3538 PART 13 Neurologic Disorders

at lower doses with minimal side effects. However, the response to

ketamine is transient, which has led to several approaches to maintain

treatment response, such as repeated ketamine delivery. The mechanism underlying ketamine’s antidepressant action is not known, and

its action as an NMDA receptor antagonist has recently been called

into question. Nevertheless, ketamine’s striking clinical efficacy has

stimulated animal research on the role of glutamate neurotransmission

and synaptic plasticity in key limbic regions. Recent evidence supports

a role for TORC1 or BDNF activation, as blockade of either blocks the

antidepressant-like effects of ketamine in animal models. Mechanisms

by which ketamine activates these signaling cascades are currently an

active area of investigation.

A major goal in the field of substance use disorders has been to

identify neuroadaptive mechanisms that lead from recreational use to

addiction. Such research has determined that repeated intake of abused

drugs induces specific changes in cellular signal transduction, leading

to changes in synaptic strength (long-term potentiation or depression)

and neuronal structure (altered dendritic branching or cell soma size)

within the brain’s reward circuitry. These drug-induced modifications are mediated in part by changes in gene expression, achieved

by regulation of transcription factors (e.g., CREB [cAMP response

element-binding protein] and ΔFosB [a Fos family protein]) and their

target genes. Such alterations in gene expression are associated with

lasting alterations in epigenetic modifications, including histone acetylation and methylation and DNA methylation. These adaptations provide opportunities for developing treatments targeted to drug-addicted

individuals. The fact that the spectrum of these adaptations differs in

part depending on the particular addictive substance used raises hope

that treatments could be developed that are specific for different classes

of addictive drugs and less likely to disturb basic mechanisms that govern normal motivation and reward.

Increasingly, causal relationships are being established between

individual molecular and cellular adaptations and specific behavioral

abnormalities that characterize the addicted state. For example, acute

activation of μ-opioid receptors by morphine or other opiates activates

Gi/o proteins, leading to inhibition of adenylyl cyclase (AC), resulting

in reduced cyclic AMP (cAMP) production, protein kinase A (PKA)

activation, and activation of the transcription factor CREB. Repeated

administration of these drugs (Fig. 451-2) evokes a homeostatic

response involving upregulation of ACs and PKA and increased activation of CREB. Such upregulation of cAMP-CREB signaling has been

identified in the locus coeruleus (LC), periaqueductal gray, ventral

tegmental area (VTA), nucleus accumbens (NAc), and several other

central nervous system (CNS) regions and contributes to opiate craving and signs of opiate withdrawal. The fact that endogenous opioid

peptides do not produce tolerance and dependence, while morphine

and heroin do, may relate to the observation that, unlike endogenous

opioids, morphine and heroin are weak inducers of μ-opioid receptor

desensitization and endocytosis. Therefore, these drugs cause prolonged receptor activation and inhibition of ACs, which provides a

powerful stimulus for the upregulation of cAMP-CREB signaling that

characterizes the opiate-dependent state.

■ SYSTEMS NEUROSCIENCE

The study of interconnected brain circuits that drive behavior has been

greatly advanced through newer methods in brain imaging that have

documented abnormalities in neural function and connectivity in

psychiatric disorders. Electroceutical devices, which use electrical or

magnetic stimulation to control neuronal activity, have had some success in depression, obsessive-compulsive disorder, pain, and addiction.

The past decade has also witnessed the development of revolutionary

new techniques—optogenetics, designer receptors, and ligands—that

provide unprecedented temporal and spatial control of neural circuits.

The development of genetically encoded calcium detectors and electrode arrays has allowed in vivo monitoring of thousands of neurons

in multiple brain regions simultaneously. Advances in histology and

microscopy now permit three-dimensional imaging of specific proteins

in the intact brain, while advances in endoscopic microscopy allow

imaging of hundreds of neurons within deep brain structures in awake,

freely moving animals. These new methods are revolutionizing our

ability to understand the circuit basis of brain function.

Positron emission tomography (PET), diffusion tensor imaging

(DTI), and functional magnetic resonance imaging (fMRI) have

identified neural circuits that contribute to psychiatric disorders, for

example, defining the neural circuitry of mood within the brain’s

limbic system (Fig. 451-3). Integral to this system are the NAc (important also for brain reward—see below), amygdala, hippocampus, and

regions of prefrontal cortex. Recent optogenetic research in animals,

where the activity of specific types of neurons in defined circuits can

be controlled with light, has confirmed the importance of this limbic

circuitry in controlling depression-related behavioral abnormalities.

Given that many symptoms of depression (so-called neurovegetative

symptoms) involve physiologic functions, a key role for the hypothalamus is presumed as well. A subset of depressed individuals shows a

small reduction in hippocampal size, as noted above. In addition, brain

imaging investigations have revealed increased activation of the amygdala by negative stimuli and reduced activation of the NAc by rewarding stimuli. There is also evidence for altered activity in prefrontal

cortex, such as hyperactivity of subgenual area 25 in anterior cingulate

cortex. Such findings have led to trials of deep brain stimulation (DBS)

of either the NAc or subgenual area 25 (see Fig. 30-1), which appears

to be therapeutic in some severely depressed individuals.

