Mark Germine
P.O. Box 7176
Loma Linda, CA 92354
Teenage and young-adult violence is a growing epidemic. Both suicide and homicide in the adolescent age group (13 to 21 years old) have risen dramatically in the past twenty years. Suicidal and homicidal behavior are closely linked in epidemiological studies, and, together, are just the tip of growing iceberg of adolescent discontent and anger. We are now seeing more and more depression in younger and younger people. The depression of the "baby boom" generation was manifested at a later age than we are now seeing, and has, in no small part, contributed to a depressed and angry societal structure into which children are born.
We tend to identify angry, violent, and aggressive adolescents as troubled individuals, and to deny that it is we, collectively, who are troubled. As mental health professionals, we try to take these troubled individuals and treat them in isolation from our troubled world. We are aghast at the outbreaks of murder in our schools, of gang violence, and of uncontrolled adolescent anger. We poor billions of dollars into police departments and prisons, yet the problems continue to grow.
The properly-functioning social system is an organism. It is an organic whole of internally-connected members who share a single, unconscious process. Reinforcement of the separate ego, which is disconnected from the unconscious, social, organic whole, leads to a dysfunctional social system in which internal and self-organizing processes are replaced the external contingencies of conditioned learning. This leads to a different kind of self-organizing system that is, fundamentally, based on violence. This is the so-called natural selection or survival model that science now holds to be the fundamental way of nature.
The organic social organism that is comprised of internally-connected members has an intelligence which guides it toward a stable and renewable future. Internal self-organization organizes the species and social groups into a collective mind system that is united on an unconscious level. The other kind of self-organizing, dynamical system, in which members are internally disconnected, and which operates on the principle of natural selection, is, by its nature, unstable. The supreme irony of social Darwinism is that, when it assumes a central role in self-organization of a social organism, it does not lead to survival, but to death or extinction.
The danger of the application of Darwinism to an organic system is seen in the case of the human body. Ordinarily, the various tissues and organs of the body function as an internally-related organic whole in which each part is constrained in its growth and function through its relation to the whole. If a particular cell line develops outside of the constraint, it will cease to function as a part of the organism and will grow at the expense of the other tissues. This cell line will become a cancerous tumor, invade the surrounding tissues, spread throughout the organism, and kill the organism, as well as itself.
The collective mind of the Darwinian social organism is at odds with itself. Its members fight among one another to secure more for themselves. Human beings then degenerate to the sub-organic level, where aggression no longer serves a biological purpose. Paradoxically, aggression comes to the foreground of our emotional constitutions through the conscious denial of our own aggressive and violent behavior within the dysfunctional social system. This is an example of the principle of conscious/unconscious complementarity. Emotions have an unconscious origin, and so, very often, we hold within us those emotions which we suppress from our consciousness. This unconscious structure of anger and aggression is collective. We talk about peace and cooperation but practice emotional violence and exercise an unconscious malice. This is the setting of societal violence.
We seek to solve the problem of teenage violence by making explicitly violent adolescents into implicitly violent adults. Teenage violence thus becomes a kind of rite of passage, a boot camp for a violent society. Very often, our solutions are part of the problem. Our educational system is competitive and achievement oriented. We’ve created a competitive collective mentality that is a thin veil for the violence that we are breeding into our children.
We violate our children with our expectations. We violate their deep need to be part of an organic whole when we educate them to succeed in the Darwinian social system. We create a class of "Olympians" in both physical and mental education. We emotionally disenfranchise those children that do not or can not achieve the standards of our own, collective, competitive calling. This is the root cause of teenage violence.
Our violent teens are failures. Some are failures to achieve, due to learning problems, lack of physical prowess, or "emotional problems." Others are failures to "fit in" to an inhuman social structure. We label them failures, implicitly, and then wonder why they are angry and discontent. We tell them that they are not good enough, hold before them the bleak prospects of a future that is not good enough, and then send them to counselors to learn self-esteem and positive thinking. We disengage them from society, and then wonder why they are antisocial.
The Neuroanatomy of Aggression
Aggression is deeply rooted in our evolutionary heritage. The basic physiological response, which we share with all other mammals, is called affective aggression or the fight-or-flight response. Affective aggression, in humans, serves as a defense against predators. We are not born predators, but we are born with the instincts to fight or flee when we feel that we are in danger, and to become enraged when we are wounded.
