Historical Perspective
First-Generation Studies
The earliest formal first part of the 20th century. They were generally of limited scale, relied on institutional records, and used small groups of informants for their data. These were “convenience” studies in which, instead of initiating the surveys themselves, epidemiologists assembled health data from those persons who had already received treatment for a medical problem or had committed suicide. A notable exception was Brugger’s study in Thuringia, in which he attempted to use census tracts to identify mental illness in a defined population. Ferris and Dunham’s relatively large pre–World War II study examined the geographic distribution of patients with mental disorders in mental hospitals in the Chicago area. They found that manic-depressive illness was distributed equally throughout the geographic area, whereas schizophrenia clustered in the lower socioeconomic areas.
Conclusion
Until the late 1980s, becoming a psychoanalyst in the United States meant doing postdoctoral work, primarily post-MD, in an approved institute of the American Psychoanalytic Association. Of the 3000 or so certified analysts, the majority were psychiatrists or other physicians who had completed 4–5 years of additional course work, undertaken a personal analysis, and passed written and oral assessments of their capacities as clinicians and therapists. In addition to the 29 institutes of the American Psychoanalytic Association, nonmedical institutes exist, some of them run by psychologists and other non-psychiatrists. With the death of Freud and the passing of the generation of psychiatrist-psychoanalysts who knew him personally, and with the rise of biological and laboratory methods in psychiatric research, American psychoanalysis confronts new demands.
Self Psychology
A similar use of developmental theory and observations occurs in another major contemporary school, that of self psychology. Led by Kohut, self psychologists focus their attention on the qualities and consequences of early child-parent interactions. A core technical term is self-object, which refers to Kohut’s explication of the parent’s ability to maintain a child’s self-esteem. In a broader sense, the term encompasses all the ways a parent provides ego functioning for a child, not just the regulation of self-esteem. A self-object has three crucial characteristics: (1) It is a person, (2) who performs ego functions for another person, and (3) who cannot perform them for the person’s self. Failures in self-object regulation between infant and adult occur because failure occurs in one or all three parts of the infant-adult interaction. For example, an infant who is grossly impaired neurologically may not be able to receive and process what would otherwise be good-enough care. When it seems possible to locate the source of self-object failure in the parent’s response, and not in the child’s neurologic defects, we can speak about parental failures in empathic communication. Better yet, we can speak of partial failures in empathic communication and partial failures, therefore, in ego maturation.
Psychoanalytic Clinical Findings
Psychoanalytic technique, especially the sustained empathic investigation of the patient’s lived experience, aims to foster ego-syntonic regression, which permits the patient to observe psychological processes that would otherwise go unnoticed. In this sense the psychoanalytic situation, like the telescope in astronomy, permits the observer to record new facts about human behavior. These newly discovered facts constitute the core clinical findings of psychoanalysis. Chief among these findings are (1) the decentering of consciousness, (2) the massive complexity of desire and self-experience, and (3) the ubiquity of transference events. The decentering of consciousness refers to the psychoanalytic aim of enlarging the scope of patients’ conscious awareness of their motivations and thoughts. Freud called this his Copernican revolution, because it revealed that human beings are not always masters of their own psyche, just as the earth is not at the center of the solar system. Second, central to psychoanalytic theory and practice is the attempt to follow the contours of a patient’s multiple desires (sexual, aggressive, narcissistic, and altruistic). In many important ways, contemporary research has refined classical theory about childhood fantasies about love.
Psychoanalytic Theory Applied
Psychological Testing
All psychological tests that claim to be projective derive ultimately from psychoanalysis through either Freud or his pupils, such as Jung. For example, Rorschach, originator of the famous inkblot test that bears his name, was influenced by Jung. The Rorschach Inkblot Test, Thematic Apperception Test (TAT), Draw-a-Person Test, and hundreds of other instruments all presume validity of the psychoanalytic concepts of internal psychic conflict and ego defense, especially projection and displacement. Thirty years ago projective testing fell into disrepute and seemed on the verge of collapse, but some contemporary research psychoanalysts have sought to place the Rorschach on rigorous, objective footings.
