Andrew Edmund Slaby, MD, PhD, MPH
Laurence R. Tancredi, MD, JD
Dr. Slaby is clinical professor of psychiatry at New York University and New York Medical College, both in New York City.
Dr. Tancredi is clinical professor of psychiatry at New York University.
Acknowledgments: The authors report no financial, academic, or other support of this work.
Discovery in the mid-1950s that chlorpromazine alters the thinking of psychotic patients and that tricyclic antidepressants and monoamine oxidase inhibitors impact mood has resulted, in the ensuing decades, in a paradigm shift in our perception of how the human brain functions. This shift has increasingly extolled the biophysical basis of both abnormal and normal behavior. The concept that brain and mind are unitary has gained such prominence that few physicians today would argue that the mind and brain are separate, or that most psychiatric disturbances are solely dependent on how the mind is nurtured. Gone are the days in which we blame skewed or schizomatic families or schizophrenogenic mothers for the etiology of schizophrenia. Traditional dichotomies of depression, such as biological vs nonbiological, melancholic vs neurotic, familial vs nonfamilial, and neurovegetative vs reactive, as noted by Stahl1 and others, are of no help in predicting who will respond to antidepressants. Research on brain function has revealed an intimate relationship between the physiochemical processes of neuronal transmission and mental functioning on virtually all levels, from simple cognitive processes to complex pattern recognition and creative outcomes. The biochemistry of the brain has become the central target for researching normal and abnormal mental states. Stressful life events, culture, and family may play roles, but it appears that their impact is modulated by the degree to which an individual’s specific genetic endowment predisposes to changes in neurotransmitter balance.
Accompanying this shift in perspective on the mind/brain relationship has been a growing awareness that descriptions of symptoms combined to create psychiatric disease categories no longer provide the most scientifically precise basis for the taxonomy of mental disorders. Traditionally defined clinical entities such as major depression are very broad and phenomenological in nature. Clinical diagnosis has, up to the present, entailed the identification of symptoms that frequently cluster together into syndromes without specifically indicating the underlying psychobiological abnormalities that induce these syndromes. We are increasingly recognizing, however, that a neurotransmitter dysregulation alone or coupled with others may be responsible for the problem with which a patient presents.
The idea that genetically determined transmitter dysregulations may be as different as the individuals presenting with them would explain the remarkable variability we observe in responses to antidepressants. For illustration, inadequacy of serotonin in parts of the limbic system and perhaps elsewhere can induce suicidal thoughts and behavior, as well as anger which may be associated, in some cases, with homicidal acts.2 In fact, Asberg and colleagues3 have found that impulsive, unpredictable, violent suicides and homicides are more related to decreased brain serotonin than to any specific diagnosis. Historically, suicidal thoughts and behaviors are aggregated with other symptoms to determine the diagnosis of depression. Impulsive suicide, however, occurs at times with little or no clinical evidence of depression. Research in suicide2 reveals that predisposition to impulsivity, even more than depression or hopelessness, may explain self-inflicted death in those who are not depressed and seem to have everything to live for. Where specific symptoms, such as suicidal thoughts, cluster with other symptoms used to diagnose depression, the cause of those other symptoms may be different; they may be due to a lack or excess of several neurotransmitters. For example, the inability of a person to experience pleasure (anhedonia) seen with mood disturbances appears to be mediated through receptors for dopamine. Lack of energy, listlessness, and fatigue are mollified by reestablishing appropriate balances of norepinephrine or dopamine.
We know that while approximately 85% of depressions respond to antidepressants, only about 33% to 40% show a complete remission. Complete remission rates could be increased by identification of patient-specific neurotransmitter imbalances. Some depressions may be due to dopamine dysregulation, some to serotonin dysregulation, others to norepinephrine dysregulation, and still others to combinations of these as well as other neurotransmitters. In some instances, a single reuptake inhibitor—bupropion, or a selective serotonin reuptake inhibitor (SSRI) such as citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline—may be sufficient to bring about complete remission of a depression, because only one neurotransmitter (dopamine or serotonin, respectively) is deficient. In other patients, a combination of agents (a so-called “individualized cocktail”) or a multifocal antidepressant such as venlafaxine, nefazodone, or mirtazapine may be required because the depression is due to an imbalance of two or more neurotransmitters (eg, norepinephrine and serotonin). Use of patient-specific agents or combinations of agents for the treatment of mood disorders is comparable to the use of multiple medications in the management of hypertension, diabetes, or epilepsy.
