Ch53 dis of mood thought & memory
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Ch53 dis of mood thought & memory

Course Number: NURS ne31a, Summer 2009

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CHAPTER Disorders of Thought, Mood, and Memory Sandra Kawczynski Pasch 53 Other Types of Dementia Vascular Dementia Picks Disease Creutzfeldt-Jakob Disease Wernicke-Korsakoff Syndrome Huntingtons Disease EVOLUTION IN UNDERSTANDING OF MENTAL ILLNESS Historical Perspectives Treatment of Mental Illness The Role of Heredity in Mental Illness ANATOMIC AND NEUROCHEMICAL BASIS OF BEHAVIOR Behavioral Anatomy of the...

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of CHAPTER Disorders Thought, Mood, and Memory Sandra Kawczynski Pasch 53 Other Types of Dementia Vascular Dementia Picks Disease Creutzfeldt-Jakob Disease Wernicke-Korsakoff Syndrome Huntingtons Disease EVOLUTION IN UNDERSTANDING OF MENTAL ILLNESS Historical Perspectives Treatment of Mental Illness The Role of Heredity in Mental Illness ANATOMIC AND NEUROCHEMICAL BASIS OF BEHAVIOR Behavioral Anatomy of the Brain Cerebral Cortical Structures The Limbic System Physiology of Perception, Thought, and Memory Learning and Memory Disorders of Perception Hallucinations Delusions Role of Neuromediators Emergence of Psychotropic Medications Neuroimaging DISORDERS OF THOUGHT AND VOLITION Schizophrenia Manifestations Neurophysiology of Symptoms Diagnostic Criteria Treatment DISORDERS OF MOOD Depression Manifestations Neurophysiology of Symptoms Diagnostic Criteria Treatment ANXIETY DISORDERS Panic Disorder Generalized Anxiety Disorder Obsessive-Compulsive Disorder Social Anxiety Disorder DISORDERS OF MEMORY AND COGNITION: DEMENTIAS Alzheimers Disease Pathophysiology Manifestations Diagnosis and Treatment P sychiatric disorders are characterized by changes in a persons thoughts, mood, or behaviors that preclude ordinary functioning in one or more spheres of life. Throughout the course of history, persons in the healing professions have tried to uncover the causes and nd effective treatments for diseases that alter the way in which people experience the world and behave in it. Over the centuries, the pendulum has swung between those practitioners who espouse the view that mental disease arises from inadequate interpersonal relationships and those who espouse the view that mental disease arises from alterations in brain structure or activity. In the late 20th century, and now in the early years of the 21st century, the conversation between these two apparently divergent philosophies continues, perhaps to conclude with a new synthesis of nurture versus nature and therefore new and effective therapies for those with mental illness. The purpose of this chapter is to review the evolution in understanding of the pathogenesis and treatment of mental illness, to relate the anatomy of the brain and its integrated regional functions to the causes, manifestations, and treatment of selected thought, mood, and cognitive disorders. Evolution in Understanding of Mental Illness After completing this section of the chapter, you should be able to meet the following objectives: Dene the terms biologic psychiatry and psychosocial psychiatry and compare them in terms of their denitions of the origins of mental disease 1265 1266 UNIT XII Neural Function Describe the changes in the treatment of mental illness over the past three centuries Explain the role that heredity plays in the epidemiology and development of mental illness HISTORICAL PERSPECTIVES Psychiatry was not an organized specialty before the end of the 18th century, but mental disorders are as old as the human race. Artifacts and cave drawings from a half million years ago indicate that what we have come to call psychotic disorders were known then. Over the ages, the explanations of mental disorders have ranged from possession by gods and demons, to the breaking of taboos, to the idea that a harmful substance had entered the body. Persons with psychiatric disorders were treated with prayers, magic, and exorcisms. In some communities, the mentally ill were viewed with fear and often turned out of their homes, villages, and towns. In other communities, families took care of the mentally ill, but often these people were neglected or locked up in barns or cellars.1 The history of our understanding of psychiatric illnesses reveals a tension between two schools of thought as to the origin of mental disease. The pendulum has swung between these two apparently opposite viewpoints across the centuries. One view of psychiatric illness is that mental disorders are due to anatomic, developmental, and functional disorders of the brain, and is called biologic psychiatry. Another view is that mental disorders are due to impaired psychological development, a consequence of poor child rearing or environmental stress, and is called psychosocial psychiatry.1 These differences of emphasis in terms of the pathogenesis of mental illness are important because the prevailing theory about the origins of mental disease inuences what therapies for psychiatric illness predominate. Early biologic psychiatry in the late 1800s to early 1900s emphasized the correlation of neurologic symptoms with postmortem microscopic study of anatomic changes in the brain. Although this research was of immense importance in terms of regional localization of brain functions (e.g., Wernickes aphasia), it provided little help to the clinical psychiatrist of the time. Emil Kraepelin, a German psychiatrist, was the rst to begin to classify psychiatric disorders by systematically studying the natural history of the disease. The intent was to be able to predict outcomes. In the sixth edition of his textbook, Psychiatrie (1899), Kraepelin laid the groundwork for the Diagnostic and Statistical Manual of Mental Disorders (DSM; the current 4th edition [revised] is abbreviated DSM-IV-TR) of the American Psychiatric Association. He divided all mental disorders into 13 groups, including psychoses, which he divided into two distinct groups: those with an affective component, which he called manic-depressive psychosis, and those without, which he called dementia praecox.1 In the mid-20th century, the psychoanalytic view of mental disorders took hold, reaching its zenith in the 1950s and 1960s. Psychiatric illness was explained as the result of unconscious conicts over events in an individ- uals past. Alterations in nurture, not nature, became the underlying cause of psychiatric illness. In the last half of the 20th century, biologic psychiatry became important once again. During the 1970s, techniques of neuroimaging became available that allowed the neuroscientist to visualize brain structures and function.1 The results of genetic studies examining the correlation between family relationships and incidence of psychiatric illness, in particular the studies of monozygotic and dizygotic twins, suggested that depression and schizophrenia had a strong genetic component. The introduction of chlorpromazine (i.e., Thorazine) as a treatment for schizophrenia revolutionized psychiatry because although it did not cure psychosis, it did control the symptoms of the disease, increasing the potential for more traditional therapies to work and allowing previously institutionalized individuals to lead much more normal lives. It also suggested strongly that mental illness had a biologic foundation. Chlorpromazine soon was followed by other drugs for psychosis and depression. This move to biologic psychiatry, however, has not excluded the healing value of the therapistclient relationship. It appears that pharmacotherapy in conjunction with psychotherapy is of greater healing power than either alone. Perhaps the distinction drawn between biologic and psychosocial disease is arbitrary. Indeed, experiments indicate that learning and sensory stimulation or deprivation can in fact weaken or strengthen synaptic connections, which in turn could change brain function and thus behavior.2 Treatment of Mental Illness Asylums have existed since the Middle Ages, but until the end of the 18th century, their only function was custodial. One of the oldest asylums was the Priory of St. Mary of Bethlehem, founded in London in the 13th century. Its name was eventually shortened to Bedlam, a term that has become synonymous with madness. The asylum as a therapeutic establishment did not become an important concept until the end of the 18th century.1 At this time, madness was viewed as an excessive irritation of the nerves; therefore, establishing a calming environment was crucial. These asylums often had a very rigid schedule of daily activities meant to focus the patient and afford mental rest. It was also during this time that practitioners attempted to systematize the techniques known to establish a therapeutic relationship between the doctor and the patient. In the 1800s, the number of patients in asylums was, at the most, in the hundreds. By the mid-1900s, the number was in the thousands. Unfortunately, by the early 1900s, asylums had become little more than warehouses for the chronically mentally ill.3 Whether this was due to the failure of asylums as a therapeutic environment or to the increased number of persons housed in them, overwhelming the available resources, remains a matter of debate. The reason for the increased numbers of persons in the asylum in the 19th century also is debated. Was there an increased incidence of mental illness, or did society become increasingly intolerant of deviant behavior? CHAPTER 53 Disorders of Thought, Mood, and Memory 1267 Earlsworth Asylum, Redhill England/T.S. Crowther. Courtesy the National Library of Medicine, National Institutes of Health. This debate exploded in the 1960s, during which time several writers suggested that there was no such thing as mental illness but rather a medicalizing of deviance and that psychiatric institutions were evil. Schizophrenia in this view was a gifted and creative state of consciousness, not an illness. This antipsychiatry attitude, coupled with the advent of psychopharmacology, laid the foundations for the deinstitutionalization of the mentally ill and the move to community psychiatry. Unfortunately, deinstitutionalization was neither carefully planned nor adequately funded, leaving many mentally ill homeless and without proper care.1 THE ROLE OF HEREDITY IN MENTAL ILLNESS Who we are and how we express ourselves through behavior depend on the complex inuences of genetic and environmental factors on neural development and function. Since the early 1990s, the scientic knowledge base in genetics has grown exponentially and has created new tools to study the role of genetic inheritance in the development of mental illness. Research into the complexities of the regulation of gene expression can only deepen our understanding of the etiology of mental disorders, increase our ability to treat the disorders with more precisely targeted psychotherapeutic drugs, and ultimately lead to the discovery of ways to prevent the development of psychiatric illness. Epidemiologic studies of twins, of adopted children, and of family histories or pedigrees have shed light on the debate over the relative inuence of nurture versus nature in the development of mental illness. Twin studies compared the incidence of mental illness among monozygotic (identical) twins, dizygotic (fraternal) twins, and their siblings. If a disease were at all genetically determined, higher rates of coexistence of the disorder (concordance) would be expected among monozygotic twins as compared with dizygotic twins, nontwin siblings, or the general population. Adoption studies questioned whether children with a genetic history of mental illness, adopted by parents with no history of psychiatric illness, had a greater risk for developing mental illness than children with no genetic history of mental illness who were adopted by parents with a psychiatric illness. Also, if a mental illness has a genetic component, it would be expected that higher numbers of persons in a family would have the disorder than would be found in the general population.46 The overwhelming conclusions of these studies have been that both genetic vulnerability and environmental inuences play signicant roles in the development of mental illness. For example, studies of twins have shown a 45% concordance for schizophrenia among monozygotic twins, compared with 15% for dizygotic twins or other siblings.7 1268 UNIT XII Neural Function With bipolar depression, there is an 80% concordance in monozygotic twins, compared with 10% for siblings. In monozygotic twins living apart, the concordance rate for affective disorders is 40% to 60%.8 Even the concordance rates among siblings for these two disorders is suggestive of a genetic inuence because schizophrenia has approximately a 1% incidence and depression a 5% incidence among the general population.7,8 The rate of occurrence of either disorder also is higher in the biologic families of adopted children than in the adoptive families. The incidence of suicide is six times higher among biologic relatives of adoptees with depressive illness than among the biologic relatives of adoptees without depression. Although the evidence for a genetic basis for mental illness is compelling, the fact that the concordance among monozygotic twins is not 100% indicates that other factors may be involved in the development of a mental illness. It certainly is highly likely that mental illnesses are polygenic and multifactorial rather than simply inherited through transmission of a classic disordered dominant or recessive mendelian trait (see Chapter 6). In addition, mental disorders exhibit variable expressivity. It is possible that a person with the disease genotype needs to have the right environmental stressors (i.e., viral illness, physical or emotional abuse, substance abuse) to express the disease phenotype, or that there are genegene interactions that inuence the extent to which a mental illness is manifested.4 In summary, psychiatric disorders are characterized by alterations in thought, mood, or behavior that may interfere with a persons ability to engage in ordinary social interactions and may in some instances require temporary or long-term institutionalization. Our understanding of the pathogeneses of mental disease is still in its infancy, and the historical debate about the relative importance of nurture and nature in the development of mental illness continues. It is likely that the cause of mental illness is multifactorial and includes a dynamic interplay among genetic predisposition, alterations in early neurodevelopment, and dysfunctional social interactions in a family. Name the major neuromediators in the brain, their major location and source in the brain, and the possible involvement of each in the manifestations of mental illness BEHAVIORAL ANATOMY OF THE BRAIN There is increasing scientic evidence that anatomic and biochemical alterations in the brain play a critical role in the behaviors observed in mental illness. The brain is extraordinarily complex, divided into several distinct groups of functional neurons that also are highly interconnected and thus able to inuence each others activity.9 The information processing happens within nanoseconds. However, for persons with brain injury or degenerative changes, information processing and cognitive function may be impaired. Cerebral Cortical Structures The cerebral cortex covers the outermost part of the brain. The cortex, which contains the centers for elaboration of thought, voluntary motor and sensory function, speech, and memory patterns, has extensive connections with deeper parts of the brain. The thalamus, in particular, forms important connections with the cerebral cortex. Thalamic excitation is necessary for almost all cortical activity. Thus, the loss of function is much greater when the thalamus is damaged along with the cortex than when the damage is limited to the cortex. Table 53-1 summarizes the cerebral cortical structures and their functions. Anatomic and Neurochemical Basis of Behavior After completing this section of the chapter, you should be able to meet the following objectives: The Prefrontal Cortex. The frontal lobe is the largest lobe and often is referred to as the chief administrator of the brain (Fig. 53-1). It is responsible for planning, problem solving, intellectual insight, judgment, and expression of emotion. It is the function of the prefrontal areas to keep tract of many bits of information simultaneously and then to recall this information as it is needed for subsequent intellectual tasks. Before the discovery of modern drugs to treat psychiatric conditions, some patients were treated surgically with a procedure, called a prefrontal lobotomy, that severed the connections between the prefrontal areas of the brain and the remainder of the brain.10 Subsequent studies of these patients revealed a lack of ability to solve complex problems, to link sequential tasks together, and to learn to do parallel tasks at the same time. Their social responses were inappropriate, and their levels of aggression were decreased to the point at which they lost all ambition. They were still able to perform at their previous level of motor function, talk, and comprehend language, but they were unable to carry through with any long-term trains of thought. The Temporal Lobe. The temporal lobe integrates and interprets somatic, visual, and auditory information that is critical for recognition of the familiar as well as for appropriate interpretation of and response to social contexts. The temporal lobe also contains the area of the brain (Wernickes area) that is responsible for language comprehension. It is one of the more important areas of the brain in terms of intellect because almost all intellectual functions are language based. Name the cerebral cortical structures and structures from the primitive brain involved in thought and emotion Describe the major functions of each brain structure in terms of thought processes, learning, and emotion Describe the cortical pathways by which learning and the development of memory occur Dene the terms synapse, synaptic transmission, and neuromediators CHAPTER 53 Disorders of Thought, Mood, and Memory 1269 TABLE 53-1 Frontal Lobe Selected Functions of Several Brain Regions Temporal Lobe Visual-spatial recognition Attention Motivation Emotional modulation and interpretation Impulse and aggression control Interpretation and meaning of social context Aspects of sexual action and meaning Parietal Lobe Sensory integration and spatial relations Bodily awareness Filtration of background stimuli Personality factors and symptom denial Memory and nonverbal memory Concept formation Occipital Lobe Vision Possible information holding area Abstract vs. concrete reasoning Motivationvolition Concentration Decision making Purposeful behavior Memory and historical sense of self Sequencing Making meaning of language Speech organization Speech production (Brocas area) Aspects of emotional responseblunting Central fissure (Rolando) Frontal lobe Parietal lobe Parieto-occipital fissue Occipital lobe Part of appropriate social response is the accurate interpretation of emotions and the ability to respond with the level of emotionality and language deemed socially congruent. Impulse control, the management of aggression and sexual expression, including the culturally determined stereotypy of what it means to be male or female in a given society, also are temporal lobe functions. Emotion originates in the amygdala of the limbic system (discussed later), but the modulation and ne-tuning of that emotion into an appropriate level of intensity occurs in the temporal lobe. Parietal Lobe. The parietal lobe is essential in the integration and processing of sensory (visual, tactile, and auditory) input. It is in the parietal lobe that sensory experiences rst begin to coalesce into the cognitions we experience as thinking in the frontal lobes. The coordination of spatial awareness occurs in the parietal lobe and involves not only visual content but also the ability to experience, claim, and care for all of ones body. Another important parietal lobe function is to lter out extraneous information. The ability to lter out background and extraneous noise and sensations is critical to normal daily functioning. (Sylvius) Transverse fissure Temporal lobe Cingulate gyrus Prefrontal lobe Corpus callosum Anterior nucleus of thalamus Fornix Occipital Lobe. The occipital lobe is the most posterior of the lobes and is responsible for receiving visual information from the eyes. The visual association cortex of the occipital lobe is important for the interpretation of visual experiences, including depth perception and location in space. Association Areas. A large part of the cerebral cortex forms Olfactory bulb Mammilary body Amygdala Parahippocampus gyrus Temporal lobe Hippocampus FIGURE 53-1 (A) Lateral aspects of the cerebral hemispheres, including the frontal, temporal, parietal, and occipital lobes. (B) The structure of the limbic cortex, which include the limbic cortex (cingulate gyrus, parahippocampal gyrus, hippocampus) and associated subcortical structures (thalamus, hypothalamus, amygdala). association areas that add perception and meaning to incoming sensory information. The most important of these are the parieto-occipitotemporal association area, the prefrontal association area, and the limbic association area (Fig. 53-2). The parieto-occipitotemporal association area lies in the large parieto-occipital cortical space bounded by the somatosensory cortex, the visual cortex, and the auditory cortex (see Chapter 49). This association area computes the coordinates of incoming visual, auditory, and somatosensory information, providing information about the 1270 UNIT XII Neural Function FIGURE 53-2 Map of specic functional areas in the cerebral cortex, showing especially Wernickes and Brocas areas of language comprehension and speech production, which in 95% of all people is located in the left hemisphere. (Adapted from Guyton A.C., Hall J.E. [2000]. Textbook of medical physiology [10th ed., p. 655]. Philadelphia: W.B. Saunders). location of body parts and their relationship to the environment. It also contains the major area for comprehending language, processing visual language (reading), and naming objects. The prefrontal association area functions in close connection with the motor cortex to plan and execute complex motor movements. This area uses input from sensory receptors in muscles and joints as well as sensory input from the skin and vestibular system. The prefrontal association area is also important in carrying out thought processes that involve input from multiple sensory modalities. It is often described as being the area for short-term working memories that are used to analyze each new thought as it is entering the brain. A special area of the frontal cortex, called Brocas area, provides the neural circuitry for word formation. The limbic association area is found in the anterior pole of the temporal lobe and in the cingulated gyrus on the medial aspect of the brain. It is concerned primarily with behavior, emotions, and motivation. as other parts of the limbic system. The hippocampus plays a major role in the encoding, consolidation, and retrieval of memories. Almost all types of sensory information activate some part of the hippocampus. In turn, the hippocampus distributes information to the anterior thalamus, hypothalamus, and other parts of the limbic system. The hippocampus also groups and schematizes input in preparation for memory encoding. It plays a signicant role in converting short-term memory to long-term memory. Hippocampal atrophy has been noted in diseases in which memory problems play an important role, such as Alzheimers disease. The amygdala is located deep in the medial temporal lobe. It receives neuronal signals from the temporal and occipital lobes of the cortex and has many bidirectional connections with the hypothalamus as well as other parts of the limbic system. Through these connections, the amygdala helps a person relate to the surrounding environment and then pattern appropriate behavior. Because of the many connections, the amygdala has been called the window through which a person sees the world. The amygdala is important in emotional function and regulation and modulation of affective responses in social settings. Sexual arousal, aggression, and fear also are functions of the amygdala. The hypothalamus, although not strictly an anatomic part of the limbic system, plays a critical role in it because of the extensive connections it has with the limbic system. The hypothalamus has a multitude of regulatory functions related to basic survival needs of the body, such as regulation of body temperature, sleeprest patterns, hunger, sexual drive, and hormonal secretion. PHYSIOLOGY OF PERCEPTION, THOUGHT, AND MEMORY Perception is the nal stage of information processing. It is the conscious awareness of sensory stimuli and results in behavioral responses to that sensation. Information from the senses is received by the thalamus and then projected to the somatosensory cortex and prefrontal association area. The prefrontal association area keeps track of where information has been put in long-term memory and is responsible for retrieving and then integrating memories with sensory input for decision making. Learning and Memory The Limbic System The limbic system is a complex group of neurons that regulate our emotional behavior. It includes several discrete structures in the deep part of the brain, including the hippocampus, the parahippocampal gyrus, cingulate gyrus, amygdala, and a bridgelike structure called the fornix, which is a bundle of nerve bers connecting the hippocampus with the hypothalamus (see Fig. 53-1). Higher and lower brain centers communicate with the limbic system to link thoughts and autonomic nervous system responses to emotions. The hippocampus, along with its adjacent temporal and parietal lobe structures, has numerous indirect connections with many portions of the cerebral cortex as well Behavior is altered by environmental cues that are processed through learning and memory. Learning is the process of acquiring knowledge, whereas memory is the process of storing and retrieving what has been learned. There are two forms of memory: implicit memory, which is involved in learning reexive motor and perceptual skills; and explicit memory, which is involved with processing the factual knowledge of persons, places, and things and its meaning.11 Psychiatric patients and brain-injured persons not only experience specic cortical dysfunctions but also may experience difculty in the proposed pathways for learning and memory. These difculties are likely to inuence their behavior and may have an impact on the design of effective interventions. CHAPTER 53 Disorders of Thought, Mood, and Memory 1271 Thought processes probably involve a pattern of stimuli from many parts of the nervous system at the same time and in a denite sequence. Each thought requires simultaneous input from portions of the cerebral cortex, the thalamus, the limbic system, and the reticular formation in the brain stem. The prefrontal association cortex processes information from many areas of the brain and is necessary to achieve thinking. It has the ability to keep track of bits of information and recall them simultaneously from working memory. This allows us to plan, set goals, and solve problems. Thoughts are expressed in the form of language through the