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ANNUAL
REVIEWS Further Diagnosis and Treatment of
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Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,

Houston, Texas 77030; email: stuarty@bcm.tmc.edu
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Annu. Rev. Med. 2010. 61:121–33 Key Words

The Annual Review of Medicine is online at
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neuroimaging, neurobehavioral, biopsychosocial,
psychopharmacology
Abstract
Neuropsychiatry is the subspecialty of psychiatry that deals with disor-
ders at the intersection of neurology and psychiatry. Neuropsychiatric
disorders are complex and incompletely understood. Neuroscience re-
search is beginning to elucidate the biological underpinnings of many
of these disorders. These advances have the potential to improve di-
agnosis, inform treatment selection, and facilitate development of new
and better interventions.

121
 AREV402-ME61-09 ARI 11 December 2009 14:30

INTRODUCTION assist the clinician in the diagnostic assessment.

The recent evolution of neuropsychiatry
as a subspecialty of psychiatry represents a
paradigm shift regarding the responsibility
of psychiatrists in diagnosing and managing
behavioral disorders with concomitant and
demonstrable brain pathology. Such disor-
ders as dementia, brain injury, and cognitive
processing disorders, as well as psychiatric man-
ifestations accompanying many neurological
disorders including epilepsy, cerebrovascular
accidents, and movement and degenerative
disorders, can be in the province of neuropsy-
chiatry (Table 1). In addition, the biological
Annu. Rev. Med. 2010.61:121-133. Downloaded from www.annualreviews.org
These neurobehavioral functions are believed
to occur by way of circuits that start and end
in areas of prefrontal cortex, with pathways
that traverse the brain (Figure 1) (1–4). The
cortico-subcortical circuits are quite extensive
and are believed to have both direct (Figure 1)
and indirect loops, pathways, and supporting
elements. Recognition that the cerebellum also
participates in the circuits supporting neurobe-
havioral functions is relatively recent (5–8). It is
essential to understand that lesions in multiple
positions along a circuit can result in similar
clinical presentations. This uncertainty makes

underpinnings of many traditional mental determining the relationship between brain and
illnesses are now being described in terms of behavior all the more difficult. Key aspects of
their anatomy and physiology. Many evaluative functional anatomy are summarized in Table 2.
by Boston University on 04/14/13. For personal use only.

modalities, particularly neuroimaging (both Neuropsychiatric disorders are often

structural and functional) and electrophysiol- disabling. The World Health Organization
ogy, are vital to the field of neuropsychiatry. estimates that at least 20% of illness-related
Their applications include not only diagnosis disability worldwide can be attributed to
but also estimating course of illness and neuropsychiatric disorders (9). Unlike other
treatment response, as well as development of chronic illnesses, these disorders often begin
new medications. quite early in life. They account for ∼40% of
A fundamental understanding of the cor- the medical burden for younger people (aged
tical and subcortical anatomy involved in 15–44 years) in the United States and Canada
executive function, memory, and emotion will (10). Mortality is also elevated. As much as
90% of suicides may be associated with mental
Table 1 Epidemiology of neuropsychiatric disorders (59, 60) illnesses (10).
Disorder Prevalence per 100,000
Alzheimer’s disease 7700 RECOGNITION AND
Panic disorder 2700 EVALUATION OF
Epilepsy 1700 NEUROPSYCHIATRIC DISEASE
Obsessive-compulsive disorder 1000–2000
Evaluation must always begin with a thor-
Schizophrenia 900
ough history and physical examination, includ-
Traumatic brain injury 800
ing questions regarding changes in cognition,
Bipolar disorder 500–1500
seizures, brain trauma, recent changes in per-
Cerebral vascular disease 600
sonality, family history of neuropsychiatric ill-
Parkinson’s disease 133
nesses, and focal neurological signs (Table 3). It
Brain tumors 80 is important to bear in mind that a wide range of
Multiple sclerosis 60 conditions can produce neuropsychiatric symp-
Autism 50–100 toms (Table 4). With this information in hand,
Pick’s disease 24 the clinician can decide whether other testing,
Huntington’s disease 19 such as neuroimaging or electrophysiology, is
Narcolepsy 10–100 warranted. The results of these tests may help
Wilson’s disease 10 clarify diagnostic questions, inform treatment
Prion diseases <0.1 decisions, and inform prognosis. These tests