Clues for the choice of a specific agent for treatment are found by identifying accompanying symptoms or behaviors suggesting a specific neurotransmitter deficit. For example, those who smoke or have problems with concentration may seek nicotine because of a dopamine dysregulation, which would be corrected by administration of a dopamine agonist (eg, bupropion). The presence of obsessions (including forced vomiting, trichotillomania, kleptomania, and sexual impulsivity), panic, or anxiety may indicate the need for serotonin augmentation. This approach to the management of an affective illness can be used to enhance patient response in the treatment of psychiatric disorders. To illustrate, if smoking, alcohol, or drug addiction exists because of a specific neurotransmitter dysregulation, we should logically assume that remission of the substance abuse will occur if we provide therapeutically that which the substance abuser seeks from recreational drugs.
Conceptualizing psychiatric symptoms as patient-specific imbalances of neurotransmitters also helps us to understand why one patient develops a side effect while another patient does not. When we employ a psychotropic agent that increases a neurotransmitter that a patient does not lack, an imbalance may be created and further exaggerated at the synaptic site, leading to side effects such as nausea and agitation with SSRIs, or anxiety and irritability with dopamine agonists. Identification of symptoms that correspond to patient-specific neurotransmitter dysregulations, rather than the clustering of symptoms to embody clinical syndromes, facilitates early implementation of individualized treatment with expected therapeutic success, rather than seeking a cure by trial and error.
Basic to the review that follows is the principle that disorders of mood, thought, and behavior represent specific neurotransmitter dysregulations in the unique chemical factory within each patient’s brain. Identification of the deficient or excess neurotransmitters is the first major step toward effective treatment. Patient and family compliance with treatment will be improved when they are aware that we as physicians are not acting blindly by targeting depression or another disorder in general, but rather attempting to identify a specific patient’s needs through associated behaviors that suggest genetically determined vulnerability to neurotransmitter imbalances. Side effects of lack of response are clues that a different approach is needed because we have failed to target the specific biochemical imbalance. In instances where specific behavioral traits, such as inattentiveness, anergia, and smoking suggest a specific pharmacologic choice (eg, a dopamine agonist), response may be rapid and often complete. When a patient presents with a variety of accompanying symptoms indicating an imbalance involving more than one neurotransmitter, the response may be less complete unless a multifocal agent, such as venlafaxine, or a “cocktail” is used to meet the patient’s needs.
Dopamine Neurotransmitter Dysregulations
Dopamine is associated with pleasure. Reinforcing behaviors that bring on feelings of pleasure involve dopamine metabolism. Comparably, motivation, attention, and concentration are enhanced by increasing dopamine (see Table 1). Increasing both norepinephrine and dopamine reduces the hypersomnia, hyperlethargy, and hyperphagia seen with some affective disorders. Addictive disorders such as cocaine snorting, cigarette smoking, alcohol abuse, and excessive eating—often associated with depression—are postulated to involve the reward circuits of the amygdala and nucleus accumbens.4 Dopamine increase, especially in the nucleus accumbens, underlies the effects of psychostimulant drugs such as cocaine and methylphenidate.5 Stimulant drugs increase extracellular dopamine by blocking dopamine transporters.6,7 Bupropion (a dopamine reuptake inhibitor), amphetamines, and methylphenidate are all dopamine enhancers. These three agents are used to increase focus in attention-deficit/hyperactivity disorder (ADHD). In addition, unlike SSRIs, which decrease libido and sexual behavior in some people by increasing serotonin, dopamine agonists often enhance sexual behavior. Hence, bupropion is used to neutralize the diminished sexual interest in some patients taking SSRIs, and is associated with increased sexual desire in other patients who use the drug. Bupropion additionally facilitates smoking cessation by stimulating the brain in a manner similar to nicotine, and is frequently associated with weight loss (or, at least, zero weight gain). Weight loss is also seen with chronic stimulant use and smoking.
