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Specific Anti-hostility Effects of Atypical Antipsychotics in Persons with Schizophrenia: From Clozapine to Cariprazine

Citrome, Leslie MD, MPH; Volavka, Jan MD

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Harvard Review of Psychiatry: 1/2 2021 - Volume 29 - Issue 1 - p 20-34
doi: 10.1097/HRP.0000000000000275

Abstract

Persons with schizophrenia are complex, with psychopathology that can include positive symptoms (such as hallucinations and delusions), negative symptoms (such as blunted affect and emotional withdrawal), cognitive impairments (including poor attention and impaired memory), depressed mood, and hostility. Hostility is often encountered within the context of acute psychosis and can be associated with hallucinations and delusions. Especially when persistent, hostility can interfere with relationships and overall functioning. It may lead to aggressive behavior. This narrative review examines the potential anti-hostility effects that can be observed with available atypical antipsychotics.

Hostility is a term that can be vague. It may include temper tantrums, irritability, refusal to cooperate, jealousy, suspicion, and many other attitudes and behaviors.1 Hostility is included as an item in the Positive and Negative Syndrome Scale (PANSS), a rating instrument that often serves as the primary outcome measure in randomized, controlled trials of antipsychotic medications for the treatment of schizophrenia.2 The PANSS hostility item is specifically defined as “verbal and nonverbal expressions of anger and resentment, including sarcasm, passive–aggressive behavior, verbal abuse, and assaultiveness,” and is rated on a scale of 1 (absent) to 7 (extreme).3 Because of the ubiquity of using the PANSS in clinical research in schizophrenia, hostility item scores are readily available from these studies and permit the exploration of several important clinical issues and, in particular, the question, “Do antipsychotics have a specific anti-hostility effect, or is this effect dependent on the reduction of psychotic symptoms in general?”

The observation that hostility may be a specific treatment domain for antipsychotic medication is supported by factor analyses of PANSS data from randomized clinical trials in persons with schizophrenia.4 A five-factor solution has consistently identified excitement/hostility as a separate domain from the other factors—consisting of positive symptoms, negative symptoms, cognition, and depression/anxiety.4

A caveat is that hostility differs conceptually from agitation, aggression, and violence. Hostility can be thought of as an underlying negative attitude toward situations and other people. Not all people with measurable hostility are agitated, aggressive, or violent, although interactions with family, friends, and coworkers can be strained because of hostility. Nonetheless, persons who have a hostile attitude can become agitated, which is defined as excessive verbal or motor activity and often experienced as distressing.5 Similarly, persons with a hostile attitude can become violent. In a national U.S. study of violence in schizophrenia, “for each unit increase on the PANSS rating of hostility, the odds of serious violence increased by a factor of 1.65 (P < 0.001).”6 The PANSS hostility item has been combined with the PANSS items of excitement, tension, uncooperativeness, and poor impulse control to create the PANSS Excited Component (PEC), which has been used as the primary outcome measure in developing medications for agitation.7

Although persons who are hostile and agitated are not necessarily aggressive, hostility and agitation may sometimes escalate to aggressive behavior, as defined by overt behavior involving intent to inflict noxious stimulation (verbal) or to physically behave destructively toward other people or objects.8–11 Of note, violence is a more specific term that denotes physical aggression among humans and is not used to describe animal behavior.11 The term aggression is favored in biomedical and psychological research, and violence (or violent crime) is more commonly used in criminology, sociology, law, and public policy.

When clozapine became available for people who did not have an adequate response to typical (first-generation) antipsychotics, clinicians observed that clozapine appeared to work especially well in managing persistent aggressive behavior.12 These effects appeared enduring and differed from the transient calming/sedation associated with antipsychotics when administered to an acutely agitated person. When other atypical (second-generation) antipsychotics were developed, it was hoped that they would be similarly efficacious as clozapine, but safer and better tolerated.

What follows is a summary of the evidence supporting the idea that a specific anti-hostility effect exists for at least some of the available atypical antipsychotics, as determined by reductions on the hostility item of the PANSS (or in the case of older studies, the hostility item on the Brief Psychiatric Rating Scale [BPRS]) over the course of several weeks. Described are studies that have tested clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, iloperidone, asenapine, lurasidone, brexpiprazole, and cariprazine.

