Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression
Psychiatry Service-Mount Sinai School of Medicine and the Bronx VA Medical Center, 130 West Kingsbridge Road, PO Box 1168, Bronx, NY 10468, USA. Psychopharmacology
(Impact Factor: 3.88).
12/2004; 176(3-4):451-8. DOI: 10.1007/s00213-004-1913-8
Impulsive aggressive personality disordered patients have been shown to have decreased relative glucose metabolism in orbito-frontal cortex and anterior cingulate gyrus compared with normal subjects. In addition, patients with impulsive aggression have an attenuation of symptoms with selective serotonin reuptake inhibitor (SSRI) treatment.
The goals of the present study were to attempt to replicate the finding of improvement in impulsive aggression in borderline personality disorder with SSRIs and to investigate the specific cortical areas modified by medication, which might underlie the observed clinical improvement using (18)FDG-PET.
Ten impulsive aggressive patients with borderline personality disorder were imaged with (18)F-deoxyglucose positron emission tomography at baseline and after receiving fluoxetine at 20 mg/day for 12 weeks. Anatomical MRIs were coregistered to PET and relative metabolic rates were obtained in 39 Brodmann areas.
Brodmann areas 11 and 12 in the orbito-frontal cortex showed significant increases in relative metabolic rate. Significant clinical improvement was also observed as assessed by the Overt Aggression Scale-Modified.
These changes are consistent with a normalizing effect of fluoxetine on prefrontal cortex metabolism in impulsive aggressive disorder.
Available from: Mark R Serper
- "Cortical dysfunction has been implicated as a possible anatomical correlate of certain acts of aggressive behavior (e.g., Brower and Price, 2001; Davidson et al., 2000; Hoptman et al., 2002) and has been speculated to be a core feature underlying SZ illness (e.g., Barch et al., 2001; Lewis, 2012). Damage to the prefrontal cortical area, for example, has been hypothesized to be associated with heightened aggression, emotional outbursts, disorganization, and impulsive, risk-taking and aggressive behavior (Raine et al., 1998; New et al., 2004). Since cortical dysfunction is believed to underlie aggression as well as contribute to SZ illness, examination of cognition and aggression in SZ may be seen as a natural experiment aimed at examining a common denominator implicated in both. "
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ABSTRACT: Aggression committed by patients with schizophrenia and other serious and persistent mental illnesses represents a major public health concern affecting patients, their families, treating clinicians as well as the community at large. Cortical dysfunction has been implicated as an anatomical correlate of acts of aggression as well as a fundamental feature associated with individuals with schizophrenia (SZ). As a result, examination of neurocognitive deficits may serves as a natural experiment to explore the relationship between cognition and aggression committed by SZ patients. Past studies, however, have yielded inconsistent and complex results regarding the relevance of cognitive impairment to aggressive behavior.
Available from: Giuseppe Di Giovanni
- "Similarly to the time-frame of the antidepressant effects of these agents, their antiaggressive potential is generally observed only following prolonged treatment (2-3 weeks), likely as a result of neuroplastic adaptive mechanisms resulting in receptor desensitization or synaptic remodelling. Chronic SSRI administration has been shown to restore the metabolic activity of the PFC (New et al., 2004), suggesting that the reduction in aggression induced by these compounds may depend on the integrity of the prefrontal function, which is essential for impulse control as well as emotional appraisal of social contexts. In support of this possibility, Troisi and colleagues (Troisi et al., 1995) documented that, in a subset of patients affected by mental retardation and epilepsy, chronic treatment with fluoxetine led to enhanced, rather than reduced aggressiveness. "
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ABSTRACT: Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies.
Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions.
Available from: Aki Takahashi
- "Clinically, chronic treatment (i.e. >3 weeks) with selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce aggressive outbursts and violent behavior in psychiatric patients (Barkan et al. 2006; Blader 2006; Bond 2005; Coccaro and Kavoussi 1997; New et al. 2004; Reist et al. 2003; Walsh and Dinan 2001). However, SSRIs have occasionally been reported to increase the incidence of aggressive and suicidal behavior, and the causes of these paradoxical effects remain unknown (Spigset 1999; Troisi et al. 1995). "
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ABSTRACT: Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT(1A) receptor) can often result in inconsistent results on aggression, due to "phasic" effects of pharmacological agents versus "trait"-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT(1A) and 5-HT(1B)) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene-environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT (e.g., MAOA) determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT(1B), 5-HT transporter, Pet1, MAOA) or indirectly [e.g., BDNF, neuronal nitric oxide (nNOS), αCaMKII, Neuropeptide Y]. The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.
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