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Editors: Koda-Kimble, Mary Anne; Young, Lloyd Yee; Alldredge, Brian K.; Corelli, Robin L.; Guglielmo, B.
Joseph; Kradjan, Wayne A.; Williams, Bradley R.
Title: Applied Therapeutics: The Clinical Use Of Drugs, 9th Edition
Schizophrenia is a debilitating and emotionally devastating illness with long-term impact on patients' lives. Many
experts consider schizophrenia to be the most severe expression of psychopathology, encompassing significant
disruptions of thinking, perception, emotion, and behavior. Schizophrenia is usually a lifelong psychiatric disability.
Family relationships, social functioning, and employment are frequently affected, and periodic hospitalizations are
common. The management of schizophrenia involves multiple strategies to optimize the patient's functional
capacity, reduce the frequency and severity of symptom exacerbations, and reduce the overall morbidity and
mortality from this disorder. Many patients require comprehensive and continuous care over the course of their
lives.
The aim of this chapter is to provide a framework for the clinician to develop skills in schizophrenia management by
considering the pathophysiology, assessment, clinical course, and treatment of schizophrenia.
Epidemiology In the United States, approximately 1% of the population develops schizophrenia during their lifetime. Although
schizophrenia affects men and women with equal frequency, there are differences in the age of onset and course of
illness. The onset of schizophrenia usually occurs during late adolescence or early adulthood. Studies have shown
women have, on average, an onset of schizophrenia 3 to 5 years after men.1 Women also have their first admission
due to psychiatric illness 3 to 6 years after men on average.1 Prevalence rates are similar throughout the world, but
pockets of high prevalence have been reported in some areas. After adjusting for differences in diagnostic criteria for schizophrenia, similar prevalence rates across cultures have been observed.
Economic Burden Mental disorders constitute a large part of the global burden of disease, with schizophrenia being among the
greatest causes of disability in the United States and the world.2 Unlike other chronic diseases such as diabetes and
hypertension, which occur late in life, schizophrenia usually affects people when they are young followed by a
chronic course persisting throughout the patient's lifetime. Most people with schizophrenia experience multiple
hospitalizations and generally require social assistance. Even during relatively stable phases of their illness, most
people with schizophrenia require support that ranges from a family member to daytime hospitalization. As of 2002,
total costs for schizophrenic patients in the United States averaged $62.7 billion annually, taking into account direct
and indirect costs, as well as unemployment costs. Direct costs include hospitalization, rehabilitation, professional
services, medication, and office visits. Indirect costs include loss of productivity caused by illness, disability,
premature death, and economic burden to families.3 Schizophrenia accounts for approximately 2.5% of total annual
health care costs in the United States. Persons afflicted by schizophrenia represent approximately 10% of this
country's permanently disabled population and consume 20% of Social Security benefit days.4,5 In 2004, it was
estimated that 70% of patients with schizophrenia receive medications through Medicaid. Because of the advent of
newer atypical antipsychotics over the past 20 years, the cost of psychotropic medications now exceeds $10 billion
annually.6
Etiology (Neurobiology) Schizophrenia is a complex disorder with multiple causes. Considering the lack of consistent neuropathology or
biomarkers, current theories of the disorder have moved away from the view that it is a single entity, toward a
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conceptualization of schizophrenia as a collection of etiologically disparate disorders with common clinical
features.7,8 In this section, the genetic and environmental factors, neuroanatomical, and neurochemical features of
schizophrenia are considered.
