Clozapine adverse effects

Grohmann, R. et al. (1989). Adverse effects of clozapine. Psychopharmacology, 99, S101 4. 

Clozapine and olanzapine are atypical antipsychotic drugs used in the treatment of schizophrenia. Their strnctnres are depicted in Scheme 2.36. The use of clozapine and olanzapine, which are more effective than standard neuroleptic drugs in the treatment of refractory schizophrenia, is, however, limited becanse of their adverse effects. These adverse effects are ascribed to the formation of the corresponding cation-radicals in living organisms under oxidation by bone marrow cells. These cation-radicals eliminate protons from the NH fragments and generate their nitrenium cations. The nitreninm cations are covalently bonnd to the life-important proteins. This results in the toxic effects of clozapine and olanzapine (Sikora et al. 2007). 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

Agranulocytosis Because of a significant risk of agranulocytosis, a potentially life-threatening adverse reaction, reserve clozapine for use in the treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with clozapine, it... 

All antipsychotics except clozapine have a similar potential for producing tardive dyskinesia, the most serious adverse effect. Clozapine is reserved for patients who have failed to respond to therapy with at least two other antipsychotics and for those who have disabling tardive dyskinesia. Therapy with clozapine has been reported to salvage up to half of otherwise treatment-refractory pa-... 

In this context, the first role of the laboratory is to detect specific adverse effects to target organs (see Role of the Laboratory later in this chapter). Monitoring will generally be tailored to the specific therapy used because of its known potential for causing certain problems. Examples include periodic blood counts with carbamazepine or clozapine and thyroid and renal function studies with long-term maintenance lithium. 

Fortunately, for most psychotropics, side effects are minimal, usually involving nuisance complaints. With some agents, such as clozapine, however, the potential for more serious adverse effects does exist and must be carefully explained to the patient and family. Although managed care has successfully controlled overall financial costs, it is our responsibility to advocate for the optimal delivery of treatment, which necessarily takes into consideration not only the immediate expense of treatment but the impact of appropriate care in the long-term. As importantly, one should always factor in the cost of not providing adequate treatment, including ... 

Given clozapine s significant adverse effects, Lieberman and colleagues ( 39) recommend its use only in psychotic patients who are clear nonresponders to other agents, in that they ... 

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

The introduction of clozapine, risperidone, quetiapine, and ziprazidone has had a dramatic impact on the decision-making process in choosing an antipsychotic. Thus, these agents both minimize neurological adverse effects and may qualitatively improve some psychotic symptoms to a greater degree than neuroleptics. 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

Sedation, ataxia, and cognitive impairment occur more frequently with high BZD dosages. Other adverse effects reported when BZDs were used to treat schizophrenia include behavioral disinhibition, exacerbation of psychosis, and increase in anxiety and depression ( 163, 188, 189,190, 191,192, 193,194 and 195, 351). Concomitant use of a BZD and the atypical antipsychotic clozapine may increase the risk of sedation, dizziness and collapse with loss of consciousness ( 196). Respiratory compromise has also been reported with this combination (395, 396). 

Although clozapine has been considered an alternate agent, as mentioned earlier there is also a risk with this agent ( 494, 495 and 496). An unusual adverse effect of clozapine, apparently unrelated to NMS, is hyperthermia in 10% to 15% of patients (usually 0.5°C to 1°C, but virtually never above 40°C [104°F]). This symptom usually occurs between the fifth and the fifteenth days of treatment, after which, temperature returns to normal. Benzodiazepines (e.g., lorazepam) have also been recommended to either avoid or at least minimize the dose of antipsychotic. 

Another example of a serious adverse effect that can surface through close systematic monitoring is the association of clozapine treatment with venous thromboembolytic complications (514, 515). Six cases of pulmonary embolism and six cases of venous thrombosis were reported to the Swedish Adverse-Reaction... 

Grohmann R, Ruther E, Sassim N, et al. Adverse effects of clozapine. Psychopharmacoiogy 1989 99(suppl) S101-S104. 

T effects OF amiodarone, astemizole, atorvastadn, barbiturates, bepridil, bupropion, cerivastatin, cisapride, clorazepate, clozapine, clarithromycin, desipramine, diazepam, encainide, ergot alkaloids, estazolam, flecainide, flurazepam, indinavir, ketoconazole, lovastatin, meperidine, midazolam, nelfinavir, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, simvastatin, SSRIs, TCAs, terfenadine, triazolam, troleandomycin, zolpidem X effects W/ barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John s wort, tobacco X effects OF didanosine, hypnotics, methadone, OCPs, sedatives, theophylline, warfarin EMS T Effects of amiodarone, diazepam, midazolam and BBs, may need X- doses concurrent use of Viagra-type drugs can lead to hypotension X- effects of warfarin concurrent EtOH use can T adverse effects T glucose ODs May cause an extension of adverse SEs symptomatic and supportive Rivasrigmine (Exelon) [Cholinesterase Inhibitor/Anri ... 

In 48 patients with schizophrenia taking clozapine, olanzapine, risperidone, or typical neuroleptic drugs, and 31 untreated healthy control subjects newer neuroleptic drugs, such as clozapine and olanzapine, compared with typical agents, were associated with adverse effects on blood glucose regulation (774). 

Weight gain related to the use of atypical neuroleptic drugs in children and adolescents, in whom this adverse effect is of particular concern, has been reviewed (804). The published data suggest that clozapine and olanzapine... 

Abidi S, Bhaskara SM. From chlorpromazine to clozapine—antipsychotic adverse effects and the clinician s dilemma. Can J Psychiatry. 2003 48 749-755. 

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