Some drug abusers are deficient in dopamine. When they use stimulants such as cocaine and nicotine, they are actually self-medicating. In these instances, a dopamine agonist may serve to decrease or eliminate the abuse behavior, such as we see when bupropion is administered to nicotine addicts and to some patients with ADHD who abuse cocaine to reduce hyperactivity and augment concentration. Not all abusers of stimulant drugs, however, would be expected to remit with dopamine agonists. In some cases, the drug abuser suffers from an associated compulsivity, impulsivity, and obsessiveness, which is manifested by drug rituals. Some of these abusers are even tolerant to pleasure and adverse reactions.8 By reducing impulsivity, compulsivity, and obsessiveness, an SSRI may facilitate drug abstinence in abusers. Remarkably, a subpopulation of cocaine-abusing ADHD patients, when given methylphenidate, not only show improvement in their attentional deficits, but also in their cocaine abuse. In contrast, cocaine abusers who do not have ADHD experience increased cravings when they are administered stimulants, which further increases their risk of cocaine abuse. Clinical clues help us determine the presence of dopamine dysregulation and direct us to appropriate treatments.
Conflicting data on the use of dopamine agonists and SSRIs are also seen in the treatment of obesity. Some individuals with eating disorders lose weight and stop binge eating with bupropion, while others remit with an SSRI. A recent study has linked dopamine dysregulation to obesity.9 Obesity frequently accompanies depression, and in Sheldon’s classification of somatotypes and mental illness, endomorphs were characterized by overweight condition and seen at greater risk for a manic depressive disorder. The depressions seen in bipolar illness are frequently of a hypersomnic, hyperlethargic, hyperphagic nature. Interestingly, obese subjects were found by Wang9 to have fewer dopamine receptors than control subjects, and therefore they experienced less pleasure. Food, Wang felt, was used to compensate for the dysregulation. They ate more to stimulate the pleasure circuits of the brain. This research suggests that a subgroup of obese patients would lose weight from the use of both behavioral modification and bupropion. Another group that compulsively binges may respond to high doses of an SSRI, which would expectedly counter their obsession with food and compulsive eating.
In summary, dopamine neurotransmitter dysregulations appear to include nicotine addiction; depressions characterized by anergia, hypersomnia, and weight gain; as well as some forms of obesity, ADHD, and substance abuse. Evidence of any one indicant of dopamine dysregulation in concert with another (eg, nicotine addiction and hyperlethargic depression) suggests the need for a dopamine agonist.
Serotonin Neurotransmitter Dysregulations
Serotonin dysregulation is clearly the basis of many depressions and a significant component in the cause of others (see Table 2). Decreased cerebrospinal fluid metabolites of serotonin have been found in individuals who attempt suicide, as well in those who attempt murder. The greatest decreases in cerebral serotonin have been found in those individuals who commit heinous murders (ie, killing a spouse, lover, parent, or child, as opposed to killing a person in a barroom brawl) and in those who die by violent suicide (ie, hanging, jumping, use of knives or guns).3 Decreased serotonin at the receptor site has been shown in obsessive-compulsive disorders and in behaviors that have an obsessive or compulsive component, such as gambling, the paraphilias (disorders associated with abnormal sexual urges), kleptomania, eating disorders, and trichotillomania.10 While decreased serotonin appears associated with sexual impulsivity, increased serotonin is associated with decreased libido and, in some instances, delayed ejaculation. Increasing serotonin at neurotransmitter sites decreases impulsivity and compulsivity.
Irritability is also associated with serotonin dysregulation. Irritability and depression suggest the need for serotonin enhancement. Dopamine agonists, while increasing energy, may increase irritability, except perhaps in ADHD patients. SSRIs, even if used in female patients only during the immediate premenstrual days, appear to decrease symptoms including irritability, impulsive behavior, anxiety, and, more specifically, panic, of a late luteal phase dysphoric disorder by increasing serotonin at receptor sites. Anxiety associated with depression suggests the need for serotonin enhancement. Patients with anxiety disorders often respond to relatively small doses of SSRIs, which indicates that a smaller imbalance induces anxiety, whereas the treatment of other depressive and obsessive-compulsive disorders requires much greater doses of an SSRI (see Figure).
We are finding that not all drugs that block serotonin reuptake are equally effective in a particular patient. A patient with symptoms of anxiety and depression may respond to one SSRI but not to another. In some instances, combining SSRIs enhances the patient’s response. Comparably, side effects vary among SSRIs, as well as among the patients reporting them. This is due both to individual differences in the imbalance of neurotransmitters as well as to the fact that SSRIs differ in their mechanisms of action. For example, paroxetine is both a serotonin and norepinephrine agonist. Sertraline blocks both serotonin and dopamine reuptake.
