Top-Up Clozapine for Risperidone LAI-Related Acute Dystonia and TR Bipolar in an Adolescent with ID-Putting the Cart before the Horse?

Abstract

Objectives

Young patients with intellectual disability (ID) have both diagnostic and therapeutic challenges. These include, inter alia, diagnostic overshadowing, diagnostic slippage and heightened vulnerability to adverse drug reactions. These would portent a generally poor prognostication.

Methods

This is a case-study of an adolescent with intellectual disability long-hospitalized for co-morbid treatment-resistant bipolar mood disorder that failed to respond to ECT. Patient partially responded to LAI risperidone with repeated ADRs. Top-up with low-dose clozapine (100 mg/d) was pursued.

Results

Low-dose clozapine top-up complemented therapeutic response (mood lability and paranoia) and strikingly safeguarded effectively against risperidone-related extrapyramidal side effects.

Conclusions

Add-on clozapine remains a viable option, albeit off-label, in young patients with ID and treatment-resistant affective/schizophreniform psychoses. Clozapine has an edge over other agents in the setting of dyskinesias.

Case Vignette. F, a 15-year old Kuwaiti youngster, known case of mild intellectual disability (FSIQ = 60), maintained on LAI risperidone 37.5 mg IM q 2 wks for disruptive behaviour, was admitted to our IP facility for few weeks history of pronounced hyperactivity, heightened upbeat mood, lack of sleep, loquacious speech with obscenities and inappropriate sexual behaviours. A diagnosis of superimposed bipolar mood disorder I was entertained. YMRS scored 49 on admission. Valproate was introduced and titrated up to 1000 mg/d, LAI risperidone increased to 50 mg IM q 2 wks, with add-on lorazepam 2 mg/d. After 4 weeks on this regimen, patient continued to exhibit marked mood lability, fleeting paranoia and grandiosity and episodic dyscontrol that mandated frequent brief physical restraints and PRN olanzapine Zydis. Moreover, she experienced repeated acute dystonic reactions (oculogyric crisis and torticollis). Procyclidine 5 mg/d was added but contributed to mood instability. Treating team was also concerned about the anti-cognitive burden of procyclidine in a patient with baseline ID. Since patient qualified to TR bipolar mood disorder, ECT was suggested and parental consent obtained. Medical clearance was undertaken and she had 12 bitemporal modified ECT under GA with adequate seizure over another 4 wks. The response was at best mediocre and she continued to have EPS. A top-up of low-dose clozapine was discussed on grand rounds. Metabolic bundle, CBC with differential and ECG were all done beforehand. Procyclidine was phased out gradually. Over 2 wks, clozapine was titrated up to 100 mg/d. Tangible improvement was clearly noticeable, 2 wks later, with YMRS down to 15. Trial was achieved with great tolerability. Strikingly, no EPS was experienced since then. Three months have elapsed at time of writing this report and patient was discharged and seen in OPD faring pretty well and therapeutic response is well sustained.

Psychopharmacology-Science and Art. As this case amply illustrates, patient qualified to treatment-resistant bipolar mood disorder. She was unresponsive to ECT treatment as well. Instead of swapping to clozapine and then augment with high-potency D2 blocker, we opted to do it the other way around. We kept risperidone in place as this meant 80% mesolimbic D2 blockade as evidenced by repeated EPS and top-up with low-dose clozapine was pursued to tackle other transporters instead (as dopalytic actions would sound mechanistically redundant) whilst making use of clozapine anticholinergic drive to safeguard against EPS- akin to an old tradition of using TCA (with anticholinergic activity) to safeguard against EPS associated with conventional high-potency antipsychotics (Naguy A, Personal Communication). Clozapine has been similarly used successfully to address TDs, cerebellar tremors, and dyskinesias.¹

Clinical Efficacy of Clozapine in CAP population. Clozapine has been demonstrated to have an even greater differential efficacy in early-onset schizophrenia compared to adult counterparts spanning different symptom domains.² Efficacy in CAP population has been shown for treatment-resistant schizophrenia and mania as well. This might be related to clozapine’s unique composite mechanism of action (Table 1). Nonetheless, clozapine is clearly underutilized in child psychiatry. Off-label use is typically plagued with a host of serious side effects, barring 5 black box warnings.

Table 1. Pharmacologic Portfolio of Clozapine.

• D1, 2, 3, 4, 5 blockade - low potency & rapidly-dissociating (hit-and-run) 100 times • 5HT1A, 2A, 2C, 6, 7 blockade • M1, 2, 3, 5 blockade - highly anticholinergic • M4 agonism - sialorrhea • H1 blockade - highly sedating and weight gain • α 1, α 2 blockade - orthostasis • increases GABA turnover in N. accumbens (avoid clozapine-benzodiazepines concomitantly) • normalizes sensory gating abnormalities • GlyT inhibition - procognitive

Some Practicalities of Clozapine Use in CAP population. Younger age is associated with greater weight gain. Metformin is strongly recommended from the outset.³ A reasonable starting dose is 0.3 mg/kg. Titration generally based on tolerability. CAP population require higher doses and plasma levels. This is typically correlated with dosing at 3–6 mg/kg. Divided dosing is necessary early in treatment with the main bulk given at bedtime. Clozapine-to-norclozapine metabolic ratio is a bit higher in adolescents (1.6 vs. 1.32 for adults).⁴ Apart from metabolic syndrome, akathisia⁵ is unusually commonplace in CAP population (20%).

Anticholinergic Drive of Clozapine. (Table 2) Clozapine is strongly anticholinergic. It blocks M1, M2, M3 and M5 muscarinic receptors (but agonist at M4 which might contribute to sialorrhea). Ileus remains a definite risk.

Table 2. Anticholinergic Drive of Clozapine.

Clozapine 50 mg = Benzotropine 1 mg = Trihexphenidyl 2.5 mg = Diphenhydramine 25 mg