Dose-related Manic Switch with Psychotic Features Following Bupropion Titration: A Case Report

Abstract

Bupropion is an antidepressant commonly considered to have a relatively low risk of inducing manic switch in the treatment of bipolar depression. However, in certain cases—particularly at higher doses and in the presence of psychotic features—manic switching may occur. In this report, we present a male patient with bipolar I disorder who developed a psychotic manic episode following an increase in bupropion XL dose from 150 mg to 300 mg/day while receiving lithium treatment. This case highlights that, despite its reputation as a relatively safe antidepressant in bipolar depression, bupropion may precipitate dose-related manic and psychotic switches. Based on the clinical findings observed in this patient, cautious dose titration beyond 150 mg/day may be considered in individuals with bipolar disorder with psychotic features, with particular attention to close clinical monitoring following any dose escalation.

INTRODUCTION

The treatment of bipolar depression remains challenging, as antidepressants may alleviate depressive symptoms while increasing the risk of manic switching. Bupropion, a dopamine and noradrenaline reuptake inhibitor, has been reported to carry a lower risk of mood switching compared with selective serotonin reuptake inhibitors [1,2]. Nevertheless, recent reports suggest that manic or psychotic episodes may occur, particularly at higher doses and following dose escalation [3,4].

Moreover, cases of bupropion-induced mania have been described even in patients receiving mood stabilizers such as lithium or valproate [5,6]. Dopaminergic activation may further increase vulnerability to psychotic symptoms, especially in patients with a prior history of psychosis [7]. In this report, we present a case of psychotic manic switch following bupropion dose escalation to 300 mg/day despite therapeutic lithium levels.

Ethics Approval and Informed Consent

Written informed consent was obtained from the patient for the publication of this case report. Ethical committee approval was not required due to the descriptive nature of a single anonymized case.

CASE

The patient was a 30-year-old male, working as a miner, with a middle school education. He was single and living with his family. He had been diagnosed with bipolar I disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria and had a history of previous episodes with psychotic features.

His first documented mood episode occurred in 2021, when he developed a manic switch following treatment with fluoxetine. In the subsequent period, long-term mood stabilizer treatment was maintained initially with valproate and later with lithium. Over the following years, he experienced both depressive episodes and episodes of psychotic mania, requiring intermittent psychiatric hospitalizations.

On October 11, 2025, the patient was admitted to our psychiatric unit with symptoms of loss of motivation, insomnia, decreased energy, reduced speech, and marked functional decline, and he was diagnosed with a depressive episode of bipolar I disorder. At admission, his treatment regimen consisted of lithium (300 mg three to four times daily; serum level 0.9 mmol/L), olanzapine (15 mg/day, administered as a single evening dose), lurasidone (40 mg/day, administered as a single evening dose), and alprazolam (0.25 mg twice daily). To target persistent depressive symptoms, bupropion XL 150 mg/day (administered as a single morning dose) was added to the treatment on October 14, 2025. Throughout the hospitalization, all pharmacological treatments were administered under the direct supervision of the clinical staff, ensuring full medication adherence and close clinical monitoring. Furthermore, to ensure diagnostic consistency and inter-rater reliability, all psychometric evaluations (Hamilton Depression Rating Scale [HAM-D] and Young Mania Rating Scale [YMRS]) were administered and independently cross-checked by the same two physicians throughout the patient’s hospitalization.

After the first week of treatment, a partial clinical improvement was observed, and the patient’s HAM-D score decreased from 28 to 20. However, due to the persistence of depressive symptoms, the dose of bupropion XL was increased to 300 mg/day (administered as a single morning dose) on October 28, 2025. Within two days of this dose escalation, the patient developed severe insomnia, psychomotor agitation, marked increase in speech, heightened sexual drive, and religious and grandiose ideation. On October 29, his YMRS score was 33, and psychotic features, including grandiose delusions and auditory hallucinations, became prominent.

At that time, the measured serum lithium trough level (drawn in the morning in a fasting state, 12 hours after the last evening dose) was 0.77 mmol/L, which remained within the therapeutic range and had been stable during hospitalization. Other potential causes of acute mood switching, including drug toxicity, active infection, thyroid dysfunction, substance use, and pharmacological interactions, were systematically excluded. Routine laboratory investigations, including complete blood count, liver and renal function tests, thyroid function tests, and toxicology screening, revealed no abnormalities. No evidence of substance use, excessive caffeine intake, acute medical illness, or recent severe sleep deprivation prior to the dose increase was identified during hospitalization. These findings further supported the interpretation that the manic switch was temporally related to the escalation of bupropion treatment. Given the close temporal relationship between dose escalation and symptom onset, the manic switch was considered most likely related to the increase in bupropion dose.

On October 30, 2025, bupropion XL was discontinued. The dose of olanzapine was increased from 15 mg/day to 20 mg/day (administered as a single evening dose), the dose of lurasidone was increased to 80 mg/day (administered as a single evening dose), and a second mood stabilizer, valproate 1,000 mg/day (500 mg twice daily), was added to the treatment regimen. Over the following two weeks, a rapid and marked improvement in manic and psychotic symptoms was observed. At discharge, the patient’s HAM-D score had decreased to 7, and his YMRS score to 4. His overall clinical condition was stable, and no adverse effects or additional toxicity were observed during hospitalization.