Personality disorders that have an impulsive component, such as the borderline personality disorder with impulsive drug abuse, violence towards self or others, and sociopathic behavior suggest the need for increased serotonin. Positron emission tomography (PET) studies have demonstrated a decrease in the rise of serotonin response to fenfluramine in the prefrontal cortex areas of patients who have made serious suicide attempts, supporting the role of decreased serotonin in impulsive suicides regardless of diagnosis.11
In summary, SSRIs appear most effective in managing depressions associated with anxiety, agitation, and symptoms of panic. They are effective in disorders of impulse and those characterized by compulsive and/or obsessive behavior. Drug abuse and eating disorders presenting with an obsessive and/or compulsive component also indicate the need for serotonin augmentation.
Other Neurotransmitter Dysregulations
In addition to deficiencies of dopamine and serotonin, there are other neurotransmitter dysregulations that exist alone or in combination. Dysregulation of norepinephrine at receptor sites is characterized by disturbances of attention and working memory, fatigue, psychomotor retardation, and apathy (see Table 3). Monoamine oxidase inhibitors target three neurotransmitters—dopamine, norepinephrine, and serotonin—by decreasing the breakdown of monoamines. Venlafaxine has a dual action, with serotonin enhancement at lower doses and a norepinephrine surge at higher doses. Mirtazapine and nefazodone have comparable dual mechanisms of action.
Quetiapine, a novel antipsychotic, is an agonist at multiple neurotransmitter sites, including serotonin, dopamine, histamine, and adrenergic receptors. The affinity for histamine receptor antagonism is associated with sedation. Quetiapine induces an antipsychotic effect with only transiently high dopamine D2 occupancy. This explains quetiapine’s lack of extrapyramidal side effects and prolactin elevation. As in the case of other atypical antipsychotics, such as olanzapine and risperidone, quetiapine causes dopamine release where needed to manage disruptive positive symptoms in the mesolimbic dopamine pathway, with the opposite1 occurring in the mesocortical dopamine pathway, with concomitant improvement in negative symptoms. Quetiapine also appears to improve symptoms of depression through multiple action, a property that risperidone and olanzapine may also share. Quetiapine differs from risperidone in producing fewer extrapyramidal side effects, and from olanzapine in causing less weight gain. The new antipsychotic ziprasidone may actually have greater antidepressant properties, making it effective for psychotic patients with an affective component. For such patients, the ideal medication would impact neuroreceptor sites that not only decrease positive and negative symptoms, but also relieve symptoms associated with depression.
We can comparably conceptualize the neurotransmitters involved in the memory disturbances associated with some of the dementias. Donepezil and rivastigmine are selective inhibitors of acetylcholinesterase. Inhibitors of the breakdown of acetylcholine at the receptor site lead to the improvement of attention and memory early in the course of illnesses such as Alzheimer disease.
Conclusion: Looking Towards the Future
In conclusion, the expansion of our understanding of brain chemistry and chemical imbalances has progressed remarkably over the past 50 years, effectively changing the way we understand human thoughts, feelings, and behaviors. New developments in genetics resulting from the delineation of the human genome offer opportunities for furthering our understanding of brain chemistry. In the future, we will have the tools to not only assess clinically what imbalances exist in a patient’s brain, but also to make such assessments with greater accuracy, as well as concomitantly determine an individual’s potential for specific adverse reactions to a medication.
It will not be long before an individual’s genetic code will be routinely delineated at birth through analysis of umbilical cord blood. When such a process occurs, potential enzymatic abnormalities will be possible to identify. We will be able to profile a newborn’s physiology, as well as his or her psychological potential. This profiling may lead to more effective diagnosis of patients, such as the differentiation of drug abusers with ADHD from those without ADHD, and the differentiation of depressed patients with significant suicidal risk from those without such risk, strengthening our ability to provide effective therapeutic interventions and programs of prevention.
Psychotherapy (eg, cognitive, behavioral, interpersonal) will remain an important component in our armamentarium against mental illness. The new paradigm unifying the mind and brain, however, shifts our perception of the impact of psychotherapy on mental processes alone to its effect on brain biology, which is plastic and therefore responsive to external stimulation. Effective verbal therapies may be identified by their impact on neurochemical changes in the brain. Just as it appears that antidepressants cause neurogenesis, so too may we find positive chemical changes in the brain with effective psychotherapy. The fact that neurogenesis occurs with psychopharmacotherapy provides hope not only for patients with mental disorders, but also for those who care for and love them.
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