Successful Add-on Viloxazine to Clozapine-Responsive Schizophrenia Mitigated Cognitive, Negative and Metabolic Domains

Abstract

Early-onset schizophrenia is notorious for poor prognostication and treatment-refractoriness. Clozapine remains a viable option, albeit off-label, but is clearly underutilized in this population. Use is typically fraught with panoply of drastic side effects. Here, authors report on an adolescent case with schizophrenia that responded ultimately to clozapine. Add-on viloxazine was advantageous spanning different symptom domains, mitigating metabolic parameters and addressing clozapine-sialorrhea. This might open new venues for such complicated, yet commonplace, clinical scenarios.

Early-onset schizophrenia (EOS), by definition, has an onset before age of 18. It is notorious for heavy genetic load, soft neurologic signs, male preponderance, insidious onset, mainly negative and cognitive domains presentation, gross functional impairment, poor prognostication, and generally poor antipsychotic response. Clozapine has shown an even greater differential efficacy in EOS compared to adult counterparts spanning different symptom domains.¹ This might be related to clozapine’s unique composite mechanism of action. Nonetheless, clozapine is clearly underutilized in child psychiatry. Use is typically plagued with a host of serious side effects.

Here, we are reporting on an adolescent case with EOS that has favourably and ultimately responded to clozapine but with problematic weight gain and sialorrhea. We embarked on a trial of add-on viloxazine to address cognitive facets. Viloxazine surprisingly helped with both cognitive and negative domains, mitigated metabolic parameters and successfully tacked sialorrhea as well. This might open new venues for such refractory cases.

A 15-year-old Bahrini male youngster was casualty petitioned by his parents for disorganized behaviour coupled with serious scholastic drop with one year incipient onset of social withdrawal, barricading himself from others, neglected self-hygiene, fitful sleep, vague and digressive speech, and scholastic unattainment. School reported escalating hostile behaviour recently, unkempt dishevelled appearance and academic failure. At home, he began to exhibit total insomnia, pervasive suspiciousness, and, unfounded inordinate giggling. At times, he was noticed to be muttering under breath. This ran a progressively deteriorating course and reached a nadir when the patient, in jactitation, held a knife to ‘protect’ himself from those ‘stealing his thoughts’ as he put it. The patient has a schizophrenic home-bound paternal uncle that is currently maintained on LAI paliperidone. He has unremarkable developmental trajectories, apart from occasional motor tics as mother has reported. He was hospitalized for safety concerns. Full work-up for a ‘first-episode psychosis’ was undertaken including baseline laboratory investigations, TFT, B12, Prolactin, Toxicology screen, electrocardiogram, electroencephalogram, and brain scan, all with negative yield. The patient has failed adequate sequential trials on aripiprazole, olanzapine, and paliperidone monotherapies, despite ensured compliance, in a private psychiatric clinic. He had put on much weight, though. Clozapine was then proposed and psychoeducation with bibliotherapy was provided. Clozapine was titrated up to 300 mg/d over 4 weeks with a weekly CBC monitoring protocol. Tangible improvement was noticed chiefly in the positive and aggressive domains. He was discharged to follow up at outpatient clinic. Despite symptomatic remission, weight gain together with negative and cognitive domains remained very much impairing both socially and academically. Sialorrhea was dose-limiting when we attempted to push up clozapine dosage and meanwhile too bothersome side effect both to the patient and caregivers. Viloxazine was suggested for cognitive concomitants and parents’ consent obtained. Digital Symbol Substitution Test (DSST) was administered beforehand (and read 35). It was titrated up to 400 mg/d, over 4 weeks (weight of 65 kg), whilst bringing clozapine down to 200 mg/d. Better interpersonal socialization was noted. Negative symptomatology clinical improvement was objectified on 4-item brief negative symptom assessment (from baseline of 23 down to 7). DSST was readministered to assess cognitive domain and the results were very impressive (it went up to 47) going in tandem with reported gains on selected academic tasks that he started to pursue as part of cognitive remediation therapy with our occupational therapy staff. No pharmacokinetic drug interactions of significance were observed. Strikingly, the patient experienced significant weight loss with viloxazine (59 kg at time of writing this report), which was advantageous given previous psychotropic-induced weight gain. This further brightened his mood. Sialorrhea totally diminished (rated on drooling severity and frequency scale DSFS from 9 down to 4). He is now being engaged in social skills training facility and following up with a nutritionist for dietary advice.

Viloxazine, originally marketed as a bicyclic antidepressant, and FDA-designated as an orphan drug for narcolepsy/cataplexy, was recently approved for ADHD in children aged 6–17 years at 100–400 mg/d, as an NRI, a non-stimulant, akin to atomoxetine.²

It seems that boosting nor-adrenergic (NE) drive in the prefrontal cortex (PFC) by viloxazine accounts for its procongnitive effects akin to its mechanism in ADHD. Norepinephrine reuptake inhibition (NRI) by viloxazine with subsequent disinhibition of dopaminergic projections to the dorsolateral PFC corrects the dopamine hypofrontality underlying the negative symptoms. Moreover, decreased NE in chronic schizophrenics is well-documented in the literature and psychotropics acting primarily to increase NE (e.g., milnacipran, mirtazapine, atomoxetine) were reported to mitigate negative symptoms.^3–5 This might explain, in part, how viloxazine can help with deficit state. Weight loss seen in this case might be ascribed to anorexogenic effects of viloxazine. This resonates with the case of the NRI reboxeine use in metabolic syndrome in anecdotal reports.⁶ Importantly, viloxazine by inhibiting CYP 1A2, to which clozapine is a substrate, can spare higher doses (as in our case where we could reduce it down to 200 mg/d without losing therapeutic efficacy). And since metabolic syndrome could be dose-dependent (at least for some AAP, Naguy; Personal Communication), this could be a pharmacological strategy to mitigate metabolic syndrome. Similarly, fluvoxamine, an SSRI with CYP 1A2 inhibitor activity, helped clozapine-related metabolic syndrome.⁷ Diminished sialorrhea on viloxazine can be attributed again to increased NE drive, similar to the reported successful use of the norepinephrine-dopamine reuptake inhibitor bupropion for clozapine-induced sialorrhea.⁸

Cognitive enhancers, like viloxazine, remain a viable option to tackle residual negative and cognitive domains in schizophrenia that adversely and enormously impact functioning. This might also be possibly a novel strategy to counteract metabolic syndrome that plagued treatment with atypical antipsychotics, now increasingly and oftentimes indiscriminately used in paediatric population who are especially at heightened risk by virtue of age. Furthermore, it can also be an option to deploy for the bothersome clozapine-induced sialorrhea that might jeopardize treatment-adherence. Definitely, large, well-designed studies are needed to replicate this finding to gauze its exact role in the psychopharmacotherapy of EOS algorithms.