Serotonin Dysfunction, Aggressive Behavior, and Mental Illness

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Serotonin dysfunction, aggressive behavior, and mental illness: exploring the link using a dimensional approach. Mirko Manchia, Bernardo Carpiniello, Flavia Valtorta, and Stefano Comai ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.6b00427 • Publication Date (Web): 05 Apr 2017 Downloaded from http://pubs.acs.org on April 6, 2017

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ACS Chemical Neuroscience

Serotonin dysfunction, aggressive behavior, and mental illness: exploring the link using a dimensional approach. Mirko Manchia,†,§ Bernardo Carpiniello,† Flavia Valtorta,∥ Stefano Comai∥,* †

Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari,

Cagliari, Italy §

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

∥San

Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy

*Address correspondence to this author at the Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Via Olgettina 58, 20132 Milan, Italy. E-mail: [email protected];

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Abstract Aggressive individuals have higher rates of mental illness compared to non-aggressive individuals. Multiple factors, including psychosocial, genetic, and neurobiological determinants modulate the liability to both aggressive behavior and mental illness. Concerning the latter factors, multiple lines of evidence have shown a dysfunction in the serotonin (5-HT) system occurring in aggressive and in mentally ill individuals. In particular, a reduced 5-HT activity has been associated with depression as well as with aggressive behavior, especially with impulsive aggression. Consistently, psychopharmacological interventions aimed at boosting the 5-HT system (e.g. with selective serotonin reuptake inhibitors) have demonstrated therapeutic efficacy in a high percentage of patients with either or both pathological conditions. Current knowledge does not yet allow to clearly disentangle whether 5-HT dysfunction, most often a 5-HT deficiency, is the consequence of the aggressive/violent behavior, of the underlying mental disease/s, or the expression of the comorbidity. Future studies are thus needed to clarify the association between changes in 5-HT levels, altered activity of 5-HT receptors and their intracellular signaling cascades, and modifications of 5-HT genes, and in particular the neurobiological link between the altered 5-HT machinery and aggressive behavior in the context or in the absence of mental illness. In this review, we employ a dimensional approach to discuss the trivariate relationship among the 5-HT system, aggressive behaviour, and mental illness, focusing our attention on 5-HT levels, 5-HT receptors, metabolic enzymes and their genes. Emphasis is given to controversial findings, still unanswered questions, and future perspectives.

KEYWORDS: serotonin, aggressive behavior, depression, schizophrenia, bipolar disorder.


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Multiple lines of research including, neurochemical, neurobiological, neuropsychopharmacological, genetic, and neuroimaging studies, have consistently pointed to serotonin [5-hydroxytryptamine (5HT)] and related biochemical pathways as a key element in the pathophysiology of severe mental illness (SMI) and abnormal behavioral manifestations such as aggression and violence. This neurotransmitter, synthesized from the essential amino acid tryptophan, appears to regulate emotion, feeding, cognition, arousal, motor and autonomic functioning,1 and is considered crucial for the development of the brain.2 Although there is evidence supporting the link between aggressive behavior, mental illness and the involvement of 5-HT in the pathophysiology of both phenotypic traits, no studies have specifically examined this trivariate relationship. Achieving a precise understanding of this trivariate link is not only of theoretical value but has substantial research and clinical implications. Indeed, only a subset of patients affected by SMI develops aggression. It is possible that these patients share distinct alterations predisposing to aggression, including alterations involving the 5-HT system.3 However, only prospective longitudinal observations of aggressive SMI patients could establish whether: 1) a hyper- or hypo- activity of the 5-HT system is causative of aggressive behavior in SMI; 2) an alteration of the 5-HT system precedes the manifestation of aggression or vice versa; and 3) which element(s) of the 5-HT pathway is the main culprit. This could lead to the identification and validation of biomarkers for aggression in SMI patients. Once incorporated in predictive models, 5HT system biomarkers could help identifying a priori mentally affected individuals prone to aggression. Further, molecular targets identified through clinical research could be tested in basic neuroscience models to identify the precise neurobiological mechanisms altered in aggression. Recent studies have used, e.g., behavioral animal models,4 optogenetics,5 and brain imaging techniques6 with promising results.


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The identification of reliable markers of aggression in SMI, as well as of the precise neurobiological underpinnings of aggression, has been significantly hindered by the relatively high degree of clinical (phenotypic) heterogeneity of both traits. Patients can manifest aggressive behavior in the context of diverse psychopathological imbalance. For instance, psychotic patients can be aggressive as a consequence of a hallucinatory command, manic bipolar patients might become aggressive in the context of behavioral disinhibition and dyscontrol, patients affected by personality disorders might show instrumental aggressive behavior. In an attempt to decrease the impact of clinical heterogeneity, and to facilitate the comprehension of psychopathological alterations in terms of neuroscience, psychiatry research is currently shifting toward a dimensional rather than a categorical nosological approach. In this context, the National Institute of Mental Health (NIMH) has developed the Research Domain Criteria (RDoC) with the aim of integrating many levels of information (from genomics to self-report) to better understand basic dimensions of functioning underlying the full range of human behavior, from normal to abnormal.7 According to RDoC, aggression is a frustrating-non-reward construct within the Negative Valence System (NVS) domain. With the aim of studying the dimensional transdiagnostic underpinnings of aggression, Verona and Bresin8 showed that the interplay between Negative Valence and Cognitive Systems processing was significantly associated with aggression proneness, particularly reactive aggression. Specifically, individuals higher on aggression proneness showed reduced processing of inhibitory cues in the context of salient threat. As discussed previously, the identification of shared pathways to aggression, which might include different levels of information from psychopathology to “omics“ markers, can facilitate a preventive approach to aggression. Using a dimensional, trans-nosographic approach, here we attempt to clarify whether the observed 5-HT dysfunction might be the consequence of the aggressive/violent behavior, and/or of the underlying mental disease/s, or, alternatively, whether it might be an expression of their concomitant occurrence. To this aim, we review the role of biological markers within the 5-HT


