Electroencephalography identifies encephalopathy associated with adjunctive lithium and zuclopenthixol

To the Editor

Lithium used in combination with antipsychotics is considered to be the first-line treatment for bipolar and schizoaffective disorders. However, sporadic reports highlight possible synergistic toxic effects of concurrent use of lithium with neuroleptics including reports of encephalopathy following lithium–risperidone combination (Boora et al., 2008) and lithium–olanzapine combination (Swartz, 2001).

Here, we report patient MP, a 56-year-old male with schizoaffective disorder, admitted with relapse of symptoms. He was initially commenced on Lithium XR 900 mg and lurasidone 160 mg, but he continued to have severe symptoms necessitating electroconvulsive therapy (ECT). A clozapine trial was attempted but discontinued as he developed myocarditis. He was commenced on zuclopenthixol acetate and showed significant improvement. Considering this good response and a history of noncompliance, zuclopenthixol decanoate 400 mg every 2 weeks was added to his existing regimen of Lithium XR 900 mg daily, lurasidone 160 mg daily and weekly ECTs. Since the commencement of the zuclopenthixol depot, MP developed tiredness and myoclonic jerks, and on examination, he showed features of drug-induced Parkinsonism. Considering these side effects, lurasidone was stopped and benztropine was commenced, but the clinical situation continued to deteriorate, associated with increasing apathy, disorientation and memory impairment, especially delayed recall. ECT was ceased because of evident cognitive deterioration. Except for a mild renal impairment, his baseline investigations were normal, and his serum lithium levels remained within the therapeutic range (0.4–0.6 mmol/L). The presence of myoclonic jerks together with gradual cognitive decline was assessed further by a neurologist, in particular, to exclude a progressive neurodegenerative disorder, such as Creutzfeldt–Jakob disease (CJD). Investigations included magnetic resonance imaging (MRI) that was normal and electroencephalography (EEG) that showed generalised slowing suggestive of encephalopathy. Given a possible lithium–neuroleptic-induced encephalopathy, lithium was ceased, and zuclopenthixol depot injection was reduced to 300 mg every 2 weeks. Following the cessation of lithium, MP started showing remarkable improvement in extrapyramidal symptoms, myoclonic jerks as well as his cognitive functions.

It is important to note that the combination of lithium and neuroleptics is effective for many patients, and encephalopathy is rare. The possible reasons for neurotoxicity with lithium–neuroleptic combination therapy remains uncertain, but inhibition of striatal dopamine synthesis has been demonstrated in rats given lithium, thereby supporting a synergistic inhibition of dopamine-related transmission (Goldman, 1996). The EEG manifestations of diffuse slowing or triphasic waves have been suggested as a useful method to differentiate organic brain pathology from purely psychiatric causes. Careful monitoring and early recognition, combined with neurological examination and investigations, especially EEG, will facilitate diagnosis and early intervention to cease this treatment combination and avoid more serious and possibly irreversible neurological sequela.