CHAPTER 47

CHRONIC FATIGUE SYNDROME

Stephen E. Straus†

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652

Chronic fatigue syndrome (CFS) is the current name for a Estimates of the prevalence of CFS have depended on
disorder characterized by debilitating fatigue and several the case definition used and the method of study. Chronic
associated physical, constitutional, and neuropsychological fatigue itself is a common symptom, occurring in as many
complaints (Table 47-1).This syndrome is not new; in the as 20% of patients attending general medical clinics; CFS
past, patients diagnosed with conditions such as the vapors, is far less common. Community-based studies find that
neurasthenia, effort syndrome, chronic brucellosis, epi- 100–300 individuals per 100,000 population in the
demic neuromyasthenia, myalgic encephalomyelitis, hypo- United States meet the current CDC case definition.
glycemia, multiple chemical sensitivity syndrome, chronic
candidiasis, chronic mononucleosis, chronic Epstein-Barr PATHOGENESIS
virus (EBV) infection, and postviral fatigue syndrome may The diverse names for the syndrome reflect the many
have had what is now called CFS. A subset of ill veterans and controversial hypotheses about its etiology. Several
of military campaigns suffer from CFS. The U.S. Centers common themes underlie attempts to understand the
for Disease Control and Prevention (CDC) has developed disorder: (1) it is often postinfectious; (2) it is associated
diagnostic criteria for CFS based upon symptoms and the with mild immunologic disturbances and sedentary
exclusion of other illnesses (Table 47-2). behavior during childhood; and (3) it is commonly
accompanied by neuropsychological complaints, somatic
preoccupation, and/or depression.
EPIDEMIOLOGY
Many studies over the past quarter century sought to
Patients with CFS are twice as likely to be women as link CFS to acute and/or persisting infections with EBV,
men and are generally 25–45 years of age, although cases cytomegalovirus, human herpesvirus type 6, retroviruses,
in childhood and in later life have been described. enteroviruses, Candida albicans, Mycoplasma spp., or
Cases are recognized in many developed countries. Coxiella burnetii, among other microbial pathogens.
Most arise sporadically, but many clusters have also Compared to findings in age-matched control subjects,
been reported. Famous outbreaks of CFS occurred in the titers of antibodies to some microorganisms are ele-
Los Angeles County Hospital in 1934; in Akureyri, Ice- vated in CFS patients. Reports that viral antigens and
land, in 1948; in the Royal Free Hospital, London, in nucleic acids could be specifically identified in patients
1955; and in Incline Village, Nevada, in 1985. While with CFS, however, have not been confirmed. One study
these clustered cases suggest a common environmental from the United Kingdom failed to detect any associa-
or infectious cause, none has been identified. tion between acute infections and subsequent prolonged
†
Deceased.
650
TABLE 47-1 Changes in numerous immune parameters of uncertain 651
SPECIFIC SYMPTOMS REPORTED BY PATIENTS functional significance have been reported in CFS. Modest
WITH CHRONIC FATIGUE SYNDROME elevations in titers of antinuclear antibodies, reductions in
immunoglobulin subclasses, deficiencies in mitogen-driven
SYMPTOM PERCENTAGE
lymphocyte proliferation, reductions in natural killer cell
Fatigue 100 activity, disturbances in cytokine production, and shifts in
Difficulty concentrating 90 lymphocyte subsets have been described. None of these
Headache 90 immune findings appears in most patients, nor do any cor-
Sore throat 85
Tender lymph nodes 80
relate with the severity of CFS. Comparison of monozy-
Muscle aches 80 gotic twin pairs discordant for CFS showed no substantive
Joint aches 75 immunologic differences between affected and unaffected
Feverishness 75 individuals. In theory, symptoms of CFS could result from
Difficulty sleeping 70 excessive production of a cytokine, such as interleukin 1,
Psychiatric problems 65 which induces asthenia and other flulike symptoms; how-
Allergies 55 ever, compelling data in support of this hypothesis are
Abdominal cramps 40
lacking. A recently published population-based study from
Weight loss 20
Rash 10 Wichita, Kansas, reported differences in gene expression
Rapid pulse 10 patterns and in candidate gene polymorphisms between
Weight gain 5 CFS patients and controls; these results are controversial
Chest pain 5 and await confirmation.
Night sweats 5 In some but not the more recent studies, patients
with CFS commonly manifested sensitivity to sustained
Source: From SE Straus: J Infect Diseases 157:405, 1988; with upright posture or tilting, resulting in hypotension and
permission.
syncope, so as to suggest a form of dysautonomia.