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system in aggressive individuals affected by the two main categories of SMI, schizophrenia (SCZ), and mood disorders (bipolar disorder [BD], or major depressive disorder [MDD]). We also briefly discuss the role of 5-HT in two other psychiatric disorders, intermittent explosive disorder (IED) and antisocial personality disorder (APD), which are both conditions characterized by pathological aggression. We first present the epidemiological evidence of the association between SMI and aggressive behavior. Then, we give a brief overview of the risk factors modulating the liability threshold for aggressive behavior in SMI. At the core of our review is the evidence on the link between 5-HT in the peripheral or central nervous system (CNS), 5-HT receptors, 5-HT transporter (5-HTT), 5-HT pathway metabolic enzymes, and the development of SMI and/or aggressive behavior. To this end, we have considered neurobiological, genetic and psychopharmacological determinants. A final introductory remark is needed. Aggressive behavior has been considered as a unique entity of several different neuro-psychobiological manifestations, including but not limited to agitation, anger, hostility, irritability, and impulsivity, because at present there is a lack of a consensus definition. Specific details on the different definitions of aggressive behavior can be found elsewhere9, 10 or within the text. In addition, we have only examined aggressive behavior toward others (hetero-aggression), excluding suicidal behavior and self-harm. Although several studies have identified a strong association between aggression and suicide in terms of both psychopathology and neurobiological mechanisms, including the 5-HT system,11 this relationship seems unstable and still requires clarification. Overall, current knowledge highlights the important role of the 5-HT system in modulating the risk for SMI and aggressive behaviour, but further research is still required to clearly disentangle whether the alterations observed in the 5-HT system are specific to SMI, aggression, or their cooccurrence.


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Aggression in severe mental illness Aggression and violence are widespread behaviors that represent a substantial burden for the public health system worldwide.12 Prevalence estimates show that in 2000, 0.03% of the general population died as a consequence of aggression and violence (henceforth defined as aggression or aggressive behavior) in 2000, a figure corresponding to 1.6 million lives lost.12 Although only a minority of SMI patients develops aggressive behavior over the course of their illness,13 the manifestation of aggression is more prevalent in patients affected by SMI compared to unaffected individuals.14 Specifically, the Epidemiologic Catchment Area (ECA) surveys of Swanson et al.14 showed that SCZ patients had a 6-fold increase in the rate of aggressive behavior compared to unaffected subjects, a figure similar to those found in BD and in MDD patients. Of interest, patients with anxiety disorder did not show an increased frequency of aggressive behavior compared to unaffected subjects.14 However, it should be pointed out that the 1-year population attributable risk, which takes into account both the magnitude of risk and the number of people in the risk category within the population of aggression associated with SMI alone was found to be only 4% in the ECA surveys.14, 15 Further, the MacArthur Violence Risk Assessment Study, which followed up a cohort of more than 1000 discharged psychiatric inpatients over 1 year, found that there was no increase in the risk of violence in those patients who had only mental illness and no substance abuse compared to randomly selected people living in their neighborhoods.16 Epidemiological findings such as those from the ECA surveys confirmed the multifactorial contribution to the development of aggressive behavior. Indeed, patients with alcohol or drug use disorders had a risk of developing aggressive behavior significantly higher as compared to not only unaffected subjects, but also than SMI patients.14 Further, the presence of substance abuse disorder interacted significantly with SMI in increasing the liability to aggressive behavior.14 This observation was also corroborated by the works of Lindqvist and Allebeck,17 and Blomhoff et al.18 Interestingly, Elbogen and Johnson,19 using data from the National Epidemiologic Survey on ACS Paragon Plus Environment

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Alcohol and Related Conditions (NESARC), found that only when substance abuse and/or dependence was present, subjects affected by SMI had a higher risk of aggression, challenging the view that SMI represents an independent risk factor for this disruptive behavior. Indeed, SMI itself was predictive of any violence in multivariate analysis only when included with personal history factors (history of violence, having witnessed parental fighting, juvenile detention, history of physical abuse by parent), clinical factors (comorbid substance disorders, perception of hidden threats), dispositional factors (younger age, male sex, lower income), and proximal factors (victimization in the past year, being divorced or separated in the past year, and being unemployed in the past year).19 However, Van Dorn et al. 20 performed a reanalysis of NESARC data confirming that SMI patients, irrespective of substance abuse status, were significantly more likely to manifest aggression than those with no mental or substance use disorders. Further, it was also reiterated that patients with comorbid SMI and substance abuse had the highest risk of aggressive behavior.20 Differently from Elbogen and Johnson,11 when examining recent violence these authors based their analysis on past year diagnoses of mental illness instead of lifetime diagnosis.12 Further, they created and analyzed a homogeneous comparison group and created an ‘other’ mental disorder group, instead of using a diagnostically heterogeneous comparison group that combined people with no mental illness with people with other mental illnesses, including personality disorders.12 Finally, they included other relevant variables that were excluded from the statistical models used by Elbogen and Johnson.11 Taken together, these findings indicate that SMI patients might have a moderate increase in the risk of aggression compared to unaffected individuals and that the presence of substance abuse/dependence can increase substantially this liability.