functions of Brocas area for word formation and Wernickes area for language comprehension. Physiologically, thought and memories are the result of synaptic transmission between neurons. During the process, new or reactivated pathways transmit neural circuits, sometimes called memory traces, through the brain.10 Although we often think of memories as being positive recollections of past experiences, the greatest share of memories are probably negative encounters that the brain disregards as adverse or unimportant information. It is the basal regions of the limbic system that determine whether information is important and whether to store the thought as a memory trace or to suppress it. This aspect of memory selection is vital to the brain. Without it, the constant inundation of sensory information would exceed the capacity of the brain within minutes. Memories can last minutes, hours, months, or years. For the purpose of classication, memory can be classied as short-term, intermediate-term, or long-term. Short-term memory is typically conned to the remembering of information for a period of several seconds to minutes (e.g., 7 to 10 digits of a telephone number). It is thought that these memories involve nerve signals that travel around and around a temporary memory trace.11 Intermediate-term memory involves the remembering of information for a period that may last many minutes or weeks. These memories become lost unless memory traces are established. Long-term memory, which lasts for years, is generally thought to result from actual structural changes in the synapses. For example, there might be an increase in the presynaptic structures responsible for the neurotransmitter synthesis or release. DISORDERS OF PERCEPTION Two disorders of information processing, hallucinations and delusional thinking, are common symptoms of many psychiatric disorders. These symptoms may also occasionally occur in healthy persons, they may accompany other health problems, or they may be a side effect of drugs. Hallucinations Within the realm of perception reside the input of sensory information from the outside world and the processing of this information into meaning. All sensory information from the external world is transmitted to the thalamus; from there, it is relayed to various parts of the brain and then transformed into meaningful experience. For example, visual stimuli from the retina are transmitted to cen- ters in the thalamus through the optic nerve; from there, they are relayed to the primary visual cortex in the occipital lobe and then to the visual association cortex, where they gain meaning (see Chapter 54). Hallucinations can be described as sensory perceptions that occur without external stimulation of the relevant sensory organ.12 Hallucinations should be differentiated from illusions, which are misinterpreted sensory perceptions that are stimulated by actual external stimuli. The pathophysiology of hallucinations can occur at several levels. The disorder may originate at the end organ, occur during sensory transmission, or be based on abnormal cortical reception, perception, or interpretation. Hallucinations can be classied in several ways, such as by the structure or function involved, the etiology, or the affected sense perception. One functional method categorizes hallucinations as release hallucinations and ictal hallucinations.12 Release hallucinations occur when a normal sensory input is blocked, and as a replacement, stored images are experienced; whereas ictal hallucinations are produced by abnormal neuronal discharges. Visual ictal hallucinations tend to be brief, stereotyped in content, and geometric in design. These are the type of hallucinations that occur during the aura in people with epilepsy. Hallucinations that are classied according to etiology may occur as the result of disorders of brain structure or function (brain tumors, epilepsy, metabolic disorders), drug reactions, sensory deprivation, or psychotic disorders. The type and content of hallucinations often provides insight into their etiology. The most commonly used classication is based on the sensory perception involved (e.g., visual, auditory, olfactory, tactile). Within this method, hallucinatory experiences involving the visual system are the most clearly categorized. Several types of visual hallucinations are normal life experiences (e.g., images seen in a dream). Also, several ophthalmologic stimuli are accompanied by visual hallucinations. Ocular phosphenes, which are produced by vigorous rubbing of the eye, are a form of visual hallucination. The Charles Bonnet syndrome is an organic disorder occurring in the elderly that is characterized by complex visual hallucinations. It is associated with loss of vision and is seen in older adults with preserved intellectual functions.13 In one study, 10% of persons (mean age of 75 years) with severe visual disability experienced visual hallucinations.14 These persons retained insight into the problem and needed only reassurance that their hallucinations did not represent mental illness. Visual hallucinations associated with psychiatric disorders tend to be complex, may be enhanced by auditory hallucinations, and often lead to delusional beliefs. Auditory hallucinations include misperceptions of sounds such as ringing and buzzing noises, musical sounds, and voices. Although they commonly occur in psychiatric disorders, particularly schizophrenia, they also occur in other disorders. Musical hallucinations featuring the perception of music without an external stimulus can be seen in disorders ranging from deafness to temporal lobe pathology. When associated with brain pathology, the lesion is usually on the right side of the brain. Auditory hallucinations are commonly reported as an aura of epilepsy. 1272 UNIT XII Neural Function Tinnitus, the perception of ringing, buzzing, or whistling sounds, is often the result of disorders of the inner ear (see Chapter 55). Withdrawal states, particularly from alcohol, are known to cause auditory hallucinations. A variety of psychiatric disorders are accompanied by auditory hallucinations, such as the sound of voices. Often, the source of the sound, which is sensed as occurring within the head, is difficult to localize. The voice often comments on the persons behavior and echoes their thoughts. Voices are rarely described as supportive; they are most often described as critical and negative in tone. Strategies of distraction used by persons hearing voices include listening to music, especially through headphones, or snapping rubber bands on their wrists. Additionally, keeping a record helps identify hallucinatory precipitants and thus helps individuals avoid those situations that act as precipitants.15 Hallucinations involving smell and taste are often the result of damage to the olfactory bulb. Tumors at the base of the brain that extend into the olfactory cortex can produce olfactory hallucinations. Persons with migraine headaches may also experience an aura consisting of olfactory or gustatory hallucinations. Somatosensory hallucinations, such as phantom limb pain, are discussed in Chapter 50. Delusions Delusions are characterized by a false belief and the persistent, unshakable acceptance of the false belief. In contrast to hallucinations, which are abnormalities of perception, delusions are abnormalities of thought. Delusions commonly incorporate input from multiple sensory systems, whereas hallucinations are conned to a single sensory modality. Delusions are formed from and colored by an individuals background, including personal, family, and social experiences; educational background; and cultural (including religious) inuences. Delusional thinking may include, among others, delusions of persecution (e.g., believing ones self or property is being threatened), inuence (e.g., believing thoughts can move through radio or atomic rays), ill health, grandeur (e.g., believing oneself to be a great person, such as the King of England), poverty, and possession (e.g., believing ones body is possessed by God or some great power). The causes and mechanisms underlying delusional thinking are unclear. It has been suggested that delusional thinking is the product of repeated stress, rather than a disorder based on a single, acute situational problem.12 Interestingly, delusions have been associated with conditions that produce sensory deprivation, such as hearing loss. In one study that used a case-control method, elderly persons with late-life psychoses that included paranoid symptomatology were four times more likely to have hearing impairments compared with control subjects.16 cate with one another. Nerve cells of discrete brain regions communicate with each other rapidly and over long distances by electrochemical signals that are propagated along the length of each neuron. The point at which two neurons meet is called a synapse, and the process by which the signal from one neuron to another is communicated is called synaptic transmission or neurotransmission (see Chapter 49). Chemical substances called neurotransmitters or neuromediators are released from the axonal terminal of one neuron (presynaptic cell), cross the synapse, bind to receptors on the postsynaptic cells, and cause excitatory or inhibitory actions.17 Neurotransmission involves several discrete steps: (1) the synthesis of a transmitter substance, (2) the storage and release of the transmitter, (3) binding of the transmitter to receptors on the postsynaptic membrane, and (4) removal of the transmitter from the synaptic cleft. The classic neurotransmitters include small-molecule transmitters and neuroactive peptides. These molecules typically are stored in vesicles in the presynaptic axonal terminal and released by the process of exocytosis18 (see Chapter 49, Fig. 49-8). The substances generally agreed to be neurotransmitters and implicated in mental illness include acetylcholine, the biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin), and amino acids (gamma-aminobutyric acid [GABA], glutamate, glycine, and aspartate). Table 53-2 summarizes the major source and effect of each neurotransmitter. Emergence of Psychotropic Medications The treatment of many psychiatric disorders is based on pharmacologic interventions that alter neurotransmitter or receptor properties of the brain. In the 1950s, a French neurosurgeon, Henri Laborit, was searching for a drug that would reduce the effects of preoperative anxiety-induced histamine release in his patients. Through trial and error, he found chlorpromazine to be the most effective calming agent and recommended the drug to his psychiatric colleagues. It was subsequently found that high doses of chlorpromazine were efcacious in calming agitated persons with schizophrenia and bipolar disorders. It eventually became clear that chlorpromazine was not simply a tranquilizer but also had some specic antipsychotic effects. Chlorpromazine and related drugs in the phenothiazine class attenuated or abolished delusions, hallucinations, and disordered thinking. There are now four major groups of antipsychotic agents used to treat schizophrenia, divided into two major categories: the typical and the atypical antipsychotics. The typical antipsychotics include the phenothiazines (e.g. chlorpromazine), butyrophenones (haloperidol), and thioxanthene (Navane). The atypical antipsychotics, exemplied rst by clozapine, are more effective in treating the negative symptoms of schizophrenia (discussed later) and produce fewer extrapyramidal effects. Both categories of drugs exert their effect by blocking dopamine receptors, although the atypical antipsychotics have a more rened blockade action. The atypical antipsychotics also exert some of their effects through blockade of serotonin (5-HT) receptors. ROLE OF NEUROMEDIATORS Many of the new advances in the understanding and treatment of mental illness are derived from an increased understanding of how nerve cells in the brain communi- CHAPTER 53 Disorders of Thought, Mood, and Memory 1273 TABLE 53-2 Neuromediator The Source and Effect of Brain Neuromediators Major Source in the Brain Formed in many synapses of the brain; in high concentration in basal ganglia and motor cortex Derived from choline Substantia nigra and ventral segmental area in the midbrain Derived from tyrosine Effect and Implications for Mental Illness Can be excitatory or inhibitory, depending on the area of the brain Underactivity implicated in Alzheimers disease Usually excitatory Involved in motivation, thought, and emotional regulation Overactivity thought to be involved in schizophrenia and other psychotic disorders Can be excitatory or inhibitory, depending on the area of the brain Noradrenergic pathways to cerebral cortex, limbic system, and brain stem Underactivity thought to be involved in some depressions Involved in the regulation of attention and complex cognitive functions Pathways to cerebral cortex, limbic system, and brain stem Underactivity thought to be involved in some depressions and obsessive-compulsive disorder GABA and glycine usually are inhibitory; glutamate is excitatory Implicated in anxiety disorders Acetylcholine (Ach) Dopamine (DA) Norepinephrine (NE) and epinephrine (E) Locus ceruleus in brain stem Derived from dopamine Serotonin (5-HT) Raphe nucleus in the brain stem Derived from tryptophan -Aminobutyric acid (GABA), glutamate, aspartate, and glycine No single major source Psychopharmacology has been particularly productive in developing highly effective treatments for affective disorders. Antidepressants alleviate depressive symptoms by increasing the activity of norepinephrine and serotonin at postsynaptic membrane receptors. The most widely used antidepressants can be divided into four major categories: the monoamine oxidase inhibitors (MAOIs), the