DISCUSSION

Bupropion is generally regarded as one of the antidepressants with a relatively lower risk of manic switching compared with other antidepressants, although switching may still occur in a subset of patients [1,2]. For instance, a comprehensive review by Thase and Sachs reported that the general risk of manic switching during acute antidepressant therapy under the protection of mood stabilizers is approximately 5% to 10% [2]. Specifically, regarding bupropion, a large comparative trial by Post et al. [1] demonstrated that the rate of manic switch remained relatively low, ranging from 4% to 14% depending on the stringency of the evaluation criteria. However, dose-related vulnerability has been emphasized in several reports [3,4].

In the present case, the patient remained clinically stable at 150 mg/day, whereas a full manic episode developed within 72 hours after dose escalation to 300 mg/day. This temporal relationship strongly supports a dose-dependent effect and highlights that even moderate dose increases may precipitate manic switching in susceptible individuals. Consistent with this rapid temporal relationship, previous reports have highlighted acute mood destabilization following dose escalation; for example, Goren and Levin [3] observed mania emerging after surpassing a 450 mg/day threshold, while Omri et al. [4] described a severe psychotic episode developing within just 24 hours of increasing the bupropion dose from 150 mg to 300 mg/day. Moreover, the rapid resolution of manic symptoms—evidenced by the YMRS score decreasing from 33 to 4 within two weeks after bupropion discontinuation—serves as a positive dechallenge, further reinforcing the dose-dependent temporal relationship. However, it should be acknowledged that the patient had a prior history of antidepressant-induced mania, which likely contributed to his increased vulnerability to mood destabilization.

Importantly, although concurrent treatment with mood stabilizers and atypical antipsychotics provides a robust prophylactic shield, manic switching associated with bupropion under such coverage, while relatively rare, is not an unexpected clinical phenomenon. Although lithium has well-established antimanic properties, bupropion-induced mania has been reported despite therapeutic lithium levels. Aggarwal and Sharma [6] described an irritable manic episode following bupropion 300 mg/day in a patient receiving lithium, while Kahyacı Kılıç et al. [5] reported psychotic manic switches under lithium and valproate at the same dose. In our patient, mania emerged despite therapeutic lithium levels (0.77 mmol/L), underscoring the need for close clinical monitoring even under mood stabilizer prophylaxis. Furthermore, the emergence of manic symptoms occurred despite concurrent treatment with olanzapine and lurasidone. This observation aligns with literature suggesting that antidepressant-induced switching may occur even in the context of complex psychopharmacological regimens [5,6].

As a dopamine and noradrenaline reuptake inhibitor, bupropion may increase dopaminergic activity and thereby facilitate the emergence of psychotic symptoms [4,7]. Dose escalation to 300 mg/day may abruptly increase dopamine transporter occupancy beyond a critical threshold, leading to a surge in dopaminergic transmission within mesolimbic pathways, which has been proposed as one potential mechanism contributing to manic and psychotic symptoms [3,4,7]. The noradrenergic enhancement may further exacerbate arousal and insomnia, contributing to the severity of the episode. However, the precise neurobiological processes underlying antidepressant-induced switching remain incompletely understood. Dwyer and Hieber [8] reported religiously themed psychotic mania following bupropion 150 mg/day, while Omri et al. described a de novo psychotic episode associated with bupropion 300 mg/day [4]. Consistent with these reports, our patient developed grandiose and sexually themed delusions after dose escalation, highlighting the need for caution when prescribing dopaminergic antidepressants in patients with a history of psychotic episodes.

In a systematic review conducted by Kumar et al. [7], a prior history of psychosis, heightened dopaminergic sensitivity, and high-dose bupropion treatment were identified as significant risk factors for the development of psychotic symptoms. Our patient exhibited both a history of psychotic episodes and exposure to the 300 mg/day dose threshold, which likely increased his vulnerability to a manic and psychotic switch. Mechanistically, regarding the concurrent use of lurasidone, this second-generation antipsychotic features a high affinity for D2 and 5-HT2A receptors, as well as notable 5-HT7 antagonism and partial agonism at 5-HT1A receptors, and is primarily effective in the treatment of bipolar depression [9,10]. In the present case, despite ongoing lurasidone treatment at 40 mg/day, a manic switch occurred following bupropion dose escalation. One possible explanation is that the dopaminergic and noradrenergic enhancement induced by bupropion may have exceeded the stabilizing capacity of lurasidone’s D2 receptor antagonism at this dose [11]. Additionally, lurasidone’s pharmacodynamic profile, which includes antidepressant properties, may not provide sufficient protection against mood elevation in vulnerable individuals. Therefore, its concurrent use may not have fully mitigated the risk of antidepressant-associated switching in this patient, suggesting that bupropion dose escalation beyond 150 mg/day warrants careful clinical consideration in bipolar patients with a history of psychotic features.

In conclusion, this case demonstrates that, although bupropion is generally regarded as a relatively safe antidepressant in the treatment of bipolar depression, it may carry a clinically significant risk of dose-related manic and psychotic switching. Notably, as observed in this case, mood stabilizer prophylaxis with lithium may not provide absolute protection in highly susceptible patients.

In the context of a complex polypharmacy regimen—including lithium, olanzapine, lurasidone, and alprazolam—careful consideration is warranted when escalating the bupropion dose beyond 150 mg/day. Potential cumulative drug interactions, including the effects of polypharmacy, as well as concurrent receptor-level actions, may contribute to an increased vulnerability to manic switching and the emergence of manic episodes; this highlights the importance of close clinical monitoring in at-risk patients. Nevertheless, given the observational nature of a single case report, these findings should be interpreted cautiously and further studies are required to clarify the relationship between bupropion dose escalation and manic switching.