. Hyperprolactinemia

            In vitro (Lamberts et al., 1990) and rat (Meltzer et al., 1979) studies indicated that, in effect, clozapine stimulates prolactin secretion, but its effects were much lower than those of first-generation antipsychotics. Clinical studies indicate that clozapine effects on prolactin are minimal and temporary (Safferman et al., 1991). A clozapine RCT estimated that clozapine effects are 5 to 20 times lower than haloperidol’s and it should be rare to find clinically relevant prolactin elevations in patients taking clozapine (e.g., a female on very high clozapine doses) (de Leon et al., 2004). As clozapine has very limited risk for clinically relevant prolactin elevations, it has been a good antipsychotic for patients with antipsychotic-induced gynecomastia (Uehlinger & Baumann, 1991) or osteoporosis (Lin et al., 2012). Quetiapine and aripiproazole are other good options (de Leon et al., 2012).

            Other second-generation antipsychotic guidelines (de Leon et al., 2009a) recommend that the annual follow-up include consideration of hyperprolactinemia by (1) assessing serum prolactin level; (2) breast examination (including a note regarding the presence or absence of galactorrhea in women and gynecomastia in men); (3) assessing changes in menstruation or libido in females, when appropriate. This can be included in the clozapine guideline if standardization of annual assessments across all antipsychotics is desired.

7.2.8. Sexual ADRs

            Antipsychotics can cause sexual ADRs including desire, arousal, and orgasm dysfunction that may be explained by the blockade of peripheral α, M and H receptors (Serreti & Chiesa, 2011). In antipsychotics that cause greater prolactin elevations than clozapine, hyperprolactinemia may be a contributing factor to sexual ADRs, too.  Clozapine, along with haloperidol, thioridazine, olanzapine and risperidone, may be the group of antipsychotics with the highest risk of sexual ADRs, in some studies ranging in prevalences from 40% to 60% (Serreti & Chiesa, 2011).

            Clozapine has rarely been associated with priapism, which may be related to α₁ receptor blockade and possible α₂ receptor blockade (Sood et al., 2008).

7.2.9. Urinary Incontinence

Some individuals taking clozapine develop urinary incontinence, particularly at night. Lin et al. (1999) completed a retrospective review of urinary incontinence in 61 Chinese inpatients with schizophrenia who were treated with clozapine for more than 3 months. They found 44% had urinary incontinence and 25% had persistent urinary incontinence. Jeong et al. (2008) did a 2-year prospective follow-up study of lower urinary tract symptoms in 101 Korean patients treated with clozapine. Only 11% (11/101) had reported actual incontinence or lower urinary tract symptoms including hesitancy, voiding difficulty and residual sensations.

Conservative measures are the preferred interventions for urinary incontinence, including avoiding fluid intake at night, scheduling middle-of-the-night awakenings to empty the bladder and using enuresis alarms.  Several pharmacological agents have been used, including (1) alpha-adrenergic agonists (e.g., ephedrine), (2) antimuscarinic drugs (oxybutynin or trihexyphenidyl), and (3) desmopressin, but it is not clear they are helpful (Jeong et al., 2008).

Clozapine, as with all antimuscarinic drugs, has the potential to cause urinary retention, particularly when it is combined with other antimuscarinic drugs (Cohen et al., 1994).

7.2.10. Hypertension

Clozapine is the only antipsychotic consistently associated with hypertension, which can ocasionally be severe (Visscher & Cohen, 2011). The number of patients who develop hypertension during clozapine treatment is usually considered small (4%)  (Safferman et al., 1991), but a retrospective chart review of 82 clozapine patients indicated that 27% received antihypertensive treatment after clozapine initiation (Henderson et al., 2004). Clinical experience indicates that patients who develop hypertension on clozapine typically have a past history of hypertension or had borderline blood pressures at baseline (Villanueva et al., 2006). The mechanism behind clozapine-induced hypertension is not well understood but α receptor dysregulation has been proposed and treatment with a β-blocker recommended (Shiwach, 1998). 