tricyclic compounds, the serotonin reuptake inhibitors (SRIs), and the novel, or atypical, antidepressants. MAOIs increase the concentration of serotonin and norepinephrine by reducing the degradation of these neurotransmitters by monoamine oxidase. Tricyclics block the reuptake of serotonin and norepinephrine by the presynaptic membrane, whereas the SRIs inhibit the reuptake of serotonin. Formulations of the SRIs vary and target different neurotransmitters. These include the selective serotonin reuptake inhibitors (SSRIs), the serotonin antagonist and reuptake inhibitors (SARIs), and the serotonin norepinephrine reuptake inhibitors (SNRIs). The atypical antidepressants affect serotonergic and noradrenergic neurotransmission. The therapeutic effect of the antipsychotic and antidepressant drugs probably is not entirely due to increasing or decreasing the neural levels of one or more neurotransmitters. For example, the clinical effect of the antidepressants typically is slow (weeks), even though the drugs rapidly block receptors. This suggests that the real mechanism of these drugs may be due to their effects on expression of receptors at the cellular membrane or on other intracellular pathways that regulate protein synthesis.19 NEUROIMAGING Abnormalities in brain structure and function can contribute to the manifestations of mental illness. Since the early 1970s, imaging techniques have been developed that allow practitioners and researchers to map brain anatomy in exquisite detail and to estimate brain activity by measuring brain blood ow and metabolic rate. These imaging studies have suggested intriguing correlations between brain pathologies and psychiatric manifestations that provide clues to the pathogenesis of mental disorders. Brain imaging techniques, however, remain research tools and have not yet been applied clinically, which means that imaging cannot be used to make a diagnosis of mental illness. The techniques include computed tomography (CT) scans, magnetic resonance imaging (MRI), positron-emission tomography (PET), and single photon emission computed tomography (SPECT). A CT scan of the brain provides a three-dimensional view of brain structures that can differentiate ne densities. Abnormalities in a CT scan are not diagnostic of any particular mental illness; however, they suggest a brain-based problem. Structural abnormalities of the brain have been measured in people with schizophrenia, mood disorders, and dementias. MRI is used primarily for diagnosis of structural changes in the brain, although newer techniques are able to measure brain function as well. Unlike CT, MRI is able to distinguish between gray and white matter. The basis of PET is the variable brain tissue uptake of an infused radioactive substance (Fig. 53-3). The tissue uptake of the 1274 UNIT XII Neural Function FIGURE 53-3 PET scan showing differences in frontal lobe activity of a pair of twins, one with a mental disorder of schizophrenia, and one who does not have the disorder. (From Boyd M.A. [2002]. Psychiatric nursing: Contemporary practice. [2nd ed., p. 98]. Philadelphia: Lippincott Williams & Wilkins. Courtesy Drs. K.F. Berman and D.R. Weinberger, Clinical Brain Disorders Branch, National Institutes of Mental Health) substance depends on tissue type and metabolic activity. Labeled drugs can be infused to study neurotransmitter receptor activity or concentration in the brain. SPECT is similar to PET but is less expensive and uses more stable substances and different detectors to visualize blood ow patterns. This is useful for diagnosis of cerebrovascular accidents and brain tumors.19,20 In summary, the symptoms of mental illness arise from alterations in neural functioning or from destruction of neurons in the brain. Because the brain integrates the processes of learning, memory, and emotions, the manifestations of mental disease may be primarily cognitive impairment, emotional impairment, or a combination of both. Psychiatric patients and brain-injured persons not only experience specic cortical dysfunctions but also may experience difculty in the proposed pathways for learning and memory. These difculties are likely to inuence behavior and may have an impact on the design of effective interventions. Many of the new advances in the understanding and treatment of mental illness and symptoms such as hallucinations, mood disruptions, and cognitive dysfunctions are derived from an increased understanding of how nerve cells in the brain communicate with one another. Neurotransmission involves several discrete steps: (1) the synthesis of a transmitter substance, (2) the storage and release of the transmitter, (3) the binding of the transmitter to receptors on the postsynaptic membrane, and (4) the removal of the transmitter from the synaptic cleft. The substances generally agreed to be neurotransmitters and implicated in mental illness include acetylcholine, the biogenic amines, and amino acids. New diagnostic tools, such as increasingly sophisticated neuroimaging techniques, may help to develop more precise correlations between behavior, thought, and mood disorders and microscopic alterations in brain structure and neuron function. In addition, an increased understanding of the complex interactions among the different parts of the brain will assist in the development of more effective psychotherapies and more efcacious psychotropic drugs. Disorders of Thought and Volition After completing this section of the chapter, you should be able to meet the following objectives: Dene the term schizophrenia Describe the epidemiology of schizophrenia Describe the manifestations of schizophrenia, both positive and negative symptoms, and their underlying neuropathophysiology Cite the diagnostic criteria for schizophrenia according to the DSM-IV-TR classication Describe the treatment for the positive and negative manifestations of schizophrenia SCHIZOPHRENIA Schizophrenia refers to the disconnection between thought and language that occurs in this disease. Although the word schizophrenia means splitting of the mind, it should CHAPTER 53 Disorders of Thought, Mood, and Memory 1275 not be confused with split personality. Schizophrenia accounts for 25% of all hospital admissions,21 and it is estimated that between 20% and 25% of the homeless have some form of severe and persistent mental illness, such as schizophrenia.22 The onset of the disorder typically occurs between 17 and 25 years of age. The peak age of onset for males is between late teens and 25 years of age, and for females, between 25 and 35 years of age. Ninety percent of those in treatment are between 15 and 55 years of age. Onset before age 10 or after age 60 years is rare. Men and women seem to be affected equally, but the age of onset is later in women than in men. Risk factors for schizophrenia include having a close relative with schizotypal personality disorder or schizophrenia (rst-degree relatives of a person with schizophrenia have a 10-fold greater prevalence of the illness than the population at large), winter/spring birth date, second-trimester prenatal inuenza infection, and early history of attentional decits.23,24 Manifestations Schizophrenia is a psychotic disorder with many subtypes characterized by positive or negative symptoms. Positive symptoms are those that reflect the presence of abnormal behaviors and include disorganized, incomprehensible speech; delusions (e.g., that one is being controlled by an outside force); hallucinations (hearing voices is the most common); and grossly disorganized or catatonic behavior. Alterations in speech patterns can include using invented words (neologisms), derailment (loose associations), tangentiality (inability to stick to the original point), incoherence (loss of logical connections), or word salad (groups of disconnected words) (Fig. 53-4). Frequently, persons with schizophrenia lose the ability to sort appropriately and interpret incoming stimuli, which impairs the ability to respond appropriately to the environment. An enhancement or a blunting of the senses is very common in the early stages of schizophrenia. Sounds may be experienced as louder and more intrusive; colors may be brighter and sharper. In addition, the person with schizophrenia often experiences sensory overload owing to a loss of the ability to screen external sensory stimuli.2326 Delusions and hallucinations may be a natural outgrowth of the inability of the person with schizophrenia to interpret and respond appropriately to stimuli. Delusions are false ideas believed by the affected person that cannot be corrected by reason. They range from simply believing that people are watching them to beliefs that they are being controlled and manipulated by others. Delusions of being a historical gure (e.g., Jesus Christ or the President) also are common. Sometimes, the delusions include a belief that the affected person is able to control others with his or her thoughts.25 Hallucinations are very common in schizophrenia, especially the auditory type. In these cases, the individual sees and hears things that are not in the external world but nevertheless are very real phenomena to the person experiencing them. Hallucinations may represent the end of the spectrum of increasing intensity of sensual stimuli. Auditory hallucinations range from simple repetitive sounds to many voices speaking at once. Sometimes, the voices FIGURE 53-4 A schizophrenic woman expresses her incoherent thinking, combined with neologisms, in this drawing. (From Sadock B.J., Sadock V.A. [2003]. Kaeplan and Sadocks synopsis of psychiatry. [9th ed., p. 494]. Philadelphia: Lippincott Williams & Wilkins. Courtesy of Heniz E. Lehaman) are pleasant, but much more often, they accuse and curse. When visual hallucinations occur, they usually are in conjunction with auditory hallucinations.2325,27 The negative symptoms of schizophrenia reect the absence of normal social and interpersonal behaviors and include alogia (tendency to speak very little), avolition (lack of motivation for goal-oriented activity), apathy, affective attening (lack of emotional expression), and anhedonia (an inability to experience pleasure in things that ordinarily are pleasurable). Some persons with schizophrenia have a blunted response to pain. Negative symptoms often are severe and persistent between acute episodes of illness.23,26 Paranoid schizophrenia manifests with persecutory or grandiose delusions. Auditory hallucinations are common. Interactions with others are rigid, intense, and controlled. Paranoid schizophrenia often has a sudden onset, and negative symptoms are not prominent. The prognosis of this form of schizophrenia seems to be better, with less evidence of disturbance in the anatomy of the brain and less cognitive decits than in those types in which negative symptoms predominate.28 Disorganized schizophrenia is characterized by a disintegration of the personality and a predominance of negative symptoms. Socially, the person is withdrawn and inept. Speech often is disorganized and incoherent. Personal grooming is neglected and because behavior is aimless, the person with this disorder often is not able to 1276 UNIT XII Neural Function complete activities of daily living. The person also may have cognitive and psychomotor decits. In general, the prognosis is not as good as that for the paranoid schizophrenic type.28 Catatonic schizophrenia was common decades ago, but is now rare in the United States and Europe.29 This disorder is characterized by intense psychomotor disturbance (retardation or excitement), extreme negativism, and peculiar voluntary movements such as grimacing, posturing, and echolalia (repeating what is said by another) or echopraxia (imitating the movements of others).28 D-aspartate ity of glutamate through dysfunction of its N-methylreceptor (see Chapter 52). Norepinephrine and GABA have also been identified in the pathophysiology of schizophrenia.30 Diagnostic Criteria According to the DSM-IV-TR classication system, a diagnosis of schizophrenia requires that two or more of the following symptoms must be present for a signicant portion of 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms.31 In addition, one or more areas of functioning must be signicantly impaired compared with premorbid abilities, and continuous signs of the disturbance must persist for at least 6 months.31 Neurophysiology of Symptoms The pathogenesis of schizophrenia is unknown. However, abnormalities in brain structure that are characteristic of this disorder are present at the first episode and in unmedicated persons. This suggests that the anatomic alterations are not the result of progressive brain deterioration due to repeated psychotic episodes or to effects of psychotropic drugs, but rather are caused by abnormalities in neurodevelopment in intrauterine and early postnatal life. The lateral and third ventricles are enlarged, the thalamus and hippocampus are somewhat smaller, and the left hemisphere is both smaller and smoother than that of persons without the illness. These changes are accompanied by a change in brain volume. Schizophrenia also is characterized by hypofrontality (reduced metabolic activity in the frontal cortex), although marked decreases in activity can be seen in almost every area of the brain, depending on the individual and the particular symptoms being experienced at the time of the scan (see Fig. 53-3). It is not known at what age these differences might be visible with imaging because children usually are not subjected to imaging techniques without a specic event indicating a clinical need for the procedure. Nevertheless, adolescents and young adults who are at high risk for development of schizophrenia because of a strong family history have enlarged ventricles and smaller medial temporal lobes.30 An additional