Multifactorial contribution to aggressive behavior in severe mental illness As introduced previously, multiple determinants of risk appear to modulate the liability threshold to aggressive behavior in SMI. Socio-demographic14, clinical,21-24 developmental,25, ACS Paragon Plus Environment

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anatomical/structural,9, 10 and treatment-related factors28, 29 appear to influence the manifestation of aggression in SMI. Concerning the first set of determinants, Swanson et al.14 showed that male gender, a younger age, and a lower socioeconomic status were all predictors of the development of aggressive behavior in SMI patients. Further, several clinical factors have been found to contribute to the liability for aggressive behavior. In this regard, the case of IED is illustrative. Coccaro et al.21 found that the presence of seropositive status to Toxoplasma gondii (T. gondii), a protozoan parasite that persists in host tissues, including brain, was associated with higher aggression scores irrespective of the presence of a diagnosis of IED. Interestingly, these authors found that IED patients had higher rates of T. gondii seropositive status compared to non-IED psychiatric patients and to unaffected subjects.21 This finding is clinically relevant, since IED is traditionally considered a disorder characterized by pathological aggression. Importantly, patients with IED appear to have a significant deficit in the 5-HT system.30 A recent functional magnetic resonance imaging (fMRI) study investigated how a selective serotonin reuptake inhibitor, escitalopram, affected the neural mechanisms of social–emotional processing in IED.31 Interestingly, these authors found that escitalopram increased amygdala activity during social–emotional processing in controls, but not in IED. Another case in point is APD. This severe chronic condition has a prevalence between 2 and 3% among community samples, which increases to 60% among male prisoners.32 There is evidence that the 5-HT system might be altered in ASD, particularly in a subset of patients with callousunemotional traits. In this regard, Moul et al.33 found that functional single nucleotide polymorphisms (SNPs) in the 5-HT1B and 5-HT2A receptor genes are associated with callousunemotional traits. In addition, lower levels of serum serotonin predicted high callous-unemotional traits. The same group reported altered methylation levels of 5-HT1B in boys with antisocial behavior problems.34 Lower levels of 5-HT1B gene methylation, (i.e. increased expression) were associated with higher levels of callous-unemotional traits.34


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Specific psychopathological manifestations, particularly in SCZ patients, also appear to increase the risk of aggressive behavior.22-24 Indeed, a systematic review of studies investigating the relationship between paranoia and aggression found a positive correlation between these two factors, particularly when this psychopathological symptom was assessed using standardized methods.22 In addition, Bulgari et al.23 found that higher levels of negative symptoms predicted a lower risk of verbal aggression in a longitudinal prospective observation of 50 SCZ patients with a past history of violence and 37 SCZ patients without a history of violence. Interestingly, van Dongen et al.24 observed that only psychopathic traits were significantly associated with aggressive behavior in a cohort of 59 male SCZ inpatients. The study of the longitudinal developmental trajectory of aggression in SMI has identified the predictive role of childhood trauma.25, 26 Indeed, using a nationwide Swedish sample to test whether specific triggers for aggression were associated with an increased risk for this behavior in 34,903 SCZ, 26,692 BD patients and 2,763,012 unaffected controls, Sariaslan et al.25 found that the death of a parent was associated with a 5-fold increase in the risk of aggression in SCZ patients compared to controls. Further, the work from Oakley et al.26 found that childhood adversities, particularly their cumulative number, were strongly associated with adult propensity to aggressive behavior. Predictive model of aggression in SMI would benefit from considering genetic determinants. It should be noted, however, that the evidence available so far appears contradictory. In their quantitative genetic analysis of 923,259 Swedish twin-sibling pairs, Sariaslan et al.27 found that SCZ was a stronger predictor of aggressive behavior than BD. Nonetheless, they observed that genetic influences unique to BD explained approximately one fifth of the increased risk of aggression while equivalent genetic influences in SCZ did not contribute to such risk increases.27 Structural and/or functional modifications in neural networks regulating emotions have been related to both SMI and aggressive behavior and may partly explain their high co-morbidity. The most important brain regions implicated in the regulation of aggressive behavior are prefrontal cortex (particularly orbitoprefrontal cortex and anterior cingulate cortex), amygdala, hypothalamus, ACS Paragon Plus Environment

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hippocampus, septal nuclei, periaqueductal gray of the midbrain, and midbrain monoamine nuclei such as the dorsal raphe nucleus.9,

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A meta-analysis of voxel-based morphometry studies in

schizophrenia indicated that patients with chronic schizophrenia had lower gray matter volumes in frontotemporal regions, left dorsolateral prefrontal lobe and thalamus compared with controls, and antipsychotics (especially typical antipsychotics), which are used for both SCZ and aggression, induce hypertrophy in these brain regions.35 Volumetric reductions of the hippocampus, basal ganglia and orbitofrontal cortex along with dynamic changes sex- and disease progressiondependent in the amygdala have been consistently found in patients with MDD.36 In addition, metabolic abnormalities were also highlighted in some of these brain regions, but importantly, they normalized after adequate antidepressant treatment

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. Of note, antidepressants including selective

serotonin reuptake inhibitors (SSRIs) are also used as anti-aggressive medications, although some warnings have to be considered.38 Finally, treatment related factors appear of importance in modulating the risk of aggression in SMI. Indeed, aggressive behavior can be a severe and dangerous complication of SCZ if not treated properly and timely.29 Olanzapine, an atypical antipsychotic with prominent antagonistic activity on 5-HT2A receptors, has been shown to be superior to typical (haloperidol, perphenazine) and other atypical (risperidone, quetiapine, ziprasidone) antipsychotics in treating aggression in SCZ patients.28,

