3553Psychiatric Disorders CHAPTER 452

type). Such subtyping is more state- than trait-specific, as individuals

may transition from one profile to the other over time. Determination

of whether an individual satisfies the primary criterion of significant

low weight is complex and must be individualized, using all available

historical information and comparison of body habitus to international

body-mass norms and guidelines.

Individuals with anorexia nervosa frequently lack insight into their

condition and are in denial about possible medical consequences; they

often are not comforted by their achieved weight loss and persist in

their behaviors despite having met previously self-designated weight

goals. Alterations in the circuitry of reward sensitivity and executive

function have been reported in anorexia, implicating disturbances in

frontal cortex and anterior insula regulation of interoceptive awareness

of satiety and hunger. Neurochemical findings, including the role of

ghrelin, remain controversial.

Onset is most common in adolescence, although onset in later life can

occur. Many more females than males are affected, with a lifetime prevalence in women of up to 4%. The disorder appears most prevalent in postindustrialized and urbanized countries and is frequently comorbid with

preexisting anxiety disorders. The medical consequences of prolonged

anorexia nervosa are multisystemic and can be life-threatening in severe

presentations. Changes in laboratory values may be present, including

leukopenia with lymphocytosis, elevations in blood urea nitrogen, and

metabolic alkalosis and hypokalemia when purging is present. History

and physical examination may reveal amenorrhea in females, skin abnormalities (petechiae, lanugo hair, dryness), and signs of hypometabolic

function, including hypotension, hypothermia, and sinus bradycardia.

Endocrine effects include hypogonadism, growth hormone resistance,

and hypercortisolemia. Osteoporosis is a longer-term concern.

The course of the disorder is variable, with some individuals recovering after a single episode, while others exhibit recurrent episodes or

a chronic course. Untreated anorexia has a mortality of 5.1/1000, the

highest among psychiatric conditions. Maudsley Anorexia Nervosa

Treatment for Adults (MANTRA) and eating disorder–focused cognitive behavior therapy have proven to be effective therapies, with strict

behavioral contingencies used when weight loss becomes critical. No

pharmacologic intervention has proven to be specifically beneficial,

but comorbid depression and anxiety should be treated. Weight gain

should be undertaken gradually with a goal of 0.5–1 pound per week

to prevent refeeding syndrome. Most individuals are able to achieve

remission within 5 years of the original diagnosis.

■ BULIMIA NERVOSA

Bulimia nervosa describes individuals who engage in recurrent and

frequent (at least once a week for 3 months) periods of binge eating and

who then resort to compensatory behaviors, such as self-induced purging, enemas, use of laxatives, or excessive exercise, to avoid weight gain.

Binge eating itself is defined as excessive food intake in a prescribed

period of time, usually <2 h. As in anorexia nervosa, disturbances in

body image occur and promote the behavior, but unlike in anorexia,

individuals are of normal weight or even somewhat overweight. Subjects typically describe a loss of control and express shame about their

actions, and often relate that their episodes are triggered by feelings

of negative self-esteem or social stresses. The lifetime prevalence in

women is ~2%, with a 10:1 female-to-male ratio. The disorder typically begins in adolescence and may be persistent over a number of

years. Transition to anorexia occurs in only 10–15% of cases. Many

of the medical risks associated with bulimia nervosa parallel those of

anorexia nervosa and are a direct consequence of purging, including

fluid and electrolyte disturbances and cardiac conduction abnormalities. Physical examination often results in no specific findings, but

dental erosion and parotid gland enlargement may be present. Effective

treatment approaches include SSRI antidepressants, usually in combination with cognitive-behavioral, emotion regulation, or interpersonalbased psychotherapies.

■ BINGE-EATING DISORDER

Binge-eating disorder is distinguished from bulimia nervosa by the

absence of compensatory behaviors to prevent weight gain after an

episode and by a lack of effort to restrict weight gain between episodes. Other features are similar, including distress over the behavior

and the experience of loss of control, resulting in eating more rapidly

or in greater amounts than intended or eating when not hungry. The

12-month prevalence in females is 1.6%, with a much lower female-tomale ratio than bulimia nervosa. Little is known about the course of

the disorder, given its recent categorization, but its prognosis is markedly better than for other eating disorders, both in terms of its natural

course and response to treatment. Transition to other eating disorder

conditions is thought to be rare.

PERSONALITY DISORDERS

■ CLINICAL MANIFESTATIONS

Personality disorders are characteristic patterns of thinking, feeling,

and interpersonal behavior that are relatively inflexible and cause

significant functional impairment or subjective distress for the individual. The observed behaviors are not secondary to another mental

disorder, nor are they precipitated by substance abuse or a general

medical condition. This distinction is often difficult to make in

clinical practice, because personality change may be the first sign of

serious neurologic, endocrine, or other medical illness. Patients with

frontal-lobe tumors, for example, can present with changes in motivation and personality while the results of the neurologic examination

remain within normal limits. Individuals with personality disorders

are often regarded as “difficult patients” in clinical medical practice

because they are seen as excessively demanding and/or unwilling to

follow recommended treatment plans. Although DSM-5 portrays

personality disorders as qualitatively distinct categories, there is an

alternative and emerging perspective that personality characteristics

vary as a continuum between normal functioning and formal mental

disorder, the essential features being moderate or greater impairment

in self/interpersonal functioning and one or more pathological personality traits.

Personality disorders have been grouped into three overlapping

clusters. Cluster A includes paranoid, schizoid, and schizotypal

personality disorders. It includes individuals who are odd and

eccentric and who maintain an emotional distance from others.

Individuals have a restricted emotional range and remain socially isolated. Patients with schizotypal personality disorder frequently have

unusual perceptual experiences and express magical beliefs about the

external world. The essential feature of paranoid personality disorder is a pervasive mistrust and suspiciousness of others to an extent

that is unjustified by available evidence. Cluster B disorders include

antisocial, borderline, histrionic, and narcissistic types and describe

individuals whose behavior is impulsive, excessively emotional, and

erratic. Cluster C incorporates avoidant, dependent, and obsessivecompulsive personality types; enduring traits are anxiety and fear.

