Efficacy of Dextromethorphan/Quinidine for Patients With Psychosis-Related Aggression: A Retrospective Case Series

Efficacy of Dextromethorphan/Quinidine for Patients With
Psychosis-Related Aggression: A Retrospective Case Series

QiLiang Chen, PhDa; Haley E. Calcagno, MSa; and Mujeeb Shad, MD, MSCSa,b,*

ABSTRACT

Background: Treatment-resistant aggressive behavior is a complex psychoneurological phenomenon with high health care and societal costs commonly observed in mental illnesses involving psychosis. Here, we report a preliminary evaluation of treatment with dextromethorphan/quinidine in 4 adult patients with significant history of psychosis-related aggression and impulsive behaviors.

Methods: The files of 4 inpatients with DSM-5–defined psychotic disorder and treatment-resistant aggression treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were retrospectively analyzed. The patients (age: mean ± SD = 59.8 ± 7.6) received open-label treatment with dextromethorphan/quinidine (final dose 20 mg/10 mg twice daily) for at least 12 weeks. Outcome was measured on the basis of patient self-report, treatment team evaluation, and physical examination by psychiatrists and primary care physicians.

Results: Three of the 4 patients were considered responders to dextromethorphan/quinidine based on clinical impressions of reduction in aggression and impulsive behavior. The nonresponder, who had a history of multiple traumatic brain injuries, showed mild improvement in agitation but continued to display impulsive self-harm behavior despite treatment. Dextromethorphan/quinidine was generally well-tolerated. No metabolic, gastrointestinal, or cardiovascular side effects were observed.

Conclusions: These preliminary findings support dextromethorphan/quinidine as a potential alternative to conventional regimens for treating aggression and impulsive behavior in patients with psychotic disorder. These results should be interpreted cautiously, as extended, double-blinded, placebo-controlled studies with a larger sample size are needed to validate findings from this retrospective case series.

Prim Care Companion CNS Disord 2018;20(3):18m02284

To cite: Chen Q, Calcagno HE, Shad M. Efficacy of dextromethorphan/quinidine for patients with psychosis-related aggression: a retrospective case series. Prim Care Companion CNS Disord. 2018;20(3):18m02284.

To share: https://doi.org/10.4088/PCC.18m02284

© Copyright 2018 Physicians Postgraduate Press, Inc.

aSchool of Medicine, Oregon Health & Science University, Portland, Oregon

bDepartment of Psychiatry, Oregon State Hospital, Salem, Oregon

*Corresponding author: Mujeeb Shad, MD, MSCS, Oregon Health & Science University, 2600 Center St NE, Salem, OR 97301 (shad@ohsu.edu).

Aggressive behavior is one of the most important features of many psychosis-related illnesses, such as schizophrenia, dementia, and brain injuries, and often leads to significant social stigma, prolonged hospitalization, and increased health care and societal costs.1,2 Aggression in psychosis is thought to be related to psychosocial causes, such as persistent delusion or hallucination, substance abuse, and cognitive disorientation,3–5 but the precise neurobiological mechanism responsible for the psychopathological aggressive symptoms remains unclear, making treatment options for these patients limited.

A number of neurotransmitter systems, including serotonin (5-HT), dopamine, norepinephrine, and glutamate, are implicated in the pathogenesis of aggressive behavior.6 With the presumed action on these neurotransmitter systems, common regimens for patients with psychosis-related aggression have mostly focused on lithium, antipsychotics (eg, haloperidol), and anticonvulsants (eg, valproic acid).6,7 However, some patients can become resistant to these treatments.8 Atypical antipsychotics with minimal extrapyramidal symptoms, such as clozapine, have been shown to be effective in reducing aggressive behavior in schizophrenia patients, making these medications a valid alternative for treatment-resistant patients.9–11 However, these atypical antipsychotics have potential serious side effects, such as metabolic syndrome, cardiotoxicity, and agranulocytosis,8,12,13 and may be contraindicated in some patients with significant predisposing risk factors. Thus, a different pharmacologic regimen with a milder side effect profile is highly desirable for patients who are treatment refractory or who develop significant adverse effects with other psychotropic medications.

Dextromethorphan is a common cough suppressant. But, we recently reported14 initial success in treatment of agitation and aggression in a patient with frontotemporal dementia when used in combination with quinidine, which presumably increases dextromethorphan bioavailability via cytochrome P450 inhibition.15,16 Here, we present a case series showing the effectiveness of the dextromethorphan/quinidine formulation in treating psychosis-related aggression and impulsive behavior over an extended period of time. Furthermore, we discuss the potential mechanism of this pharmacologic regimen.

