Clozapine Withdrawal Related Mania in an Adolescent: Case Report

Abstract

Clozapine discontinuation is known to trigger withdrawal-associated psychosis, but non-psychotic withdrawal symptoms, though clinically significant, are less frequently discussed. Proposed mechanisms include dopaminergic receptor upregulation, cholinergic rebound, and serotonergic dysregulation. No previous reports describe clozapine withdrawal-associated mania in pediatric patients, and only three cases of withdrawal-related mania have been described in adults. We describe a 16-year-old female with schizophrenia who had previously shown limited response and poor tolerability to multiple antipsychotics. Since clozapine is known to be effective in psychotic symptoms nonresponsive to other antipsychotics, it was initiated during hospitalization and titrated to 250 mg/day. It was stopped after 7 days at the target dose due to suspected myocarditis. After 4 days, the patient presented with elated mood, tachypsychia, hypersexuality, and decreased need for sleep, without psychotic symptoms. Symptoms resolved over 10 days with olanzapine. Psychotic symptoms re-emerged post-discharge, in the absence of mood features. This appears to be the first report of clozapine withdrawal-associated mania in an adolescent without a previous mood disorder. Earlier cases have only involved adults with schizoaffective disorder and long-term treatment. While schizoaffective disorder was considered in this case, the brief duration of symptoms, full remission with antipsychotic monotherapy, and close temporal link to clozapine cessation favor a withdrawal-related phenomenon. This case exposes for the first time in the literature the onset of manic symptoms following clozapine withdrawal in an adolescent with only psychotic symptoms before this trial. This report raises awareness for the importance of monitoring different effects during and after psychopharmacologic treatment, other than the reappearance of psychotic symptomatology. It also raises questions about diagnostic evolution in early-onset psychosis.

Introduction

We present the case of a 16-year-old female with a previous diagnosis of schizophrenia and inadequate response to multiple antipsychotic trials, in whom clozapine was initiated during psychiatric hospitalization. Treatment was abruptly discontinued due to suspected myocarditis. Following withdrawal, the patient developed acute manic symptoms. To our knowledge, this is the first reported case of clozapine withdrawal-associated mania in a pediatric patient.

Case Description

A 16-year-old female was admitted to an Adolescent and Young Adult Inpatient Psychiatric Unit in October 2024 due to psychotic symptoms, including disorganized behavior, persecutory delusions, delusional interpretations, and thought diffusion phenomena.

She had a previous diagnosis of schizophrenia, according to the DSM-5 diagnostic criteria, ¹ and two previous psychiatric hospitalizations for psychotic episodes, the first in 2022, lasting three weeks, and the second in 2024, lasting four weeks. Three trials of different antipsychotics at therapeutic doses of olanzapine (10 mg/day), risperidone (3 mg/day), and aripiprazole (15 mg/day) were unsuccessful due to limited efficacy and intolerable side effects. In the case of olanzapine, 10 mg/day was tolerated, but sedation and weight gain prevented higher dosing, limiting its overall effectiveness. Due to inadequate response and tolerability, clozapine was initiated following the Maudsley Prescribing Guidelines. ² Due to excessive somnolence, titration was slowed near the target dose. After 16 days, the patient reached a dose of 250 mg/day, which follows adult female non-smoker targets; we note that pediatric dosing guidelines for clozapine are extrapolated from adult regimens due to limited evidence.

After 7 days on 250 mg/day, she developed tachycardia, fever, flu-like symptoms, fatigue, dyspnea, and chest pain. Myocarditis was suspected, and Pediatric Cardiology was consulted, with clozapine being immediately discontinued. No corticosteroids or other medications with affective side effects were administered.

A complete blood count at that time showed leukocytosis (12,300/µL) with no eosinophilia, and C-reactive protein was mildly elevated (12 mg/L). Myocarditis was later ruled out based on normal troponin and echocardiogram findings.