The boundaries between cluster types are to some extent artificial,

and many patients who meet criteria for one personality disorder also

meet criteria for aspects of another. The risk of a comorbid major

mental disorder is increased in patients who qualify for a diagnosis of

personality disorder.

■ ETIOLOGY AND PATHOPHYSIOLOGY

Genetic studies have increasingly suggested a genetic contribution

to the development of personality disorders. One study of 106,000

subjects identified nine loci significantly linked to aspects of

neuroticism.

TREATMENT

Personality Disorders

Dialectical behavior therapy (DBT) is a cognitive-behavioral

approach that focuses on behavioral change while providing acceptance, compassion, and validation of the patient. Several randomized trials have demonstrated the efficacy of DBT in the treatment

of personality disorders. Antidepressant medications and low-dose

3554 PART 13 Neurologic Disorders

antipsychotic drugs have some efficacy in cluster A personality disorders, whereas anticonvulsant mood-stabilizing agents and

MAOIs may be considered for patients with cluster B diagnoses

who show marked mood reactivity, behavioral dyscontrol, and/

or rejection hypersensitivity. Anxious or fearful cluster C patients

often respond to medications used for axis I anxiety disorders

(see above). It is important that the physician and the patient have

reasonable expectations vis-à-vis the possible benefit of any medication used and its side effects. Improvement may be subtle and

observable only over time.

SCHIZOPHRENIA

■ CLINICAL MANIFESTATIONS

Schizophrenia is a heterogeneous syndrome characterized by perturbations of language, perception, thinking, social activity, affect, and volition. There are no pathognomonic features. The syndrome commonly

begins in late adolescence, has an insidious (and less commonly, acute)

onset, and, often, a poor outcome, progressing from social withdrawal

and perceptual distortions to recurrent delusions and hallucinations.

Patients may present with positive symptoms (such as conceptual

disorganization, delusions, or hallucinations) or negative symptoms

(loss of function, anhedonia, decreased emotional expression, impaired

concentration, and diminished social engagement) and must have at

least two of these for a 1-month period and continuous signs for at least

6 months to meet formal diagnostic criteria. Disorganized thinking or

speech and grossly disorganized motor behavior, including catatonia,

may also be present. As individuals age, positive psychotic symptoms

tend to attenuate, and some measure of social and occupational function may be regained. “Negative” symptoms predominate in one-third

of the schizophrenic population and are associated with a poor longterm outcome and a poor response to drug treatment. However, marked

variability in the course and individual character of symptoms is typical.

The term schizophreniform disorder describes patients who meet

the symptom requirements but not the duration requirements for

schizophrenia, and schizoaffective disorder is used for those who

manifest symptoms of schizophrenia and independent periods of

mood disturbance. The terms schizotypal and schizoid refer to specific

personality disorders and are discussed in that section. The diagnosis

of delusional disorder is used for individuals who have delusions of

various content for at least 1 month but who otherwise do not meet

criteria for schizophrenia. Patients who experience a sudden onset

of a brief (<1 month) alteration in thought processing, characterized

by delusions, hallucinations, disorganized speech, or gross motor

behavior, are most appropriately designated as having a brief psychotic

disorder. Catatonia is recognized as a nonspecific syndrome that can

occur as a consequence of other severe psychiatric/medical disorders

and is diagnosed by the documentation of three or more of a cluster of

motor and behavioral symptoms, including stupor, cataplexy, mutism,

waxy flexibility, and stereotypy, among others. Prognosis depends not

on symptom severity but on the response to antipsychotic medication.

A permanent remission without recurrence does occasionally occur.

About 10% of schizophrenic patients commit suicide.

Schizophrenia is present in 0.85% of individuals worldwide, with a

lifetime prevalence of ~1–1.5%. An estimated 300,000 episodes of acute

schizophrenia occur annually in the United States, resulting in direct

and indirect costs of $155.7 billion.

■ DIFFERENTIAL DIAGNOSIS

The diagnosis is principally one of exclusion, requiring the absence of

significant associated mood symptoms, any relevant medical condition,

and substance abuse. Drug reactions that cause hallucinations, paranoia, confusion, or bizarre behavior may be dose-related or idiosyncratic; parkinsonian medications, clonidine, quinacrine, and procaine

derivatives are the most common prescription medications associated

with these symptoms. Drug causes should be ruled out in any case

of newly emergent psychosis. The general neurologic examination

in patients with schizophrenia is usually normal, but motor rigidity,

tremor, and dyskinesias are noted in one-quarter of untreated patients.

■ EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Epidemiologic surveys identify several risk factors for schizophrenia,

including genetic susceptibility, early developmental insults, winter

birth, and increasing parental age. Genetic factors are involved in at

least a subset of individuals who develop schizophrenia. Schizophrenia is observed in ~6.6% of all first-degree relatives of an affected

proband. If both parents are affected, the risk for offspring is 40%.

The concordance rate for monozygotic twins is 50%, compared to

10% for dizygotic twins. Schizophrenia-prone families are also at risk

for other psychiatric disorders, including schizoaffective disorder and

schizotypal and schizoid personality disorders, the latter terms designating individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal

relationships, eccentric behavior, and mild perceptual distortions.

Large-scale genomewide association studies have identified >100

small effect risk loci and a few larger effect copy number variants,

along with epigenetic effects and have led to initial exploration in the

clinical use of polygenic risk scores in diagnosis and prognosis. Pathways identified include ones involved in immunity, inflammation, and

cell signaling.

TREATMENT

Schizophrenia

Antipsychotic agents (Table 452-10) are the cornerstone of acute

and maintenance treatment of schizophrenia and are effective in

the treatment of hallucinations, delusions, and thought disorders,

regardless of etiology. The mechanism of action involves, at least in

part, binding to dopamine D2

/D3

 receptors in the ventral striatum;

the clinical potencies of traditional antipsychotic drugs parallel

their affinities for the D2

 receptor, and even the newer “atypical”

agents exert some degree of D2

 receptor blockade. All neuroleptics

induce expression of the immediate-early gene c-fos in the nucleus

accumbens, a dopaminergic site connecting prefrontal and limbic

cortices. The clinical efficacy of newer atypical neuroleptics, however, may involve N-methyl-d-aspartate (NMDA) receptor blockade, α1

- and α2

-noradrenergic activity, altering the relationship

between 5-HT2

 and D2

 receptor activity, and faster dissociation of

D2

 binding and effects on neuroplasticity.