METHODS

In this retrospective case series, the files of 4 patients with history of dementia, aggression, agitation, and impulsive or disinhibited behavior treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were analyzed. All psychiatric diagnoses were reevaluated and confirmed by certified psychiatrists at hospital admission using DSM-5 criteria.17 The patients were white men with a mean ± SD age of 59.8 ± 7.6. Aggressive and impulsive symptoms had persisted in these patients despite multiple trials of anticonvulsant and antipsychotic drugs. The diagnoses, demographic information, treatment history with antipsychotic drugs, and rationale for treatment with dextromethorphan/quinidine are presented in Table 1.

The initiation of dextromethorphan/quinidine treatment and the evaluations of response were based on the clinical impression of patients’ mood lability and the degree of aggressive behaviors after ruling out bipolarity. Dextromethorphan/quinidine was initiated at the daily dosage of 20 mg/10 mg and progressed to the final dosage of 20 mg/10 mg 2 times per day by the second week. Dextromethorphan/quinidine was maintained at the final dosage over 12 weeks or stopped if the patient developed adverse effects or targeted symptoms worsened (eg, patients showed increased aggression or agitation). All patients received 12-lead electrocardiogram (ECG) testing prior to initiating dextromethorphan/quinidine and dosage change and then monthly to monitor possible treatment adverse effects. The activity, diet, safety, and general well-being of the patients were recorded and assessed by clinical staff and attending psychiatrists daily. The changes in each patient’s symptoms were evaluated and recorded by attending psychiatrists. The potential adverse effects were monitored by patient self-reports, nursing staff, and monthly physical examinations (eg, weight, blood pressure) and laboratory tests (eg, complete blood count and metabolic panel).

Concomitant psychiatric medications (Table 2) were titrated monthly based on symptoms or serum level. Patients who presented decreased target symptoms, which include verbal or physical aggression, paranoia, agitation, irritability, or number of seclusion events, while taking dextromethorphan/quinidine received a rating of “improved” and were considered responders. Those who showed no improvement on target symptoms or worsening symptoms received a rating of “no change” and were considered nonresponders.

RESULTS

The dextromethorphan/quinidine treatment responses are summarized in Table 2. Three of the 4 patients completed at least 12 weeks of treatment with dextromethorphan/quinidine.

In general, dextromethorphan/quinidine was well-tolerated, and all patients were compliant with treatment. No serious adverse effects were noted. Specifically, there were no cardiovascular side effects (eg, chest pain, palpitations, dizziness, or syncope) reported, and no significant change on ECG was noted compared to pretreatment baseline. There were also no gastrointestinal complaints (eg, diarrhea, constipation, nausea, abdominal discomfort) or weight changes noted.

The 3 treatment responders were continued on dextromethorphan/quinidine per patient records. One of the responders was initially diagnosed with schizophrenia due to persistent psychotic symptoms but later received the final diagnosis of frontotemporal dementia after review of recent neuroimaging evidence. All responders showed reduction in agitation, aggression, and impulsivity within 4 weeks of treatment initiation, with a decreasing number of behavioral interventions to control these behaviors. They also reported significant improvement in their mood and were able to start engaging in conversation with peers and staff. However, minimal changes were observed in their delusions and thought processes. All 3 responders were either discharged or pending to be discharged to community care facilities, as they required a lower level of care after treatment with dextromethorphan/quinidine.

The patient who did not respond to treatment had a history of schizophrenia and multiple psychotic episodes and suicide attempts that required psychiatric hospitalizations. He had displayed increasing self-harm behavior under command hallucinations, which prompted his transfer to the Oregon State Hospital. His medical history is significant for comorbid hepatitis C and multiple traumatic brain injuries (TBIs). Although this patient showed mild improvements in agitation with the dextromethorphan/quinidine trial, his impulsive self-harm behavior continued to worsen. Dextromethorphan/quinidine treatment for this patient was discontinued.

DISCUSSION

The current case series describes our initial clinical impressions regarding treatment of aggressive and impulsive behavior secondary to treatment-resistant psychosis with dextromethorphan/quinidine in 4 inpatients. Our preliminary report14 on the patient with frontotemporal dementia (patient 1 in Table 1) showed success in controlling aggression, agitation, and impulsive behavior (eg, binge eating, sexual disinhibition) within 2 weeks of starting dextromethorphan/quinidine treatment, and the benefit persisted beyond 12 weeks. This patient was discharged from the state hospital. Two inpatients with similar presentations who had previously failed multiple antipsychotic treatments also benefited from dextromethorphan/quinidine and were discharged from the hospital. Furthermore, dextromethorphan/quinidine at the recommended dosage (20 mg/10 mg twice a day) showed a minimal side effect profile, suggesting that this combination may be a safe and tolerable choice to treat behavioral dysfunction in this patient population.

