The Frontiers of Pharmacology

When we think of what makes somebody unique, we not only call forth an image of what he or she looks like -- blond hair and blue eyes, for example -- but we see this image flavored by that person's particular personality. Some have a dour, pessimistic temperament while others seem perpetually cheerful. Many of us know people who are impulsive, doing things without really thinking about their consequences, while others may seem odd -- a bit out of step.

Yet while we're accustomed to thinking of personality as something that is shaped by early experiences, primarily with parents and other caregivers, researchers are now discovering specific genetic and biologic factors that flavor normal personality and may play an important role in the development of personality disorder -- just as they do for the color of one's eyes or hair.

The idea of a biology of temperament -- that is, the innate tendencies toward how someone relates to their environment -- is not a new one. We have now, however, arrived at a point in our understanding of the brain that we can begin to explore the underlying mechanisms that contribute to specific temperamental styles. New tools to probe brain chemicals, as well as new imaging techniques to actually visualize how the brain works, allow scientists to get a clearer idea of how individual differences in brain functioning might contribute to differences in personality.

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While temperament may be present at birth, personality develops, through ongoing experience, over the course of a lifetime. Personality is a complex constellation of traits, coping strategies, and defenses against seemingly built-in vulnerabilities. Some people struggle through life, for example, because they fly off the handle too easily; others seem to be born already armed with a set of defensive tools to combat life's difficulties.

In our laboratory, we try to identify and evaluate certain traits to discover how they relate to personality and its related disorders and discomforts.

Frank was a middle-aged man who came to our evaluation program because his boss suggested he seek psychiatric treatment. He was a good accountant but nevertheless was always passed over for promotion because he couldn't supervise other employees. Quiet and conservative, he rarely made eye contact with colleagues and, when faced with pressure or deadlines, he would perceive coworkers' questions as intrusive and become angry and abusive. He generally felt misunderstood by others and considered himself a loner.

When he completed the testing program, I reviewed some of the findings with Frank. I explained to him that his ability to organize information seemed to decline rapidly when he was under stress and became upset. At this point he would lash out at what he imagined was the source of his distress, often finding meanings in events or comments where they were not warranted.

In the course of our discussion, Frank began to feel that some of his angry behavior and peculiarities were finally being understood by someone. He also latched on to the idea that a chemical imbalance in his brain may have caused his problem. I explained that much of our research was still preliminary, but that, with proper medication, the disorganization he experienced under stress (which was causing many of his problems with people) might be alleviated.

THREE KEY TRAITS

While a knowledge of the biology of the brain and its relation to personality will not allow us to predict an individual's behavior, it may offer us a vocabulary to understand why some people are more prone to outbursts of anger, for instance, while others are painfully shy, and fearful of social contact.

In addition, understanding the biologic vulnerabilities to traits such as impulsivity or irritability may also help physicians to identify medications that will reduce these troublesome tendencies. It should also help them find more adaptive solutions to their life dilemmas.

In our program, we focus on three personality traits -- impulsivity, emotional reactivity (which can also be thought of as sensitivity or irritability), and eccentricity -- in people whose disturbed thoughts, feelings, and/or behaviors are severe enough that they result in problems at work or in their relationships. In their extreme form of expression -- when they are not episodic but characteristic of how someone relates to the world around them -- these traits are analogous to more serious mental disorders: Impulsivity, for example, is related to kleptomania; emotional reactivity to depression; and eccentricity to schizophrenia.

In order to better define the biologic bases of certain personality disorders, we have focused on individual differences in neurotransmitter systems and their relation to these key traits.

The first trait, impulsivity (a tendency to act aggressively rather than reflect), rather consistently appears to relate to brain chemistry. Abnormalities in one of the brain's messenger systems -- the release and uptake of serotonin (a neurotransmitter involved in aggression and ambition, among other functions) -- have been found in people who get into trouble because they act without thinking. They may be irritable and get into fights; experience stormy, unstable relationships; or have trouble with alcohol and drugs.

Drugs such as fluoxetine (Prozac), which prolong the effect of serotonin by slowing its reuptake in the brain, might be beneficial in improving not only mood but also the tendency toward impulsive, aggressive, or self-destructive behavior.

The second key trait, emotional reactivity or sensitivity, seems to relate rather strongly to the norepinephrine system. Norepinephrine raises blood pressure, stimulates heart rate, and sharpens perceptual processing in response to new events, especially those that maybe threatening or dangerous.

In our preliminary studies, we found that people with overactive norepinephrine systems may be more likely to be the risk-takers of the world, to be irritable or in other ways overreactive to their environment -- seeking novelty and adventure whenever they can. Lower levels of norepinephrine activity often lead to depression and detachment from life.

