Sanctuary for the Abused

Monday, September 25, 2006

The Psychopharmacology of Aggression

Serotonin is released in response to pain, and reduces pain, both physical and emotional. Serotonergic cell bodies in the brain stem send fibers to all areas of the brain and spinal cord. In the spinal cord, serotonin inhibits the production of substance P, thereby reducing pain. In the brain, emotional pain is reduced by both increase in serotonin level and inhibition of substance P.

There are at least 15 subtypes of serotonin receptors in the brain that serve different functions in different locations. The relations of these receptors to pain and aggression are very complex. At the level of the spinal cord, serotonin inhibits physical pain, and withdrawal from physical pain. At the level of the brain, serotonin inhibits emotional pain, and withdrawal from emotional pain. Both actions, at least in part, involve inhibition of substance P. Emotional pain and withdrawal characterize depression.

Aggression and withdrawal, having origins in the reaction to pain and in the fight-or-flight response are part of a single process (Germine, 1998). Emotions are, most fundamentally, conscious perceptions of states of the inner gray matter of the brain by the outer gray matter of the brain, the cerebral cortex. The response of affective aggression is perceived as a cluster of emotions that include fear, anxiety, nervousness, anger, and depression, and euphoria.

The inner gray matter of the brain is closely linked with the autonomic nervous system, giving emotions the visceral quality of feelings of the heart and gut. Autonomic feelings are the core of our emotional constitutions, and it is at this level that we are most receptive to the feelings of others. The cerebral cortex is socially conditioned to suppress our receptivity to autonomic feelings, leading to the emotional or internal disconnection of people and groups of people. In the place of the organic unity that is the proper condition of human social health, social conditioning of the outer brain works on social reward and punishment, generating greed and fear as the principles of social engagement.

The cerebral cortex modulates emotions primarily through inhibition of emotional states in the inner gray matter. Inhibition by the cortex involves directed attention. States that are not inhibited are said to be disinhibited. For our adolescents in pain, anger and uncontrolled aggression are the result of a normal physiological mechanism, affective aggression, and the failure of the cerebral cortex to inhibit that aggression. This failure of inhibition occurs when the response of affective aggression is too strong to be inhibited. Part of the problem of uncontrolled aggression relates to relative deficiencies in directed attention or inhibition. Many drugs, especially alcohol, decrease directed attention and therefore inhibition. Most fundamentally, however, deficiencies in directed attention are related to attention deficit hyperactivity disorder (ADHD) and related syndromes.

Untreated ADHD Leading to Adult Psychopathy
ADHD is primarily a phenomenon of the "tail end of the bell curve" of the population’s capacity to direct attention. It involves certain polymorphisms of dopamine receptor genes, which decrease the activation of the frontal cerebral cortex in response to dopamine. Methylphenidate, the most popular treatment for ADHD, increases dopamine activity in the frontal cortex.

Conduct disorder involves uncontrolled affective aggression. Conduct disorder is a syndrome related to ADHD that shares certain genetic polymorphisms with ADHD, but also involves polymorphisms in serotonin receptor genes. The polymorphisms are called susceptibility genes, and the actually occurrence of the disorders involves multiple susceptibility genes (genotypic expression) together with environmental factors (phenotypic expression).

There appear to be two types of conduct disorder. Type 1 is characterized by uncontrolled affective aggression, and involves depression and prominent abnormalities in the function of the serotonin system. These adolescents are typically worried or troubled, and share features of generalized anxiety disorder. Type 2 is characterized by predation. Individuals with the second type are typically relatively unemotional and unexcited when engaging in aggressive acts, and derive reinforcement from aggressive acts. These types are conceptual categories that are not sharply separated. Type 1 conduct disorder is the most common, and has a better prognosis than Type 2. Type 2 more often progresses to adult antisocial personality disorder. Here we will be focusing on treatment of anger and aggression in Type 1.