Conventional neuroleptics differ in their potency and side-effect

profile. Older agents, such as chlorpromazine and thioridazine,

are more sedating and anticholinergic and more likely to cause

orthostatic hypotension, whereas higher-potency antipsychotics,

such as haloperidol, perphenazine, and thiothixene, are more likely

to induce extrapyramidal side effects. The model “atypical” antipsychotic agent is clozapine, a dibenzodiazepine that has a greater

potency in blocking the 5-HT2

 than the D2

 receptor and a much

higher affinity for the D4

 than the D2

 receptor. Its principal disadvantage is a risk of blood dyscrasias. Paliperidone is a metabolite

of risperidone and shares many of its properties. Unlike other

antipsychotics, clozapine does not cause a rise in prolactin levels.

Approximately 30% of patients who do not benefit from conventional antipsychotic agents will have a better response to this drug,

which also has a demonstrated superiority to other antipsychotic

agents in preventing suicide; however, its side-effect profile makes

it most appropriate for treatment-resistant cases. Risperidone, a

benzisoxazole derivative, is more potent at 5-HT2

 than D2

 receptor

sites, like clozapine, but it also exerts significant α2

 antagonism,

a property that may contribute to its perceived ability to improve

mood and increase motor activity. Risperidone is not as effective as

clozapine in treatment-resistant cases but does not carry a risk of

blood dyscrasias. Olanzapine is similar neurochemically to clozapine but has a significant risk of inducing weight gain. Quetiapine

is distinct in having a weak D2

 effect but potent α1

 and histamine

blockade. Ziprasidone causes minimal weight gain and is unlikely

to increase prolactin but may increase QT prolongation. Aripiprazole also has little risk of weight gain or prolactin increase but

may increase anxiety, nausea, and insomnia as a result of its partial

3555Psychiatric Disorders CHAPTER 452

agonist properties. Asenapine is associated with minimal weight

gain and anticholinergic effect but may have a higher than expected

risk of extrapyramidal symptoms (EPSs). Cariprazine, a D2/D3

partial agonist, has no QT or prolactin elevation risk, but can result

in EPS as well.

Antipsychotic agents are effective in 70% of patients presenting

with a first episode. Improvement may be observed within hours

or days, but full remission usually requires 6–8 weeks. The choice

of agent depends principally on the side-effect profile and cost of

treatment or on a past personal or family history of a favorable

response to the drug in question. Atypical agents appear to be more

effective in treating negative symptoms and improving cognitive

function. An equivalent treatment response can usually be achieved

with relatively low doses of any drug selected (i.e., 4–6 mg/d of

haloperidol, 10–15 mg of olanzapine, or 4–6 mg/d of risperidone).

Doses in this range result in >80% D2

 receptor blockade, and there

is little evidence that higher doses increase either the rapidity or

degree of response. Maintenance treatment requires careful attention to the possibility of relapse and monitoring for the development of a movement disorder. Intermittent drug treatment is less

effective than regular dosing, but gradual dose reduction is likely

to improve social functioning in many schizophrenic patients who

have been maintained at high doses. If medications are completely

discontinued, however, the relapse rate is 60% within 6 months.

Long-acting injectable preparations (risperidone, paliperidone,

olanzapine, aripiprazole) are considered when noncompliance with

oral therapy leads to relapses but should not be considered interchangeable, because the agents differ in their indications, injection

intervals and sites/volumes, and possible adverse reactions, among

other factors. In treatment-resistant patients, a transition to clozapine usually results in rapid improvement, but a prolonged delay in

response in some cases necessitates a 6- to 9-month trial for maximal benefit to occur.

Antipsychotic medications can cause a broad range of side

effects, including lethargy, weight gain, postural hypotension, constipation, and dry mouth. Extrapyramidal symptoms such as dystonia, akathisia, and akinesia are also frequent with first-generation

agents and may contribute to poor adherence if not specifically

addressed. Anticholinergic and parkinsonian symptoms respond

well to trihexyphenidyl, 2 mg bid, or benztropine mesylate, 1–2 mg

bid. Akathisia may respond to beta blockers. In rare cases, more

serious and occasionally life-threatening side effects may emerge,

TABLE 452-10 Antipsychotic Agents

NAME USUAL PO DAILY DOSE (mg) SIDE EFFECTS SEDATION COMMENTS

First-Generation Antipsychotics

Low potency

Chlorpromazine (Thorazine)

Thioridazine (Mellaril)

100–1000

100–600

Anticholinergic effects; orthostasis;

photosensitivity; cholestasis; QT

prolongation

+++ EPSEs usually not prominent; can

cause anticholinergic delirium in

elderly patients

Midpotency

Trifluoperazine (Stelazine) 2–50 Fewer anticholinergic side effects ++ Well tolerated by most patients

Perphenazine (Trilafon) 4–64 Fewer EPSEs than with higher-potency

agents

++

Loxapine (Loxitane) 30–100 Frequent EPSEs ++

Molindone (Moban) 30–100 Frequent EPSEs 0 Little weight gain

High potency

Haloperidol (Haldol) 5–20 No anticholinergic side effects; EPSEs

often prominent

0/+ Often prescribed in doses that are too

high; long-acting injectable forms of

haloperidol and fluphenazine available

Fluphenazine (Prolixin) 1–20 Frequent EPSEs 0/+

Thiothixene (Navane) 2–50 Frequent EPSEs 0/+

Second-Generation Antipsychotics

Clozapine (Clozaril) 150–600 Agranulocytosis (1%); weight gain;

seizures; drooling; hyperthermia

+ + Requires weekly WBC count for first

6 months, then biweekly if stable

Risperidone (Risperdal) 2–8 Orthostasis + Requires slow titration; EPSEs

observed with doses >6 mg qd

Olanzapine (Zyprexa) 10–30 Weight gain ++ Mild prolactin elevation

Quetiapine (Seroquel) 350–800 Sedation; weight gain; anxiety +++ Bid dosing

Ziprasidone (Geodon) 120–200 Orthostatic hypotension +/++ Minimal weight gain; increases QT

interval

Aripiprazole (Abilify) 10–30 Nausea, anxiety, insomnia 0/+ Mixed agonist/antagonist; ER available