7.2.11. Effusions and Polyserositis

            Clozapine has occasionally been associated with eosinophilic pleural effusions (Huggins & Sahn, 2004) and with polyserositis (Waller et al., 2007).

7.2.12. Eosinophilia

            Eosinophilia has been described in < 1% of clozapine patients (Lieberman, Kane, & Johns, 1989). It is important to pay attention to eosinophilia since it can be associated with more serious ADRs including polyserositis (Patel et al., 2012), myocarditis (Chatterton, 1997), and pancreatitis (Huang et al., 2009). 

7.2.13. Abnormal Liver Tests

            Elevations in liver enzyme are usually transitory during clozapine treatment (Erdogan et al., 2004), but very rare cases of toxic hepatitis and liver failure have been associated with clozapine (Section 7.3.12).  According to Raja (2011) asymptomatic elevations of liver enezymes may occur in 30-50% patients.  

7.2.14. CK Elevations

            Clozapine has occasionally been associated with important CK elevation in the absence of other explanations for this elevation (Meltzer et al., 1996; Scelsa et al., 1996; Reznik et al., 2000; Melkersson, 2006). When CK elevations are found in patients taking clozapine it is important to rule out other causes, including catatonia and NMS.

7.3. Potentially Lethal ADRs

            The clozapine potentially lethal ADRs include (1) agranulocytosis, (2) myocarditis, (3) long QT_C syndrome and arrhythmias, (4) NMS, (5) cerebrovascular accidents (and death in demented patients), (6) pancreatitis, (7) paralytic ileus and other lethal GI complications, (8) heat stroke, (9) diabetic ketoacidosis, (10) severe allergic reactions, (11) acute renal failure, (12) acute severe hepatitis and (13) aspiration pneumonia.

            In spite of this large list of potentially lethal ADRs, there is some data that clozapine may decrease mortality in patients with schizophrenia. Walker et al. (1997), in an epidemiologic study of 67,000 cases of clozapine-treated patients in the U.S. between 1989 and 1996, adjusted for age, sex, and race, found that all-cause mortality was lower during the period of clozap­ine use than during nonuse. There was a dramatic decrease in suicide in clozapine users while death associated with pulmonary embolism and respiratory disorders increased (Walker et al., 1997).  In a study (Tiihonen et al., 2009b) of the entire population of those in Finland with schizophrenia, clozapine was associated with the lowest risk for overall mortality. Clozapine was associated with lower suicide risk, but the study suggested that other factors may be important since clozapine was one of the four antipsychotics with the best mortality profiles for ischemic heart disease. As in any naturalistic study, this study had limitations and led to various comments, including petitions for better prospective studies (Blasco-Fontecilla et al., 2010; De Hert et al., 2010). A recent US retrospective cohort study found no differences in cardiovascular mortality between risperidone and clozapine (Kelly et al., 2010). Even assuming that clozapine is actually associated with reduced mortality in schizophrenia, it is not known whether this clozapine-reducing mortality data in schizophrenia can be extrapolated to adults with IDs.

7.3.1. Agranulocytosis

Agranulocytosis, defined as ANC < 500/mm³ (Novartis Pharmaceutical Corporation, 2011), is the most serious clozapine ADR. The negative perception of this risk has limited clozapine’s use.  The incidence of agranaulocytosis is 0.31% in China, according to Tang et al. (2008).

Based on the occurrence of cases in the US during the clinical testing of clozapine prior to domestic marketing, a cumulative incidence of 1.3% over one year is described (Novartis Pharmaceutical Corporation, 2011).  After 5 years’ experience with the CNR, the estimates suggested a cumulative rate of 0.9% (Alvir et al., 1993).  The risk seems to peak by the third month and declines significantly after the sixth month, but never reaches zero (Alvir et al., 1993).  This finding led to the WBC monitoring decrease to biweekly after 6 months of clozapine therapy. 

Agranulocytosis risk appears to increase with age and to be higher in women than in men, and is particularly high in Ashkenazi Jews (Lieberman et al., 1990).  Agranulocytosis is potentially fatal and considered a medical emergency.  The best approach for preventing it is careful monitoring.  If agranulocytosis develops, clozapine should be discontinued and the individual should be hospitalized for specialized treatment in an appropriate setting.  