METHODS

After collating the published work done on this topic by the authors (LC and JV) from 1993 through 2019, including study reports and reviews, an additional search was conducted for completeness. A search of the U.S. National Library of Medicine’s PubMed.gov resource using the terms “(schizophrenia OR schizoaffective) AND (PANSS OR BPRS) AND (hostility OR aggression OR violence) AND (antipsychotic OR clozapine OR risperidone OR olanzapine OR quetiapine OR ziprasidone OR aripiprazole OR asenapine OR iloperidone OR lurasidone OR brexpiprazole OR cariprazine)” for English-language articles (no time constraints) revealed 105 entries as queried on 12 April 2020. Articles that addressed specific anti-hostility effects were identified. In general, this required an analytical plan where reductions in hostility were examined in relation to (1) any reductions in positive psychotic symptoms other than hostility (i.e., delusions, conceptual disorganization, hallucinatory behavior, grandiosity, suspiciousness/persecution, and unusual thought content), and (2) any potential effects on either (a) akathisia (as measured either by either the Barnes Akathisia Rating Scale or the occurrence of a treatment-emergent adverse event of akathisia) or (b) sedation/somnolence (usually as measured by the presence of a treatment-emergent adverse event of that type or by a rating scale score if available). Excluded were studies of one-time or one-day use of antipsychotics for acute agitation. No additional articles were identified after the extended search. In the case of absence of any published articles describing specific anti-hostility effects for a particular atypical antipsychotic, available poster presentations are summarized, as are other analyses that describe related outcomes (such as for the PEC or the PANSS excitement/hostility factor) over time.

ANTI-HOSTILITY EFFECTS OF ATYPICAL ANTIPSYCHOTICS

Clozapine

Clozapine has been available since 1989 for the indication of treatment-resistant schizophrenia and since 2002 for the indication of suicidality in persons with schizophrenia or schizoaffective disorder.13–16 It has long been thought to be a useful medication for aggressive behavior.12,17 Its clinical use requires monitoring for agranulocytosis, is commonly associated with weight gain and metabolic abnormalities, and requires careful dose titration.14–16

The specific anti-hostility effect of clozapine was first reported in an analysis of a clinical treatment program spanning 21 state hospitals in New York in the early days of clozapine prescribing.18 A total of 223 patients with schizophrenia receiving clozapine had the BPRS completed at baseline, 6 weeks, 12 weeks, and endpoint. Like the PANSS, the BPRS has a hostility item.19 The effect of clozapine on the hostility score was compared to the effect on the “psychosis factor,” defined as the sum of the other BPRS items that measured positive symptoms. A selective effect of clozapine on hostility was found, statistically independent of clozapine’s general antipsychotic effects. This is consistent with other uncontrolled studies published shortly thereafter, including a report of 11 patients with schizophrenia treated with clozapine where the reduction in aggression (as measured by the use of restraints and seclusion) was greater than the modest improvement noted in the BPRS,20 and a report of 47 patients with schizophrenia where the BPRS hostility score decreases were at least partly independent from changes in the BPRS items for conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content.21

The availability of risperidone and olanzapine, atypical antipsychotics approved in 1994 and 1996, respectively, inspired the planning and execution of a National Institute of Mental Health (NIMH)–funded randomized, controlled trial comparing these agents with clozapine in treatment-resistant schizophrenia among 157 inpatients at state hospitals.22 One of the pre-planned analyses was to examine the effects that these agents may have on hostility.23 Patients were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol double-blind for 14 weeks. Mean dose levels (mg/d) achieved during the last 6 weeks of the study were 526.6 for clozapine, 30.4 for olanzapine, 11.6 for risperidone, and 25.7 for haloperidol. For the hostility analysis, the PANSS hostility item was the principal outcome measure. Covariates included the items that reflect other positive symptoms of schizophrenia and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). The hostility scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone, but not olanzapine (neither risperidone nor olanzapine showed superiority to haloperidol). The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on the other PANSS positive symptoms and independent of sedation. An important limitation of this study is that the patients were not selected specifically because they had a history of aggressive and hostile behavior, but because they had an inadequate treatment response to prior antipsychotic medication. Although overt hostility was demonstrated largely by verbal expression of resentment rather than by physical assault, a secondary analysis of incidents of overt aggression did demonstrate superiority of clozapine over haloperidol on this measure as well,24 and supports the notion that the PANSS hostility item can be informative regarding aggression risk.

The above findings were consistent with that of a NIMH-funded, 12-week clinical trial that enrolled 110 physically assaultive subjects with schizophrenia or schizoaffective disorder who were inpatients in state psychiatric facilities.25 Patients were not required to be treatment resistant. Patients were randomized to receive clozapine, olanzapine, or haloperidol. Mean dose levels (mg/d) achieved during the last 6 weeks of the study were 565.5 for clozapine, 24.7 for olanzapine, and 23.3 for haloperidol. Clozapine was superior to both olanzapine and haloperidol in reducing the number and severity of physical assaults and in reducing overall aggression, and olanzapine was superior to haloperidol; yet, there were no significant differences among the three medication groups in improvement of psychiatric symptoms as measured by the PANSS total score and the three PANSS subscales. The differences in aggression could not be explained by differences in the sedative properties of clozapine, olanzapine, or haloperidol because the rates of sedation among the participants in the three medication groups were not significantly different.