There is a particular subtype of serotonin (5-HT) receptor, 5-HT2C, which appears to be active in the disinhibition of anger and aggression in certain groups of individuals (Germine and others, 1992). This action is thought to be mediated through stimulation of inhibitory GABA interneurons in the frontal cortex, which decreases the inhibitory action of the frontal cortex. Depression and uncontrolled aggression are both related to relative deficiencies in serotonin in the cerebral cortex, or a reduction in serotonergic tone, leading to a hypersensitivity of serotonergic receptors, including 5-HT2C. The decreased hormonal response to serotonin stimulation in depressed, anxious, and angry individuals seems to be the result of habituation (Germine and others, 1994), rather than serotonin hyposensitivity. This may explain why there is a reversal from increased hormonal response to decreased hormonal response to serotonergic agents between adolescence and adulthood is individuals with uncontrolled anger and aggression.

Affective aggression involves a sudden pulse of serotonin from the dorsal raphe nucleus of the brainstem to the frontal cortex. This is phasic as opposed to tonic stimulation. The effects of phasic serotonergic stimulation are greater in individuals with low serotonergic tone, due to hypersensitivity of serotonin receptors. In the case of 5-HT2C, and, perhaps, other receptors, including as 5-HT1B/1D, 5-HT2A, and 5-HT2B, this hypersensitivity can lead to both facilitation of the response of affective aggression and disinhibition of cortical control.

LSD is an agonist or stimulant of 5-HT2A and 2C (i.e. disinhibition of cortical control). Its hallucinogenic activity is thought to relate primarily to its 2A agonism. Atypical antispychotics such as clozaril, risperidone, and olanzapine are antagonists at 5-HT2A. The antidepressants nefazodone, trazodone, and mirtazapine are antagonists at 5-HT2A, but do no appear to have antipsychotic activity. The antidepressant mirtazapine and certain antipsychotics including clozaril and loxapine are antagonists at 5-HT2C.

Studies involving intravenous (IV) administration of MCPP, which stimulates 5-HT2C receptors, show a marked self-rated anger response in patients with generalized anxiety disorder (GAD). This response is highly correlated with baseline (pre-administration) levels of self-rated anger, indicating that disinhibition of anger is involved (Germine and others, 1992a; 1992c). This anger response seems relatively specific to GAD patients (Germine and others, 1992b), and is highly-correlated with later response to buspirone, a serotonergic antianxiety agent (Germine and others, 1992c).

All groups of subjects, including normal controls, have a prominent increase of autonomic activity and self-rated anxiety after administration of sufficient doses of MCPP. The autonomic activity includes increases in heart rate, blood pressure, sweating, and a variety of panic attack symptoms. A "high" feeling or euphoria is commonly observed in all groups of subjects, including normal controls (Germine and others, 1994). The euphoria associated with 5-HT2C-induced affective aggression is particularly problematic, in that it leads to reinforcement of aggressive behavior.

Overall, uncontrolled violent behavior seems to be associated with low serotonergic tone and hypersensitivity of serotonin receptors, with a prominent anger and/or euphoric response to 5-HT2C stimulation. Therefore mirtazapine, a compound that increases serotonergic tone and blocks 5-HT2C, would be a good candidate for use in individuals with uncontrolled anger and/or habitual aggressive behavior.

Currently, the most widely used compounds in the treatment of conduct disorder are lithium, valproate, clonidine, and methylphenidate. All of these agents decrease impulsivity, and thus tend to reduce impulsive aggression without having much of an effect on uncontrolled anger. Serotonin reuptake inhibitors, such as fluoxetine, paroxetine, and sertraline, are also widely used. They are effective in depression, but their effects on uncontrolled anger and aggression are modest and highly variable. In some cases, they increase irritability, anger, and aggression. There is clearly a need for other options in the treatment of conduct disorder that specifically reduce the extreme anger that is characteristic of many adolescents.
shared by Barbara at 2:48 AM


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