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Importantly, the presence of aggression, quantified through a related measure,

hostility, could decrease substantially the adherence to pharmacological treatments, further complicating the management of this disruptive behavior in SCZ, and SMI in general.28 In summary, there is evidence that a series of determinants (clinical, genetic, treatment-related, developmental, anatomical/structural) might modulate the pathway to aggression in SMI. As detailed in this review, some of these determinants have clearly demonstrated neurobiological underpinnings related to the 5-HT pathway (one example are positive or negative symptoms). Therefore, they should be taken into account when examining the trivariate relationship between aggression, SMI, and 5-HT. ACS Paragon Plus Environment

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5-HT levels, severe mental illness, and aggression In 1965, Schildkraut39 proposed the monoamine (mainly norepinephrine but also serotonin) hypothesis of mood disorders (BD and MDD), on the basis of available data that, at that time, pointed to a substantial dysregulation of this neurochemical pathway. Although an enormous amount of research has been conducted on this topic, more than 50 years later this hypothesis has not yet translated into a clear pathophysiological explanation of mood disorders, and certainly the situation is far more complex than originally hypothesized. Currently, the most important proof of the possible involvement of 5-HT in the pathogenesis of mood disorders is the observation that SSRIs are among the first line treatment for depression and anxiety disorders. However, it is as yet unclear whether their therapeutic effects are really dependent on an increase of 5-HT extracellular levels.40 In addition, the fact that drug-induced variations in 5-HT are effective in relieving symptoms of depression and anxiety does not imply a causative role of 5-HT dysfunction in such diseases. To study the link between 5-HT function, particularly 5-HT levels, and the pathophysiology and psychopharmacology of SMI, three experimental approaches has been mainly employed: 1) measurement of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), 2) tryptophan depletion, and 3) the prolactin response to dl-fenfluramine (an indirect central 5-HT agonist). A detailed analysis of these studies is out of the aim of this review and can be found elsewhere.9,

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All together, these studies suggest that only a certain

subgroup of mood disorder patients with common biochemical signatures have disturbance of the 5HT turnover. Indeed, only a percentage of patients with depression and/or anxiety fully respond to SSRIs. The relationship between 5-HT levels and aggressive behavior has also been the topic of decades of research. Incongruent findings have been reported in the scientific literature regarding CSF 5-HIAA levels in individuals showing aggressive behavior compared with people who never showed such behavior. Importantly, these findings were mostly derived from analyses of individuals suffering ACS Paragon Plus Environment

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from mental illness of varying severity including depression and/or personality disorders,45-47 or from studies in which psychopathology was not considered/assessed as a possible confounding or contributing factor. In a milestone paper for the field, Brown et al.46 found that aggression scores were negatively correlated with CSF 5-HIAA in military men with no history of SMI, but with various personality disorders. This earlier finding was then confirmed by Coccaro et al.,45 who showed an association between reduced prolactin response to fenfluramine and ratings of impulsive aggression in patients with personality disorder but not with MDD. Consistently, Linnoila et al.47 reported lower CSF 5-HIAA in impulsive rather than in paranoid or passive aggressive murderers. A detailed discussion of the numerous studies assessing CSF 5-HIAA levels and their correlation with aggressive behavior and/or SMI illness, of the contrasting findings and limitations is beyond the aim of this review and can be found elsewhere.9, 48 However, it should be emphasized that CSF 5-HIAA is not directly an index of post-synaptic 5-HT activity and that for ethical and methodological reasons, 5-HIAA levels have been generally determined in the lumbar and not in the ventricular CSF which could provide a better index of 5-HIAA and consequently of 5-HT activity in the brain.49 Although evidence demonstrates that the storage, uptake and release of 5-HT in blood platelets is similar to that occurring in brain 5-HT neurons (for details see the review by Stahl50), peripheral levels of 5-HT in the blood may not be used for neurobiological studies on brain 5-HT, given that 5HT does not cross the blood-brain barrier. However, it is interesting to note that increased levels of plasma or serum 5-HT have been reported as markers of SMI including SCZ,51 attention deficit hyperactivity disorder (ADHD),52 and autism.53 Similarly, we recently demonstrated that also aggressive inmates presented higher serum 5-HT levels compared to non-aggressive individuals54 likely as a consequence of downregulation of MAOA enzymatic activity due to hypermethylation of the MAOA gene promoter.55 Of note, a large proportion of aggressive inmates was affected by SMI. In particular, 56% of them had a mood disorder and 80% of them an APD.


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Collectively, studies have indicated on one hand low brain 5-HT levels (measured as reduced CSF 5-HT levels), and on the other hand high peripheral 5-HT levels (measured as increased serum 5HT levels), in patients with SMI and aggression. This inverse relationship between peripheral and central 5-HT levels and activity in the presence of SMI and aggression warrants to be further investigated. Although evidence from genome-wide association studies (GWAS) shows that variants within genes encoding for elements of the monoaminergic pathway (including the 5-HT pathway) might influence 5-HT levels, particularly in the CSF,56 there are no studies directly investigating aggressive behavior. It is plausible, however, that SNPs in genes of the 5-HT pathway might be involved in aggressive behavior in SMI. Indeed, the link between 5-HT genes and SMI has been deeply investigated through candidate genes57,

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and non-hypothesis driven approaches.59 Specifically, SNPs within

genes coding for tryptophan hydroxylase-1 (TPH1),57,

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tryptophan hydroxylase-2 (TPH2),58

monoamine oxidase A (MAOA),59 5-HT transporter (5-HTT),59 5-HT1A, 5-HT2A and 5-HT3B receptor59 have been identified as risk variants for the development of MDD, BD, and SCZ. However, the risk conferred by these variants remains of small magnitude as shown, e.g., by the effect size of TPH1 rs1800532 SNP (OR = 1.24) and TPH2 rs11178998 and rs7954758 SNPs (OR = 1.33 and 1.36, respectively) in BD.44, 46 As a consequence, some studies have also attempted to identify an association between markers in genes encoding for 5-HT receptors and related enzymes, and aggression in SMI.

