Second to none: rationale,timing,and clinical management of clozapine use in schizophrenia

Abstract

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine’s wide-ranging superior efficacy – for treatment-resistant schizophrenia (TRS) and beyond – and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients’ benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine’s unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine’s full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Keywords

antipsychotics clozapine mortality re-challenge schizophrenia treatment resistance

Introduction

With a life-time prevalence of 4.8–7.2 per 1000,^1,2 schizophrenia is one of the most common mental disorders with a high number of disability-adjusted life years.³ Roughly two-thirds of all patients suffer from a recurrent or chronic course of illness,⁴ and about 30% of all patients develop resistance against standard antipsychotic treatment.^5–7

More than 65 years after its discovery and more than 30 years after the seminal study by Kane and colleagues,⁸ clozapine remains the only effective antipsychotic drug for patients with treatment-resistant schizophrenia (TRS).^9–12 Moreover, the superior efficacy of clozapine for crucial clinical aspects of schizophrenia beyond narrowly defined treatment resistance is very well established.^13–15 Although these findings are reflected in all major national and international treatment guidelines,^16–20 converging evidence from developed countries clearly indicates that clozapine remains substantially underused.²¹ It has been suggested that one major reason for this situation is a lack of sufficient training and experience regarding clozapine treatment in a considerable number of psychiatrists.^22,23 While specific prescriber-related obstacles remain rather poorly understood,²² they may include a delayed detection of TRS, incomplete knowledge of clozapine’s broad beneficial effects, and an unfounded hesitance to use or maintain clozapine in accordance with guideline recommendations out of respect for its potential side-effects.²⁴

Here, we review the current literature on all clinically relevant aspects of clozapine treatment with a particular emphasis on those we deem most pertinent to help rectify these issues. This includes guidance for optimal side-effect monitoring and management geared toward maximizing the number of patients, who can be treated safely with clozapine, while minimizing the overall number of treatment discontinuations. Moreover, by highlighting the current evidence for the full range of its clinical effects, we want to encourage increased use of clozapine not only in TRS but also in other patient groups, for which this unique medication can provide unmatched benefits.

Literature selection

We based our review on a MEDLINE and Google Scholar search for all relevant topics, selecting both relevant individual clinical studies as well as meta-analyses and reviews. We included all articles that were published until November 2022. We searched for publications containing the following MeSH terms: treatment-resistant schizophrenia [AND] criteria, treatment-resistant schizophrenia [AND] treatment, treatment-resistant schizophrenia [AND] neurobiology, clozapine [AND] xx, with xx reflecting the topic we aimed to focus at that timepoint (e.g. side-effects, neutropenia, agranulocytosis, hypersalivation, pneumonia, myocarditis, re-challenge, re-challenge [AND] myocarditis, re-challenge [AND] neutropenia, withdrawal, discontinuation, pregnancy, breastfeeding elderly, metabolic syndrome, gastrointestinal side effects, sedation, mortality, pharmacokinetics, pharmacodynamics, valproate, clinical effects, clozapine-resistant schizophrenia). In addition, we manually screened reference lists of topical review articles. In cases in which we did not have any access to the full article, we contacted the study authors. Literature selection was also informed by our own clinical experience in the use of clozapine.

Treatment-resistant schizophrenia

The international guidelines by the Treatment Response and Resistance in Psychosis (TRRIP) Working Group provide a clear consensus definition of TRS.²⁵ A central criterion is the presence of persistent symptoms of at least moderate severity despite adequate standard antipsychotic treatment.²⁵ Importantly, persistent symptoms do not need to cause subjective distress in patients but must have some degree of objectifiable detrimental functional impact. Moreover, pseudo-resistance due to continued use of hallucinogenic drugs or insufficient antipsychotic plasma levels needs to be excluded.^25,26 Pseudo-resistance can also result from side-effects or comorbid medical conditions masking the clinical effects of antipsychotic treatment.^13,25 In this context, the importance of therapeutic drug monitoring is underscored by evidence from a naturalistic clinical setting indicating that approximately 30% of patients with suspected treatment resistance should in fact be classified as ‘pseudo-resistant’ because of subtherapeutic antipsychotic plasma levels.^27–29 Finally, a comprehensive diagnostic workup is essential to rule out other underlying disorders.

The minimal criteria for TRS encompass the following points:

Persistent symptoms (positive, negative, and cognitive symptoms) over at least three months of at least moderate severity causing at least moderate functional impairments. Symptoms classification and thresholds require the use of standardized, validated clinical rating scales.

Insufficient response to treatment with at least two different antipsychotic drugs with a minimum duration of treatment of twelve weeks (six weeks for each drug). This corresponds to a minimum chlorpromazine dose equivalent of 600 mg per day.

Ascertainment of sufficient treatment adherence defined as patients having taken at least 80% of the prescribed doses. To this end, at least two of the following methods need to be employed: counting pills, patient and caregiver report, and chart and record reviews. In addition, blood plasma drug levels should be monitored at least once for each antipsychotic.

In addition to these minimal TRS criteria (Figure 1), which are most relevant for clinical practice, optimal criteria have been proposed, which are geared more toward use in clinical trials.²⁵

Figure 1.

Treatment-resistant schizophrenia.

The neurobiology of treatment resistance

Importantly, in 70–80% of cases, treatment resistance emerges already during the first psychotic episode, highlighting the need for an early detection of this condition.^5,6,30,31 Several risk factors for the development of TRS have been identified. These include male sex, living in a less urban area, younger age, family history of psychosis, a high load of schizophrenia risk genes, longer duration of untreated psychosis, substance abuse, and a higher number of relapses due to non-adherence.^4,32–34 Obstetric complications, lower premorbid social adjustment, a history of suicide attempts, extended hospitalization, impaired illness insight, and comorbid personality disorders have also been associated with an increased risk for TRS.^32,34–36

The exact neurobiological underpinnings of TRS remain elusive. Some authors distinguish between primary and secondary TRS.^7,37–40 While primary TRS is present at illness onset, secondary TRS manifests during later stages of the disorder after an initially sufficient response to antipsychotic treatment.^7,39,40 Dopaminergic supersensitivity has been discussed as one likely cause of secondary TRS.^7,41 Upregulation of striatal postsynaptic dopamine D2 receptors in response to antipsychotic treatment can lead to psychotic exacerbation despite continuous treatment. Consecutive dose increases of antipsychotics can induce further receptor upregulation inducing dopaminergic supersensitivity. In general, serotonin dysregulation and inflammation as well oxidative stress have been proposed to be involved in the pathophysiology of TRS.⁷ There is also converging evidence that abnormalities in glutamatergic neurotransmission might contribute to the emergence of treatment resistance,⁴¹ which would also be compatible with the existence of a normodopaminergic subtype of schizophrenia.^7,37,38 A higher genetic load for schizophrenia also appears to increase the risk for TRS.^7,33,42,43

Clinical effects of clozapine

Unequivocal evidence supports the superior efficacy of clozapine for the reduction of positive symptoms and global psychopathology in TRS compared with other antipsychotics.^8,12,44–46 Patients treated with clozapine also show improved treatment adherence¹¹ and reduced rehospitalization rates.^47–52 It is crucial to emphasize that there is no evidence for a comparable efficacy of antipsychotic polypharmacy, that is, the combination of two non-clozapine antipsychotics.¹⁶ Therefore, offering clozapine should always take precedence when treating patients with TRS.

Importantly, the beneficial effects of clozapine go far beyond positive symptoms. Clozapine is among the most effective antipsychotics for improving negative symptoms.^14,46,53 It also shows a similar level of efficacy against depressive symptoms,¹⁴ which constitute a common, independent risk factor for suicidality in schizophrenia.⁵⁴ Accordingly, clozapine leads to a stronger reduction of both suicidal behavior^55–57 and suicide mortality compared with other antipsychotics.¹⁵ Some guidelines therefore explicitly recommend clozapine for persistent suicidality independent of treatment resistance.^16–20 Compared with other antipsychotics, clozapine also shows superior efficacy in reducing aggressive and violent behavior.^58–62 Furthermore, clozapine lowers the risk of developing a substance use disorder (SUD),⁵² and also reduces relapse rates in patients with a comorbid SUD.^52,63

Response rates to antipsychotic treatment in drug-naïve patients are estimated at 75%.^64,65 Conversely, response rates to a second trial with a standard antipsychotics are considerably lower, ranging between 20% and 45%.^64,65 Estimates for overall response rates range between 40% and 60%.^66,67 Clinical efficacy of clozapine depends crucially on early treatment initiation.^66,68–70 Response rates for treatment initiation within the first 2–3 years after establishing treatment resistance can reach up to 80%.^64,66,71 For later treatment initiation, response rates can be as low as 30%.⁶⁶ Combined with the clear evidence for a predominantly early onset of treatment resistance, these findings underscore the vital importance of offering and starting clozapine early.

Pharmacodynamics

Clozapine is an antagonist at all dopamine-receptor subtypes (D1–D5).⁷² Among them, the antipsychotic effects of clozapine appear to be primarily mediated via D2 receptor antagonism.⁷³ In this regard, clozapine mirrors other antipsychotics, but its superior efficacy for positive symptoms appears to be the result of additional pharmacological properties. Even after decades of clinical use, the neurobiological mechanisms underlying the broad superior clinical efficacy of clozapine remain elusive. Currently, effects in the glutamatergic^74–77 as well as the GABAergic system are discussed as likely explanations.^78–80 The pleiotropic effects of clozapine, however, also encompass neurobiological systems not directly related to neurotransmission,^{37,75,81–83} but their relevance remains unclear.

By comparison, the properties underlying clozapine’s side-effect profile are relatively well established. The nearly complete absence of extrapyramidal symptoms is most likely attributable to rapid dissociation of clozapine from striatal D2-receptors.⁸⁴ Antagonism at serotonergic 5HT2C- and 5HT2A-receptors^85,86 and at histaminergic H1-receptors is implicated in clozapine-associated weight gain.⁸⁵ Antagonism at H1-histaminergic receptors^87,88 as well as agonism at gamma-aminobutyric acid (GABA) B receptors have been implicated in sedation.⁸⁰ Serotonergic antagonism appears to be involved in clozapine-associated obsessive compulsive symptoms.^89,90 Clozapine’s unique muscarinic profile is responsible for several highly relevant side effects. Agonistic effects at M4-receptors are the primary cause of hypersalivation. Conversely, antagonism at M2-receptors is implicated in clozapine-induced gastrointestinal hypomotility (CIGH). Anticholinergic mechanisms might also worsen symptoms associated with cognitive decline, cause delirium, and urinary retention.⁹¹ In addition, clozapine’s antagonistic properties at adrenergic receptors have been linked to nocturnal enuresis, hypotension, and hypersalivation.^92,93

Pharmacokinetics and interactions

Clozapine’s half-life is approximately 14 h.^94,95 Its metabolism is influenced by several factors including hormones like estrogens, concurrent medication, smoking,⁹⁶ sex, with higher blood plasma levels in females,^97,98 and age.^96,99–102 Ethnicity can also have an effect, with people of Asian descent generally reaching sufficient clozapine plasma levels at lower doses than Caucasians.¹⁰⁰

The following cytochrome P450 (CYP)-enzymes are mainly involved in clozapine metabolism: CYP1A2 (30%), CYP2C19 (24%), CYP3A4 (22%), CYP2C9 (12%), and CYP2D6 (6%).¹⁰³ Among them, CYP1A2 induction or inhibition can lead to clinically relevant changes in plasma clozapine levels.^94,95 Inhibitors include caffeine,¹⁰⁴ and C-reactive protein (CRP),^105–107 which can be triggered by infections. This is underscored by recent reports of toxic plasma clozapine levels during SARS-CoV-2 infections.^108,109 Oral contraceptives containing estrogens also inhibit CYP1A2 and CYP2C19 enzyme activity leading to clinically relevant plasma level increases.^110,111 Polycyclic aromatic hydrocarbons (PAHs) contained in cigarette smoke are the most relevant CYP1A2 inducers.^112,113 Importantly, after abrupt smoking cessation, enzyme activity typically normalizes within three days,¹¹² which can lead to toxic plasma clozapine levels.^113–121 Notably, nicotine patches and e-cigarettes are not associated with a comparable interaction risk.^28,122–125

Optimal plasma clozapine levels for the treatment of TRS fall in the range of 350–600 µg/L.^126,127 Plasma clozapine levels above 600 µg/L increase the risk for side-effects considerably.¹²⁸ Plasma clozapine levels above 1000 µg/L are considered toxic, are associated with an at least two-fold increase in mortality risk,¹²⁹ and require immediate dose reduction and intensified pharmacovigilance. Plasma clozapine levels above 2000 µg/L are acutely life-threatening.^130,131 Notably, clozapine intoxication is associated with a delayed plasma peak due to clozapine’s extensive enterohepatic circulation and its induction of gastrointestinal hypomotility.¹³² In general, international guidelines strongly recommend regular monitoring of plasma clozapine levels to increase both patient safety and response rates.^28,29

In rare cases, rapid metabolism of clozapine due to yet unknown causes may preclude reaching sufficient plasma clozapine levels.^133–135 Here, augmentation with low doses of fluvoxamine, a strong CYP1A2 inhibitor, should be considered.^136–138 A total of 25–50 mg of fluvoxamine can raise plasma clozapine levels five- to ten-fold within 2–4 weeks^139–141 and also triple clozapine’s half-life.¹⁴² Consequently, frequent screening for side effects and therapeutic drug monitoring are crucial during augmentation with fluvoxamine.^28,29

In summary, there are several relevant pharmacokinetic and pharmacodynamic interactions clinicians need to be aware of (Tables 1 and 2). When addressing such interactions, switching to safer alternatives for interacting drugs wherever possible should be the primary strategy. Discontinuation of clozapine should only be considered as a last resort.

Table 1.

Pharmacokinetic interactions.

CYP inducers	CYP inhibitors
Omeprazole¹⁴³	Selective serotonin re-uptake inhibitors (SSRIs; e.g. fluvoxamine und fluoxetine; sertraline in high doses)^104,143
Carbamazepine^128,144	Quinolone antibiotics (e.g. ciprofloxacin)^104,143
St. John’s wort¹²⁸	Macrolide antibiotics (e.g. erythromycin)¹⁴³
PAH¹⁴³	Caffeine¹⁰⁴
	Ethinyl estradiol^104,143
	Propranolol¹⁴⁵

CYP, cytochrome P450; PAH, polycyclic aromatic hydrocarbon.

Table 2.

Pharmacodynamic interactions.

Side-effects	Most relevant medications
Hypotension	Tricyclic antidepressants (TCA), antihypertensive medication (e.g. propranolol, ACE inhibitor)^73,146
Sedation	Benzodiazepines⁷³
Anticholinergic gastrointestinal side-effects	TCA, anticholinergic drugs^73,92,147
Other anticholinergic side-effects (e.g. delirium)	TCA, anticholinergic drugs, opioids, antihistaminergic drugs^73,92,94,147
Hematological side-effects	Carbamazepine, metamizole, TCA, mirtazapine, bupropion, valproate, carbimazole, cytostatic drugs, chloramphenicol, sulfonamide, co-trimoxazole^{73,94,148–150}
Reduction of seizure threshold	Bupropion, lithium, TCA^{73,94,151–153}
QT prolongation	Macrolide antibiotics (e.g. erythromycine), quinolone antibiotics (e.g. moxifloxacin), TCA^73,154–156
Myocarditis	Valproate^94,157–159

ACE, angiotensin-converting enzyme.