Paliperidone (Invega) 3–12 Restlessness, EPSEs, increased

prolactin, headache

+ Active metabolite of risperidone

Iloperidone (Fanapt) 12–24 Dizziness, hypotension 0/+ Requires dose titration; long-acting

injectable available

Asenapine (Saphris) 10–20 Dizziness, anxiety, EPSEs, minimal

weight gain

++ Sublingual tablets; bid dosing

Lurasidone (Latuda) 40–80 Nausea, EPSEs ++ Uses CYP3A4

Brexpiprazole (Rexulti) 1–4 Anxiety, dizziness, fatigue ++ CYP3A4 and 2D6 interactions

Pimavanserin (Nuplazid) 34 Edema, confusion, sedation ++ Approved for Parkinson’s disease

psychosis

Cariprazine (Vraylar)

Lumateperone (Caplyta)

1.5–6

42

EPSEs, vomiting

Fatigue, dry mouth; no apparent

metabolic/motor effects

++

++

Preferential D3 receptor affinity

5HTa>D2 receptor affinity

Abbreviations: EPSEs, extrapyramidal side effects; WBC, white blood cell.

3556 PART 13 Neurologic Disorders

including hyperprolactinemia, ventricular arrhythmias, gastrointestinal obstruction, retinal pigmentation, obstructive jaundice, and

neuroleptic malignant syndrome (characterized by hyperthermia,

autonomic dysfunction, muscular rigidity, and elevated creatine

phosphokinase levels). The most serious adverse effects of clozapine

are agranulocytosis, which has an incidence of 1%, and induction

of seizures, which has an incidence of 10%. Weekly white blood

cell counts are required, particularly during the first 3 months of

treatment.

The risk of type 2 diabetes mellitus appears to be increased in

schizophrenia, and second-generation agents as a group, with the

exception of lumateperone, produce greater adverse effects on glucose regulation, independent of effects on obesity, than traditional

agents. Clozapine, olanzapine, and quetiapine seem more likely to

cause hyperglycemia, weight gain, and hypertriglyceridemia than

other atypical antipsychotic drugs. Close monitoring of plasma

glucose and lipid levels is indicated with the use of these agents.

A serious side effect of long-term use of first-generation and, to a

lesser extent, second-generation antipsychotic agents is tardive dyskinesia, characterized by repetitive, involuntary, and potentially irreversible movements of the tongue and lips (bucco-linguo-masticatory

triad) and, in approximately half of cases, choreoathetosis. Tardive

dyskinesia has an incidence of 2–4% per year of exposure and a

prevalence of 20% in chronically treated patients. The prevalence

increases with age, total dose, and duration of drug administration

and may involve formation of free radicals and perhaps mitochondrial energy failure. Valbenazine, a vesicular monoamine transporter 2 inhibitor that depletes presynaptic dopamine, has recently

received FDA approval for treatment of tardive dyskinesia.

The CATIE study, a large-scale investigation of the effectiveness

of antipsychotic agents in “real-world” patients, revealed a high rate

of discontinuation of treatment >18 months. Olanzapine showed

greater effectiveness than quetiapine, risperidone, perphenazine, or

ziprasidone but also a higher discontinuation rate due to weight gain

and metabolic effects. Surprisingly, perphenazine, a first-generation

agent, showed little evidence of inferiority to newer drugs.

Drug treatment of schizophrenia is by itself insufficient. Educational efforts directed toward families and relevant community

resources have proved to be necessary to maintain stability and

optimize outcome. A treatment model using social cognition interventions and involving a multidisciplinary case-management team

that seeks out and closely follows the patient in the community has

proved particularly effective. Attempts to prevent schizophrenia

through early identification and treatment (both psychosocial and

psychopharmacologic) of high-risk children and adolescents are

currently being evaluated.

ASSESSMENT AND EVALUATION

OF VIOLENCE

Primary care physicians may encounter situations in which family,

domestic, or societal violence is discovered or suspected. Such an

awareness can carry legal and moral obligations; many state laws

mandate reporting of child, spousal, and elder abuse. Physicians

are frequently the first point of contact for both victim and abuser.

Approximately 2 million older Americans and 1.5 million U.S. children

are thought to experience some form of physical maltreatment each

year. Spousal abuse is thought to be even more prevalent. An interview

study of 24,000 women in 10 countries found a lifetime prevalence of

physical or sexual violence that ranged from 15–71%; these individuals are more likely to suffer from depression, anxiety, and substance

abuse and to have attempted suicide. In addition, abused individuals

frequently express low self-esteem, vague somatic symptomatology,

social isolation, and a passive feeling of loss of control. Although it is

essential to treat these elements in the victim, the first obligation is to

ensure that the perpetrator has taken responsibility for preventing any

further violence. Substance abuse and/or dependence and serious mental illness in the abuser may contribute to the risk of harm and require

direct intervention. Depending on the situation, law enforcement

agencies, community resources such as support groups and shelters,

and individual and family counseling can be appropriate components

of a treatment plan. A safety plan should be formulated with the victim, in addition to providing information about abuse, its likelihood

of recurrence, and its tendency to increase in severity and frequency.

Antianxiety and antidepressant medications may sometimes be useful

in treating the acute symptoms, but only if independent evidence for

an appropriate psychiatric diagnosis exists.

■ FURTHER READING

Breilman J et al: Benzodiazepines versus placebo for panic disorder in

adults. Cochrane Database Syst Rev 3:CD010677, 2019.

Cipriani A et al: Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive

disorder: a systematic review and network meta-analysis. Lancet

391:1357, 2018.

Crespo-Facorro B et al: The burden of disease in early

schizophrenia—a systematic literature review. Curr Med Res Opin

37:109, 2020.

Cyr S et al: Posttraumatic stress disorder prevalence in medical populations: A systematic review and meta-analysis. Gen Hosp Psychiatry

69:81, 2021.

