Background

It is estimated that approximately 1% of the world population has schizophrenia.¹ Of those individuals, between 20% and 60% will experience residual symptoms causing functional impairment despite adequate adherence with antipsychotic monotherapy.² If symptoms persist after 2 medication trials, the patient is considered to have treatment-resistant schizophrenia (TRS), and the only FDA-approved medication is clozapine.^3-5 However, in a 21-study review by Siskind et al, 60% of patients with TRS failed to respond to clozapine.⁶ At this point, treatment guidelines are not well-established although several other treatments are frequently trialed clinically to augment clozapine response. These strategies include antidepressant or mood stabilizer augmentation, electroconvulsive therapy, recurrent transcranial magnetic stimulation, and dual antipsychotic treatment.⁷ The theoretical benefit of dual antipsychotic therapy is the synergistic effect of targeting different receptor types, particularly the dopamine-2 (D2) and non-D2 receptors when combining first-generation and second-generation antipsychotic medication.⁸

Poor medication adherence is a prevalent issue in patients with schizophrenia. A 20% reduction in adherence has been correlated with a 3.1-point increase on the Positive and Negative Syndrome Scale score.⁹ Patients with schizophrenia may struggle for several reasons, some of which are inherent to the disease itself. For example, lack of insight, avolition, and deficits in prospective memory can all compromise the ability to take medication or recall if it has been taken. Impaired recognition memory among patients with schizophrenia, as somewhat evidenced by poor performance on the Wisconsin Card Sort Test (WCST), also contributes to difficulty identifying and separating individual pills. The WCST is a neuropsychological exam that tests a subject’s proficiency to sort items based on new or changing rules. Recognition memory is integral to good performance.⁹ Clozapine is associated with numerous severe adverse effects that may make tolerating it difficult. Adding an additional antipsychotic further increases the likelihood of adverse effects and inability to tolerate the treatment regimen.¹ For patients with TRS on clozapine, the addition of a long-acting injectable (LAI) antipsychotic medication has previously been shown to reduce length of hospital stay and risk of subsequent hospitalizations.¹⁰ LAIs have frequently been used in conjunction with clozapine for dual antipsychotic therapy to reduce symptoms and improve quality of life through guaranteed treatment continuity.

In patients with TRS, the reduced hazard ratio for rehospitalization found in the oral clozapine and LAI treatment group was lost for patients who have had more than 6 past hospitalizations.¹¹ Therefore, patients with TRS and an extensive history of hospitalizations may benefit from removing oral antipsychotic medications entirely.¹² The use of dual LAIs has become increasingly common in clinical practice, a phenomenon best described by Cipolla et al in 2024.¹³ Greater symptom resolution, better control of medication plasma concentrations, and increased medication adherence were consistently reported across the 15 articles included in the review. Furthermore, dual LAI therapy exhibited no further adverse effects than the previously reported safety profiles of LAI monotherapy. However, the review conducted by Cipolla et al also reveals the lack of studies available on this topic. To our knowledge, there are currently no additional publications available on this topic since the 2024 systematic review.^2,14-19 In this case report, we offer another successful trial of dual antipsychotic LAI in a patient with TRS.

Case Report

A 53-year-old male with a past psychiatric history of schizoaffective disorder bipolar type and past medical history of hypertension, hypercholesterolemia, and hypothyroidism presented to the hospital from his nursing home with reports of poor impulse control, aggression, reacting to internal stimuli, and being hyperverbal in the context of medication nonadherence for 2 weeks prior to admission. He was first hospitalized psychiatrically at age 17 and has been hospitalized or otherwise institutionalized (incarcerated, etc) several times each year since his initial diagnosis. He was initially trialed on clozapine at his nursing home in 2008, but it was discontinued due to poor adherence. He was later incarcerated for a prolonged period of time, and clozapine was restarted during a state hospitalization. He has been on this medication at least since 2022 though the exact start date is difficult to determine. Paliperidone palmitate intramuscular injection was started during a January 2024 admission after a prolonged period of medication nonadherence. Prior to his current presentation, he had been stable on clozapine 200 mg by mouth nightly, paliperidone palmitate intramuscular (IM) 234 mg monthly, and escitalopram 10 mg by mouth daily. Baseline clozapine concentrations were unavailable as they were not done on admission and patient resides at a nursing home. At baseline, he is friendly and sociable, albeit consistently with a disorganized thought process and frequently reacting to internal stimuli.