Clozapine metabolites

Clozapine is mainly demethylated to n-desmethylclozapine (norclozapine) and oxidized to clozapine-n-oxide.⁹⁵ In contrast to clozapine-n-oxide, norclozapine is pharmacologically active. Compared with clozapine, norclozapine shows diverging effects on dopaminergic and muscarinic receptors^98,160 and also affects serotonergic receptors among others.^161–164 While it has no antipsychotic properties, norclozapine appears to contribute to the overall side-effect burden including sedation, hypersalivation, constipation, metabolic complications, and seizures.¹⁶³

Recently, the clozapine:norclozapine ratio has received growing attention.^98,136,165 Based on clinical observations, the optimal clozapine: norclozapine ratio is deemed to be around two. Higher values are indicative of a non-trough blood sample, a recently missed dose, or decreased CYP1A2 enzyme activity. Lower values appear to be indicative of increased CYP1A2 enzyme activity.^136,165,166 Other authors, however, recommend using the total clozapine C/D ratio, with C representing the sum of the clozapine and norclozapine trough steady-state plasma concentration and D representing the daily dose of clozapine.⁹⁸

Side effects of clozapine

Owing to the relatively high side-effect burden associated with clozapine (Figure 2 and Table 3), extensive pharmacovigilance as well as early and consistent management of side-effects are of particular importance.¹⁶⁷ Frequent consultation of both patients and their families is an important element of this strategy.¹⁰¹ In addition to clozapine’s broad antagonistic and agonistic effects on key neurotransmitter systems outlined above, immunomodulatory effects, which might partly explain clozapine’s unique efficacy, have also been implicated in adverse drug reactions (ADRs) including eosinophilia, myocarditis, pancreatitis, and nephritis.¹⁶⁷ Side-effect risk decreases with slower initial dose titration regimes.¹⁰¹ This is particularly important in light of evidence for an association between rapid initial dose escalation and risk for both myocarditis and neutropenia.⁹² Owing to the clear dose dependency of some side effects (Table 3), dose reductions should be attempted first whenever feasible before considering other options.¹⁰¹

Figure 2.

Clozapine-associated side effects.

Table 3.

Management of clozapine-associated side effects.

Side-effect	Monitoring and diagnostics	Prevention and management
Metabolic syndrome* (obesity, hypertension, dyslipidemia, diabetes)^168–170	• Baseline-screening: weight/BMI, lipid profile, HbA1c ○ BMI/weight: monthly 1st/2nd/3rd/6th month, then yearly^171–173 ○ Lipid profile: quarterly^174,175 ○ Diabetes screening: quarterly⁹⁴	Non-pharmacological treatment:• Lifestyle changes, psychotherapy^176,177 Pharmacological treatment:• Obesity/weight gain: as early as possible; mandatory in cases of weight gain of ⩾7% and in cases with BMI ⩾25: ○ Metformin^{13,16,178,179} - contraindication for metformin: eGFR of <30 ml/min - frequent monitoring of vitamin B₁₂ level¹⁷⁷ ○ Alternative options: GLP1-receptor agonists,¹⁸⁰ topiramate^181–184 • Hypertension: antihypertensive drugs^176,185,186 • Dyslipidemia: statins¹⁷⁶
Hypersalivation (increases risk for pneumonia)^187–191	• Regular clinical assessment using standardized rating scales, for example, the Drooling severity scale or Nocturnal Hypersalivation Rating Scale^192,193	• Sugar free chewing gum during the day to promote saliva swallowing; elevation of upper body during the night¹⁹³ • Pirenzepine (25–100 mg/d); Cave: anticholinergic load^16,94,191 • Alternative options: atropine drops s.l., ipratropium bromide s.l.¹⁹¹ • Botulinumtoxin injection (incobotulinum toxin A) into the parotid and submandibular glands^{16,189,194–198}
Sinus tachycardia^199,200	• Regular clinical assessment including ECG¹²⁶ • Diagnostics: 12 channel ECG, 24-h Holter monitoring; consider stress ECG, TTE, laboratory tests according to established guidelines^201,202	• Treatment with ivabradine (no depressogenic effects reported) or cardio-selective beta blockers (Cave: hypotension, bronchospasm, depressogenic)^{16,94,199,203,204}
Constipation, CIGH*^205,206	• Regular clinical assessment^94,101,167	• Physical activity, sufficient fluid intake, fiber-rich diet^{16,94,207,208} • Discontinue non-essential drugs that increase anticholinergic load^209,210 • Treatment with laxatives^207,208,211
Hematological side-effects^212,213	• Complete differential blood count: at baseline, once weekly (1st–18th week), then monthly; in case of discontinuation continue monitoring for 4 weeks^73,94,214 • Leukopenia (white blood cells [WBCs] <4/nl) versus CIN (ANC <1.5/nl) versus CIA (ANC <0.5/nl)^73,214–216 ○ In cases of WBC 3–3.5/nl and ANC 1.5–2/nl: Monitoring twice per week^94,217–221 • Eosinophilia >3/nl: search for CIM, pancreatitis, DRESS syndrome, CIA• BEN: does not constitute a contraindication; consider expanding monitoring^221–225 • Most hematological changes are only transient²²⁶	• Confirmed CIA (ANC <0.5/nl): discontinue clozapine, infection prevention, consider administration of G-CSF/GM-CSF^16,217–221• Thrombocytopenia <50/nl: discontinue clozapine temporarily^227,228 • Eosinophilia >3/nl: discontinue clozapine temporarily; do not restart clozapine unless eosinophil count <1/nl^{73,94,217,229–233}
Sedation*^88,190,234	• Regular clinical assessment• Most commonly transient in nature^88,190,234	• Titration to lowest effective dose^16,190,234 • Minimize daytime doses^190,234 • Avoid concomitant sedating drugs^94,190,234
Myocarditis, cardiomyopathy^235,236	• Highest risk during the first 4 weeks of treatment• Risk factors: rapid dose titration (>25 mg/d), higher age, concomitant valproate²³⁷ • Mandatory clinical, electrophysiological, and laboratory monitoring at baseline and during the first 8 weeks of treatment: heart rate; ECG; TTE (if available); CRP, troponin, CK, BNP, full blood count^94,238,239 • Clinical signs: cardiac symptoms/gastrointestinal and urogenital disturbances including non-specific flu-like symptoms, dyspnea, diarrhea, fever; increased heart rate by ⩾20–30/min, signs of reduced left ventricular function^94,239 • Cardiac monitoring signs: unspecific changes in ECG; TTE: changes in pericardial effusion, cardiac wall motion abnormalities²⁴⁰ • Laboratory signs: CRP, troponin, CK, BNP: ↑, eosinophilia (delayed)^94,239,241	• Mandatory discontinuation of clozapine in case of CRP level increases of more than 10× upper limit normal (ULN) or troponin level increases of more than 2× ULN^{212,235,236,242} • Cardioprotective treatment: ACE-inhibitors and beta blockers²⁴³ • In severe cases, transfer to intensive care unit^94,244 • Symptoms improve within 5 days of treatment termination; most common course: restitutio ad integrum,^94,242 cardiomyopathy is a potential complication
QT prolongation*^{141,154–156}	• Frequent ECGs: weekly for the 1st month, afterwards at least quarterly^{94,141,154–156,245} • Use corrected QT-time with appropriate formula (e.g. Fridericia)¹⁴¹	• Avoid concomitant drugs causing QT prolongation whenever possible^141,246 • Slow dose titration^141,246 • Avoid hypokalemia and hypomagnesemia^245,247 • Consider oral supplementation of magnesium¹⁴¹ • Search for signs of CIM¹⁴¹
Seizures*^{163,248–250}	• EEG: at baseline, after 3 months, afterwards every 6 months⁹⁴ • Risk factors: higher doses, rapid dose titration, history of seizures or head trauma, concomitant medication or compounds resulting in pharmacodynamic or pharmacokinetic changes (e.g. lithium, smoking cessation), physical illness (e.g. hyponatremia), substance abuse^{73,94,104,162,249} • Pre-existing and sufficiently medically controlled epilepsy does not constitute a contraindication^94,250	• Consider clozapine dose reduction by about 50%• Combine with anticonvulsant medication: lacosamide (Cave: neutropenia), gabapentine, lamotrigine;^{94,151,249–251} avoid valproate (risk factor for CIM)
Obsessive compulsive symptoms^252,253	• Regular clinical assessment• Largely independent of dose and treatment duration⁸⁹	• Clozapine dose reduction• CBT, SSRI, consider combination with aripiprazole^89,94
Akathisia*^94,254–256	• Regular clinical assessment• Cave: can be present without overt motor signs²⁵⁷	• Dose reduction^92,258,259 • Propranolol (30–120 mg) – Cave: drug–drug interaction via CYP450-enzymes^145,255,260 • Mirtazapine (7.5–15 mg)^255,260
Pneumonia²⁶¹	• Risk factor: hypersalivation, sedation, older age, male sex, concomitant medication (e.g. via promoting sedation)^261–263	• Prevention: early treatment of hypersalivation^153,264,265 • In case of pneumonia: adjust clozapine dose, increase frequency of monitoring and consider increased risk for interactions associated with CYP450 enzymes (e.g. CRP, antibiotics)^94,266 • Ensure sufficient respiratory disease vaccination status (influenza and SARS-CoV2)
Other clinically relevant side effects: hepatitis, nephritis, pancreatitis,^267,268 delirium*, enuresis, NMS,^{93,94,167,269,270,271} DRESS syndrome,^230,272 venous thromboembolism,^212,273 diabetic ketoacidosis, hyperosmolar coma^212,274	• Clinical assessment, laboratory parameter²⁷⁵ • Cave: delirium associated with high clozapine doses and with abrupt clozapine discontinuation^275,276 • NMS: rare (clozapine is the drug of first choice after NMS)^269,271,277 • Pancreatitis: screen for signs of exocrine and endocrine pancreas insufficiency• DRESS syndrome: assess laboratory parameters frequently (especially eosinophils, lymphocytes);^230,272 risk factor: combination with lithium, anticonvulsants (including valproate)	• Enuresis: avoid late fluid intake, continence training, desmopressin^94,270,278 • Hepatitis, pancreatitis, nephritis: rare; discontinue clozapine, initiate specific treatment^94,268,279 • Delirium: pause clozapine,^73,275,280 treat delirium⁹⁴ • DRESS syndrome: discontinue clozapine; initiate symptomatic treatment (e.g. antipyretic, antihistaminergic, immunosuppression with steroid/intravenous immunoglobulins)^230,272

ACE, angiotensin-converting enzyme; ANC, absolute neutrophil count; BEN, benign ethnic neutropenia; BMI, body mass index; BNP, brain natriuretic peptide; CBT, cognitive behavioral therapy; CIA, clozapine-induced agranulocytosis; CIGH, clozapine-induced gastrointestinal hypomotility; CIM, clozapine-induced myocarditis; CIN, clozapine-induced neutropenia; CK, creatine kinase; CRP, C-reactive protein; CYP, cytochrome P450; DRESS, drug reaction with eosinophilia and systemic symptom; ECG, electrocardiography; EEG, electroencephalography; G-CSF, granulocyte colony-stimulating factor; GLP1, glucagon-like peptide-1; GM-CSF, granulocyte-macrophage colony-stimulating factor; NMS, neuroleptic malignant syndrome; SSRI, selective serotonin re-uptake inhibitor; TTE, transthoracic echocardiogram.

Dose-dependent side-effect.

Hematological side effects

Not least for historic reasons,²⁸¹ clozapine is closely associated with agranulocytosis and other, less serious forms of neutropenia. An absolute neutrophil count (ANC) of 1–1.5/nl is referred to as mild neutropenia while ANCs of 0.5–1.0/nl are referred to as moderate neutropenia. ANCs of <0.5/nl constitute severe neutropenia.²⁸² ANCs below 0.5/nl are also typically referred to as agranulocytosis.^215,283,284 However, strictly speaking agranulocytosis requires near absence of neutrophils, that is, ANCs below 0.1/nl.^283,285 The clinical syndrome of agranulocytosis is commonly associated with a triad of symptoms encompassing fever, mouth ulcers, and sore throat.²¹⁵ Pragmatically equivalating severe neutropenia and agranulocytosis is motivated by the substantial risk for opportunistic infections associated with ANCs below 0.5/nl,²¹⁵ which triggers several clinical actions discussed in detail below. For pragmatic purposes, we will therefore likewise refer to ANCs of 1.5–0.5/nl as clozapine-induced neutropenia (CIN) and to ANCs of <0.5/nl as clozapine-induced agranulocytosis (CIA).

Owing to an increased risk for CIN and CIA, frequent blood cell counts are mandatory throughout treatment.^212,281,286 This procedure has reduced risk of death from CIA to less than 1 in 10,000 patients.²³⁸ Risk for CIN and CIA is estimated to be 3% and 0.4–0.7%, respectively.^217,287 Although CIN or CIA can occur at any time during treatment,^288,289 the highest incidence rates have been observed during the first 6–18 weeks of treatment (49% cases of neutropenia, 82% cases of agranulocytosis) with a clear subsequent risk decrease after six months.^{73,213,217,287,290} This should be considered when a comorbid somatic disorder necessitates treatment with a drug also linked to blood dyscrasia. Whenever possible, treatment with such drugs should be initiated after the critical first six months.²¹³

Currently, safety thresholds for neutrophil counts during clozapine treatment vary slightly across health systems. Importantly, discontinuation should require clear evidence for a downward dynamic of the neutrophil count,^219,220,291 as cases of transient neutropenia under clozapine treatment have also been observed.²⁹² Moreover, an immediate thorough search for other causes of blood dyscrasia is essential, as this would have important implications for a potential re-challenge of clozapine.^217,218,287 Important causes include concomitant medication – including antibiotics^273,293 and psychotropic compounds like carbamazepine and valproate^294,295 – or viral infections.²⁹⁶

Confirmed CIN and CIA stipulate immediate discontinuation of clozapine. In addition, CIA requires the administration of granulocyte colony-stimulating factor (G-CSF). Moreover, further actions to prevent and treat infections, for example, administration of antibiotics and protective isolation, might be necessary.^297–299

In cases of mild neutropenia even before treatment onset, benign ethnic neutropenia (BEN) is an important differential diagnosis, which does not constitute a contraindication.^221–225 Safety thresholds for patients with a confirmed diagnosis of BEN are lower (Figure 3(a) and Table 3).³⁰⁰ Pseudo-neutropenia resulting from physiologically reduced neutrophil counts due to higher cortisol levels in the morning should also be considered.²¹⁷

Figure 3.

Screening and management of clozapine-induced neutropenia (CIN) and clozapine-induced myocarditis (CIM). (a) Color code categorization of CIN screening parameters and required action. Absolute neutrophil counts within the green range do not require any action except regular monitoring. ANCs within the yellow range require intensified full blood monitoring and searching for an alternative cause. ANCs within the red range necessitate immediate discontinuation of clozapine, daily monitoring of full blood count, and searching for an alternative cause. (b) Color code to categorization of CIM screening parameters and required action. Results within the green range do not require any action except regular monitoring. Results within the yellow range require intensified monitoring and searching for an alternative cause. Results within the red range necessitate immediate discontinuation of clozapine, daily monitoring, initiation of cardioprotective treatment, and searching for an alternative cause.

