Schizophrenia: Textbook of Psychiatry

The American Psychiatric Publishing
TEXTBOOK OF PSYCHIATRY
Fifth Edition
Edited by Robert E. Hales, M.D., M.B.A., Stuart C. Yudofsky, M.D., Glen O. Gabbard, M.D.
© 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
CHAPTER 10
Schizophrenia
Michael J. Minzenberg, M.D., Jong H. Yoon, M.D.,
Cameron S. Carter, M.D.
Slide show includes…

Topic Headings
Tables and Figures
Key Points
The American Psychiatric Publishing Textbook of Psychiatry, Fifth Edition. Edited by Hales RE, Yudofsky SC, 1
Gabbard GO. © 2008 American Psychiatric Publishing, Inc. All rights reserved. www.appi.org
CHAPTER 10 • Topic Headings
Treatment of First-Episode
HISTORICAL OVERVIEW ETIOLOGY AND PATHOPHYSIOLOGY
Psychosis
Genetics
CLINICAL FEATURES Maintenance Treatment in
Environmental Factors
Positive Symptoms Schizophrenia
Neurochemical Factors
Hallucinations Treatment-Refractory Schizophrenia
Dopamine
Delusions Other Adjunctive Biological
Other Monoamines
Negative Symptoms Treatments for Schizophrenia
Glutamate and N-Methyl-D-Aspartate
Affective Deficits Psychosocial Treatments for
Gamma-Aminobutyric Acid
Social Deficits Schizophrenia
Anatomical and Histological Studies
Cognitive Deficits Overview: The Importance of
Cognitive and Information Processing
Disorganization Integrated Treatment for
Deficits
Cognitive Impairment Schizophrenia
Early Sensory-Processing Deficits
Soft Neurological Signs Case Management and Assertive
Affect Processing
SUBTYPES OF SCHIZOPHRENIA Community Treatment
Social Cognition
Paranoid Schizophrenia Cognitive-Behavioral Therapy
Functional Neuroimaging
Disorganized Schizophrenia Cognitive Remediation and
Functional Imaging Studies of
Catatonic Schizophrenia Rehabilitation
Higher-Order Cognitive Deficits
Undifferentiated Schizophrenia Social Skills–Based Therapies
Neural Basis of Symptoms
Residual Schizophrenia Vocational Rehabilitation
INTERVENTION AND MANAGEMENT Family Therapy
DIAGNOSIS Antipsychotic Medications Individual Psychotherapy
DIFFERENTIAL DIAGNOSIS Brief History of Antipsychotic
RELATED PSYCHOTIC DISORDERS
Development
CLINICAL COURSE Schizoaffective Disorder
Mechanism of Action
Premorbid Functioning Delusional Disorder
Clinical Comparison of Second-
Prodrome to Schizophrenia Schizophreniform Disorder and
Generation Antipsychotics With
Early Period of Psychotic Brief Psychotic Disorder
First-Generation Antipsychotics
Illness in Schizophrenia Treatment of Acute Psychosis CONCLUSION
Long-Term Outcome
CHAPTER 2 • Tables and Figures
Table 10–1. Major symptoms in schizophrenia

