Occipital Seizures and Visual Pseudohallucinations Associated With the Addition of Bupropion to Clozapine A Case Report
To the Editors: he addition of newer antidepressants (ADs) to second-generation antipsychotics (SGAs) is a frequently adopted strategy in clinical practice. However, the relative lack of studies combining newer ADs and SGAs significantly undermines the possibility of evidence-based decisions.1 Among others, the efficacy of bupropionVa combined dopamine and norepinephrine agonistVin schizophrenia is biologically plausible, and the risk for bupropion-related psychosis seems negligible.2 However, adverse effects after adding bupropion to SGAs and dose correction factors are still to be determined.1 Seizure risk seems particularly worrisome,3 especially in association with clozapine, given its known epileptic potential at all stages of treatment and at common therapeutic dosage.4 Herein, we report the case of a clozapinetreated patient whose antipsychotic therapy was augmented with bupropion. To our knowledge, this is the first report on a patient treated with clozapine-bupropion combination, who developed visual hallucinatory experiences referable to occipital epileptic seizures. We aim to inform clinicians about this particular type of seizure that can be associated with clozapine in association regimen.
CASE Mr M is a 33-year-old white Italian male with a long history of psychiatric illness involving prolonged psychiatric hospitalizations and a current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (American Psychiatric Association, 2013). His medication history was characterized by several treatment attempts with antipsychotic drugs (aripiprazole, haloperidol, risperidone, and paliperidone). At the time of the initiation of clozapine, the patient’s clinical status was dominated by paranoid delusions and severe impairment of psychosocial functioning. His Positive and Negative Symptoms Scale total score was 109, and his Hamilton-Depression Rating Scale total score was 6. Over the subsequent months, the patient’s clozapine dose was gradually
increased to a total of 500 mg/d. The titration was slowed by the emergence of several adverse effects (drooling, tachycardia, hypotension, sedation, constipation, blurred vision, and increased appetite). By the end of the new medication titration period, the patient’s clinical condition noticeably improved, the severity of his positive symptoms decreased, and the patient was much less hostile and suspicious. Adverse effects decreased in parallel with mental status improvements except for sialorrhea, which remained as the only bothersome clinical problem. Positive and Negative Symptoms Scale score decreased to 71, revealing a substantial persistence of negative symptoms, with subscores shifted from 18 to 5 for Positive Symptoms and 37 to 24 for Negative Symptoms. Moreover, Hamilton-Depression Rating Scale total score increased to 17, along with the emergence of symptoms of mild depression, possibly associated with the acquisition of partial insight. Therefore, a decision was made to address the depressive symptoms pharmacologically. After an initial trial with fluoxetine 20 mg/d that yielded no significant improvement, bupropion was selected among other ADs and was added to the patient’s regimen in the attempt to reduce apathy and low mood. The patient was started on bupropion XR 150 mg/d. The dose of bupropion was never increased given concerns that the association with clozapine might lower the patient’s seizure threshold. The patient received a combination of clozapine 500 mg/d and bupropion XR 150 mg/d for about a month. On day 25, he began to complain of occasional visual misperceptions consisting in blurred figures he could not better define. After an indepth clinical interview, he succeeded in describing the phenomenon more clearly. It consisted of moving lights and shadows resembling unidentifiable, achromatic people and objects at the periphery of his visual field. These experiences had occurred once or twice daily for no longer than 5 minutes in the previous 4 days and were preceded by a vibratory sensation associated with deja`-vecu. These phenomena appeared to be adequately distinguished by the patient among several other bizarre experiences that had previously been reported to physicians with a complete lack of insight. After a thorough psychiatric and neurological evaluation, they were clearly recognized by physicians as pseudohallucinations. Despite several abnormal psychotic experiences, the patient had never previously reported hallucinations of any type. A full neurological examination was otherwise unremarkable. An electroencephalographic
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Letters to the Editors
(EEG) recording revealed slowing of background activity and diffuse slow abnormalities intermingled with spikes over temporo-occipital areas (Fig. 1A), whereas a brain magnetic resonance imaging scan was normal. Bupropion was discontinued with a rapid resolution of visual disperceptions. Given the concomitant finding of a high plasma concentration of clozapine and its metabolite norclozapine (1826.2 ng/mL; reference range, 350-600; conversion factor, nmol/L = ng/mL 3.0), the drug was then gradually reduced to a maintenance target of 200 mg/d. After 7 weeks, a retest of clozapine levels demonstrated values nearing normalization (875.9 ng/mL), and a second EEG recording showed almost complete disappearance of interictal epileptiform abnormalities (Fig. 1B). At a 6-month follow-up, the patient was clinically stable and never disclosed visual pseudohallucinatory experiences.
