Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

Seizures

Seizures may be a relatively common and potentially life-threatening adverse effect of clozapine. ⁶⁸ In fact, clozapine may lower the seizure threshold not only in individuals at risk of epilepsy, but also in apparently healthy subjects. ⁶⁹ The seizure risk during clozapine treatment has been estimated at roughly 1–6%, is usually dose dependent and may appear more frequently in younger patients.^70,71 It has been reported that rapid titration and higher dosages of clozapine (⩾600 mg/day) were associated with greater risk than medium (300–600 mg/day) or low dosages (<300 mg/day). ⁷²

Moreover, rapid clozapine titration may further increase seizure onset. ⁷⁰ Even if a higher risk of seizures during clozapine titration has been reported, this adverse effect may appear during all phases of treatment, even after several years of therapy. ⁷³ Patients who develop seizures during clozapine titration or maintenance treatment may continue clozapine with dose reduction, or better still, the addition of an antiepileptic medication. Valproate may be the best choice, even if this combination must be carefully monitored.^74,75 Electroencephalography and clozapine plasma blood-level monitoring are recommended to avoid or minimize seizure risk.^76,77

Weight gain and the risk of MetS

Second-generation antipsychotics are generally associated with weight gain, particularly olanzapine and clozapine, and with related risks of metabolic disturbances such as insulin resistance, type 2 diabetes, dyslipidemia and diabetic ketoacidosis (DKA). ⁷⁸

Weight gain is a common adverse effect of clozapine that, per se, may be not potentially life threatening if properly managed and treated. ⁷⁷ If not, the consequent development of MetS may be a major health concern which highly increases the risk of developing type 2 diabetes mellitus and cardiovascular diseases.^79,80 A relationship between weight gain and clozapine doses has been proposed, but this point remains controversial. ⁸¹

Clozapine metabolic abnormalities are mostly linked to 5-HT2A and 5-HT2C receptor blockade, but the effects on histaminergic and adrenergic receptors are also thought to play a significant role.^82–84

Even if the prevalence of MetS in patients with schizophrenia is higher compared with the general population, going up to 40%, the effect of clozapine is remarkable with a prevalence rate varying from 11% to 64% among treated patients.^85,86 Allison and colleagues reported that clozapine treatment was associated with an average gain of 9.8 lb over 10 weeks and this was the highest figure of all antipsychotics. ⁸⁷ The incidence of clozapine-related weight gain is considered to be the most significant at 5–35%, and almost half of patients may gain 20% or more of their initial body weight, especially if they are on polypharmacy, have a sedentary lifestyle or are not overweight at baseline. ⁸⁸ Several studies have also associated clozapine treatment with the development of dyslipidemia and hypertension,^77,89–91 all factors that may affect MetS or make it worse. The metabolic risk associated with clozapine treatment may be increased in the short term after treatment initiation. In fact, it has been demonstrated that the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables are also likely to affect the metabolic risk during the lifespan. ⁹²

Clozapine treatment may also be associated with diabetes and DKA.^93,94 Regarding DKA, Cohen and colleagues ⁹⁵ found a 1-year incidence rate of 1.2–3.1% and a case fatality rate of 20–31%, making DKA one of the riskiest side effects, with higher mortality than agranulocytosis with an incidence of 3.8–8.0% and case fatality rate of 2.2–4.2%. Therefore, the authors proposed that the screening guidelines should be modified with an early detection of treatment-emergent hyperglycemia through an obligatory monthly measurement of fasting plasma glucose. It has also been demonstrated that clozapine-related DKA typically occurs early in the course of treatment, when clozapine treatment duration is short and doses are low. ⁹⁶

Especially with combined behavioral interventions consisting of both nutritional counseling and diet modification), aripiprazole, topiramate, orlistat and metformin additions have been shown to be beneficial in reducing clozapine-induced weight loss, even if the evidence is based on a limited number of randomized controlled trials and further studies are needed.^88,97,98 Counseling for patients needing proper diet and exercise for weight and glucose control should always be recommended. ⁹⁹