In schizophrenia, structural and functional imaging studies have

confirmed earlier pathologic studies that show enlargement of the ventricular system and reduction of cortical and subcortical gray matter

CREB

Altered gene expression

Nucleus

Regulation of

proteins by PKA

phosphorylation

Increased

excitability

Ca2+

AC

cAMP

PKA

-opioid

receptor

C C

R R

C C

+

+

+

– –

P

Gi/o

K+

FIGURE 451-2 Opiate action in the locus coeruleus (LC). Binding of opiate agonists

to μ-opioid receptors on LC neurons catalyzes nucleotide exchange on Gi

 and Go

proteins, leading to inhibition of adenylyl cyclase (AC), neuronal hyperpolarization

via activation of K+

 channels and perhaps inhibition of Ca2+ channels. Inhibition of

AC reduces protein kinase A (PKA) activity and phosphorylation of several PKA

substrate proteins, thereby altering their function. For example, opiates reduce

phosphorylation of the cAMP response element-binding protein (CREB), which

initiates longer term changes in neuronal function. Chronic administration of opiates

increases levels of AC isoforms, PKA catalytic (C) and regulatory (R) subunits, and

the phosphorylation of several proteins, including CREB (indicated by red arrows).

These changes contribute to the altered phenotype of the drug-addicted state. For

example, the excitability of LC neurons is increased by enhanced cAMP signaling.

Activation of CREB causes upregulation of AC isoforms and tyrosine hydroxylase,

the rate-limiting enzyme in catecholamine biosynthesis.

3539Biology of Psychiatric Disorders CHAPTER

Amy

451

NAc

HP

LC

DR

VTA

Hyp

FC

Glutamatergic

GABAergic

Dopaminergic

Peptidergic

FIGURE 451-3 Neural circuitry of depression and addiction. The figure shows a simplified summary of a series of

limbic circuits in brain that regulate mood and motivation and are implicated in depression and addiction. Shown

in the figure are the hippocampus (HP) and amygdala (Amy) in the temporal lobe, regions of prefrontal cortex,

nucleus accumbens (NAc), and hypothalamus (Hyp). Only a subset of the known interconnections among these brain

regions is shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons. The

ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures. Norepinephrine (from the

locus coeruleus [LC]) and serotonin (from the dorsal raphe [DR] and other raphe nuclei) innervate all of the regions

shown. In addition, there are strong connections between the hypothalamus and the VTA-NAc pathway. Important

peptidergic projections from the hypothalamus include those from the arcuate nucleus that release β-endorphin and

melanocortin and from the lateral hypothalamus that release orexin.

in frontal and temporal lobes and in the limbic system. Functional

imaging studies show reduced metabolic (presumably neural) activity

in the dorsolateral prefrontal cortex at rest and when performing tests

of executive function, including working memory. There is also evidence for impaired structural and task-related functional connectivity,

mainly in frontal and temporal lobes. The reduction in cortical thickness seen in schizophrenia is associated with increased cell packing

density and reduced neuropil (defined as axons, dendrites, and glial

cell processes) without an apparent change in neuronal cell number. Specific classes of interneurons in prefrontal cortex consistently

show reduced expression of the gene encoding the enzyme glutamic

acid decarboxylase 1 (GAD1), which synthesizes γ-aminobutyric

acid (GABA), the principal inhibitory neurotransmitter in the brain.

Recently, results from well-powered genome-wide association studies

point to synaptic pruning, including the involvement of microglia, as

a potential contributing mechanism. In the region of the genome most

strongly associated with schizophrenia risk, variations in the relative

expression of two isotypes of complement component 4, C4A and C4B,

have been found to account for a significant proportion of this genetic

signal. Studies of loss of C4 in mice show deficient synaptic pruning,

leading to the hypothesis that increased expression of C4A in humans

may result in excessive synaptic pruning. Such results point to the

potential for a gene-driven understanding of pathophysiology; however, the findings also leave some important questions unanswered.

The strongest effect haplotype in humans still only accounts for a very

small increase in risk, with an odds ratio of <1.3. In contrast, having

a sibling with schizophrenia increases risk approximately tenfold. In

short, whether this allele reflects a driving pathophysiologic mechanism remains to be determined. Moreover, humans have diverged at

the C4 locus compared with rodents such that only a single C4 isotype

is present in the mouse, preventing any

analysis of the putative effects of changing

the ratio of C4A to C4B—the phenomenon

associated with disease risk in humans.

Nonetheless, all the aforementioned findings support the notion that schizophrenia is a developmental neurodegenerative

disorder with some evidence pointing to

loss of cortical interneurons in frontal and

temporal lobes.

Work in rodent and nonhuman primate models of addiction has established

the brain’s reward regions as key neural

substrates for the acute actions of drugs of

abuse and for addiction induced in vulnerable individuals by repeated drug administration (Fig. 451-3). Midbrain dopamine

neurons in the VTA function normally as

rheostats of reward: they are activated by

natural rewards (food, sex, social interaction) or even by the expectation of such

rewards, and many are suppressed by the

absence of an expected reward or by aversive stimuli. These neurons thereby transmit crucial survival signals to the rest of

the limbic brain to promote reward-related

behavior, including motor responses to

seek and obtain the rewards (NAc), memories of reward-related cues and contexts

(amygdala, hippocampus), and executive

control of obtaining rewards (prefrontal

cortex).

Drugs of abuse alter neurotransmission through initial actions at different

classes of ion channels, neurotransmitter

receptors, or neurotransmitter transporters

(Table 451-1). Studies in animal models have demonstrated that although the

initial targets differ, the actions of these

drugs converge on the brain’s reward circuitry by promoting dopamine

neurotransmission in the NAc and other limbic targets of the VTA. In

addition, some drugs promote activation of opioid and cannabinoid

receptors, which modulate this reward circuitry. By these mechanisms,

drugs of abuse produce powerful rewarding signals, which, after

repeated drug administration, corrupt a vulnerable brain’s reward

circuitry in ways that promote addiction. Three major pathologic adaptations have been described. First, drugs produce tolerance in reward

circuits and increased activity in stress circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal

that promotes relapse. Second, sensitization to the rewarding effects of

the drugs and associated cues is seen during prolonged abstinence and

also triggers relapse. Third, executive function is impaired in such a

way as to increase impulsivity and compulsivity, both of which promote

relapse.