DISCUSSION To our knowledge, this is the first report of an attempt to treat postpsychotic depression with clozapine in addition to bupropion, which resulted in the development of visual hallucinations associated with posterior EEG abnormalities. The association of bupropion and clozapine rather than a safer AD was motivated by (1) the predominance of anhedonia as a residual prominent symptom; (2) pharmacological considerations relative to the implication of dopamine in reward and motivational systems and a supposed relative frontal dopaminergic deficiency in treated schizophrenia; (3) the presence of persistent profuse sialorrhea and evidence of possible efficacy of bupropion on clozapine-related sialorrhea5; (4) bupropion adverse effect of weight loss; (5) and the presence in the literature of several data that support the possibility of an association between the 2 agents.6 Given that the finding of clozapine and bupropion-induced electroencephalographic abnormalities without clinical symptoms is not uncommon, it was not possible a priori to discriminate with certainty between occipital seizures and psychotic hallucinations. Indeed, sporadic visual hallucinations with fluctuating insight could be explained by schizophrenia per se.7 However, our patient had never complained of hallucinations of any type before, his reality testing on these visual experiences was preserved in sharp contrast with other delusional beliefs he still retained, and above all, the described features were more suggestive for occipital seizures. Moreover, hallucinatory symptoms responded to the interruption of bupropion treatment combined with a reduction of www.psychopharmacology.com
FIGURE 1. A, EEG recording performed when the subject was receiving a combination of clozapine 500 mg/d and buproprion XR 150 mg/day. Evidence of slowing of background activity and diffuse slow abnormalities intermingled with spikes over temporo-occipital areas. B, EEG recording performed when the subject was receiving clozapine 200 mg/d. Documentation of almost complete disappearance of slow and epileptiform interictal abnormalities. Epoch 20 sec.
clozapine dose, confirming our diagnostic hypothesis. Because clozapine plasma levels before the addition of bupropion are not available and because of the subsequent reduction of clozapine dose from 500 mg/d to 200 mg/d, it is not possible to discriminate between the causative roles of the 2 agents and their synergistic effect.
Although a relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities has been reported, the paucity of reliable data does not allow definitive conclusions.4 Anyway, it has to be noted that our patient had fairly high blood levels of clozapine, especially while taking 500 mg/d (over
1500 Kg/L), and that 3 other case reports (4 patients) suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 Kg/L.4 Twenty percent of patients taking bupropion have abnormal, asymptomatic EEG findings,8 but bupropion in monotherapy rarely induces epileptic seizures at doses equal to
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150 mg/d.3 However, its synergistic activity cannot be excluded, given the absence of pharmacokinetic and pharmacodynamic data on the interaction between clozapine and bupropion. Indeed, it is possible that a synergistic, pharmacodynamic effect occurred in a subject that was already at high risk for clozapine-related seizures given the elevated plasma clozapine concentrations. Our observations warrant further exploration; in particular, we further point up the need of (1) a correlational and regression analysis between clozapine dose and plasma levels and epileptogenic risk and (2) pharmacokinetic and pharmacodynamic drug interaction studies to better establish whether dose correction factors after adding bupropion to clozapine are required to reduce adverse effects. Most importantly, it is worth noting that in this case, it might have been better to wait patiently for clozapine to work, in the attempt to avoid the association with bupropion at least during clozapine dose titration. Indeed, clozapine remains to date the most effective antipsychotic agent for negative symptoms9 because the current literature does not support the use of ADs to address them.10 Although recent data support the efficacy of ADs on mild depressive symptoms in schizophrenia,10 the evidence base for this approach is not currently robust enough to recommend their widespread use in clinical practice,11 and common sense suggests that caution is still needed. Finally, it seems relevant that in this case the epileptic presentation resembles a common psychopathological symptom. Even if the tonic-clonic variety is the most frequently described drug-related seizure, other subtypes, such as myoclonic, atonic, or partial seizures, may occur as well.12 These latter subtle types of seizures are more difficult for clinicians to recognize given the similarity with common psychopathological signs.13,14 Indeed, the relatively low frequency of reported partial seizures could depend on underrecognition of epileptic discharges presenting with more subtle symptoms that partially overlap with psychiatric psychopathology.
