01 - 1.1 Introduction

1.1 Introduction

Neural Sciences 1.1 Introduction The human brain is responsible for our cognitive processes, emotions, and behaviors— that is, everything we think, feel, and do. Although the early development and adult function of the brain are shaped by multiple factors (e.g., epigenetic, environmental, and psychosocial experiences), the brain is the final integrator of these influences. Despite the many advances in neural sciences over the last several decades, including the “decade of the brain” in the 1990s, and the wide acceptance of the brain as the biological substrate for normal and abnormal mental functions, there has not been a true transformational advance in the treatment of mental disorders for more than half a century. The most obvious reason for the absence of more progress is the profound complexity of the human brain. A perhaps less obvious reason is the current practice of psychiatric diagnosis, which, for most clinicians, is based on syndrome-based classification systems. The purpose of this chapter is to introduce the neural sciences sections, which describe the anatomy and function of the human brain, and then to discuss how an evolution of thinking toward a brain-based or biologically based diagnostic system for mental illness might facilitate our efforts to advance brain research, to develop better treatments, and to improve patient care. In other fields of medicine, diagnosis is based on physical signs and symptoms, a medical history, and results of laboratory and radiological tests. In psychiatry, a diagnosis is based primarily on the clinician’s impression of the patient’s interpretation of his or her thoughts and feelings. The patient’s symptoms are then cross-referenced to a diagnostic or classification manual (e.g., Diagnostic and Statistical Manual of Mental Disorders [DSM-5], International Statistical Classification of Diseases and Related Health Problems [ICD]) containing hundreds of potential syndromes, and one or more diagnoses are applied to the particular patient. These standard classification systems represent significant improvements in reliability over previous diagnostic systems, but there is little reason to believe that these diagnostic categories are valid, in the sense that they represent discrete, biologically distinct entities. Although a patient with no symptoms or complaints can be diagnosed as having diabetes, cancer, or hypertension on the basis of blood tests, X-rays, or vital signs, a patient with no symptoms cannot be diagnosed with schizophrenia, for example, because there are no currently recognized objective, independent assessments. The goals of clinicians and researchers are to reduce human suffering by increasing our understanding of diseases, developing new treatments to prevent or cure diseases,

and caring for patients in an optimal manner. If the brain is the organ of focus for mental illnesses, then it may be time to be more ambitious in building the classification of patients with mental illnesses directly from our understanding of biology, rather than only from the assessment of a patient’s symptoms. THE HUMAN BRAIN The following neural sciences sections each address a field of brain biology. Each of these fields could be relevant to the pathophysiology and treatment of mental illnesses. Although the complexity of the human brain is daunting compared with other organs of the body, progress can only be made if one approaches this complexity consistently, methodically, and bravely. The neuronal and glial cells of the human brain are organized in a characteristic manner, which has been increasingly clarified through modern neuroanatomical techniques. In addition, our knowledge of normal human brain development has become more robust in the last decade. The human brain clearly evolved from the brain of lower animal species, allowing inferences to be made about the human brain from animal studies. Neurons communicate with one another through chemical and electrical neurotransmission. The major neurotransmitters are the monoamines, amino acids, and neuropeptides. Other chemical messengers include neurotrophic factors and an array of other molecules, such as nitric oxide. Electrical neurotransmission occurs through a wide range of ion channels. Chemical and electrical signals received by a neuron subsequently initiate various molecular pathways within other neurons that regulate the biology and function of individual neurons, including the expression of individual genes and the production of proteins. In addition to the central nervous system (CNS), the human body contains two other systems that have complex, internal communicative networks: the endocrine system and the immune system. The recognition that these three systems communicate with each other has given birth to the fields of psychoneuroendocrinology and psychoneuroimmunology. Another property shared by the CNS, the endocrine system, and the immune system is the regular changes they undergo with the passage of time (e.g., daily, monthly), which is the basis of the field of chronobiology. PSYCHIATRY AND THE HUMAN BRAIN In the first half of the 20th century, the advances in psychodynamic psychiatry, as well as in social and epidemiological psychiatry, led to a separation of psychiatric research from the study of the human brain. Since the 1950s, the appreciation of the effectiveness of medications in treating mental disorders and the mental effects of illicit drugs, have reestablished a biological view of mental illness, which had already been seeded by the introduction of electroconvulsive therapy (ECT) and James Papez’s description of the limbic circuit in the 1930s. This biological view has been reinforced further by the development of brain imaging techniques that have helped reveal how the brain