On admission, he exhibited agitation, mood lability, and aggressive behavior toward staff and other patients. To reduce the symptoms of mania, escitalopram was discontinued, and paliperidone palmitate was given 5 days early. Clozapine was slowly retitrated due to an unclear history of possible seizures during a prior clozapine titration. On day 10, he was prescribed clozapine 100 mg with only intermittent refusals. By day 12, he consistently refused all psychotropics. On day 20, he spontaneously requested quetiapine and was briefly adherent for 5 days before consistently refusing. (See the Table for full medication administration and/or refusal.) On day 29, the clozapine was discontinued. Efforts continued to encourage the patient to take his maintenance paliperidone palmitate injection, but the patient continued to decline until day 33 when the dose was administered.

During the admission, he became increasingly uncooperative, agitated, aggressive, intrusive, paranoid, and hypersexual. This presentation, combined with the patient’s inconsistent adherence with his oral antipsychotic medications, led to the decision to start the patient on a second LAI. He had received up to 15 mg of haloperidol during this inpatient admission, previously had been prescribed oral haloperidol 10 mg twice daily in 2012, and was on 100 mg of haloperidol decanoate in 2011. The team agreed to start an IM dose of haloperidol 10 times his recently tolerated oral dose of haloperidol, and after patient consent, he was given 150 mg of haloperidol decanoate on day 40. By day 46, he was observed with a less disorganized thought process, was less hyperverbal, had more redirectable speech, and began exhibiting some goal orientation with regards to pursuing his hobbies. Although still reacting to internal stimuli, he had overall less internal stimulus as exhibited by his ability to carry conversations with his peers or care team for longer periods of time. Notably, whereas he was previously unable to tolerate speaking with more than 1 individual at a time, he was able to handle conversations with 2 or more people after dual LAI.

Most prominently, his aggressive behaviors were largely resolved, as exemplified by the lack of emergency medications administered after dual LAI. Prior to receiving the second LAI, he required 10 emergency antipsychotic medications over 2 weeks. By day 47, he was friendly, frequently seen helping the staff set up for or clean up from groups, and was less overtly hypersexual with female staff and visitors. Because the nursing home declined to accept the patient until medications were at steady state and the decanoate was not administered at a loading dose, the team started oral haloperidol 10 mg on day 48 to facilitate discharge. After receiving his second LAI and becoming adherent with oral haloperidol, he required only 1 emergency antipsychotic medication over the course of 2 weeks. Additionally, he went from being labile and largely irritable to predominantly euthymic. The care team watched carefully for adverse side effects from the dual LAI treatment, such as extrapyramidal symptoms, anticholinergic effects, or excessive sedation, but no adverse side effects were noted.

TABLEAntipsychotic administration and refusal during admission

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Some symptoms did not change with treatment. The patient continued to be somewhat sexually inappropriate and exhibit bizarre behaviors, such as flushing clothing items down the toilet. However, per the psychiatric team—including individual clinicians who have become familiar with the patient over several years of hospitalizations—the patient largely returned to his baseline by day 51 of admission, and the physical examination noted pacing that had been consistent throughout admission but no rigidity in upper extremities.

Discussion

For TRS for which dual antipsychotic therapy is indicated, dual LAI offers a clinically relevant solution for patients who struggle with oral medication adherence or might struggle with electroconvulsive therapy. Furthermore, in this patient with TRS who failed the addition of LAI paliperidone palmitate to oral clozapine, dual LAI therapy led to successful symptom improvement. This case illustrates a potential solution to the problem presented in Tien et al, in which patients with TRS on clozapine who have a history of more than 6 past hospitalizations did not benefit from the addition of LAI.¹¹ Based on this case report, patients with TRS on clozapine who have an extensive hospitalization history and fail the addition of an LAI may be trialed on dual LAI therapy. Dual LAI had no adverse side effects in this patient, which is consistent with previous studies. Dual LAI can reduce symptom burden, decrease hospitalization duration, and contribute to improved quality of life.¹³ However, further research using larger sample sizes and standardized assessments is still required to establish the use of dual LAI in national and international guidelines.

Conclusion

We present a patient with TRS and poor oral medication adherence who, after consenting to dual LAI, had great symptom resolution of his aggressive behaviors and was largely restored to his baseline presentation without adverse side effects. Our report contributes another case of successful dual LAI to the limited literature available on this topic. Additionally, this case may offer a solution to improve treatment for patients with TRS on clozapine who have an extensive history of hospitalizations and fail the addition of an LAI.