Download Disorders of Thought, Mood, and Memory

CHAPTER
53
Disorders of Thought,
Mood, and Memory
Sandra Kawczynski Pasch
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
Alzheimer’s Disease
Pathophysiology
Manifestations
Diagnosis and Treatment
Other Types of Dementia
Vascular Dementia
Pick’s Disease
Creutzfeldt-Jakob Disease
Wernicke-Korsakoff Syndrome
Huntington’s Disease
P
sychiatric disorders are characterized by changes in a
person’s 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 find 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:
✦ Define the terms biologic psychiatry and psychosocial psychiatry and compare them in terms of their definitions
of the origins of mental disease
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✦ 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 influences 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., Wernicke’s aphasia), it provided little help to the
clinical psychiatrist of the time. Emil Kraepelin, a German
psychiatrist, was the first 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 conflicts over events in an individ-
ual’s 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 therapist–client 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?
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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 influences of genetic and environmental factors on neural development and function.
Since the early 1990s, the scientific 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 influence 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.4–6 The overwhelming conclusions of these studies have been that
both genetic vulnerability and environmental influences
play significant 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
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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 influence 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 gene–gene interactions that influence 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 person’s 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.
Anatomic and Neurochemical Basis
of Behavior
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ 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
✦ Define the terms synapse, synaptic transmission, and
neuromediators
✦ 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 scientific 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 influence each other’s 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.
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 (Wernicke’s
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.
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TABLE 53-1
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Selected Functions of Several Brain Regions
Frontal Lobe
Temporal Lobe
Parietal Lobe
Occipital Lobe
Abstract vs. concrete reasoning
Motivation–volition
Concentration
Decision making
Purposeful behavior
Memory and historical sense
of self
Sequencing
Making meaning of language
Speech organization
Speech production
(Broca’s area)
Aspects of emotional
response—blunting
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
Sensory integration and spatial
relations
Bodily awareness
Filtration of background stimuli
Personality factors and
symptom denial
Memory and nonverbal
memory
Concept formation
Vision
Possible information
holding area
Central fissure
(Rolando)
Parietal lobe
Frontal lobe
Parieto-occipital
fissue
Occipital
lobe
(Sylvius)
Temporal lobe
Cingulate
gyrus
Prefrontal
lobe
Transverse
fissure
Corpus callosum
Anterior nucleus
of thalamus
Fornix
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 “fine-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 first
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 one’s body. Another important parietal lobe
function is to filter out extraneous information. The ability
to filter out background and extraneous noise and sensations is critical to normal daily functioning.
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
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FIGURE 53-2 Map of specific functional areas in the cerebral cortex,
showing especially Wernicke’s and Broca’s 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 Broca’s 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 significant
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
Alzheimer’s 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, sleep–rest patterns, hunger, sexual drive, and hormonal secretion.
PHYSIOLOGY OF PERCEPTION, THOUGHT,
AND MEMORY
Perception is the final 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 fibers 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 reflexive 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 specific cortical dysfunctions but also
may experience difficulty in the proposed pathways for
learning and memory. These difficulties are likely to influence their behavior and may have an impact on the design
of effective interventions.
CHAPTER 53
Thought processes probably involve a pattern of stimuli from many parts of the nervous system at the same time
and in a definite 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 Broca’s area for word formation
and Wernicke’s 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 classification, memory can be classified
as short-term, intermediate-term, or long-term. Short-term
memory is typically confined 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-
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1271
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 classified 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 classified 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 classification 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.
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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 person’s 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 confined to a single sensory modality.
Delusions are formed from and colored by an individual’s background, including personal, family, and social experiences; educational background; and cultural
(including religious) influences. Delusional thinking may
include, among others, delusions of persecution (e.g., believing one’s self or property is being threatened), influence
(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 one’s 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
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-
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 efficacious in calming agitated persons with
schizophrenia and bipolar disorders. It eventually became
clear that chlorpromazine was not simply a tranquilizer
but also had some specific 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, exemplified first 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 refined
blockade action. The atypical antipsychotics also exert
some of their effects through blockade of serotonin (5-HT)
receptors.
CHAPTER 53
TABLE 53-2
Disorders of Thought, Mood, and Memory
1273
The Source and Effect of Brain Neuromediators
Neuromediator
Major Source in the Brain
Effect and Implications for Mental Illness
Acetylcholine (Ach)
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
Can be excitatory or inhibitory, depending on
the area of the brain
Underactivity implicated in Alzheimer’s disease
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
γ-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
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
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 flow 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 fine 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
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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 flow 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 specific cortical dysfunctions but also may experience difficulty in the proposed
pathways for learning and memory. These difficulties are likely
to influence 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 efficacious psychotropic drugs.