performs in normal and abnormal conditions. During this period, countless discoveries have been made in basic neural science research using experimental techniques to assess the development, structure, biology, and function of the CNS of humans and animals. Psychopharmacology The effectiveness of drugs in the treatment of mental illness has been a major feature of the last half-century of psychiatric practice. The first five editions of this textbook divided psychopharmacological treatment into four chapters on antipsychotic, antidepressant, antianxiety, and mood-stabilizing drugs. The prior division of psychiatric drugs into four classes is less valid now than it was in the past for the following reasons: (1) Many drugs of one class are used to treat disorders previously assigned to another class; (2) drugs from all four categories are used to treat disorders not previously treatable by drugs (for example, eating disorders, panic disorders, and impulse control disorders); and (3) drugs such as clonidine (Catapres), propranolol (Inderal), and verapamil (Isoptin) can effectively treat a variety of psychiatric disorders and do not fit easily into the aforementioned classification of drugs. The primary motivation for this change was that the variety and application of the drug treatments no longer clearly fit a division of disorders into psychosis, depression, anxiety, and mania. In other words, the clinical applications of biologically based treatments did not neatly align with our syndrome-based diagnostic system. An implication of this observation could be that drug response might be a better indicator of underlying biological brain dysfunction than any particular group of symptoms. For example, although the DSM-5 distinguishes major depressive disorder from generalized anxiety disorder, most clinicians are aware that these are often overlapping symptoms and conditions in clinical practice. Moreover, the same drugs are used to treat both conditions. The animal models that are used to identify new drug treatments may also have affected our ability to advance research and treatment. Many major classes of psychiatric drugs were discovered serendipitously. Specifically, the drugs were developed originally for nonpsychiatric indications, but observant clinicians and researchers noted that psychiatric symptoms improved in some patients, which led to focused study of these drugs in psychiatric patients. The availability of these effective drugs, including monoaminergic antidepressants and antipsychotics, led to the development of animal models that could detect the effects of these drugs (e.g., tricyclic antidepressants increase the time mice spend trying to find a submerged platform in a “forced swim” test). These animal models were then used to screen new compounds in an attempt to identify drugs that were active in the same animal models. The potential risk of this overall strategy is that these animal models are merely a method for detecting a particular molecular mechanism of action (e.g., increasing serotonin concentrations), rather than a model for a true behavioral analog of a human mental illness (e.g., behavioral despair in a depressed patient).

Endophenotypes A possible diagnosis-related parallel to how this textbook separated the four classes of psychotropic drugs into approximately 30 different categories is the topic of endophenotypes in psychiatric patients. An endophenotype is an internal phenotype, which is a set of objective characteristics of an individual that are not visible to the unaided eye. Because there are so many steps and variables that separate a particular set of genes from the final functioning of a whole human brain, it may be more tractable to consider intermediate assessments such as endophenotypes. This hypothesis is based on the assumption that the number of genes that are involved in an endophenotype might be fewer than the number of genes involved in causing what we would conceptualize as a disease. The nature of an endophenotype, as considered in psychiatry, is biologically defined on the basis of neuropsychological, cognitive, neurophysiological, neuroanatomical, biochemical, and brain imaging data. Such an endophenotype, for example, might include specific cognitive impairments as just one of its objectively measured features. This endophenotype would not be limited to patients with a diagnosis of schizophrenia because it might also be found in some patients with depression or bipolar disorder. The potential role of an endophenotype can be further clarified by stating what it is not. An endophenotype is not a symptom, and it is not a diagnostic marker. A classification based on the presence or absence of one or more endophenotypes would be based on objective biological and neuropsychological measures with specific relationships to genes and brain function. A classification based on endophenotypes might also be a productive approach toward the development of more relevant animal models of mental illnesses, and thus the development of novel treatments. PSYCHIATRY AND THE HUMAN GENOME Perhaps 70 to 80 percent of the 25,000 human genes are expressed in the brain, and because most genes code for more than one protein, there may be 100,000 different proteins in the brain. Perhaps 10,000 of these are known proteins with somewhat identified functions, and no more than 100 of these are the targets for existing psychotherapeutic drugs. The study of families with the use of population genetic methods over the last 50 years has consistently supported a genetic, heritable component to mental disorders. More recent techniques in molecular biology have revealed that specific chromosomal regions and genes are associated with particular diagnoses. A potentially very powerful application of these techniques has been to study transgenic models of behavior in animals. These transgenic models can help us understand the effects of individual genes as well as discover completely novel molecular targets for drug development. It may be a natural response to resist “simple” genetic explanations for human features. Nonetheless, research on humans generally has found that approximately 40 to 70 percent of aspects of cognition, temperament, and personality are attributable to