Table 10–2. DSM-IV-TR diagnostic criteria for schizophrenia
Table 10–3. Soft neurological signs most frequently assessed in schizophrenic patients
Table 10–4. DSM-IV-TR subtypes of schizophrenia
Table 10–5. Differential diagnosis of schizophrenia
Figure 10–1. Natural course of schizophrenia.
Figure 10–2. Candidate schizophrenia genes.
Figure 10–3. Positron emission tomography (PET) images of cognition.
Figure 10–4. Chandelier cell ultrastructure and physiology.
Table 10–6. Certainty and doubt in schizophrenia neuropathology
Figure 10–5. Relation between disorganization symptoms and change in signal intensity in right dorsolateral
prefrontal cortex as a function of working memory load for 17 patients with schizophrenia.
Figure 10–6. Activation of Heschl’s gyrus during auditory hallucinations and in response to acoustical stimulation.
Table 10–7. Relative neurotransmitter receptor affinities for antipsychotics at therapeutic doses
Summary Key Points
Although active debate continues on the relative merits and validity of the various symptom
classification systems that have been proposed, in this chapter we mostly rely on a scheme that
segregates clinical findings into positive, negative, and disorganized symptoms (Table 10–1). This
system is simple and has received empirical validation in factor analytic studies. The term positive
symptom refers to the presence of abnormal mental processes, whereas negative symptom refers to
the absence of normal mental function. The disorganized category refers to the linguistic and
behavioral abnormalities.
TABLE 10–1. Major symptoms in schizophrenia
Three positive symptoms of schizophrenia are generally recognized: hallucinations, delusions, and
disorganized speech or behavior (often referred to as thought disorder). The fact that the presence
of certain types of hallucinations and delusions satisfies criterion A of the DSM-IV-TR (American
Psychiatric Association 2000) criteria for schizophrenia (Table 10–2) reflects the relative importance
placed on these two symptoms.
TABLE 10–2. DSM-IV-TR diagnostic criteria for schizophrenia
(continued)
TABLE 10–2. (continued)
In modern research, substantial and growing evidence now indicates a higher prevalence of
subtle neurological deficits—most notably, the so-called soft neurological signs (e.g., motor
dyscoordination)—in schizophrenia patients (Table 10–3).
TABLE 10–3. Soft neurological signs most frequently assessed in schizophrenic patients
Source. Reprinted from

Bombin I, Arango C,
Buchanan RW: “Significance
and Meaning of Neurological
Signs in Schizophrenia: Two
Decades Later.”
Schizophrenia Bulletin
31:962–977, 2005 (Table 1
[p. 963]). Copyright 2005,
Oxford University Press.
Used with permission.
DSM-IV-TR recognizes five subtypes of schizophrenia:
paranoid, disorganized, catatonic, undifferentiated, and
residual (Table 10–4).
TABLE 10–4. DSM-IV-TR subtypes of schizophrenia
The diagnosis of schizophrenia continues to rest solely on the history of illness and a thorough
mental status examination (Table 10–5).
TABLE 10–5.
Differential
diagnosis of
schizophrenia
(continued)
TABLE 10–5. (continued)
Any description of the clinical course of schizophrenia should address periods of development occurring
well before the onset of overt psychotic symptoms, especially given the neurodevelopmental perspective
on this illness (Figure 10–1). Good evidence indicates that in groups of individuals who will later develop
schizophrenia, some signs are present long before onset of psychosis, as early as childhood. These signs
tend to be subtle and do not warrant a diagnosis of any particular psychiatric disorder.
FIGURE 10–1. Natural course of schizophrenia.
Note. Asterisks indicate critical periods for early detection or intervention.
Source. Keshavan MS, Hogarty GE: “Brain Maturational Processes and Delayed Onset in Schizophrenia.” Development and Psychopathology 11:525–543, 1999
(Figure 1 [p. 526]). Copyright 1999. Reprinted with the permission of Cambridge University Press.
In the past 10 years, with the development of novel study designs and high-throughput methods, we
have witnessed a tremendous proliferation in the number of putative schizophrenia risk genes (Figure
10–2). An interesting aspect of this list is that many of these genes are related to neurodevelopmental
processes involved in the establishment of neural networks (e.g., neuronal migration and synapse
formation or the regulation of synaptic transmission).
FIGURE 10–2. Candidate

schizophrenia genes.
Linkages that reached

genomewide significance on their
own (red) or those that have
received strong support from
more than one sample (blue) are
shown. The red arrows refer to
the location of chromosomal
abnormalities associated with
schizophrenia. The yellow arrows
and circles show the locations of
the genes discussed in the source
article (Owen et al. 2005).
Source. Reprinted from Owen MJ, Craddock N,