Thus, the initial findings that clozapine has a specific anti-hostility effect—as determined by an audit of “real-world” use of clozapine when introduced in a large state-operated mental health inpatient system18—has been confirmed in a randomized clinical trial that examined the PANSS hostility item,23 and is validated by another randomized clinical trial that measured actual rates of aggression directly.25 Unlike some other trials testing effects of medication on aggression, this latter study selected subjects who were physically assaultive. The results showed that clozapine was superior to olanzapine and haloperidol in reducing the number and severity of physical assaults, and that olanzapine was superior to haloperidol on these measures. Collectively, these studies suggest that clozapine is superior to haloperidol for treating hostility/aggression in persons with schizophrenia, and also potentially superior to olanzapine and risperidone. The strength and level of the evidence (randomized, controlled trials with pre-specified analyses regarding hostility or aggression) are more robust than the post hoc analyses done for the other atypical antipsychotics, as detailed below.

Risperidone

Risperidone and its main active metabolite, 9-OH-risperidone (paliperidone), are first-line treatments for schizophrenia, approved in 1993 and 2006, respectively.26–30

Supporting the notion that risperidone may have a specific anti-hostility effect is a post hoc analysis31 using data from registrational studies.32,33Table 1 summarizes the results.31,34–47 These results differ, however, from those in the study comparing clozapine, risperidone, olanzapine, and haloperidol described earlier, where no difference was observed between risperidone and haloperidol.23 These divergences may reflect the different patient populations (large, multicenter, industry-sponsored trial in persons who are not treatment resistant vs. a smaller, primarily NIMH-funded study that was conducted at fewer sites and enrolled a treatment-resistant patient population at state-operated psychiatric centers). It is possible that the anti-hostility effect of risperidone varies with dosage and degree of treatment refractoriness. Regarding dosing, it is suggested that the optimal tolerability dose range during maintenance treatment is ≤5 mg/d48 and that doses ≥10 mg/d do not appear to confer any advantage over any other dose ranges and cause more adverse effects, especially for movement disorders, including akathisia,49 with the latter potentially associated with adverse behavioral outcomes.