Disorders of Thought and Volition
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Define 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 classification
✦ 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 (first-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 influenza
infection, and early history of attentional deficits.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.23–26
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 figure (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 Sadock’s 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.23–25,27
The negative symptoms of schizophrenia reflect 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
flattening (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 deficits 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
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complete activities of daily living. The person also may
have cognitive and psychomotor deficits. 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
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 specific 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 finding 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-
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
D-aspartate
Diagnostic Criteria
According to the DSM-IV-TR classification system, a diagnosis of schizophrenia requires that two or more of the following symptoms must be present for a significant 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 significantly impaired compared with premorbid
abilities, and continuous signs of the disturbance must
persist for at least 6 months.31
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 reflect the absence of the normal social and interpersonal relationships
such as lack of motivation, apathy, and affective flattening
of emotional expression.
CHAPTER 53
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.
Disorders of Mood
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Define 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 classification
✦ 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 classified
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-
Disorders of Thought, Mood, and Memory
1277
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.35–38
As with schizophrenia, genetic factors appear to play
an important role in the development of mood disorders.
Several studies have identified genetic loci that 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 classified 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 first 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 individual’s
independence and quality of life.
Unipolar Depression. Unipolar depression has various
subclassifications 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 significant 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 classification 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 specifier
is applied if symptoms of major depression persist for
2 years or longer. A postpartum specifier is included if the
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Neural Function
onset is within 4 weeks of childbirth. Dysthymic disorder,
a type of unipolar depression that is not classified as a
major depression, is characterized by a persistent but mild
depression that lasts longer than 2 years.35–37
Bipolar Depression. Bipolar depression, or manic-depressive
illness, also has multiple subclassifications, 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, inflated 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 fluctuates 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.
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 flow 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 disorders—with 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 influence 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 flat 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 specific type of depression known as seasonal
affective disorder (SAD) is triggered for persons in the win-
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 specific 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 sleep–wake 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 finding 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
first manic episode to occur when someone “pulls an allnighter” studying for final 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.
Diagnostic Criteria
The DSM-IV-TR diagnostic criteria for a major depressive
episode include the simultaneous presence of five or more
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.35–37,46 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. Lithium’s 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 efficacious in the treatment of bipolar depression, although
the mechanism by which the drugs work is not completely
understood.
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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 classified 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.
Anxiety Disorders
After completing this section of the chapter, you should be able to
meet the following objectives:
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 classification system, anxiety is subdivided into five
types, depending on clinical characteristics and response
to pharmacologic agents. These five 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
✦ Define 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 classification
✦ Describe the treatment for panic disorder, generalized
anxiety disorder, social phobia, and obsessive-compulsive
disorder
Anxiety disorders are extremely common, and the
intensity of disability experienced by the person living
with anxiety varies widely. Anxiety disorders affect ap-
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.
CHAPTER 53
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
α2-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 α2-adrenergic agonist, has
been shown to block the panic-inducing effect of yohimbine. However, clonidine has not proved to be an efficacious 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
GENERALIZED ANXIETY DISORDER
In 1980, generalized anxiety disorder was first 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 flow of chloride ions across the cell membrane, hyperpolarizing the membrane and thus inhibiting
the firing 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 β-blockers.29,32
Disorders of Thought, Mood, and Memory
1281
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 world’s 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
deficit 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 specific, 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 person’s 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. β-Adrenergic blockers are useful in specific social performance situations. Social phobia also has
been particularly responsive to behavioral and cognitive
therapies.35,49,54
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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 specific, intense, irrational, and persistent fear
of being scrutinized or negatively evaluated by others.
Disorders of Memory and Cognition:
Dementias
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ State the criteria for a diagnosis of dementia
✦ Compare the causes associated with Alzheimer’s disease,
✦
✦
✦
✦
vascular dementia, Pick’s disease, Creutzfeldt-Jakob
disease, Wernicke-Korsakoff syndrome, and
Huntington’s disease
Describe the changes in brain tissue that occur with
Alzheimer’s disease
Use the three stages of Alzheimer’s disease to describe
its progress
Cite the difference between Wernicke’s disease and the
Korsakoff component of the Wernicke-Korsakoff
syndrome
State the pros and cons for the presymptomatic use of
genetic testing for Huntington’s disease
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
Alzheimer’s disease, multi-infarct dementia, Pick’s disease,
Creutzfeldt-Jakob disease, Wernicke-Korsakoff syndrome,
and Huntington’s 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.
ALZHEIMER’S DISEASE
Dementia of the Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s-type dementia also is expected
to increase.
Pathophysiology
Alzheimer’s disease is characterized by cortical atrophy
and loss of neurons, particularly in the parietal and temporal lobes (Fig. 53-6). With significant atrophy, there is
ventricular enlargement (i.e., hydrocephalus) from the loss
of brain tissue.
FIGURE 53-6 Alzheimer’s disease.
(A) Normal brain. (B) The brain of
a patient with Alzheimer’s 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
The major microscopic features of Alzheimer’s disease
are the presence of amyloid-containing neuritic plaques
and neurofibrillary tangles. The neurofibrillary tangles,
found in the cytoplasm of abnormal neurons, consist of
fibrous 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 flat areas composed of clusters of degenerating nerve terminals arranged
around a central core of amyloid β-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 fibers. 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 fluid. In Alzheimer’s
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 fibrils.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 Alzheimer’s 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 Alzheimer’s disease. The
hippocampus is crucial to information processing, acquisition of new memories, and retrieval of old memories.