Imaging studies in humans confirm that addictive drugs, as well

as craving for them, activate the brain’s reward circuitry. In addition,

patients who abuse alcohol or psychostimulants show reduced gray

matter in the prefrontal cortex as well as reduced activity in anterior cingulate and orbitofrontal cortex during tasks of attention and

inhibitory control. It is thought that damage to these cortical areas

contributes to addiction by impairing decision-making and increasing

impulsivity.

■ NEUROINFLAMMATION

There is increasing evidence for the involvement of inflammatory

mechanisms in a wide range of psychiatric syndromes. For example, a

subset of depressed patients displays elevated blood levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and other proinflammatory cytokines. Moreover, rodents exposed to chronic stress exhibit

3540 PART 13 Neurologic Disorders

TABLE 451-1 Initial Actions of Drugs of Abuse

DRUG

NEUROTRANSMITTER

AFFECTED DRUG TARGET (ACTION)

Opiates Endorphins, enkephalins μ- and δ-opioid receptors

(agonist)

Psychostimulants

(cocaine,

amphetamine,

methamphetamine)

Dopamine Dopamine transporter

(antagonist—cocaine;

reverse transport—

amphetamine,

methamphetamine)

Nicotine Acetylcholine Nicotinic cholinergic

receptors (agonist)

Ethanol GABA GABAA receptors (positive

allosteric modulator)

Glutamate NMDA glutamate receptors

(antagonist)

Acetylcholine Nicotinic cholinergic

receptors (allosteric

modulator)

Serotonin 5-HT3

 receptor (positive

allosteric modulator)

Others Calcium-activated K+

 channel

(activator)

Marijuana Endocannabinoids

(anandamide,

2-arachidonoylglycerol)

CB1

 receptor (agonist)

Phencyclidine Glutamate NMDA glutamate receptor

(antagonist)

Abbreviations: GABA, γ-aminobutyric acid; NMDA, N-methyl-d-aspartate

similar increases in peripheral levels of these cytokines, and peripheral

or central delivery of those cytokines to normal rodents increases

their susceptibility to chronic stress. These findings have led to the

novel idea of using peripheral cytokines as biomarkers of a subtype of

depression and the potential utility of developing new antidepressants

that oppose the actions of specific cytokines.

Recent evidence has also linked proinflammatory signaling in

the brain to addiction, particularly to alcohol. Human alcoholism is

associated with impaired innate immunity, increases in circulating

proinflammatory cytokines, and increases in brain expression of

several immune-related genes. Many of these genes are expressed by

astrocytes and microglia, and by neurons under certain pathologic

conditions, where they play important roles in modifying neuronal

function and plasticity. For example, cytokine monocyte chemotactic

protein-1 (MCP-1) modulates the release of certain neurotransmitters

and, when administered into the VTA, increases neuronal excitability, promotes dopamine release, and increases locomotor activity.

Gene expression studies of alcohol drinking in mice have identified

a network of regulated neuroimmune proteins in brain, and a role

in regulation of alcohol consumption has been validated for several,

including chemokines MCP-1 and chemokine (C-C motif) ligand 3

(CCL3), beta-2 microglobulin, CD14, IL-1 receptor antagonist, and

cathepsins S and F. This work has led to discovery of anti-inflammatory

medications that reduce alcohol intake in animals, such as antagonists

of phosphodiesterase 4, which regulates cAMP availability, or agonists

of peroxisome proliferator-activated receptors (PPARs), which are

transcription factors that repress key inflammatory signaling molecules such as nuclear factor-κB (NF-κB) and nuclear factor of activated

T cells (NFAT). A major focus of current research is to define the sites

and mechanisms by which proinflammatory cytokines impair brain

function to elicit a depressive episode or promote drug abuse.

■ CONCLUSIONS

This brief narrative illustrates the substantial progress that is being made

in understanding the genetic and neurobiological basis of mental illness.

It is anticipated that biologic measures will be used increasingly to more

accurately diagnose and subtype psychiatric disorders and that targeted

therapeutics will become available for these complex conditions.

■ FURTHER READING

Gandal MJ et al: The road to precision psychiatry: Translating genetics into disease mechanisms. Nat Neurosci 19:1397, 2016.

Koob GF, Volkow ND: Neurobiology of addiction: A neurocircuitry

analysis. Lancet Psychiatry 3:760, 2016.

Rajasethupathy P et al: Targeting neural circuits. Cell 165:524, 2016.

Ron D, Barak S: Molecular mechanisms underlying alcohol-drinking

behaviours. Nat Rev Neurosci 17:576, 2016.

Sanders SJ et al: Insights into autism spectrum disorder genomic

architecture and biology from 71 risk loci. Neuron 87:1215, 2015.

Satterstrom FK et al: Large-scale exome sequencing study implicates

both developmental and functional changes in the neurobiology of

autism. Cell 180:568, 2020.

Willsey JA et al: Coexpression networks implicate human mid-fetal

deep cortical projection neurons in the pathogenesis of autism. Cell

155:997, 2013.

Wohleb ES et al: Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 17:497, 2016.

Psychiatric disorders are common in medical practice and may present

either as a primary disorder or as a comorbid condition. The prevalence of mental or substance use disorders in the United States is

~30%, but only one-third of affected individuals are currently receiving

treatment. Global burden of disease statistics indicates that 4 of the 10

most important causes of morbidity and attendant health care costs

worldwide are psychiatric in origin.