Genetic and Environmental Risk Factors First-degree biologic relatives of persons with schizophrenia have a tenfold higher risk of developing the disease
than the general population.9 The risk is highest (40%–50%) in a monozygotic (identical) twin of a person with
schizophrenia.10,11 There is also higher concordance for schizophrenia in monozygotic twins compared with dizygotic
twins, with respective rates being approximately 50% and 15%.12 Because the concordance rate is not 100% in
monozygotic twins or 50% in dizygotic twins, other nongenetic factors must contribute to the development of the
disorder. Environmental factors such as prenatal difficulties (e.g., malnutrition in the first trimester of pregnancy or
influenza in the second trimester), perinatal complications, and various nonspecific stressors may also influence the
development of schizophrenia. Despite the overwhelming evidence that schizophrenia is an inherited illness, a single
“schizophrenia gene” has not been found. Risk for schizophrenia is, to some extent, genetically transmitted and is
probably determined by multiple genes. A review of the molecular genetics of schizophrenia cited linkage studies
implicating chromosomes 6, 8, 10, 13, and 22.13
Neuroanatomy Studies comparing the brains of individuals with schizophrenia with the brains of normal controls have uncovered a
number of important differences. Although these studies suggest that anatomical and functional abnormalities are
associated with schizophrenia, no single pathognomonic abnormality consistently has been found. In addition,
localization of the site(s) responsible for the pathophysiology of schizophrenia remains elusive.
The most consistent structural finding seen with computed tomography and magnetic resonance imaging in patients
with schizophrenia has been enlarged ventricles, particularly the lateral and third ventricles. In addition, there
seems to be a relationship between brain asymmetry and the disease process.14 When unilateral abnormalities have
been reported, they have typically involved the left hemisphere.14 As imaging technology has advanced, magnetic
resonance imaging studies in schizophrenia frequently have shown morphologic abnormalities involving the temporal,
frontal, and parietal lobes, and the subcortical structures.15,16,17,18,19 Findings include decreased neuronal volume
and density, decreased synaptic connections, decreases in synaptophysin (a membrane protein of synaptic vesicles),
and loss of microtubule associated protein and synaptosomal protein in certain regions of the cortex.20,21 The lack of
gliosis in association with the neuroantomical abnormalities in the brains of schizophrenia patients suggests that
these changes occur neurodevelopmentally.22 Functional imaging studies, such as positron emission tomography,
single photon emission computed tomography, and functional magnetic resonance imaging have demonstrated
alterations in either cerebral perfusion or glucose metabolism in frontal, temporal, and basal ganglia areas of the
brain.23,24,25,26 Additional attention has been directed toward the correlation of regional brain abnormalities with
specific symptoms or subtypes of schizophrenia. Thus far, the most robust findings have been found in the relation
between negative symptoms and the prefrontal cortex, positive symptoms and temporal lobes, and thought disorder
and the planum temporale.27
In summary, neuroimaging studies have identified anatomical and functional abnormalities that affect different
areas of the brain, particularly the prefrontal and temporal areas, corresponding with the impairments observed in
schizophrenia.28 Medial temporal structures are important for the processing of sensory information, and
abnormalities in this area may explain distortions in the interpretation of external reality that are characteristic of
schizophrenia. The prefrontal cortex is responsible for some of the complex and highly evolved human functions,
including the integration of information from other cortical areas. The prefrontal cortex is largely responsible for
the regulation of working memory, which involves maintaining information in temporary memory while that
information is used for executive functions. Hence, these abnormalities in prefrontal areas could explain the deficits
in working memory and attention that are often present in schizophrenia. New theories of schizophrenia that have
been proposed include the “cognitive dysmetria” theory (implicating the thalamus and its cortical and cerebellar connections), the “disconnection
model” (implicating temporolimbic and prefrontal disconnections), and the “asynchronous neural firing”
model.29,30,31
Neurochemistry The discovery of the antipsychotic properties of chlorpromazine led to a fundamental understanding of the
neurochemistry of schizophrenia. The finding that chlorpromazine and other antipsychotic drugs decrease dopamine
activity by blocking specific postsynaptic receptors served as the foundation for the dopaminergic hypothesis of
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J.C. exhibits many of the classic Schneider's first-rank symptoms of schizophrenia, including auditory hallucinations
(hearing voices from “dead people” telling him that he will be killed), delusions (“Jazz musicians will save us all.
