Implications

These findings may have important implications for the theoretical and clinical understanding of aggression in schizophrenia [18,47]. From a theoretical perspective, the findings refine our understanding of the role of impulsivity in aggression. Thus, not all impulsivity is the same, and many aspects of impulsivity are not elevated in chronic schizophrenia. On the basis of self-report measures, only the emotional components (i.e., urgency) of the construct were elevated. Moreover, the neural circuitry related to urgency involves the structural integrity of ventral prefrontal regions and their functional connections to limbic and executive regions. Dysfunction of these circuits, which are implicated in emotional regulation, may predispose an individual toward aggression [48]. The extant literature suggests the importance of emotional dysregulation deficits in schizophrenia [49].

From a clinical perspective, the results suggest implications for treatment. Targets may include cognitive interventions to enhance regulation of impulsivity and aggression. These could include techniques such as reappraisal of negative emotional experiences, or suppression of negative affect [50]. It is not yet known if these interventions can be used to effectively reduce aggression in patients with schizophrenia. However, their use, including techniques related to acceptance of emotional experiences [51], might lessen the impact of distress associated with strong emotional states, and thereby prevent urgency-related aggression.

The literature also points to neural targets. Some antipsychotic medications appear to have specific antiaggressive effects, particularly clozapine [52,53]. Although second-generation antipsychotic agents have mixed effects on neurotransmitters, they do affect serotonin systems. Abnormalities in these systems have been associated with violent behavior in a number of populations. Of relevance to aggressive behavior, serotonin transporter sites are selectively reduced in ventral prefrontal regions in suicide victims compared to those with depression only [54]. It would be important to examine serotonin transporter distribution patterns in violent patients with schizophrenia. Moreover, it would be interesting to examine the effects of clozapine on urgency in patients with schizophrenia. In the study by Hoptman et al. [18], patients taking clozapine had lower urgency ratings on the UPPS-P than patients taking other medications. Clearly, a better definition of the multidimensional construct of aggression may lead to better treatment decisions and outcomes [55].

Other treatment approaches also may be useful to reduce impulsivity-based aggression. Transcranial magnetic stimulation (TMS) has traditionally been unable to reach cortical depths of greater than 2 cm, thereby rendering it unable to stimulate ventral prefrontal regions. However, we can apply our knowledge from big data approaches such as the Functional Connectomes Project [56] to identify circuits that are functionally connected to ventral prefrontal regions. Thus, it may be efficacious to stimulate regions such as the dorsolateral prefrontal cortex or precuneus in order to modulate activation in ventral prefrontal regions. Alternatively, deep TMS has the potential to reach depths of up to 6 cm from the cortical surface. This technique has shown treatment utility in a number of disorders involving emotional dysregulation, including major depression, hallucinations and delusions in schizophrenia, bipolar depression, and Asperger’s syndrome [57]. Neither of these TMS approaches has been specifically applied to impulsive aggression in schizophrenia, but such methods may prove useful from both mechanistic and treatment perspectives.

Another potentially interesting approach is the use of real-time fMRI neurofeedback [58] to modulate the neural circuitry related to impulsivity and aggression. Real-time fMRI has been applied to the “default mode network” (DMN [59]) – a set of brain regions, including medial prefrontal cortex, posterior cingulate, and lateral parietal regions, that typically shows increased activity during rest, compared to task, conditions. Studies on DMN suggest its involvement in self-directed cognition [60]. Real-time fMRI has had limited application in schizophrenia so far [61]. In principle, one could identify critical circuitry for urgency and train patients to modulate their own circuitry. Recent studies show that orbitofrontal circuitry can be manipulated in this manner in healthy subjects with contamination anxiety [62], and that anterior insula circuitry can be modulated in criminal psychopaths [63], which suggests that this approach might be applicable in other populations with abnormalities in such circuitry.