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 AREV402-ME61-09 ARI 11 December 2009 14:30

Midline medial (parasagittal) Lateral Inferior (bottom)

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CORTEX Dorsolateral prefrontal Orbitofrontal Anterior cingulate CORTEX

BASAL BASAL
Dorsolateral caudate
GANGLIA GANGLIA
Ventromedial caudate
Ventral putamen
Nucleus accumbens
Olfactory tubercle

Dorsomedial globus pallidus Rostromedial globus pallidus

Substantia nigra Ventral globus pallidus

THALAMUS Ventral anterior Dorsomedial Anterior THALAMUS

PONS Pontine nuclei PONS

Crus 1 & II Dentate nucleus

CEREBELLUM CEREBELLUM
Vermis Fastigial nucleus

Figure 1
The three major cortico-subcortical circuits important for neurobehavioral functions that are frequently impaired in neuropsychiatric
conditions are color-coded onto representative magnetic resonance images (top) and diagrammed below. The circuit that begins/ends in
dorsolateral prefrontal cortex (pink) mediates executive functions such as organization, planning, and attention. The circuit that
begins/ends in orbitofrontal cortex (blue) mediates socially appropriate behavior, impulse control, and empathy. The circuit that
begins/ends in anterior cingulate cortex ( green) produces motivation by balancing the inhibitory input of the supplemental motor area
with its own stimulus that supports wakefulness and arousal. (Adapted with permission from Mid-Atlantic Mental Illness Research,
Education and Clinical Center.)

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 AREV402-ME61-09 ARI 11 December 2009 14:30

Table 2 Functional anatomy essentials

Anatomic area Summary of functions
Dorsolateral prefrontal Cognition, executive function, focused attention
Orbital prefrontal Social conduct, insight, judgment, mood
Parietal Sensation, speech production/conduction, and deficit recognition
Mesial temporal lobe, hippocampus, Memory formation and storage
parahippocampus, amygdala
Basal ganglia Suppression/modulation of involuntary movements; contributes to memory, cognition,
behavior, and mood
Thalamus Key “relay station” for memory, emotion, cognition, behavior, motor, and sensory functions
Hypothalamus Physiological response to emotional stimuli; temperature control, sleep, water metabolism,
hormone secretion, satiety, circadian rhythms
Pons Contains locus ceruleus (norepinephrine production) and portions of the reticular formation
(alertness)
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Cerebellum Equilibrium, fine motor coordination; associated with cognition and executive functions
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alone cannot make a neuropsychiatric diagno-
sis (with a few exceptions, e.g., space-occupying
lesions and infections); nor can they specify a
psychiatric treatment plan or prognosis. They
must be incorporated into a comprehensive for-
mulation of the clinical picture. As noted above,
the emotion, memory, and behavioral func-
tions of the brain occur in a series of complex
circuits with inhibitory and excitatory neuro-
transmission occurring in response to sensory
input and social context (Figure 1). Thus, a
systems-theory approach to brain function can
be helpful in placing neurodiagnostic results in
perspective (11).
Computed tomography (CT) and magnetic
resonance imaging (MRI) are the techniques

Table 3 Focused clinical examination

History of present illness (from patient and/or secondary sources)
Chief complaint and history of present illness
Risk factors: developmental, brain injury or disease, alcohol and drug use, poison/toxin exposure, polypharmacy with drug
interactions, sexually transmitted diseases, uncontrolled hypertension, recent travel to high-risk environments (e.g., farms, outside of
the United States), eating raw or undercooked meats
Recent changes: appetitive functions, personality, mentation, behavior (especially aggression), cognitive changes, staring spells with
loss of time
Family and social history
Past psychiatric and neurological history
Review of systems, both general medical and psychiatric
Allergies
Mental status examination
Speech: articulation, production, recognition, prosody
Movement: strength, tone, posture, gait, speed and smoothness of initiation/execution, presence of abnormal movements
(e.g., tremor, tics, stereotypy), presence of abnormal action (e.g., perseveration, environment-driven responses)
Mental: orientation; affect; mood; attention; memory; thought (form and content); language (e.g., reading, writing, naming);
visuospatial skills; awareness of deficit; grooming; suicidal and homicidal ideas, intent, plans; judgment; insight; ability to abstract
Other: primitive reflexes, neurological soft signs
General physical examination