CHAPTER 47
TABLE 47-2
Disturbances in hypothalamic-pituitary-adrenal func-
tion have been identified in several controlled studies of
CDC CRITERIA FOR DIAGNOSIS OF CHRONIC
CFS, with some evidence for normalization in patients
FATIGUE SYNDROME
whose fatigue abates. These neuroendocrine abnormali-
A case of chronic fatigue syndrome is defined by the ties could contribute to the impaired energy and
presence of: depressed mood of patients.
1. Clinically evaluated, unexplained, persistent or
Mild to moderate depression is present in one-half

Chronic Fatigue Syndrome

relapsing fatigue that is of new or definite onset; is not
the result of ongoing exertion; is not alleviated by rest;
to two-thirds of patients. Much of this depression may
and results in substantial reduction of previous levels be reactive, but its prevalence exceeds that seen in other
of occupational, educational, social, or personal chronic medical illnesses. Some propose that CFS is
activities; and fundamentally a psychiatric disorder and that the vari-
2. Four or more of the following symptoms that persist or ous neuroendocrine and immune disturbances arise
recur during six or more consecutive months of illness secondarily.
and that do not predate the fatigue:
• Self-reported impairment in short-term memory or
concentration MANIFESTATIONS
• Sore throat
• Tender cervical or axillary nodes Typically, CFS arises suddenly in a previously active
• Muscle pain individual. An otherwise unremarkable flulike illness or
• Multijoint pain without redness or swelling some other acute stress leaves unbearable exhaustion in
• Headaches of a new pattern or severity its wake. Other symptoms, such as headache, sore throat,
• Unrefreshing sleep tender lymph nodes, muscle and joint aches, and fre-
• Postexertional malaise lasting ≥ 24 h quent feverishness, lead to the belief that an infection
persists, and medical attention is sought. Over weeks to
Note: CDC, U.S. Centers for Disease Control and Prevention.
months, despite reassurances that “nothing serious is
Source: Adapted from K Fukuda et al: Ann Intern Med 121:953,
1994; with permission. wrong,” the symptoms persist and other features of the
syndrome become evident—disturbed sleep, difficulty in
concentration, and depression (Table 47-1).
fatigue. Another study found that chronic fatigue did not Depending on the dominant symptoms and the beliefs
develop after typical upper respiratory infections but did of the patient, additional consultations may be sought from
in some individuals after infectious mononucleosis.Thus, allergists, rheumatologists, infectious disease specialists, psy-
while antecedent infections are associated with CFS, a chiatrists, ecologic therapists, homeopaths, or other profes-
direct microbial causality is unproven and unlikely. sionals, frequently with unsatisfactory results. Once the
 652 pattern of illness is established, the symptoms may fluctu- that should not be simply dismissed as additional sub-
ate somewhat. Many patients report that CFS symptoms, jective complaints.
including cognitive problems, are exacerbated by intensive Many symptoms of CFS respond to treatment. Nons-
physical or other stressors, yet recent prospective studies teroidal anti-inflammatory drugs alleviate headache, dif-
have not confirmed this impression. fuse pain, and feverishness. Allergic rhinitis and sinusitis
Most patients remain capable of meeting family, work, are common; when present, antihistamines or decon-
or community obligations despite their symptoms; discre- gestants may be helpful. Although the patient may be
tionary activities are abandoned first. Some feel unable to averse to psychiatric diagnoses, depression and anxiety
engage in any gainful employment. A minority of indi- are often prominent and should be treated. Expert psy-
viduals requires help with the activities of daily living. chiatric assessment is sometimes advisable. Nonsedat-
Econometric analyses conducted by the CDC have ing antidepressants improve mood and disordered
confirmed that CFS exacts a significant toll on house- sleep and may attenuate the fatigue. Even modest
hold and workforce productivity. improvements in symptoms can make an important dif-
Ultimately, isolation, frustration, and pathetic resigna- ference in the patient’s degree of self-sufficiency and
tion can mark the protracted course of illness. Patients ability to appreciate life’s pleasures.
may become angry at physicians for failing to acknowl- Practical advice should be given regarding life-style.
edge or resolve their plight. Fortunately, CFS does not Sleep disturbances are common; consumption of heavy
appear to progress. On the contrary, many patients experi- meals, alcohol, and caffeine at night can make sleep even
ence gradual improvement, and a minority recover fully. more elusive, compounding fatigue. Total rest leads to fur-
ther deconditioning and the self-image of being an invalid,
DIAGNOSIS whereas overexertion may worsen exhaustion and lead to
total avoidance of exercise. A carefully graded exercise reg-
A thorough history, physical examination, and judicious
imen should be encouraged and has been proven to
use of laboratory tests are required to exclude other causes
relieve symptoms and enhance exercise tolerance.
of the patient’s symptoms. Prominent abnormalities argue
SECTION IV