Table 1 - Post Hoc Analyses of Industry-Sponsored Studies of Atypical Antipsychotics, in Order of Year of Publication31,34-47
Antipsychotic Study Diagnosis Dose n Length Findings
Risperidone Czobor et al. (1995)31 Schizophrenia 6, 10, or 16 mg/d 139 8 weeks In patients with a baseline hostility score ≥3, risperidone had a greater selective effect on the PANSS hostility item, controlling for effects on other positive symptoms, than did haloperidol or placebo.
Quetiapine Chengappa et al. (2003)34 Schizophrenia 150–750 mg/d 257 6 weeks A specific anti-agitation effect was observed as measured by the BPRS items of hostility, anxiety, tension, uncooperativeness, and excitement, and controlling for effects on conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content.
No such effect was observed for persons who were randomized to haloperidol 12 mg/d, where path analysis did not demonstrate a specific anti-agitation effect.
Olanzapine or risperidone, combined with valproate Citrome et al. (2004)35 Schizophrenia Olanzapine 15 mg/d or risperidone 6 mg/d, and valproate up to 30 mg/kg/d 249 4 weeks Combination therapy had a significantly greater anti-hostility effect at days 3 and 7 than monotherapy.
This result was not seen beyond the first week of treatment, but there was a trend toward a difference in effect for the entire treatment period.
The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting positive symptoms.
The advantage of combination therapy over monotherapy remained significant when the covariates of baseline Barnes Akathisia Scale scores, somnolence, ethnicity, or use of lorazepam, chloral hydrate, benztropine, or propranolol were used.
Quetiapine Arango & Bernardo (2005)36 Schizophrenia 150–750 mg/d 389 6 weeks Although patients who received quetiapine had significantly greater improvements on the BPRS hostility item (as well as on other measures that included the BPRS hostility item), the improvements were highly correlated with improvements with positive symptoms in general.
Aripiprazole Volavka et al. (2005)37 Schizophrenia or schizoaffective disorder 2–30 mg/d 1476 4 weeks Effect of aripiprazole on the PANSS hostility item during the first 4 weeks of treatment was superior to that of placebo but not significantly different from that for haloperidol (5–20 mg/d).
The anti-hostility effects of aripiprazole were statistically independent of other positive symptoms and of sedation (spontaneously reported adverse event) after the first 2 weeks of treatment.
Ziprasidone Citrome et al. (2006)38 Schizophrenia or schizoaffective disorder Mean doses of 20 mg/d of the IM formulation for up to 3 days and then 116 mg/d of the oral formulation 572 6 weeks Although randomized with blinded raters, this study was open label.
Compared were sequential IM and oral ziprasidone with sequential IM and oral haloperidol.
Ziprasidone demonstrated specific anti-hostility effects over time (as measured by the BPRS hostility item and controlled for using the covariates of other positive symptoms and akathisia [Barnes Akathisia Scale global score]) throughout the 42-day study period and significant superiority to haloperidol on hostility in the first week of treatment (mean IM haloperidol dose ~7 mg/d for up to 3 days, followed by a mean oral dose of 11.5 mg/d).
Aripiprazole Marder et al. (2007)39 Schizophrenia 10–30 mg/d 1187 4–6 weeks Agitation (measured by the PEC) was significantly decreased in patients with higher baseline agitation.
These improvements appeared to be independent of benzodiazepine use or excessive sedation effects.
Iloperidone Citrome et al. (2011)40 Schizophrenia 4–24 mg/d 1941 4–6 weeks Efficacy was demonstrated on the excitement/hostility factor (excitement, hostility, uncooperativeness, and poor impulse control) for the iloperidone 4–8, 10–16, and 20–24 mg/d dose groups, as well as for the risperidone 4–8 mg/d, haloperidol 15 mg/d, and ziprasidone 160 mg/d active control groups.
Lurasidone Citrome et al. (2014)41 Schizophrenia 40–160 mg/d 1148 6 weeks In subjects with a PANSS hostility item score ≥2 at baseline, lurasidone was significantly superior to placebo in reducing the PANSS hostility item throughout the 6-week study period, starting at week 1 and at all subsequent study visits.
After adjusting for symptom change on other positive symptoms, lurasidone was found to be significantly better than placebo in decreasing the PANSS hostility item starting at week 2 and at every subsequent time point measured throughout the 6-week study period.
To control for the presence of akathisia or somnolence/sedation (recorded as a spontaneously reported adverse event), the analysis was repeated by also introducing the presence of akathisia or somnolence as a covariate.
In this analysis, lurasidone significantly reduced the PANSS hostility item relative to placebo beginning at week 2 and at every time point measured thereafter, except for week 6.
The proportion of patients who demonstrated any improvement (≥1-point change) on the PANSS hostility item score from baseline to endpoint was 63.1% (489/775) for patients randomized to lurasidone and 55.0% (205/373) for patients randomized to placebo (NNT = 13).
Aripiprazole lauroxil (long-acting injectable) Citrome et al. (2016)42 Schizophrenia 441 mg monthly IM or 882 mg monthly IM 442 12 weeks Among patients with a baseline PANSS hostility item score ≥2, although all persons randomized to aripiprazole lauroxil exhibited a significant improvement in the PANSS hostility item vs. placebo, it was only for those patients in the 882 mg dose group where this effect remained significant after introducing other positive symptoms, somnolence/sedation (as reported as an adverse event), or akathisia (as reported as an adverse event) as covariates.
The proportion of patients with a PANSS hostility item score ≥2 at endpoint was significantly lower with aripiprazole lauroxil vs. placebo (e.g., 66.3% vs. 46.1% for the 882 mg monthly dose strength vs. placebo, resulting in an NNT of 5).
Outcomes were also in favor of aripiprazole lauroxil for agitation as measured by the PEC and for aggressive behavior as measured by the Personal and Social Performance scale, with a possible dose response in favor of 882 mg.
Cariprazine Citrome et al. (2016)43 Schizophrenia 1.5–9.0 mg/d 1466 6 weeks Cariprazine was superior to placebo on the PANSS hostility item, which was also the case after adjustment for other positive symptoms and sedation/somnolence (as reported as a treatment-emergent adverse event).
The magnitude of hostility change increased with greater levels of baseline severity.
A significant difference in change from baseline to week 6 on the PEC in favor of cariprazine vs. placebo supported the principal PANSS hostility item analysis.
Asenapine Citrome et al. (2017)44 Schizophrenia 5 mg BID 753 6 weeks Improvement in the PANSS hostility item was significantly greater with asenapine 5 mg BID than with placebo at all time points after day 7.
After adjustment for other PANSS positive symptoms and sedation/somnolence (reported as an adverse event), the differences remained significant at some time points but not at day 42.
Asenapine Citrome et al. (2017)45 Bipolar mania or mixed 5–10 mg BID 929 3 weeks Examined were changes from baseline to day 21 on the Young Mania Rating Scale and the PANSS hostility-related item scores in asenapine- or placebo-treated patients with at least minimal or mild symptom severity, and on the PEC in agitated patients.
A specific anti-hostility effect was noted for asenapine after controlling for improvements in overall mania symptoms.
Lurasidone Allen et al. (2017)46 Schizophrenia 40–160 mg/d 1527 6 weeks Improvement in agitation did not appear to be attributable to either increased use of concomitant benzodiazepines or to reduction in akathisia.
The effect of lurasidone on agitation in this study was independent of the severity of positive symptoms at baseline.
Brexpiprazole Citrome et al. (2019)47 Schizophrenia 2 or 4 mg/d (acute studies); 1–4 mg/d (long-term study) 1076 (acute studies); 346 (long-term study) 6 weeks; 1 year In the acute studies, brexpiprazole was superior to placebo on the PEC, with a possible dose response.
For the subset of patients with a baseline PANSS hostility item score ≥3 (538 patients), brexpiprazole was statistically superior to placebo on the PANSS hostility item, controlling for other positive symptoms, akathisia (Barnes Akathisia Rating Scale Global score), and somnolence/sedation (reported as a treatment-emergent adverse event).
A dose response appears evident, with brexpiprazole 4 mg/d demonstrating a larger numerical difference from placebo than the 2 mg/d dose group.
This result is consistent with that observed in a supportive analysis of the subgroup of subjects scoring ≥2 on the PANSS hostility item at baseline—where brexpiprazole 4 mg/d was superior to placebo at week 6 with regard to change in the PEC and PANSS hostility item score but where the 2 mg/d dose group showed numerical advantages over placebo—but was not statistically significant.
Among the 346 brexpiprazole-treated patients rolled over into the long-term study (dose range 1 to 4 mg/d), benefits were maintained regarding the PANSS hostility item score and the PEC.
BID, bis in die (twice a day); BPRS, Brief Psychiatric Rating Scale; IM, intramuscular; NNT, number needed to treat; PANSS, Positive and Negative Syndrome Scale; PEC, PANSS–Excited Component (includes the items of hostility, excitement, tension, uncooperativeness, and poor impulse control).