The pathophysiology of CIN and CIA remains poorly understood, but an autoimmune mechanism appears most likely. Eosinophilia is another important but rare hematological side effect. Importantly, eosinophilia does not warrant permanent discontinuation of clozapine.^212,301 Treatment can be restarted at eosinophil counts below 1/nl. Eosinophilia, however, should prompt a search for other clozapine-induced ADRs including CIA, clozapine-induced myocarditis (CIM), pancreatitis, and drug reaction with eosinophilia and systemic symptom (DRESS) syndrome.^227,302

Notably, a recent longitudinal study revealed an increased risk for hematological malignancies in patients receiving clozapine.³⁰³ This risk, however, is smaller than the reduction of all-cause mortality associated with clozapine. Moreover, mortality rates in clozapine users diagnosed with a hematological malignancy were lower compared with patients treated with nonclozapine antipsychotics.^303–305 Therefore, while these findings necessitate increased vigilance regarding signs of hematological malignancy in clozapine users, they do not undermine the general case for clozapine.^304,305

Cardiac side effects

CIM is among the most important and yet underdiagnosed side effects. CIM risk is the highest during the first 4 weeks after treatment initiation,^306,157 but also during re-exposure following a first successful trial.⁹⁴ Moreover, rare cases of CIM after long-term treatment of more than a decade have also been observed.^73,307,308 Compared with CIN and CIA, the incidence of CIM is noticeably higher.^157,309 The timely detection of CIM might be impeded by its often unspecific clinical presentation, which can include flu-like symptoms like fever, dyspnea, myalgia, and vague complaints of fatigue and malaise.^242,309,310 Patients might also experience symptoms reflecting cardiac involvement such as chest pain, hypotension, palpitation, tachycardia, and peripheral edema.^242,309,310 These more specific symptoms, however, are by no means mandatory. By contrast, there have been reports of cases solely presenting with gastrointestinal and urogenital disturbances like diarrhea, dysuria, and vomiting.^{241,242,310,311} Hence, frequent screening for clinical, electrophysiological, and laboratory signs of CIM is mandatory.^{94,147,167,241} Electrocardiographic (ECG) findings in CIM are characterized by non-specific alterations such as T-wave inversion and ST elevation or depression.^242,312 Transthoracic echocardiogram (TTE) might reveal left ventricular impairments and pericardial effusion, while cardiac magnetic resonance imaging (MRI) can provide more direct evidence for myocardial inflammation.^240,313 In addition, endomyocardial biopsy can be performed to rule out viral myocarditis.³¹⁴ Mandatory laboratory screening at baseline and during the first 8 weeks of treatment encompasses troponin, CRP, creatine kinase (CK), and brain natriuretic peptide (BNP)^{13,242,310,312,315} are highly sensitive markers for CIM.

Importantly, while monitoring of clinical symptoms is important to inform CIM diagnosis, confirmation of a suspected CIM should rely primarily on objective parameters, that is, laboratory parameters exceeding pre-specified thresholds (Figure 3(b) and Table 3), to prevent premature and unnecessary discontinuation but also to ensure patient safety in cases of unspecific clinical symptoms.³¹⁰ Clearly established CIM necessitates immediate termination of clozapine,^246,310 strict avoidance of major physical activity,²⁴⁴ and initiation of a cardioprotective pharmacotherapy with a beta-blocker and an angiotensin-converting enzyme (ACE) inhibitor.^{73,241,242,246,316} Serious cases of CIM might require treatment in an intensive care unit.^4,244,317 Severe outcomes of CIM – typically as a consequence of delayed or missed diagnosis and treatment³¹⁸ – include ventricular arrhythmia, persistent heart failure, and sudden death.^{158,244,246,312} Importantly, early intervention increases the chance for a restitutio ad integrum,²⁴² underscoring the relevance of CIM screening during the initial titration of clozapine.³¹⁸

Based on its early onset and titration speed dependency, a hypersensitivity reaction is discussed as a likely pathophysiological mechanism of CIM,^{235,244,246,319–323} but current evidence remains inconclusive.¹⁵⁷ Thus far, no reliable predictors for an individual’s CIM risk have been established. Several risk factors for CIM, however, have been identified,¹⁵⁷ chiefly among them concurrent treatment with valproate.^157,237,324 Consequently, valproate should not be prescribed concurrently with clozapine, neither for treatment of any residual psychopathology nor for seizures. There is also preclinical and clinical evidence that rapid titration increases the risk of CIM.^237,319,325 This suggests that people with slow clozapine metabolism might be at a higher risk for CIM. Higher age and higher clozapine doses also appear to constitute risk factors.^157,326

Cardiomyopathy constitutes another potential cardiac side effect with reported incidence rates ranging between 0.02% and 1%.^215,222 Importantly, undetected and self-limiting myocarditis has been implicated as a likely cause.^198,215,222 Hence, prevention and adequate management of CIM might also reduce the risk of clozapine-associated cardiomyopathy.

Gastrointestinal side effects

The most common gastrointestinal side-effect is constipation, which occurs in up to 60% of patients.^327–329 Furthermore, at least 50% of patients show unambiguous evidence of CIGH in colonic transit studies.³²⁷ Potentially severe consequences of CIGH include dysphagia, ileus, intestinal obstruction, bowel ischemia, and megacolon,^328,329 which are associated with a considerable mortality rate.³³⁰ Importantly, the prevalence of CIGH is markedly higher than the prevalence of CIM and CIA.^329,331 CIGH arises primarily due to the anticholinergic and antiserotonergic effects of clozapine¹⁷⁶ and shows a clear dose dependence.^167,327 Polypharmacy, which adds to clozapine’s inherent anticholinergic load or otherwise affects gastrointestinal motility, constitutes a risk factor for CIGH.^209,210 As a first step, prevention and management of CIGH requires lifestyle and dietary modifications, that is, physical exercise, sufficient fluid intake, and fiber supplementation. As a second-line approach, current guidelines recommend specific pharmacological treatment including laxatives (first line: osmotic laxatives, second line: stimulant laxatives), prosecretory agents, and serotonergic agonists.^207,208,211

Metabolic side effects

Irrespective of medication, patients with schizophrenia have an increased risk for developing a metabolic syndrome, encompassing hypertension, dyslipidemia, obesity, and diabetes.^168–170 For clozapine, the prevalence of metabolic syndrome is estimated to be approximately 50%.^332,333 Weight gain represents a crucial risk factor for developing metabolic syndrome³³⁴ and an important psychological stressor.^{177,335–337} Moreover, it reduces quality of life,³³⁵ treatment adherence,^337,338 and contributes to cognitive dysfunction.^339–341 Importantly, weight gain typically occurs during the early stages of antipsychotic treatment.^342,343 More than two-thirds of patients show a gain of more than 7% of their baseline weight during the first year of treatment.^177,344,345 This underscores the necessity of frequent monitoring of body weight and metabolic parameters and of early weight-stabilizing interventions (Table 4).^333,346 Regular physical exercise, a Mediterranean diet, and smoking cessation to decrease cardiovascular risk are the primary recommendations to counteract weight gain.^226,347 Among pharmacological interventions, adjunctive metformin shows a good safety profile and the best efficacy for stabilizing weight gain.^{177,178,348,349} Consequently, the first guideline for metformin use during antipsychotic treatment advocates a routine early initiation in addition to behavioral interventions to most effectively minimize weight gain and cardiometabolic risk.¹⁷⁷ On average, treatment with metformin leads to a weight loss of about 3.2 kg. As the feasibility of reversing weight gain remains limited, weight stabilization should be the primary goal. The recommended daily dose of metformin is 2000 mg when tolerable. Gastrointestinal issues such as nausea, diarrhea and vomiting as well as lactic acidosis are the most relevant side effects. Before and during treatment with metformin, renal function and vitamin B₁₂ level should be monitored routinely.

Table 4.

Management of clozapine-resistant schizophrenia.

Predominant persistent symptoms	Recommended augmentation strategies^350,351
Positive symptoms and combined positive and negative symptoms	• Intensify CBT and psychosocial interventions• ECT• Add-on treatment with amisulpride or aripiprazole
Negative symptoms	• Intensify CBT and psychosocial interventions• Add-on treatment with antidepressants (i.e. SSRI)• Add-on treatment with mood stabilizer (avoid valproate)• ECT
Suicidality	• Mood stabilizers (lithium or lamotrigine, avoid valproate)• Antidepressant• ECT
Aggressive behavior	• Add-on treatment with mood stabilizer or another antipsychotic drug

CBT, cognitive behavioral therapy; ECT, electroconvulsive therapy; SSRI, selective serotonin re-uptake inhibitor.

More recent findings indicate that glucagon-like peptide-1 (GLP1) receptor agonists could also be effective for mitigating clozapine-associated metabolic comorbidity.¹⁸⁰ Topiramate can also be considered as its efficacy appears to be comparable with metformin.^{181–184,352} Recently, samidorphan – an opioid receptor antagonist – was introduced as an adjunctive treatment for olanzapine-associated weight gain.^353,354 This might be also a promising approach for clozapine.

Treatment of manifest diabetes in patients treated with clozapine should closely follow current guidelines including the use of insulin when indicated.^355,356 Adequate antidiabetic treatment substantially reduces cardiovascular risk and the risk for ketoacidosis or hyperosmolar coma.²⁷⁴ Importantly, pre-existing diabetes mellitus in patients with TRS does not constitute a contraindication for clozapine treatment,³⁵⁷ but rather requires intensified antidiabetic treatment. This is underscored by converging findings indicating that, for clozapine, the risk for diabetes is not excessive compared with second-generation antipsychotics as a whole, but rather falls in the higher range within this class of drugs.^343,358 In conclusion, it needs to be emphasized that strict management of metabolic side effects can notably improve the associated cardiovascular risk factors³⁵⁹ and that overall clozapine treatment is actually associated with a relevant reduction of cardiovascular mortality.^15,46

Hypersalivation and pneumonia

Clozapine-induced hypersalivation (CIH) constitutes a frequent side-effect with incidence rates ranging between 30% and 92%, which typically occurs early during treatment and shows no clear dose dependence.^187,360 Agonism at muscarinic M4 receptors and antagonism at α2-adrenergic receptors have primarily been implicated in its etiology.^188,361,362 Predominantly, patients report nightly hypersalivation.¹⁸⁷ CIH can cause psychological distress due to embarrassment and social stigma, as well as lead to somatic adverse events like skin irritation, parotitis, and aspiration pneumonia.^73,194 Management of CIH commonly requires early pharmacological intervention, usually with anticholinergic, that is, antimuscarinic, drugs. Evidence for their efficacy remains limited, however. Moreover, systemically acting drugs such as pirenzepine increase the overall anticholinergic load, raising the risk for CIGH.^209,210,363 Sublingual administration of atropine eye drops^73,364,365 and regular botulinum toxin injections into the parotid and submandibular glands can avoid this problem.^195,366 Before recommending treatment with sublingual atropine eye drops, prescribers need to ensure that patients can adequately follow instructions regarding the finely dosed topical application to prevent accidental ingestion of relevant amounts of fluid. Importantly, CIH increases the risk of clozapine-associated pneumonia via salivary aspiration.³⁶⁷ In this context, it is crucial to acknowledge the higher mortality rates of patients with schizophrenia due to pneumonia and increased rates for additional pulmonary diseases including chronic obstructive pulmonary disease.³⁶⁸ Importantly, pneumonia elevates CRP levels, thus decreasing CYP1A2 enzyme activity and increasing plasma clozapine levels.^{105,369–372} This underscores the necessity for preventive measures for clozapine-associated pneumonia. Furthermore, health care professionals should ensure a sufficient vaccination status of their patients for respiratory diseases including COVID-19 and influenza in order to reduce mortality rates.^368,373

Sedation

Clozapine-induced sedation (CIS) ranks among the most commonly reported side-effects.^{189,374–376} It shows a clear dose dependence, but is often at least partly transient.^{88,190,234,377} Importantly, while there are established protocols regarding other important side-effects, data regarding the management of CIS remain limited, despite the relevance of CIS as a key determinant of treatment adherence.^{80,87,88,189,234} Management of CIS should start with patient education about its potentially transient nature¹⁹⁰ and about healthy habits regarding sleep hygiene.¹⁹⁰ It also includes minimizing daytime clozapine administration, avoiding concomitant sedating drugs and clozapine dose reduction whenever possible.^190,234,378 Importantly, recent findings indicate that clozapine administration partly during daytime may not reduce the burden of sedation.³⁷⁹ Emphasizing nocturnal administration whenever possible while taking into account individual preferences appears to be more promising also given that complex dosing instructions might be too demanding for some patients.³⁷⁹ Adding aripiprazole constitutes another option.^88,378 Augmentation with modafinil has also been discussed, but findings from a placebo-controlled pilot trial were not generally supportive.^73,380 Furthermore, there are reports indicating a pharmacokinetic interaction between clozapine and modafinil, which could lead to a considerable increase of clozapine plasma levels.³⁸¹

Discontinuation and re-challenge of clozapine

Managing discontinuation

Approximately 30–40% of patients discontinue clozapine over the course of treatment,³⁸² mainly because of side effects, non-compliance to monitoring protocols or patient preference.^234,383 Both immediate and gradual clozapine termination can result in withdrawal symptoms, especially cholinergic and serotonergic discontinuation syndrome.^{276,384–387}

Cholinergic rebound symptoms observed in up to 50% of cases include agitation, delirium, and hallucinations,³⁸⁶ vomiting, diarrhea, headache, diaphoresis, dystonia, and dyskinesia.^384,385,388 Clinical management includes supportive care and treatment with anticholinergic compounds.³⁸⁶ Serotonergic rebound symptoms comprise agitation, diaphoresis, clonus, and hyperreflexia. In addition to supportive care, termination of concomitant serotonergic medication might be indicated as well as short-term use of cyproheptadine for moderate and severe cases.³⁸⁵ Current evidence supports olanzapine as well as risperidone and long-acting aripiprazole as the best alternative options,^389,390 but without matching the efficacy of a clozapine re-challenge.^391–393

Hence, discontinuation of clozapine often leads to a considerable worsening of psychopathology with potentially severe short- and long-term clinical and functional consequences.^{217,389,390,394–396} While withdrawal symptoms also contribute to this deterioration, supersensitivity mechanisms^397–401 and a lack of sufficiently effective alternative antipsychotics are regarded as the main causes.³⁸⁴ Catatonia and persistent psychotic exacerbation are the most common sequelae.^386,397,402 Here, benzodiazepines and electroconvulsive therapy (ECT) constitute crucial treatment options.^402–404 There is no evidence for a sufficient medium- and long-term efficacy of ECT without clozapine in most patients with TRS, however.^395,405

Based on these findings, current guidelines strongly recommend a hyperbolic discontinuation regime, if discontinuation is inevitable.^217,385,406 Immediate termination of clozapine should be limited to potentially life-threatening side effects including agranulocytosis, myocarditis, ileus or subileus, neuroleptic malignant syndrome (NMS), venous thromboembolism, and diabetic ketoacidosis or hyperosmolar coma.²¹⁷ Most importantly, because of the complications outlined above and its superior efficacy, permanent discontinuation of clozapine should be avoided whenever possible.^217,221

Rather, the singular status of clozapine underscores the importance to seriously consider a re-challenge even after severe side-effects. This notion is supported by a growing body of evidence for a positive risk–benefit ratio and considerable success rates for clozapine re-challenges after neutropenia,^217,395 NMS,⁴⁰⁷ and to a lesser extent myocarditis.^224,408,409 Any re-challenge must only be attempted in an appropriate hospital setting with sufficient support by relevant specialists, that is, cardiologists or hematologists.^224,410

Re-challenge after neutropenia

Current evidence clearly argues against a re-challenge after CIA.^269,407 After CIN, a re-challenge based on a strict risk–benefit assessment is considered to be a reasonable clinical option.⁴⁰⁷ Importantly, time of onset of CIN during a re-challenge is typically shorter.⁴¹¹ In general, a slower re-titration rate of clozapine might reduce risk of re-occurrence of CIN.²²¹ Based on published cases, the success rate is estimated at about 66%.⁴⁰⁷ Current evidence indicates that concomitant treatment with lithium markedly increases success rates.^269,412,413 Plasma lithium levels above 0.4 mmol/L have consistently been associated with increased neutrophil counts, most likely due to bone marrow induction.^{269,414–416} Lithium treatment should be initiated at least two weeks prior to a clozapine re-challenge and maintained long-term,²¹⁷ because its discontinuation increases the risk for a re-occurrence of blood dyscrasia.⁴¹² While it is overall considered to be safe, concomitant treatment with clozapine and lithium can markedly decrease the seizure threshold.^151,417,418

Treatment with G-CSF is an alternative approach, which increases re-challenge success rates.^{287,291,419,420} To this end, G-CSF can be administered on a regular prophylactic basis during a re-challenge irrespective of current absolute neutrophil count (ANC).⁴²¹ Alternatively, G-CSF can be administered on an as-required basis in the event of predefined neutrophil counts to maintain clozapine treatment. Current evidence indicates that both approaches are safe and effective.⁴²¹ Importantly, currently available evidence indicates that long-term use of G-CSF is not associated with significant morbidity in other patient populations.⁴²² Therefore, such a strategy has been proposed for patients in which discontinuation of G-CSF results in recurrent neutropenia.⁴²¹ Long-term safety and efficacy data are currently lacking, however.^{419,421,423–426}

To summarize, lithium can be suitable for persistent forms of mild neutropenia, while more severe forms of neutropenia require the use of G-CSF.