O’Donovan MC: “Schizophrenia: Genes at Last?”
Trends in Genetics 21:518–525, 2005 (Figure 1
[p. 520]). Copyright 2005, Elsevier Limited.
Used with permission.
Neuroimaging has made significant contributions to our evolving understanding of the
neurochemical basis for schizophrenia. Imaging modalities such as positron emission tomography
(PET) and single photon emission computed tomography (SPECT) are allowing researchers to
assess the functional status of neurotransmitter systems (Figure 10–3).
FIGURE 10–3. Positron emission tomography (PET) images of cognition.
The PET image represents the activity recorded from 30 to 60 minutes after injection of 13.3 mCi in a 37-year-old
healthy female volunteer. A, B, Sagittal view, illustrating the contrast between cortical and cerebellar activities.
C, D, Transaxial view, at the level of the head of caudate, putamen, and thalamus. E, F, Coronal view, at the
level of the anterior striatum, illustrating the lower level of activity in the ventral striatum compared with the
caudate and putamen. G, H, Coronal view, at the level of the hippocampus, illustrating low levels of activity in
thalamus, hippocampus, and parahippocampal gyrus. Putamen and caudate activities are still visualized. NNC
112 = (+)-5-
(7-benzofuranyl)-8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Source. Reprinted from Abi-Dargham A, Mawlawi O, Lombardo I, et al.: “Prefrontal Dopamine D 1 Receptors and Working Memory in Schizophrenia.” Journal of
Neuroscience 22:3708–3719, 2002 (Figure 3 [p. 3713]). Copyright 2002, Society for Neuroscience. Used with permission.
FIGURE 10–3. (enlarged)
Source. Reprinted from Abi-Dargham A, Mawlawi O, Lombardo I, et al.: “Prefrontal Dopamine D 1 Receptors and Working Memory in Schizophrenia.” Journal of
Neuroscience 22:3708–3719, 2002 (Figure 3 [p. 3713]). Copyright 2002, Society for Neuroscience. Used with permission.
Chandelier cells can terminate on several hundreds of pyramidal cells, setting the stage for the
synchronization of many cells (Figure 10–4). Together with wide arbor cells, chandelier cells are thought to
coordinate the fine control of the synchrony and spatial extent of pyramidal cell activity in the prefrontal
cortex. The disruption of these functions in schizophrenia would be expected to lead to the loss of temporal
and spatial organization in neuronal activity necessary for higher-order cognitive processes.
FIGURE 10–4. Chandelier cell

ultrastructure and physiology.
(a) Electron micrographs of two of the multiple boutons (labeled b1 and b2,3) from an electrophysiologically
recorded, biocytin-filled axo-axonic cell (AAC) synapsing on the biocytin-filled axonal initial segment (AIS) of a
postsynaptic pyramidal cell. Arrows indicate synaptic contacts. Note the morphological differences between the
boutons. (b) Firing pattern of two AACs from rat hippocampus in response to a 500-ms depolarizing pulse. Note
that (i) shows a nonadapting pattern, whereas (ii) shows a strongly adapting pattern, documenting that AAC
physiology is heterogeneous, even within one species and brain area.
(c,d) Theta waves (c) and fast ripples (d) in the stratum pyramidale. Extracellularly recorded theta waves and fast
ripples are shown in the upper parts of (c,i) and (d,i), respectively, above the simultaneous juxtacellular spike
rasters of single AACs in each case. (c,ii) Stratum pyramidale extracellular (black) and pyramidal cell intracellular
(blue) theta rhythms, corresponding to histograms of spike firing probability in pyramidal cells (blue) and AACs
(red), averaged over several cells. Note that AAC firing is antiphase to pyramidal cell intracellular theta waves and
firing but only slightly phase-delayed from extracellular theta waves. (d,ii) Extracellular fast ripples and
concomitant spike firing probability in pyramidal cells (blue) and AACs (red), averaged over several cells. Note that
AACs increase firing probability just before the fast ripple and depress firing after the fast ripple. Scale bars in (c,i):
unit, 0.5 mV; theta, 0.2 mV; time, 300 ms. Scale bars in (d,i): unit, 0.5 mV; fast ripple, 0.1 mV; time, 50 ms.
Source. Reprinted from Howard A, Tamas G, Soltesz I: “Lighting the Chandelier: New Vistas for Axo-Axonic Cells.” Trends in Neurosciences 28:310–316, 2005 (Figure 3
[p. 313]). Copyright 2005, Elsevier Limited. Used with permission.
Source. Reprinted from Howard A, Tamas G, Soltesz I: “Lighting the Chandelier: New Vistas for Axo-Axonic Cells.” Trends in Neurosciences 28:310–316, 2005 (Figure 3
[p. 313]). Copyright 2005, Elsevier Limited. Used with permission.
The emergence of modern neuroimaging and molecular
techniques has led to a renewed interest in the study of
structural abnormalities in the brains of individuals with
schizophrenia. Neuroimaging studies have shown consistent
evidence of whole-brain volume deficits, and modern
neuropathology studies have uncovered provocative clues
pointing to alterations in the microscopic neuroanatomy in
schizophrenia (Table 10–6).
TABLE 10–6. Certainty and doubt in