Controlled therapeutic trials have established that

strongly in favor of alternative diagnoses. No laboratory
acyclovir, fludrocortisone, galantamine, modafinil, and IV
test, however, can diagnose this condition or measure its
immunoglobulin, among other agents, offer no signifi-
severity. In most cases, elaborate, expensive workups are not
cant benefit in CFS. Low doses of hydrocortisone provide
helpful. Early claims that MRI or single photon emission
modest benefit but may lead to adrenal suppression.
CT can identify abnormalities in the brain of CFS patients
Countless anecdotes circulate regarding other tradi-
have not withstood further study. The dilemma for patient
tional and nontraditional therapies. It is important to
Chronic Fatigue Syndrome

and clinician alike is that CFS has no pathognomonic fea-

guide patients away from those therapeutic modalities
tures and remains a constellation of symptoms and a diag-
that are toxic, expensive, or unreasonable.
nosis of exclusion. Often the patient presents with features
The physician should promote the patient’s efforts to
that also meet criteria for other subjective disorders such as
recover. Several controlled trials conducted in the United
fibromyalgia and irritable bowel syndrome. Questions have
Kingdom, in Australia, and in the Netherlands showed
been raised as to the relative merits of rendering a diagno-
cognitive-behavioral therapy to be helpful in adolescents
sis of CFS. Being diagnosed can provide validation of a
and adults with CFS. This approach aims to dispel mis-
patient’s perceived symptoms but may also perpetuate or
guided beliefs and fears about CFS that can contribute to
exacerbate them. Refusal to label a patient as having CFS,
inactivity and despair. For CFS, as for many other condi-
however, can deny the patient the opportunity to under-
tions, a comprehensive approach to physical, psychologi-
take treatments that are of proven merit.
cal, and social aspects of well-being is in order.

Treatment:
CHRONIC FATIGUE SYNDROME
FURTHER READINGS
After other illnesses have been excluded, there are sev-
BAKER R, SHAW EJ: Diagnosis and management of chronic fatigue
eral points to address in the long-term care of a patient syndrome or myalgic encephalitis (or encephalopathy): Summary
with chronic fatigue. of NICE guidance. BMJ 335:446, 2007
The patient should be educated about the illness JONES JF et al: An evaluation of exclusionary medical/psychiatric
and what is known of its pathogenesis; potential impact conditions in the definition of chronic fatigue syndrome. BMC
on the physical, psychological, and social dimensions of Med 7:57, 2009
life; and prognosis. Periodic reassessment is appropriate KILMAS NG, KONERU AO: Chronic fatigue syndrome: inflamma-
to identify a possible underlying process that is late in tion, immune function, and neuroendocrine interactions. Curr
Rheumatol Rep 9:482, 2007
declaring itself and to address intercurrent symptoms
PRINS JB et al: Chronic fatigue syndrome. Lancet 367:346, 2006
SECTION V

PSYCHIATRIC
DISORDERS
 CHAPTER 48

BIOLOGY OF PSYCHIATRIC DISORDERS

Steven E. Hyman ■ Eric Kandel

Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Challenges with Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . 656
Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

Psychiatric disorders are a diverse group of brain disor- disorders, schizophrenia, and to some extent other psychi-
ders with symptoms that primarily involve emotion, atric disorders constitute the most potent risk factors for
higher cognitive function, and the ability to control suicide, a leading cause of death worldwide.
complex behaviors. A compendium of psychiatric disor-
ders can be found in the Diagnostic and Statistical Manual ANATOMY
of Mental Disorders, 4th edition (DSM-IV) of the Ameri- Progress in understanding the pathophysiology of psychi-
can Psychiatric Association. This compendium illustrates atric disorders has been slow, despite its fundamental
that the boundary between psychiatric and neurologic importance. Perhaps the most significant challenge is
disorders, another heterogeneous group of brain disor- posed by the difficulties inherent in understanding the
ders, is arbitrary and shifting. In areas of overlap such as high-level cognitive and affective functions of the brain
autism, Tourette’s disorder, and Alzheimer’s disease, the that are disrupted in psychiatric disorders. As a result,
disorder is often treated by either a psychiatrist or a neu- unlike many neurologic disorders, the common psychi-
rologist.The term mental disorders, while still widely used, atric disorders appear to involve widely distributed neural
fails to acknowledge the neural substrates of these distur- networks and lack an obvious, localized neuropathology,
bances and their effects on physiology and behavior. which, if present, would help to narrow the hunt for cel-
The major psychiatric disorders are common and lular pathology and for underlying biochemical and mol-
often run a chronic course.The chronic disorders include ecular causes.Thus, the motor disturbances in Parkinson’s
anxiety disorders, attention deficit hyperactivity disorder, disease, Huntington’s disease, and amyotrophic lateral scle-
autism, obsessive-compulsive disorder, and schizophrenia. rosis result from discrete macroscopic lesions in different
Other psychiatric disorders such as depressive disorders parts of the motor system. By contrast, in psychiatric dis-
recur across the life span, but even bipolar disorder, classi- orders, when candidate regions have been identified, as in
cally characterized as episodic, can run a chronic course. schizophrenia, depression, and autism, it has proven diffi-
The symptoms of psychiatric disorders often begin cult to differentiate convincingly, these abnormalities from
early, impairing the ability of children and adolescents to normal variation partly because these target regions form
learn and compromising the functioning of adults at work only one component of a disorder involving a much
and in other life roles. As a result of their high prevalence, larger neural circuit (Chap. 15).
early onset, and persistence, psychiatric disorders con-
tribute substantially to the burden of illness in all coun- GENETIC CONSIDERATIONS
tries in which they have been studied. In the United Given the challenges of identifying relatively sub-
States they are not only a leading cause of disability but tle neuropathology, it has long been hoped that the
also a significant cause of premature death, because mood
654
identification of genetic variants conferring risk for psy- powerful tools to investigate the neural basis of the dis- 655
chiatric disorders would provide effective clues to those ease by putting the mutated gene into worms, flies, or
underlying neural abnormalities that contribute to the mice in order to study the mechanisms of pathogenesis.