Re-challenge after myocarditis

At present, there are no established consensus guidelines for re-challenges after CIM, but rather protocols based on case series.^{243,309,315,407,410,427–431} Importantly, a re-challenge should only be attempted after patients have made a full recovery from CIM.⁴²⁷ It requires intensive clinical, laboratory and electrophysiological (ECG, TTE) monitoring (e.g. every second to third day) and very slow dose titration (e.g. 12.5–25 mg per week),^{243,408–410,427,432} which reduces CIM recidivism risk.^315,427 Re-challenge success rates after CIM are currently estimated at approximately 60%,⁴³¹ but with a high degree of uncertainty. Notably, compared with re-challenges after CIN, the number of published cases is an order of a magnitude lower.⁴⁰⁷ Therefore, re-challenges after CIM must not be regarded as a routine procedure and warrant exceptional caution.

Pregnancy and breastfeeding

A switch from a non-clozapine antipsychotic to clozapine might increase fertility as a result of alleviated hyperprolactinemia and amenorrhea.⁷³ Currently, there is no evidence for a reduced safety of clozapine for pregnant women.⁴³³ Several side-effects, however, may be exacerbated including weight gain, constipation, sedation, and orthostatic hypotension.⁴³⁴ Close monitoring for emerging gestational diabetes is therefore mandatory.^435,436 Notably, CYP1A2 enzyme activity decreases by approximately 33% during the first trimester and by approximately 65% during the last trimester.⁴³⁷ This necessitates monthly monitoring of plasma clozapine levels throughout pregnancy, repeated a week after delivery.⁷³

To date, there is no conclusive evidence for detrimental neurodevelopmental and cognitive long-term effects resulting from fetal exposure to clozapine.^{434,438–440} Clozapine is not associated with greater teratogenic effects than other antipsychotics.^440–442 Furthermore, there is no evidence for increased rates of prematurity, delivery complications, or changes in birth weight and height compared with other antipsychotics.⁴³⁴ Given its unique efficacy for TRS, for the majority of pregnant women receiving clozapine, switching to another antipsychotic is not a feasible option.^434,436 In most cases, the considerable risk for illness exacerbation associated with such a switch outweighs the risks associated with continued clozapine treatment during pregnancy.^436,439 Therefore, a thorough risk–benefit assessment is indispensable before any treatment change. Using the lowest effective dose of clozapine is especially crucial during pregnancy, however.^{73,433,434,436,438} Furthermore, frequent gynecological consultations and antenatal screenings should be encouraged and supported.^{73,433,434,436,438}

The level of clozapine excretion into breast milk is considerable.^436,438 Owing to insufficient short- and long-term safety data, breastfeeding during clozapine treatment should therefore be avoided.⁴³⁴

Clozapine treatment in the elderly

There are a number of changes in the pharmacokinetics and pharmacodynamics of clozapine in elderly patients, which warrant particular caution including lower maintenance doses.^73,443,444 Rates of CIA, CIMs, seizures, and metabolic syndrome increase in older patients.^445–447 The anticholinergic properties of clozapine may increase the risk for cognitive decline.⁹¹ Overall, clozapine appears to be both safe and effective in the majority of elderly people when adhering to very low dose titrations and providing increased pharmacovigilance.⁴⁴³

Management of clozapine-resistant schizophrenia

The markedly delayed onset of its full therapeutic effect is a unique characteristic of clozapine, which appears to be only partly attributable to the necessarily slow initial dose titration.^79,448 Consequently, the current TRRIP consensus guidelines strongly recommend deferring treatment evaluation in accordance with the main target symptoms while also ensuring a plasma clozapine level above 350 µg/L (Table 4).³⁵⁰ For predominant positive and mixed (both negative and positive symptoms) symptoms, treatment evaluation after three months is considered to be adequate.³⁵⁰ For negative and cognitive symptoms, an evaluation after four months is recommended, while eight weeks are deemed appropriate for aggression and suicidality.³⁵⁰

About 40% of patients show an insufficient response to clozapine despite clozapine plasma levels within the recommended range.^25,67,350 These cases are classified as ultra-treatment-resistant or clozapine-resistant schizophrenia (CRS).²⁵ A high genetic load for schizophrenia appears to increase the risk for a poor treatment response.^33,449 Compared with TRS, CRS is characterized by later clozapine initiation and associated with higher mortality rates.^127,350 Importantly, clozapine should not be discontinued in patients with CRS, but rather augmented (Table 3).^127,350 For predominant positive symptoms, recommended augmentation strategies include a combination with amisulpride or aripiprazole as well as ECT.^350,351 Furthermore, while there is no evidence for clinically meaningful symptom improvements produced by cognitive behavioral therapy (CBT) in CRS, pragmatic individual trials might still be indicated.⁴⁵⁰

Impact on mortality

Despite its side-effect burden and its detrimental influence on metabolic parameters in particular, clozapine reduces not only suicide mortality but also all-cause mortality to a greater degree than any other oral antipsychotic. Its positive effects on cardiovascular mortality – while less pronounced – are nonetheless comparable with other antipsychotics.^15,46,451 Clozapine’s mortality reducing effects are likely attributable to its superior efficacy regarding positive symptoms and suicidality, to improved treatment adherence and relapse rates,⁴⁶ as well as to mitigating the increased mortality risk associated with comorbid SUDs.⁴⁵² Consequently, the likelihood of an adequate diagnosis and treatment of somatic comorbidities should also increase.⁴⁵³ This might also be facilitated partly by the stricter pharmacovigilance regime required for clozapine. In light of the high rates of somatic comorbidities and the considerable overall increased mortality rates in people with schizophrenia,^454,455 these findings constitute another crucial argument in favor of a broader use of clozapine while also underscoring its safety.⁴⁵⁶

Clinical implications

The singular extent of clozapine’s efficacy outlined above has important clinical implications for the treatment of schizophrenia. First and foremost, existing clinical and neurobiological lines of evidence provide little to no reason to be reluctant regarding clozapine use. Consequently, clozapine must never be regarded as an antipsychotic of ‘last resort’ but rather the drug of choice for patients nonresponsive to first-line treatment and more generally for patients with an emerging unfavorable course of illness.⁴⁵⁷ In this regard, stringent use of TRS criteria and close adherence to current recommendations provide excellent guidance for clinical decision-making. The high rates of treatment resistance in first-episode patients underscore the need for early recognition and treatment of TRS.

Slow dose titration is essential to avoid titration-related side effects including sedation, myocarditis, and neutropenia. To this end, dose titration rates of 12.5 mg per day or less during the initial weeks of treatment should be seriously considered. Systematic pharmacovigilance and a timely management of ADRs are very feasible and also among the most important elements of a successful treatment strategy. Furthermore, clozapine might be essential when aiming to address substance abuse and sufficient treatment of somatic comorbidities. Even major pre-existing problems in these areas should not automatically be regarded as obstacles for offering clozapine.⁴⁵⁸ After clozapine initiation, clinicians should exhaust every reasonable option to minimize permanent all-cause discontinuation. This includes carefully re-challenging patients even after serious adverse events like myocarditis and neutropenia. Furthermore, treatment algorithms involving clozapine can and should be very simple. Clozapine use is key for reducing antipsychotic polypharmacy and the associated side-effect burden.⁴⁵⁹ Accordingly, clozapine should always first be used as an antipsychotic monotherapy in both TRS and non-TRS patients. For persistent positive symptoms despite adequate clozapine use, augmentation with an appropriate second antipsychotic should be the first treatment escalation (Table 4), before offering ECT as a second treatment escalation step. Finally, clozapine use requires a long-term approach acknowledging the late onset of clozapine’s full effects. In this context, clinicians also need to be mindful of the fact that some key benefits like reduced suicidality and mortality rates may be next to invisible.

Conclusion

Underutilization and delayed initiation of clozapine regardless of the continuously mounting evidence and contrary to all recommendations remain a major concern. This underscores the urgent need for intensified research into the real and perceived barriers for clozapine treatment, continued education of psychiatrists, and appropriate structural adjustments of routine clinical care. These efforts are justified not least by the very high patient satisfaction with clozapine despite the considerable complexity of its use and its potential side effects.^10,286,460 Most importantly however, they are imperative because – going into the sixth decade of its clinical use – compared with all other available pharmacological treatment options, the broad beneficial impact of clozapine on patients’ life remains second to none.

Footnotes

Acknowledgements

The authors thank Martina Hahn, Alkomiet Hasan, and G. Herzog for comments on an earlier version of this manuscript.

Declarations

ORCID iDs

Mishal Qubad

Robert A. Bittner

References

Simeone

Ward

Rotella

, et al. An evaluation of variation in published estimates of schizophrenia prevalence from 1990–2013: a systematic literature review. BMC Psychiatry 2015; 15: 193.

McGrath

Saha

Chant

, et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008; 30: 67–76.

World Health Organization. The world health report: 2001: mental health: new understanding, new hope. Geneva: World Health Organization, 2001.

Carbon

Correll

. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci 2014; 16: 505–524.

Kane

Agid

Baldwin

, et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry 2019; 80: 18com12123.

Meltzer

. Treatment-resistant schizophrenia – the role of clozapine. Curr Med Res Opin 1997; 14: 1–20.

Potkin

Kane

Correll

, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr 2020; 6: 1.

Kane

Honigfeld

Singer

, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796.

Leucht

Corves

Arbter

, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31–41.

10.

Lewis

Barnes

Davies

, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715–723.

11.

McEvoy

Lieberman

Stroup

, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163: 600–610.

12.

Siskind

McCartney

Goldschlager

, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2016; 209: 385–392.

13.

Correll

Agid

Crespo-Facorro

, et al. A guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia. CNS Drugs 2022; 36: 659–679.

14.

Huhn

Nikolakopoulou

Schneider-Thoma

, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394: 939–951.

15.

Taipale

Tanskanen

Mehtälä

, et al. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 2020; 19: 61–68.

16.

Leitliniengruppe DeVHfrd. S3-Leitlinie Schizophrenie. Langfassung. Version 1.0, 2019, https://register.awmf.org/de/leitlinien/detail/038-009

17.

Addington

Abidi

Garcia-Ortega

, et al. Canadian guidelines for the assessment and diagnosis of patients with schizophrenia spectrum and other psychotic disorders. Can J Psychiatry 2017; 62: 594–603.

18.

Buckley

. Treatment-resistant schizophrenia. Focus 2020; 18: 364–367.

19.

Hasan

Falkai

Wobrock

, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia part 3: update 2015 management of special circumstances: depression, suicidality, substance use disorders and pregnancy and lactation. World J Biol Psychiatry 2015; 16: 142–170.

20.

Remington

Addington

Honer

, et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry 2017; 62: 604–616.

21.

Bachmann

Aagaard

Bernardo

, et al. International trends in clozapine use: a study in 17 countries. Acta Psychiatr Scand 2017; 136: 37–51.

22.

Taylor

. Reply. Acta Psychiatrica Scand 2014; 130: 157–157.

23.

Verdoux

Quiles

Bachmann

, et al. Prescriber and institutional barriers and facilitators of clozapine use: a systematic review. Schizophr Res 2018; 201: 10–19.

24.

Nielsen

Dahm

Lublin

, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010; 24: 965–971.

25.

Howes

McCutcheon

Agid

, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry 2017; 174: 216–229.

26.

Howes

Thase

Pillinger

. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry 2021; 27: 58–72.

27.

McCutcheon

Beck

D’Ambrosio

, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018; 137: 39–46.

28.

Hiemke

Bergemann

Clement

, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018; 51: 9–62.

29.

Schoretsanitis

Kane

Correll

, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry 2020; 81: 19cs13169.

30.

Demjaha

Lappin

Stahl

, et al. Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med 2017; 47: 1981–1989.

31.

Lally

Ajnakina

Di Forti

, et al. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med 2016; 46: 3231–3240.

32.

Chan

SKW

Chan

HYV

Honer

, et al. Predictors of treatment-resistant and clozapine-resistant schizophrenia: a 12-year follow-up study of first-episode schizophrenia-spectrum disorders. Schizophr Bull 2021; 47: 485–494.

33.

Frank

Lang

Witt

, et al. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry 2015; 20: 150–151.

34.

Wimberley

Støvring

Sørensen

, et al. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry 2016; 3: 358–366.

35.

Costas-Carrera

Garcia-Rizo

Bitanihirwe

, et al. Obstetric complications and brain imaging in schizophrenia: a systematic review. Biol Psychiatry Cogn Neurosci Neuroimaging 2020; 5: 1077–1084.

36.

Elkis

Buckley

. Treatment-resistant schizophrenia. Psychiatr Clin North Am 2016; 39: 239–265.

37.

Solomon

DeLisi

. Clozapine pharmacogenomics: a review of efficacy, pharmacokinetics, and agranulocytosis. Curr Opin Psychiatry 2018; 31: 403–408.

38.

Mouchlianitis

McCutcheon

Howes

. Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. Lancet Psychiatry 2016; 3: 451–463.

39.

Correll

Howes

. Treatment-resistant schizophrenia: definition, predictors, and therapy options. J Clin Psychiatry 2021; 82: MY20096AH1C.

40.

Kinon

. The group of treatment resistant schizophrenias. Heterogeneity in treatment resistant schizophrenia (TRS). Front Psychiatry 2018; 9: 757.

41.

Wada

Noda

Iwata

, et al. Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Mol Psychiatry 2022; 27: 2950–2967.

42.

Fusar-Poli

Rutten

BPF

van Os

, et al. Polygenic risk scores for predicting outcomes and treatment response in psychiatry: hope or hype? Int Rev Psychiatry. Epub ahead of print 27 July 2022. DOI: 10.1080/09540261.2022.2101352.

43.

Gasse

Wimberley

Wang

, et al. Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia. Schizophr Res 2019; 212: 79–85.

44.

Chakos

Lieberman

Hoffman

, et al. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518–526.

45.

Mizuno

McCutcheon

Brugger

, et al. Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis. Neuropsychopharmacology 2020; 45: 622–631.

46.

Wagner

Siafis

Fernando

, et al. Efficacy and safety of clozapine in psychotic disorders-a systematic quantitative meta-review. Transl Psychiatry 2021; 11: 487.

47.

Reid

Mason

. Psychiatric hospital utilization in patients treated with clozapine for up to 4.5 years in a state mental health care system. J Clin Psychiatry 1998; 59: 189–194.

48.

Stroup

Gerhard

Crystal

, et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry 2016; 173: 166–173.

49.

Tiihonen

Haukka

Taylor

, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011; 168: 603–609.

50.

Tiihonen

Mittendorfer-Rutz

Majak

, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry 2017; 74: 686–693.

51.

Tiihonen

Wahlbeck

Lönnqvist

, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333: 224.