anatomic nding is an increased density of dopamine (D2) receptor sites, particularly in the basal ganglia. With the additional information that effective antipsychotic drugs are dopamine antagonists and that dopamine-releasing agents such as amphetamine can cause psychosis, the dopamine hypothesis was developed; it proposes that the symptoms of schizophrenia are due to dopaminergic overactivity. However, this hypothesis cannot explain types of schizophrenia in which negative symptoms predominate or explain the residual symptoms of an acute psychotic episode. In addition, it is possible that the increased density of dopamine receptors found in some studies is related to the effects of antipsychotic drugs. In contrast, there is emerging evidence of a presynaptic dopaminergic autoreceptor abnormality such that there is a dysregulation or hyperresponsiveness of the neurons.30 Other transmitters implicated in the development of schizophrenia include a decreased activity of serotonin through the 5-HT2A receptor and a decreased activ- Treatment The goals of treatment for schizophrenia are to induce a remission, prevent a recurrence, and restore behavioral, cognitive, and psychosocial function to premorbid levels. Initially, in some cases, the goal may be primarily to reduce agitation and the risk of physical harm. Both pharmacotherapy and psychotherapy are essential components in the treatment of persons with schizophrenia. The positive symptoms of schizophrenia (delusion, hallucinations, agitation, and thought broadcasting) are most likely to respond to drug therapy. Both typical and atypical antipsychotic drugs address these positive symptoms. The negative symptoms of schizophrenia respond more favorably to the atypical antipsychotic drugs (e.g., olanzapine, ziprasidone). Often, antipsychotics are combined with benzodiazepines or antiparkinsonian agents during the acute phase of treatment to reduce the risk for extrapyramidal effects from large doses of antipsychotic agents. Psychotherapy (individual and group) is particularly important after the acute phase of therapy to help patients gain insight into the illness, to enhance their socialization skills, and to support and educate them in the maintenance of pharmacotherapy. SCHIZOPHRENIA Schizophrenia is a psychotic disorder of thought and language that is characterized by disorganized speech, delusions, visual and auditory hallucinations, and possible catatonic behavior. The positive symptoms of schizophrenia include delusions, or false beliefs, and hallucinations, or abnormal sensory perceptions, that occur without external visual or auditory input. The negative symptoms of schizophrenia reect the absence of the normal social and interpersonal relationships such as lack of motivation, apathy, and affective attening of emotional expression. CHAPTER 53 Disorders of Thought, Mood, and Memory 1277 In summary, schizophrenia is a mental illness classified as a disorder of thought and volition. Schizophrenia and its various subtypes are psychotic mental alterations in which thought and language become disconnected. It is characterized by both positive symptoms and negative symptoms. Positive symptoms are abnormal behaviors (e.g., incomprehensible speech), delusions, and auditory or visual hallucinations. Negative symptoms are abnormal social and interpersonal behaviors (e.g., lack of emotional expression) and an inability to experience pleasure. The onset of the disorder typically occurs between the ages of 17 and 25 years, with an equal incidence in men and women. Risk factors for schizophrenia include having a close relative with schizotypal personality disorder or schizophrenia. The pathogenesis of schizophrenia is unknown, although neuroimaging reveals several anatomic and functional changes in regions of the brain. Abnormalities in neurotransmission have been implicated, including changes in concentration and activity of the neurotransmitters dopamine, serotonin, norepinephrine, GABA, and glutamate. Treatment includes both psychotherapy and antipsychotic drugs. pears to be increasing. Prevalence of depression is higher in individuals from families with a history of mood disorders than in the population at large, indicating a genetic component to the etiology. Mood disorders are thought to occur with equal prevalence among races, although it is more frequently misdiagnosed as schizophrenia among nonwhite populations.32,34 Bipolar depression appears more frequently in the higher socioeconomic groups, although there is no correlation between major depression and socioeconomic status.3538 As with schizophrenia, genetic factors appear to play an important role in the development of mood disorders. Several studies have identied genetic that loci might contribute to the vulnerability to depression in families and individuals. However, the expression of affective disorders is not 100% in vulnerable families, which strongly suggests that environmental factors also play a critical role in the development of mood disorders.9 Manifestations Depression is classied as a mood disorder and is characterized by the following: depressed mood, anhedonia (inability to experience pleasure), feelings of worthlessness or excessive guilt, decreased concentration, psychomotor agitation or retardation, insomnia or hypersomnia, decreased libido, change in weight or appetite, and thoughts of death or suicidal ideation. Depression can vary in intensity and often is recurrent. The earlier and more frequent the onset of symptoms, the more likely it is that the affected individual will require medications for symptom relief. Depression in the elderly often appears with an element of confusion and often is left untreated. A rst episode of depression that occurs after 65 years of age can be a precursor to dementia and should precipitate both assessment and treatment of the depression as well as a thorough evaluation for dementia. Early intervention often greatly retards the progression of dementia, maintaining the individuals independence and quality of life. Disorders of Mood After completing this section of the chapter, you should be able to meet the following objectives: Dene the terms unipolar depression and bipolar depression Describe the epidemiology of unipolar and bipolar depression Describe the manifestations of unipolar depression, bipolar depression, and mania and the underlying neuropathophysiology of each Cite the diagnostic criteria for depression according to the DSM-IV-TR classication Describe the treatment modalities for depression DEPRESSION Depression is a disorder of emotion rather than a disturbance of thought. It is a common and highly underdiagnosed and undertreated illness. Major depression, which affects approximately 20% of the population, is classied as either unipolar (characterized by a persistent unpleasant mood) or bipolar (characterized by alternating periods of depression and mania). The prevalence of unipolar depression among women is double that of men, while the prevalence of bipolar disorder is more equally distributed between men and women. Men more often have the manic phase in the initial episode, whereas women more often have the depressed phase as the initial episode. Approximately 20% to 40% of adolescents who present with major depression develop bipolar disorder within 5 years.32,33 The average age of onset of bipolar disorder is the middle to late 20s and for unipolar depression, the mid30s; however, the age of onset of both disorders has been decreasing. In addition, the incidence of depression ap- Unipolar Depression. Unipolar depression has various subclassications distinguished by symptom patterns. Depression with melancholic features is characterized by depression that is worse in the morning, insomnia with early morning awakening, anorexia with signicant weight loss, psychomotor retardation or agitation, excessive or inappropriate guilt, loss of interest in activity, inability to respond to pleasurable stimuli, and a complete loss of capacity for joy. The symptoms of atypical depression are the opposite of melancholic depression; it is characterized by a depression that becomes worse as the day progresses, overeating, and hypersomnia (excessive sleep). Depression with psychotic features involves the presence of delusions or hallucinations that may or may not be mood congruent. The classication of depression with catatonic features is applied when symptoms include excessive mobility or motoric immobility, extreme negativism, repetitive speech, and peculiar voluntary movements. The chronic specier is applied if symptoms of major depression persist for 2 years or longer. A postpartum specier is included if the 1278 UNIT XII Neural Function onset is within 4 weeks of childbirth. Dysthymic disorder, a type of unipolar depression that is not classied as a major depression, is characterized by a persistent but mild depression that lasts longer than 2 years.3537 Neurophysiology of Symptoms In some cases of familial unipolar and bipolar depression, PET and MRI studies have demonstrated a reduction in the volume of gray matter in the prefrontal cortex, with an associated decrease in activity in the region. Clinical studies have suggested that this area of the brain is important for mood states and has extensive connections with the limbic system. Physiologically, there is evidence of decreased functioning in the frontal and temporal lobes, although it is not known whether this is a cause or an effect of depression because the activity returns to normal with the resolution of the symptoms38,43,44 (Fig. 53-5). The amygdala tends to have increased blood ow and oxygen consumption during depression.38 Unlike those areas where function returns to normal with the resolution of depression, the amygdala continues to be excessively active for 12 to 24 months after the resolution of depression. It is hypothesized that relapse into depression is more likely to occur if medications are decreased or stopped before the amygdala returns to normal functioning. Neurologic disorders of the limbic system and basal ganglia are also involved in the development of mood disorders.33 A number of neurotransmitters, serotonin and norepinephrine in particular, are implicated in depression.35,37,45 The biogenic amine hypothesis suggests that decreased levels of these hormones in the synaptic cleft, due either to decreased presynaptic release or decreased postsynaptic sensitivity, is the underlying pathology in depression. The hypothesis is derived from the fact that drugs that depleted brain serotonin and norepinephrine caused depression, and drugs that increased brain levels of norepinephrine and serotonin decreased depression. Dopamine activity has also been implicated in mood disorderswith decreased dopamine activity found in depression, and increased dopamine activity in mania.32 It has become increasingly clear, however, that a simple decrease in the concentration of amines in neuronal synapses cannot entirely explain the complexities of depression. Neuromodulatory systems in the brain interact with each other in complex ways. For example, cholinergic and GABA-ergic pathways also may play a role in the development of depression because both of these pathways inuence the activity of brain norepinephrine neurons.35,37,45 Disturbances in the function of the hypothalamicpituitary-adrenal (HPA) axis also may play a critical role in depression. In the general population, cortisol levels usually are at from late in the afternoon until a few hours before dawn, when they begin to rise. In persons with depression, cortisol levels spike erratically over the 24 hours of the day. Cortisol levels return to the normal pattern as depression resolves. In 40% of those diagnosed with depression, hypersecretion of cortisol is resistant to feedback inhibition by dexamethasone, indicating a dysfunction of the HPA axis.45 About 5% to 10% of persons with depression have a decrease in thyroid function; in which case, the person is less likely to have a vigorous response to medical intervention.32 Circadian rhythms also are an area of serious research interest.42 A specic type of depression known as seasonal affective disorder (SAD) is triggered for persons in the win- Bipolar Depression. Bipolar depression, or manic-depressive illness, also has multiple subclassications, all of which are usually characterized by episodes of elation and irritability (mania) with or without episodes of depression.37,39 Although the occurrence of mania without associated depression (unipolar mania) can occur, it is rare. Mania can be precipitated by antidepressant medications in persons with bipolar disorder. The manifestations of mania include decreased need for food and sleep, labile mood, irritability, racing thoughts, high distractibility, rapid and pressured speech, inated selfesteem, and excessive involvement with pleasurable activities, some of which may be high risk. In its minor forms, the subjective experience of mania can be quite pleasurable to the individual, with a heightened sense of wellbeing and increased alertness.40 The severity of manic symptoms runs the gamut from a condition called cyclothymia, in which mood uctuates between mild elation and depression and severe delusional mania.39 Mania may begin abruptly within hours or days or develop over a few weeks. Mixed states with features of both mania and depression present at the same time often are not well recognized. Bipolar episodes, left untreated, become more severe with age. Rapid cycling is said to occur when an individual has four or more shifts in mood from normal within a 1-year period. Women are more likely than men to be rapid cyclers.41 Kindling is a hypothesized phenomenon in which a stressor creates an electrophysiologic vulnerability to future stressful events by causing