You are with the FBI. They will bury me alive.”), and thought broadcasting (“The newscasters on the television are
reading my mind.”). Other target symptoms include agitation, suspiciousness, loose associations, poor grooming and
hygiene, impaired sleep, decreased social skills, and impaired insight and judgment. These target symptoms are the
basis of assessing a change in clinical status and monitoring J.C.'s response to medications.
Typical Course and Outcome
Onset of Illness
The onset of schizophrenia starts with the prodromal phase that begins with the first changes in behavior and lasts
until the onset of psychosis.51,52,53 It is characterized by a slow and gradual onset of signs and symptoms that can last
weeks to years, but typically persists for at least a year.51 Common prodromal signs and symptoms include anxiety,
blunted affect, depression or dysphoric mood, irritability, loss of initiative, low energy, poor concentration, sleep
disturbance, social isolation and withdrawal, and suspiciousness. Subthreshold or attenuated positive symptoms, and
mild disorganization (digressive, vague, overly abstract, or concrete thinking) may begin during the prodrome.
Gradual deterioration in functioning commonly occurs. The prodrome is difficult to recognize; however, family
members may interpret the earliest subtle changes as normal adolescence, a phase, relational problems, depression,
or drug use. Some researchers have viewed the prodromal phase as the optimal point to begin pharmacologic
intervention. Research has shown that many patients are ill for months or even years before seeking treatment; this
delay in treatment is related to outcome and level of remission. Early recognition of the prodrome could lead to
interventions that delay or prevent the emergence of psychosis. Eventually, a symptom characteristic of the active
phase appears (Table 78-1, criterion A), marking the disturbance as schizophrenia.
Course of Illness
In contrast with the notion of an inevitable progressive deterioration in schizophrenia as proposed by Kraepelin, longitudinal studies of schizophrenia suggest that the course of illness is highly variable. The majority suffers from
episodic exacerbations and remissions with some degree of residual symptoms.45,54,55,56 Complete remission (i.e., a
return to full premorbid functioning) is not common in this disorder. Of the patients who remain ill, some seem to
have a relatively stable course, whereas others show a progressive worsening associated with severe disability.
Reported remission rates range from 10% to 60%, and a reasonable estimate is that 20% to 30% of all schizophrenic
patients are able to lead somewhat normal lives. About 20% to 30% of patients continue to experience moderate
symptoms, and 40% to 60% of patients remain significantly impaired by their disorder for their entire lives. Early in
the illness, negative symptoms may manifest as prodromal features. Subsequently, positive symptoms appear.
Because these positive symptoms are particularly responsive to treatment, they typically diminish, but in many
individuals negative symptoms persist between episodes of positive symptoms. As patients with schizophrenia age,
the frequency and severity of acute episodes may decrease; however, negative symptoms may become more
prominent in some individuals, a state often referred to as burn-out.54,56,57
Prognosis
Predictors of an improved long-term outcome in patients with schizophrenia include female gender, a positive family
history of an affective disorder, a negative family history of schizophrenia, good premorbid functioning, higher IQ,
married marital status, acute onset with precipitating stress, fewer prior episodes (both number and length), a
phasic pattern of episodes and remissions (i.e., fewer residual symptoms), advancing age at onset, minimal
comorbidity, paranoid subtype, and symptoms that are predominantly positive (delusions, hallucinations) and not
disorganized (thought disorder, disorganized behavior).58 Despite modern treatment advancements, schizophrenia
remains a severe disease with a relatively poor outcome. Many patients experience repeated hospitalizations and
exacerbations of symptoms, and suicide attempts are relatively common. Individuals with schizophrenia have a 20%
shorter life expectancy than the general population.59 This is due in part, to an increased incidence of general
medical illness (such as diabetes or cardiovascular disease) and suicide.58 Patients with schizophrenia have
approximately a 50% lifetime risk for a suicide attempt and as many as 9% to 13% complete suicide.60
2. What other factors in J.C.'s history are consistent with the diagnosis of schizophrenia, and what is his
prognosis?