Concept of Science
Classical theory (including Freud’s work from 1900 on and the concept of ego psychology) retained a 19th-century ideal of scientists as external observers who are to describe the forces and constraints that give rise to structure. All sciences are to be unified, sooner or later, into a single, coherent picture of the knowable universe. That which cannot be known by science in this way cannot be spoken of intelligibly. Unification also presupposes that truths in one science, such as math or physics, cannot be contradicted by claims in other sciences, especially in the less rigorous sciences such as biology and psychology. When Freud speaks of psychic energy, he does so within the constraints of the physics of his time. Hence psychic energy must obey the second law of thermodynamics and have all the tensor qualities that 19th-century scientists said were true of physical energies. Also, because physical energies are interchangeable with all forms of energy (ie, heat may be transformed into mechanical power), psychic energies are also interchangeable. Thus the psyche, too, should show similar transformations. For example, pregenital energies, genital energies, and the theory of sublimation reflect 19th-century physics.
Foundations of Psychoanalytic Theory
As a form of inquiry, psychoanalysis originated in Sigmund Freud’s modification of 19th-century medical consultations on what were then termed neurasthenias and other disabling psychological conditions, especially hysteria. The majority of all forms of psychiatry that claim a dynamic or cognitive orientation derive from Freud’s original work and from that of his students. Although psychoanalysis began primarily as a theory of neurotic functioning and character pathology, in the past 70 years it has changed dramatically to include severe psychopathology, addictions and eating disorders, sexual abuse, and other maladies.
Conclusion
The emergence of molecular neurobiology has profoundly changed the traditional focus of neuropsychopharmacologic research, shifting it toward events occurring beyond the receptors. One can now entertain the possibility that abnormal behavior patterns—affective, cognitive, and somatosensory—might be the consequence of a disarray in the temporal regulation of gene expression in response to internal (ie, neurohumoral, endocrine) and external (ie, environmental) stimuli that have rendered the individual vulnerable to psychiatric disorder. The demonstration that a nurturing defect in mice is linked to the absence of transcription factor Fos B in the preoptic area of the hypothalamus suggests that this transcription factor controls a complex behavior.
Signal Transduction from Synapse to Nucleus
Most psychotherapeutic drugs (eg, antidepressants, antipsychotic drugs, lithium) require long-term administration to be optimally effective. Apparently, acute interaction at various steps in the agonist-receptor-mediated transduction cascades is not directly responsible for their therapeutic effects. The activation of intracellular messenger pathways and the regulation of neuronal gene expression appear to play a central role in long-term adaptive changes in neuronal function. By altering programs of gene expression, the CNS adapts to conditions that threaten the physical and psychic emotional well-being of the organism. Ultimately changes in programs of gene expression determine the intensities of incoming signals; the sensitivities of neuronal systems to those signals; and the nature, amplitude, and duration of CNS responses (ie, the plasticity of the CNS). In this way, the clinically important actions of psychotropic drugs can be viewed as the restoration of neural plasticity, a plasticity that appears to be impaired in patients with affective or cognitive disorders.
Mechanisms of Regulation of Receptor Function
The regulation of receptor function is associated closely with the plasticity of signal transduction. The homeostasis of signal transduction is a prerequisite for emotional health. Signal transduction appears to be destabilized in patients who have emotional and cognitive disorders. Receptors are regulated at the level of their gene expression (by transcription or translation) and by posttranslational covalent modifications (eg, phosphorylation). In general, the density of receptors is upregulated in response to a decrease of their corresponding neurotransmitters and downregulated in response to an increase of the neurotransmitter. For example, ß-adrenoceptor density increases after depletion of norepinephrine by reserpine and decreases after the blocking of norepinephrine reuptake by antidepressants. The phenomenon of receptor desensitization has been studied extensively in the ß-adrenoceptor–G protein–coupled adenylate cyclase system. The desensitization of the ß-adrenoceptor–G protein–coupled adenylate cyclase system is accomplished by receptor phosphorylation. Two types of protein kinases are involved in receptor phosphorylation: PKA, activated by cAMP; and a second messenger–independent G protein–coupled protein kinase, beta-adrenergic receptor kinase (BARK 1). BARK 1 phosphorylates G protein–coupled receptors (such as the ß-adrenoceptor), predominantly when they are occupied by agonists. BARK 1–mediated phosphorylation has also been implicated in the sequestration of ß-adrenoceptors. Furthermore, the 5-HT2C receptor is phosphorylated by agonist treatment, which results in desensitization of receptor signaling.