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Table 4 Conditions producing neuropsychiatric symptoms

Type of condition Examples
Developmental Autism, Down’s syndrome, seizure disorders
Degenerative Alzheimer’s disease, amyotrophic lateral sclerosis, central pontine myelinolysis, Huntington’s disease,
Parkinson’s disease, Pick’s disease
Metabolic Adrenal cortical disease, B12 deficiency, electrolyte imbalance, hypoglycemia, hypothyroidism, hypoxia,
parathyroid disease, thiamine deficiency, uremia, Wilson’s disease
Poisons/toxins Carbon monoxide, cyanide, heavy metals (e.g., lead, mercury, arsenic, cadmium), methanol, organophosphates
(e.g., pesticides, neurotoxins), solvents (e.g., toluene, glue, gasoline), intoxication or withdrawal (e.g., alcohol,
hallucinogens, opiates, stimulants, sedatives, hypnotics)
General medical Infections (e.g., hepatitis C, AIDS, brain abscess, prion disease, viral encephalitis, meningitis, toxoplasmosis,
conditions urinary tract infection)
Neoplasms (e.g., glioma, hypothalamic hamartoma, meningioma, pituitary tumors, metastatic tumors)
Traumas (e.g., closed head injury, postoperative damage, axonal shearing injury, subdural hematomas)
Annu. Rev. Med. 2010.61:121-133. Downloaded from www.annualreviews.org

Vascular (e.g., aneurysms, arteriovenous malformations, cerebrovascular accidents, lacunar infarcts if multiple)
Immune (e.g., multiple sclerosis, systemic lupus erythematosus)
Organ failure (e.g., chronic obstructive pulmonary disease, congestive heart failure, hepatic encephalopathy,
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renal failure)

used for structural brain imaging (12). They
provide information about the physical state of
the brain, including structural integrity. Clin-
ically utilized functional imaging techniques
that measure some aspect of brain metabolic
state include positron-emission tomography
(PET) and single-photon-emission computed
tomography (SPECT) (12). These provide
some measure (e.g., blood flow, glucose uptake,
oxygen extraction) indirectly related to brain
activity. In addition, functional imaging tech-
niques are available (generally only in academic
settings) to measure various neurotransmit-
ter receptor systems (13). Electrophysiological
techniques measure neuronal activity directly
(14). These include electroencephalography,
evoked potential and event-related potential
studies, polysomnography, and magnetoen-
cephalography.
The importance of imaging in patients with
dementia or significant cognitive change is well
established. Imaging of the cognitively im-
paired patient may assist in the differential di-
agnosis of Alzheimer’s disease, multi-infarct de-
mentia, or cognitive decline due to another
cause (15, 16). In addition, several recent stud-
ies support the utility of imaging nondemented
psychiatric patients. In a retrospective study of
referrals for MRI made by psychiatrists in a
Veterans Administration medical center due to
suspected “organic syndromes,” Erhart et al.
found that useful clinical indications included
subsyndromal cognitive deficits, unusual age
at symptom onset, unusual symptom evolu-
tion, personality changes, accompanying neu-
rological signs/symptoms, unusual symptoms
(symptoms outside clinical norms), and sus-
tained confusion/delirium (17). In a retrospec-
tive study of hospitalized patients referred for
CT or MRI at a Swiss university psychiatric
clinic either for screening purposes or to eval-
uate signs, symptoms, or laboratory values sug-
gestive of a neuropsychiatric condition, Mueller
et al. found that focal neurological signs, ad-
vanced age, and history of potential risk fac-
tors (e.g., head injury, seizures, substance abuse)
were the clinical findings most often associated
with imaging abnormalities (18). Clinical in-
dications for neuroimaging are summarized in
Table 5. Functional imaging (SPECT, PET)
may be even more useful than structural imag-
ing (CT, MRI). Sheehan & Thurber’s prospec-
tive study of referrals in a small rural hospital
made by a psychiatrist based on strict guide-
lines (history of traumatic brain injury, atyp-
ical symptom presentation, and/or symptoms