Serotonin receptors, severe mental illness, and aggression 5-HT receptors have been investigated in preclinical and clinical studies for their role in mental diseases but also specifically in aggressive behavior. Knockout mice for the 5-HT1A receptors display reduced levels of aggression whereas, on the contrary, knockout mice for the 5-HT1B


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receptors have enhanced aggressive behavior.9 The involvement of these two 5-HT receptor subtypes in aggression has also been confirmed by pharmacological studies indicating that 5-HT1A agonists and partial agonists and mixed 5-HT1A/5-HT1B partial agonists have potent anti-aggressive properties in animal paradigms of aggressive behavior.60 Preclinical and clinical studies also indicated the involvement of the 5-HT2 receptor family in aggressive and impulsive behavior. In rats, 5-HT2A receptor antagonists decreased measures of impulsivity whereas 5-HT2C receptor antagonists produced an opposite effect. Remarkably, the magnitude of these effects was related to the state of the endogenous 5-HT system.61 In agreement, patients with current physical aggression display greater orbitofrontal 5-HT2A receptor availability than patients without current physical aggression and healthy subjects,62 and atypical antipsychotics with marked 5-HT2A antagonist properties have shown important anti-aggressive properties in several clinical studies (for a review see Comai et al.38). Several studies have examined changes in 5-HT receptors in various mental disorders known to be associated with increased aggression, but without considering this possible behavioral trait. Using positron emission tomography (PET), a widespread reduction in 5-HT1A receptor binding across many brain regions has been found in patients with MDD,63, 64 although a more recent study did not confirm these findings.65 Post-mortem and imaging studies have demonstrated increased 5-HT1A receptor density in SCZ patients,

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and males but not females with bipolar depression.67 However,

no difference in 5-HT1A receptor density between medicated euthymic patients with BD type 1 and controls has been also reported.68 Collectively, these studies suggest a dysregulation of 5-HT1A receptors in SMI, but possibly due to different experimental protocols (medicated versus medication-free patients, unbalanced sex differences, heterogeneity of psychiatric diagnosis), the magnitude of changes in 5-HT1A receptor density still needs to be accurately quantified. No changes in 5-HT2 binding potential was found in untreated patients with depression

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or with

SCZ,70 whereas drug-free patients with mania showed reduced 5-HT2 receptor binding potential.71 In contrast to the PET study70, a postmortem study found a decrease in 5-HT2 receptors in patients ACS Paragon Plus Environment

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with SCZ, that was likely independent of the antipsychotic treatment.72 Despite some controversies between imaging and post-mortem studies, and possible differences among distinct mental disorders regarding a pathophysiological involvement of 5-HT2 receptors, this receptor seems important from a treatment perspective. Indeed, several antidepressant and anxiolytic drugs as well as atypical and classical antipsychotics show high affinity for 5-HT2 receptors.38 More recent and sparse evidence links other 5-HT receptors subtypes with SMI and/or aggressive behavior. For instance, there is now clear evidence showing a role for 5-HT3 receptors in MDD,73, 74 aggression,75 and SCZ.76 Indeed, presynaptic and postsynaptic 5-HT3 receptors modulate the release of neurotransmitters including serotonin and dopamine. Recently, using the chronic social isolation paradigm, it has been demonstrated that 5-HT3 receptors are implicated in the aggressive behavior and depressive-like phenotype of mice undergoing this protocol.77 The use of another paradigm, i.e. the exposure to anabolic androgenic steroids during development, that stimulates offensive aggression while reducing anxiety, highlighted the important neurobiological contribution of 5-HT3 receptors (especially those located within the anterior hypothalamus) in aggression and anxiety.78 In this behavioral test, altered levels of aggression and anxiety are achieved by a daily subcutaneous injection of an anabolic/androgenic steroid mixture composed by testosterone, nandrolone and boldenone, from post-natal day 27 to 56.78 In summary, these studies were not able to clearly disentangle whether 5-HT3 receptors were more associated to aggression, depression and/or anxiety, or the co-occurrence. Concerning genetic determinants of aggression, there is paucity of studies investigating the role of polymorphisms within genes encoding for 5-HT receptors; in particular, studies have been conducted in SCZ patients. In a candidate gene association study conducted in 186 SCZ patients characterized for aggressive behavior, Tsai et al.79 did not found an overrepresentation of allelic or genotypic frequencies of 5-HT6 receptor in aggressive versus non-aggressive SCZ patients. In addition, Hong et al.80 investigated the specific role of the A-161T polymorphism in the 5-HT1B


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gene in 110 SCZ patients and did not find any association of genotypic or allelic frequencies with aggressive behaviour. Given the still limited evidence, further research is needed to clarify a possible association between genes encoding for 5-HT receptors and aggression in SCZ.