The development of neurofibrillary 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, Alzheimer’s 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 drugs—tacrine, donepezil, rivastigmine, and galantamine—inhibit 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 Alzheimer’s disease is caused by several
factors that interact differently in different persons. Progress
on the genetics of inherited early-onset Alzheimer’s disease
shows that mutations in at least three genes—the APP gene
on chromosome 21; presenilin-1 (PS1), a gene on chromosome 14; and presenilin-2 (PS2), a gene on chromosome 1—
can cause Alzheimer’s disease in certain families.57,59,60 The
Disorders of Thought, Mood, and Memory
1283
APP gene is associated with an autosomal dominant form
of early-onset Alzheimer’s disease, and can be tested clinically. Persons with Down syndrome (trisomy 21) develop
the pathologic changes of Alzheimer’s 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 identified as a risk factor for lateonset Alzheimer’s disease.
Manifestations
Alzheimer’s-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
Alzheimer’s dementia have been identified, each characterized by progressive degenerative changes (Chart 53-1). The
first stage, which may last for 2 to 4 years, is characterized by
short-term memory loss that often is difficult 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 Alzheimer’s 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
that provide support for family and friends have become
available, with support from the Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s disease.63 There also is interest in the use of
agents such as antioxidants (e.g., vitamin E, ginkgo), antiinflammatory agents, and estrogen replacement therapy in
women to prevent or delay the onset of the disease.
with Alzheimer’s 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 Alzheimer’s
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 deficits. 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 difficulty 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.
Dementia associated with cerebrovascular disease does not
result directly from atherosclerosis, but rather is caused by
multiple infarctions throughout the brain—hence 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 Alzheimer’s 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
Pick’s Disease
Alzheimer’s disease is essentially a diagnosis of exclusion.
There are no peripheral biochemical markers or tests for
the disease. The diagnosis can be confirmed only by microscopic examination of tissue obtained from a cerebral
biopsy or at autopsy. The diagnosis is based on clinical
findings. Guidelines for the early recognition and assessment of Alzheimer’s disease have been published by the
Agency for Health Care Policy and Research (AHCPR).61 A
diagnosis of Alzheimer’s 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 deficits.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 deficiency, thyroid dysfunction,
and electrolyte imbalance.
There is no curative treatment for Alzheimer’s 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 person’s socialization and providing support for the family. Self-help groups
Pick’s 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 Pick’s
disease is 38 years. The disease is more common in women
than men. Behavioral manifestations may be noticed earlier than memory deficits, 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.
OTHER TYPES OF DEMENTIA
Vascular Dementia
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
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. Wernicke’s 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 deficiency 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 difficulty in dealing with abstractions,
and the person’s capacity to learn is defective. Confabulation (i.e., recitation of imaginary experiences to fill in gaps
in memory) probably is the most distinctive feature of the
disease. Polyneuritis also is common. Unlike Wernicke’s
disease, Korsakoff’s psychosis does not improve significantly with treatment.
Huntington’s Disease
Huntington’s 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 fifth 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 Huntington’s cases involve juvenile onset.66 Children
with the disease rarely live to adulthood.
Huntington’s 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 Huntington’s disease.
Likewise, the levels of acetylcholine, an excitatory neurotransmitter in the basal ganglia, are reduced in persons
with Huntington’s disease. The dopaminergic pathway of
the nigrostriatal system, which is affected in parkinsonism, is preserved in Huntington’s disease, suggesting that
an imbalance in dopamine and acetylcholine may contribute to manifestations of the disease.
Disorders of Thought, Mood, and Memory
1285
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 Huntington’s disease. The treatment is largely symptomatic. Drugs may be used to treat
the dyskinesias and behavioral disturbances. Study of the
genetics of Huntington’s 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 Alzheimer’s disease,
vascular dementia, Pick’s disease, Creutzfeldt-Jakob disease,
Wernicke-Korsakoff syndrome, and Huntington’s disease. Multiinfarct dementia is associated with vascular disease, and
Pick’s 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. Huntington’s 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 Alzheimer’s 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
Alzheimer’s 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.
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 traffic 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. Periodically she laughs for no apparent reason and often
1286
UNIT XII
Neural Function
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?
6.
7.
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?
8.
9.
10.
11.
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?
12.
D. What is the possible role of thyroid and adrenal
hormones?
13.
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 difficulty understanding questions and cooperated as long
as she could pace. The husband relates that his wife had
been under much stress in her job and had recently lost
some important clients.
14.
A. What are some manifestations of her panic?
18.
B. What is the biologic cause of anxiety disorders—the
brain structures and neurotransmitters?
19.
C. Describe the physiologic manifestations of a panic
attack.
15.
16.
17.
20.
21.
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