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Table 5 Clinical indications for imaging in psychiatric patients

Medical conditions or working diagnoses
Traumatic brain injury (including sudden deceleration or blast injuries)
Significant alcohol abuse
Seizure disorders with psychiatric symptoms
Movement disorders
Autoimmune disorders
Eating disorders
Poison or toxin exposure
Delirium
Clinical factors
Psychiatric symptoms outside “clinical norms” or with any unusual presentation or course
New onset mental illness after age 50
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Presentations at an atypical age for the working diagnosis

Initial psychotic break
Focal neurological signs
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Catatonia
Dementia or cognitive decline
Sudden personality changes

refractory to standard treatments) for SPECT management (either diagnosis or treatment) in

imaging found that 81% (51/63) had clearly ab-
normal perfusion scans (19). In general, patients
whose clinical symptoms do not fit the clas-
sic historical picture for the working diagnosis
should be considered for some form of func-
tional imaging (15, 20–29). Excluding a gen-
eral medical condition (e.g., delirium) and ex-
cluding a specific neurological problem (e.g.,
epilepsy) are the most frequent reasons for an
electrophysiology referral (14). Clinical indica-
tions for electrophysiology are unusual presen-
tations and atypical age of onset.
Presence of a brain abnormality may
change the diagnosis, support alterations in
the treatment plan, and/or impact prognosis.
Erhart et al. reported imaging abnormalities in
55% (138/253) and found that treatment was
changed in 15% (38/253) as a result of MRI
findings (17). In contrast, Mueller et al. re-
ported unequivocal imaging abnormalities in
only 14% (62/435) and a change in therapeu-
tic management in <1% (18). This contrast
is likely due, at least in part, to the very dif-
ferent bases for referral. Sheehan & Thurber
found that SPECT results altered clinical
79% (50/63) of cases (19). Neuroimaging for
differential diagnosis may clarify directions for
treatment. Acetylcholinesterase inhibitors are
helpful in the management of early-stage cog-
nitive impairment. Finding brain lesions can
alert the clinician to avoid psychotropic agents
suspected to slow neuronal repair (e.g., typi-
cal neuroleptics) and agents documented to in-
crease confusion in the brain-injured patient
(e.g., lithium or strongly anticholinergic agents)
(30). If periventricular white-matter abnormal-
ities are seen on imaging, then small-vessel
hypertensive disease (poorly controlled blood
pressure) may be present. More aggressive con-
trol of blood pressure is then indicated (31).
Future Directions
One important application of the wide range
of evaluative modalities now available is basic
research into the neurobiological substrates of
each disorder (32–36). This has the potential to
inform and improve both diagnosis and treat-
ment (10). For example, functional magnetic
resonance imaging (fMRI) in near relatives of

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 AREV402-ME61-09 ARI 11 December 2009 14:30

patients with schizophrenia has shown a sim-
ilar (but milder) pattern of brain abnormali-
ties, suggesting that it may be possible to use
imaging indices as biomarkers (37). Also un-
der consideration is incorporation of imaging-
based information, such as fMRI biomarkers,
into the major systems for classifying psychi-
atric disorders (38). Studies of several neu-
ropsychiatric disorders support the potential of
imaging-based measures (e.g., structural mea-
sures, blood-flow-based measures) for predict-
ing and/or tracking response to treatment (36,
37, 39–41). Up until recently, fMRI data analy-
sis depended on postprocessing because of the
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Parkinson’s disease from conditions such as hy-
permanganesemia, and imaging receptor occu-
pancy in order to determine correct dosages for
new drugs (13).
TREATMENT OF
NEUROPSYCHIATRIC DISEASE
As in other areas of medicine, a biopsychoso-
cially oriented disease-management model is
now standard of practice in neuropsychia-
try (43). There is an increasing emphasis on
evidence-based medicine and treatment opti-
mization (9). Implementation science is impor-

heavy computational demands. It is now feasi- tant to these efforts, as facilitating adoption
ble to process fMRI data in real time, allow- of evidence-based practices can be challenging
ing this imaging technique to be used as part (44, 45).
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of neurofeedback training (37). Magnetic res-