Guidi J, Fava G: Sequential combination of pharmacotherapy and

psychotherapy in major depressive disorder: A systematic review and

meta-analysis. JAMA Psychiatry 78:261, 2021.

Himmerich H et al: Pharmacological treatment of eating disorders,

comorbid mental health problems, malnutrition and physical consequences. Pharmacol Ther 217:107667, 2021.

Huhn M et al: Comparative efficacy and tolerability of 32 antipsychotics for the acute treatment of adults with multi-episode schizophrenia:

A systematic review and network meta-analysis Lancet 394:939, 2019.

Huprich S: Personality disorders in the ICD-11: Opportunities and

challenges for advancing the diagnosis of personality disorders. Curr

Psychiatry 22:40, 2020.

Lee Y et al: Development and implementation of guidelines for the

management of depression: A systematic review. Bull World Health

Organ 98:683, 2020.

Mcintyre R et al: Bipolar disorders. Lancet 396:10265, 2020.

Pennix B et al: Anxiety disorders. Lancet 397:914, 2021.

Alcohol (beverage ethanol) has diverse and widespread effects on the

body and impacts directly or indirectly on almost every neurochemical system in the brain. A large majority of patients in most clinical

settings consume alcohol, with the highest proportions of drinkers of

at least modest levels of alcohol seen in more educated and affluent

patient groups. At even relatively low doses, this drug can exacerbate

most medical problems and affect medications metabolized in the

liver, and at higher doses, it can temporarily mimic many medical

(e.g., diabetes) and psychiatric (e.g., depression) conditions. The

lifetime risk for repetitive serious alcohol problems (e.g., alcohol use

disorders as described below) in patients is at least 20% for men and

10% for women, regardless of a person’s education or income, and

U.S. yearly costs for these disorders exceed $249 billion. Although

low doses of alcohol might have healthful benefits, drinking more

than three standard drinks per day enhances the risk for cancer and

vascular disease, and alcohol use disorders decrease the life span by

~10 years. Unfortunately, most clinicians have had only limited

453 Alcohol and Alcohol Use

Disorders

Marc A. Schuckit

3557Alcohol and Alcohol Use Disorders CHAPTER 453

training regarding identifying and treating alcohol-related disorders.

This chapter presents a brief overview of clinically useful information

about alcohol use and associated problems.

■ PHARMACOLOGY AND NUTRITIONAL

IMPACT OF ETHANOL

Ethanol blood levels are expressed as milligrams or grams of ethanol

per deciliter (e.g., 100 mg/dL = 0.10 g/dL), with values of ~0.02 g/dL

resulting from the ingestion of one typical drink. In round figures,

a standard drink is 10–12 g of ethanol, as seen in 340 mL (12 oz) of

beer, 115 mL (4 oz) of nonfortified wine, and 43 mL (1.5 oz) (a shot)

of 80-proof (40% ethanol by volume) beverage (e.g., whisky); 0.5 L

(1 pint) of 80-proof beverage contains ~160 g of ethanol (~16 standard

drinks), and 750 mL of wine contains ~60 g of ethanol. These beverages

also have additional components (congeners) that affect the drink’s taste

and might contribute to adverse effects on the body. Congeners include

methanol, butanol, acetaldehyde, histamine, tannins, iron, and lead. As

a depressant drug, alcohol acutely decreases neuronal activity and has

similar behavioral effects and cross-tolerance with other depressants,

including benzodiazepines, barbiturates, and some anticonvulsants.

Alcohol is absorbed from mucous membranes of the mouth and

esophagus (in small amounts), from the stomach and large bowel

(in modest amounts), and from the proximal portion of the small

intestine (the major site). The rate of absorption is increased by rapid

gastric emptying (as seen with carbonation); by the absence of proteins, fats, or carbohydrates (which interfere with absorption); and

by dilution to a modest percentage of ethanol (maximum at ~20% by

volume).

Between 2% (at low blood alcohol concentrations) and 10% (at high

blood alcohol concentrations) of ethanol is excreted directly through

the lungs, urine, or sweat, but most is metabolized to acetaldehyde,

primarily in the liver. The most important pathway occurs in the cell

cytosol where alcohol dehydrogenase (ADH) produces acetaldehyde,

which is then rapidly destroyed by aldehyde dehydrogenase (ALDH)

in the cytosol and mitochondria (Fig. 453-1). A second pathway

occurs in the microsomes of the smooth endoplasmic reticulum (the

microsomal ethanol-oxidizing system [MEOS]) that is responsible for

≥10% of ethanol oxidation at high blood alcohol concentrations.

Although a standard drink contains ~300 kJ, or 70–100 kcal, these

are devoid of minerals, proteins, and vitamins. In addition, alcohol

interferes with absorption of vitamins in the small intestine and

decreases their storage in the liver with modest effects on folate (folacin

or folic acid), pyridoxine (B6

), thiamine (B1

), nicotinic acid (niacin, B3

),

and vitamin A.

Heavy drinking in a fasting, healthy individual can produce transient hypoglycemia within 6–36 h, secondary to the acute actions of

ethanol that decrease gluconeogenesis. This can result in temporary

abnormal glucose tolerance tests (with a resulting erroneous diagnosis of diabetes mellitus) until the heavy drinker has abstained for

Ethanol

MEOS

20% Acetaldehyde

Alcohol

dehydrogenase

Aldehyde

dehydrogenase

80% Acetaldehyde

Acetate

Citric acid

cycle

CO2 + Water

Acetyl CoA

Fatty acids

FIGURE 453-1 The metabolism of alcohol. CoA, coenzyme A; MEOS, microsomal

ethanol oxidizing system.

2–4 weeks. Alcohol ketoacidosis, probably reflecting a decrease in fatty

acid oxidation coupled with poor diet or persistent vomiting, can be

misdiagnosed as diabetic ketosis. With alcohol-related ketoacidosis,

patients show an increase in serum ketones along with a mild increase

in glucose but a large anion gap, a mild to moderate increase in serum

lactate, and a β-hydroxybutyrate/lactate ratio of between 2:1 and 9:1

(with normal being 1:1).