Receptor Adaptation & Receptor Cross-Talk
The actions mediated by psychotropic drugs on receptors occur rapidly. These actions do not explain the therapeutic effect that is generally delayed for weeks after initiation of treatment. This discrepancy in the time course, particularly evident with antidepressants, has led to studies on the effect of anti-depressants on more slowly developing receptor-mediated adaptive processes in brain. These studies have revealed that chronic antidepressant treatment (ie, using MAO inhibitors, tricyclic antidepressants, and electroconvulsive therapy) causes a desensitization of the ß-adrenoceptor-coupled adenylate cyclase system in brain, usually associated with downregulation of the density of ß-adrenoceptors. These findings have shifted the focus of research onto the mode of action of antidepressants and the pathophysiology of affective disorders, from acute presynaptic to delayed postsynaptic adaptive processes in the cascade of signal transduction. Besides causing adaptations at the ß-adrenoceptor, chronic administration of antidepressants alters the density of various subtypes of 5-HT receptors (eg, 5-HT2A, 5-HT1A, and 5-HT1B).
Psychotropic Drugs
All major psychotropic drugs (ie, antidepressants, antipsychotics, anxiolytics) affect directly or indirectly the various receptors that are linked via regulatory G proteins to effector systems, either enzymes or ion channels (Figure 3-7). G proteins are heterotrimers consisting of 
ß and subunits that are linked to specific intracellular effector systems in a stimulatory (Gs) or inhibitory (Gi) manner. Effector enzymes catalyze the formation of second messengers that activate various protein kinases leading to phosphorylation and activation of pivotal proteins (metabotropic action). Receptors linked to ion channels modify the flux of ions through the membrane (ionotropic action).
Catecholamine Catabolism
Two enzymes are responsible for the catabolism of catecholamines: monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT).
Monoamine Oxidase
MAO catalyzes the oxidative deamination of amines and is a major enzyme in the metabolism of the biogenic amines (ie, norepinephrine, dopamine, and serotonin). MAO is found throughout the CNS. It is present in both glia and neurons. Studies on the subcellular distribution of the enzyme indicate that it is principally associated with the mitochondrial fraction, although it is also present in a microsomal fraction. In the mitochondrial fraction, the enzyme is present in the outer membrane. The enzyme requires flavin adenine dinucleotide as a cofactor.
Basic Neuropharmacology
Neuropharmacology is the pharmacology of the nervous system. The nervous system coordinates cellular activity, and the neuron is its basic component. The principal mechanism by which neurons communicate with one another is through the release of chemical mediators known as neurotransmitters. A chemical substance must possess several qualities before it can be classified as a neurotransmitter (Table 3-1).
Neuropsychopharmacology: Introduction
An understanding of neuropsychopharmacology provides a basis for sound therapeutics. Used as tools to probe the central nervous system (CNS), psychotropic drugs have contributed more than anything else to our understanding of the function of the brain. They have helped to establish biological psychiatry as a branch of medicine, and they have contributed to the generation of heuristic hypotheses concerning the biological basis of mental illness.
Neuropsychopharmacology reached prominence as a consequence of seminal contributions made by a number of basic scientists and astute clinical psychiatrists. Many of these contributions are acknowledged in the individual sections of this chapter.