Serotonin transporter, severe mental illness, and aggression Knock-out mice for 5-HTT display a depressive- and anxious-like phenotype,81 but a reduced aggressive behavior in the resident-intruder paradigm.82 In this test, one male mouse (the intruder) is placed into the home cage of another male mouse (the resident) and then left to interact for a certain period of time. Constitutively, 5-HTT knockout mice have increased basal levels of extracellular 5-HT that yield to several compensatory alterations including a reduction in dorsal raphe neuronal firing activity and a desensitization of 5-HT1A autoreceptors.83 This is intriguing since it presents complex and apparently contradictory modifications within the 5-HT system. Indeed, the observed modifications are compatible both with a reduced 5-HT activity, and consequently a depressive phenotype, and with increased levels of 5-HT, and thus reduced aggressive levels. As previously mentioned, blockage of the 5-HTT with either SSRIs or less selective compounds including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and serotonin antagonist and reuptake inhibitors, represents the first line treatment for depressive and anxiety disorders. However, given the 2-4 weeks latency to obtain a therapeutic effect, the sole inhibition of the transporter, and thus the subsequent immediate increase in synaptic levels of 5-HT, appears not to be sufficient to explain the therapeutic effects of these drugs. Indeed, several modifications within the 5-HT system at both presynaptic and postsynaptic levels83 have also to take place before observing a clinical improvement of the diseases. SSRIs have also been shown to reduce aggressive behavior in SCZ,84 in personality disorders,85 and in violent offenders.86 However, there are


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preclinical and clinical reports indicating that SSRIs may instead enhance aggressive behavior,87, 88 confirming that the link between 5-HT and aggression is not simply a matter of increased or decreased levels of the neurotransmitter. The investigation of the interplay among genetic variation within the 5-HTT gene (SLC6A4), SMI and aggression has produced contrasting results. Most of these studies focused on the linked polymorphic region (LPR) of the 5-HTT gene. This highly polymorphic region has two main alleles: the short (S) variant, which is associated with reduced 5-HTT protein availability and function,89 and the long (L) form, which determines higher levels of 5-HTT expression. The S allele appears to be associated with higher anxiety levels and neuroticism.89 Therefore, in keeping with evidence from animal studies, a lower expression of 5-HTT determined by the S allele appears to determine a more depressive-prone symptomatology. In this context, researchers have attempted to identify whether the 5-HTTLPR was associated with aggression in SCZ.90-93 Frisch et al.90 identified a novel allele of 13 repeat units in a SCZ patient of Jewish Libyan origin who manifested severe aggression. In subsequent studies, Kim et al.92 did not find a significant difference in the allelic and genotypic frequencies of the 5-HTT-linked polymorphic region (5-HTTLPR) between 46 aggressive and 57 nonaggressive SCZ patients. This finding was consistent with the work of Nolan et al.93 However, Han et al.91 observed that LL carriers of the 5-HTTLPR had higher total aggression scores, as expressed by the Overt Aggression Scale (OAS), compared to SL and SS. The latter finding was consistent with the hypothesis, stemmed from previously reviewed animal model studies81,

82

that reduced levels of 5-HTT

expression, as determined by the S allele, might be associated with lower aggression levels. Further evidence on the role of 5-HTTLPR in aggression comes from studies in MDD.94 Gonda et al.94 found that subjects carrying the S allele scored significantly higher in the guilt, irritability, indirect hostility, negativism, resentment, and verbal aggression subscales of the Buss–Durkee Hostility Inventory, and had a significantly higher global aggression score compared to S nonACS Paragon Plus Environment

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carriers. Interestingly, Silva et al.95 reported on the effectiveness of fluoxetine, an SSRI, in controlling impulsivity and aggression in patients affected by personality disorders. Specifically, they observed that 5-HTTLPR L/L carriers had a significantly better response to fluoxetine than patients carrying an S allele. Although intriguing, these results are significantly hindered by the lack of a homogeneous definition of the aggressive behavior phenotype, the diverse diagnosis under study, and by possibly not adequately powered samples sizes. Therefore, any conclusive assessment of the role of 5-HTTLPR in aggression should await studies with proper design, especially considering that the phenotypic expression of variations within the 5-HTTLPR can be moderated by developmental and life events.96

Serotonin pathway metabolic enzymes, severe mental illness, and aggression An overall reduction of 5-HT brain activity obtained after genetic deletion of TPH2, the rate limiting enzyme in the biosynthesis of brain 5-HT, produces, in agreement with the 5-HT deficiency hypothesis of mood disorders, a depressive-like phenotype,97 but also an increase of aggressive behavior.97, 98 However, concerning aggressive behavior, some authors found apparently contrasting findings showing a positive rather than a negative correlation between TPH-2 activity and levels of aggression.99-101 Young (from 1 to 90 days) mice knocked out for monoamine oxidase A (MAOA, the enzyme which degrades 5-HT to 5-hydroxyindolacetaldehyde that is then oxidized into 5-HIAA), display increased levels of 5-HT in the brain,102 paired to severe behavioral abnormalities including reduced levels of depressive-like behavior and anxiety, but increased aggressiveness. A study conducted in rats showed that stressful experiences during the peripubertal period resulted in higher and sustained levels of aggression but also of anxiety-like and depression-like behaviors in adulthood.103 These behavioral abnormalities were paralleled by amygdala hyperfunctioning and medial orbitofrontal