CHAPTER 48
psychiatric disorder in question. This hope is based on While such tools are only a beginning, and indeed have
the significant body of data derived from family, twin, not yet led to development of therapies, gene identifica-
and adoption studies demonstrating that heredity plays a tion and the study of its function have already created a
significant role in the risk of major psychiatric disorders, strong platform for investigation. It permits, for example,
including schizophrenia, bipolar disorder, depressive dis- the spatiotemporal characterization in the brain of the
orders, and many others. For example, the rate of schiz- expression of disease-related genes, the generation of

Biology of Psychiatric Disorders

ophrenia in the general population is ~1%. However, antibodies against the normal and altered proteins, and
when one member of a monozygotic twin pair is diag- the production by genetic engineering of worm, fly, and
nosed with schizophrenia, the other twin, who is geneti- mouse models that could serve as assays for testing pos-
cally identical, has nearly a 50% chance of also manifest- sible therapies. Moreover, the identification of rare,
ing the disease. A first-degree relative of an affected Mendelian forms of Parkinson’s disease, Alzheimer’s dis-
proband (who shares on average 50% of DNA ease, amyotrophic lateral sclerosis, and epilepsy has pro-
sequences) has a 9% risk of schizophrenia. Adoption-at- vided significant insights into the more common forms
birth studies provide additional strong support for a of these disorders. Thus far, however, no Mendelian
genetic contribution to schizophrenia spectrum disor- form of any of the common early-onset psychiatric dis-
ders; in one study from Finland, a schizophrenia-related orders of the brain has been identified convincingly. A
illness was present in nearly one-quarter of adoptees small number of Mendelian disorders have symptoms
whose biologic mother carried a similar diagnosis. that overlap with those of common psychiatric disor-
While there continue to be promising leads in the ders. For example, Rett syndrome, which results from
search for risk-conferring alleles, research over the past mutations in the methyl DNA binding protein MECP2,
two decades has not succeeded in identifying with cer- includes autistic-like symptoms but also many severe
tainty risk genes for psychiatric disorders.There have been symptoms that are not characteristic of autism.
large efforts using a variety of strategies, including linkage In psychiatric disorders such as schizophrenia, genes
studies and candidate gene studies, in attempts to identify are not, by themselves, causative; other factors, a “second
genes responsible for schizophrenia, and more recently hit,” must contribute. Unfortunately, these potential envi-
several groups have begun to undertake whole-genome ronmental factors, the “second hits,” have been difficult
association studies. The strongest candidates include: dis- to identify. One interesting finding, documented in the
rupted in schizophrenia (DISC1), a gene that was dis- Netherlands following World War II and in China, is that
rupted by a balanced chromosomal translocation in a maternal famine during gestation is correlated with an
Scottish family with schizophrenia-like symptoms; distro- increased incidence of schizophrenia, perhaps by con-
brevin-binding protein 1 (DTNBP1); and neuroregulin 1 tributing to de novo germ-line mutations. Other poten-
(NRG1), which encodes a protein involved in neuronal tial risk factors include urban birth, migration, increasing
migration and in expression of N-methyl-D-aspartate paternal age, and intrauterine exposure to viral infection.
(NMDA) glutamate receptors. Other potential candidates New genetic technologies are now available for the
include DAOA, RGS4, and AKT1, but the evidence sup- investigation of genetically complex disorders; these
porting them is weaker (Table 48-1). include more complete maps of human genetic variabil-
One problem in identifying risk genes for psychiatric ity, high-density whole-genome association methods, and
diseases has been the failure to replicate convincingly efficient high-throughput sequencing technologies using
the discovery of putative risk genes.The failure stems in single nucleotide polymorphism (SNP) arrays.The use of
large part from the complex nature of risk for psychi- these tools has already begun to yield significant results
atric disorders, which appears to involve multiple genes for several common complex disorders, such as inflam-
of small effect interacting with nongenetic factors. In matory bowel disease, age-related macular degeneration,
addition, there appear to be different risk genes in dif- and type 2 diabetes mellitus. Psychiatric disorders are
ferent population groups, perhaps reflecting new or well positioned to benefit from these new approaches. In
recent mutations. addition, it is expected that additional emerging tech-
It is now relatively straightforward to identify genes nologies, including cost-efficient methods for whole-
that exert large causal effects on disease. Several less genome sequencing, will soon be available, further
common neurologic disorders result from deleterious increasing the likelihood that risk-conferring alleles for
mutations within single genes. Thus, genes have been psychiatric disorders will be identified within the next
identified that contribute to the muscular dystrophies, few years. To take full advantage of these new methods,
triplet repeat disorders such as Huntington’s disease and the psychiatric research community will need to collect
fragile X, and Down’s syndrome. The discovery of the very large populations for sufficiently powered genetic
Huntington gene was followed by the development of studies, and identify (by high-resolution imaging, gene
 656 TABLE 48-1
SCHIZOPHRENIA CANDIDATE GENES

