Introduction

Despite adequate pharmacotherapy, approximately one-third of individuals with schizophrenia will have an inadequate response to treatment and are considered to have treatment resistant schizophrenia (TRS).¹However, before diagnosing someone with TRS, alternative etiologies should be ruled out, including pharmacokinetic or pharmacodynamic failures, treatment nonadherence, active substance use, drug-drug interactions, subtherapeutic antipsychotic serum levels, and inadequate prior treatment failures.^2,3 Erroneously diagnosing someone with TRS can result in complicated medication regimens and suboptimal outcomes, and a prior study of individuals diagnosed with TRS found that nearly half had subtherapeutic drug plasma levels.³

The following case describes an individual admitted to a state psychiatric hospital with a diagnosis of TRS. However, a more in-depth review identified that this diagnosis was preliminary and based on inaccurate information.

Case Presentation

Mr. J was brought by police to a community hospital after exhibiting disorganized and bizarre behavior in public. While in the emergency department, he received intramuscular haloperidol, lorazepam, and diphenhydramine, and was placed in physical restraints after assaulting a staff member. He verbalized persecutory delusions, and his thought process was pressured and illogical. A urine drug screen was not conducted. During his hospital course, he was the aggressor in several assaults against peers. He was started on haloperidol, but due to inefficacy, it was rapidly cross titrated to quetiapine. His quetiapine was titrated to 400mg twice daily, and lorazepam and valproic acid were added; his valproic acid level was 77 mcg/mL. He remained threatening towards others. Because of his aggression and presumptive TRS, he was recommended to begin a trial of clozapine but refused. He was also offered risperidone but refused based on a self-reported history of sexual dysfunction. After a serious assault against another peer following an argument about a chair in the dining area, he was transferred to a state psychiatric hospital for continued treatment.

Patient History

At the state facility, his quetiapine and valproate were initially continued. A review of prior hospital records revealed a lengthy history of treatment nonadherence, “cheeking” medication, and substance abuse. Additionally, he had presented to a different emergency department two weeks before presenting to the community hospital, and his urine drug screen was positive for cocaine, cannabis, and phencyclidine (PCP). At that time, he presented as agitated and delusional, and received intramuscular olanzapine. His behavior and mental state improved, and he was discharged. A further review into his aggressive behaviors at the referring hospital indicated that although he presented to the hospital disorganized, delusional, and aggressive, there were no overt delusions or hallucinations coinciding with his subsequent aggressive behaviors. They appeared to be largely impulsive as well as predatory in nature, rather than motivated by psychosis.

Treatment and Management

Given his nonadherence to treatment, he was felt to be a strong candidate for a long-acting injectable antipsychotic (LAI). He stated that he did well in the past on oral aripiprazole, and based on this preference and past tolerability, aripiprazole LAI was selected. Quetiapine was tapered, he remained on valproic acid, and he received 21 consecutive days of oral aripiprazole in conjunction with intramuscular aripiprazole lauroxil 1064 mg with a plan for gluteal injections every 8 weeks. Thus far, he has received one injection of aripiprazole lauroxil with a plan for a second injection in four weeks.

Results and Follow-Up

To date there has been no physical aggression or evidence of hallucinations or delusions. He shows poor insight into the reasons behind his hospitalization, minimizes his assaults, and minimizes the impact that substance abuse plays on his behaviors. He acknowledged being nonadherent on his psychotropic medication while in the community. At times, he will threaten to “go off” if his needs are not immediately met and is largely focused on housing. He remains hospitalized and the case is currently ongoing. If aripiprazole does not ameliorate his symptoms, olanzapine LAI will be considered.

Discussion

Nonadherence to treatment is a leading contributor to hospital readmissions. Among an estimated 163,500 Medicaid index admissions for schizophrenia in 2020, the 30-day all-cause readmission rate was 23.1%.⁴ Medication nonadherence is common among individuals with schizophrenia, with estimates suggesting that approximately half of patients do not take their medications as prescribed.⁵

When this is done without clinician knowledge, it can be considered clandestine nonadherence and can result in a diagnosis of TRS when it is actually “pseudo” treatment-resistance. Pseudo resistance occurs when the diagnosis of TRS is given based on an erroneous belief that the patient is adherent with treatment. It can result in complex medication regimens, the utilization of clozapine, and frequent medication adjustments.