Other factors that are consistent with schizophrenia in J.C. include onset of illness in early adulthood (typical age of
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functioning (e.g., continues work, keeps close contact with social workers, attends medication groups),
discontinuation of therapy can be considered.
When J.C. has been stabilized for a total of approximately 1 year on olanzapine 10 mg/day, then the dose can be
reduced by 20% every 3 to 6 months until it is discontinued or relapse occurs. If he exhibits recurrent target
symptoms of schizophrenia or decompensation, then the dose should be increased to the previous effective dose (or
medication restarted if it was discontinued). Because it is likely that J.C. will require lifelong antipsychotics, it is
important to determine the minimal effective dose to prevent recurrence, while minimizing the risk of adverse
effects. J.C. is not a candidate for intermittent therapy during the stable phase. He is not a decanoate candidate
because he is compliant with treatment.
Long-Acting Depot Injectables
Long-acting depot medications are not recommended for acute psychotic episodes because these medications take
months to reach a steady-state concentration and are eliminated very slowly.58 Hence, it is difficult to correlate
clinical effect with dosage, and it is extremely difficult to make dosage adjustments to manage side effects.
However, long-acting depot medications can be useful for maintenance therapy in patients with a history of
nonadherence to their oral medication and in those who prefer the convenience of long-acting or depot injections.
In these situations, the oral form of available depot medications should be initiated first. If the oral form has been
shown to be safe and effective, the patient can be converted to the depot form. Fluphenazine, haloperidol, and
risperidone are available as long-acting decanoate injections. Long-acting injectable risperidone appears to combine
the most valuable features of an atypical antipsychotic (broadly efficacious and well tolerated) with those of
injectable long-acting antipsychotics (improved bioavailability and assured medication delivery).141,142
Pharmacokinetics and Drug Interactions
Dosing considerations also have a major influence on safe and effective antipsychotic selections. Specific factors
include the number of times a day a medication needs to be administered, the difference between a starting dose
and a “target” therapeutic dose (i.e., titration required), and the risk for drug–drug interactions. The long half-life
(12–24 hours) and active metabolites of most oral antipsychotic drugs allow for once- to twice-daily dosing.143 Most
antipsychotics, with the exception of clozapine and ziprasidone, can be safely given once a day. Most antipsychotics
achieve a steady-state concentration in 4 to 7 days, but it is important to understand that the onset of antipsychotic
effect is not related to achieving steady state. Pharmacologic effects often persist for longer than pharmacokinetics
would imply. In some instances, treatment is initiated at a subtherapeutic dose and gradually titrated upward to an
effective dose. This approach is taken to allow the patient to develop tolerance to adverse events such as sedation
or orthostatic hypotension. In the case of acute agitation, antipsychotic doses are also often divided, despite the
long half-lives of these drugs, such that the sedative effects are maintained over the day. Once a patient has been
stabilized or has become tolerant to the adverse effects, the goal is to give medication once a day, usually at
bedtime. Bedtime dosing enhances medication adherence and concentrates ongoing adverse effects such as sedation
at night.
Both pharmacokinetic and pharmacodynamic drug interactions can occur with antipsychotic agents. Cytochrome
P450 enzymes, especially the 1A2, 2D6, and 3A4 isoenzymes, are responsible for the metabolism of many
antipsychotics.144 Induction or inhibition of these enzymes by other drugs may result in clinically important drug
interactions. Table 78-9 summarizes the metabolic pathways for commonly used antipsychotic drugs. In the case of
clozapine, serious complications such as seizures can occur when drug interactions cause serum concentrations of
clozapine to rise significantly. Examples of drugs that have the potential to cause serious interactions with
antipsychotics include fluvoxamine (CYP 1A2 inhibitor), erythromycin, ketoconazole, and ritonavir (CYP 3A4
inhibitors), quinidine, risperidone, fluoxetine, and paroxetine (CYP 2D6 inhibitors), and cimetidine (multiple enzyme
inhibition).145 Conversely, inducers of drug metabolism such as carbamazepine (induces multiple enzymes) or
cigarette smoking (induces CYP 1A2) can reduce the plasma concentrations of antipsychotic drugs. For example,
carbamazepine has been shown to reduce plasma concentrations of haloperidol by 50%.146 Cigarette smoking has
been shown to increase the metabolism of clozapine and olanzapine.144 Pharmacodynamic interactions may occur
when medications with similar unwanted properties are concurrently prescribed. For example, concomitant use of
low-potency typical agents or clozapine along with diphenhydramine or hydroxyzine may cause augmentation of
anticholinergic effects. Pharmacodynamic drug interactions of greatest concern are those that can cause significant orthostatic hypotensive, anticholinergic effects, and sedation. Pharmacokinetic and dosing information
for the antipsychotics are provided in Tables 78-9 and 78-10.