long-lasting changes in neuronal function. This may be the basis for the phenomenon of rapid cycling in bipolar depression. The more frequently a person has a shift in mood, cycling into either mania or depression, the easier it becomes to have another episode. There now is evidence that many psychiatric disorders, not just bipolar, are subject to this phenomenon. The better the control of the illness and the fewer cycles an individual has, the better his or her quality of life is likely to be.42 MOOD DISORDERS Mood disorders, which include unipolar depression and bipolar depression, represent a disturbance in emotion rather than thought. Depression is characterized by feelings of worthlessness and guilt, decreased concentration, alterations in sleep and appetite, and possible suicidal ideation. Bipolar depression is characterized by alternating periods of depression and mania during which there is a decreased need for food and sleep, racing thoughts, irritability, and high distractibility. CHAPTER 53 Disorders of Thought, Mood, and Memory 1279 FIGURE 53-5 Acute effects of antidepressant medications in patients with affective disorder showing widespread effects on the cortex that vary dramatically with the medication used. Positron-emission tomography is useful in revealing specic patterns of metabolic change in the brain and in providing clues to the mechanisms of antidepressant response (Courtsey of Monte S. Buchsbaum, MD. The Mount Sinai Medical Center and School of Medicine, New York, NY) ter by the shortening of daylight hours as fall commences, with symptoms of depression usually resolving in the spring when daylight hours again lengthen. Alteration in the sleepwake cycle is common in many mental illnesses and often is one of the prodromal signs of relapse. Researchers have found that the normal sleep cycle is reversed in depression. Persons with depression often have what is called dream pressure sleep. The depressed individual falls into light and dream-state sleep early in the sleep cycle and reaches deep stage 4 sleep only late in the sleep cycle. This nding helps explain why many inpatients report they did not sleep all night and the staff reports that the patient was asleep all night. Although the sleep cycle usually reverts to normal after the resolution of the depression, it may not be completely normal for weeks to months. Decreasing or halting medications before the sleep disturbances resolve may lead to a relapse of depressive symptoms. Circadian rhythm considerations are critical in symptom management for persons with bipolar depression. One of the fastest ways to precipitate a manic episode is for the individual to stay up all night. It is not unusual for a rst manic episode to occur when someone pulls an allnighter studying for nal examinations. Persons with bipolar disorder should have a fairly rigid schedule for sleeping and awakening if cycling is to be minimized. Although exercise is important, the person with bipolar disorder should exercise before mid-afternoon to prevent the normal increase in metabolic rate from disrupting the sleep cycle. of the aforementioned symptoms during a 2-week period, and these must represent a change from previous functioning.31 Depression must be differentiated from grief reactions, medication side effects, and sequelae of medical illnesses. Bipolar disorder is diagnosed on the basis of the pattern of occurrence of manic, hypomanic, and depressed episodes over time that are not due to medications or other therapies. The frequency, duration, and severity of the manic or depressive periods are unique to each individual.35,37 Mania, particularly in its severe delusional forms, also needs to be differentiated from schizophrenia or drug-induced states. Treatment Effective treatments exist for unipolar and bipolar illnesses, including antidepressant drugs, electroconvulsive therapy, lithium, anticonvulsants, and psychotherapy.3537,46 The antidepressants most often used are SRIs, which inhibit the reuptake of serotonin; atypical antidepressants; MAOIs, which block the degradation of norepinephrine and serotonin; and tricyclic compounds, which block the reuptake of norepinephrine and serotonin. Electroconvulsive therapy, a procedure that electrically stimulates a generalized seizure, is a highly effective treatment for depression, with 70% to 90% of clients showing a good response. Lithium and several anticonvulsant agents are used in the treatment of bipolar depression. Lithiums exact mechanism of action is unknown. It is known to block the enzymatic breakdown of inositol triphosphate (IP3), increasing its intracellular concentration. IP3 is an important regulator of intracellular calcium levels. The anticonvulsants agents, carbamazepine and valproate, also have proved efcacious in the treatment of bipolar depression, although the mechanism by which the drugs work is not completely understood. Diagnostic Criteria The DSM-IV-TR diagnostic criteria for a major depressive episode include the simultaneous presence of ve or more 1280 UNIT XII Neural Function Psychotherapy is an important component of therapy for persons and families with major depressive disorders. Individuals and families can learn how to deal with stressful life events and heal disrupted interpersonal relationships. Many people who have bipolar disorder do not believe they need treatment, particularly during the manic phase of the illness, and tend to self-medicate with alcohol or recreational drugs. It is not unusual for people with bipolar depression to be diagnosed with substance abuse. When in the manic phase, they often feel exceptionally creative and talented. When helping people make the decision to enter treatment, it is important that they understand the treatment will not stop their creativity. In summary, depression is a disorder of emotion rather than of thought and is classied as unipolar, characterized by a persistent unpleasant mood, or bipolar, characterized by alternating periods of depression and mania. Depression is characterized by an inability to experience pleasure, feelings of worthlessness and excessive guilt, alterations in sleeping patterns and appetite, and thoughts of death or suicidal ideation. Mania is characterized by elation, irritability, high distractibility, and, often, engagement in high-risk pleasurable activities. As with schizophrenia, genetic factors appear to play an important role in the development of mood disorders. Neuroimaging techniques have revealed several anatomic and functional abnormalities in different regions of the brain. Abnormalities in neurotransmission also have been implicated in the development and maintenance of depression, including changes in concentration and activity of the neurotransmitters norepinephrine, serotonin, acetylcholine, and GABA. Treatment includes antidepressant drugs and psychotherapy. proximately 15% of all individuals, women more often than men. The common feature of anxiety disorders is increased fearfulness that sometimes is intense. The basic symptoms that are common to all anxiety disorders occur with the activation of the sympathetic cascade through the HPA axis. The core issue with anxiety disorders is that these symptoms occur without a precipitating potentially dangerous event. Anxiety disorders have a higher rate of occurrence among family members, but there is not yet any clearly delineated genetic process. According to the DSMIV-TR classication system, anxiety is subdivided into ve types, depending on clinical characteristics and response to pharmacologic agents. These ve types include panic disorder, post-traumatic stress disorder (PTSD), generalized anxiety disorder, social phobia, and obsessive-compulsive disorder (OCD). See Chapter 9 for the discussion of PTSD. PANIC DISORDER Epidemiologic studies suggest that panic disorder has a lifetime prevalence of between 1.5% and 3%. First-degree relatives of persons with panic disorder have a 3- to 21-fold higher risk for developing panic disorder than unrelated persons.32 Panic disorder is characterized by neurologic symptoms (dizziness or lightheadedness, paresthesias, fainting), cardiac symptoms (tachycardia, chest pain, palpitations), respiratory symptoms (shortness of breath, feeling of smothering or choking), and psychological symptoms (feelings of impending doom, fear of dying, and a sense of unreality). The attacks, which are unexpected and not related to external events, usually last 15 to 30 minutes, but sometimes continue for an hour. Depression may coexist in 40% to 80% of persons with panic disorder.32 Responses to medications suggest that multiple mechanisms and neurotransmitters are involved in initiating the panic attack. Norepinephrine, serotonin, and GABA are the three neurotransmitters most associated with this disorder.32 Persons experiencing panic attacks have been Anxiety Disorders After completing this section of the chapter, you should be able to meet the following objectives: Dene the terms panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder Describe the epidemiology of panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder Describe the manifestations of panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder and the underlying neuropathophysiology of each Cite the diagnostic criteria for panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder according to the DSM-IV-TR classication Describe the treatment for panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder ANXIETY DISORDERS Anxiety disorders constitute a group of disorders that are characterized by intense episodes of fearfulness with symptoms related to activation of the sympathetic nervous system through the hypothalamic-pituitary-adrenal axis. Generalized anxiety disorder is characterized by excessive, uncontrollable worry. Obsessive-compulsive disorder is characterized by repetitive thoughts and compulsions. Panic disorder is characterized by an experience of intense fear with neurologic, cardiac, respiratory, and psychological symptoms. Social phobia is an intense fear reaction to social interaction. Anxiety disorders are extremely common, and the intensity of disability experienced by the person living with anxiety varies widely. Anxiety disorders affect ap- CHAPTER 53 Disorders of Thought, Mood, and Memory 1281 found to have somewhat lower levels of serotonin than do persons with no known mental illness, but the mechanism for that decrease is not known. The SSRIs are effective in the treatment of panic, but full response to medication can easily take 12 or more weeks. The tricyclic antidepressants also may be helpful, but their risk with overdose may limit their use in the treatment of panic in an effort to reduce suicides.47,48 Responses to yohimbine and clonidine indicate that the adrenergic system clearly is involved. Yohimbine, an 2-adrenergic receptor blocker, precipitates panic attacks in persons who are susceptible to the attacks but not in others. This suggests that alterations in the adrenergic system may be part of the etiology of this disorder. The administration of clonidine, an 2-adrenergic agonist, has been shown to block the panic-inducing effect of yohimbine. However, clonidine has not proved to be an efcacious treatment for panic disorder.49 Gamma-aminobutyric acid is the third neurotransmitter system hypothesized to be involved in panic disorder. It has been suggested that persons experiencing panic disorder may have excess inverse agonists to GABA, which is generally an inhibitory transmitter. The benzodiazepines, which act on GABA receptor sites, are effective in the treatment of panic. One of the risks is that of addiction among persons who may have a propensity for substance misuse. There has been some out-of-class use of the GABAergic anticonvulsants in the treatment of panic disorder.49 Many individuals may require the use of more than one class of medication for the management of panic attacks. However, treatment is most effective when psychotherapy focused on cognitive and behavioral changes is included as part of a comprehensive program. If inadequately treated, persons with panic disorder frequently develop phobias, particularly agoraphobia, which can be so debilitating that the person cannot leave his or her house.47,49,50 OBSESSIVE-COMPULSIVE DISORDER Obsessive-compulsive disorder is characterized by obsessions (repeated thoughts) and compulsions (repeated acts), which are attempts to reduce the anxiety associated with the obsessions.51,52 These obsessions are time consuming or distressing to the individual. Usually, the person experiencing the symptoms recognizes that the rituals are unreasonable. For instance, the person may have to recheck the stove many times before she is able to leave for work or may have to check the stairwells repeatedly at work for debris to ensure that no one is injured. Between 2% and 3% of the worlds population has OCD. This disorder is found with equal frequency among men and women, and there is a higher prevalence among family members. The average age of onset is approximately 20 years, although the disorder also may occur in children and, undiagnosed, may appear as behavior problems and angry outbursts that can seem impulsive and may be confused with attention decit or hyperactivity disorders.51,53 There is evidence from CT and MRI studies that patients with OCD have bilaterally smaller caudates.32 There also appear to be consistent physiologic changes represented by increased activity in the anterior cingulate and the caudate. Some studies have suggested increased activity in the thalamus and the putamen as well as a decrease in serotonin activity.53 Treatment of OCD involves a combination of medication (SSRIs or certain tricyclic antidepressants) and psychotherapy. This disorder is particularly amenable to cognitive