52.

Lähteenvuo

Luykx

Taipale

, et al. Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts. Br J Psychiatry 2022; 221: 758–765.

53.

Stępnicki

Kondej

Kaczor

. Current concepts and treatments of schizophrenia. Molecules 2018; 23: 2087.

54.

Siris

. Suicide and schizophrenia. J Psychopharmacol 2001; 15: 127–135.

55.

Meltzer

Alphs

Green

, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 82–91.

56.

Hennen

Baldessarini

. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res 2005; 73: 139–145.

57.

Meltzer

. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses 2012; 6: 134–144.

58.

Frogley

Taylor

Dickens

, et al. A systematic review of the evidence of clozapine’s anti-aggressive effects. Int J Neuropsychopharmacol 2012; 15: 1351–1371.

59.

Patchan

Vyas

Hackman

, et al. Clozapine in reducing aggression and violence in forensic populations. Psychiatr Q 2018; 89: 157–168.

60.

Buchanan

Kreyenbuhl

Kelly

, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36: 71–93.

61.

Citrome

Volavka

Czobor

, et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv 2001; 52: 1510–1514.

62.

Krakowski

Czobor

Citrome

, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2006; 63: 622–629.

63.

Brunette

Drake

Xie

, et al. Clozapine use and relapses of substance use disorder among patients with co-occurring schizophrenia and substance use disorders. Schizophr Bull 2006; 32: 637–643.

64.

Agid

Arenovich

Sajeev

, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72: 1439–1444.

65.

Kahn

Winter Van Rossum

Leucht

, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5: 797–807.

66.

Yoshimura

Yada

, et al. The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. Psychiatry Res 2017; 250: 65–70.

67.

Siskind

Kisely

. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry 2017; 62: 772–777.

68.

Jones

Upthegrove

Price

, et al. Duration of prior psychotic illness and clozapine response: a retrospective observational study using electronic health records. Ther Adv Psychopharmacol. Epub ahead of print 20 June 2022. DOI: 10.1177/20451253221103353.

69.

Shah

Iwata

Brown

, et al. Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study. Eur Arch Psychiatry Clin Neurosci 2020; 270: 11–22.

70.

Griffiths

Millgate

Egerton

, et al. Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis. Psychol Med 2021; 51: 376–386.

71.

John

EKF

Dominic

. Delayed initiation of clozapine continues to be a substantial clinical concern. Can J Psychiatry 2018; 63: 526–531.

72.

Meltzer

Bastani

Ramirez

, et al. Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatry Neurol Sci 1989; 238: 332–339.

73.

Bleakley

Taylor

. Clozapine handbook. Warwickshire: Lloyd-Reinhold Communications, 2013.

74.

Hribkova

Svoboda

Bartecku

, et al. Clozapine reverses dysfunction of glutamatergic neurons derived from clozapine-responsive schizophrenia patients. Front Cell Neurosci 2022; 16: 830757.

75.

McQueen

Sendt

K-V

Gillespie

, et al. Changes in brain glutamate on switching to clozapine in treatment-resistant schizophrenia. Schizophr Bull 2021; 47: 662–671.

76.

Moghaddam

Javitt

. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012; 37: 4–15.

77.

Tuominen

Tiihonen

Wahlbeck

. Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res 2005; 72: 225–234.

78.

Daskalakis

George

. Clozapine, GABAB, and the treatment of resistant schizophrenia. Clin Pharmacol Ther 2009; 86: 442–446.

79.

Gammon

Cheng

Volkovinskaia

, et al. Clozapine: why is it so uniquely effective in the treatment of a range of neuropsychiatric disorders? Biomolecules 2021; 11: 1030.

80.

Nair

McKinnon

Miners

, et al. Binding of clozapine to the GABAB receptor: clinical and structural insights. Mol Psychiatry 2020; 25: 1910–1919.

81.

Fukuyama

Kato

Murata

, et al. Clozapine normalizes a glutamatergic transmission abnormality induced by an impaired NMDA receptor in the thalamocortical pathway via the activation of a group III metabotropic glutamate receptor. Biomolecules 2019; 9: 234.

82.

Lidsky

Yablonsky-Alter

Zuck

, et al. Anti-glutamatergic effects of clozapine. Neurosci Lett 1993; 163: 155–158.

83.

Veerman

Schulte

De Haan

. The glutamate hypothesis: a pathogenic pathway from which pharmacological interventions have emerged. Pharmacopsychiatry 2014; 47: 121–130.

84.

Seeman

. Clozapine, a fast-off-D2 antipsychotic. ACS Chem Neurosci 2014; 5: 24–29.

85.

Abela

, et al. Clozapine reliably increases the motivation for food: parsing the role of the 5-HT2c and H1 receptors. Psychopharmacology 2020; 237: 957–966.

86.

Gunes

Melkersson

Scordo

, et al. Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol 2009; 29: 65–68.

87.

De Berardis

Rapini

Olivieri

, et al. Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine. Ther Adv Drug Saf 2018; 9: 237–256.

88.

Ramos Perdigués

Sauras Quecuti

Mané

, et al. An observational study of clozapine induced sedation and its pharmacological management. Eur Neuropsychopharmacol 2016; 26: 156–161.

89.

Kim

Barr

, et al. Clozapine-associated obsessive-compulsive symptoms and their management: a systematic review and analysis of 107 reported cases. Psychother Psychosom 2020; 89: 151–160.

90.

Kim

Barr

White

, et al. Clozapine-induced obsessive–compulsive symptoms: mechanisms and treatment. J Psychiatry Neurosci 2019; 44: 71–72.

91.

Kirrane

Majumdar

Richman

. Clozapine use in old age psychiatry. BJPsych Adv 2018; 24: 204–211.

92.

Skokou

Karavia

Drakou

, et al. Adverse drug reactions in relation to clozapine plasma levels: a systematic review. Pharmaceuticals 2022; 15: 817.

93.

Tanzer

Warren

McMahon

, et al. Treatment strategies for clozapine-induced nocturnal enuresis and urinary incontinence: a systematic review. CNS Spectr. Epub ahead of print 28 January 2022. DOI: 10.1017/S1092852922000050.

94.

Benkert

Hippius

. Kompendium der Psychiatrischen Pharmakotherapie. Berlin: Springer, 2021.

95.

Jann

Grimsley

Gray

, et al. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet 1993; 24: 161–176.

96.

Haring

Fleischhacker

Schett

, et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry 1990; 147: 1471–1475.

97.

Anderson

Livingston

Couchman

, et al. Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey. Ann Gen Psychiatry 2015; 14: 39.

98.

Schoretsanitis

Kane

Ruan

, et al. A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Rev Clin Pharmacol 2019; 12: 603–621.

99.

Haring

Meise

Humpel

, et al. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology 1989; 99(Suppl.): S38–S40.

100.

Chong

Lambert

, et al. An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. Int Clin Psychopharmacol 2005; 20: 163–168.

101.

Nielsen

Damkier

Lublin

, et al. Optimizing clozapine treatment. Acta Psychiatr Scand 2011; 123: 411–422.

102.

Perry

Bever

Arndt

, et al. Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry 1998; 44: 733–738.

103.

Olesen

Linnet

. Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. J Clin Pharmacol 2001; 41: 823–832.

104.

Thorn

Müller

Altman

, et al. PharmGKB summary: clozapine pathway, pharmacokinetics. Pharmacogenet Genomics 2018; 28: 214–222.

105.

Clark

Warren

Kim

, et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res 2018; 192: 50–56.

106.

De Leon

Diaz

. Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1059–1063.

107.

Leung

Nelson

Takala

, et al. Infection and inflammation leading to clozapine toxicity and intensive care: a case series. Ann Pharmacother 2014; 48: 801–805.

108.

Cranshaw

Harikumar

. COVID-19 infection may cause clozapine intoxication: case report and discussion. Schizophr Bull 2020; 46: 751.

109.

Tio

Schulte

PFJ

Martens

HJM

. Clozapine intoxication in COVID-19. Am J Psychiatry 2021; 178: 123–127.

110.

Schoretsanitis

Kane

De Leon

. Adding oral contraceptives to clozapine may require halving the clozapine dose: a new case and a literature review. J Clin Psychopharmacol 2020; 40: 308–310.

111.

Lam

YWF

. Oral contraceptives and clozapine. Brown Univ Psychopharm Update 2020; 31: 2–3.

112.

Faber

Jetter

Fuhr

. Assessment of CYP1A2 activity in clinical practice: why, how, and when. Basic Clin Pharmacol Toxicol 2005; 97: 125–134.

113.

Barrangou-Poueys-Darlas

Guerlais

Laforgue

, et al. CYP1A2 and tobacco interaction: a major pharmacokinetic challenge during smoking cessation. Drug Metab Rev 2021; 53: 30–44.

114.

Bondolfi

Morel

Crettol

, et al. Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Ther Drug Monit 2005; 27: 539–543.

115.

Bozikas

Papakosta

Niopas

, et al. Smoking impact on CYP1A2 activity in a group of patients with schizophrenia. Eur Neuropsychopharmacol 2004; 14: 39–44.

116.

Chiu

Huang

, et al. Heavy smoking, reduced olanzapine levels, and treatment effects: a case report. Ther Drug Monit 2004; 26: 579–581.

117.

Chochol

Kataria

OʼRourke

, et al. Clozapine-associated myoclonus and stuttering secondary to smoking cessation and drug interaction: a case report. J Clin Psychopharmacol 2019; 39: 275–277.

118.

Derenne

Baldessarini

. Clozapine toxicity associated with smoking cessation: case report. Am J Ther 2005; 12: 469–471.

119.

Eap

Bender

Jaquenoud Sirot

, et al. Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol 2004; 24: 214–219.

120.

Faber

Fuhr

. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 2004; 76: 178–184.

121.

Van Der Weide

Steijns

van Weelden

. The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 2003; 13: 169–172.

122.

Hukkanen

Jacob

III Peng

, et al. Effect of nicotine on cytochrome P450 1A2 activity. Br J Clin Pharmacol 2011; 72: 836–838.

123.

Van Der Plas

Pouly

Blanc

, et al. Impact of switching to a heat-not-burn tobacco product on CYP1A2 activity. Toxicol Rep 2020; 7: 1480–1486.

124.

Blacker

. Clinical issues to consider for clozapine patients who vape: a case illustration. Focus 2020; 18: 55–57.

125.

Tomko

Ahmed

Kuntz

, et al. A reasonable alternative to clozapine in the chronically relapsing smoking patient? a retrospective analysis. Hosp Pharm 2016; 51: 834–840.

126.

Rubio

Kane

. How and when to use clozapine. Acta Psychiatr Scand 2020; 141: 178–189.

127.

Wagner

Löhrs

Siskind

, et al. Clozapine augmentation strategies – a systematic meta-review of available evidence. Treatment options for clozapine resistance. J Psychopharmacol 2019; 33: 423–435.

128.

Stark

Scott

. A review of the use of clozapine levels to guide treatment and determine cause of death. Aust N Z J Psychiatry 2012; 46: 816–825.

129.

Kitchen

Till

Xavier

. Routine clozapine assay monitoring to improve the management of treatment-resistant schizophrenia. BJPsych Bull 2022; 46: 267–270.

130.

Aldenhoff

A-LSM

Messer

. Toxische Clozapin-Plasmaspiegel nach Zigarettenabstinenz. Nervenheilkunde 2008; 27: 78–79.

131.

Hägg

Spigset

Edwardsson

, et al. Prolonged sedation and slowly decreasing clozapine serum concentrations after an overdose. J Clin Psychopharmacol 1999; 19: 282–284.

132.

Sparve

Nordberg

Forsberg

, et al. Acute clozapine intoxication. J Clin Psychopharmacol 2009; 29: 302–304.

133.

Jann

. Do Asians patients require only half of the clozapine dose prescribed for Caucasians? A critical review. Indian J Psychol Med 2020; 42: 1–3.

134.

Sachse

Brockmöller

Bauer

, et al. Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999; 47: 445–449.

135.

Zhou

Yang

Zhou

, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J 2009; 11: 481–494.

136.

Légaré

Grégoire

De Benedictis

, et al. Increasing the clozapine: norclozapine ratio with co-administration of fluvoxamine to enhance efficacy and minimize side effects of clozapine therapy. Med Hypotheses 2013; 80: 689–691.

137.

Lane

Chen

, et al. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry 2000; 61: 594–599.

138.

Silver

. Fluvoxamine as an adjunctive agent in schizophrenia. CNS Drug Rev 2001; 7: 283–304.

139.

Hinze-Selch

Deuschle

Weber

, et al. Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight. Psychopharmacology 2000; 149: 163–169.

140.

Polcwiartek

Nielsen

. The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology 2016; 233: 741–750.

141.

Wenzel-Seifert

Wittmann

Haen

. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int 2011; 108: 687–693.

142.

Wetzel

Anghelescu

Szegedi

, et al. Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol 1998; 18: 2–9.

143.

Sandson

Cozza

Armstrong

, et al. Clozapine case series. Psychosomatics 2007; 48: 170–175.

144.

Spina

Pisani

De Leon

. Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychotics. Pharmacol Res 2016; 106: 72–86.

145.

Tóth

Csukly

Sirok

, et al. Potential role of patients’ CYP3A-status in clozapine pharmacokinetics. Int J Neuropsychopharmacol 2017; 20: 529–537.

146.

Tanzer

Brouard

Pra

, et al. Treatment strategies for clozapine-induced hypotension: a systematic review. Ther Adv Psychopharmacol 2022; 12.

147.

De Berardis

Serroni

Campanella

, et al. Update on the adverse effects of clozapine: focus on myocarditis. Curr Drug Saf 2012; 7: 55–62.

148.

Lucca

Madhan

Ram

, et al. Incidence and predictors of adverse drug reactions caused by drug-drug interactions in psychiatric patients – an empirical study. Trop J Med Research 2015; 19: 29–35.

149.

Demler

Trigoboff

. Are clozapine blood dyscrasias associated with concomitant medications. Innov Clin Neurosci 2011; 8: 35–41.

150.

Ibáñez

Vidal

Ballarín

, et al. Agranulocytosis associated with dipyrone (metamizol). Eur J Clin Pharmacol 2005; 60: 821–829.

151.

Wong

Delva

. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry 2007; 52: 457–463.

152.

Garcia

Crismon

Dorson

. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol 1994; 14: 426–428.

153.

Yang

Liao

Liu

, et al. Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study. J Clin Psychiatry 2013; 74: e79–e86.

154.

Dhillon

Bastiampillai

Tee

, et al. Clozapine and associated QTc prolongation. Aust N Z J Psychiatry 2011; 45: 1098–1099.

155.

Grande

Pons

Baeza

, et al. QTc prolongation: is clozapine safe? Study of 82 cases before and after clozapine treatment. Hum Psychopharmacol 2011; 26: 397–403.

156.

Kang

Kwon

Ahn

, et al. Electrocardiographic abnormalities in patients treated with clozapine. J Clin Psychiatry 2000; 61: 441–446.

157.

Vickers

Ramineni

Malacova

, et al. Risk factors for clozapine-induced myocarditis and cardiomyopathy: a systematic review and meta-analysis. Acta Psychiatr Scand 2022; 145: 442–455.

158.

Ronaldson

Fitzgerald

McNeil

. Clozapine-induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr Scand 2015; 132: 231–240.

159.

Sangüesa

Cirujeda

Concha

, et al. Pharmacokinetic interactions between clozapine and valproic acid in patients with treatment-resistant schizophrenia: does UGT polymorphism affect these drug interactions? Chem-Biol Interact 2022; 364: 110042.

160.

Costa-Dookhan

Agarwal

Chintoh

, et al. The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy. Expert Opin Drug Saf 2020; 19: 43–57.

161.