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Although medication expenditures represent only a small portion of total resource utilization associated with the
management of schizophrenia, concern exists about the cost of atypical antipsychotics and whether their relative
advantages over typical agents are worth their increased cost.147 Drug acquisition costs for atypical antipsychotics
can be 100-fold higher than typical antipsychotics. Most pharmacoeconomic studies with atypical antipsychotics
show that these agents are at least cost neutral and may offer cost advantages compared with traditional agents
when total mental health costs are considered.148 Depending on the individual study, the higher costs associated
with atypical antipsychotics are offset by decreased number of hospital admissions, length of inpatient stay, and
number of outpatient visits. Hence, drug costs should not be the sole factor considered when selecting an
antipsychotic. The selection of a medication should be individualized and factors such as efficacy, side effects,
patient acceptance, and total health care costs should be considered.
Adverse Effects
An important factor in the selection of an antipsychotic is the potential risk for adverse events. Key adverse effects
that differentiate the antipsychotics include EPS, anticholinergic side effects, cardiac effects, hyperprolactinemia,
metabolic effects and sedation. Table 78-7 compares antipsychotic agents with regard to the risk of these adverse
effects.
Extrapyramidal Side Effects and Tardive Syndromes
EPS is a broad term that describes several types of acute and chronic drug-induced movement disorders. Acute
dystonia, parkinsonism, and akathisia all occur early in treatment, whereas TD, tardive dystonia, and tardive
akathisia have a late onset, usually after years of treatment. The acute forms of EPS usually develop soon after the
initiation of antipsychotics, are dose dependent, and are generally reversible soon after discontinuation of the
offending agent.149 It has been estimated that 60% of patients who receive typical antipsychotics develop some form
of EPS acutely.58 In general, typical agents are more likely to cause EPS than atypical agents when these medications
are used at usual therapeutic doses. Among the seven currently available atypical agents, clozapine and quetiapine
are associated with the lowest risk for EPS. The rising prescription rate of atypical antipsychotics (and decrease in
use of the typical agents) have substantially reduced the problem of EPS. Similarly, the risk of antipsychotic-induced
TD is suggested to be lower with atypical agents compared with typical agents. Most of the evidence documenting a
decreased incidence of TD with atypical agents is derived from data and clinical experience with clozapine,
risperidone, olanzapine, and quetiapine.150,151,152,153
Acute Dystonia
Acute dystonia has the earliest onset of all the EPS symptoms. Most cases occur within the first few hours or days
after initiation or dose increase of antipsychotic medication. Dystonia is characterized by sustained muscle
contractions. Common presentations of antipsychotic-induced dystonia include a sudden onset of brief or sustained
abnormal postures, including tongue protrusion, oculogyric crisis (eyes rolling back into head), trismus (spasm of the
jaw), torticollis (torsion of the neck); opisthotonos (arching of back), and unusual positions in the trunk, limbs, and
toes. Laryngeal dystonias are the most serious dystonias and are potentially fatal. Risk factors for acute dystonia
include younger age, male gender, high dosage of high-potency typical antipsychotics, and previous history of
dystonia.58
The exact pathophysiology of acute dystonia is uncertain. Conflicting theories describe either a hypodopaminergic or
hyperdopaminergic state after an antipsychotic-induced blockade of postsynaptic dopamine receptors. Acute
dystonia likely is caused by dysregulation of the dopamine system and imbalance between neurotransmitter systems after acute antipsychotic administration.154 P.78p17
Table 78-10 Antipsychotic Relative Potency and Adult Dosing
Drug and Chemical Class
Dose
Equivalence
Usual Starting
Dose (mg/day)
Acute Phase
Dosage (mg/day)
Maintenance/Stable Phase
Dosage (mg/day)
Typical Agents–Phenothiazines
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10. J.P., a 19-year-old man, was brought to the psychiatric ED because of assaultive behavior toward his
mother. J.P. states he struck her because the devil told him to do it. Trifluoperazine 5 mg IM Q 4 to 6 hr PRN
was started to control his assaultive behavior. He received four IM injections over 24 hours and was converted
to 15 mg PO HS. On day 2 of the admission he complained of a stiff neck and protruding tongue. J.P. became
very upset and wanted to leave the hospital and never take these medications again. No other medical
conditions were noted. What evidence suggests that J.P. is experiencing an acute dystonia reaction?