In the brain, alcohol affects almost all neurotransmitter systems,

with acute effects that are often the opposite of those seen following

desistance after a period of heavy drinking. The most prominent

acute actions relate to boosting γ-aminobutyric acid (GABA) activity,

especially at GABAA receptors. Enhancement of this complex chloride

channel system contributes to anticonvulsant, sleep-inducing, antianxiety, and muscle relaxation effects of all GABA-boosting drugs.

Acutely administered alcohol produces a release of GABA, and continued use increases density of GABAA receptors, whereas alcohol

withdrawal states are characterized by decreases in GABA-related

activity. Equally important is the ability of acute alcohol to inhibit

postsynaptic N-methyl-d-aspartate (NMDA) excitatory glutamate

receptors, whereas chronic drinking and desistance are associated with

an upregulation of these excitatory receptor subunits. The relationships

between greater GABA and diminished NMDA receptor activity during acute intoxication and diminished GABA with enhanced NMDA

actions during alcohol withdrawal explain much of intoxication and

withdrawal phenomena.

As with all pleasurable activities, alcohol acutely increases dopamine

levels in the ventral tegmentum and related brain regions, and this

effect plays an important role in continued alcohol use, craving, and

relapse. The changes in dopamine pathways are also linked to increases

in “stress hormones,” including cortisol and adrenocorticotropic hormone (ACTH), during intoxication and in the context of the stresses

of withdrawal. Such alterations are likely to contribute to both feelings

of reward during intoxication and depression during falling blood

alcohol concentrations. Also closely linked to alterations in dopamine

(especially in the nucleus accumbens) are alcohol-induced changes in

opioid receptors, with acute alcohol causing release of β-endorphins.

Additional neurochemical changes include increases in synaptic

levels of serotonin during acute intoxication and subsequent upregulation of serotonin receptors. Acute increases in nicotinic acetylcholine

systems contribute to the impact of alcohol in the ventral tegmental

region, which occurs in concert with enhanced dopamine activity. In

the same regions, alcohol impacts on cannabinol receptors, with resulting release of dopamine, GABA, and glutamate as well as subsequent

effects on brain reward circuits.

■ BEHAVIORAL EFFECTS, TOLERANCE,

 AND WITHDRAWAL

The acute effects of a drug depend on the dose, the rate of increase

in plasma, the concomitant presence of other drugs, and past experience with the agent. “Legal intoxication” with alcohol in most states

is based on a blood alcohol concentration of 0.08 g/dL, some states

are considering lowering acceptable levels to <0.05 g/dL, and levels

of 0.04 g/dL are cited for pilots in the United States and automobile

drivers in some other countries. However, behavioral, psychomotor,

and cognitive changes are seen at 0.02–0.04 g/dL (i.e., after one to

two drinks) (Table 453-1). Deep but disturbed sleep can be seen at

0.15 g/dL in individuals who have not developed tolerance, and death

can occur with levels between 0.30 and 0.40 g/dL. Beverage alcohol is

probably responsible for more overdose deaths than any other drug.

Repeated use of alcohol contributes to the need for a greater number

of standard drinks to produce effects originally observed with fewer

drinks (acquired tolerance), a phenomenon involving at least three

compensatory mechanisms. (1) After 1–2 weeks of daily drinking,

metabolic or pharmacokinetic tolerance can be seen, with up to 30%

increases in the rate of hepatic ethanol metabolism. This alteration

disappears almost as rapidly as it develops. (2) Cellular or pharmacodynamic tolerance develops through neurochemical changes that maintain relatively normal physiologic functioning despite the presence of

alcohol. Subsequent decreases in blood levels contribute to symptoms

3558 PART 13 Neurologic Disorders

of withdrawal. (3) Individuals learn to adapt their behavior so that

they can function better than expected under the influence of the drug

(learned or behavioral tolerance).

The cellular changes caused by chronic ethanol exposure may not

resolve for several weeks or longer following cessation of drinking.

Rapid decreases in blood alcohol levels before that time can produce a

withdrawal syndrome, which is most intense during the first 5 days, but

with some symptoms (e.g., disturbed sleep and anxiety) lasting up to

4–6 months as part of a “protracted withdrawal” syndrome.

THE EFFECTS OF ETHANOL ON

ORGAN SYSTEMS

Relatively low doses of alcohol (one or two drinks per day) may have

potential beneficial effects of increasing high-density lipoprotein

cholesterol and decreasing aggregation of platelets, with a resulting

possible decrease in risk for occlusive coronary disease and embolic

strokes. Red wine has additional potential health-promoting qualities

at relatively low doses due to flavinols and related substances. Such

modest drinking might also decrease the risk for vascular dementia

and, possibly, Alzheimer’s disease. However, any potential healthful

effects disappear with the regular consumption of three or more drinks

per day, and knowledge about the deleterious effects of alcohol can

both help the physician to identify patients with alcohol use disorders

and supply them with information that might help motivate changes

in behavior.

■ NERVOUS SYSTEM

Approximately 35% of drinkers overall, including as many as 50% of

drinking college students and a much higher proportion of individuals with alcohol use disorders, ever experience a blackout. This is

an episode of temporary anterograde amnesia, in which the person

was awake but forgot all (en bloc blackouts at blood alcohol levels

>0.20 mg/dL) or part (fragmentary blackouts at >0.12 mg/dL) of what

occurred during a drinking period.

Another common problem, one seen after as few as one or two

drinks shortly before bedtime, is disturbed sleep. Although alcohol

might initially help a person fall asleep, it disrupts sleep throughout

the rest of the night. The stages of sleep are altered, and times spent

in rapid eye movement (REM) and deep sleep early in the night are

reduced. Alcohol relaxes muscles in the pharynx, which can cause

snoring and exacerbate sleep apnea; symptoms of the latter occur in

75% of men with alcohol use disorders aged ≥60 years. Patients may

also experience prominent and sometimes disturbing dreams later in

the night. All these sleep impairments can contribute to relapses to

drinking in persons with alcohol use disorders.

Other common consequences of alcohol use even at relatively low

alcohol levels are impaired judgment and coordination, which increase

the risk of injuries. In the United States, ~40% of drinkers have at some

time driven while intoxicated. Heavy drinking can also be associated

with headache, thirst, nausea, vomiting, and fatigue the following day,

a hangover syndrome that is responsible for much missed work and

school time and temporary cognitive deficits.