onance spectroscopy (MRS) is also advancing
rapidly. New approaches allow spectroscopic
imaging acquisitions in less than a minute (42).
Results from MRS studies of glutamate in
autism and schizophrenia have implications for
both pathophysiology and treatment (42). Ex-
citing developments in molecular neuroimag-
ing include imaging of neuroinflammation with
ligands for the peripheral benzodiazepine re-
ceptor (present in activated microglia), using
ligands for the dopamine system to differentiate
Pychotherapeutic and
Behavioral Treatments
The quality of the clinician-patient relation-
ship is fundamental to the efficacy of psy-
chotherapeutic and behavioral interventions.
It is essential to build and maintain a solid
therapeutic relationship, regardless of the spe-
cific treatment approach (Table 6) or goal.
Psychotherapeutic and behavioral treatments
can be used alone or in combination with

Table 6 Psychotherapeutic and behavioral treatments

Therapy type
Psychoanalytic
(psychodynamic)
Interpersonal
Rational-emotive (cognitive)
Behavioral (e.g., biofeedback,
relaxation, imagery, hypnosis,
skills training, conditioning)
Eye movement desensitization
and reprocessing
Principal premise
Unconscious factors (e.g., traumatic incidents, broken
relationships) motivate current behaviors
Both conscious and unconscious factors contribute to
unhealthy patterns of relationships
Negative thoughts (e.g., catastrophizing, jumping to
negative conclusions) strongly influence emotional
states
Pathological reaction patterns (e.g., phobias, anxiety
disorders) are learned behaviors
Pathological reaction patterns result from inadequate
processing of negative experiences
Focus of treatment
Assisting patients in developing insight
into these factors
Teaching examples to promote change
Helping patients change underlying
thoughts to gain more control over their
own emotional states
Teaching more adaptive responses.
Behavioral treatments such as cognitive
rehabilitation are also useful in helping
patients recover skills impaired by a
neurological event
Stimulating the patient’s own information
processing, thus allowing proper
integration and adaptive resolution