The sudden appearance of a stiff neck and a protruding tongue in J.P. is consistent with acute dystonia. In addition,
J.P.'s young age, male gender, and use of a high-potency typical antipsychotic agent also place him at high risk for
experiencing a dystonic reaction.
11. How should acute dystonia be treated in J.P.?
Acute dystonic reactions are sudden in onset, dramatic in appearance, and can cause patients great distress. It
requires immediate treatment. The initial goal of treatment is to relieve symptoms as soon as possible with either
benztropine 1 to 2 mg or diphenhydramine 25 to 50 mg by IM injection. Although the IV route has a faster onset of
action, it is not needed in J.P. because his reaction is not severe. If symptoms do not resolve within 15 to 30
minutes, then the dose should be repeated. If there are contraindications to the use of anticholinergic drugs,
lorazepam 1 to 2 mg IM can be used. J.P. must be reassured that this is a temporary condition that can be prevented
and treated. To prevent another reaction, J.P. should be given oral anticholinergic drugs in doses commonly used for
pseudoparkinsonism for 2 weeks after this dystonic reaction.154
Parkinsonism
The clinical presentation of antipsychotic-induced parkinsonism includes bradykinesia or akinesia, which may be
associated with decreased arm swinging, a masklike face, drooling, decreased eye blinking, and soft, monotonous
speech, tremor, which is most commonly a rhythmic, resting tremor, and rigidity of the extremities, neck or trunk
(most identifiable in the limbs as a “cogwheel” rigidity during passive motion).154 Antipsychotic-induced
parkinsonism occurs in approximately 20% of patients treated with antipsychotic agents.58 Symptoms can occur at
any time, but usually develop within 4 weeks after antipsychotic initiation or a dose increase. Advanced age, antipsychotic dose and potency, and preexisting EPS are the major risk factors for antipsychotic-induced
Atypical Agents
Risperidone (Risperdal) 2 1–2 2–16 2–8
Clozapine (Clozaril) 50 12.5–25 150–900 150–600
Olanzapine (Zyprexa) 5 5–10 10–20 10–20
Quetiapine (Seroquel) 75 50–100 300–750 400–600
Ziprasidone (Geodon) 60 40–80 80–200 80–160
Aripiprazole (Abilify) 7.5 10–15 10–30 15–30
Paliperidone (Invega) 3 6 6–12 6–12
aDosages can be exceeded with caution, but high-dose therapy is rarely needed.
Compiled from references 57, 66, 80, 144, 151, 239, 241, and 256.
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floor, was unable to sit or lie down for longer than 10 minutes at a time, and subjectively had a feeling that he
described as “I have ants in my pants.” J.P. is observed rocking back and forth from one foot to the other while
standing in line for his dinner. He has no symptoms of antipsychotic-induced parkinsonism. Should the dose of
trifluoperazine be increased?