7.3.2. Myocarditis

Myocarditis is a rare and potentially fatal clozapine ADR (Kilian et al., 1999).  Novartis has strengthened the box warning regarding the risk of clozapine-associated myocarditis based on post-marketing surveillance data, which revealed fatalities in multiple countries.  The range of these reports represent an incidence of 5.0-96.6 cases/100,000 patient-years and the number of fatalities represent an incidence of 2.8-32.2 cases/100,000 patient-years (Novartis Pharmaceutical Corporation, 2011). The risk may be highest during the first month of therapy, but it continues as long as the drug is administered (Novartis Pharmaceutical Corporation, 2011). Merrill et al. (2005) estimated the risk of potentially fatal myocarditis to be 0.015-0.188% (or 1/6,666 to 1/532 patients).  Cohen et al. (2012a) provided an incidence of clozapine-induced myocarditis of 7-34 per 1000 in Australia and of 0.07-0.6 per 1000 in other countries. The mortality rate among myocarditis cases was 0-13% in Australia and 0-68% in other countries.

            In an Australian case-control study with 105 cases and 296 controls (Ronaldson et al., 2012) the risk of myocarditis increased by 26% for each additional 250 mg of clozapine administered in the first nine days of clozapine titration (odds ratio 1.26; 95% confidence interval 1.02-1.55; p=0.03).  Concomitant sodium valproate more than doubled the risk (2.59; 1.51-4.42; 0.001). Further, each successive decade in age was associated with a 31% increase in risk (1.31; 1.07-1.60; 0.009).

            According to the prescribing information (Novartis Pharmaceutical Corporation, 2011), the possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias.

            Recently in Australia, Ronaldson et al. (2011) have proposed some guidelines that are described here in a simplified version. They recommend asking caregivers to monitor symptoms including fever, cough, chest pain, shortness of breath, diarrhea, vomiting, nausea, sore throat, myalgia, headache, sweatiness, and urinary discomfort or frequency.  If any of these symptoms are present or heart rate ≥ 120 bpm or increased > 30 bpm, the prescriber should consider measuring troponin and CRP. If troponin ≤ 2ULN or CRP 50-100 mg/L, clozapine can be continued but troponin and CRP levels should be ordered daily until they normalize.  If troponin > 2ULN or CRP > 100 mg/L, clozapine should be stopped, an echocardiogram should be ordered and a cardiologist consulted. 

            The Dutch guideline advocates a stepped risk management approach with special attention during the first two months to flu-like symptoms (unexplained fever, fatigue, or lethargy), hypotension or tachycardia. Should any of these symptoms occur, as a second step laboratory tests (hypereosinophilia, CRP, creatine kinase-MB or troponin) may help to differentiate myocarditis from benign ADRs which commonly occur during clozapine initiation. If dyspnea, orthopnea, increased central venous pressure, third or fourth sound, pericardial friction rub, souffle consistent with mitral or tricuspid insufficiency, peripheral edema and/ or crepitations over the lungs are observed, the patient must be referred to a cardiologist immediately (third step) (Netherlands Clozapine Collaboration Group, 2009).

7.3.3. Long QTc Syndrome and Arrhythmias

            Antipsychotics cause blockade of heart potassium repolarizing channels and can cause QTc prolongations. The first-generation antipsychotics have been definitively associated with increased sudden deaths; however, there is no clear data that atypical antipsychotics can lead to torsade de pointes (Titier et al., 2005). Clozapine can also cause blockade of heart potassium repolarizing channels, according to in vitro studies (Tie et al., 2001) and has occasionally been associated with QTc prolongations (Dhillon et al., 2011), but in most patients clozapine effects on QTc may not be clinically relevant (Kang et al., 2000; Grande et al., 2011). It is not definitively established that clozapine causes torsade de pointes (Warner & Hoffmann, 2002). In an Israeli hospital study of sudden death, the prevalence in clozapine patients was 1.07% (6/561) versus 0.28% (14/4918) in other patients (Modai et al., 2000). The prescribing information (Novartis Pharmaceutical Corporation, 2011) recommends discontinuing clozapine if QTc > 500 msec.