genetic factors. Because these are the very domains that are affected in mentally ill patients, it would not be surprising to discover a similar level of genetic influence on mental illness, especially if we were able to assess this impact at a more discrete level, such as with endophenotypes. Individual Genes and Mental Disorders Several types of data and observations suggest that any single gene is likely to have only a modest effect on the development of a mental disorder, and that when a mental disorder is present in an individual, it represents the effects of multiple genes, speculatively on the order of five to ten genes. This hypothesis is also supported by our failure to find single genes with major effects in mental illnesses. Some researchers, however, still consider it a possibility that genes with major effects will be identified. “Nature” and “Nurture” within the CNS In 1977, George Engel, at the University of Rochester, published a paper that articulated the biopsychosocial model of disease, which stressed an integrated approach to human behavior and disease. The biological system refers to the anatomical, structural, and molecular substrates of disease; the psychological system refers to the effects of psychodynamic factors; and the social system examines cultural, environmental, and familial influences. Engel postulated that each system affects and is affected by the others. The observation that a significant percentage of identical twins are discordant for schizophrenia is one example of the type of data that support the understanding that there are many significant interactions between the genome and the environment (i.e., the biological basis of the biopsychosocial concept). Studies in animals have also demonstrated that many factors—including activity, stress, drug exposure, and environmental toxins—can regulate the expression of genes and the development and functioning of the brain. Mental Disorders Reflect Abnormalities in Neuroanatomical Circuits and Synaptic Regulation Although genes lead to the production of proteins, the actual functioning of the brain needs to be understood at the level of regulation of complex pathways of neurotransmission and intraneuronal signaling, and of networks of neurons within and between brain regions. In other words, the downstream effects of abnormal genes are modifications in discrete attributes such as axonal projections, synaptic integrity, and specific steps in intraneuronal molecular signaling. Why Not a Genetic-Based Diagnostic System? Some researchers have proposed moving psychiatry toward a completely genetic-based

diagnostic system. This proposal, however, seems premature based on the complexity of the genetic factors presumably involved in psychiatric disorders, the current absence of sufficient data to make these genetic connections, and the importance of epigenetic and environmental influences on the final behavioral outcomes resulting from an individual’s genetic information. LESSONS FROM NEUROLOGY Clinical and research neurologists seem to have been able to think more clearly than psychiatrists about their diseases of interest and their causes, perhaps because the symptoms are generally nonbehavioral. Neurologists have biologically grounded differential diagnoses and treatment choices. This clarity of approach has helped lead to significant advances in neurology in the last two decades, for example, clarification of the amyloid precursor protein abnormalities in some patients with Alzheimer’s disease, the presence of trinucleotide repeat mutations in Huntington’s disease and spinocerebellar ataxia, and the appreciation of alpha-synucleinopathies, such as Parkinson’s disease and Lewy body dementia. The continued separation of psychiatry from neurology is in itself a potential impediment to good patient care and research. Many neurological disorders have psychiatric symptoms (e.g., depression in patients following a stroke or with multiple sclerosis or Parkinson’s disease), and several of the most severe psychiatric disorders have been associated with neurological symptoms (e.g., movement disorders in schizophrenia). This is not surprising given that the brain is the organ shared by psychiatric and neurological diseases, and the division between these two disease areas is arbitrary. For example, patients with Huntington’s disease are at much greater risk for a wide range of psychiatric symptoms and syndromes, and thus many different DSM5 diagnoses. Because we know that Huntington’s disease is an autosomal dominant genetic disorder, the observation that it can manifest with so many different DSM-5 diagnoses does not speak to a very strong biological distinction among the existing DSM-5 categories. EXAMPLES OF COMPLEX HUMAN BEHAVIORS The goal to understand the human brain and its normal and abnormal functioning is truly one of the last frontiers for humans to explore. Trying to explain why a particular individual is the way he or she is, or what causes schizophrenia, for example, will remain too large a challenge for some decades. It is more approachable to consider more discrete aspects of human behavior. It is not the role of textbooks to set policies or to write diagnostic manuals, but rather to share knowledge, generate ideas, and encourage innovation. The authors believe, however, that it is time to reap the insights of decades of neural science and clinical brain research and to build the classification of mental illnesses on fundamental principles of biology and medicine. Regardless of official diagnostic systems, however, clinicians and researchers should fully understand the biological component of the