Small quasi-experimental studies have not supported an anti-aggressive effect for risperidone superior to that observed for typical antipsychotics, as evidenced among 20 patients at a maximum security forensic facility50 and 27 patients at a state hospital.51

Thus, the strength of the evidence for a specific anti-hostility effect of risperidone is weak, based on a single post hoc analysis of a registrational trial comparing risperidone with placebo or haloperidol. When compared within trials, clozapine and olanzapine performed better than risperidone (see sections on clozapine [above] and olanzapine [below] for details). Analogous analyses have not been reported for paliperidone or for the long-acting formulations of either risperidone (risperidone microspheres or risperidone subcutaneous injection) or paliperidone (paliperidone palmitate).

Olanzapine

In 1996, olanzapine was the third atypical antipsychotic to be approved in the United States for use in persons with schizophrenia.26,52–55 Although considered to have a favorable efficacy profile,52 its use has been limited by adverse metabolic effects.54

Olanzapine was observed to be “second-best” after clozapine when examining overt aggression in the randomized, double-blind study, described above, that enrolled physically assaultive patients.25 Olanzapine moves to the top position when clozapine is no longer a comparator, as evidenced in post hoc analyses of two large effectiveness studies: the 18-month Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study56 that enrolled about 1500 chronically ill persons with schizophrenia in the United States and the 12-month European First Episode Schizophrenia Trial (EUFEST) that enrolled 498 patients who were earlier in their disease course.57 In the CATIE hostility analysis, the effects of double-blinded olanzapine, perphenazine, risperidone, quetiapine, and ziprasidone were examined after randomization.58 The PANSS was administered at baseline and at 1, 3, 6, 9, 12, 15, and 18 months after randomization. The PANSS hostility item was assessed in a subset of 614 patients who showed at least minimal hostility (a score ≥2) at baseline. Positive symptoms other than hostility were used as a covariate in order to be able to report specific anti-hostility effects. Olanzapine was significantly superior to perphenazine and quetiapine at months 1, 3, 6, and 9. It was also significantly superior to ziprasidone at months 1, 3, and 6, and to risperidone at months 3 and 6. In the EUFEST trial the effects of open-label haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility were evaluated.59 The PANSS was administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. The PANSS hostility item was assessed in a subset of 302 patients who showed at least minimal hostility (a score ≥2) at baseline. Olanzapine was significantly superior to haloperidol, quetiapine, and amisulpride in reducing hostility at months 1 and 3, and these effects were at least partly specific to hostility after controlling for other positive symptoms.