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ARI 11 December 2009 14:30
medication. Psychosocial interventions such as
cognitive-behavioral therapies (CBT) have the
strongest evidence base (43, 46, 47). CBT in-
cludes cognitive techniques (e.g., cognitive re-
structuring) and behavioral techniques (e.g.,
prolonged-exposure therapy), as well as other
approaches (e.g., eye movement desensitization
and reprocessing, psychodynamic psychother-
apy, skills training) (46). There have been few
properly controlled clinical trials of psychoan-
alytic approaches. The recent publication of a
randomized controlled trial of psychoanalytic
psychotherapy for treatment of panic disorder
suggests that this may change in the future
(48).
Somatic Treatments
The principal somatic treatment approach
is medication (49). At the present time,
medication selection is primarily symptom-
based (Table 7). Neuropsychiatric patients
commonly present with one or more of five
symptom constellations: depression (includes
apathy), psychosis (includes disturbances of
perception and/or thought), agitation (includes
anxiety and mania), behavioral dyscontrol
(includes aggression and impulsivity), and
cognitive disturbances (includes amnesia and
dementia). Many factors, particularly neu-
rological illness and medications, can affect
symptom presentation. Thus, it is essential to
fully consider the medical and neurological
condition of the patient in order to correctly
attribute symptoms and avoid unnecessary
or unhelpful medications. Social factors (e.g.
abuse, neglect, caregiver conflict, excessive or
diminished sensory stimuli) can also contribute
to or be the source of symptoms. It is important
to rule these out prior to initiating medications.
Because neuropsychiatric patients are of-
ten more sensitive to medication side effects,
the clinician is advised to limit polyphar-
macy by treating with as few medications
as possible. A slower medication titration
may be required, and frequent and persis-
tent reassessment for fine dosage adjustment
128 Taber · Hurley · Yudofsky
is recommended. Undertreatment is com-
mon. Be alert for signs of toxicity and drug-
drug interactions, especially additive anti-
cholinergic or sedative effects. If brain in-
jury is suspected, minimize the use of agents
that impair cognition, increase sedation, in-
crease disinhibition, or impede neuronal re-
covery (e.g., benzodiazepines, anticholinergics,
seizure-inducing agents, antidopaminergics).
Patients who do not achieve a good clinical
response to a single medication may benefit
from augmentation therapy (50). Electrocon-
vulsive therapy (ECT) is an option for de-
pression in patients who are not responsive to
medications, are rapidly deteriorating, or are
imminently suicidal.
Future Directions
Although research studies have provided many
exciting findings, these have not yet resulted in a
clear reduction in morbidity or mortality from
mental illness (10, 47). Even trials of medica-
tions with the strongest evidence base delivered
under optimal clinical conditions achieved re-
mission in less than one third of patients (47).
Neuroscience research elucidating the specific
mechanisms of action of neuropsychiatric med-
ications is essential to developing pharmaco-
logical interventions that provide higher effi-
cacy for specific symptom domains with fewer
side effects (51). Basic research into the neuro-
biological substrates of each disorder is essen-
tial for understanding disease processes suffi-
ciently to develop interventions to normalize
function (33). Research is beginning to shed
light on the factors that underlie individual dif-
ferences in medication response. For example,
differences in dopamine release (measured in
vivo) and dopamine terminal density in caudate
(measured post mortem) correlate with treat-
ment response/resistance to antipsychotics in
patients with schizophrenia (52).
New noninvasive methods to stimulate the
brain are being evaluated as treatment ap-
proaches for neuropsychiatric illnesses. Vagal
nerve stimulation, originally developed as a
 AREV402-ME61-09 ARI 11 December 2009 14:30
Table 7 Summary of somatic treatments by common symptom groupings
Symptom constellation
Depression (includes apathy). Often
associated with neurological diseases
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Psychosis (includes disturbances of
perception and/or thought)
Agitation (includes anxiety and mania).
Often associated with neurological
diseases, medical conditions (e.g., urinary
tract infection), or medications
Behavioral dyscontrol (includes aggression
and impulsivity). Care must be taken to
differentiate these states from the agitation
constellation of symptoms. They are often
associated with neurological diseases,
which will influence preferred treatment
Treatment
Selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine,
sertraline, paroxetine, citalopram
Selective serotonin-norepinephrine
reuptake inhibitors (SNRIs), e.g.,
venlafaxine, duloxetine
Tricyclic antidepressants, e.g.,
nortriptyline, desipramine,
amitriptyline, doxepin
Atypical antidepressants, e.g.,
bupropion, mirtazapine
Psychostimulants, e.g.,
methylphenidate,
dextroamphetamine
Electroconvulsive therapy (ECT)
Atypical antipsychotics,a
e.g., risperidone, quetiapine,
aripiprazole
Typical antipsychotics, e.g.,
haloperidol, perphenazine
Anticonvulsants (e.g.,
carbamazepine, sodium valproate,
gabapentin, lamotrigine), beta
blockers, or atypical antipsychotics
SSRIs
Buspirone, hyroxyzine,
benzodiazepines
Atypical antipsychotics
Benzodiazepines
Typical antipsychotics
Anticonvulsants or atypical
antipsychotics