Gastrointestinal hypomotility and constipation

The anticholinergic peripheral properties of clozapine as well as its H1 antagonism properties were related to several grades of impairment of intestinal peristalsis ranging from transient to obstinate constipation and paralytic ileus up to intestinal obstruction.^100,101 It is known that even low or therapeutic doses of clozapine may prolong colonic transit time (CTT). ¹⁰²

These effects are mainly mediated by the clozapine antagonism on cholinergic and serotoninergic receptors in the gut wall. ¹⁰³ It has been demonstrated that clozapine, but not norclozapine, has potent effects on the motility of the colon of a rabbit, thus inhibiting neurogenic contractions at lower concentrations and myogenic contractions at higher concentrations. ¹⁰⁴ These effects may be mediated by cholinergic and serotonergic receptors, presumably via M1–M3 and 5HT-3 and 5HT-7 receptors. Moreover, de Alvarenga and colleagues ¹⁰⁵ showed that clozapine significantly reduced the frequency of cycles of contractions of zebrafish larvae gastrointestinal tracts through anticholinergic action.

These adverse effects are bothersome for several patients who develop mild constipation, which is often a treatment discontinuation cause, but it may become severe and potentially life threatening in some others who develop moderate to severe untreated constipation or even an adynamic ileus. ¹⁰³ In fact, constipation is very frequent in patients treated with clozapine with an estimate range varying from 15% to 60% in accordance with several studies.^106,107 Moreover, Every-Palmer and Ellis ¹⁰⁸ reviewed all reports of serious clozapine-induced gastrointestinal hypomotility (CIGH, also known as clozapine-related ‘slow gut’) submitted to the Australian Therapeutic Goods Administration and New Zealand Pharmacovigilance Centre between 1992 and 2013 and found that the reported prevalence of serious CIGH was 37/10,000, likely an underestimation of the true prevalence. CIGH is relatively common as between 50% and 80% of patients treated with clozapine have unambiguous objective evidence of CIGH in colonic transit studies, ¹⁰² with mean transit times that are four times longer than normal, affecting all regions of the colon. ¹⁰⁶ It is worth noting that studies which have relied on reporting of constipation are not very sensitive in diagnosing slow gut.

In fact, rare but potentially fatal clozapine-related adverse effects are intestinal obstructions and a paralytic ileus that occur in almost 2% of treated patients. ¹⁰⁹ In severe cases, constipation progresses to ileus and bowel ischemia, with multiple fatalities related to aspiration of feculent vomit, sepsis and perforation, as described in the literature. ¹¹⁰ Prolonged gastrointestinal hypomotility and constipation may promote ischemia, increasing intraluminal pressure and compression of mucosal vessels. As a consequence, bacterial translocation, inflammation and ischemia of the segment of bowel proximal to the obstruction will develop.^111–113 One case of clozapine-induced severe constipation leading to a silent presentation of pneumonia with a subsequent respiratory arrest ¹¹⁴ has also been reported.

Clozapine-related ileus has been reported to be dose dependent and may occur several days after initiation of treatment as well as at any time during treatment, with the latter often triggered by concomitant medications known to affect the gastrointestinal system, especially those with anticholinergic properties. ¹¹⁵ Therefore, early detection and treatment of constipation and ileus are mandatory to avoid fatalities.

The recommendation of an adequate intake of fluids, especially in the presence of hypersalivation, and regular physical activity is mandatory in such patients, as well as dose reduction or laxative prescriptions to avoid the progression of severe gastrointestinal adverse effects.^107,116,117 Recently, Every-Palmer and colleagues ¹¹⁸ demonstrated that patients with clozapine-related constipation treated with docusate and senna augmented by macrogol had reduced CTTs and this was beneficial in treating constipation. Also, orlistat was found to be helpful, ¹¹⁹ but further studies are needed.