As has been stressed in this article, aggression has multiple causes, and a complete understanding of aggression in schizophrenia will extend the knowledge of impulsive, psychotic, and psychopathically based aggression, as well as interactions among these three types of aggression. For example, an important literature is emerging on the role of persecutory delusions in aggression in schizophrenia [64]. Significantly, it appears that delusions that engender anger are those that are most likely to lead to aggression [65], suggesting a mechanism whereby urgency could interact with psychotic symptoms to yield violent behavior. Finally, the circuitry underlying psychotic, impulsive, and predatory violence likely differs, and an understanding of these distinct circuits and their interactions will inform our ability to understand the genesis of aggression in schizophrenia [4].

It should be noted that I am not arguing that all aspects of aggression in schizophrenia are determined by urgency. However, given the role that urgency may well play in aggression in schizophrenia, as well as the fact that at least a plurality of inpatient aggression is impulsive in nature, it may be that an assessment of urgency would be useful prior to intervention. Moreover, as noted above, it could be that other causal factors might interact with urgency so that changes in urgency might have as-yet-unknown effects on those factors. It would thus be important to know to what extent treatments typically used to address impulsively based aggression work through the construct of urgency and/or via related circuitry.

More generally, the literature on impulsivity and violence in schizophrenia points to the need for a better understanding of the regulation of emotionally based impulsivity and aggression in this disorder, as well as the need to better understand the regulation of other problematic behaviors associated with emotionally based impulsivity. This conceptualization places the problem in the context of a phenomenon that we know to be an issue transdiagnostically [66], in keeping with the NIMH’s RDoC mission. It will be important to use information on regulation of impulsivity and aggression more broadly to help understand how it plays out in schizophrenia and other disorders.

Challenges

There are several important challenges in this line of work. First, there is no known paradigm that ideally probes urgency, which makes it difficult to objectively evaluate this construct in imaging studies. It may be that urgency has such strong trait properties that it cannot be easily modified. Alternatively, behavioral tasks that are typically used to measure impulsivity may have to be adapted to include a strong emotional component in order to better investigate this construct. Even if urgency cannot be easily manipulated, initial approaches might include (a) finding tasks that are closely related to urgency that can be modulated and/or (b) modulating urgency-related circuitry with the goal of examining its downstream effects on impulsively based aggression,

Paradigms such as the TAP or PSAP might be promising. Although the PSAP is part of the RDoCmatrix, the task requires substantial motor activity and thus might be difficult to implement in fMRI studies. The TAP has been used in some fMRI studies. In particular, Dambacher et al. [67] used the go/no-go task to measure response inhibition and the TAP to measure reactive aggression in healthy men. They found that both failed response inhibition (compared to go trials) and reactive aggression were associated with activation of the anterior insula, suggesting a role for that region in self-control. This same group showed that theta burst TMS in the right anterior insula and superior frontal cortex leads to impairments in both action restraint (go/no-go task) and action cancellation (stop task) in the former, and in action restraint in the latter compared to sham stimulation [68]. By identifying regions indirectly stimulated by TMS in these studies, a better understanding of the circuitry associated with reactive aggression, action restraint, and action cancellation could be derived.

Conclusion

This article focuses on impulsive aggression. In general, imaging studies point to the role of abnormalities in circuitry involving ventral prefrontal, medial temporal, and subcortical regions as playing a key role in these behaviors. The recent finding that urgency plays a special role in aggression in schizophrenia suggests several novel approaches to better understand and treat these dysfunctional behaviors, and these approaches may have utility for other problematic behaviors associated with urgency, as well. Nonetheless, aggression in schizophrenia is not homogeneous across individuals, and a complete understanding of these behaviors will consider this heterogeneity. Newer assessments and guidelines for inpatient aggression are explicitly doing just that [69,70]. By improving this understanding, we will be better equipped to manage aggressive behavior in schizophrenia, leading to reductions in harm, trauma, healthcare costs, and stigma.

Disclosures

Matthew Hoptman has the following disclosures: NIMH, researcher, research support (grants); Kessler Foundation, consultant, consulting fees.