The third trait, eccentricity, may lead people to appear somewhat odd and experience reality in a peculiar fashion. Some may feel, for example, that they are constantly being watched because they are "bad"; some may be suspicious or wary of the motivations of others. In these people, increases in the brain chemical dopamine, which is important in initiating and regulating thoughts and behaviors, may be involved. Here, drugs that block the activity of dopamine may mute the suspiciousness and distorted perception of more paranoid individuals, including schizotypal patients -- that is people with disturbances in thinking and perception.

In our program at Mt. Sinai, we have developed and are in the process of implementing several specialized tests designed to evaluate people who are troubled by these feelings of impulsivity, emotional reactivity, and/or eccentricity -- people who have altered perceptions of the world around them and difficulty connecting with others. We use a variety of psychophysiologic, information-processing, neuropsychologic, brain-imaging, and neurochemical tests -- as well as complete diagnostic, psychologic, and family history evaluations to better understand the biologic roots of these personality traits.

SEROTONIN AND IMPULSIVITY

At the National Institute of Mental Health (NIMH), in the lab of researcher Dennis Murphy, I worked on a study of hormone responses to a medication called fenfluramine, an anti-obesity agent that causes the brain to release serotonin. This serotonin release in turn stimulates production of a hormone called prolactin. By measuring levels of prolactin in blood samples taken before and after fenfluramine is given, we may get a reflection of serotonin activity in the brain.

In the NIMH study, patients who reported feeling depressed showed a reduced prolactin response to fenfluramine, suggesting lower levels of serotonin activity. Later, in our work at Mt. Sinai, my colleague, Emil Coccaro, and I found that both depressed and borderline personality disorder patients -- including those who acted impulsively, exhibited angry outbursts, or had made suicide attempts -- had the same lowered prolactin response to fenfluramine. In fact, the degree to which the response was blunted, or decreased, was directly proportional to how much the patients exhibited impulsive or aggressive behavior such as getting into fights and losing their temper easily.

These results appear to support our belief that reduced serotonin activity contributes to impulsive and/or aggressive behavior. In fact, low serotonin activity might make it harder for people to actually learn from their experiences, especially those with negative consequences, and to turn life's sometimes difficult lessons into positive methods for improvement. Impulsive or antisocial people don't seem to respond to punishment, for example, and have trouble suppressing behaviors that are later punished.

Joey came to our clinic depressed after losing his job and getting divorced. While he did not meet criteria for major depression, he was upset and angry. A scrapper all his life, as a child he was constantly hauled into the principal's office for getting into fights. His parents were divorced and he lived with his mother and six brothers and sisters. As a teenager he joined a gang but was really at the margins of the group because of his erratic behavior and hot temper.

In his early twenties he married and had two children, but drifted from job to job because he was constantly being fired for getting into arguments with coworkers. Just prior to coming to the hospital for evaluation, he had slammed his fist through a plaster wall. In a rage like this, he reported, he would often throw things, get into fights, or sometimes even take it out on himself by cutting his arm.

On his admission into the hospital for testing, his mood varied widely. In our evaluation program on mood and personality disorders, Joey scored high on rating scales for hostility, aggression, and impulsivity. He also showed one of the most markedly reduced prolactin responses to fenfluramine we had ever seen, indicating very low serotonin activity.

As a result, we started him on fluoxetine. Soon after, his mood improved, his wide fluctuations of emotion were reduced, and he was ultimately discharged from the hospital and followed as an out-patient.

NOREPINEPHRINE AND REACTIVITY

Another neurotransmitter that may be related to both impulsivity and emotional reactivity is norepinephrine, which acts on other brain systems to enhance the signal of incoming information. Basically, it serves as an arousal system that says, "Pay attention! This may be important!" It is particularly reactive to events that act as stressors and is quiet during restitutive functions such as sleeping, resting, or eating.

Abnormalities in this system have been suggested to play an important role in depression. Decreased efficiency of this neurotransmitter may be in part responsible for the altered states of arousal, sleep, daily activity, and goal-directed behavior of depression. Since norepinephrine enhances information processing-- akin to increasing the contrast and intensity of color on a television set--reductions in its activity might contribute to a lack of pleasure and engagement with life, analogous to watching a bland, washed-out picture on TV.

In contrast, increased activity may be associated with impulsivity and seeking stimulation in activities such as gambling or sexual promiscuity.

Like all neurotransmitters, norepinephrine acts in the nervous system by attaching to specific receptors, initiating a cascade of events in the receiving cell. The responsiveness of these receptors appears to be blunted in people who suffer from major depressive episodes.

Here, we test the system by administering clonidine, a medication for high blood pressure. Clonidine acts on one type of norepinephrine receptor to stimulate growth-hormone secretion. By measuring growth hormone in blood samples taken before and after clonidine administration, we may be able to gauge the system's efficiency.

