Aripiprazole Long-acting Injectable Two-injection Start to Manage Supersensitivity Psychosis: A Case Report

Abstract

Dopamine supersensitivity psychosis (DSP) is characterized by treatment resistance, tardive dyskinesia, and worsening psychotic symptoms due to long-term antipsychotic use. A 52-year-old woman with treatment-resistant schizophrenia and possible DSP continued to experience persistent psychotic symptoms despite high-dose antipsychotic treatment. Through close follow-up, symptom improvement was observed following the gradual reduction of antipsychotic doses and the introduction of the aripiprazole long-acting injectable (LAI) two-injection start regimen. This approach may offer a rapid and effective strategy for stabilizing dopamine receptors in patients with DSP. This case highlights the potential role of aripiprazole LAI in DSP management and symptom improvement in complex clinical presentations.

INTRODUCTION

Approximately 30% of patients with schizophrenia experience persistent severe symptoms despite appropriate pharmacotherapy, a condition termed treatment-resistant schizophrenia (TRS) [1,2]. Furthermore, up to 60% of patients with TRS may not respond even to clozapine [3,4]. Dopamine supersensitivity psychosis (DSP) has been proposed as a contributing factor in the etiology of TRS [5,6]. Initially described by Chouinard et al. [7] in 1978, DSP is characterized by a worsening of psychotic symptoms upon treatment cessation, necessitating higher drug doses to manage psychosis, often accompanied by tardive dyskinesia [8]. This phenomenon is hypothesized to result from compensatory upregulation of D2 receptors following prolonged antipsychotic treatment [9]. Although DSP was originally described in the context of first-generation antipsychotics, subsequent research has also documented its occurrence with second-generation antipsychotics [9].

Aripiprazole, an atypical antipsychotic with unique dopamine D2 receptor partial agonist properties, is often referred to as a “dopamine system stabilizer” [10]. While it has demonstrated efficacy in preventing and improving DSP in animal models, caution is advised when switching DSP patients to aripiprazole, as it may exacerbate symptoms during transition [11,12]. Nevertheless, aripiprazole has been suggested as a potential monotherapy or adjunctive therapy to mitigate DSP and improve treatment outcomes [9].

High doses of antipsychotics with short half-lives are more likely to induce DSP than those with longer half-lives [13]. Strategies to manage DSP include intermittent dosing, long-acting injectable antipsychotics (LAI), and modified electroconvulsive therapy (ECT) [9,14]. LAIs offer additional benefits, such as consistent bioavailability and reduced plasma level fluctuations [15]. Notably, aripiprazole LAI has shown promise in managing DSP when combined with modified ECT [16]. Recently, the European Medicines Agency approved a novel initiation strategy for aripiprazole LAI involving two separate 400 mg injections administered concurrently at different sites, accompanied by a single 20 mg oral dose, thereby eliminating the need for a 14-day overlap with oral aripiprazole [17,18].

Here, a case of TRS with possible supersensitivity psychosis is presented, demonstrating stabilization after many years with aripiprazole LAI initiated using the two-injection regimen in combination with clozapine.

CASE

A 52-year-old woman with a long-standing history of schizophrenia first experienced symptoms during her university years, including irritability, fear, paranoia, and referential delusions. During her initial psychiatric evaluation, she was prescribed pimozide and biperiden, which allowed her to return to her studies and work as a computer operator. After four years, she re-enrolled in university but discontinued treatment, believing her symptoms had resolved. However, she experienced a recurrence of fear and paranoia, leading to a prescription for melperone, which she discontinued within a few months due to nonadherence.

Her first psychiatric hospitalization occurred during her second year at university. At the time, she exhibited severe symptoms, including locking doors due to fear, spraying insecticide on her body because of a sensation of insects, believing her family members were imposters, and refusing to eat home-cooked food. Physical and neurological examinations, routine laboratory tests, electroencephalography (EEG), and cranial CT revealed no abnormalities. A diagnosis of schizophrenia was established, and she was started on haloperidol (20 mg/day) and biperiden (4 mg/day). Due to side effects, her treatment was switched to carbamazepine (400 mg/day) and diazepam (15 mg/day). However, her discharge prescription was unclear, and she was readmitted to the clinic 10 days later with worsening symptoms. Haloperidol and biperiden were reintroduced for five days before her family requested discharge.