Kuoppamäki

Syvälahti

Hietala

. Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol 1993; 245: 179–182.

162.

Ellison

Dufresne

. A review of the clinical utility of serum clozapine and norclozapine levels. Ment Health Clin 2015; 5: 68–73.

163.

Tan

MSA

Honarparvar

Falconer

, et al. A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions. Psychopharmacology 2021; 238: 615–637.

164.

Rajji

Mulsant

Davies

, et al. Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine. Am J Psychiatry 2015; 172: 579–585.

165.

Costa-Dookhan

Agarwal

Chintoh

, et al. The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy. Expert Opin Drug Saf 2020; 19: 43–57.

166.

Couchman

Morgan

Spencer

, et al. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993–2007. Ther Drug Monit 2010; 3232: 438–447.

167.

De Berardis

Rapini

Olivieri

, et al. Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine. Ther Adv Drug Saf 2018; 9: 237–256.

168.

Correll

Robinson

Schooler

, et al. Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA Psychiatry 2014; 71: 1350–1363.

169.

De Hert

Dekker

Wood

, et al. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 2009; 24: 412–424.

170.

Ventriglio

Gentile

Stella

, et al. Metabolic issues in patients affected by schizophrenia: clinical characteristics and medical management. Front Neurosci 2015; 9: 297.

171.

Galletly

Castle

Dark

, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 2016; 50: 410–472.

172.

Cohn

Sernyak

. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry 2006; 51: 492–501.

173.

Murtagh

Petrovici

Wong

, et al. Improving monitoring for metabolic syndrome using audit. Ir J Psychol Med 2011; 28: i–iv.

174.

American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27: 596–601.

175.

Citrome

Volavka

. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care 2004; 27: 2087–2088.

176.

Gurrera

Gearin

Love

, et al. Recognition and management of clozapine adverse effects: a systematic review and qualitative synthesis. Acta Psychiatr Scand 2022; 145: 423–441.

177.

Fitzgerald

O’Connell

Keating

, et al. Metformin in the management of antipsychotic-induced weight gain in adults with psychosis: development of the first evidence-based guideline using GRADE methodology. Evid Based Ment Health 2022; 25: 15–22.

178.

Zimbron

Khandaker

Toschi

, et al. A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. Eur Neuropsychopharmacol 2016; 26: 1353–1365.

179.

Chen

Huang

Kao

, et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2013; 74: e424–30.

180.

Siskind

Hahn

Correll

, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: a systematic review and individual participant data meta-analysis. Diabetes Obes Metab 2019; 21: 293–302.

181.

Afshar

Roohafza

Mousavi

, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 2009; 23: 157–162.

182.

Dayabandara

Hanwella

Ratnatunga

, et al. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat 2017; 13: 2231–2241.

183.

Ellinger

Ipema

Stachnik

. Efficacy of metformin and topiramate in prevention and treatment of second-generation antipsychotic-induced weight gain. Ann Pharmacother 2010; 44: 668–679.

184.

Zhuo

Liu

, et al. Topiramate and metformin are effective add-on treatments in controlling antipsychotic-induced weight gain: a systematic review and network meta-analysis. Front Pharmacol 2018; 9: 1393.

185.

Grover

Sahoo

Mahajan

. Clozapine-induced hypertension: a case report and review of literature. Ind Psychiatry J 2017; 26: 103–105.

186.

Yuen

JWY

Kim

Procyshyn

, et al. Clozapine-induced cardiovascular side effects and autonomic dysfunction: a systematic review. Front Neurosci 2018; 12: 203–203.

187.

Maher

Cunningham

O’Callaghan

, et al. Clozapine-induced hypersalivation: an estimate of prevalence, severity and impact on quality of life. Ther Adv Psychopharmacol 2016; 6: 178–184.

188.

Corrigan

MacDonald

Reynolds

. Clozapine-induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 1995; 167: 412.

189.

Gupta

Khastgir

Croft

, et al. Management of clozapine-induced sialorrhoea. Bjpsych Advances 2020; 26: 106–108.

190.

Citrome

McEvoy

Saklad

. Guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses 2016; 10: 163–177.

191.

Sockalingam

Shammi

Remington

. Clozapine-induced hypersalivation: a review of treatment strategies. Can J Psychiatry 2007; 52: 377–384.

192.

Kreinin

Miodownik

Sokolik

, et al. Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation. World J Biol Psychiatry 2011; 12: 620–626.

193.

Praharaj

Arora

Gandotra

. Clozapine-induced sialorrhea: pathophysiology and management strategies. Psychopharmacology 2006; 185: 265–273.

194.

Bird

Smith

Walton

. Current treatment strategies for clozapine-induced sialorrhea. Ann Pharmacother 2011; 45: 667–675.

195.

Verma

Anand

. Botulinum toxin: a novel therapy for clozapine-induced sialorrhoea. Psychopharmacology 2018; 235: 369–371.

196.

Jost

Bäumer

Laskawi

, et al. Therapy of sialorrhea with botulinum neurotoxin. Neurol Ther 2019; 8: 273–288.

197.

Oliveira

Filho, Silva

Almeida

. Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review. Einstein 2016; 14: 431–434.

198.

Ruiz-Roca

Pons-Fuster

Lopez-Jornet

. Effectiveness of the botulinum toxin for treating sialorrhea in patients with Parkinson’s disease: a systematic review. J Clin Med 2019; 8: 317.

199.

Caetano

Delgado Alves

. Heart rate and cardiovascular protection. Eur J Intern Med 2015; 26: 217–222.

200.

Cohen

Loewenthal

Matar

, et al. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry 2001; 179: 167–171.

201.

Hindricks

Potpara

Dagres

, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42: 373–498.

202.

Brugada

Katritsis

Arbelo

, et al. 2019 ESC Guidelines for the management of patients with supraventricular tachycardia The Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC): developed in collaboration with the Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2020; 41: 655–720.

203.

Lally

Brook

Dixon

, et al. Ivabradine, a novel treatment for clozapine-induced sinus tachycardia: a case series. Ther Adv Psychopharmacol 2014; 4: 117–122.

204.

Stryjer

Timinsky

Reznik

, et al. Beta-adrenergic antagonists for the treatment of clozapine-induced sinus tachycardia: a retrospective study. Clin Neuropharmacol 2009; 32: 290–292.

205.

Oke

Schmidt

Bhattarai

, et al. Unrecognized clozapine-related constipation leading to fatal intra-abdominal sepsis – a case report. Int Med Case Rep J 2015; 8: 189–192.

206.

Shirazi

Stubbs

Gomez

, et al. Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis. Int J Mol Sci 2016; 17: 863.

207.

Paquette

Varma

Ternent

, et al. The American Society of Colon and Rectal Surgeons’ clinical practice guideline for the evaluation and management of constipation. Dis Colon Rectum 2016; 59: 479–492.

208.

Włodarczyk

Waśniewska

Fichna

, et al. Current overview on clinical management of chronic constipation. J Clin Med 2021; 10: 1738.

209.

Chew

Mulsant

Pollock

, et al. A model of anticholinergic activity of atypical antipsychotic medications. Schizophr Res 2006; 88: 63–72.

210.

Lieberman

III . Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry 2004; 6(Suppl. 2): 20–23.

211.

DGNM. Aktualisierte S2k-Leitlinie chronische Obstipation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutsche Gesellschaft für Neurogastroenterologie & Motilität (DGNM), 2022, https://register.awmf.org/assets/guidelines/021-019l_S2k_Chronische_Obstipation_2022-04_01.pdf

212.

Taylor

Barnes

Young

. The Maudsley prescribing guidelines in psychiatry. Hoboken, NJ: Wiley-Blackwell, 2021.

213.

Myles

Xia

, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand 2018; 138: 101–109.

214.

Borrelli

Lee

Caffrey

. Clozapine and hematologic adverse reactions: impact of the risk evaluation and mitigation strategy program. Ment Health Clin 2020; 10: 70–75.

215.

Mijovic

MacCabe

. Clozapine-induced agranulocytosis. Ann Hematol 2020; 99: 2477–2482.

216.

Dale

. How I diagnose and treat neutropenia. Curr Opin Hematol 2016; 23: 1–4.

217.

Nielsen

Correll

Manu

, et al. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry 2013; 74: 603–613; quiz 613.

218.

Wiciński

Węclewicz

. Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring. Curr Opin Hematol 2018; 25: 22–28.

219.

Oloyede

Whiskey

Casetta

, et al. Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study. Lancet Psychiatry 2022; 9: 636–644.

220.

Sultan

Olfson

Correll

, et al. Evaluating the effect of the changes in FDA guidelines for clozapine monitoring. J Clin Psychiatry 2017; 78: e933–e939.

221.

Silva

Higgins

Hammer

, et al. Clozapine rechallenge and initiation despite neutropenia – a practical, step-by-step guide. BMC Psychiatry 2020; 20: 279.

222.

Manu

Sarvaiya

Rogozea

, et al. Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. J Clin Psychiatry 2016; 77: e909–e916.

223.

Oloyede

Dzahini

Barnes

, et al. Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals. BMC Psychiatry 2021; 21: 502.

224.

Richardson

Greenway

Bousman

. Clozapine-induced myocarditis and patient outcomes after drug rechallenge following myocarditis: a systematic case review. Psychiatry Res 2021; 305: 114247.

225.

Palmblad

Höglund

. Ethnic benign neutropenia: a phenomenon finds an explanation. Pediatr Blood Cancer 2018; 65: e27361.

226.

De Filippis

Gaetano

Schoretsanitis

, et al. Clozapine management in schizophrenia inpatients: a 5-year prospective observational study of its safety and tolerability profile. Neuropsychiatr Dis Treat 2021; 17: 2141–2150.

227.

Grover

Shouan

Chakrabarti

, et al. Haematological side effects associated with clozapine: a retrospective study from India. Asian J Psychiatr 2020; 48: 101906.

228.

Kate

Grover

Aggarwal

, et al. Clozapine associated thrombocytopenia. J Pharmacol Pharmacother 2013; 4: 149–151.

229.

Aneja

Sharma

Mahajan

, et al. Eosinophilia induced by clozapine: a report of two cases and review of the literature. J Family Med Prim Care 2015; 4: 127–129.

230.

De Filippis

Soldevila-Matías

De Fazio

, et al. Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review. Expert Rev Clin Pharmacol 2020; 13: 875–883.

231.

Lally

OʼConnor

Fullam

, et al. Rechallenge following clozapine-associated eosinophilia: a case report and literature review. J Clin Psychopharmacol 2019; 39: 504–506.

232.

McArdle

Siskind

Kolur

, et al. Successful rechallenge with clozapine after treatment associated eosinophilia. Australas Psychiatry 2016; 24: 365–367.

233.

Tiihonen

Paanila

. Eosinophilia associated with clozapine. Lancet 1992; 339: 488.

234.

Legge

Hamshere

Hayes

, et al. Reasons for discontinuing clozapine: a cohort study of patients commencing treatment. Schizophr Res 2016; 174: 113–119.

235.

Kilian

Kerr

Lawrence

, et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999; 354: 1841–1845.

236.

Layland

Liew

Prior

. Clozapine-induced cardiotoxicity: a clinical update. Med J Aust 2009; 190: 190–192.

237.

Ronaldson

Fitzgerald

Taylor

, et al. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res 2012; 141: 173–178.

238.

Beck

McCutcheon

Bloomfield

, et al. The practical management of refractory schizophrenia – the Maudsley Treatment REview and Assessment Team service approach. Acta Psychiatr Scand 2014; 130: 427–438.

239.

Ronaldson

Fitzgerald

McNeil

. Evolution of troponin, C-reactive protein and eosinophil count with the onset of clozapine-induced myocarditis. Aust N Z J Psychiatry 2015; 49: 486–487.

240.

Curto

Girardi

Lionetto

, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep 2016; 18: 68.

241.

Ronaldson

Fitzgerald

Taylor

, et al. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry 2011; 45: 458–465.

242.

Higgins

San

Lagnado

, et al. Incidence and management of clozapine-induced myocarditis in a large tertiary hospital. Can J Psychiatry 2019; 64: 561–567.

243.

Shivakumar

Thomas

Sollychin

, et al. Protocol for clozapine rechallenge in a case of clozapine-induced myocarditis. Can J Psychiatry 2019; 65: 448–453.

244.

Caforio

Pankuweit

Arbustini

, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: 2636–2648a, 2648a–2648d.

245.

Kallergis

Goudis

Simantirakis

, et al. Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review. Sci World J 2012; 2012: 212178.

246.

Merrill

Dec

Goff

. Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol 2005; 25: 32–41.

247.

Chen

Guo

Sun

, et al. Effect of serum electrolytes within normal ranges on QTc prolongation: a cross-sectional study in a Chinese rural general population. BMC Cardiovasc Disord 2018; 18: 175.

248.

Bolu

Akarsu

Pan

, et al. Low-dose clozapine-induced seizure: a case report. Clin Psychopharmacol Neurosci 2017; 15: 190–193.

249.

Pacia

Devinsky

. Clozapine-related seizures. Experience with 5,629 patients. Neurology 1994; 44: 2247–2249.

250.

Williams

Park

. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs 2015; 29: 101–111.

251.

Rao

Sheth

Varambally

. Lacosamide precipitated neutropenia in a patient with bipolar disorder and comorbid epilepsy. Indian J Psychol Med 2018; 40: 496–497.

252.

Lin

Pan

. Higher plasma drug concentration in clozapine-treated schizophrenic patients with side effects of obsessive/compulsive symptoms. Ther Drug Monit 2006; 28: 303–307.

253.

Schirmbeck

Zink

. Clozapine-induced obsessive-compulsive symptoms in schizophrenia: a critical review. Curr Neuropharmacol 2012; 10: 88–95.

254.

Cohen

Keck

Satlin

, et al. Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry 1991; 29: 1215–1219.

255.

Hirjak

Kubera

Bienentreu

, et al. Antipsychotikaassoziierte motorische Symptome bei schizophrenen Psychosen – Teil 1. Der Nervenarzt 2019; 90: 1–11.

256.

Poyurovsky

Weizman

. Treatment of antipsychotic-induced akathisia: role of serotonin 5-HT(2a) receptor antagonists. Drugs 2020; 80: 871–882.

257.

Kern

Lang

. Acute akathisia. In: Friedman

(ed.) Medication-induced movement disorders. Cambridge: Cambridge University Press, 2015, pp. 3–19.

258.

Grover

Sahoo

. Clozapine induced akathisia: a case report and review of the evidence. Indian J Pharmacol 2015; 47: 234–235.

259.

Takeshima

Ishikawa

Kikuchi

, et al. Successful management of clozapine-induced akathisia with gabapentin enacarbil: a case report. Clin Psychopharmacol Neurosci 2018; 16: 346–348.

260.

Benkert

Hippius

. Kompendium der Psychiatrischen Pharmakotherapie. Berlin: Springer, 2019.

261.

Kuo

Yang

Liao

, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39: 648–657.

262.

Lam

YWF

. Pneumonia risk in patients receiving clozapine. Brown Univ Psychopharm Update 2021; 32: 2–3.

263.

Schoretsanitis

Ruan

Rohde

, et al. An update on the complex relationship between clozapine and pneumonia. Expert Rev Clin Pharmacol 2021; 14: 145–149.

264.

Hinkes

Quesada

Currier

, et al. Aspiration pneumonia possibly secondary to clozapine-induced sialorrhea. J Clin Psychopharmacol 1996; 16: 462–463.

265.

Hung

Liu

Yang

, et al. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study. J Clin Psychiatry 2016; 77: 60–66.

266.

De Leon

Ruan

Verdoux

, et al. Clozapine is strongly associated with the risk of pneumonia and inflammation. Gen Psychiatr 2020; 33: e100183.

267.