Blood dyscrasias and agranulocytosis/granulocytopenia

Blood dyscrasias, such as mild to moderate leukopenia decreased white blood cell count, mild neutropenia, anemia, eosinophilia and leukocytosis, are often seen with clozapine but, if cautiously monitored, in the majority of the cases this may be transient or benign.^127,128

The most severe and potentially life-threatening clozapine-related blood dyscrasias is neutropenia, which may eventually develop into clozapine-induced agranulocytosis or granulocytopenia. This occurs in roughly 0.8–2% of patients and requires mandatory hematological monitoring.^20,129 The occurrence of agranulocytosis or granulocytopenia even led to the partial withdrawal of clozapine from the market and strong restrictions to its use in the mid 1970s. ¹³⁰

Neutropenia was defined in the 2005 clozapine guidelines as an absolute neutrophil count (ANC) below 1500 and occurs in approximately 3% of treated patients, ¹³¹ whereas agranulocytosis was defined as an ANC below 500/mm³.^132,133 A transient neutropenia (1 week) or weekly variations of ANC are relatively common during clozapine treatment and do not necessarily require treatment discontinuation, but it is not known why some patients develop transient neutropenia whereas others progress to having agranulocytosis.^134,135

Although the highest risk of agranulocytosis has been reported to occur during the first 12 weeks from clozapine titration and during the first 6 months of treatment, patients may develop severe blood dyscrasia anytime during the treatment, even if the risk decreases exponentially over time after the first 6 months of treatment. ¹³⁵ However, some cases of late-onset clozapine-induced agranulocytosis have been reported.^136,137 The development of agranulocytosis may be independent of dosage and risk factors include older age, female sex, human leukocyte antigen haplotypes and concomitant treatment with other drugs known to cause agranulocytosis.^52,138–142 Interestingly, in cases with severe clozapine-induced agranulocytosis, the occurrence did not depend on the clozapine dosage. ¹⁴³

To explain this dangerous adverse effect, several studies have hypothesized a potential interaction between clozapine and the immune system, suggesting an immune-mediated mechanism to be involved in its adverse effects or even in its clinical efficacy.^144,145 It is also possible that some subjects may be genetically predisposed; oxidative clozapine degradation may cause the development of some metabolites with reactive nitrenium ions, which may covalently bind to human leukocytes, resulting in direct toxicity or leading to the development of aptenic formation of an antigenic structure that will stimulate a targeted immune response.^146–148

The 2015 US Food and Drugs Administration guidelines for hematologic monitoring during clozapine therapy^149–151 recommend that treatment is not discontinued in the case of mild neutropenia (⩾1000–1499/mm³), with ANC monitored three times weekly until it is at least 1500/mm³. However, in the case of moderate neutropenia (⩾500–999/mm³), they recommend that treatment is interrupted when clozapine-induced neutropenia is suspected, with daily monitoring performed until ANC is at least 1000/mm³ (when treatment may resume), and consequently monitoring carried out three times weekly until ANC is at least 1500/mm³, then proceeding with weekly checks for 4 weeks, and finally returning to the patient’s last normal range ANC monitoring plan.

In the case of severe neutropenia (<500/mm³), all patients must interrupt treatment for suspected clozapine-induced neutropenia and clozapine rechallenge should not be considered unless the prescriber, along with a hematologist consultation, determines that the benefits outweigh the risks. ¹⁵² Recently, some studies have pointed out that granulocyte colony-stimulating factor may be beneficial in the treatment of clozapine-induced agranulocytosis, ¹⁵³ but more evidence is needed and withdrawing clozapine is still mandatory in such cases.

Clozapine rechallenge is always a risk after an episode of agranulocytosis as several reports observed a new episode of blood dyscrasia.^154,155 However, there are also some reports that observed no blood dyscrasia when clozapine was reintroduced after an episode of agranulocytosis with or without adjuvant therapies.^156–158 Dunk and colleagues ¹⁵⁹ conducted clozapine rechallenge in 53 patients who developed leucopenia or neutropenia during previous clozapine treatment and found that 38% experienced a further blood dyscrasia whereas 55% did not. More recently, Prokopez and colleagues ¹⁶⁰ analyzed the results of a clozapine rechallenge after leucopenia or neutropenia in 19 patients and observed that almost 70% of the patients did not develop a new hematological adverse effect, whereas the remaining 30% had a faster but less serious neutropenia. In conclusion, clozapine rechallenge requires careful evaluation and should be taken into consideration on a case-by-case basis when the risks outweigh the benefits for all other strategies.