So far, we have found that depressed patients have a more blunted response to clonidine than normal volunteers, while high responses indicate an increase in emotional reactivity or sensitivity.

Carol, another patient who came to our clinic for evaluation, had been moody and volatile for as long as she could remember. Her father had been an alcoholic and her mother was frequently depressed. At age 10 she took an overdose of aspirin, and as a teenager she started abusing drugs and was quite promiscuous.

By her mid-20s, as a divorced mother, she reported feeling "angry and worthless." Her relationships were stormy and unstable, usually ending in a violent argument. In her initial interview in our program, she appeared engaging, almost childlike; however, she became irritable and angry when discussing her boyfriend or child.

When we administered the fenfluramine test, we found her prolactin response was lowered, suggesting she had reduced levels of serotonin. Then, when we gave her the clonidine test, we found that she had an exaggerated growth-hormone response, which suggested increased norepinephrine responsiveness. The combination of the two may have contributed to her difficulty with feelings of impulsivity and irritability -- the impulsivity might stem from her low serotonin level and the irritability from her overactive norepinephrine system.

After her evaluation, she was started on sertraline (Zoloft) -- a cousin of fluoxetine that leaves some patients feeling less of a "jittery" side effect. After several days her mood brightened up. Soon she no longer felt the need to abuse drugs and alcohol and felt much more comfortable with herself.

DOPAMINE AND ECCENTRICITY

Scientists are now trying to understand what might cause the abnormalities in brain structure and function that account for personality traits such as eccentricity, social isolation, and suspiciousness. Some hypothesize that alterations in the development of the brain -- for example, the migration of nerve cells to their appointed spots -- may somehow go awry. It is also possible that key chemicals are deficient in regions of the brain such as the frontal lobe.

One candidate for such chemical deficiency is dopamine, which seems to be important in the maintenance of "working memory" -- that is, in holding information on line for further processing. It is precisely this function that is apparently problematic in people with eccentric personalities who have difficulty processing information.

On the assumption that making more dopamine available in these regions might improve cognitive function, we evaluated patients' performance on an information processing task called the Wisconsin Card Sorting Test (WCST) after giving them amphetamine -- a drug that releases dopamine. The WCST is a kind of solitaire game in which subjects must sort a deck of cards marked with four different colors, numbers, and shapes. They are given no rules as to how to initially sort the cards -- in fact, the rules change periodically throughout the test.

Our preliminary results indicated that people with eccentric personality disorders do worse on this test than patients with other personality disorders. In fact, these people actually performed better on the WCST after amphetamine was administered than after a placebo, raising the possibility that dopamine or related chemicals might actually improve their cognitive performance. With further experimentation, we may be able to determine whether long-term administration of medications designed to increase dopamine might help improve the social isolation of eccentric personality types.

Paradoxically, too little dopamine in the frontal cortex may be the result of too much in the more primitive areas of the brain -- those regions regulating emotions. This oversupply may contribute to suspiciousness and distortions in the perception of reality. In fact, people who have taken amphetamines (as a recreational drug) in too high doses for too long a time may become paranoid, fear others are watching them, or focus on repetitive thoughts and behaviors -- in effect mimicking those with eccentric disorders.

One might imagine the role of dopamine in these people with subtle alterations in brain structure and processing as akin to the powerful amplifier in a stereo system. The static and noise on an old record is similar to the slippage and errors of cognitive processing in the eccentric person. But when such a record is played on a powerful stereo that amplifies the distortions, the result is a horrendous cacophony of sounds, with much of the music being lost. Medications that block the receptors for dopamine appear to "turn down the noise."

Barry was a man in his early 50s who looked perhaps 10 years older than his real age. His shoulders were stooped, he wore ill-fitting pants, a belt that was only partially buckled, and a shirt with ink stains on the front pocket. He appeared at the same time out of place and forlorn. He lived alone in an apartment, spending the day doing crossword puzzles and watching TV, going out only occasionally to grocery shop.

While Barry never became "clinically" depressed (such that he lost weight, had a poor appetite or trouble sleeping), he derived little pleasure from his life and felt that the rest of humanity was like a passing parade of which he was only an observer. He was wary of others' motives and rarely confided in anybody.

In his initial interview, he showed little emotion and his voice had a flat, monotonous quality. On the WCST, he made numerous errors, but his performance greatly improved after he got amphetamine. It changed little with the placebo. We also performed a spinal lumbar tap to remove and test a sample of cerebral spinal fluid -- and found that concentrations of a dopamine breakdown product were slightly low, indicating lowered levels of dopamine.