Bergemann

Ehrig

Diebold

, et al. Asymptomatic pancreatitis associated with clozapine. Pharmacopsychiatry 1999; 32: 78–80.

268.

Lally

Al Kalbani

Krivoy

, et al. Hepatitis, interstitial nephritis, and pancreatitis in association with clozapine treatment: a systematic review of case series and reports. J Clin Psychopharmacol 2018; 38: 520–527.

269.

Manu

Sarpal

Muir

, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 2012; 134: 180–186.

270.

Dhillon

Heun

. Nocturnal enuresis is an under-recognised side effect of clozapine: results of a systematic review. Global Psychiatry 2020; 2: 21–30.

271.

Karagianis

Phillips

Hogan

, et al. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999; 33: 623–630.

272.

De Filippis

Soldevila-Matías

Guinart

, et al. Unravelling cases of clozapine-related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in patients reported otherwise: a systematic review. J Psychopharmacol 2021; 35: 1062–1073.

273.

Flanagan

Dunk

. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23(Suppl. 1): 27–41.

274.

Koller

Schneider

Bennett

, et al. Clozapine-associated diabetes. Am J Med 2001; 111: 716–723.

275.

Das

Minner

Krain

, et al. Delirium on clozapine: a tale of friend turned foe – a case report. Int J Psychiatry Med 2021; 56: 446–458.

276.

Stanilla

De Leon

Simpson

. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997; 58: 252–255.

277.

Agarwal

Omoruyi

Perai

, et al. Neuroleptic malignant syndrome (NMS) on clozapine with a potential atypical interaction with paliperidone. Case Rep Psychiatry 2021; 2021: 5584104.

278.

Young

Bowers

Jr Mazure

. Management of the adverse effects of clozapine. Schizophr Bull 1998; 24: 381–390.

279.

Rodriguez

Hanley

Arias

, et al. Successful clozapine rechallenge following recurrent clozapine-associated pancreatitis: a case report. BMC Pharmacol Toxicol 2020; 21: 35.

280.

Spring

Goldstein

Buster

, et al. Physostigmine for facilitation of care in clozapine-associated anticholinergic delirium. J Clin Psychopharmacol 2022; 42: 329–331.

281.

Idänpään-Heikkilä

Alhava

Olkinuora

, et al. Letter: clozapine and agranulocytosis. Lancet 1975; 306: 611.

282.

Lustberg

. Management of neutropenia in cancer patients. Clin Adv Hematol Oncol 2012; 10: 825–826.

283.

Lorenzo-Villalba

Alonso-Ortiz

Maouche

, et al. Idiosyncratic drug-induced neutropenia and agranulocytosis in elderly patients. J Clin Med 2020; 9: 1808.

284.

Sun

Zhao

Yuan

, et al. Detection of drug safety signal of drug-induced neutropenia and agranulocytosis in all-aged patients using electronic medical records. Pharmacoepidemiol Drug Saf. Epub ahead of print 28 October 2022. DOI: 10.1002/pds.5559.

285.

Sedhai

Lamichhane

Gupta

. Agranulocytosis. Treasure Island, FL: StatPearls Publishing, 2022.

286.

Taylor

Shapland

Laverick

, et al. Clozapine – a survey of patient perceptions. Psychiatr Bull 2000; 24: 450–452.

287.

Silva

Higgins

Hammer

, et al. Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital. Ther Adv Psychopharmacol 2021; 11.

288.

Duggal

Singh

. Re: late-onset neutropenia with clozapine. Can J Psychiatry 2006; 51: 125; author reply 125–126.

289.

Small

Weber

Klapper

, et al. Rechallenge of late-onset neutropenia with clozapine. J Clin Psychopharmacol 2005; 25: 185–186.

290.

Johannsen

Petersen

Nielsen

, et al. Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: a retrospective cohort study. Ther Adv Psychopharmacol 2022; 12.

291.

Taylor

Vallianatou

Whiskey

, et al. Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis. Schizophrenia 2022; 8: 21.

292.

Hummer

Kurz

Barnas

, et al. Transient neutropenia induced by clozapine. Psychopharmacol Bull 1992; 28: 287–290.

293.

Nooijen

Carvalho

Flanagan

. Haematological toxicity of clozapine and some other drugs used in psychiatry. Hum Psychopharmacol 2011; 26: 112–119.

294.

Malik

Lally

Ajnakina

, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res 2018; 195: 267–273.

295.

Meyer

Gee

Whiskey

, et al. Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis. J Clin Psychiatry 2015; 76: e1410–6.

296.

Moga

Teodorescu

Ifteni

, et al. Clozapine and neutropenia in patients with schizophrenia and SARS-CoV-2 infection. Neuropsychiatr Dis Treat 2022; 18: 977–983.

297.

Herold

. Innere Medizin 2023 [Internal medicine]. Berlin; Boston, MA: De Gruyter, 2023.

298.

Fenelon

. Protective isolation: who needs it? J Hosp Infect 1995; 30(Suppl.): 218–222.

299.

Schnell

Azoulay

Benoit

, et al. Management of neutropenic patients in the intensive care unit (NEWBORNS EXCLUDED) recommendations from an expert panel from the French Intensive Care Society (SRLF) with the French Group for Pediatric Intensive Care Emergencies (GFRUP), the French Society of Anesthesia and Intensive Care (SFAR), the French Society of Hematology (SFH), the French Society for Hospital Hygiene (SF2H), and the French Infectious Diseases Society (SPILF). Ann Intensive Care 2016; 6: 90.

300.

Silva

Higgins

Hammer

, et al. Clozapine rechallenge and initiation despite neutropenia – a practical, step-by-step guide. BMC Psychiatry 2020; 20: 279.

301.

Lam

YWF

. Eosinophilia associated with clozapine therapy. Brown Univ Psychopharm Update 2021; 32: 2–2.

302.

Roberts

Mortenson

Merrill

, et al. Successful rechallenge with clozapine after eosinophilia. Am J Psychiatry 2011; 168: 1147–1151.

303.

Tiihonen

Tanskanen

Bell

, et al. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry 2022; 9: 353–362.

304.

De Leon

De Las Cuevas

Sanz

, et al. Clozapine and the risk of haematological malignancies. Lancet Psychiatry 2022; 9: 537–538.

305.

Schulte

Cohen

Veerman

, et al. Clozapine and the risk of haematological malignancies. Lancet Psychiatry 2022; 9: 538–539.

306.

Van Der Horst

Van Houwelingen

Luykx

. Isolated nausea and vomiting as the cardinal presenting symptoms of clozapine-induced myocarditis: a case report. BMC Psychiatry 2020; 20: 568.

307.

Lang

Willbring

Von Golitschek

, et al. Clozapine-induced myocarditis after long-term treatment: case presentation and clinical perspectives. J Psychopharmacol 2008; 22: 576–580.

308.

Tan

Suetani

Clark

, et al. Late onset myocarditis with clozapine use. Aust N Z J Psychiatry 2015; 49: 295.

309.

Bellissima

Tingle

Cicović

, et al. A systematic review of clozapine-induced myocarditis. Int J Cardiol 2018; 259: 122–129.

310.

Segev

Iqbal

McDonagh

, et al. Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy. Br J Psychiatry 2021; 219: 644–651.

311.

Haas

Hill

Krum

, et al. Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993–2003. Drug Saf 2007; 30: 47–57.

312.

Siskind

Sidhu

Cross

, et al. Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy. Aust N Z J Psychiatry 2020; 54: 467–481.

313.

Ariyarajah

Shaikh

Garber

, et al. Cardiovascular magnetic resonance in mild to moderate clozapine-induced myocarditis: is there a role in the absence of electrocardiographic and echocardiographic abnormalities? J Magn Reson Imaging 2010; 31: 1473–1476.

314.

Karatolios

Pankuweit

Maisch

. Diagnosis and treatment of myocarditis: the role of endomyocardial biopsy. Curr Treat Options Cardiovasc Med 2007; 9: 473–481.

315.

Riggs

Cooper

. Clozapine-induced myocarditis. US Pharm 2018; 43: HS2–HS7.

316.

Reinders

Parsonage

Lange

, et al. Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Aust N Z J Psychiatry 2004; 38: 915–922.

317.

Cheng

Ahmed

Shuaib

. Intravenous immunoglobulin and methylprednisolone for clozapine-associated perimyocarditis. Am J Ther 2019; 26: e485–e486.

318.

Ronaldson

Fitzgerald

Taylor

, et al. Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophr Res 2011; 128: 161–165.

319.

Abdel-Wahab

Metwally

. Clozapine-induced cardiotoxicity: role of oxidative stress, tumour necrosis factor alpha and NF-κβ. Cardiovasc Toxicol 2015; 15: 355–365.

320.

Devarajan

Kutcher

Dursun

. Clozapine and sudden death. Lancet 2000; 355: 841; author reply 843.

321.

Hägg

Spigset

Bate

, et al. Myocarditis related to clozapine treatment. J Clin Psychopharmacol 2001; 21: 382–388.

322.

Pollmächer

Schuld

Kraus

, et al. [On the clinical relevance of clozapine-triggered release of cytokines and soluble cytokine-receptors]. Fortschr Neurol Psychiatr 2001; 69(Suppl. 2): S65–S74.

323.

Wang

Min

Hampton

, et al. Clozapine-induced myocarditis: role of catecholamines in a murine model. Eur J Pharmacol 2008; 592: 123–127.

324.

Jahołkowski

Niewiadomska

Wciórka

, et al. Clozapine-induced myocarditis during co-administration of valproate: a case report. Psychiatr Pol 2019; 53: 9971002.

325.

Arzuk

Karakuş

Orhan

. Bioactivation of clozapine by mitochondria of the murine heart: possible cause of cardiotoxicity. Toxicology 2021; 447: 152628.

326.

De Leon

Rhee

Kondracke

, et al. Rapid titration and decreased clozapine clearance may help explain five cases of clozapine-induced myocarditis in a New York Hospital. Psychosomatics 2020; 61: 102–103.

327.

Every-Palmer

Ellis

. Clozapine-induced gastrointestinal hypomotility: a 22-year bi-national pharmacovigilance study of serious or fatal ‘slow gut’ reactions, and comparison with international drug safety advice. CNS Drugs 2017; 31: 699–709.

328.

Fowler

. Clozapine-induced gastrointestinal hypomotility: more than just constipation. Ment Health Clin 2011; 1: 92–93.

329.

Palmer

McLean

Ellis

, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 2008; 69: 759–768.

330.

Handley

Every-Palmer

Ismail

, et al. Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992–2017. Br J Psychiatry 2022; 220: 355–363.

331.

Every-Palmer

Nowitz

Stanley

, et al. Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine 2016; 5: 125–134.

332.

Lamberti

Olson

Crilly

, et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163: 1273–1276.

333.

Tso

Kumar

Jayasooriya

, et al. Metabolic monitoring and management among clozapine users. Australas Psychiatry 2016; 25: 48–52.

334.

Galletly

. Premature death in schizophrenia: bridging the gap. Lancet Psychiatry 2017; 4: 263–265.

335.

Allison

Mackell

McDonnell

. The impact of weight gain on quality of life among persons with schizophrenia. Psychiatr Serv 2003; 54: 565–567.

336.

Mizock

. The double stigma of obesity and serious mental illnesses: promoting health and recovery. Psychiatr Rehabil J 2012; 35: 466–469.

337.

Kane

Kishimoto

Correll

. Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 2013; 12: 216–226.

338.

Weiden

Mackell

McDonnell

. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004; 66: 51–57.

339.

Bora

Akdede

Alptekin

. The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis. Psychol Med 2017; 47: 1030–1040.

340.

Hagi

Nosaka

Dickinson

, et al. Association between cardiovascular risk factors and cognitive impairment in people with schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry 2021; 78: 510–518.

341.

Moritz

Silverstein

Dietrichkeit

, et al. Neurocognitive deficits in schizophrenia are likely to be less severe and less related to the disorder than previously thought. World Psychiatry 2020; 19: 254–255.

342.

Kelly

Sheitman

Hamer

, et al. A naturalistic comparison of the long-term metabolic adverse effects of clozapine versus other antipsychotics for patients with psychotic illnesses. J Clin Psychopharmacol 2014; 34: 441–445.

343.

Lund

Perry

Brooks

, et al. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry 2001; 58: 1172–1176.

344.

Bai

Chen

, et al. Weight gain with clozapine: 8-year cohort naturalistic study among hospitalized Chinese schizophrenia patients. Schizophr Res 2009; 108: 122–126.

345.

Henderson

Cagliero

Gray

, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000; 157: 975–981.

346.

Lydon

Vallely

Tummon

, et al. Routine screening and rates of metabolic syndrome in patients treated with clozapine and long-acting injectable antipsychotic medications: a cross-sectional study. Ir J Psychol Med 2021; 38: 40–48.

347.

Lappin

Wijaya

Watkins

, et al. Cardio-metabolic risk and its management in a cohort of clozapine-treated outpatients. Schizophr Res 2018; 199: 367–373.

348.

De Silva

Suraweera

Ratnatunga

, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry 2016; 16: 341.

349.

Jiang

W-L

Cai

D-B

Yin

, et al. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry 2020; 10: 117.

350.

Wagner

Kane

Correll

, et al. Clozapine combination and augmentation strategies in patients with schizophrenia – recommendations from an international expert survey among the treatment response and resistance in psychosis (TRRIP) working group. Schizophr Bull 2020; 46: 1459–1470.

351.

Petrides

Malur

Braga

, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Focus 2019; 17: 76–82.

352.

Wang

Shi

, et al. Outcomes and safety of concomitant topiramate or metformin for antipsychotics-induced obesity: a randomized controlled trial. Ann Gen Psychiatry 2020; 19: 68.

353.

Correll

Newcomer

Silverman

, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry 2020; 177: 1168–1178.

354.

Rehan

Siddiqui

Khan

, et al. Samidorphan/olanzapine combination therapy for schizophrenia: efficacy, tolerance and adverse outcomes of regimen, evidence-based review of clinical trials. Ann Med Surg 2022; 79: 104115.

355.

American Diabetes Association. Introduction: standards of medical care in diabetes – 2022. Diabetes Care 2021; 45: S1–S2.

356.

Taylor

Yazdi

Beitelshees

. Pharmacological treatment of hyperglycemia in type 2 diabetes. J Clin Invest 2021; 131: e142243.

357.

Popli

Konicki

Jurjus

, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58: 108–111.

358.

Wang

Glynn

Ganz

, et al. Clozapine use and risk of diabetes mellitus. J Clin Psychopharmacol 2002; 22: 236–243.

359.

Quek

See

Yee

, et al. Metabolic syndrome and cardiovascular risk between clozapine and non-clozapine antipsychotic users with schizophrenia. Asian J Psychiatr 2022; 74: 103192.

360.

Syed

Cahill

, et al. Pharmacological interventions for clozapine-induced hypersalivation. Cochrane Database Syst Rev 2008; 3: CD005579.

361.

Baldessarini

Huston-Lyons

Campbell

, et al. Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry 1992; 160(Suppl. 17): 12–16.

362.

Zorn

Jones

Ward

, et al. Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 1994; 269: R1–R2.

363.

Rehse

Bartolovic

Baum

, et al. Influence of antipsychotic and anticholinergic loads on cognitive functions in patients with schizophrenia. Schizophr Res Treatment 2016; 2016: 8213165.

364.

Van Der Poorten

De Hert

. The sublingual use of atropine in the treatment of clozapine-induced sialorrhea: a systematic review. Clin Case Rep 2019; 7: 2108–2113.

365.

Mustafa

Khan

Burke

, et al. Sublingual atropine for the treatment of severe and hyoscine-resistant clozapine-induced sialorrhea. Afr J Psychiatry 2013; 16: 242.

366.