The single-celled organism is irritable. It withdraws from a noxious stimulus, exercising the cytoskeleton. Worms have a network of autonomic nerves that causes them to withdraw when injured. Jellyfish and other invertebrates have autonomic ganglia than allow them to move away from a noxious stimulus.
Chordates, including vertebrates such as humans, have pain receptors that connect to the spinal cord via nerve fibers. Interneurons in the spinal cord carry the signals to cell bodies in the central gray matter, from whence the nerve fibers cross over to motor neurons on the opposite side. Together with the more primitive, same-sided withdrawal reflex, this crossed-over or contralateral withdrawal reflex allows a more complex mechanism for escape from noxious stimuli.
The nerve system that mediates withdrawal and response to pain is the fundamental basis of defensive/aggressive behavior and of a variety of emotional and cognitive responses in the brain. The contralateral sensory and motor innervation of the brain is a further elaboration of the crossed withdrawal reflex. The interneurons of the spinal cord central gray matter, which mediate pain, are the developmental and evolutionary progenitors of the gray matter of the brain.
The central gray matter expands considerably in size from the spinal cord to the brainstem, where it mediates the complex behavioral responses of affective aggression. The nuclei of the brainstem are groups of cell bodies which send fibers up to the rest of the brain, and down to the spinal cord and to the autonomic nervous system, leading to activation of both the brain and the sympathetic nervous system. In development and evolution, the brain unfolds like a flower, so that the inner gray matter of spinal cord and brainstem becomes the outer gray matter of the cerebral cortex.
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.
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. 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.
Mirtazapine Inhibition of Uncontrolled Adolescent Aggression
Mirtazapine is a novel antidepressant that acts: 1) as an antagonist at presynaptic noradrenergic alpha 2 autoreceptors, thereby decreasing feedback inhibition of norepinephrine (NE), and increasing NE transmission, 2) as an antagonist at presynaptic alpha2 heteroreceptors on serotoninergic (5-HT) neurons, thereby decreasing inhibition of 5-HT release by NE, and increasing 5-HT transmission, and 3) as an antagonist at postsynaptic 5-HT2A, 2B, and 2C receptors and 5HT3 receptors (DeBoer, 1996).
The following case reports indicate that, in some cases, uncontrolled affective aggression in conduct disorder can be rapidly and fully inhibited by mirtazapine.
Case 1: H is a 16 year-old male who evidenced conduct problems in kindergarten at age 5. At age 8 he was suspended from school twice for physical assaults. Around this time it was noted that he was frequently disruptive in class, engaged in name-calling, and was perceived as the "class clown." At age 10 he was suspended from school for urinating on a classmate. By this time he had developed a pattern of disregard for the rights of others and violation of age-appropriate behavioral norms. He was noted at age 11 to be angry, physically and verbally aggressive, and cruel, a pattern that continued for the next 5 years. In Little League baseball he was noted to have a "bad attitude." He had numerous suspensions for physical assault. At age 12 H was diagnosed with attention-deficit hyperactivity disorder (ADHD), inattentive type, primarily on the basis of impulsivity and low frustration tolerance. He was started on methylphenidate, with only marginal results in improving attention. Pemoline caused excessive stimulation and worsening of behavioral problems. From ages 13 to 15 H was treated with imipramine, 10 mg in the morning and at noon, with marginal results of improved attention and mild sedation.
H was first seen at age 15. Although H exhibited some signs of ADHD, diagnostic criteria for ADHD were not met at that time. He easily met criteria for conduct disorder, childhood onset. He had marked interpersonal hostility, impulsivity, affective lability, angry affect, and was provoked to intense anger readily and in a variety of situations. He was noted to be mildly depressed, with loss of interest and pleasure, and to have a history of brief periods of depression which were reactive in nature and did not meet criteria for dysthymia or major depression. . He had prominent worry that centered on issues of social rejection and school performance, along with generalized anxiety, and met criteria for generalized anxiety disorder. He preferred solitary activities, and was, in general, undersocialized. He was prescribed fluoxetine, 20 mg/day, with a modest improvement in depressive and anxiety symptoms, but no change in behavior.
H used blaming and superficial rationalization to explain his violent behavior. He continued to have frequent episodes of violent anger, leading to fights, suspensions, and finally placement in a special school for adolescents with behavioral problems.
In his new school H engaged in frequent truancy and cigarette smoking on school grounds, with some use of cannabis and possible cannabis abuse. He made homicidal threats to at least one classmate. He later reported suicidal and homicidal ideations, loss of interest and pleasure, and feelings of low self-worth, meeting criteria for mild major depression. Fluoxetine was increased to 30 mg/day, about one year after it was started, with improvement of depression and remission of both suicidal and homicidal ideations, but continued worsening of conduct. About three months later, at age 16, he was convicted of assault in juvenile court and sentenced to six months probation.