The licensed dose range of olanzapine extends up to 20 mg/d, administered once daily, although almost all the aforementioned studies allowed doses that exceeded this threshold (in some instances up to 40 mg/d). Although for most patients an olanzapine daily dose ≤20 mg may be optimal,60 larger doses may be preferred for patients who are persistently aggressive.61

The overall strength of the evidence for a specific anti-hostility effect of olanzapine is moderate. Although olanzapine did not separate from haloperidol on anti-hostility effect in the aforementioned randomized, controlled study in treatment-resistant schizophrenia,23 it was superior to haloperidol in the randomized, controlled study that specifically enrolled aggressive patients.25 Moreover, olanzapine demonstrated (post hoc) superior anti-hostility effects compared to several other agents in large, longer-term effectiveness trials that enrolled first-episode patients57,59 and outpatients with chronic schizophrenia.56,58 Analogous analyses have not been reported for the long-acting formulation of olanzapine (olanzapine pamoate).

Olanzapine or Risperidone: Polypharmacy with Valproate

Valproate, an anticonvulsant and mood stabilizer, has been commonly prescribed in combination with antipsychotics in people with schizophrenia, as observed in psychiatric centers operated by New York State, where the rate of use among persons hospitalized with schizophrenia has approached 35%.62 A rationale for such extensive use is that it may reduce aggressive and impulsive behavior better than antipsychotic treatment alone.63

Adding valproate to risperidone or olanzapine was tested in double-blind, randomized clinical trials to garner regulatory approval for valproate (divalproex sodium) for general adjunctive use in persons with schizophrenia.64,65 A relevant post hoc analysis from the one positive trial64 is available,35 demonstrating an anti-hostility effect, particularly in the first week of treatment (Table 1).

However, the idea that adjunctive valproate can have a specific anti-hostility effect was not supported in an eight-week, open-label, randomized clinical trial comparing risperidone monotherapy with risperidone-valproate combination in 33 hospitalized adults diagnosed with schizophrenia and also demonstrating hostile behavior.66 Although significantly fewer patients randomized to monotherapy completed the study compared to those who received combination treatment, no significant differences between monotherapy and combination treatment were observed on any of the efficacy outcome measures, including the hostility item of the PANSS.

Overall, the evidence for the clinical usefulness of valproate in combination with risperidone or olanzapine for the treatment of schizophrenia and hostility is weak.67

Quetiapine

Available since 1997, quetiapine is a first-line treatment for persons with schizophrenia that is available in two oral daily formulations (immediate-release, extended-release).26,68–71

In addition to the quetiapine data from the CATIE and EUFEST analyses discussed above, a post hoc analysis36 of 389 persons with schizophrenia drew its data from 3 pivotal clinical trials of quetiapine.72–74 Summarized in Table 1, this study was not supportive of a specific anti-hostility effect. However, another post hoc analysis from one of the three trials included above demonstrated a specific anti-agitation effect34 (Table 1).

Given these studies, the evidence for the clinical usefulness of quetiapine as an anti-hostility agent is weak. The data available come from post hoc analyses and is conflicting, with the one supportive study focusing on agitation rather than hostility,34 possibly reflecting quetiapine’s sedative profile.68 In both the CATIE58 and EUFEST59 trials, olanzapine performed better than quetiapine on anti-hostility effect.

Ziprasidone

Ziprasidone received approval in the United States in 2001 for the treatment of persons with schizophrenia and was seen to have a more favorable weight/metabolic profile than other atypical antipsychotics available at the time, though it is associated with a lengthening of the ECG QT interval.26,75–80

Ziprasidone demonstrated a specific anti-hostility effect as evidenced in a post hoc analysis38 of an industry-sponsored study;81 the results are summarized in Table 1. However, the ziprasidone data from the CATIE and EUFEST analyses discussed above did not show advantages for ziprasidone compared to the other antipsychotics.

Thus, the evidence for the clinical usefulness of ziprasidone as an anti-hostility agent is weak. The data available come from post hoc analyses and, other than CATIE or EUFEST, are limited to one open-label study reflecting a narrow use of ziprasidone (short-acting intramuscular, followed by oral). In the CATIE study, olanzapine performed better than ziprasidone on anti-hostility effect.58

Aripiprazole

Aripiprazole was initially approved in the United States in 2002 for the treatment of persons with schizophrenia; its introduction was heralded by some as a “third-generation” antipsychotic, as it was the first dopamine D2 receptor partial agonist marketed for schizophrenia.82–86 Often mentioned is aripiprazole’s propensity to cause akathisia,82,84 making this medication counterintuitive for use as an anti-hostility agent.