behavioral therapy. Studies indicate that there are physiologic changes in affected areas in response to this psychotherapeutic intervention.51,52 SOCIAL ANXIETY DISORDER Social anxiety disorder is a generalized or specic, intense, irrational, and persistent fear of being scrutinized or negatively evaluated by others. Diagnostic criteria include the development of symptoms of anxiety when the person is exposed to the feared social situation, recognition by the person that the fear is irrational, avoidance by the person of the social situation, and interference of the anxiety or avoidance behavior with the persons normal routine. The fear must not be related to any physiologic effects of a substance and must be present for at least 6 months.35,49,54 Social phobia is a fairly common disorder with a lifetime prevalence of 3% to 13%, with a slight tendency to occur more often in women than in men. Typically, the onset is between 11 and 19 years of age. The major adverse effects of social anxiety disorder are felt in employment and school, causing a loss of earning power and socioeconomic status. In addition, approximately one half of persons with social phobia also have a drug or alcohol problem. Several drugs have proved efficacious for the treatment of social phobia, including SSRIs, benzodiazepines, and MAOIs. -Adrenergic blockers are useful in specic social performance situations. Social phobia also has been particularly responsive to behavioral and cognitive therapies.35,49,54 GENERALIZED ANXIETY DISORDER In 1980, generalized anxiety disorder was rst recognized as a separate entity from panic disorder in the DSM-III. Since then, the diagnostic criteria have been sharpened in an attempt to improve the ability of practitioners to discriminate the disorder. The central characteristic of generalized anxiety disorder is prolonged (more than 6 months) excessive worry that is not easily controlled by the person. The characteristics of the disorder include muscle tension, autonomic hyperactivity, and vigilance and scanning (exaggerated startle response, inability to concentrate). Drugs that are particularly effective in treating this disorder are the benzodiazepines (chlordiazepoxide, diazepam). These drugs increase the activity of the GABAA receptor, which increases the ow of chloride ions across the cell membrane, hyperpolarizing the membrane and thus inhibiting the ring of target cells.35,49 Other medications used in the treatment of generalized anxiety disorder include antidepressants (tricyclic antidepressants [TCAs], SSRIs, and atypical antidepressants) and -blockers.29,32 1282 UNIT XII Neural Function In summary, anxiety disorders include generalized anxiety, panic disorder, OCD, and social phobia. A common characteristic of the disorders is an intense fear that occurs in the absence of a precipitating dangerous event. The symptoms of anxiety disorders suggest an inappropriate and intense activation of the sympathetic nervous system. Panic disorder is characterized by neurologic, cardiac, respiratory, and psychological symptoms. The central characteristic of generalized anxiety disorder is excessive worry not easily controlled by the person and lasting more than 6 months. OCD is characterized by repetitive thoughts and acts. Social anxiety disorder is a generalized or specic, intense, irrational, and persistent fear of being scrutinized or negatively evaluated by others. Dementia is a syndrome of intellectual deterioration severe enough to interfere with occupational or social performance. It may involve disturbances in memory, language use, perception, and motor skills and may interrupt the ability to learn necessary skills, solve problems, think abstractly, and make judgments. Dementia can be caused by any disorder that permanently damages large association areas of the cerebral hemispheres or subcortical areas subserving memory and learning. The dementias include Alzheimers disease, multi-infarct dementia, Picks disease, Creutzfeldt-Jakob disease, Wernicke-Korsakoff syndrome, and Huntingtons chorea. Depression is the most common treatable illness that may masquerade as dementia, and it must be excluded when a diagnosis of dementia is considered. This is important because cognitive functioning usually returns to baseline levels after depression is treated. Disorders of Memory and Cognition: Dementias After completing this section of the chapter, you should be able to meet the following objectives: ALZHEIMERS DISEASE Dementia of the Alzheimers type occurs in middle or late life and accounts for 50% to 70% of all cases of dementia. The disorder affects approximately 4 million Americans and may be the fourth leading cause of death in the United States.55 The risk for developing Alzheimers disease increases with age, and the prevalence doubles for every 5 years beyond age 65 years.56 As the elderly population in the United States continues to increase, the number of persons with Alzheimers-type dementia also is expected to increase. State the criteria for a diagnosis of dementia Compare the causes associated with Alzheimers disease, vascular dementia, Picks disease, Creutzfeldt-Jakob disease, Wernicke-Korsakoff syndrome, and Huntingtons disease Describe the changes in brain tissue that occur with Alzheimers disease Use the three stages of Alzheimers disease to describe its progress Cite the difference between Wernickes disease and the Korsakoff component of the Wernicke-Korsakoff syndrome State the pros and cons for the presymptomatic use of genetic testing for Huntingtons disease Pathophysiology Alzheimers disease is characterized by cortical atrophy and loss of neurons, particularly in the parietal and temporal lobes (Fig. 53-6). With signicant atrophy, there is ventricular enlargement (i.e., hydrocephalus) from the loss of brain tissue. FIGURE 53-6 Alzheimers disease. (A) Normal brain. (B) The brain of a patient with Alzheimers disease shows cortical atrophy, characterized by slender gyri and prominent sulci. (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1511]. Philadelphia: Lippincott-Raven) CHAPTER 53 Disorders of Thought, Mood, and Memory 1283 The major microscopic features of Alzheimers disease are the presence of amyloid-containing neuritic plaques and neurofibrillary tangles. The neurofibrillary tangles, found in the cytoplasm of abnormal neurons, consist of brous proteins that are wound around each other in a helical fashion. These tangles are resistant to chemical or enzymatic breakdown, and they persist in brain tissue long after the neuron in which they arose has died and disappeared. The senile plaques are patches or at areas composed of clusters of degenerating nerve terminals arranged around a central core of amyloid -peptide (BAP).57 These plaques are found in areas of the cerebral cortex that are linked to intellectual function. BAP is a fragment of a much larger membrane-spanning amyloid precursor protein (APP). The function of APP is unclear, but it appears to be associated with the cytoskeleton of nerve bers. Normally, the degradation of APP involves cleavage in the middle of the BAP portion of the molecule, with both fragments being lost in the extracellular uid. In Alzheimers disease, the APP molecule is cut at both ends of the BAP segment, thereby releasing an intact BAP molecule that accumulates in neuritic plaques as amyloid brils.57 Some plaques and tangles can be found in the brains of older persons who do not show cognitive impairment. The number and distribution of the plaques and tangles appear to contribute to the intellectual deterioration that occurs with Alzheimers disease. In persons with the disease, the plaques and tangles are found throughout the neocortex and in the hippocampus and amygdala, with relative sparing of the primary sensory cortex.58 Hippocampal function in particular may be compromised by the pathologic changes that occur in Alzheimers disease. The hippocampus is crucial to information processing, acquisition of new memories, and retrieval of old memories. The development of neurobrillary tangles in the entorhinal cortex and superior portion of the hippocampal gyrus interferes with cortical input and output, thereby isolating the hippocampus from the remainder of the cortex and rendering it functionless. Neurochemically, Alzheimers disease has been associated with a decrease in the level of choline acetyltransferase activity in the cortex and hippocampus. This enzyme is required for the synthesis of acetylcholine, a neurotransmitter that is associated with memory. The reduction in choline acetyltransferase is quantitatively related to the numbers of neuritic plaques and severity of dementia. Several drugs have been shown to be effective in slowing the progression of the disease by potentiating the available acetylcholine. The drugstacrine, donepezil, rivastigmine, and galantamineinhibit acetylcholinesterase, preventing the metabolism of endogenous acetylcholine. Thus far, such therapy has not halted disease progression, but it can establish a meaningful plateau in decline. It is likely that Alzheimers disease is caused by several factors that interact differently in different persons. Progress on the genetics of inherited early-onset Alzheimers disease shows that mutations in at least three genesthe APP gene on chromosome 21; presenilin-1 (PS1), a gene on chromosome 14; and presenilin-2 (PS2), a gene on chromosome 1 can cause Alzheimers disease in certain families.57,59,60 The APP gene is associated with an autosomal dominant form of early-onset Alzheimers disease, and can be tested clinically. Persons with Down syndrome (trisomy 21) develop the pathologic changes of Alzheimers disease and a comparable decline in cognitive functioning at a relatively young age. Virtually all persons with Down syndrome who survive past 50 years of age develop the full-blown pathologic features of dementia. Because the APP gene is located on chromosome 21, it is thought that the additional dosage of the gene product in trisomy 21 predisposes to accumulation of BAP.57 There is some indication that PS1 and PS2 mutant proteins alter the processing of APP.57 A fourth gene, an allele of the apolipoprotein E gene, APOE e4, has been identied as a risk factor for lateonset Alzheimers disease. Manifestations Alzheimers-type dementia follows an insidious and progressive course. The hallmark symptoms are loss of shortterm memory and a denial of such memory loss, with eventual disorientation, impaired abstract thinking, apraxias, and changes in personality and affect. Three stages of Alzheimers dementia have been identied, each characterized by progressive degenerative changes (Chart 53-1). The rst stage, which may last for 2 to 4 years, is characterized by short-term memory loss that often is difcult to differentiate from the normal forgetfulness that occurs in the elderly, and usually is reported by caregivers and denied by the patient. Although most elderly have trouble retrieving from memory incidental information and proper names, persons CHART 53-1 Stages of Alzheimers Disease Stage 1 Memory loss Lack of spontaneity Subtle personality changes Disorientation to time and date Stage 2 Impaired cognition and abstract thinking Restlessness and agitation Wandering, sundown syndrome Inability to carry out activities of daily living Impaired judgment Inappropriate social behavior Lack of insight, abstract thinking Repetitive behavior Voracious appetite Stage 3 Emaciation, indifference to food Inability to communicate Urinary and fecal incontinence Seizures (From Matteson M.A., McConnell E.S. [1988]. Gerontological nursing [p. 251]. Philadelphia: J.B. Lippincott) 1284 UNIT XII Neural Function with Alzheimers disease randomly forget important and unimportant details. They forget where things are placed, get lost easily, and have trouble remembering appointments and performing novel tasks. Mild changes in personality, such as lack of spontaneity, social withdrawal, and loss of a previous sense of humor, occur during this stage. As the disease progresses, the person with Alzheimers disease enters the second or confusional stage of dementia. This stage may last several years and is marked by a more global impairment of cognitive functioning. During this stage, there are changes in higher cortical functioning needed for language, spatial relationships, and problem solving. Depression may occur in persons who are aware of their decits. There is extreme confusion, disorientation, lack of insight, and inability to carry out the activities of daily living. Personal hygiene is neglected, and language becomes impaired because of difculty in remembering and retrieving words. Wandering, especially in the late afternoon or early evening, becomes a problem. The sundown syndrome, which is characterized by confusion, restlessness, agitation, and wandering, may become a daily occurrence late in the afternoon. Some persons may become hostile and abusive toward family members. Persons who enter this stage become unable to live alone and should be assisted in making decisions about supervised placement with family members or friends or in a community-based facility. Stage 3 is the terminal stage. It usually is relatively short (1 to 2 years) compared with the other stages, but it has been known to last for as long as 10 years.61 The person becomes incontinent, apathetic, and unable to recognize family or friends. It usually is during this stage that the person is institutionalized. that provide support for family and friends have become available, with support from the Alzheimers Disease and Related Disorders Association. Day care and respite centers are available in many areas to provide relief for caregivers and appropriate stimulation for the patient. Although there is no current drug therapy that is curative for Alzheimers