Changes in health care delivery underscore the need for primary

care physicians to assume responsibility for the initial diagnosis and

treatment of the most common mental disorders. Prompt diagnosis

is essential to ensure that patients have access to appropriate medical

services and to maximize the clinical outcome. Validated patient-based

questionnaires have been developed that systematically probe for signs

and symptoms associated with the most prevalent psychiatric diagnoses and guide the clinician into targeted assessment. The Primary Care

Evaluation of Mental Disorders (PRIME-MD; and a self-report form,

the Patient Health Questionnaire) and the Symptom-Driven Diagnostic System for Primary Care (SDDS-PC) are inventories that require

only 10 min to complete and link patient responses to the formal

diagnostic criteria of anxiety, mood, somatoform, and eating disorders

and to alcohol abuse or dependence. A variety of smart phone apps for

assessment and monitoring of psychiatric conditions and for psychological and pharmacologic treatment interventions are also available.

A physician who refers patients to a psychiatrist should know not

only when doing so is appropriate but also how to refer because societal

misconceptions and the stigma of mental illness impede the process.

Primary care physicians should base referrals to a psychiatrist on the

presence of signs and symptoms of a mental disorder and not simply

on the absence of a physical explanation for a patient’s complaint. The

physician should discuss with the patient the reasons for requesting

the referral or consultation and provide reassurance that he or she

will continue to provide medical care and work collaboratively with

the mental health professional. Consultation with a psychiatrist or

transfer of care is appropriate when physicians encounter evidence of

psychotic symptoms, mania, severe depression, or anxiety; symptoms

of posttraumatic stress disorder (PTSD); suicidal or homicidal preoccupation; or a failure to respond to first-order treatment. This chapter

reviews the clinical assessment and treatment of some of the most

common mental disorders presenting in primary care and is based on

452 Psychiatric Disorders

Victor I. Reus

3541Psychiatric Disorders CHAPTER 452

the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

(DSM-5), the framework for categorizing psychiatric illness used in

the United States. Eating disorders are discussed later in this chapter,

and the biology of psychiatric and addictive disorders is discussed

in Chap. 451.

■ GLOBAL CONSIDERATIONS

The DSM-5 and the tenth revision of the International Classification

of Diseases (ICD-10), which is used more commonly worldwide, have

taken somewhat differing approaches to the diagnosis of mental illness,

but considerable effort has been expended to provide an operational

translation between the two nosologies. Both systems are in essence

purely descriptive and emphasize clinical pragmatism, in distinction

to the Research Domain Criteria (RDOC) proposed by the National

Institute of Mental Health, which aspires to provide a causal framework

for classification of behavioral disturbance. None of these diagnostic

systems has as yet achieved adequate validation. The Global Burden of

Disease Study (2019), using available epidemiologic data, nevertheless

has reinforced the conclusion that, regardless of nosologic differences,

mental and substance abuse disorders are the major cause of life-years

lost to disability among all medical illnesses, affecting >300 million

individuals worldwide. There is general agreement that high-income

countries will need to build capacity in professional training in

low- and middle-income countries in order to provide an adequate

balanced care model for the delivery of evidence-based therapies for

mental disorders. Recent surveys that indicate a dramatic increase in

mental disorder prevalence in rapidly developing countries, such as

China, may reflect both an increased recognition of the issue, but also

the consequence of social turmoil, stigma, and historically inadequate

resources. A salient example of the ways in which societal disruption

and isolation may contribute to exacerbating already unmet mental

health needs can be seen in the COVID-19 pandemic, which has

resulted in an increased incidence of diagnosed psychiatric disorders

in both affected and unaffected individuals, as well as caregivers. The

need for improved prevention strategies and for more definitive and

effective interventional treatments remains a global concern.

ANXIETY DISORDERS

Anxiety disorders, the most prevalent psychiatric illnesses in the general community, are present in 15–20% of medical clinic patients. Anxiety, defined as a subjective sense of unease, dread, or foreboding, can

indicate a primary psychiatric condition or can be a component of, or

reaction to, a primary medical disease. The primary anxiety disorders

are classified according to their duration and course and the existence

and nature of precipitants.

When evaluating the anxious patient, the clinician must first determine whether the anxiety antedates or postdates a medical illness or

is due to a medication side effect. Approximately one-third of patients

presenting with anxiety have a medical etiology for their psychiatric

symptoms, but an anxiety disorder can also present with somatic symptoms in the absence of a diagnosable medical condition.

■ PANIC DISORDER

Clinical Manifestations Panic disorder is defined by the presence

of recurrent and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, shortness of

breath, chest pain, dizziness, and a fear of impending doom or death.

Paresthesias, gastrointestinal distress, and feelings of unreality are also

common. Diagnostic criteria require at least 1 month of concern or

worry about the attacks or a change in behavior related to them. The

lifetime prevalence of panic disorder is 2–3%. Panic attacks have a

sudden onset, developing within 10 min and usually resolving over the

course of an hour, and they occur in an unexpected fashion. Some may

occur when waking from sleep. The frequency and severity of panic

attacks vary, ranging from once a week to clusters of attacks separated

by months of well-being. The first attack is usually outside the home,

and onset is typically in late adolescence to early adulthood. In some

individuals, anticipatory anxiety develops over time and results in a

generalized fear and a progressive avoidance of places or situations

in which a panic attack might recur. Agoraphobia, which occurs commonly in patients with panic disorder, is an acquired irrational fear of

being in places where one might feel trapped or unable to escape. It

may, however, be diagnosed even if panic disorder is not present. Typically, it leads the patient into a progressive restriction in lifestyle and,

in a literal sense, in geography. Frequently, patients are embarrassed

that they are housebound and dependent on the company of others

to go out into the world and do not volunteer this information; thus,

physicians will fail to recognize the syndrome if direct questioning is

not pursued.