7.3.4. NMS

            Clozapine has occasionally been associated with NMS. In a review of 68 published NMS cases associated with second-generation antipsychotics, there were 21 clozapine cases (Ananth et al., 2004). Atypical presentations have been described at times (Nama & Aftab, 2012).  In spite of these cases, clozapine is probably the best antipsychotic for rechallenging patients who developed NMS with other antipsychotics (Weller & Kornhuber, 1992).  Manu et al. (2012) reviewed the cases of five clozapine-induced NMS patients who were rechallenged with clozapine slow titrations and CK monitoring; all five were successful and did not develop NMS.

7.3.5. Cerebrovascular Accidents and Death in Demented Patients

            When compared with placebo there is an increase of death in elderly demented patients on many antipsychotics. This increased mortality may be partly explained by increased strokes (Sink et al., 2005). Venous thromboembolism may also be slightly increased in the elderly taking antipsychotics (Liperoti et al., 2005). Kales et al. (2007) proposed that the increased mortality of demented patients taking antipsychotic treatment is probably multifactorial and not well understood. Gill and Seitz (2012) indicated that increased death in demented patients taking antipsychotics may be a combination of (1) cerebrovascular adverse events, (2) pneumonias, and (3) ventricular arrhythmias. Other causes of sudden death possibly associated with antipsychotics include (1) pulmonary embolism, (2) aspirations, and (3) myocardial infarcts.

            Clozapine has been associated with both venous thromboembolism (Paciullo, 2008) and pulmonary embolism (Srihari & Lee, 2008).  Some studies indicate that clozapine may increase the risk of infections (Landry et al., 2003) or pneumonias (Kuo et al., 2013).

7.3.6. Pancreatitis

            Pancreatitis is a potentially lethal illness that has very rarely been associated with antipsychotics, but it is hard to determine a causal connection with the antipsychotic treatment. Using the FDA surveillance program, Koller et al. (2003) identified 192 cases of pancreatitis during antipsychotic treatment, including 72 on clozapine monotherapy, and found a mortality of 11%. In some patients other possible causes of pancreatitis, such as valproate, were present. Published case reports indicate that the connection with clozapine is possible since some of them are associated with recurrence after rechallenge (Huang et al., 2009). 

7.3.7. Paralytic Ileus and Other Potentially Lethal GI Complications

            On rare occasions untreated clozapine-induced constipation (Section 7.1.4) can lead to major complications and be potentially lethal; clozapine may present the highest ileus risk among antipsychotics (Nielsen & Meyer, 2012).  Palmer et al. (2008) used the term clozapine-induced GI hypomotility to include all of these complications (including, among others, paralytic ileus, ischemic colitis, bowel perforation and acquired megacolon). By reviewing the literature and pharmacoepidemiology databases in New Zealand and Australia, they compiled a database of 102 cases with a 28% mortality rate, largely due to bowel resection. The risk factors included high clozapine dose or concentration, concomitant anticholinergic use, or intercurrent illness. In a review of a French pharmacoepidemiology database over ten years, 38 patients with ischemic colitis and gastrointestinal necrosis were identified in patients taking antipsychotics but only seven taking clozapine, indicating that other antipsychotics with antimuscarinic activity and/or combined with anticholinergics can lead to the same complications (Peyrière et al., 2009). Cohen et al. (2012a) provided an incidence of clozapine-induced GI hypomotility ranging from 4-8 per 1000 and a mortality of 15-28% among ileus cases.

7.3.8. Heat Stroke

            Clozapine, as with other antipsychotics, can interfere with heat regulation. The risk is clear when patients are exposed to heat and/or strenuous exercise (Martin-Latry et al., 2007; Stadnyk & Glezos, 1983). Kerwin et al. (2004) described a case of heat stroke associated with clozapine treatment.

7.3.9. Diabetic Ketoacidosis

     Diabetic ketoacidosis is characterized by (1) hyperglycemia, (2) an ion gap metabolic acidosis and (3) ketonemia. Cohen et al. (2012a) provided an incidence of clozapine-induced diabetic ketoacidosis ranging from 0.1-3.2 per 1000 and a mortality of 20-31% of the cases.