QT prolongation

It has been reported that clozapine may be associated with QT prolongation in a dose-dependent manner.^161,162 In most cases, drug-induced QT prolongation is not significant per se, whether it is symptomatic or malignant, ¹⁶³ but in some individuals it may lead to the life-threatening torsades de pointes, a sudden and often fatal arrhythmia. ¹⁶⁴

The effect on QTc is not peculiar to clozapine; it is often seen with other antipsychotics, especially FGAs, and other psychiatric drugs.^165–167 Almost all of the drugs known to prolong the QT interval both directly or through one of their metabolites seem to preferentially block the rapid component of the delayed rectifier outward K+ current, IKr, of an ion channel in ventricular cardiomyocytes, whose α subunit is encoded by the human ether-a-go-go related gene (HERG). ¹⁶⁸

Clozapine has demonstrated the capability to block HERG currents and this may account for drug-induced QT prolongation. ¹⁶⁹ However, it is known that clozapine may induce an increased heart rate and this may influence the QTc determination (when using Bazett’s formula), leading to an overestimation of this effect. ¹⁷⁰

All considered, clozapine seems to rarely influence QT traits. However, electrocardiogram monitoring is always useful when clozapine is commenced or when administered together with other drugs, and in elderly patients.^171–175 The QT interval should be calculated using methods involving linear regression, adjusting for age and sex, as recommended by the American Heart Association, ¹⁷⁶ and not with Bazett’s formula. Clozapine dose reductions may be useful for QT prolongation, especially in the case of polypharmacy. ¹⁷⁷

Clozapine-induced cardiomyopathy, myocarditis and pericarditis

Clozapine may be associated with the occurrence of severe cardiovascular side effects, including dilated cardiomyopathy, myocarditis and pericarditis, which may be fatal when not timely recognized and managed.^10,170

Dilated cardiomyopathy is an uncommon, dose-independent, but potentially life-threatening adverse effect of clozapine treatment. It may occur even after a longer drug exposure and is often confused with myocarditis. ¹⁷⁸ The clinical manifestations of clozapine-induced cardiomyopathy range from subclinical forms to severe ones with fulminant pulmonary edema and cardiogenic shock.^179,180 Often the symptoms are insidious and include persistent tachycardia at rest, palpitations, arrhythmias, dyspnea, chest pain, malaise and other signs and symptoms that may be underestimated by the clinicians until the symptoms resemble the clinical picture of heart failure or myocardial infarction. ¹⁸¹

Myocarditis is an uncommon, dose-independent, life-threatening adverse effect and occurs in up to 3% of treated patients.^182,183 Moreover, several sudden deaths reported with clozapine use may be due to an unrecognized or fulminant myocarditis. ¹⁸⁴ Although myocarditis has a tendency to appear at any time during treatment with clozapine, this has been reported more frequently from 4 days to 22 weeks after treatment initiation, ¹⁸⁵ with a particular ‘danger period’ during the first 4 weeks following initiation. ¹⁸⁶

The clinical presentation of clozapine-related myocarditis in adults may be highly variable, ranging from subclinical diseases to fulminant heart failure.^187,188 Flu-like symptoms such as fatigue, fever, myalgias, dizziness, arthralgias, nasal congestion and sensations of ‘scratchy throat’ may often be the first to appear and are sometimes unrecognized or underestimated.^189,190

Respiratory symptoms, such as dyspnea, cough, subjective sensations of chest discomfort and orthopnea, as well as cardiovascular symptoms, such as persistent resting tachycardia, increased heart rate, palpitations, chest pain, syncope, arrhythmias and hypotension, are the main symptoms that drive the diagnosis. However, in some cases, clozapine-related myocarditis may develop in an atypical form without accompanying symptoms and these cases are often fatal.^191,192