Differential Diagnosis A diagnosis of panic disorder is made

after a medical etiology for the panic attacks has been ruled out. A

variety of cardiovascular, respiratory, endocrine, and neurologic conditions can present with anxiety as the chief complaint. Patients with true

panic disorder will often focus on one specific feature to the exclusion

of others. For example, 20% of patients who present with syncope as

a primary medical complaint have a primary diagnosis of a mood,

anxiety, or substance abuse disorder, the most common being panic

disorder. The differential diagnosis of panic disorder is complicated by

a high rate of comorbidity with other psychiatric conditions, especially

alcohol and benzodiazepine abuse, which patients initially use in an

attempt at self-medication. Some 75% of panic disorder patients will

also satisfy criteria for major depression at some point in their illness.

When the history is nonspecific, physical examination and focused

laboratory testing must be used to rule out anxiety states resulting

from medical disorders such as pheochromocytoma, thyrotoxicosis,

or hypoglycemia. Electrocardiogram (ECG) and echocardiogram may

detect some cardiovascular conditions associated with panic such as

paroxysmal atrial tachycardia and mitral valve prolapse. In two studies,

panic disorder was the primary diagnosis in 43% of patients with chest

pain who had normal coronary angiograms and was present in 9% of

all outpatients referred for cardiac evaluation. Panic disorder has also

been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome.

Etiology and Pathophysiology The etiology of panic disorder is

unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial

aggregation; the disorder is concordant in 30–45% of monozygotic

twins, and genome-wide screens have identified suggestive risk loci.

Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium

lactate evokes an attack in two-thirds of panic disorder patients, as do

the α2

-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide

(CCK-4), and carbon dioxide inhalation. It is hypothesized that each

of these stimuli activates a pathway involving noradrenergic neurons

in the locus coeruleus and serotonergic neurons in the dorsal raphe.

Resting-state fMRI has identified abnormalities in the default mode

network involving the medial temporal lobe, with greater activation

in the sensorimotor cortex in panic disorder and in amygdala-frontal

connectivity in social anxiety disorder. Agents that block serotonin

reuptake can prevent attacks. Patients with panic disorder have a

heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic

intervention involves altering the patient’s cognitive interpretation of

anxiety-producing experiences as well as preventing the attack itself.

TREATMENT

Panic Disorder

Achievable goals of treatment are to decrease the frequency of panic

attacks and to reduce their intensity. The cornerstone of drug therapy is antidepressant medication (Tables 452-1 through 452-3).

Selective serotonin reuptake inhibitors (SSRIs) benefit the majority

of panic disorder patients and do not have the adverse effects of

tricyclic antidepressants (TCAs). Fluoxetine, paroxetine, sertraline,

and the selective serotonin-norepinephrine reuptake inhibitor

3542 PART 13 Neurologic Disorders

(SNRI) venlafaxine have received approval from the U.S. Food and

Drug Administration (FDA) for this indication. These drugs should

be started at one-third to one-half of their usual antidepressant dose

(e.g., 5–10 mg fluoxetine, 25–50 mg sertraline, 10 mg paroxetine,

venlafaxine 37.5 mg). Monoamine oxidase inhibitors (MAOIs)

are also effective and may specifically benefit patients who have

comorbid features of atypical depression (i.e., hypersomnia and

weight gain). Insomnia, orthostatic hypotension, and the need to

maintain a low-tyramine diet (avoidance of cheese and wine) have

limited their use, however. Antidepressants typically take 2–6 weeks

to become effective, and doses may need to be adjusted based on the

clinical response.

Because of anticipatory anxiety and the need for immediate

relief of panic symptoms, benzodiazepines are useful early in the

course of treatment and sporadically thereafter (Table 452-4).

FDA-approved agents include alprazolam and clonazepam. A recent

Cochrane review found no difference between antidepressants

and benzodiazepines in response rate, although benzodiazepines

were somewhat better tolerated by patients. In treatmentresistant cases, short-term augmentation with aripiprazole,

TABLE 452-1 Antidepressants

NAME

USUAL DAILY

DOSE (mg) SIDE EFFECTS COMMENTS

SSRIs

Fluoxetine (Prozac)

Sertraline (Zoloft)

Paroxetine (Paxil)

Fluvoxamine (Luvox)

Citalopram (Celexa)

Escitalopram (Lexapro)

10–80

50–200

20–60

100–300

20–60

10–30

Headache; nausea and other GI effects; jitteriness;

insomnia; sexual dysfunction; can affect plasma

levels of other medicines (except sertraline);

akathisia rare

Once-daily dosing, usually in the morning; fluoxetine

has very long half-life; must not be combined with

MAOIs

TCAs and Tetracyclics

Amitriptyline (Elavil)

Nortriptyline (Pamelor)

Imipramine (Tofranil)

Desipramine (Norpramin)

Doxepin (Sinequan)

Clomipramine (Anafranil)

Maprotiline (Ludiomil)

Protriptyline (Vivactil)

Trimipramine (Surmontil)

Amoxapine (Asendin)