Kahl

Hagenah

Zapf

, et al. Botulinum toxin as an effective treatment of clozapine-induced hypersalivation. Psychopharmacology 2004; 173: 229–230.

367.

Chen

Ravindran

Zhang

, et al. Treatment strategies for clozapine-induced sialorrhea: a systematic review and meta-analysis. CNS Drugs 2019; 33: 225–238.

368.

Olfson

Gerhard

Huang

, et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 2015; 72: 1172–1181.

369.

De Leon

. Reflections on the complex history of the concept of clozapine-induced inflammation during titration. Psychiatr Danub 2022; 34: 411–421.

370.

De Leon

Schoretsanitis

Smith

, et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 2022; 55: 73–86.

371.

Dean

Kane

. Clozapine therapy and CYP genotype. In: Pratt

Scott

Pirmohamed

, et al. (eds) Medical genetics summaries. Bethesda, MD: National Center for Biotechnology Information, 2012.

372.

Ruan

Zang

Cheng

, et al. Around 3% of 1,300 levels were elevated during infections in a retrospective review of 131 Beijing hospital in-patients with more than 24,000 days of clozapine treatment. Psychother Psychosom 2020; 89: 255–257.

373.

Nemani

Olfson

, et al. Association of psychiatric disorders with mortality among patients with COVID-19. JAMA Psychiatry 2021; 78: 380–386.

374.

De Fazio

Gaetano

Caroleo

, et al. Rare and very rare adverse effects of clozapine. Neuropsychiatr Dis Treat 2015; 11: 1995–2003.

375.

Gürcan

Hun Şenol

Anıl Yağcıogğlu

, et al. Common side effects and metabolic syndrome due to clozapine: relationship with the clinical variables and disability. Turk Psikiyatri Derg 2021; 32: 87–99.

376.

Iqbal

Govind

Romero

, et al. The side effect profile of clozapine in real world data of three large mental health hospitals. PLoS ONE 2020; 15: e0243437.

377.

Yada

Kitagawa

Sakamoto

, et al. The relationship between plasma clozapine concentration and clinical outcome: a cross-sectional study. Acta Psychiatr Scand 2021; 143: 227–237.

378.

Fernandez-Egea

Chen

Jenkins

, et al. The effect of clozapine on self-reported duration of sleep and its interaction with 23 other medications: a 5-year naturalistic study. J Clin Psychopharmacol 2021; 41: 534–539.

379.

Kuzo

Haen

, et al. Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. Epub ahead of print 29 December 2022. DOI: 10.1007/s00406-022-01542-1.

380.

Freudenreich

Henderson

Macklin

, et al. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry 2009; 70: 1674–1680.

381.

Dequardo

. Modafinil-associated clozapine toxicity. Am J Psychiatry 2002; 159: 1243–1244.

382.

Davis

Fuller

Strauss

, et al. Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients. Acta Psychiatr Scand 2014; 130: 30–39.

383.

Pai

Vella

. Reason for clozapine cessation. Acta Psychiatr Scand 2012; 125: 39–44.

384.

Blackman

Oloyede

. Clozapine discontinuation withdrawal symptoms in schizophrenia. Ther Adv Psychopharmacol 2021; 11.

385.

Blackman

Oloyede

Horowitz

, et al. Reducing the risk of withdrawal symptoms and relapse following clozapine discontinuation – is it feasible to develop evidence-based guidelines? Schizophr Bulletin 2022; 48: 176–189.

386.

Shiovitz

Welke

Tigel

, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull 1996; 22: 591–595.

387.

Stevenson

Schembri

Green

, et al. Serotonin syndrome associated with clozapine withdrawal. JAMA Neurology 2013; 70: 1054–1055.

388.

Galova

Berney

Desmeules

, et al. A case report of cholinergic rebound syndrome following abrupt low-dose clozapine discontinuation in a patient with type I bipolar affective disorder. BMC Psychiatry 2019; 19: 73.

389.

Luykx

Stam

Tanskanen

, et al. In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine. Br J Psychiatry 2020; 217: 498–505.

390.

Stam

Taipale

Tanskanen

, et al. Persistence of antipsychotic use after clozapine discontinuation: a real-world study across antipsychotics. Clin Transl Sci 2020; 13: 1170–1177.

391.

Keks

Schwartz

Hope

. Stopping and switching antipsychotic drugs. Aust Prescr 2019; 42: 152–157.

392.

Leucht

Cipriani

Spineli

, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–962.

393.

Masuda

Misawa

Takase

, et al. Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies. JAMA Psychiatry 2019; 76: 1052–1062.

394.

Krivoy

Malka

Fischel

, et al. Predictors of clozapine discontinuation in patients with schizophrenia. Int Clin Psychopharmacol 2011; 26: 311–315.

395.

Miura

Tanaka

Kemuriyama

, et al. Clinical outcomes after clozapine discontinuation in patients with schizophrenia: a systematic review. Pharmacopsychiatry 2022; 55: 181–192.

396.

Mustafa

Burke

Abukmeil

, et al. ‘Schizophrenia past clozapine’: reasons for clozapine discontinuation, mortality, and alternative antipsychotic prescribing. Pharmacopsychiatry 2015; 48: 11–14.

397.

Chouinard

Samaha

Chouinard

, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom 2017; 86: 189–219.

398.

Cosci

Chouinard

. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom 2020; 89: 283–306.

399.

Diamond

Borison

. Basic and clinical studies of neuroleptic-induced supersensitivity psychosis and dyskinesia. Psychopharmacol Bull 1986; 22: 900–905.

400.

Moncrieff

. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 2006; 114: 3–13.

401.

Viguera

Baldessarini

Hegarty

, et al. Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry 1997; 54: 49–55.

402.

Lander

Bastiampillai

Sareen

. Review of withdrawal catatonia: what does this reveal about clozapine? Transl Psychiatry 2018; 8: 139.

403.

Hawkins

Archer

Strakowski

, et al. Somatic treatment of catatonia. Int J Psychiatry Med 1995; 25: 345–369.

404.

Sienaert

Dhossche

Vancampfort

, et al. A clinical review of the treatment of catatonia. Front Psychiatry 2014; 5: 181.

405.

Sinclair

DJM

Zhao

, et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev 2019; 3: CD011847.

406.

Shore

Matthews

Cott

, et al. Clinical implications of clozapine discontinuation: report of an NIMH workshop. Schizophr Bull 1995; 21: 333–338.

407.

Manu

Lapitskaya

Shaikh

, et al. Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 cases. Am J Ther 2018; 25: e218–e223.

408.

Bowers

Rosenkrantz

Palanci

, et al. A slow, cautious, and successful clozapine rechallenge after myocarditis. Prim Care Companion CNS Disord 2022; 24: 21cr02976.

409.

Hosseini

Skrzypcak

Yasaei

, et al. Successful clozapine re-challenge after suspected clozapine-induced myocarditis. Am J Case Rep 2020; 21: e926507-1–e926507-6.

410.

Danilewitz

Rafizadeh

Bousman

. Successful clozapine rechallenge after suspected clozapine-associated myocarditis: a case report. J Clin Psychopharmacol 2021; 41: 218–220.

411.

Prokopez

Armesto

Gil Aguer

, et al. Clozapine rechallenge after neutropenia or leucopenia. J Clin Psychopharmacol 2016; 36: 377–380.

412.

Boazak

Goldsmith

Cotes

. Mask off? Lithium augmentation for clozapine rechallenge after neutropenia or agranulocytosis: discontinuation might be risky. Prim Care Companion CNS Disord 2018; 20: 18l02282.

413.

Martina

Lamberti

. A case of clozapine induced agranulocytosis 25 years after starting treatment: effective use of lithium for augmentation in rechallenge. Schizophr Res 2019; 210: 308–309.

414.

Brunoni

Kobuti Ferreira

Gallucci-Neto

, et al. Lithium as a treatment of clozapine-induced neutropenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 2006–2007.

415.

Kutscher

Robbins

Kennedy

, et al. Clozapine-induced leukopenia successfully treated with lithium. Am J Health Syst Pharm 2007; 64: 2027–2031.

416.

Whiskey

Taylor

. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs 2007; 21: 25–35.

417.

Bender

Linka

Wolstein

, et al. Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol 2004; 7: 59–63.

418.

Rachamallu

Haq

Song

, et al. Clozapine-induced microseizures, orofacial dyskinesia, and speech dysfluency in an adolescent with treatment resistant early onset schizophrenia on concurrent lithium therapy. Case Rep Psychiatry 2017; 2017: 7359095.

419.

Béchard

Corbeil

Plante

, et al. Clozapine rechallenge following neutropenia using granulocyte colony-stimulating factor: a Quebec case series. J Psychopharmacol 2021; 35: 1152–1157.

420.

Shuman

Moss

Dilich

. Never say never: successful clozapine rechallenge after multiple episodes of neutropenia. Focus 2021; 19: 66–70.

421.

Myles

Clark

, et al. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: a systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry 2017; 51: 980–989.

422.

Shaw

Confer

Hwang

, et al. A review of the genetic and long-term effects of G-CSF injections in healthy donors: a reassuring lack of evidence for the development of haematological malignancies. Bone Marrow Transplant 2015; 50: 334–340.

423.

Dale

Bolyard

Marrero

, et al. Long-term effects of G-CSF therapy in cyclic neutropenia. N Engl J Med 2017; 377: 2290–2292.

424.

Freeman

Martin

. G-CSF dosing to prevent recurrent clozapine-induced agranulocytosis. Am J Psychiatry 2016; 173: 643–643.

425.

Hägg

Rosenius

Spigset

. Long-term combination treatment with clozapine and filgrastim in patients with clozapine-induced agranulocytosis. Int Clin Psychopharmacol 2003; 18: 173–174.

426.

Johannesen

Khomenko

Baldaranov

, et al. Safety, tolerability and monitoring of long-term G-CSF compassionate use in ALS patients (P3.181). Neurology 2016; 86: P3181.

427.

Ronaldson

Fitzgerald

Taylor

, et al. Observations from 8 cases of clozapine rechallenge after development of myocarditis. J Clin Psychiatry 2012; 73: 252–254.

428.

Toni-Uebari

Rees

. Successful rechallenge with clozapine following ‘red alert’. BMJ Case Rep 2013; 2013: bcr2012007172.

429.

Cook

Ferguson

Cotes

, et al. Clozapine-induced myocarditis: prevention and considerations in rechallenge. Psychosomatics 2015; 56: 685–690.

430.

Knoph

Morgan

3rd Palmer

, et al. Clozapine-induced cardiomyopathy and myocarditis monitoring: a systematic review. Schizophr Res 2018; 199: 17–30.

431.

Noël

Powell

Burton

, et al. Clozapine-related myocarditis and rechallenge: a case series and clinical review. J Clin Psychopharmacol 2019; 39: 380–385.

432.

Nguyen

Bastiampillai

, et al. Successful clozapine re-challenge following myocarditis. Australas Psychiatry 2017; 25: 385–386.

433.

Beex-Oosterhuis

Samb

Heerdink

, et al. Safety of clozapine use during pregnancy: analysis of international pharmacovigilance data. Pharmacoepidemiol Drug Saf 2020; 29: 725–735.

434.

Beex-Oosterhuis

Van Gool

Heerdink

, et al. Clozapine treatment during pregnancy and the postpartum period: a systematic literature review. J Clin Psychiatry 2021; 83: 21r13952.

435.

Heinonen

Forsberg

Nörby

, et al. Antipsychotic use during pregnancy and risk for gestational diabetes: a national register-based cohort study in Sweden. CNS Drugs 2022; 36: 529–539.

436.

Mehta

Van Lieshout

. A review of the safety of clozapine during pregnancy and lactation. Arch Womens Ment Health 2017; 20: 1–9.

437.

Tracy

Venkataramanan

Glover

, et al. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol 2005; 192: 633–639.

438.

Imaz

Oriolo

Torra

, et al. Clozapine use during pregnancy and lactation: a case-series report. Front Pharmacol 2018; 9: 264.

439.

Uygur

ÖF

Uygur

. Neurodevelopmental and growth follow-up of the baby exposed to antipsychotics during pregnancy and lactation: a case report. Psychiatr Clin Psychopharmacol 2019; 29: 744–747.

440.

Duran

Ugur

Turan

, et al. Clozapine use in two women with schizophrenia during pregnancy. J Psychopharmacol 2008; 22: 111–113.

441.

Hatters Friedman

Moller-Olsen

Prakash

, et al. Atypical antipsychotic use and outcomes in an urban maternal mental health service. Int J Psychiatry Med 2016; 51: 521–533.

442.

Sreeraj

Venkatasubramanian

. Safety of clozapine in a woman with triplet pregnancy: a case report. Asian J Psychiatr 2016; 22: 67–68.

443.

Law

Croucher

. Prescribing trends and safety of clozapine in an older persons mental health population. Int Psychogeriatr 2019; 31: 1823–1829.

444.

Mukku

SSR

Sivakumar

Varghese

. Clozapine use in geriatric patients – challenges. Asian J Psychiatr 2018; 33: 63–67.

445.

Alvir

Lieberman

Safferman

, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993; 329: 162–167.

446.

Gareri

De Fazio

Russo

, et al. The safety of clozapine in the elderly. Expert Opin Drug Saf 2008; 7: 525–538.

447.

Herst

Powell

. Is clozapine safe in the elderly? Aust N Z J Psychiatry 1997; 31: 411–417.

448.

Fabrazzo

La Pia

Monteleone

, et al. Is the time course of clozapine response correlated to the time course of clozapine plasma levels? A one-year prospective study in drug-resistant patients with schizophrenia. Neuropsychopharmacology 2002; 27: 1050–1055.

449.

Kappel

Legge

Hubbard

, et al. Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores. Biol Psychiatry 2023; 93: 149–156.

450.

Morrison

Pyle

Gumley

, et al. Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Lancet Psychiatry 2018; 5: 633–643.

451.

Van Der Zalm

Foldager

Termorshuizen

, et al. Clozapine and mortality: a comparison with other antipsychotics in a nationwide Danish cohort study. Acta Psychiatr Scand 2021; 143: 216–226.

452.

Lähteenvuo

Batalla

Luykx

, et al. Morbidity and mortality in schizophrenia with comorbid substance use disorders in Finland and Sweden. Eur Psychiatry 2021; 64: S237–S238.

453.

Solmi

Tiihonen

Lähteenvuo

, et al. Antipsychotics use is associated with greater adherence to cardiometabolic medications in patients with schizophrenia: results from a nationwide, within-subject design study. Schizophr Bull 2022; 48: 166–175.

454.

Hjorthøj

Stürup

McGrath

, et al. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry 2017; 4: 295–301.

455.

Tanskanen

Tiihonen

Taipale

. Mortality in schizophrenia: 30-year nationwide follow-up study. Acta Psychiatr Scand 2018; 138: 492–499.

456.

Vermeulen

Van Rooijen

Van De Kerkhof

MPJ

, et al. Clozapine and long-term mortality risk in patients with schizophrenia: a systematic review and meta-analysis of studies lasting 1.1–12.5 years. Schizophr Bull 2019; 45: 315–329.

457.

Farooq

Taylor

. Clozapine: dangerous orphan or neglected friend? Br J Psychiatry 2011; 198: 247–249.

458.

Till

Silva

. A case report of the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion. BMC Psychiatry 2019; 19: 37.

459.

Ochi

Tagata

Hasegawa

, et al. Clozapine treatment is associated with higher prescription rate of antipsychotic monotherapy and lower prescription rate of other concomitant psychotropics: a real-world nationwide study. Int J Neuropsychopharmacol 2022; 25: 818–826.

460.

Hodge

Jespersen

. Side-effects and treatment with clozapine: a comparison between the views of consumers and their clinicians. Int J Ment Health Nurs 2008; 17: 2–8.