1994] particularly those of the tonic—clonic type. Another report [Simpson and Cooper, 1978] also found seizures occurring at levels above 1300 μg/l in two patients and proposed a safe therapeutic maximum clozapine level of 600 μg/l. Authors of all three reports emphasized the importance and usefulness of clozapine plasma level monitoring in the prevention of adverse effects related to raised concentrations. Table 4. Incidence of CFTR inhibitor clozapine-induced seizures against plasma levels. Conversely, 3 out of 50 patients investigated by Freudenreich

and associates had seizures with low clozapine levels. However, these patients had pre-existing seizure disorders, confirming the importance of obtaining a full clinical Inhibitors,research,lifescience,medical history Inhibitors,research,lifescience,medical [Freudenreich et al. 1997]. Neurotoxic

adverse effects are associated with higher clozapine plasma levels and therapeutic drug monitoring has been advocated to ensure that clozapine levels are kept around the accepted therapeutic threshold. Such an approach is also likely to be valuable in assessing and monitoring the risk of clinical toxicity [Greenwood-Smith et al. 2003]; however, there is no clear, statistically significant evidence Inhibitors,research,lifescience,medical to support this suggestion. Case reports Clozapine-induced myoclonic seizures, myoclonic jerks, drop attacks, ‘leg folding’, stuttering and facial tics Clozapine may cause myoclonus, at times occurring alone [Antelo et al. 1994; Berman et al. 1992; Gouzoulis et al. 1991] or preceding a generalized Inhibitors,research,lifescience,medical tonic-clonic seizure [Haddad and Sharma, 2007; Haberfellner, 2002; Sajatovic and Meltzer, 1996; Meltzer and Ranjan, 1994; Gouzoulis et al. 1993; Berman et al. 1992]. Myoclonus affects approximately 2% of clozapine-treated patients [Lieberman and Safferman, 1992]. It is a potentially serious motor phenomenon presenting as spontaneous brief jerking movements of the head, face, trunk, fingers or toes, alone or in clusters and can be epileptic or nonepileptic in nature [Sajatovic and Meltzer, 1996]. Myoclonic seizures tended to occur during the clozapine initiation phase [Taner et al. 1998] and at doses ranging between 150 mg [Haberfellner,

2002] and 500 mg [Gouzoulis Inhibitors,research,lifescience,medical et al. 1993]. Associated EEG abnormalities were observed and ranged from paroxysmal (epileptiform) patterns [Haberfellner, 2002; Gouzoulis et al. 1991] to generalized spike-wave complexes [Gouzoulis et al. 1993]. Sajatovic and Meltzer encountered much an equal number of patients (2 out of 11) experiencing myoclonus alone and myoclonus followed by a generalized seizure. Thus the authors, along with others, postulated that myoclonus may be a harbinger of generalized seizures [Dhar et al. 2008; Haberfellner, 2002; Taner et al. 1998; Sajatovic and Meltzer, 1996; Antelo et al. 1994; Gouzoulis et al. 1993; Berman et al. 1992]. Three case studies reported clozapine-induced myoclonic jerks along with ‘drop attacks’ or ‘leg folding’ [Dhar et al. 2008; Antelo et al. 1994; Berman et al. 1992].