150–300

50–200

150–300

150–300

150–300

150–300

25–150

15–40

75–200

100–300

Anticholinergic (dry mouth, tachycardia,

constipation, urinary retention, blurred vision);

sweating; tremor; postural hypotension; cardiac

conduction delay; sedation; weight gain

Nausea, anxiety, dry mouth

Drowsiness, constipation, dry mouth

Once-daily dosing, usually qhs; blood levels of most

TCAs available; can be lethal in overdose (lethal

dose = 2 g); nortriptyline best tolerated, especially

by elderly

FDA-approved for OCD

TID or QID dosing required

Lethality in OD, EPS possible

Mixed Norepinephrine/Serotonin Reuptake Inhibitors (SNRI) and Receptor Blockers

Venlafaxine (Effexor), XR 75–375 Nausea; dizziness; dry mouth; headaches; increased

blood pressure; anxiety and insomnia

Bid–tid dosing (extended-release available);

lower potential for drug interactions than SSRIs;

contraindicated with MAOIs

Desvenlafaxine (Pristiq) 50–400 Nausea, dizziness, insomnia Primary metabolite of venlafaxine; no increased

efficacy with higher dosing

Duloxetine (Cymbalta) 40–60 Nausea, dizziness, headache, insomnia, constipation May have utility in treatment of neuropathic pain and

stress incontinence

Mirtazapine (Remeron) 15–45 Somnolence, weight gain; neutropenia rare Once-a-day dosing; 5HT3 antagonist

Vilazodone (Viibryd) 40 Nausea, diarrhea, headache; dosage adjustment if

given with CYP3A4 inhibitor/stimulator

Also 5-HT1a receptor partial agonist

Vortioxetine (Trintellix) 5–20 Nausea, diarrhea, sweating, headache; low

incidence of sedation or weight gain

No specific p450 effects; 5-HT3a and 5-HT7

 receptor

antagonist, 5-HT1b partial agonist, and 5-HT1a agonist

Levomilnacipran (Fetzima) 40–120 Nausea, constipation, sweating; rare increase in

blood pressure/pulse

Most noradrenergic of SNRIs

Mixed-Action Drugs

Bupropion (Wellbutrin), CR,

XR

250–450 Jitteriness; flushing; seizures in at-risk patients;

anorexia; tachycardia; psychosis

Tid dosing, but sustained-release also available;

fewer sexual side effects than SSRIs or TCAs; may

be useful for adult ADD

Trazodone (Desyrel) 200–600 Sedation; dry mouth; ventricular irritability; postural

hypotension; priapism rare

Useful in low doses for sleep because of sedating

effects with no anticholinergic side effects

Trazodone extended-release

(Oleptro)

150–375 Daytime somnolence, dizziness, nausea

Nefazodone 300–600 Headache, nausea, dizziness Rare risk of liver failure, priapism

MAOIs

Phenelzine (Nardil)

Tranylcypromine (Parnate)

45–90

20–50

Insomnia; hypotension; edema; anorgasmia; weight

gain; neuropathy; hypertensive crisis; toxic reactions

with SSRIs; narcotics

May be more effective in patients with atypical

features or treatment-refractory depression

Isocarboxazid (Marplan) 20–60 Less weight gain and hypotension than phenelzine

Transdermal selegiline

(Emsam)

6–12 Local skin reaction, hypertension No dietary restrictions with 6-mg dose

Abbreviations: ADD, attention deficit disorder; EPS, extrapyramidal symptoms; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; MAOIs, monoamine oxidase

inhibitors; OCD, obsessive-compulsive disorder; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

3543Psychiatric Disorders CHAPTER 452

divalproex sodium, or pindolol has some evidence for efficacy.

There also is no clear difference in short-term efficacy between

psychological therapies and antidepressant or benzodiazepine treatment, alone or in combination.

Early psychotherapeutic intervention and education aimed at

symptom control enhance the effectiveness of drug treatment.

Patients can be taught breathing techniques, be educated about

physiologic changes that occur with panic, and learn to expose themselves voluntarily to precipitating events in a treatment program

spanning 12–15 sessions. Homework assignments and monitored

compliance are important components of successful treatment.

Once patients have achieved a satisfactory response, drug treatment

should be maintained for 1–2 years to prevent relapse. Controlled

trials indicate a success rate of 75–85%, although the likelihood of

complete remission is somewhat lower.

■ GENERALIZED ANXIETY DISORDER

Clinical Manifestations Patients with generalized anxiety disorder (GAD) have persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic arousal,

feeling “on edge” or restless, and insomnia (Table 452-5). Onset is

usually before age 20 years, and a history of childhood fears and social

inhibition may be present. The lifetime prevalence of GAD is 5–6%;

the risk is higher in first-degree relatives of patients with the diagnosis.

Interestingly, family studies indicate that GAD and panic disorder

segregate independently. More than 80% of patients with GAD also

suffer from major depression, dysthymia, or social phobia. Comorbid

substance abuse is common in these patients, particularly alcohol and/

or sedative/hypnotic abuse. Patients with GAD worry excessively over

minor matters, with life-disrupting effects; unlike in panic disorder,

complaints of shortness of breath, palpitations, and tachycardia are

relatively rare.

Etiology and Pathophysiology Most anxiogenic and anxiolytic

agents act on the γ-aminobutyric acid (GABA)A receptor/chloride

ion channel complex, implicating this neurotransmitter system in

the pathogenesis of anxiety and panic attacks. Benzodiazepines are

thought to bind two separate GABAA receptor sites: type I, which has

a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety

effects of the various benzodiazepines are influenced by their relative binding to alpha 2 and 3 subunits of the GABAA receptor, and

sedation and memory impairment to the alpha 1 subunit. Serotonin

(5-hydroxytryptamine [5-HT]), and 3α-reduced neuroactive steroids

(allosteric modulators of GABAA) also appear to have a role in anxiety,

and buspirone, a partial 5-HT1A receptor agonist, and certain 5-HT2A

and 5-HT2C receptor antagonists (e.g., mirtazapine and nefazodone)

may have beneficial effects.