schizophrenia neuropathology
Source. Reprinted from Harrison PJ: “The Neuropathology of Schizophrenia: A

Critical Review of the Data and Their Interpretation.” Brain 122 (Pt 4):593–624, 1999
(Table 8 [p. 611]). Copyright 1999, Oxford University Press. Used with permission.
Broadly following the theories set forth by Goldman-Rakic and others, which postulate that 1) the
ability to maintain information “on line” forms the basis for many higher-order cognitive processes and
behaviors and 2) the dorsolateral prefrontal cortex is the key brain region supporting the maintenance
of information on line, a series of functional imaging studies has determined that the degree of
activation of the dorsolateral prefrontal cortex in schizophrenia is highly correlated with clinical
measures of cognitive and behavioral disorganization (Figure 10–5).
FIGURE 10–5. Relation between

disorganization symptoms and
change in signal intensity in
right dorsolateral prefrontal
cortex as a function of working
memory load for 17 patients
with schizophrenia.a
Note. fMRI = functional magnetic resonance imaging.

a
Working memory was assessed with a sequential-letter
task. In the 0-back condition, the target was any letter that
matched a prespecified letter. In the 1-back condition, the
target was any letter that was identical to the one
immediately preceding it. In the 2-back condition, the target
was any letter that was identical to the one two trials back.
The signal change shown here is the percentage change of
the 2-back from the 0-back condition.
b
Includes conceptual disorganization, mannerisms and
posturing, difficulty abstracting, and poor attention from the
Positive and Negative Syndrome Scale (Kay et al. 1987).
Source. Reprinted from Perlstein WM, Carter CS, Noll DC,

et al.: “Relation of Prefrontal Cortex Dysfunction to Working
Memory and Symptoms in Schizophrenia.” American
Journal of Psychiatry 158:1105–1113, 2001 (Figure 2
[p. 1110]). Copyright 2001, American Psychiatric
Publishing, Inc. Used with permission.
Studies is elucidating the neural basis of auditory hallucinations hope to provide a neurobiological
rationale for an effective treatment for this symptom. Auditory hallucinations appear to be the result of
abnormal activation of the neural system serving auditory sensory processing. In one study involving
patients with schizophrenia with auditory hallucinations (Dierks et al. 1999), the onset and offset of the
hallucinations correlated with the engagement and disengagement of the primary auditory cortex
(Figure 10–6).
FIGURE 10–6. Activation of Heschl’s gyrus

during auditory hallucinations and in response
to acoustical stimulation.
(Top) Three-dimensional representations of the activation of