SSRIs
Beta blockers
www.annualreviews.org • Neuropsychiatric Disorders
Indications and notes
Generally considered the first-line treatment
for depression
Also first-line treatments but should not be
taken in conjunction with monoamine
oxidase inhibitors (MAOIs)
Useful but may be more difficult to tolerate
and carry higher risk of cardiac complications
and overdose
Useful but caution is needed. Bupropion
carries the risk of seizures
Useful but caution is needed. Stimulants
should not be prescribed for those with
histories of substance abuse
Effective for depression that has not responded
to medications, or when symptoms are very
severe and rapid decompensation is likely
Generally considered the first-line treatment
for psychosis
Useful but may be more difficult to tolerate,
particularly for patients with neurological
disease
Generally considered the first-line treatment
for agitation or mania. Use of lithium in
patients with known neuropsychiatric illness
is more risky due to the potential for delirium
Generally considered the first-line treatment
for anxiety
Also for anxiety. Buspirone is best tolerated if
the dose is tapered up slowly and a full
therapeutic trial is given before consideration
of agent failure. Benzodiazepines should be
avoided for long-term treatment
Generally considered the first-line treatment
for acute behavioral dyscontrol
Useful for acute behavioral dyscontrol but
require caution
Very useful; many are available in both oral
and intramuscular forms
May be useful for prolonged behavioral
dyscontrol
Have occasionally proved helpful for
prolonged behavioral dyscontrol
Successful with a slow titration in severe cases
of prolonged behavioral dyscontrol
(Continued )
129
 AREV402-ME61-09 ARI 11 December 2009 14:30
Table 7 (Continued )
Symptom constellation Treatment
Cognitive disturbances (includes mild Acetylcholinesterase inhibitors, e.g.,
cognitive impairment and dementia) donepezil, rivastigmine,
galantamine
NMDA inhibitors, e.g., memantine
Psychostimulants, modafinil
a
Atypical antipsychotics have been associated with increased mortality in patients with dementia. Clozapine is an atypical antipsychotic with strong
research support for efficacy, but it is considered a second- or third-line agent because of its side-effect profile.
treatment for epileptic seizures, has been
Annu. Rev. Med. 2010.61:121-133. Downloaded from www.annualreviews.org
approved for treatment-resistant depression
(53). It may also be useful for some anxiety
disorders (53). Repetitive transcranial magnetic
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stimulation (rTMS) is another promising tech-
nique (53, 54). Initial clinical trials have
been done in several neuropsychiatric dis-
orders, including depression, schizophrenia,
and obsessive-compulsive disorder (54). Recent
studies that combined rTMS with antidepres-
sant treatment indicate that it may also be use-
ful as an augmentation therapy (54). It is also
possible to use TMS at much higher levels to
induce seizures, a new technique called mag-
netic seizure therapy (MST) (55). It is easier to
do focal stimulation with MST than with ECT,
and there is hope of achieving therapeutic ef-
ficacy without side effects by targeting specific
areas of the brain.
Invasive techniques are used much less of-
ten (53, 56, 57). As noted in recent reviews, ab-
lative surgery has shown some success in pa-
tients with treatment-resistant depression or
obsessive-compulsive disorder. Worrisome side
effects, both acute and long-term, have been
reported in some studies. There is a grow-
ing interest in the less destructive approach of
deep brain stimulation (DBS). DBS is presently
used primarily to treat movement disorders
such as Parkinson’s disease. Some of these pa-
tients experience improvements in mood, sug-
gesting that DBS may be useful in neuropsy-
chiatric conditions (53, 56, 57). DBS has in-
duced sustained remission of symptoms in a
130 Taber · Hurley · Yudofsky
Indications and notes
Generally considered the first-line treatment
for dementia/memory deficits
May be useful either alone or as an add-on for
moderate or severe dementia
Useful for treatment of decreased
concentration and focus
substantial portion of patients with treatment-
resistant depression, although many more stud-
ies are needed (36).
CONCLUSION
Our best short-term single modality treat-
ments, whether drug or psychosocial, yield
a 60% response rate, with combined treat-
ment performing slightly better. While some
studies suggest that longer duration treat-
ment improves outcomes, fewer patients reach
remission or recover fully than respond, illus-
trating the fact that we desperately need im-
proved treatments if we are to make progress
toward a world without mental illness. We also
need to know how to personalize treatments so
that patients who stand to benefit from a treat-
ment will get it and those who will be harmed
by it will get a different hopefully equally ef-
fective treatment. Thus, while we have made
substantial progress, what is left to learn dwarfs
what we now know (43).
The interplay between an individual’s biol-
ogy (genetic endowment) and life experiences
is an area of study that is of great importance
to neuropsychiatry (33, 43, 47). At the present
time, mental illnesses are diagnosed on the ba-
sis of symptoms, typically at a relatively late
stage. Early diagnosis based on biomarkers may
make it possible to intervene prior to the devel-
opment of severe mental illness (10, 47, 58).
Specific allelic variations in neurotransmitter-
related functions (e.g., synthesis, uptake) are
 AREV402-ME61-09 ARI 11 December 2009 14:30