About six months after increasing fluoxetine and three months prior to this report, H presented with continued behavioral problems and mild to moderate depression. He had been poorly compliant with fluoxetine over the past six weeks. Fluoxetine was formally discontinued, and mirtazapine started at a dose of 30 mg at bedtime.
Within the first week of mirtazapine therapy, H began to exhibit a marked improvement in affect and attitude. Over the next month he went from feeling angry to feeling "mellow." His depressive symptoms improved rapidly. His attitude towards school changed radically. H now stated that he enjoyed and looked forward to school, and that he liked his teachers. His adult family members noticed and commented on the change in attitude. His episodes of violent anger, which had been occurring on nearly a daily basis, ceased completely. After three months on mirtazapine, no adverse behavioral events have been reported at home, on the community, or at school. His social worker and therapist described the change in H as "too good to be true," reflecting both the magnitude of the change in H’s behavior and previous experience of poor prognosis with similar patients.
Case II: U is a fifteen-year-old male whose biological mother was 13 years old and addicted to drugs and alcohol at the time he was born. He was adopted shortly after birth. His adoptive mother is a working professional who denied a history of substance abuse. His adoptive father was alcoholic and was physically abusive to U’s adoptive mother in his presence.
U had conduct problems beginning in kindergarten. He defied authority and frequently required discipline. He had frequent "temper tantrums" with destruction of property. He began writing graffiti on walls in the second grade. His adoptive father was in and out of alcohol rehabilitation, and separated from his adoptive mother when U was nine years old. U set fire to his house at age ten. He was frequently truant and has grades declined in school starting at age eleven. At twelve he started smoking cigarettes, and shortly thereafter started abusing alcohol and cannabis. He began leaving home and living on the streets for extended periods of time.
After separation from U’s adoptive father, U’s mother had another relationship with a physically abusive man, who also beat her in U’s presence. At 14 U was convicted in juvenile court of residential burglary and sentenced to probation. He stopped going to school at 15, and became progressively violent and physically abusive toward his mother. U spent most of his time out with his friends, abusing alcohol and drugs, and trying to get drugs and money. If, when he came home, his mother didn’t give him money, he would beat her.
When first seen, U’s mother was bruised and battered and U was totally out of control. He had had psychotherapy on and off since age eight and had been diagnosed with conduct disorder. After unsuccessful trials of methyphenidate and a variety of antidepressants and antipsychotics, U had been placed on dextroamphetamine, 15 mg in the morning. This was somewhat helpful, but caused mild stimulation. When first seen, U was friendly and engaging, and did not appear depressed but was irritable and angry. He had prominent worry and generalized anxiety due to his learning disorder and difficulties in school, and met criteria for generalized anxiety disorder. U was started on mirtazapine 3.75mg at bedtime. The day after the first dose, he began to become angry and was about to assault his mother, when he stopped and said, "What am I doing? This is really stupid." This was new for him.
U’s compliance with the medication was poor. On average, he took his nightly dose of mirtazapine on about one out of three days. He became violent on the days after he did not take mirtazapine, but was not be violent on the days after he did. This pattern was observed consistently over a period of three months, leaving no doubt that U has an acute antiaggressive response to mirtazapine.
Dextroamphetamine was discontinued after two months and mirtazapine was increased to a dose of 7.5mg at bedtime. U has shown some progress during his three months on mirtazapine. He has made new, more prosocial friends and has gotten away from some of his former, antisocial friends. His compliance with mirtazapine is still sporadic, and he still seems to be abusing alcohol. He still is not attending school, but has begun home study. His mother has entered therapy. U is still poorly compliant with his psychotherapy visits.
Case III: S is a fourteen-year-old child who lives with his mother, stepfather and four younger siblings. He has been brought up in a prosocial environment, and his siblings and parents are prosocial. He has childhood onset conduct disorder with frequent violence, directed at his siblings, peers, and property. His biological father was a serial rapist who is currently in prison. His antisocial behavior starkly contrasts with the good behavior of his siblings, who are offspring of his stepfather.
S’s aggression had already failed to respond to a variety of psychotropic medications, including antidepressants, lithium, and stimulants. He was started on mirtazapine 7.5mg at bedtime. After one month, he had no significant response, and subsequently dropped out of treatment.