Heschl’s gyrus in patient 1, showing transversal and coronal
sections (left) and a reconstruction of the gray/white matter
boundary of the left temporal lobe (right) during hallucinations
(a) and acoustical stimulation (b), respectively.
(Bottom) Time courses of the blood-oxygen-level-dependent
(BOLD) signal for patients 1 (first session) (a and b), 2 (c), and
3 (d), filtered with a high pass of 0.004 Hz and a low pass of
0.05 Hz, from Heschl’s gyrus (solid line). The shaded areas
indicate experimental conditions (H = hallucinations; S =
spoken text; R = reversed speech; T = pulsed tone at 2,000
Hz). For patient 3 (d), the time course of the BOLD signal in
Heschl’s gyrus (solid line) is shown together with the time
course of another area in auditory cortex (x = 57, y = 4, z = 3)
that only responds to acoustic stimulation (dotted line) (for
acoustical stimulation, the same protocol was used as in [b]).
Source. Reprinted from Dierks T, Linden DE, Jandl M, et al.: “Activation of Heschl’s Gyrus
During Auditory Hallucinations.” Neuron 22:615–621, 1999 (Figure 2 [p. 617]). Copyright 1999,
Elsevier Limited. Used with permission.
Source. Reprinted from Dierks T, Linden DE, Jandl M, et al.: “Activation of Heschl’s Gyrus During Auditory Hallucinations.” Neuron 22:615–621,
1999 (Figure 2 [p. 617]). Copyright 1999, Elsevier Limited. Used with permission.
The fact that all antipsychotics (first- and second-generation antipsychotics) have high-affinity
binding at a range of monoamine receptors in the brain may partially account for their efficacy but is
well established as being the basis for many of their side effects, which include antagonism at
muscarinic, histaminergic, and -adrenergic receptors, with predictable autonomic effects. In
addition, the monoaminergic transporter–blocking effects and 5-HT 1A receptor partial agonism or
antagonism shown by some second-generation antipsychotics suggest that these medications may
exert antidepressant and anxiolytic effects as well (Table 10–7).
TABLE 10–7. Relative

neurotransmitter receptor
affinities for antipsychotics
at therapeutic doses
Source. Adapted from Miyamoto et al. 2005.
TABLE 10–7. (enlarged)
CHAPTER 10 • Key Points
 Among medical illnesses, schizophrenia is one of the most serious for the
afflicted individual, the family of the patient, and society at large.
 Schizophrenia, like psychiatric illness in general, occurs as a function of both
a genetic predisposition and environmental factors.
 Schizophrenia is characterized by cognitive, perceptual, behavioral, and
social disturbances and has profound consequences for the individual’s
capacity for autonomy and function in the community.
 Schizophrenia is currently conceived of as a neurodevelopmental disorder,
with disturbances in development across a range of epochs, from early
gestation through late adolescence.
 The pathophysiology of schizophrenia involves several anatomical regions
and neurotransmitter and other functional systems in the brain.
 The various symptoms and problems in living that schizophrenic patients
experience can be treated with the full range of treatment modalities currently
available in psychiatry, including pharmacological and psychosocial
approaches.
(continued)
CHAPTER 10 • Key Points (continued)
 Although many patients with schizophrenia endure relapsing and remitting

periods of illness, with a significant decline in function over the early period of
illness, many can retain a measure of well-being, symptom control, and
autonomy in the community.
 Research into the causes, clinical course, and treatment of schizophrenia has
shown considerable progress in recent times and shows promise for
significant advances in the future treatment of this disorder.

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The American Psychiatric Publishing

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Table 10–1. Major symptoms in schizophrenia

TABLE 10–1. Major symptoms in schizophrenia

TABLE 10–2. DSM-IV-TR diagnostic criteria for schizophrenia

Source. Reprinted from

TABLE 10–4. DSM-IV-TR subtypes of schizophrenia

FIGURE 10–1. Natural course of schizophrenia.

Note. Asterisks indicate critical periods for early detection or intervention.

FIGURE 10–2. Candidate

Linkages that reached

Source. Reprinted from Owen MJ, Craddock N,

FIGURE 10–3. Positron emission tomography (PET) images of cognition.

FIGURE 10–4. Chandelier cell

TABLE 10–6. Certainty and doubt in

Source. Reprinted from Harrison PJ: “The Neuropathology of Schizophrenia: A

FIGURE 10–5. Relation between

Note. fMRI = functional magnetic resonance imaging.

Source. Reprinted from Perlstein WM, Carter CS, Noll DC,

FIGURE 10–6. Activation of Heschl’s gyrus

(Top) Three-dimensional representations of the activation of

TABLE 10–7. Relative

Source. Adapted from Miyamoto et al. 2005.

 Although many patients with schizophrenia endure relapsing and remitting

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