A relevant post hoc analysis is available37 assessing data from five of the registrational studies87,88 (Table 1). The reported anti-hostility effects of aripiprazole are consistent with the findings of another post hoc analysis39 (Table 1) of pooled data examining agitation.87–89

Similar analyses have been conducted with one of the long-acting injectable formulations of aripiprazole, aripiprazole lauroxil,42 using data from the pivotal study.90 A specific anti-hostility effect was reported, as well as effects on agitation and aggressive behavior (Table 1). This report is especially noteworthy as the first published analysis of a long-acting, injectable antipsychotic that specifically examines potential anti-hostility effects. Long-acting, injectable antipsychotics may be ideal for persons for whom daily medication adherence is a struggle; availability in this form is noteworthy because nonadherence with medication is associated with worsening symptoms of schizophrenia, including increased aggressive behavior.91 The result is a potentially bidirectional phenomenon, with nonadherence contributing to hostility, and hostility contributing to nonadherence.92–95 Thus, a treatment option that combines the ability to reduce medication nonadherence and improve symptoms of hostility and aggression in patients with schizophrenia is especially valuable.96 It is reasonable to assume that aripiprazole monohydrate would perform similarly to aripiprazole lauroxil in terms of specific anti-hostility effect. Specific anti-hostility effect should be examined with other long-acting injectable antipsychotics such as risperidone (intramuscular and subcutaneous formulations), paliperidone (monthly and every-three-month formulations), and olanzapine.

In sum, the evidence for the clinical usefulness of aripiprazole as an anti-hostility agent is weak. The data available come from post hoc analyses of registrational studies demonstrating superiority over placebo on anti-hostility effect. No differences were found on this outcome when comparing aripiprazole with haloperidol.

Iloperidone

Iloperidone was initially approved in the United States in 2009 for the treatment of persons with schizophrenia.97 Notable for its relative absence of antipsychotic-induced motor side effects, iloperidone does carry a warning for prolongation of the ECG QT interval similar to the warning for ziprasidone.

There are no reports of iloperidone regarding specific anti-hostility effects, although a PANSS five-factor analysis40 evaluated data from the registrational studies and found that iloperidone had efficacy on the excitement/hostility factor, as did the active comparators included in the studies (Table 1).

Asenapine

Sublingual asenapine was initially approved in the United States in 2009 for the treatment of persons with schizophrenia and bipolar mania,98 and a daily transdermal patch formulation of asenapine was approved in the United States in 2019.99

There are no published reports of asenapine’s potential specific anti-hostility effects in persons with schizophrenia, although a poster44 (Table 1) describes a specific anti-hostility effect in a post hoc analysis of pooled data on the 5 mg, twice-daily dose from the registrational studies.100–102 Of interest is an analogous study in persons with bipolar disorder45 (Table 1), where data were also pooled from the registrational studies.103–105 A specific anti-hostility effect was noted for asenapine after controlling for improvements in overall mania symptoms.

The evidence for the clinical usefulness of asenapine as an anti-hostility agent in persons with schizophrenia is weak. The data available come from unpublished post hoc analyses of registrational studies that examined only one dose strength, with no consistent demonstration of superiority over placebo. A published post hoc analysis of the bipolar registrational studies comparing asenapine with placebo did demonstrate a specific anti-hostility effect.

Lurasidone

Lurasidone was initially approved in the United States in 2010 for the treatment of persons with schizophrenia.106–109 Although lurasidone has a favorable metabolic profile, sedation and akathisia are noted as potential adverse effects and may be mitigated in part by evening dosing.109

In a post hoc analysis presented as a poster41 (Table 1), individual patient data were pooled from the positive registrational studies—five randomized, double-blind, placebo-controlled, six-week, phase 2/3 studies of fixed-dose, once-daily, oral lurasidone (40–160 mg/d) conducted in patients with acute schizophrenia.110–114 The observed specific anti-hostility effect is consistent with another post hoc analysis examining agitation46 (Table 1).

The evidence for the clinical usefulness of lurasidone as an anti-hostility agent in persons with schizophrenia is weak. The data available come from an unpublished post hoc analysis of registrational studies comparing lurasidone with placebo, with support from a published post hoc analysis of the registrational studies on lurasidone’s effects on agitation over the same time period.

Brexpiprazole

Brexpiprazole was initially approved in the United States in 2015 for the treatment of persons with schizophrenia and major depressive disorder.84,115 Similar to aripiprazole, brexpiprazole is a dopamine receptor partial agonist but has a different pharmacodynamic profile and a lower propensity for akathisia.84

Brexpiprazole’s specific effect on hostility and agitation in the short and long term were demonstrated in a post hoc analysis47 (Table 1) of pooled data from the placebo-controlled registrational studies116,117 and included data from a 52-week, open-label, extension study.118

The evidence for the clinical usefulness of brexpiprazole as an anti-hostility agent in persons with schizophrenia is weak. The data available come from a single post hoc analysis of registrational studies comparing brexpiprazole with placebo, although it is supported by longer-term data. Effects appear more consistent at the higher dose of 4 mg/d.