PROTEIN GENE CH LOCATION EVIDENCE FUNCTION

SECTION V

Disrupted in DISC1 1q42 Initially identified through Roles in microtubular

schizophrenia a balanced translocation transport and neuronal
in a single family with migration (via interactions
schizophrenia and with Lis1 and NudEL);
affective disorder; influences postsynaptic
confirmed by linkage and responses (interactions with
Psychiatric Disorders

association in different Citron); activates

populations. phosphodiesterase 4B,
increasing cAMP (target of
antidepressant rolipram).
Dysbindin (dystrobrevin- DTNBP1 6p22 Linkage and association; Wide distribution in CNS;
binding protein 1) no coding region mutations; expression in synaptic
no consistent allele or terminals of hippocampus;
haplotype implicated in in vitro, reduced levels
different studies; negative decrease glutamate in
symptoms of schizophrenia neurons.
may associate with a specific
haplotype of DTNBP1;
expression decreased in
schizophrenia brain.
Neuregulin 1 NRG1 8p12-21 Linkage and association; no Suppresses function of
coding region mutations; no NMDA receptors; role in
consistent allele or haplotype neuronal differentiation
implicated in different studies; and migration.
expression increased in
schizophrenia brain.
D-Amino oxidase activator DAOA 13q32-34 Linkage and association; no Activates D-amino oxidase
consistent allele or haplotype which oxidies D-serine, an
implicated in different studies. agonist at NMDA receptors;
reduced D-serine levels
reported in blood and CSF
in schizophrenia.
Regulator of G-protein RGS4 1q21-22 Linkage and association; Modulates postsynaptic
signaling 4 susceptibility allele may signal transduction,
impair working memory and including downregulation
regionally reduce brain of 5HT1a (serotonin)
volumes receptors.
V-akt murine thymoma AKT1 14q22-32 Inconsistent linkage, Phosphorylates and
viral oncogene association, and brain inactivates glycogen
homologue 1 expression studies. synthase kinase (GSK) 3 beta.

Note: CH, chromosome; CNS, central nervous system; CSF, cerebrospinal fluid; NMDA, N-methyl-D-aspartate.

expression patterns, or other markers) biologically mean- The diagnostic classification scheme (e.g., DSM-IV) upon
ingful phenotypes for stratification of the genetic data. which both research and clinical practice rely is derived
from expert consensus based on clusters of symptoms and
signs and disease course. As a result, failure to delineate
CHALLENGES WITH PHENOTYPING
well-defined disease entities and to reliably assign individ-
Psychiatric disorders have an additional obstacle to the uals, to affected versus nonaffected status have bedeviled
identification of risk genes or pathophysiologic processes psychiatric research.
that cannot be addressed simply by improving genetic The lack of objective tests for phenotyping presents
technologies.There are at the moment no objective diag- enormous difficulties for genetic and other forms of inves-
nostic measures for any of the common psychiatric disor- tigation. While type 2 diabetes mellitus and hypertension,
ders. There is not, as yet, a well-defined neuropathology for example, are both highly heterogeneous disorders,
for psychiatric disorders nor are there biologic markers. the measurement of glucose tolerance or of systolic and
diastolic blood pressure creates a strong framework within electroconvulsive therapy, had immediate and sustained 657
which subtyping can occur, generally based on additional responses; however, due to the invasiveness, risk, and cost,
objective measures. In contrast, it is not at all certain that this approach may not become a widespread treatment.