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cortex hypofunctioning and importantly, by an increased expression of the MAOA gene in the prefrontal cortex. Consistently, the increased aggression was reversed by chronic treatment with the MAOA inhibitor clorgyline. On the contrary, chronic treatment with clorgyline in control unstressed animals increased aggressive behavior,103 in agreement with a likely contribution of either hypo- or hyper-activity of MAOA in the pathophysiology of aggression.104 A role for MAOA epigenetic reprogramming in aggression has been also demonstrated in antisocial offenders who show increased methylation of the MAOA gene promoter yielding to a reduced MAOA activity and a subsequent positive correlation with circulating 5-HT.55 Of note, the gene encoding for MAOA is located on the short arm of the X chromosome (Xp11.4-p11.23).105 This implies that male subjects present only one copy of the gene encoding for the enzyme. In the presence of a low activity MAOA, men can be then more prone to aggression compared to homozygote women.106 There is evidence that genetic variants within genes encoding for enzymes of the 5-HT pathway might play a role in aggression in SMI, particularly SCZ and BD. Nolan et al.93 investigated the role of the intron 7 polymorphism of the TPH and the MAOA promoter variable number of tandem repeat (VNTR) polymorphism in 84 SCZ patients characterized for aggressive behaviour. Although no association was found for the MAO polymorphism, a nominal significance was found for the TPH genotype and history of aggression. Consistently, Zammit et al.107 confirmed the lack of association of MAOA and MAOB gene polymorphisms with aggression, assessed using the OAS, in 346 SCZ patients. This lack of association was also in line with the findings of Koen et al.108 in 70 acutely relapsed male SCZ patients stratified into violent and non-violent subsets, and of Fresan et al.109 The latter study, however, identified higher OAS score for verbal aggression in MAOA VNTR 4 repeat-carriers compared to MAOA VNTR 4 repeat non-carriers. The work of Kinnally et al.110 attempted to reconcile the discrepancy in MAOA results with respect to aggression considering a developmental perspective. The authors found that MDD and BD female patients with low-expressing MAOA-uVNTR alleles who experienced an early stressor


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exhibited lower impulsivity/aggression factor scores when they reported high parental care rather than low parental care. The same pattern was observed in heterozygotes but not in high-expressing MAOA-uVNTR carriers.110 Finally, Koh et al.111 observed that MDD patients homozygote for TPH1 CC genotype scored significantly higher in terms of verbal aggression and total aggression, assessed by means of the Aggression Questionnaire, compared to A-carrier genotypes, irrespective of sex and age. Taken together, these findings suggest that MAOA and TPH1 genetic variants might influence the liability to aggression in SMI.

Kynurenine pathway, severe mental illness and aggression The essential amino acid tryptophan, i.e. the precursor of 5-HT, is mainly metabolized along the so called kynurenine pathway.112, 113 Plasma levels of tryptophan, in particular the free or un-bound portion which is able to cross the blood-brain-barrier, have been related to tryptophan levels in the brain and thus brain to 5-HT levels.54 Compelling evidence has demonstrated that in several psychiatric and neurodegenerative disorders tryptophan is shunted away from the 5-HT pathway into the kynurenine pathway which leads to the formation of nicotinic acid and several neuroactive compounds with either neurotoxic or neuroprotective activities.112,

113

The first and rate-limiting

enzymes of the kynurenine pathway are indoleamino-2,3-dioxygenase (IDO) and tryptophan-2,3dioxygenase (TDO) which convert tryptophan into formylkynurenine that is then transformed into kynurenine. While IDO is widely distributed in the body and is also linked to immune function,112, 113

TDO is mainly present in the liver although a TDO-isoform 2 has been shown in both human114

and rodent115 brain. Up-regulation of the kynurenine pathway with consequent reduction of the availability of tryptophan for the 5-HT synthesis was found in depressive as well as in SCZ and BD patients.116, 117 Two very recent and independent studies found a reduction of peripheral kynurenine linked to the presence of aggressive behavior.54, 118 Coccaro et al.118 also showed that plasma levels of downstream metabolites of kynurenine are decreased in aggressive individuals. Interestingly, ACS Paragon Plus Environment

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Comai et al.54 found that in aggressive compared to non-aggressive individuals, although kynurenine levels were lower, IDO was more active in subjects displaying higher levels of aggression. In contrast, patients with hepatitis C treated with the cytokine interferon alpha which activate IDO with consequent reduction of tryptophan (and thus 5-HT), display an increase of kynurenine peripheral levels associated with high rates of depression,119 but also increased irritability.120 It could be hypothesized that on one hand,aggressive individuals have constitutively low levels of tryptophan and thus of 5-HT but also of kynurenine, and that, however, within this “low tryptophan” condition, IDO is more active in highly aggressive individuals. On the other hand, in acute or pharmacologically induced conditions, such as following interferon α (IFN-α) therapy, being the baseline levels of tryptophan similar to controls, a high percentage of the amino acid is degraded by IDO and thus the levels of kynurenine result higher compared to controls. Future studies are definitively needed to prove this assumption; in particular, preclinical studies are welcome to indicate a possible role for the different downstream metabolites of kynurenine in aggression.

Conclusions and open questions Historically, 5-HT is the most studied neurotransmitter system for its neurobiological and therapeutic involvement in SMI and aggressive behavior. As highlighted in this review and schematically summarized in Figure 1, dysfunctions at the various levels of the 5-HT machinery, namely synthesis, metabolism, re-uptake, receptors, and genes, have been consistently demonstrated in SMI and aggression. In contrast, there is still an open debate on the direction of these dysfunctions in relation to the pathophysiology of SMI. Most importantly, given the significant cooccurrence of SMI and aggressive behaviour, and the involvement of the 5-HT system in both SMI and aggression, current knowledge does not yet allow clarifying to what extent SMI contributes to


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aggression and defining the trivariate, possibly causal, relationship among SMI, aggression, and 5HT. Our review has described many inconsistencies on findings reported in the literature concerning 5HT markers in SMI, aggression, or their concomitant manifestation. One reason for these inconsistencies might be the absence of a uniform clinical definition of the different SMI as well as of aggressive behaviour. In fact, SMI are characterized by a relatively high degree of heterogeneity, which might have hindered the identification of consistent patterns of association between markers of 5-HT function (serum and CSF levels, enzymatic activity, SNPs) with the psychiatric disorder under study. Psychiatric diagnoses are based on sets of criteria that need to be met to classify a subject as affected. For instance, a major depressive episode (MDE) can be diagnosed, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), when a subject has at least five symptoms (out of 9) present for the same 2-week period. Consequently, two individuals might receive the same diagnosis of MDE, but may present a very diverse symptomatological profile, that in extreme cases might have only a negligible overlap. Further, the same DSM criteria are subject to change over time. This variation might complicate the comparison between studies performed at different times. On top of this, there is not yet a unanimous definition of aggressive behavior at both preclinical and clinical levels,38 and the various scales used to measure aggressive behaviour may capture different aspects of this complex phenomenon.38 Consequently, findings from one study may not generalize to another, and apparently contrasting data may actually result from this underlying bias. It is also plausible that, at least with regard to genetic architecture, some variants might predispose to aggression also in individuals unaffected by SMI. In fact, healthy subjects carrying the low expression allele of a functional polymorphism in the MAOA gene had higher trait aggression than individuals with the high expression allele. Further, these individuals also reported higher trait interpersonal hypersensitivity and displayed greater dorsal anterior cingulate cortex activity