associated with differences in vulnerability to molecular, cellular, and systems neuroscience

trauma. They may also underlie individual dif- research will enable early recognition, optimal
ferences in response to particular treatment differential diagnosis, and intervention tailored
modalities. The hope is that future advances in to the individual.

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

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Annual Review of
Medicine

Contents Volume 61, 2010

Using Genetic Diagnosis to Determine Individual

Therapeutic Utility
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Emotion Recollected in Tranquility: Lessons Learned
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from the COX-2 Saga

Tilo Grosser, Ying Yu, and Garret A. FitzGerald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p17
Progressive Multifocal Leukoencephalopathy in Patients on
Immunomodulatory Therapies
Eugene O. Major p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
The Future of Antiplatelet Therapy in Cardiovascular Disease
Carlo Patrono and Bianca Rocca p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Pharmacogenetics of Warfarin
Farhad Kamali and Hilary Wynne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63
Heparin-Induced Thrombocytopenia
Gowthami M. Arepally and Thomas L. Ortel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23
Clemens Bergwitz and Harald Jüppner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p91
Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary
Disease
Jeffrey A. Whitsett, Susan E. Wert, and Timothy E. Weaver p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Diagnosis and Treatment of Neuropsychiatric Disorders
Katherine H. Taber, Robin A. Hurley, and Stuart C. Yudofsky p p p p p p p p p p p p p p p p p p p p p p p p p p p 121
Toward an Antibody-Based HIV-1 Vaccine
James A. Hoxie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 135
HIV-1 Vaccine Development After STEP
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Growing Up with HIV: Children, Adolescents, and Young Adults with
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Rohan Hazra, George K. Siberry, and Lynne M. Mofenson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 169

v
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H5N1 Avian Influenza: Preventive and Therapeutic Strategies

Against a Pandemic
Suryaprakash Sambhara and Gregory A. Poland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 187
Revascularization for Coronary Artery Disease: Stents Versus Bypass
Surgery
Spencer B. King III, John Jeffrey Marshall, and Pradyumna E. Tummala p p p p p p p p p p p p p 199
Controversies in the Use of Drug-Eluting Stents for Acute Myocardial
Infarction: A Critical Appraisal of the Data
Rahul Sakhuja and Laura Mauri p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
Arrythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment
Srijita Sen-Chowdhry, Robert D. Morgan, John C. Chambers,
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Contemporary Use of Ventricular Assist Devices
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Stress Cardiomyopathy
Yoshihiro J. Akashi, Holger M. Nef, Helge Möllmann, and Takashi Ueyama p p p p p p p p p p p 271
Stem Cells in the Treatment of Heart Disease
Stefan Janssens p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287
Biological Mechanisms Linking Obesity and Cancer Risk:
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Darren L. Roberts, Caroline Dive, and Andrew G. Renehan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
Hepatocellular Carcinoma: Novel Molecular Approaches for
Diagnosis, Prognosis, and Therapy
Augusto Villanueva, Beatriz Minguez, Alejandro Forner, Maria Reig,
and Josep M. Llovet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Molecular Diagnosis and Therapy of Kidney Cancer
W. Marston Linehan, Gennady Bratslavsky, Peter A. Pinto, Laura S. Schmidt,
Len Neckers, Donald P. Bottaro, and Ramaprasad Srinivasan p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Myelodysplastic Syndromes
Bart L. Scott and H. Joachim Deeg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Nanotechnology Applications in Surgical Oncology
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Emerging Molecular Targets for the Treatment of Nonalcoholic Fatty
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Giovanni Musso, Roberto Gambino, and Maurizio Cassader p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 375
Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes
and Mechanisms of Action
Francesco Rubino, Philip R. Schauer, Lee M. Kaplan, and David E. Cummings p p p p p p p p 393

vi Contents
 AR402-FM ARI 16 December 2009 2:21

Genetic Aspects of Pancreatitis

David C. Whitcomb p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Anorexia Nervosa: Current Status and Future Directions
Evelyn Attia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 425
Structural Variation in the Human Genome and its Role in Disease
Pawel Stankiewicz and James R. Lupski p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 437
Surgical Innovations Arising from the Iraq and Afghanistan Wars
Geoffrey S.F. Ling, Peter Rhee, and James M. Ecklund p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Medicare Part D: Ongoing Challenges for Doctors and Patients
Gretchen Jacobson and Gerard Anderson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469
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Indexes
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Cumulative Index of Contributing Authors, Volumes 57–61 p p p p p p p p p p p p p p p p p p p p p p p p p p p 477

Cumulative Index of Chapter Titles, Volumes 57–61 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 481

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

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Contents vii