TREATMENT

Generalized Anxiety Disorder

A combination of pharmacologic and psychotherapeutic interventions is most effective in GAD, but complete symptomatic relief is

rare. A short course of a benzodiazepine is usually indicated, preferably lorazepam, oxazepam, clonazepam or, alprazolam, although

only the last two are FDA approved. (The first two of these agents are

metabolized via conjugation rather than oxidation and thus do not

accumulate if hepatic function is impaired; the latter also has limited

active metabolites.) Treatment should be initiated at the lowest dose

possible and prescribed on an as-needed basis as symptoms warrant.

Benzodiazepines differ in their milligram per kilogram potency,

half-life, lipid solubility, metabolic pathways, and presence of active

metabolites. Agents that are absorbed rapidly and are lipid soluble,

such as diazepam, have a rapid onset of action and a higher abuse

potential. Benzodiazepines should generally not be prescribed for

>4–6 weeks because of the development of tolerance and the serious risk of abuse and dependence. Withdrawal must be closely

monitored as relapses can occur. It is important to warn patients

that concomitant use of alcohol or other sedating drugs may exacerbate side effects and impair their ability to function. An optimistic

approach that encourages the patient to clarify environmental precipitants, anticipate his or her reactions, and plan effective response

strategies is an essential element of therapy.

Adverse effects of benzodiazepines generally parallel their relative half-lives. Longer-acting agents, such as diazepam, chlordiazepoxide, flurazepam, and clonazepam, tend to accumulate

active metabolites, with resultant sedation, impairment of cognition,

and poor psychomotor performance. Shorter-acting compounds,

such as alprazolam, lorazepam, and oxazepam, can produce daytime anxiety, early-morning insomnia, and, with discontinuation,

TABLE 452-2 Management of Antidepressant Side Effects

SYMPTOMS COMMENTS AND MANAGEMENT STRATEGIES

Gastrointestinal

Nausea, loss of appetite Usually short-lived and dose-related; consider

temporary dose reduction or administration with

food and antacids

Diarrhea Famotidine, 20–40 mg/d

Constipation Wait for tolerance; try diet change, stool softener,

exercise; avoid laxatives

Sexual dysfunction Consider dose reduction; drug holiday

 Anorgasmia/impotence;

impaired ejaculation

Bethanechol, 10–20 mg, 2 h before activity, or

cyproheptadine, 4–8 mg, 2 h before activity, or

bupropion, 100 mg bid, or amantadine, 100 mg

bid/tid

Orthostasis Tolerance unlikely; increase fluid intake, use calf

exercises/support hose; fludrocortisone,

0.025 mg/d

Anticholinergic Wait for tolerance

Dry mouth, eyes Maintain good oral hygiene; use artificial tears,

sugar-free gum

Tremor/jitteriness Antiparkinsonian drugs not effective; use dose

reduction/slow increase; lorazepam, 0.5 mg bid, or

propranolol, 10–20 mg bid

Insomnia Schedule all doses for the morning; trazodone,

50–100 mg qhs

Sedation Caffeine; schedule all dosing for bedtime;

bupropion, 75–100 mg in afternoon

Headache Evaluate diet, stress, other drugs; try dose

reduction; amitriptyline, 50 mg/d

Weight gain Decrease carbohydrates; exercise; consider

fluoxetine

Loss of therapeutic benefit

over time

Related to tolerance? Increase dose or drug

holiday; add amantadine, 100 mg bid, buspirone,

10 mg tid, or pindolol, 2.5 mg bid

TABLE 452-3 Possible Drug Interactions with Selective Serotonin

Reuptake Inhibitors

AGENT EFFECT

Monoamine oxidase inhibitors Serotonin syndrome—absolute

contraindication

Serotonergic agonists, e.g., tryptophan,

fenfluramine, triptans

Potential serotonin syndrome

Drugs that are metabolized by P450

isoenzymes: tricyclics, other SSRIs,

antipsychotics, beta blockers, codeine,

triazolobenzodiazepines, calcium

channel blockers

Delayed metabolism resulting in

increased blood levels and potential

toxicity

Drugs that are bound tightly to plasma

proteins, e.g., warfarin

Increased bleeding secondary to

displacement

Drugs that inhibit the metabolism

of SSRIs by P450 isoenzymes, e.g.,

quinidine

Increased SSRI side effects

Abbreviation: SSRIs, selective serotonin reuptake inhibitors.

3544 PART 13 Neurologic Disorders

rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely

to habituate to the adverse psychomotor effects. Withdrawal from

the longer half-life benzodiazepines can be accomplished through

gradual, stepwise dose reduction (by 10% every 1–2 weeks) over

6–12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Physicians may need to switch the patient

to a benzodiazepine with a longer half-life or use an adjunctive medication such as a beta blocker or carbamazepine, before attempting

to discontinue the benzodiazepine. Withdrawal reactions vary in

severity and duration; they can include depression, anxiety, lethargy,

diaphoresis, autonomic arousal, and, rarely, seizures.