disease, some show promise in terms of slowing the progress of the disease. The use of pharmacologic agents such as tacrine, donepezil, rivastigmine, and galantamine has been approved for symptomatic therapy in Alzheimers disease.63 There also is interest in the use of agents such as antioxidants (e.g., vitamin E, ginkgo), antiinammatory agents, and estrogen replacement therapy in women to prevent or delay the onset of the disease. OTHER TYPES OF DEMENTIA Vascular Dementia Dementia associated with cerebrovascular disease does not result directly from atherosclerosis, but rather is caused by multiple infarctions throughout the brainhence the name vascular or multi-infarct dementia. Approximately 20% to 25% of dementias are vascular in origin, and the incidence is closely associated with hypertension. Other contributing factors are arrhythmias, myocardial infarction, peripheral vascular disease, diabetes mellitus, and smoking. The usual onset is between the ages of 55 and 70 years. The disease differs from Alzheimers dementia in its presentation and tissue abnormalities. The onset may be gradual or abrupt, the course usually is stepwise progression, and there should be focal neurologic symptoms related to local areas of infarction. Diagnosis and Treatment Alzheimers disease is essentially a diagnosis of exclusion. There are no peripheral biochemical markers or tests for the disease. The diagnosis can be conrmed only by microscopic examination of tissue obtained from a cerebral biopsy or at autopsy. The diagnosis is based on clinical ndings. Guidelines for the early recognition and assessment of Alzheimers disease have been published by the Agency for Health Care Policy and Research (AHCPR).61 A diagnosis of Alzheimers disease requires the presence of dementia established by clinical examination and documented by results of a Mini-Mental State Examination, Blessed Dementia Test, or similar mental status test; no disturbance in consciousness; onset between ages 40 and 90 years, most often after age 65 years; and absence of systemic or brain disorders that could account for the memory or cognitive decits.62 Brain imaging, CT scan, or MRI is done to exclude other brain disease. Metabolic screening should be done for known reversible causes of dementia such as vitamin B12 deciency, thyroid dysfunction, and electrolyte imbalance. There is no curative treatment for Alzheimers dementia. Drugs are used primarily to slow the progression and to control depression, agitation, or sleep disorders. Two major goals of care are maintaining the persons socialization and providing support for the family. Self-help groups Picks Disease Picks disease is a rare form of dementia characterized by atrophy of the frontal and temporal areas of the brain. The neurons in the affected areas contain cytoplasmic inclusions called Pick bodies. The average age at onset of Picks disease is 38 years. The disease is more common in women than men. Behavioral manifestations may be noticed earlier than memory decits, taking the form of a striking absence of concern and care, a loss of initiative, echolalia (i.e., automatic repetition of anything said to the person), hypotonia, and incontinence. The course of the disease is relentless, with death ensuing within 2 to 10 years. The immediate cause of death usually is infection. Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease is a rare transmissible form of dementia thought to be caused by an infective protein agent called a prion64 (see Chapter 18). Similar diseases occur in animals, including scrapie in sheep and goats and bovine spongiform encephalitis (BSE; mad cow disease) in cows. The pathogen is resistant to chemical and physical methods commonly used for sterilizing medical and surgical equipment. The disease reportedly has been transmitted through corneal transplants and human growth hormone obtained from cadavers. The National Hormone and Pituitary Program halted the distribution of human pituitary CHAPTER 53 Disorders of Thought, Mood, and Memory 1285 hormone in 1985 after reports that three young persons who had received the hormone had died of CreutzfeldtJakob disease.65 Creutzfeldt-Jakob disease causes degeneration of the pyramidal and extrapyramidal systems and is distinguished most readily by its rapid course. Affected persons usually are demented within 6 months of onset. The disease is uniformly fatal, with death often occurring within months, although a few persons may survive for several years.65 The early symptoms consist of abnormalities in personality and visual-spatial coordination. Extreme dementia, insomnia, and ataxia follow as the disease progresses.64 Wernicke-Korsakoff Syndrome Wernicke-Korsakoff syndrome most commonly results from chronic alcoholism. Wernickes disease is characterized by acute weakness and paralysis of the extraocular muscles, nystagmus, ataxia, and confusion. The affected person also may have signs of peripheral neuropathy. The person has an unsteady gait and complains of diplopia. There may be signs attributable to alcohol withdrawal such as delirium, confusion, and hallucinations. This disorder is caused by a deciency of thiamine (vitamin B1), and many of the symptoms are reversed when nutrition is improved with supplemental thiamine. The Korsakoff component of the syndrome involves the chronic phase with severe impairment of recent memory. There often is difculty in dealing with abstractions, and the persons capacity to learn is defective. Confabulation (i.e., recitation of imaginary experiences to ll in gaps in memory) probably is the most distinctive feature of the disease. Polyneuritis also is common. Unlike Wernickes disease, Korsakoffs psychosis does not improve signicantly with treatment. Depression and personality changes are the most common early psychological manifestations; memory loss often is accompanied by impulsive behavior, moodiness, antisocial behavior, and a tendency toward emotional outbursts.67 Other early signs of the disease are lack of initiative, loss of spontaneity, and inability to concentrate. Fidgeting or restlessness may represent early signs of dyskinesia, followed by choreiform and some dystonic posturing. Eventually, progressive rigidity and akinesia (rather than chorea) develop in association with dementia. Symptoms of juvenile onset include dystonias and seizures. There is no cure for Huntingtons disease. The treatment is largely symptomatic. Drugs may be used to treat the dyskinesias and behavioral disturbances. Study of the genetics of Huntingtons disease led to the discovery that the gene for the disease is located on chromosome 4.57 The discovery of a marker probe for the gene locus has enabled testing that can predict whether a person will develop the disease. In summary, cognitive disorders can be caused by any disorder that permanently damages large cortical or subcortical areas of the hemispheres, including Alzheimers disease, vascular dementia, Picks disease, Creutzfeldt-Jakob disease, Wernicke-Korsakoff syndrome, and Huntingtons disease. Multiinfarct dementia is associated with vascular disease, and Picks disease with atrophy of the frontal and temporal lobes. Creutzfeldt-Jakob disease is a rare transmissible form of dementia. Wernicke-Korsakoff syndrome most often results from chronic alcoholism. Huntingtons disease is a hereditary disorder characterized by chronic and progressive chorea, psychological change, and dementia. By far the most common cause of dementia (50% to 70%) is Alzheimers disease. The condition is a major health problem among the elderly. It is characterized by cortical atrophy and loss of neurons, the presence of neuritic plaques, granulovacuolar degeneration, and cerebrovascular deposits of amyloid. The disease follows an insidious and progressive course that begins with memory impairment and terminates in an inability to recognize family or friends and the loss of control over bodily functions. The particular tragedy of Alzheimers disease and other related dementias is that they dissolve the mind and rob the victim of humanity. Simultaneously, these disorders devastate the lives of spouses and other family members, who must endure an insidious loss of the person and a valued relationship. Huntingtons Disease Huntingtons disease is a hereditary disorder characterized by chronic progressive chorea, psychological changes, and dementia. Although the disease is inherited as an autosomal dominant disorder, the age of onset most commonly is in the fourth and fth decades.1 By the time the disease has been diagnosed, the person often has passed the gene on to his or her children. Approximately 10% of the Huntingtons cases involve juvenile onset.66 Children with the disease rarely live to adulthood. Huntingtons disease produces localized death of brain cells. The first and most severely affected neurons are of the caudate nucleus and putamen of the basal ganglia. The neurochemical changes that occur with the disease are complex. The neurotransmitter GABA is an inhibitory neurotransmitter in the basal ganglia. Postmortem studies have shown a decrease of GABA and GABA receptors in the basal ganglia of persons dying of Huntingtons disease. Likewise, the levels of acetylcholine, an excitatory neurotransmitter in the basal ganglia, are reduced in persons with Huntingtons disease. The dopaminergic pathway of the nigrostriatal system, which is affected in parkinsonism, is preserved in Huntingtons disease, suggesting that an imbalance in dopamine and acetylcholine may contribute to manifestations of the disease. REVIEW EXERCISES A 45-year-old woman was brought to the emergency room after being picked up by the police. She was wandering in and out of trafc saying someone was after her and was recognized as a homeless person. Her appearance is dirty and disheveled, and she is wearing several layers of clothing although it is July. She smacks her lips and at times does not seem to understand questions. 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Disorders of thought and volition: Schizophrenia. In Kandel E.R., Schwartz J.H., Jessel T.M. (Eds.), Principles of neural science (4th ed., pp. 11881207). New York: McGraw-Hill. Marken P.A., Stanislav S.W. (2001). Schizophrenia. In KodaKimble M.A., Young L.L. (Eds.), Applied therapeutics (7th ed., pp. 76-176-40). Philadelphia: Lippincott Williams & Wilkins. Torrey E.F. (1988). Surviving schizophrenia: A family manual. New York: Harper & Row. Turner T. (1997). ABC of mental health: Schizophrenia. British Medical Journal 315, 108111. repeats the words of her questioner. She has a 20-year history of schizophrenia with multiple admissions. A. List the positive and negative signs she exhibits as well as others not listed. B. What are the brain areas and transmitters responsible for these signs? C. What are the DSM-IV-TR criteria that would have led to her diagnosis? A 35-year-old woman was recently admitted with suicidal tendencies shortly after a diagnosis of major depression. She had lost 40 pounds in the past 6 months. She appears tired and supplies only short answers to questions. She complains of dizziness and informs the nurse that it is not her business to discuss her suicidal thoughts. Her husband says she relies heavily on alcohol. A. Describe some of her manifestations. Why is she using alcohol? B. Provide an explanation for her tiredness. C. What areas of the brain and transmitters are involved in depression? How is it different from mania? D. What is the possible role of thyroid and adrenal hormones? A 40-year-old woman is seen in the emergency room in a state of severe panic. She has had panic attacks for several months and had not sought treatment until her husband came home and found her sitting in the bedroom unable to move. She had been there all day and had soiled her clothing. In the emergency room she appeared frightened and paced in one area. She had difculty understanding questions and cooperated as long as she could pace. 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EUST2011ReadingAssignmentICliffNgChunKeung 2008206894AftertheMiddleAges,fromthe16thcenturytothebeginningofthe 20thcentury,therewasagreatchangeinattitudetowardstherelations betweenthesexesinEurope.Inthe16thcentury,anincreaseinthefeelingof shamesurroundin
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Cliff Ng Chun K eung The Sexual Revolution is known as one of the greatest social U ST2011 Reading Assignment I I 2008206894 revolution in the 20th century. Although whether the Sexual Revolution is revolutionary in nature or not is still in debate, the i
CUHK - FIN - FIN4160
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
APPLE BLOSSOM I nformation is automatically updated COLOGNE COMPANY Journal Entry & General L edger update Flowchart of Financial Reporting Cycle (Integration of Accounting Process)Sales Order Entry And Accts Rec. (A/R & Sales) Cash Recepts (Cash & A/R)
St. Johns - ACC - 639
Apple Blossom Cologne Company CashMailroom ClerkA/R cash collection Prelist 1, 2, 3 Checks Prelist 2 ChecksAccounts Receivable ClerkClerkControllerPrelist 3 Deposit Ticket Cash receipts Journal A/R posting ReportTreasurerDeposit Ticket 3 Deposit T
St. Johns - ACC - 639
Remittance A dvice A/R Posting ReportAdvice Prelist Deposit Ticket Cash Posting ReportA/R Files RemittanceTicket the moneyPrelist 2 Deposit Checks Cash Remittance AdvicecopyJournal ChecksChecks DepositCash ReceiptReceiptChecks DepositTicket Cash Module Re
St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
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St. Johns - ACC - 639
AppleBlossomCologneCompany AccountsReceivableandCreditSalesInternalControl 1/12/2004 InternalControlWeaknessesCreditSalessystem 1. ArecustomersubsidiaryledgersmaintainedbyapersonwhohasnoaccesstoCash? a. No,theaccountsReceivableclerkgasaccesstocustomerchec