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Anna Castelnovo, MD Department of Health Sciences Universita` degli Studi di Milano, Italy and Department of Mental Health San Paolo Hospital Milan, Italy [email protected]
Elena Zambrelli, MD Neurology II Unit Regional Epilepsy Center San Paolo Hospital Milan, Italy
Maria Paola Canevini, MD Department of Health Sciences Universita` degli Studi di Milano, Italy and Neurology II Unit Regional Epilepsy Center San Paolo Hospital Milan, Italy
Simone Cavallotti, MD Department of Health Sciences Universita` degli Studi di Milano, Italy and Department of Mental Health San Paolo Hospital Milan, Italy
Silvio Scarone, MD Armando D’Agostino, MD Department of Health Sciences Universita` degli Studi di Milano, Italy and Department of Mental Health San Paolo Hospital Milan, Italy
Letters to the Editors 10. Barnes TR, Paton C. Do antidepressants improve negative symptoms in schizophrenia? BMJ. 2011;342:d3371. 11. Hinkelmann K, Yassouridis A, Kellner M, et al. No effects of antidepressants on negative symptoms in schizophrenia. J Clin Psychopharmacol. 2013;33:686Y690. 12. Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52:457Y463. 13. Elliott B, Joyce E, Shorvon S. Delusions, illusions, and hallucinations in epilepsy: 1. Elementary phenomena. Epilepsy Res. 2009;85:162Y171. 14. Kasper BS, Kasper EM, Pauli E, et al. Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology. Epilepsy Behav. 2010;18:13Y23.
Simple Pulmonary Eosinophilia Associated With Clozapine Treatment
REFERENCES 1. Spina E, de Leon J. Clinically relevant interactions between newer antidepressants and second-generation antipsychotics. Expert Opin Drug Metab Toxicol. 2014;10:721Y746. 2. Englisch S, Morgen K, Meyer-Lindenberg A, et al. Risks and benefits of bupropion treatment in schizophrenia: a systematic review of the current literature. Clin Neuropharmacol. 2013;36:203Y215. 3. Tripp AC. Bupropion, a brief history of seizure risk. Gen Hosp Psychiatry. 2010;32:216Y217. 4. Varma S, Bishara D, Besag FM, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol. 2011;1:47Y66. 5. Stern RG, Bellucci D, Cursi-Vogel N, et al. Clozapine-induced sialorrhea alleviated by bupropionVa case report. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1578Y1580. 6. Weiner E, Ball MP, Buchholz AS, et al. Bupropion sustained release added to group support for smoking cessation in schizophrenia: a new randomized trial and a meta-analysis. J Clin Psychiatry. 2012;73:95Y102. 7. Bracha HS, Wolkowitz OM, Lohr JB, et al. High prevalence of visual hallucinations in research subjects with chronic schizophrenia. Am J Psychiatry. 1989;146:526Y528. 8. Macaluso M, Zackula R, D’Empaire I, et al. Twenty percent of a representative sample of patients taking bupropion have abnormal, asymptomatic electroencephalographic findings. J Clin Psychopharmacol. 2010;30:312Y317. 9. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31Y41.
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To the Editors:
lthough clozapine remains the gold standard for the treatment of resistant schizophrenia, clozapine is associated with a variety of adverse effects. Taylor et al1 showed that, next to cardiovascular events, pneumonia is the second most common cause of death during clozapine therapy. Most of these pneumonias are due to aspiration pneumonia,2 but in the present report, we describe a case of eosinophilic pneumonia (EP) that was associated with clozapine treatment.
CASE REPORT A 16-year-old female patient with schizophrenia who was resistant to treatment for 3 years was examined at our facility and started on clozapine treatment (start with 25 mg/d, dosing up at 25 mg/d in every 2 to 3 days). She had no history of allergic disease or any allergies to drugs or foods. She showed significant improvement in her symptoms and had a decrease in her auditory hallucinations by day 4. When the clozapine dose reached 125 mg on day 13, she developed a fever (38.7-C) and mild cough. Physical examination showed no abnormal findings; laboratory tests revealed a slightly elevated C-reactive protein (1.04 g/dL; reference, 0.00Y0.39 g/dL), mild leukocytosis (8000 cells/mm3; reference, 3600Y9000 cells/mm3), and 1.9% eosinophils (reference, 0%Y6.0%). A high-resolution chest computed tomography (HRCT) was performed on day 14 and showed numerous www.psychopharmacology.com