Chronic high alcohol doses cause peripheral neuropathy in ~10%

of individuals with alcohol use disorders: similar to diabetes, patients

experience bilateral limb numbness, tingling, and paresthesias, all

of which are more pronounced distally. Approximately 1% of those

with alcohol use disorders develop cerebellar degeneration or atrophy,

producing a syndrome of progressive unsteady stance and gait often

accompanied by mild nystagmus; neuroimaging studies reveal atrophy

of the cerebellar vermis. Perhaps 1 in 500 individuals with alcohol

use disorders develop full Wernicke’s (ophthalmoparesis, ataxia, and

encephalopathy) and Korsakoff’s (severe retrograde and anterograde

amnesia) syndromes, although a higher proportion has one or more

neuropathologic findings related to these conditions. These result

from low levels of thiamine, especially in predisposed individuals with

transketolase deficiencies. Repeated heavy drinking can contribute

to cognitive problems and temporary memory impairment lasting for

weeks to months after abstinence. Brain atrophy, evident as ventricular

enlargement and widened cortical sulci on magnetic resonance imaging (MRI) and computed tomography (CT) scans, occurs in ~50% of

individuals with long-term alcohol use disorders; these changes are

usually reversible if abstinence is maintained. Adolescents may be

especially vulnerable to alcohol-related brain changes, as indicated by

preclinical studies and prospective investigations in humans suggesting

that alcohol exposure in the developing brain may adversely impact

future cognitive processes related to cognition, reward recognition,

and cue processing. There is no single “alcoholic dementia” syndrome;

rather, this label describes patients who have irreversible cognitive

changes (possibly from diverse causes) in the context of chronic alcohol use disorders.

Psychiatric Comorbidity As many as two-thirds of individuals

with alcohol use disorders meet criteria for another independent

or temporary substance-induced psychiatric syndrome as defined

in the fifth edition of the Diagnostic and Statistical Manual of

Mental Disorders (DSM-5) of the American Psychiatric Association (Chap. 452). A substantial proportion of those with independent psychiatric conditions (i.e., not just temporary symptoms only

seen during intoxication or withdrawal) relate to a preexisting antisocial personality disorder (ASPD) manifesting as severe impulsivity and

disinhibition that contribute to both alcohol and drug use disorders.

The lifetime ASPD risk is 3% in males, and ≥80% of such individuals

demonstrate alcohol- and/or drug-related conditions. Another common psychiatric comorbidity occurs with problems regarding other

substances of abuse. The remainder of individuals with alcohol use

disorders who have an independent psychiatric syndrome relate to

preexisting conditions such as schizophrenia, manic-depressive disease, posttraumatic stress disorder, or anxiety syndromes such as panic

disorder. The comorbidities of alcohol use disorders with independent

psychiatric disorders might represent an overlap in genetic vulnerabilities, impaired judgment regarding the use of alcohol from the independent psychiatric condition, or an attempt to use alcohol to alleviate

symptoms of the disorder or side effects of medications.

Many alcohol-related psychiatric syndromes can be seen temporarily

during heavy drinking and subsequent withdrawal. These alcoholinduced conditions include an intense sadness lasting for days to

weeks in the midst of heavy drinking seen in 40% of individuals with

alcohol use disorders, which tends to disappear over several weeks of

abstinence (alcohol-induced mood disorder); 10–30% have temporary

severe anxiety, often beginning during alcohol withdrawal, which

can persist for a month or more after cessation of drinking (alcoholinduced anxiety disorder); and 3–5% have auditory hallucinations

and/or paranoid delusions while they are otherwise alert and oriented

(alcohol-induced psychotic disorder).

Treatment of all forms of alcohol-induced psychopathology includes

helping patients achieve abstinence and offering supportive care, as

well as reassurance and “talk therapy” such as cognitive-behavioral

approaches. However, with the exception of short-term antipsychotic

medications for substance-induced psychoses, substance-induced psychiatric conditions only rarely require medications. Recovery is likely

within several days to 4 weeks of abstinence. Conversely, because

alcohol-induced conditions are temporary and do not indicate a need

for long-term pharmacotherapy, a history of heavy alcohol intake is an

important part of the workup for any patient who presents with any of

these psychiatric symptoms.

TABLE 453-1 Effects of Blood Alcohol Levels in the Absence of

Tolerance

BLOOD LEVEL, g/dL USUAL EFFECT

0.02 Decreased inhibitions, a slight feeling of intoxication

0.08 Decrease in complex cognitive functions and motor

performance

0.20 Obvious slurred speech, motor incoordination, irritability,

and poor judgment

0.30 Light coma and depressed vital signs

0.40 Death

3559Alcohol and Alcohol Use Disorders CHAPTER 453

■ THE GASTROINTESTINAL SYSTEM

Esophagus and Stomach Alcohol can cause inflammation of the

esophagus and stomach causing epigastric distress and gastrointestinal

bleeding, making alcohol one of the most common causes of hemorrhagic gastritis. Violent vomiting can produce severe bleeding through

a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastroesophageal junction.

Pancreas and Liver The incidence of acute pancreatitis (~25 per

1000 per year) is almost threefold higher in individuals with alcohol

use disorders than in the general population, accounting for an estimated 10% or more of the total cases. Alcohol impairs gluconeogenesis

in the liver, resulting in a fall in the amount of glucose produced from

glycogen, increased lactate production, and decreased oxidation of

fatty acids. These contribute to an increase in fat accumulation in liver

cells. In healthy individuals, these changes are reversible, but with

repeated exposure to ethanol, especially daily heavy drinking, more

severe changes in the liver occur, including alcohol-induced hepatitis,

perivenular sclerosis, and cirrhosis, with the latter observed in an

estimated 15% of individuals with alcohol use disorders (Chap. 342).

Perhaps through an enhanced vulnerability to infections, individuals

with alcohol use disorders have an elevated rate of hepatitis C, and

drinking in the context of that disease is associated with more severe

liver deterioration.