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(associated with rejection-related distress) to social exclusion compared with MAOA high expression allele individuals. Thus, genetic factors might determine an increased liability toward aggression even in the absence of a SMI.121 Translational research may help clarifying some of these controversies and still opened questions. In this context, some neuroanatomical/neurobiological abnormalities and as yet poorly characterized developmental defects have been observed in 5-HTT82, TPH-297, 98 and MAOA102 at preclinical level in knockout mice, and epigenetics changes in the MAOA gene promoter likely due to developmental influences have been found in aggressive antisocial individuals.55 However, these studies do not yet collectively allow to elaborate a consistent and comprehensive view of the link between 5-HT, aggression and SMI. Future electrophysiological, pharmacological, molecular and neuroanatomical studies in these mice are thus warranted. In addition, given that the pathophysiology of SMI and aggression seems to be not only a matter of 5-HT levels, but very likely relies on plastic changes occurring within 5-HT brain circuits common to both aggression and SMI, positron emission tomography and functional magnetic resonance imaging studies in selected populations are also necessary to deepen our understanding on the trivariate relationship between 5HT, SMI and aggression. Overall, the relevant conclusion that can be gathered from this data review is the following: although there is no doubt on the important role of the 5-HT system in regulating aggressive behaviour, it still remains to be established whether the alterations observed in this pathway are specific to SMI and/or aggression. In other words, open questions on this trivariate relationship concern: 1) the longitudinal trajectory of 5-HT alterations, and the onset of aggression and/or SMI; 2) whether 5-HT alterations, if antecedent to the manifestation of aggression and/or SMI, might be more pronounced when the manifestation of these traits is concomitant compared to when each trait manifests independently; 3) the functional and/or structural changes within the 5-HT system specific to SMI, aggression and/or their co-occurrence. To answer these questions, longitudinal


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prospective observations of SMI patients without history of aggression followed up for several years and with assessment of 5-HT function at both the level of stable (genetic) and variable (peripheral 5-HT levels, enzymatic activity) markers should be performed.

Author Contributions M.M. designed the review, collected references and wrote the manuscript. B.C. assisted in writing the review. F.V. assisted in writing the review. S.C. conceived and designed the review, collected references and wrote the manuscript.

Funding Sources This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Conflict of Interest The authors declare no competing financial interest.


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Figure legend Figure 1. Schematic representation of a 5-HT producing neuron in the brainstem raphe nuclei (which innervates target regions modulating mood and behaviour such as the prefrontal cortex, the hippocampus and other midbrain nuclei) and of the specific targets of the 5-HT machinery which have been shown to be implicated in the pathophysiology of both severe mental illness and aggressive behavior. In the body of the 5-HT neuron, the enzymes involved in the synthesis (TPH-2 and AADC) and catabolism (mitochondrial MAOA) of the neurotransmitters as well as the possible switch of tryptophan from 5-HT to the kynurenine pathway are indicated. 5-HTT, presynaptic and postsynaptic 5-HT1A and 5-HT3 receptors, postsynaptic 5-HT1B, 5-HT2A and 5-HT2C receptors, as well as the nucleus containing the genes coding for these targets are represented. TPH-2: tryptophan hydroxylase; AADC: aromatic L-amino acid decarboxylase; MAOA: monoamine oxidase A; 5HTT: serotonin transporter.


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For Table of Contents Use Only 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Serotonin dysfunction, aggressive behavior, and mental illness: exploring the link using a dimensional approach. Mirko Manchia,†,§ Bernardo Carpiniello,† Flavia Valtorta,∥ Stefano Comai∥,* †

Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari,

Cagliari, Italy §

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

∥San

Raffaele Scientific Institute and Vita Salute University, Via Olgettina 58, 20132 Milano, Italy


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Schematic representation of a 5-HT producing neuron in the brainstem raphe nuclei (which innervates target regions modulating mood and behaviour such as the prefrontal cortex, the hippocampus and other midbrain nuclei) and of the specific targets of the 5-HT machinery which have been shown to be implicated in the pathophysiology of both severe mental illness and aggressive behavior. In the body of the 5-HT neuron, the enzymes involved in the synthesis (TPH-2 and AADC) and catabolism (mitochondrial MAOA) of the neurotransmitters as well as the possible switch of tryptophan from 5-HT to the kynurenine pathway are indicated. 5-HTT, presynaptic and postsynaptic 5-HT1A and 5-HT3 receptors, postsynaptic 5-HT1B, 5-HT2A and 5-HT2C receptors, as well as the nucleus containing the genes coding for these targets are represented. TPH-2: tryptophan hydroxylase; AADC: aromatic L-amino acid decarboxylase; MAOA: monoamine oxidase A; 5-HTT: serotonin transporter. Figure 1 273x109mm (300 x 300 DPI)


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Serotonin Dysfunction, Aggressive Behavior, and Mental Illness

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