CHAPTER 48
the boundaries currently drawn around disorders in the Its significance lies in the putative identification of a cir-
DSM-IV lead to an underlying and distinguishable set of cuit involved in mood regulation that can be manipu-
neurobiologic factors. For example, there is much debate lated to produce therapeutic benefit.
about the boundaries of schizophrenia. The DSM-IV lists
three psychotic disorders as being independent—schizo-
phrenia, schizoaffective disorder, and schizophreniform

Biology of Psychiatric Disorders

disorder (American Psychiatric Association, 2000). Yet Treatment:
there is little agreement on whether the latter two are suf- PSYCHIATRIC DISORDERS
ficiently homogeneous clinical entities to warrant inde- The high prevalence and serious consequences of psy-
pendent recognition. chiatric disorders make the availability of effective treat-
Despite the problems with current disease classification ments a matter of great importance for public health.
in psychiatry, there is agreement on the core symptoms Since the middle of the twentieth century, several
and strong cross-cultural similarity of disease manifesta- classes of pharmacologic treatments (antipsychotic
tion. In addition, there is a strong familial nature to major drugs, antidepressant drugs, lithium, benzodiazepines,
psychiatric disorders and also a potent role for heredity, and anticonvulsants) and several standardized short-
which can be inferred from twin and adoption studies. term psychotherapies have been developed and found
These findings suggest that the central criteria for diag- to be efficacious in clinical trials. The result is an arma-
nosing schizophrenia, bipolar disorder, autism, and other mentarium of useful treatments for many of the common
major psychiatric disorders identify, however imperfectly, disorders; however, as is the case for many common,
distinctive, naturally occurring brain diseases. chronic medical disorders, there are no cures for psychi-
atric disorders. Residual symptoms and recurrences are
NEUROIMAGING common, and many pharmacologic treatments have
significant side effects.
In parallel with improved classification and genetic stud- This state of affairs is typified by schizophrenia,
ies, attempts are being made using neuroimaging to where a large number of drugs have been developed.
define anatomic abnormalities as objective, measurable Initially these drugs were thought to be useful only in
phenotypes of the disease. For example, new quantitative the treatment of schizophrenia; however, they are now
methods combined with structural MRI have suggested commonly used to treat any psychosis, irrespective of
that, in schizophrenia, there may be disease-specific pat- origin. In schizophrenia, in addition to the psychotic
terns of gray matter loss in frontal and temporal cerebral symptoms of hallucinations and delusions, referred to
cortex. Longitudinal studies of individuals with child- as positive symptoms, there are also negative symptoms
hood-onset schizophrenia have documented an acceler- (social withdrawal, impoverished speech, lack of motiva-
ated loss of gray matter. More recently, attempts have tion) and cognitive symptoms (poor executive function).
been made to associate specific DISC1 haplotypes with Both positive and negative symptoms are thought to be
reduced frontal gray matter. While these approaches are related to dopaminergic systems in the brain (Fig. 48-2).
in their early stages, the effort to define objective brain- The primary clinical benefit of antipsychotic drugs is the
based phenotypes for genetic and clinical studies appears amelioration of the positive psychotic symptoms. With
very promising. the exception of clozapine, often described as an atypi-
Functional imaging of individuals with depression cal antipsychotic drug, which produces improvement in
similarly has pinpointed abnormal activity in Brodman some patients who do not respond to other drugs, all
area 25, the subgenual prefrontal cortex, a brain region the existing antipsychotic drugs have similar efficacy
that connects to the amygdala and is thought to play a and differ primarily in their pattern of side effects. Cloza-
critical role in the processing of emotion-related infor- pine and some other atypical drugs are thought to exert
mation (Fig. 48-1). Area 25 exhibits excessive metabolic at least a modest therapeutic effect on the negative
activity in major depression, which reverses with success- symptoms of schizophrenia. None of the drugs, how-
ful antidepressant treatment. This region is also activated ever, is effective against the symptoms that are central
in normal subjects in whom sadness is induced by means to the illness. Furthermore, their residual presence
of emotion laden stimuli. This information serves as the throughout the course of the illness contributes sub-
basis for an experimental approach to severe depression stantially to the persistence of disability over the
involving the use of deep-brain stimulation of the sub- patient’s lifetime. The search for new drugs to treat
genual prefrontal cortex using implanted electrodes. In schizophrenia now focuses extensively on the ability to
an initial series, four of six patients with severe depression modify its cognitive symptoms. All antipsychotic drugs
unresponsive to all currently proven treatments, including
 658
x = –3
SECTION V
Psychiatric Disorders

Subgenual t value
PFC 0
y = 31

–2.8

CC

–5.5

FIGURE 48-1
Some patients with unipolar and bipolar disease show a of Neural Science, 4th ed. New York, McGraw-Hill, 2000;
functional abnormality in the prefrontal cortex ventral to the with permission.)
genu of the corpus callosum. (From ER Kandel et al: Principles