Another etiology of pseudo resistance is comorbid substance abuse. Substance abuse is prevalent in those with schizophrenia and can precipitate psychosis, agitation, aggression, and lead to hospitalization. In the case of Mr. J, not only was he nonadherent to treatment in the community, but he was also using cocaine, PCP, and cannabis, each of which can independently trigger an exacerbation of schizophrenia and/or aggression and erroneously lead to a mistaken diagnosis of TRS. His clinician at the community hospital had diagnosed him with TRS and recommended clozapine, having no knowledge of his substance abuse history or history of medication nonadherence.

One way to ensure treatment adherence is by observing medication administration in the form of an LAI. As such, the Treatment Response and Resistance in Psychosis (TRRIP) working group recommended that the optimal definition of TRS include at least one failed trial with an LAI.¹ Moreover, the American Psychiatric Association (APA) Schizophrenia Practice Guideline recommends LAIs for patients with a history of poor or uncertain adherence (or for those who want them).⁶ When compared to oral antipsychotics, the bulk of evidence has established that LAIs are superior at maintaining adherence, reducing relapses, rehospitalizations, and all-cause mortality.^7-10

One of the few modifiable risk factors of violence in schizophrenia is medication adherence, and there is empirical support that LAIs can reduce violent and nonviolent offending behaviors in patients with schizophrenia.^11,12 Moreover, LAIs appear to be superior to oral antipsychotics at reducing violence and preventing recidivism of violent behavior.^13-16 As such, an LAI is a recommended first-line option in patients with a history of nonadherence and subsequent violence during periods of relapse.¹⁴

Another modifiable risk factor is substance abuse. Substance abuse, regardless of whether it is accompanied by schizophrenia, is a known risk factor for violence.^14,17 Therefore, treating comorbid schizophrenia and substance use disorders with an LAI is an even more appealing option. Comparing LAIs to oral antipsychotic medication has been evaluated in several studies of patients with comorbid schizophrenia and substance use disorders. A systematic review found that most available evidence supported the use of LAIs for the treatment of co-occurring schizophrenia and substance use disorders, though noted heterogenous studies and limited overall data.¹⁸ When LAIs were compared to oral antipsychotics, LAIs were generally found to be superior to oral antipsychotics at preventing treatment failure in patients with schizophrenia and comorbid substance abuse, delaying time to treatment failure, decreasing all-cause treatment discontinuations, and lowering the risk of incarcerations.^12,19,20

Preliminary evidence from a systematic review suggests that aripiprazole may be associated with reductions in substance craving among patients with serious mental illness and co-occurring substance use disorders;²¹ however, the evidence is limited by small, heterogeneous studies, and further research is needed to confirm this effect. This reinforced the findings from a multicenter study evaluating LAI aripiprazole for the treatment of patients with schizophrenia and co-occurring substance use disorders.²²

Conclusion

Treatment nonadherence and substance abuse are two independent, modifiable risk factors for aggression and violence in patients with schizophrenia. Clandestine nonadherence, especially in the context of aggression and rehospitalization, can result in a mistaken diagnosis of TRS and complicated and unnecessary medication regimens. At times, detective work is needed to diagnosis patients. Before concluding that a patient has TRS, a thorough review of confounding variables should be conducted, such as comorbid substance abuse and pharmacokinetic or pharmacodynamic failures, including medication nonadherence. LAIs can establish and enhance treatment adherence, and have shown to be beneficial at reducing aggression, violence, and drug cravings. In the case of Mr. J, he was erroneously given a diagnosis of TRS when he had been nonadherent with his antipsychotic medication and abusing cocaine, PCP, and cannabis. An LAI was selected to control his symptoms of psychosis and aggression and enhance treatment adherence.

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Acknowledgment

Disclosures

References