■ CANCER

As few as 1.5 drinks per day increases a woman’s risk of breast cancer

1.4-fold. For both sexes, four drinks per day increases the risk for oral

and esophageal cancers approximately threefold and rectal cancers

by a factor of 1.5; seven to eight or more drinks per day produces an

approximately fivefold increased risk for many other cancers. These

consequences may result directly from cancer-promoting effects of

alcohol and acetaldehyde or indirectly by interfering with immune

homeostasis.

■ HEMATOPOIETIC SYSTEM

Ethanol causes an increase in red blood cell size (mean corpuscular

volume [MCV]), which reflects its effects on stem cells. If heavy

drinking is accompanied by folic acid deficiency, there can also be

hypersegmented neutrophils, reticulocytopenia, and a hyperplastic

bone marrow; if malnutrition is present, sideroblastic changes can be

observed. Chronic heavy drinking can decrease production of white

blood cells, decrease granulocyte mobility and adherence, and impair

delayed-hypersensitivity responses to novel antigens (with a possible

false-negative tuberculin skin test). Associated immune deficiencies

can contribute to vulnerability toward infections, including hepatitis

and HIV, and interfere with their treatment. Finally, many individuals

with alcohol use disorders have mild thrombocytopenia, which usually

resolves within a week of abstinence unless there is hepatic cirrhosis or

congestive splenomegaly.

■ CARDIOVASCULAR SYSTEM

Acutely, ethanol decreases myocardial contractility and causes peripheral vasodilation, with a resulting mild decrease in blood pressure and

a compensatory increase in cardiac output. Exercise-induced increases

in cardiac oxygen consumption are higher after alcohol intake. These

acute effects have little clinical significance for the average healthy

drinker but can be problematic when persisting cardiac disease is

present.

The consumption of three or more drinks per day results in a

dose-dependent increase in blood pressure, which returns to normal

within weeks of abstinence. Thus, heavy drinking is an important

factor in mild to moderate hypertension. Chronic heavy drinkers also

have a sixfold increased risk for coronary artery disease, related, in part,

to increased low-density lipoprotein cholesterol, and carry an increased

risk for cardiomyopathy through direct effects of alcohol on heart

muscle. Symptoms of the latter include unexplained arrhythmias in the

presence of left ventricular impairment, heart failure, hypocontractility

of heart muscle, and dilation of all four heart chambers with associated

potential mural thrombi and mitral valve regurgitation. Atrial or ventricular arrhythmias, especially paroxysmal tachycardia, can also occur

temporarily after heavy drinking in individuals showing no other

evidence of heart disease—a syndrome known as the “holiday heart.”

■ GENITOURINARY SYSTEM CHANGES, SEXUAL

FUNCTIONING, AND FETAL DEVELOPMENT

Heavy drinking in adolescence can affect normal sexual development

and reproductive onset. At any age, modest ethanol doses (e.g., blood

alcohol concentrations of 0.06 g/dL) can increase sexual drive but also

decrease erectile capacity in men. Even in the absence of liver impairment, a significant minority of chronic heavy drinking men show irreversible testicular atrophy with shrinkage of the seminiferous tubules,

decreases in ejaculate volume, and a lower sperm count (Chap. 391).

The repeated ingestion of high doses of ethanol by women can

result in amenorrhea, a decrease in ovarian size, absence of corpora

lutea with associated infertility, and an increased risk of spontaneous

abortion. Drinking during pregnancy results in the rapid placental

transfer of both ethanol and acetaldehyde, which may contribute to

a range of consequences known as fetal alcohol spectrum disorder

(FASD). One severe result is the fetal alcohol syndrome (FAS), seen in

~5% of children born to heavy-drinking mothers, which can include

any of the following: facial changes with epicanthal eye folds; poorly

formed ear concha; small teeth with faulty enamel; cardiac atrial or

ventricular septal defects; an aberrant palmar crease and limitation in

joint movement; and microcephaly with intellectual impairment. Less

pervasive FASD conditions include combinations of low birth weight,

a lower intelligence quotient (IQ), hyperactive behavior, and some

modest cognitive deficits. The amount of ethanol required and the

time of vulnerability during pregnancy have not been defined, making

it advisable for pregnant women to abstain from alcohol completely.

■ OTHER EFFECTS

Between one-half and two-thirds of individuals with alcohol use

disorders have skeletal muscle weakness caused by acute alcoholic

myopathy, a condition that improves but that might not fully remit

with abstinence. Effects of repeated heavy drinking on the skeletal

system include changes in calcium metabolism, lower bone density,

and decreased growth in the epiphyses, leading to an increased risk

for fractures and osteonecrosis of the femoral head. Hormonal changes

include an increase in cortisol levels, which can remain elevated

during heavy drinking; inhibition of vasopressin secretion at rising

blood alcohol concentrations and enhanced secretion at falling blood

alcohol concentrations (with the final result that most individuals with

alcohol use disorders are likely to be slightly overhydrated); a modest

and reversible decrease in serum thyroxine (T4

); and a more marked

decrease in serum triiodothyronine (T3

). Hormone irregularities may

disappear after a month or more of abstinence.

■ ALCOHOL USE DISORDERS

Because many drinkers occasionally imbibe to excess, temporary

alcohol-related problems are common, especially in the late teens to

the late twenties. However, repeated problems in multiple life areas can

indicate an alcohol use disorder as defined in DSM-5.

■ DEFINITIONS AND EPIDEMIOLOGY

An alcohol use disorder (also called alcoholism or alcohol dependence

in prior diagnostic manuals) is defined as repeated alcohol-related

difficulties in at least 2 of 11 life areas that cluster together in the

same 12-month period (Table 453-2). Ten of the 11 items in DSM-5

(published in 2013) were taken directly from the 7 dependence and

4 abuse criteria in DSM-IV, after deleting legal problems and adding

craving. Severity of an alcohol use disorder is based on the number of

items endorsed: mild is two or three items; moderate is four or five;

and severe is six or more of the criterion items. The 2013 diagnostic

approach is similar enough to DSM-IV that the following descriptions

of associated phenomena are still accurate.

The lifetime risk for an alcohol use disorder in most Western countries is ~10–20% for men and 5–10% for women; higher rates are seen

in individuals who seek help from health care deliverers. Between 2001