            Nihalani et al. (2007) reviewed 26 cases (23 published and three seen by them) of diabetic ketoacidosis associated with clozapine. Not surprisingly, diabetic ketoacidosis usually presents in patients who have not previously been diagnosed with diabetes. More interestingly, it is known that ketoacidosis was more frequent early in the course of treatment, when clozapine treatment duration is short (61% within three months) and can occur with low doses (38%, 10/26 had clozapine doses ≤ 300 mg/day). Guenette et al. (2013) reviewed 69 cases of ketoacidosis associated with second-generation antipsychotics (18 with clozapine). They reported one-third of the patients had no weight gain or loss, and a 7.3% mortality rate.

7.3.10. Severe Allergic Reactions

            Very rarely, clozapine has been associated with potentially lethal allergic reactions manifested as angioneurotic edema (Mishra et al., 2007) or allergic asthmatic reaction (Stoppe et al., 1992). A case of clozapine-induced systemic lupus erythematosus that reoccurred after rechallenge has been described (Rami et al., 2006).

7.3.11. Acute Renal Failure

            Very rarely, clozapine has been considered the possible cause of acute renal failure (Fraser & Jibani, 2000).  However, due to its rarity, it is difficult to establish that clozapine was the cause.

7.3.12. Acute Severe Hepatitis

            Very rare cases of toxic hepatitis and liver failure have been associated with clozapine. However, due to their rarity it is difficult to establish that they were caused by clozapine. Macfarlane et al. (1997) provided a prevalence of clozapine-induced icteric hepatitis of 0.06%. 

7.3.13. Aspiration Pneumonia

            Through a mechanism not well understood, all antipsychotics interfere with swallowing. Futhermore, clozapine, due to frequent hypersalivation and high risk for sedation, has potential to cause aspiration pneumonia (Abdelmawla & Ahmed, 2009). Some pharmacoepidemiological antipsychotic studies have associated clozapine with a particularly high risk for pneumonia (Taylor et al., 2009; Kuo et al., 2013; Yang et al., 2013) or antibiotic co-prescription (Nielsen et al., 2009). As Section 6.7.6 indicates, pneumonia can lead to clozapine intoxication.

7.4. Metabolic Syndrome

7.4.1. Weight Gain

            Weight gain is well-documented in clozapine treatment. Studies on receptor affinity indicate that H₁ affinity is the best predictor of weight gain (de Leon et al., 2012). Some animal studies indicate that blockade of other (particularly 5-HT_2C and muscarinic) receptors beyond H₁ may be needed to produce hyperphagia (Hartfield et al., 2003).  A RCT in patients has verified that clozapine is associated with increased appetite and more patients reported food craving and binge eating (Kluge et al., 2007). Allison et al. (1999) conducted a meta-analysis that demonstrated that, when compared with other antipsychotics, clozapine appears to have the worst profile in RCTs, with average increases of 4.5 Kg in 10 weeks with olanzapine being second with 4.2 Kg. More recent meta-analysis in children (Pringsheim et al., 2011; Cohen et al., 2012b) and adults (Rummel-Kluge et al., 2010) verified that clozapine is an antipsychotic with a bad profile for weight gain, similar to olanzapine.   

Different clozapine studies have reported varying incidence of weight gain with reports of mean increases of 5.3 to 6.3 kg (11.8 to 14.0 lb) and substantial percentages of individuals gaining more than 20% of their initial body weight during the first year of treatment (Meyer, 2001b).  

            In a US clozapine RCT, African-American race, higher dose and lower baseline weight were associated with greater weight gain (de Leon et al., 2007). The duration of clozapine treatment, especially during the first four years of treatment, may also be a risk factor (Henderson et al., 2000).