It has been suggested that risk factors for any cardiac complications of clozapine may be the rapid dose titration, the presence of weight gain or metabolic adverse effects, the coadministration of selective serotonin reuptake inhibitors and the use of illicit substances.^193–195 Moreover, concomitant treatment with medications that have been implicated as the cause of cardiovascular complications like myocarditis and heart failure, namely some antibacterials, cisapride, thyroxine, ranitidine, cyclophosphamide, lithium, phenotiazines and certain antidepressant agents like amytriptiline, imipramine and desipramine, may represent another risk factor when a patient is taking clozapine. ¹⁹⁶ Interestingly, some cases of clozapine-related myocarditis were detected in patients taking valproate, which is often prescribed to prevent seizures or as a mood stabilizer.^184,195,197 Hence, when clozapine is administered together with valproate, patients should be more carefully and strictly evaluated for an eventual myocarditis onset.

The early detection of clozapine-related myocarditis is mandatory as early recognition improves clinical outcome and reduces mortality.^170,198 To date, the monitoring protocol adapted from De Berardis and colleagues ¹⁰ and Ronaldson and colleagues ¹⁸⁵ seems to be scientifically sound and clinically useful in everyday clinical practice (see Figure 1).

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Figure 1.

Proposed protocol for monitoring patients commenced on clozapine for clozapine-related cardiomyopathy, myocarditis and pericarditis (adapted and modified from De Berardis et al. ¹⁰ and Ronaldson et al. ¹⁸⁵ ). ICU, intensive care unit; ULN, upper limit of normal.

When myocarditis is suspected or diagnosed, immediate clozapine cessation is mandatory as usually this may resolve the case within a few days or weeks. ⁶⁰ However, some patients may require treatment with a β blocker or angiotensin-converting enzyme inhibitor, whereas severe cases will need mechanical ventilation.^199,200 Corticosteroids have been administered in some cases, but their efficacy is uncertain.^201,202

As far as clozapine rechallenge after an episode of myocarditis is concerned, it should be noted that this strategy may be dangerous, is not recommended, and should be employed after careful evaluation of the pros and cons together with a consultation with a cardiologist,^170,203,204 even though there are some positive reports.^{191,205–207}

Moreover, several cases of clozapine-related pericarditis have been reported in the literature in patients on stable clozapine regimens for several weeks, months or even years, or during the titration phase.^208–211 In the majority of published cases, clozapine treatment was immediately discontinued, resulting in complete resolution of symptoms. ²¹² In some cases, clozapine rechallenge was tried, but this strategy is controversial as pericarditis may develop again, even though this is not the rule.^213,214

Venous thromboembolism

There are several reports on clozapine-related venous thromboembolism (VTE), but luckily it seems to be relatively rare and dose independent.^215–217 The mechanism of this dangerous adverse effect remains unknown.^218–220 Axelsson and colleagues ²²¹ compared several antipsychotics and found that clozapine was the only compound that increased platelet adhesion and aggregation, and shortened activated partial thromboplastin time, even at therapeutic concentrations. Moreover, in a case report, clozapine induced an allergic vasculitis that resulted in VTE. ²²²

Nevertheless, the risk of VTE seems to be an adverse effect of several antipsychotics including clozapine,^223,224 and may be higher in elderly patients and in women taking high doses or receiving parenteral antipsychotics.^225–228 However, it has been suggested that VTE may be more a consequence of several risk factors for VTE present in patients with psychiatric disorders, such as MetS, inactivity, low levels of water intake and other medical illnesses, than the treatment with antipsychotics itself.^229–231

All considered, caution is needed to recognize VTE symptoms early, for example painful edema of the lower limbs, chest pain and dyspnea in patients taking clozapine, especially in those with known risk factors for VTE, like patients over 65, with previous VTE episodes, obesity, MetS, inactivity, lower limb trauma, estrogen treatment, among others.^170,218,225