Discussion
In H’s case, mirtazapine therapy was associated with a rapid and dramatic improvement in the signs and symptoms of conduct disorder. This improvement involved a marked decrease in hostile interpersonal attitude and a rapid and total cessation of episodes of affective aggression. Although this change was associated with an improvement in mood, prior improvements in mood had not been associated with improvement of conduct. U had a very rapid and complete response to mirtazapine at a low dose. However, his poor compliance, chaotic social life, exposure to domestic violence, and drug and alcohol abuse have limited his benefit from the drug.
In these two adolescents, it seems that the development of conduct disorder involved episodes of affective aggression, and that improvement involved a rapid reduction in these episodes. The benefit that results from increased serotonergic tone involves down-regulation of receptors and decreased receptor sensitivity, and has a latency of about two weeks after initiating therapy. It is this action that is associated with reduction of depression and anxiety. In the first two cases presented here, the reduction of anger and aggression was almost immediate, suggesting that the mechanism of action of mirtazapine in anger and aggression is blockade of 5-HT2C receptors, thereby directly inhibiting affective aggression with no latency. In U’s case, the immediate response to a dose of 3.75mg/day strongly suggests that the 5-HT2C antagonism of mirtazipine is involved, since this action occurs at a much lower does than the effects that increase serotonergic and noradrenergic tone (DeBoer, 1996). In H’s case, additional benefit occurred due to the antidepressant effect of the drug, although this action, too, was more rapid than generally seen with serotonergic and/or noradrenergic antidepressants. Since stimulation of 5-HT2C receptors is associated with dose-dependent depression (Germine, 1994), this action may also account for the rapid antidepressant action. SB 242084 is a selective and brain penetrant 5-HT2C receptor antagonist (Kennett and others, 1997) which may show promise in treatment of affective aggression in conduct disorder. Both mirtazapine and SB 242084 may show promise in treatment of affective aggression in adults, which is the most common cause of violent crimes and imprisonment.
In adolescents and adults, facilitation of affective aggression by alchohol plays an important role in violent behavior. It is noteworthy, in this regard, that in a Finnish population alcoholic violent offenders have a higher rate of a Cys à Ser substitution in the 5-HT2C gene than normal controls (Virkkunen and others, 1996). The functional significance of this polymorphism is not known. The same polymorphism has been associated with conduct disorder and adult antisocial personality disorder, but not with ADHD and alcoholism. The 5-HT2C gene is on the X chromosome, which may help explain the higher incidence of violence in males. Socialization factors and testosterone may also contribute to male violence.
Case III is an example of Type II conduct disorder, involving directed aggression that is not associated with the symptoms of affective aggression, but rather with predatory violence. The failure to respond to mirtazapine in this case in consistent with the proposition that Type II conduct disorder is a genetically distinct subtype, as is also suggested by the history of his biological father.
Although sociopathy is generally framed as a deficit of thoughtfulness, conscience, and remorse, theoretical considerations (Germine, 1998) suggest that anger and aggression have their roots in the basic physiological response of affective aggression, which can be facilitated or inhibited neurochemically. Sociopathy would then develop through the shaping of cognition and behavior around the underlying emotional constitution of the individual. In this way, interpersonal hostility becomes ego syntonic, and mature mechanisms for coping with anger fail to develop.
Conclusions
Violent aggression in adolescents is a societal problem of immense proportions. Type I conduct disorder, with affective aggression, is the most prevalent condition associated with teenage violence, and appears to be associated with anxiety and mood disorders. Stress, along with a genetic susceptibility, are the factors leading to the development of this condition and the progression to violence. Control of teenage violence should therefore be aimed at the overall reduction in stress for children and adolescents in their homes, communities, and schools.
Clinicians are often called upon to treat adolescents who suffer from uncontrolled anger and violence. Some have the attitude that these are evil or bad people. The law prescribes punishment to discourage damaging or violent behavior. Yet neither treatment nor punishment has been effective in alleviating the suffering caused to the individual and society by violence and sociopathy.
Violence and sociopathy are collective phenomena that can and do effect large groups of people. Sociopathic behavior that is sanctioned or permitted by society may be no less immoral or harmful than that which is punished by law. Sociopathy is a phenomenon of the collective mind that arises through the emotional disconnection of individuals in social groups, which brings about the decay of the social cohesion of society as a whole. Individual sociopathy can only be addressed in the context of collective or societal sociopathy.
References