I explained to Barry that his tests showed he might have some difficulty focusing his attention, as well as holding in and organizing information from his environment. He acknowledged that sometimes he felt "overloaded" and had trouble keeping track of what was happening, and that sometimes, because of this, he worried that others were making fun of him. That was part of the reason, he said, he felt so uncomfortable around people.

Barry's treatment involved taking Wellbutrin, an antidepressant that makes dopamine more available in the brain, in the hopes that increasing his dopaminergic activity might improve his symptoms.

"FLYING LESSONS"

This model of testing, diagnosis, and treatment, while still hypothetical and based on preliminary evidence, at least illustrates how neurotransmitters--the biologic messengers of the brain--can act in a negative function to create difficulty and discomfort in people with certain personality disorders. It becomes even clearer, in certain patients, how two neurotransmitters might work in tandem to modulate problematic behaviors such as violence or suicide attempts even across different psychiatric categories.

In Carol's case, for example, her feelings of being "angry and worthless" may have stemmed from her overactive norepinephrine system, while a deficit in her serotonin activity may have contributed to her impulsive anger and led her into stormy, sometimes violent relationships.

The two systems working -- or not working -- together, influence the behavioral expression of each other. And when we consider the possibility that there are hundreds of neurotransmitter systems working together in the brain, it seems clear that we're wired for certain traits that contribute to the overall sum of who we are and how we act.

For researchers, the trick is to map out the chart of brain wirings and separate the innate from the environmental -- and to discover where the "short circuits" are. Newer and newer drugs that act more specifically on a particular "short" are appearing on the market, although further research is needed to test their ability to ease one problem without creating other, more serious discomforts.

In addition to the immediate benefits of relief for the patient, medication might also promote the learning of new, more adaptive and flexible coping strategies. For example, the impulsive individual, who cannot easily reflect upon the consequences of his behavior, may have difficulty benefiting from psychotherapy alone. Proper medication, though, may permit patients to incorporate more positive ways of interacting -- in psychotherapy as well as in relationships.

In addition, while having a "tantrum" when frustrated or upset may have brought them to the attention of their parents as children, it certainly doesn't work for them as adults -- and can lead to repeated job loss and divorce. So the calming effects of medication may in fact enable people to learn to reflect upon and talk more about their needs and frustrations without short-circuiting to the often inappropriate action that had previously gotten them nowhere.

Medication may give them the language they need to communicate in a positive, forward-moving fashion, free of the distortions and angry outbursts that clouded their life beforehand. In the words of one patient, "Medication gave me wings; now I need to learn how to fly." Psychotherapy, in this context, can be thought of as "flying lessons."

UNDERSTANDING = HELP

Finally, a simple understanding of the source of a patient's underlying temperamental vulnerabilities -- such as irritability or aggression -- can help the therapist, family members, spouses, and others close to the patient feel more empathy and have more patience with that person's particular struggles. We might learn to understand the outbursts of an impulsive person, for instance, because we know he has more difficulty weighing the consequences of his behavior before acting than most of us.

We might also have more patience with the knowledge that he is not simply ignoring his punishment -- whether it be repeated firings or relationship fights -- but that a chemical deficiency makes it difficult for him to learn from it: His behavior is not simply malevolent but stems from his difficulty in reflecting. (This does not absolve individual responsibility: He still needs to learn how to compensate for this vulnerability, just as a person with ulcers or diabetes must learn to deal with their illness and watch their diet.)

Similarly, the process of recognizing and identifying someone's underlying temperamental susceptibilities may even help the patient understand the vulnerabilities he or she is struggling with, as in Frank's or Barry's case. This understanding alone may be beneficial to the patient's recovery.

As we learn more about the biology of the brain, we may become better able to regulate and alter the neurotransmitters important in mood and personality. Of course, some may ask whether people with even "normal" variations could be in some way "improved" with medication, a question often raised in connection with drugs such as Prozac, which has reportedly "transformed" people. While these drugs may be of enormous benefit to those suffering from depression or prone to impulsivity and other disorders, it is not clear what role they would play in those not experiencing any serious distress from these problems.

The question, however, is complicated by the fact that a large proportion of the population -- up to one in five -- at one time or another may experience some form of depression. Personality disorders are also not as uncommon as we tend to think: up to 10 percent, according to some studies.

Yes, medications may have an impact on a wider population of people than has been previously imagined. We already know that stimulants such as amphetamine can improve performance and brighten mood in people who may be slightly depressed or fatigued -- yet we do not endorse the widespread use of stimulants, nor would they prove appealing to a well-rested, highly functioning person.

As we better understand the ways medications modify the brain and help individuals with specific kinds of problems, there will hopefully be a more consensual set of guidelines for the appropriate use of them. Because of the reduced side effects of newer drugs, however, their potential impact on a wide range of psychological and emotional problems seems great.

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