7.4.2. Hyperglycemia

            Several studies highlighted the increased risks of hyperglycemia and diabetes mellitus, type II, in individuals receiving clozapine and other second-generation antipsychotics (Allison et al., 1999; Gianfrancesco et al., 2002). In September 2003, the FDA issued a class labeling change regarding the risks of hyperglycemia and diabetes mellitus in association with second-generation antipsychotic medications. This was followed by a consensus guideline writen by the American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), American Psychiatric Association (APA), and North American Association for the Study of Obesity (NAASO) (2004).

            Increased weight may contribute to diabetes mellitus but there is definitive information that clozapine may have direct effects independent of weight. Clozapine (and possibly other antipsychotics) may directly increase insulin resistance by (1) decreasing insulin-sensitive glucose transporters or by causing an inability to stimulate the recruitment of glucose transporters from microsomes to the plasma membrane and/or (2) elevating serum free fatty acids and then causing insulin resistance (de Leon & Diaz, 2007).

            In a recent meta-analysis of second-generation antipsychotic RCTs, Rummel-Kluge et al. (2010) described clozapine as having similar glucose increases to olanzapine.  Reports indicate a relatively high rate of new-onset diabetes during treatment with clozapine ranging from 12% (Hagg et al., 1998) to 36.6% (Henderson et al., 2000).  Confounding factors include an increased background risk for diabetes in individuals diagnosed with schizophrenia as well as lack of physical activity, dietary intake and African American race.  Despite these factors, clozapine treatment by itself appears to carry an increased risk for diabetes mellitus.  Lack of diagnosis of clozapine-induced diabetes mellitus may contribute to diabetic ketoacidosis (Section 7.3.9)

7.4.3. Hyperlipidemia

            Increases in lipid levels have been associated with antipsychotic treatment, particularly with olanzapine and clozapine (Meyer, 2001a; Meyer & Koro, 2004). In some cases, hyperlipidemia is associated with weight gain. However, in many cases weight gain does not seem to correlate with the severity of the observed hypertriglyceridemia (Meyer & Koro, 2004). The possible direct effects of some antipsychotics on lipid levels have been associated with interferences with leptin or glucose intolerance (Meyer & Koro, 2004). However, it is not clear whether leptin changes are a cause or consequence of the effect of antipsychotics on lipids. Also, many patients with antipsychotic-induced hyperlipidemias do not appear to have obvious glucose intolerance (Meyer & Koro, 2004), suggesting that an explanation based on glucose intolerance may be unlikely.

            The association between clozapine and elevated triglyceride levels is more definitive than with hypercholesterolemia. In a recent meta-analysis of second-generation RCTs, Asenjo Lobos et al. (2010) indicated that clozapine may produce higher triglyceride levels than risperidone and quetiapine, but this finding needs replication. Elevated triglyceride levels are an independent risk for coronary atherosclerosis (Ghaeli & Dufresne, 1996; Henderson et al., 2000; Meyer, 2001a).

            In a recent meta-analysis of second-generation antipsychotic RCTs, Rummel-Kluge et al. (2010) found that clozapine is associated with cholesterol increases similar to olanzapine.

7.4.4. Interventions

            Other second-generation antipsychotic guidelines (de Leon et al., 2009a) recommended that nutritional consultation and appropriate dietary and exercise interventions should be implemented if any of the following weight gain indicators occur: (1) weight increase of 5% in 1 month, 7.5% in 3 months or 10% in 6 months; (2) waist circumference increases to more than 35 inches (87.5 cm) in females and more than 40 inches (100 cm) in males; (3) BMI increase from normal to overweight (less than 25 to 25 or higher) or from overweight to obese (25-29.9 to 30 or higher). Regarding secondary metabolic complications not responding to nutritional interventions, (1) a fasting blood glucose level of 100 mg/dl or higher should prompt appropriate medical interventions that may include a glucose tolerance test, adding antidiabetic agents and considering clozapine discontinuation; and (2) abnormal lipid (triglyceride or cholesterol levels) results should prompt an appropriate medical intervention that may include adding oral antidiabetics, lipid lowering agents, and consideration of reducing clozapine dose or discontinuing clozapine.