Over subsequent years, the patient was treated with various antipsychotics, including fluphenazine depot, risperidone, sertraline, aripiprazole, and flupentixol depot. Although partially effective, these treatments did not fully alleviate her symptoms. Since 2012, she had been under the care of a local psychiatric center. By 2023, her treatment regimen included haloperidol decanoate (150 mg/month, intramuscularly), clozapine (525 mg/day), aripiprazole (30 mg/day), amitriptyline (25 mg/day), and biperiden (4 mg/day). She presented with a blunted affect, reporting dysphoria, persecutory delusions, Schneiderian passivity phenomena, and auditory hallucinations. On examination, she exhibited head-bobbing and extremity tremors, consistent with tardive dyskinesia. Aripiprazole was tapered gradually, leading to a reduction in auditory hallucinations as the dose was lowered to 15 mg/day. Cranial MRI, EEG, and routine laboratory tests were conducted as part of her evaluation. Six weeks later, following hospitalization and discharge from a surgery clinic for ileus and an ovarian abscess, the patient was seen again. During this medical admission, all psychiatric medications were discontinued. Psychiatric treatment was gradually restarted during her hospitalization, including aripiprazole (7.5 mg/day), clozapine (200 mg/day), haloperidol decanoate (150 mg/month), and biperiden (2 mg/day). During subsequent follow-ups, dyskinesia and tremors became less pronounced, and auditory hallucinations decreased, though delusions and Schneiderian passivity phenomena persisted. Haloperidol decanoate was discontinued due to its suspected contribution to DSP. Shortly before the next scheduled depot injection, the patient experienced a resurgence of auditory hallucinations. Despite this, haloperidol decanoate was not reintroduced. Instead, aripiprazole was increased to 15 mg/day to address the worsening hallucinations while maintaining close monitoring. Over the following weeks, auditory hallucinations further decreased, and the patient reported feeling less fearful. However, her fear and paranoia intensified over time, prompting a gradual increase in clozapine, which was tapered up to 250 mg/day over the next month. As her dyskinesia and tremors resolved, biperiden was tapered and eventually discontinued.

Following the reduction in auditory hallucinations, aripiprazole LAI was initiated using the two-injection start regimen. The patient was administered two 400 mg injections at different sites on the same day, accompanied by a single 20 mg dose of oral aripiprazole. Oral aripiprazole was subsequently discontinued, and her ongoing treatment included aripiprazole LAI (400 mg/month) and clozapine (250 mg/day).

Over the ensuing weeks, the patient demonstrated significant clinical improvement. She became more socially engaged, began watching television, and exhibited reduced fear and paranoia. Her auditory hallucinations were nearly resolved, and her condition stabilized for the first time in many years.

DISCUSSION

The patient remained clinically unstable despite treatment with multiple high-dose antipsychotics. Evidence from the literature suggests that aripiprazole, when used in combination with other antipsychotic medications, may exacerbate psychotic symptoms in certain cases [19,20]. As a result, aripiprazole was initially tapered from her treatment plan. As her medical condition evolved, it became necessary to re-evaluate and adjust her treatment plan. Dopamine supersensitivity, thought to arise from the upregulation of dopamine D2 receptors after long-term antipsychotic use, was identified as a possible contributor to her recurring psychotic episodes [13]. Furthermore, tardive dyskinesia has been associated with supersensitivity psychosis and recurrent episodes of schizophrenia [21-23]. In this case, the coexistence of tardive dyskinesia and tolerance to three high-dose antipsychotics were considered strong indicators of possible DSP. Haloperidol, known for its potent D2 receptor blockade [24], was suspected to be a primary contributor to DSP in this patient. Clozapine, the only antipsychotic approved explicitly for TRS, has demonstrated notable efficacy in managing tardive dyskinesia, likely due to its loose binding affinity for dopamine D2 receptors [25,26]. Close follow-up of the patient showed that reducing side effects and improving psychotic symptoms through individualized treatment adjustments were critical to achieving stabilization.

In chronic cases, LAI formulations are particularly beneficial in maintaining patients’ quality of life and fostering social participation [27]. Aripiprazole LAI has demonstrated effectiveness in preventing relapses in patients with schizophrenia [28]. In addition to relapse prevention, aripiprazole has been considered for DSP treatment—particularly as an add-on to other antipsychotics—due to its receptor-stabilizing effect, though supporting evidence remains limited [12,13,29]. Its relevance in DSP stems from its unique pharmacodynamic profile: as a partial agonist at dopamine D2 receptors, aripiprazole is thought to enhance dopaminergic activity when dopamine levels are low and to attenuate it when levels are excessive [30]. Recent studies have also explored alternative initiation regimens for aripiprazole LAI [18,31]. The European Medicines Agency has approved both the original initiation protocol and this alternative two-injection start regimen for aripiprazole [17]. This alternative method was developed to ensure that therapeutic plasma levels of aripiprazole are reached on the first day of treatment and maintained consistently across the dosing interval [31]. In this case, immediate stabilization of dopamine receptors was deemed more advantageous, and the two-injection start regimen was administered.

The patient had struggled with persistent persecutory delusions, Schneiderian passivity phenomena, and auditory hallucinations for many years. Adding aripiprazole LAI to clozapine resulted in noticeable improvements in the patient’s condition. Psychotic symptoms diminished, social engagement increased, and emotional distress lessened significantly. This case highlights the importance of patient-specialized treatment to manage symptoms effectively. The two-injection start regimen for aripiprazole LAI may provide more rapid receptor stabilization in patients with DSP. However, further research is required to better understand its effectiveness and potential applications in broader clinical practice.