Buspirone is a nonbenzodiazepine anxiolytic agent. It is nonsedating, does not produce tolerance or dependence, does not interact with benzodiazepine receptors or alcohol, and has no abuse or

disinhibition potential. However, it requires several weeks to take

TABLE 452-4 Anxiolytics

NAME

EQUIVALENT PO

DOSE (mg) ONSET OF ACTION HALF-LIFE (h) COMMENTS

Benzodiazepines

Diazepam (Valium) 5 Fast 20–70 Active metabolites; quite sedating

Flurazepam (Dalmane) 15 Fast 30–100 Flurazepam is a prodrug; metabolites are active; quite sedating

Triazolam (Halcion) 0.25 Intermediate 1.5–5 No active metabolites; can induce confusion and delirium, especially in elderly

Lorazepam (Ativan) 1 Intermediate 10–20 No active metabolites; direct hepatic glucuronide conjugation; quite sedating;

FDA-approved for anxiety with depression

Alprazolam (Xanax) 0.5 Intermediate 12–15 Active metabolites; not too sedating; FDA-approved for panic disorder and

anxiety with depression; tolerance and dependence develop easily; difficult to

withdraw

Chlordiazepoxide (Librium) 10 Intermediate 5–30 Active metabolites; moderately sedating

Oxazepam (Serax) 15 Slow 5–15 No active metabolites; direct glucuronide conjugation; not too sedating

Temazepam (Restoril) 15 Slow 9–12 No active metabolites; moderately sedating

Clonazepam (Klonopin) 0.5 Slow 18–50 No active metabolites; moderately sedating; FDA-approved for panic disorder

Clorazepate (Tranxene) 15 Fast 40–200 Low sedation; unreliable absorption

Nonbenzodiazepines

Buspirone (BuSpar) 7.5 2 weeks 2–3 Active metabolites; tid dosing—usual daily dose 10–20 mg tid; nonsedating;

no additive effects with alcohol; useful for controlling agitation in demented or

brain-injured patients

Abbreviation: FDA, U.S. Food and Drug Administration.

TABLE 452-5 Diagnostic Criteria for Generalized Anxiety Disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more

days than not for at least 6 months, about a number of events or activities

(such as work or school performance).

B. The individual finds it difficult to control the worry.

C. The anxiety and worry are associated with three (or more) of the following six

symptoms (with at least some symptoms present for more days than not for

the past 6 months): (1) restlessness or feeling keyed up or on edge; (2) being

easily fatigued; (3) difficulty concentrating or mind going blank; (4) irritability;

(5) muscle tension; (6) sleep disturbance (difficulty falling or staying asleep, or

restless, unsatisfying sleep).

D. The anxiety, worry, or physical symptoms cause clinically significant distress

or impairment in social, occupational, or other important areas of functioning.

E. The disturbance is not attributable to the physiologic effects of a substance

(e.g., a drug of abuse, a medication) or another medical condition (e.g.,

hyperthyroidism).

F. The disturbance is not better explained by another mental disorder (e.g.,

anxiety or worry about having panic attacks in panic disorder, negative

evaluation in social anxiety disorder [social phobia], contamination or other

obsessions in obsessive-compulsive disorder, separation from attachment

figures in separation anxiety disorder, reminders of traumatic events in

posttraumatic stress disorder, gaining weight in anorexia nervosa, physical

complaints in somatic symptom disorder, perceived appearance flaws in body

dysmorphic disorder, having a serious illness in illness anxiety disorder, or the

content of delusional beliefs in schizophrenia or delusional disorder).

Source: Reprinted with permission from the Diagnostic and Statistical Manual of

Mental Disorders, 5th ed. (Copyright © 2013). American Psychiatric Association. All

Rights Reserved.

effect and requires thrice-daily dosing. Patients who were previously responsive to a benzodiazepine are unlikely to rate buspirone

as equally effective, but patients with head injury or dementia who

have symptoms of anxiety and/or agitation may do well with this

agent. Escitalopram, paroxetine, duloxetine, and venlafaxine are

FDA approved for the treatment of GAD, usually at doses that

are comparable to their efficacy in major depression, and may be

preferable to usage of benzodiazepines in the treatment of chronic

anxiety. Benzodiazepines are contraindicated during pregnancy and

breast-feeding.

Anticonvulsants with GABAergic properties may also be effective against anxiety. Gabapentin, oxcarbazepine, tiagabine, pregabalin, and divalproex have all shown some degree of benefit in a

variety of anxiety-related syndromes in off-label usage.

■ PHOBIC DISORDERS

Clinical Manifestations The cardinal feature of phobic disorders

is a marked and persistent fear of objects or situations, exposure to

which results in an immediate anxiety reaction. The patient avoids the

phobic stimulus, and this avoidance usually impairs occupational or

social functioning. Panic attacks may be triggered by the phobic stimulus or may occur spontaneously. Unlike patients with other anxiety

disorders, individuals with phobias usually experience anxiety only

in specific situations. Common phobias include fear of closed spaces

(claustrophobia), fear of blood, and fear of flying. Social phobia is

distinguished by a specific fear of social or performance situations in

which the individual is exposed to unfamiliar individuals or to possible

examination and evaluation by others. Examples include having to converse at a party, use public restrooms, and meet strangers. In each case,

the affected individual is aware that the experienced fear is excessive

and unreasonable given the circumstance. The specific content of a

phobia may vary across gender, ethnic, and cultural boundaries.

Phobic disorders are common, affecting ~7–9% of the population. Twice as many females are affected than males. Full criteria for

diagnosis are usually satisfied first in early adulthood, but behavioral

avoidance of unfamiliar people, situations, or objects dating from early

childhood is common.

In one study of female twins, concordance rates for agoraphobia,

social phobia, and animal phobia were found to be 23% for monozygotic twins and 15% for dizygotic twins. A twin study of fear conditioning, a model for the acquisition of phobias, demonstrated a heritability

of 35–45%. Animal studies of fear conditioning have indicated that