            Clinicians wanting to consider more complex interventions that include adding other drugs that may reduce complications of the metabolic syndrome should read articles specifically reviewing this subject (Baptista et al., 2004a; 2008; Meyer & Stahl, 2009; Maayan et al., 2010; Das et al., 2012). There are RCTs of metformin (Carrizo et al., 2009), modafanil (Henderson et al., 2011), sibutramine (Henderson et al., 2007) and rosiglitazone (Henderson et al., 2009) in clozapine-treated patients. Behavioral interventions for weight gain are reviewed in other articles (Loh et al., 2006; Caemmerer et al., 2012; Das et al., 2012). If any drug for treatment of the metabolic syndrome is added, clinicians should consider the potential for DDI (see Section 6.5 and Baptista et al., 2004b).
Role of the funding source: No commercial organizations had any role in the writing of these guidelienes.

Conflict of interest: In the past three years, Dr. de Leon had no conflicts of interest.

Acknowledgments: The author acknowledged Lorraine Maw, M.A., and Margaret T. Susce, R.N., M.L.T., at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, who helped in editing the article and managing the large number of articles reviewed.     

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Table 1. Most important clozapine studies in adults with IDs identified by a PubMed search^a or from other review articles^b,c                                

Authors                                                                                             N         Design                         Outcome                                                       

TO TREAT BEHAVIORS

Vyncke, 1974^b                                                                                  40        Retrospective review   improvement in target behaviors per staff

Cohen & Underwood, 1994^a                                                  6        Case reports                ↓ aggression

Hammock et al., 1995^b                                                                       1        Double blind               ↓ self-injurious behavior         

Rubin & Langa, 1995^a                                                                         2        Case reports                ↓ aggression and self-injurious behavior      

Schroeder et al., 1995^b                                                                        3        Double blind               ↓ self-injurious behavior         

Williams et al., 1995^b                                                              1        Case report                  ↓ aggression and tantrums           

Holzer et al.,  1996^a                                                                  1        Case report                  ↓ self-injurious behavior

Boachie & McGinnity, 1997^c                                                                 17        Retrospective review   ↓ aggression and self-injurious behavior

Buzan et al.,  1998^a                                                                10        Retrospective review   ↓ aggression and self-injurious behavior

Kamal & Kelly, 1999 ^b                                                                        1        Case report                  ↓ aggression and self-injurious behavior

Thuresson & Farnstrand, 1999^b                                                         51        Retrospective review   improvement in target behaviors per staff

Gobbi & Pulvirenti, 2001^a                                                       1        Case report                  ↓ aggression and self-injurious behavior                 

Hammock et al., 2001^a                                                                        2        Single blind                 ↓ aggression and self-injurious behavior      

Beherec et al.,  2011^a                                                               6        Retrospective analysis ↓ disruptive behaviors                                   

TO TREAT PSYCHOSIS

Pary, 1994^a                                                                             3        Case reports                improvement in psychosis

Sajatovic et al.,  1994^a                                                            5        Case reports                4/5 improved from schizophrenia

Rubin & Langa, 1995^a                                                                        6        Case reports                improvement in psychosis

Antonacci & de Groot, 2000^a                                                33        Retrospective review   26 remained on clozapine (used for psychosis)

Thalayasingam et al., 2004^a                                                    24        Retrospective review   >1/2 improved from psychosis

Gladston & Clarke, 2005^a                                                        1        Case report                  improvement in psychosis^d                                  

^aA PubMed search was conducted using "clozapine"[Mesh] AND ("mental retardation"[Mesh] OR "autistic disorder"[Mesh] OR "child development disorders, pervasive" [Mesh] OR "developmental disabilities" OR "intellectual disabilities" OR "intellectual disability"). On 4/9/12 the search provided 45 articles. After limiting the search to “Human” and age “All Adult (19+years)”, there were 27 articles left. Among these 27 articles there were 12 clozapine studies in adults with IDs.

^bSix clozapine articles were obtained from the review by Singh et al. (2010).

^cOne more clozapine article was obtained from the review by Deb et al. (2007).

^dVelo-cardio-facial syndrome.

Appendix 1. Clozapine Drug Utilization Review for Adults with Intellectual Disabilities (IDs)

Appendix 2. Clozapine Adverse Reactions Scale for Nurses