in current use block or diminish the action of dopamine benefit at all. When pharmacologic modalities fail in
at its D2 receptors (Fig. 48-3); they differ in their relative depression, electroconvulsive therapy continues to be an
affinity at D2 receptors and by their actions at other effective treatment option. Lithium and several anticonvul-
neurotransmitter receptors. These drugs represent sants dampen mood swings in bipolar disorder and also
important progress, but safer and more effective treat- treat acute manic episodes; however, residual depressive
ments are very much needed. symptoms, recurrences, and significant side effects are the
Drugs useful in depression act by increasing synaptic rule. The exact mechanism of action of lithium is not
levels of serotonin, norepinephrine, or less commonly known. At therapeutic levels, lithium interacts with two
dopamine (Fig. 48-4). The term antidepressant is a mis- important signaling pathways: (1) it blocks inositol
nomer for this diverse class of drugs, however, because monophosphatase, thus influencing signaling via inositol
their spectrum of action is much broader than depres- phosphates, such as IP3; and (2) it also blocks glycogen syn-
sion. These drugs are also effective in treating fear-based thase kinase 3 beta (GSK3beta).
anxiety disorders such as panic disorder and generalized Unfortunately, there are currently very few promising
anxiety disorder. In high doses, the selective serotonin drug targets that can be exploited to produce medica-
uptake inhibitors are effective for obsessive-compulsive tions with truly novel mechanisms of action. Indeed, all
disorder. The antidepressants are effective in the treat- of the major classes of drugs used to treat psychiatric
ment of depression, but only moderately so. Many disorders were identified through empirical observa-
patients require sequential trials with a number of differ- tions of drug effects in patient populations rather than
ent drugs alone or in combination to achieve clinically as a result of understanding pathophysiology. The mole-
meaningful benefit, and ~30% of patients derive no cular targets of these drugs were identified by the study
 Neocortex
Mesocortical system: 659
involved in the
Nucleus negative symptoms
accumbens of schizophrenia

CHAPTER 48
(ventral striatum)
Limbic
forebrain
Frontal
cortex

Biology of Psychiatric Disorders

Hippocampal
formation

Mesolimbic and
mesocortical Ventral
system tegmental Mesolimbic
Midbrain area system:
involved in the
positive symptoms
Hippocampal Ventral of schizophrenia
formation tegmental
area

A Midsagittal section B Coronal section

FIGURE 48-2
The major dopaminergic tracts of the brain. (From ER Kandel et al: Principles of Neural Science, 4th ed. New York,
McGraw-Hill, 2000.)

1a Tyrosine Antipsychotic
Increase of synthesis
(L-DOPA) Can produce
Tyrosine psychotic symptoms
1b
Inhibition of synthesis
(α-methyltyrosine)
DOPA
2
Interference with vesicular
storage (reserpine, Dopamine
tetrabenazine) 6
Inhibition of breakdown
(pargyline)
3
Stimulation of release of
DA at nerve terminal
(amphetamine, tyramide)
MAO
Autoreceptor
D3

Vesicular monoamine
transporter
Dopamine
4 transporter 5
Blocking of DA receptors Inhibition of reuptake
and autoreceptors (cocaine, amphetamine,
(antipsychotics: benztropine)
perphenazine, haloperidol)
COMT

D2 D2

FIGURE 48-3
The key steps in the synthesis and degradation of et al: Principles of Neural Science, 4th ed. New York,
dopamine and the sites of action of various psychoactive McGraw-Hill, 2000.)
substances at the dopaminergic synapse. (From ER Kandel
 660 Depressant
Antidepressant
1
Inhibition of synthesis Tryptophan
(p-chlorophenylalanine,
p-propyldopacetamide)
SECTION V

5-OH-Tryptophan
5-HIAA

5-HT

2
Interference with
vesicular storage 5-HT
(reserpine, 5
Psychiatric Disorders

tetrabenazine) 5-HT Inhibition of enzyme

that oxidizes 5-HT MAO inhibitors
3a (iproniazid, clorgyline)
Stimulation of MAO
autoreceptor agonist
8-Hydroxy-dipropylamino-
tetraline (8-OH-DPAT) 4
Inhibition of reuptake Tricyclics and
(imipramine, selective serotonin
3b 5-HT amitryptyline, fluoxetine,
Stimulation of 5-HT reuptake inhibitors
receptors as sertraline)
partial agonist
(lysergic acid
diethylamide)
5-HT receptor
A Serotonergic neurons

Tyrosine
1a hydroxylase
Inhibition of synthesis
Deaminated
(α-methyltyrosine)
products
1b DOPA
Inhibition of synthesis
(FLA 63)

Dopamine

2
Interference with
vesicular storage NE
(reserpine, 7
Inhibition of enzyme
tetrabenazine) that oxidizes NE MAO inhibitors
(pargyline)
3 NE
Stimulation of release of MAO
NE at nerve terminals
(amphetamine)
6
Inhibition of reuptake
(desipramine) Tricyclics
Receptor NM
4a 5
Stimulation of receptors Inhibition of enzyme
(clonidine) that inactivates NE Inactivation inhibitor
COMT (tropolone)

4b
Blocking of receptors
(phenoxybenzamine
and phentolamine)