Cariprazine

Cariprazine was initially approved in the United States in 2015 for the treatment of persons with schizophrenia and bipolar mania.84,119 Cariprazine is a dopamine receptor partial agonist that differs from other antipsychotics in that it has potent affinity for the dopamine D3 receptor and has an active metabolite with a half-life of 1–3 weeks that is the predominant circulating active moiety; movement disorders are the most common adverse effects and are dose related.119

The evidence supporting the clinical usefulness of cariprazine as an anti-hostility agent in persons with schizophrenia is weak because it is limited to a single post hoc analysis43 (Table 1) of registrational studies comparing cariprazine with placebo.120–122

DISCUSSION

In addition to hallucinations and delusions, persons with schizophrenia may exhibit hostility. The idea that atypical antipsychotic medications may have specific anti-hostility effects that are at least partially independent of effects on the “psychotic” symptoms of schizophrenia initially sprang from astute clinical observations with clozapine and was confirmed about a decade later with randomized, double-blind, controlled clinical trials of clozapine versus the leading agents available at that time.

After clozapine came the arrival in the United States of risperidone/paliperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, iloperidone, asenapine, lurasidone, brexpiprazole, and cariprazine. Encouragingly, since none of these carried the mandatory blood monitoring required for clozapine, they became more likely to be used, including in patients who are hostile. Unfortunately, except for olanzapine and risperidone, none of the newer atypical antipsychotics have been formally assessed in randomized, double-blind, controlled trials in which an a priori specific anti-hostility (or anti-aggressive) effect was tested. Although post hoc analyses of specific anti-hostility effects for most of these medications have been remarkably consistent, generalizability of these studies may be limited as participants in these trials were not selected for aggressive and hostile behavior. In addition, comparisons against placebo have limited applicability on their own, other than confirming that hostility is an independent treatment domain. Indirect comparisons through a meta-analysis may be able to help rank relative anti-hostility effects, but no such review is currently available. At present, directly comparing effects among antipsychotics is thus largely limited to the small number of extant randomized clinical trials in which specific anti-hostility (or anti-aggressive) effects were examined a priori in state hospital populations,23,25 or post hoc among all-comers in large effectiveness trials (CATIE and EUFEST) conducted mainly with outpatients.58,59 Complicating matters is that clozapine’s anti-hostility effects have been principally studied only in inpatient settings.

If the focus of attention is on physical aggression, the PANSS hostility item itself may be inadequate in that only the highest ratings of 6 or 7 may denote physical aggression. However, as noted in the introduction, each unit increase on the PANSS rating of hostility increases the odds of serious violence.6

An additional limitation is the exclusion from the clinical trials of patients with an active comorbid substance-use disorder. Alcohol and substance use are well known to increase the risk for hostility and aggression. These and other comorbidities contribute to patient heterogeneity and the likelihood of response to treatment.123 Causal pathways for hostility (and potentially aggression or violence) are complex and likely multi-determined.124,125 For example, some patients with a long history of antisocial behavior—perhaps from childhood, predating psychosis—might exhibit hostility and aggression for the same reasons that nonpsychotic, personality-disordered adults do; violence risk could thus persist even when major psychotic symptoms abate. By contrast, other patients might exhibit similar symptoms and behaviors for quite different reasons—for example, distorted cognition in reaction to excessive threat perception rooted in acute delusional psychosis. There remains a strong need to understand the mechanism(s) underlying observed specific anti-hostility effects. An antipsychotic with versus without specific anti-hostility properties may affect these two groups of patients differently.

At this juncture, the most robust evidence for a specific anti-hostility effect remains with clozapine, followed by olanzapine. For the remainder, the level and strength of evidence is, at best, weak. For persons with schizophrenia unable to tolerate clozapine or olanzapine, the available data do not point to a definitive favored choice. An empirical n = 1 trial in individual patients will determine what works, what is tolerated, and whether the patient is willing to take it. In addition to appraising the risk for adverse effects such as weight gain, sedation/somnolence, or activation/akathisia, also to be considered are the “amenities of care”—the requirement and length of time for initial titration, frequency of dosing, need for administration with food, and availability of alternate formulations such as long-acting injectables or transdermal systems, which some patients may prefer over pills.

Declaration of interest: In the past 12 months, Dr. Citrome has served as a consultant to Acadia, Alkermes, Allergan, Avanir, BioXcel, Cadent Therapeutics, Eisai, Impel, Intra-Cellular Therapies, Janssen, Lundbeck, Luye, Merck, Neurocrine, Noven, Osmotica, Otsuka, Sage, Shire, Sunovion, Takeda, and Teva. In the past 12 months, he has served as a speaker for Acadia, Alkermes, Allergan, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Merck, Neurocrine, Noven, Otsuka, Sage, Shire, Sunovion, Takeda, and Teva. He also holds a small number of shares of common stock in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, and Pfizer.

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Keywords:

aggression; atypical antipsychotics; hostility; schizophrenia; second-generation antipsychotics

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