After 4 days of withdrawal, the patient abruptly exhibited elated mood, labile affect, tachypsychism, increased libido with hypersexual behavior, and decreased need for sleep. Psychotic symptoms were absent, and she displayed new-onset insight into her previous psychotic experiences. An organic workup (routine blood tests, thyroid function, toxicology screen) was unremarkable.

Due to high-risk behaviors, olanzapine was reintroduced and titrated to 10 mg/day. Although its previous efficacy had been limited, olanzapine was selected for its sedative profile, previous short-term tolerability at 10 mg/day, and low risk of exacerbating manic excitation. It was used as a pragmatic containment strategy under inpatient monitoring.

Manic symptoms persisted for 10 days before gradually resolving. A mood stabilizer was considered, but deferred due to the transient nature of symptoms and rapid improvement. The patient maintained euthymia but lacked insight into the need for continued pharmacological treatment. No psychotic symptoms were observed until discharge, 12 days later. However, soon after discharge, psychotic symptoms recurred in the absence of mood disturbances.

Discussion

Clozapine discontinuation is known to trigger withdrawal-associated psychosis, but non-psychotic withdrawal symptoms, though clinically significant, are less frequently discussed.^2,3 Possible mechanisms include dopaminergic receptor upregulation due to chronic blockade, cholinergic rebound, and serotonergic dysregulation.^3,4 This dopaminergic hypersensitivity hypothesis, discussed in previous literature, may explain withdrawal-induced mania, as abrupt cessation leads to a rebound increase in dopaminergic activity.

A systematic review of clozapine withdrawal ² identified only three cases of withdrawal-related mania, all in adults with schizoaffective disorder and treatment durations exceeding one year. The symptoms appeared 2 days to 1 week after the discontinuation of clozapine, titrated in dosages of 50 mg to 500 mg/day. To our knowledge, no previous reports describe clozapine withdrawal-associated mania in pediatric patients.

We discussed whether this presentation could represent an emerging schizoaffective disorder. In favor of this, mood symptoms appeared independently of psychotic symptoms, were intense enough to impair functioning, and included insight into psychosis during the manic period. However, the episode was brief (10 days), resolved fully with antipsychotic monotherapy, and occurred in close temporal association with clozapine withdrawal, which more strongly suggests a withdrawal-related phenomenon rather than an emergent bipolar spectrum disorder. The patient’s future course will clarify diagnostic evolution, as a proportion of early-onset psychosis cases later meet schizoaffective criteria. ³

Moreover, although mood symptoms can occasionally occur within the course of schizophrenia itself, the abrupt onset after clozapine discontinuation and full remission within 10 days make a withdrawal-related mechanism more likely in this case.

We did not perform a formal autoimmune encephalitis antibody panel, as the pretest probability was considered low in the absence of memory deficits, altered mental status, new focal neurological deficits, or seizures. We acknowledge this as a limitation and emphasize that targeted testing should be considered if red flags emerge in similar clinical scenarios.

Conclusion

This case highlights the emergence of withdrawal-related manic symptoms in an adolescent with no previous history of mood disorder. Although the episode did not meet the full criteria for a schizoaffective disorder diagnosis, it raises concerns regarding the long-term diagnostic trajectory, particularly given her suboptimal response to antipsychotic treatment. Importantly, the typical onset of schizoaffective disorder is in early adulthood, and a significant proportion of patients initially diagnosed with schizophrenia later receive a schizoaffective disorder diagnosis. ⁴ Alternative explanations, including mood symptoms within the course of schizophrenia or an organic etiology, were considered but judged less likely in this case. As this is the first reported case of clozapine withdrawal-associated mania in an adolescent, it underscores the importance of continued monitoring into adulthood to assess the recurrence of manic episodes and the evolution of psychotic symptoms. Longitudinal and prospective follow-up will be essential to refine diagnostic accuracy, guide appropriate treatment, and improve prognostic understanding.