B Noradrenergic neurons

FIGURE 48-4
Actions of antidepressant and other drugs at serotonergic and noradrenergic synapses. (From ER Kandel et al:
Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.)

of efficacious drugs and then exploited to produce trials. Instruments such as the Depression Inventory and
improved compounds within the same class. Suicide Intent Scale are now available for measuring
Cognitive-behavioral psychotherapy designed to mental illness; these have helped to objectify research
focus on the management of specific symptoms has in psychopathology.
shown benefit in mild to moderately severe depression, New insights into the etiology of depression have
fear-based anxiety disorders, and obsessive-compulsive also helped to guide therapy. Depressed patients have a
disorder. A significant improvement in the treatment of systematic negative bias in their cognitive styles—in
depression in the past decade has been the standard- the way they think about themselves and their future.
ization of psychotherapy and its evaluation in clinical These distorted patterns of thinking reflect not simply
an unconscious conflict within the psyche but a disor-
Medication therapy
Pre Post
661
der in cognitive style and behavior that is a key etiologic
agent in maintaining the disorder.

CHAPTER 48
An approach that focuses on distorted thinking, cog-
nitive therapy has been shown in randomized trials to
be an effective psychological treatment for depression.
Psychotherapy
This approach is based on increasing the patients’ Pre Post
objectivity regarding their misinterpretations of every-
day situations (their cognitive distortions), their miseval-

Biology of Psychiatric Disorders

uation of their internal processes (body sensations,
intrusive thoughts and images), and their negative
expectancies. A wide range of professionals can use the
methods with highly positive results.
Cognitive therapy has also proved beneficial in indi- FIGURE 48-5
viduals at risk for suicide. Validated instruments exist to Patients with obsessive-compulsive disorder tend to
classify and assess suicidal behaviors, making it possible show hyperactivity in the head of the caudate. (From ER
to identify high-risk individuals prospectively. Of partic- Kandel et al: Principles of Neural Science, 4th ed. New York,
ular importance has been the identification of clinical McGraw-Hill, 2000.)
and psychological variables that predict future suicide.
Hopelessness and consequent suicidal ideation, which
are better predictors of suicide than clinical depression
per se, can be quantified and substantially reduced by FURTHER READINGS
cognitive interventions. Several studies with individuals BORA E et al: Neurobiology of human affiliative behaviour: implica-
who had recently attempted suicide have demon- tions for psychiatric disorders. Curr Opin Psychiatry 22:320,
strated that a short-term cognitive intervention can sig- 2009
nificantly reduce subsequent suicide attempts when CANNON T et al: Association of DISC1/TRAX haplotypes with
compared to a control group. schizophrenia, reduced prefrontal gray matter, and impaired
This therapy has been extended to the treatment of short- and long-term memory. Arch Gen Psychiatry 62:1205,
2005
other disorders including anxiety states and obsessive-
DORPH-PETERSEN KA et al: Primary visual cortex volume and total
compulsive disorder. With respect to obsessive-compul- neuron number are reduced in schizophrenia. J Comp Neurol
sive disorders, cognitive therapy has been shown to 501:290, 2007
reverse a metabolic abnormality, identified by neuroimag- HAHN CG et al: Altered neuregulin 1-erbB4 signaling contributes to
ing, in parallel with the clinical improvement (Fig. 48-5). NMDA receptor hypofunction in schizophrenia. Nature Med
Cognitive therapy has replaced psychoanalytically 12: 824, 2006
based dynamic psychotherapy as the principal psycho- HYMAN SE: Can neuroscience be integrated into the DSM-V? Nat
Rev Neurosci 9:725, 2007
logical treatment provided by specialists in certain
KANDEL ER et al: Principles of Neural Science, 4th ed. New York,
countries. Its success has stimulated the development McGraw-Hill, 2000
of other forms of short-term psychotherapy, including KENDLER KS et al: A Swedish national twin study of lifetime major
Interpersonal Psychiatry and Psychoanalytic-Oriented depression.Am J Psychiatry 163:107, 2006
Insight Therapy. These therapies are now also being MCCLELLAN JM et al: Maternal famine, de novo mutations, and
tested in controlled clinical trials and have been found schizophrenia. JAMA 296: 582, 2006 O’DONOVAN MC et al:
to be effective in a variety of clinical situations. Genetics of psychosis; insights from views across the genome.
Hum Genet. 126:3, 2009
Thus, paradoxically, one of the significant advances in
RESSLER KJ, MAYBERG HS: Targeting abnormal neural circuits in
the era of the new brain-based biologic psychiatry has mood and anxiety disorders: from the laboratory to the clinic.
been the development of evidence-based psychother- Nat Neurosci 10:1116, 2007
apy, a development based on the evidence that insofar ROSS CA et al: Neurobiology of schizophrenia. Neuron 52:139,
as psychotherapy and other psychiatric treatments 2006
work, they do so by altering the functioning and per-
haps even the structure of the brain.