The patient who failed to respond to dextromethorphan/quinidine provided some important insights into treatment considerations. This patient had suffered multiple TBIs prior to and throughout the evolution of his psychiatric condition, which could explain aggressive behavior18 and comorbid psychiatric illnesses.19,20 Previous neuroimaging studies have reported aggressive behavior to be associated with frontal lobe lesions in patients with prior head injuries,21,22 a brain region implicated in modulating aggression-related circuits via the serotonergic and dopaminergic systems.23 These findings are consistent with the notion that serotonergic abnormality may contribute to impulsive violence and aggression.24–26 Interestingly, unlike patients with schizophrenia or dementia, there is insufficient evidence supporting the use of antipsychotic drugs to treat TBI-related aggression,27 suggesting a different pathogenesis and psychopathology of the aggressive and impulsive symptoms in post-TBI patients, and may explain the lack of efficacy of dextromethorphan/quinidine in this patient with multiple TBIs. Another reason for the failure of dextromethorphan/quinidine and other psychotropic medications in this patient may be chronic hepatitis C, which has been linked to altered activity of cytochrome P450 (CYP) enzymes due to autoimmunity.28 This change in CYP enzyme activity may have altered the pharmacokinetics of dextromethorphan/quinidine, potentially contributing to the lack of treatment response in this patient.

Taken together, the current study provides anecdotal evidence that supports the benefit of dextromethorphan/quinidine for treating aggressive behavior in patients with schizophrenia or dementia-related psychosis and sheds light on the potential neurobiology of aggression.

Mechanistic Implications

Aggression in patients with psychotic disorder is a complex phenomenon that can be influenced by, but not limited to, genetic, molecular, and neurologic factors. Interestingly, the pharmacology of dextromethorphan/quinidine seems to affect neurotransmitter systems linked with aggression.29 Classically, the serotonergic neurotransmitter system has been implicated in aggressive behavior, with evidence demonstrating multiple 5-HT receptor subtypes associated with aggression in preclinical animal models and human studies.24–26 In both in vitro and in vivo preclinical studies, dextromethorphan has been shown to increase synaptic 5-HT availability by inhibiting its reuptake.29,30 Dextromethorphan/quinidine also affects other neurotransmitter systems associated with aggression, such as norepinephrine and glutamate.6 While dextromethorphan inhibits norepinephrine reuptake, it is also a potent antagonist to glutamatergic N-methyl-d-aspartate (NMDA) receptors at the plasma levels achieved if combined with quinidine. This is consistent with the anti-aggression effect of valproic acid and memantine, both of which have the distinct mechanisms to reduce NMDA signaling.31,32 However, while the dopaminergic system is known to be involved in circuits relevant to aggression,33 dextromethorphan/quinidine does not directly interact with dopamine receptors.30 Thus, it is theoretically plausible that dextromethorphan/quinidine indirectly affects the dopaminergic system via its effects on the glutamate and 5-HT systems, potentially contributing to its efficacy in the treatment of aggression.34

Limitations

Since this study is a case series, it is limited by the nonblinded patient care teams and an uncontrolled experimental environment. The outcome mostly relied on self-reports or qualitative assessment by the patient care team, which lacks systematic and quantitative measurement of aggression (such as utilizing the Overt Aggression Scale35).Use of a range of concomitant medications in these patients, which was difficult to avoid due to the treatment-resistant nature of their conditions, could make interpretation of the efficacy of dextromethorphan/quinidine difficult. In addition, the small sample size and the length of treatment are also major limitations.

CONCLUSION

To our knowledge, this is the first case series to report efficacy of dextromethorphan/quinidine in the treatment of aggression and impulsive behavior in difficult-to-treat inpatients with psychosis. Although additional long-term, double-blind, placebo-controlled clinical trials are still required, the current case series suggests that dextromethorphan/quinidine may be a relatively safe and tolerable option to manage aggressive behavior if other agents such as lithium and antipsychotic or anticonvulsant medications fail. These data may also help basic scientists and clinical researchers design experiments to explore the pathophysiology and potential risk factors for psychosis-related aggression.

Submitted: February 12, 2018; accepted March 29, 2018.

Published online: June 28, 2018.

Potential conflicts of interest: None.

Funding/support: None.

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