J.P.'s symptoms of rocking, pacing, agitation, and the inability to sit still are consistent with akathisia. Because his
psychiatric symptoms have improved and the new symptoms developed within 2 weeks after the initiation of
trifluoperazine, a diagnosis of akathisia is more probable than unresponsiveness to the antipsychotic medication.
Therefore, the trifluoperazine dose should not be increased because it can worsen the akathisia.
18. How should J.P.'s akathisia be managed?
Akathisia is less responsive to treatment than are antipsychotic-induced parkinsonism and dystonia.58 As an initial
approach to manage his akathisia, a small reduction (5 mg/day) in his trifluoperazine dosage should be attempted. If
symptoms of his psychosis return or if the akathisia persists, the addition of a β-blocking agent, an anticholinergic
drug, or a benzodiazepine can be considered.58,154 Propranolol would be a recommended agent because there is a
suggestion that its efficacy and safety profile may be preferable compared with other agents.159 Anticholinergic
drugs are appropriate alternatives if antipsychotic-induced parkinsonism is present. If his symptoms do not improve
in response to a dosage reduction of his trifluoperazine within 1 week, J.P. should be started on propranolol 20 mg
three times a day, and the dose should be increased by 20 mg every other day to a maximum of 120 mg, if
necessary.159 He has no contraindications to β-blocker therapy and does not have antipsychotic-induced
parkinsonism; therefore, antiparkinsonian agents (Table 78-12) are not preferred over propranolol. If the akathisia
persists after a trial of propranolol 120 mg/day therapy for 1 week, benzodiazepines should be tried or he should be
switched to an atypical antipsychotic.
Tardive Dyskinesia (TD)
TD is a syndrome characterized by involuntary choreoathetoid movements that occurs in individuals taking long-term
antipsychotics. The face (tics, blinking, grimacing), tongue (chewing, protrusion, tremor, writhing), lips (smacking,
pursing, puckering), neck and trunk (torsion and torticollis), and limbs (toe tapping, pill rolling, and writhing) are
commonly involved. The movements may be choreiform (rapid, jerky, nonrepetitive), athetoid (slow, sinuous,
continual), or rhythmic (stereotypic) in nature.
TD occurs in approximately 20% of patients who receive long-term treatment with typical agents.149 The cumulative
annual incidence is approximately 5% through the first 4 years of treatment in an adult who receives typical
antipsychotic treatment.160 Advancing age is the most consistently observed risk factor for the development of TD.161
The annual incidence rates of developing TD are three- to fivefold higher in older patients compared with younger adults.162,163 Other risk factors include higher mean daily and cumulative
antipsychotic doses, and presence of extrapyramidal signs early in treatment.162,163 Although there is some indication
that the risk of TD may be higher in women, nonwhites, patients with affective psychiatric disorders, and patients
taking concomitant anticholinergic agents, these findings have not been consistently observed.161
For most patients, TD does not seem to be progressive or irreversible; it can be reversed with discontinuation of the
antipsychotic agent. The onset of symptoms tends to be subtle with a fluctuating course.161 Most TD cases are
relatively mild. However, a portion of patients (5%–10%) may develop a form of TD that is severe enough to impair
functioning.164 Severe oral dyskinesia may result in dental and denture problems that can progress to ulceration and
infection of the mouth as well as muffled or unintelligible speech. Severe orofacial TD can impair eating and
swallowing, which in turn could produce significant health problems. Gait disturbances owing to limb dyskinesia may
leave patients vulnerable to falls and injuries.
Although the exact cause of TD is unknown, dopaminergic hypersensitivity, disturbed balance between dopamine
and cholinergic systems, dysfunction of GABAergic and noradrenergic systems and neurotoxicity via free radicals
have been proposed.149
19. C.M., a 31-year-old woman, was diagnosed with chronic paranoid schizophrenia 9 years ago. She responds
to antipsychotic drugs, but has been hospitalized six times because of nonadherence to her medications. She
has taken loxapine, haloperidol, and fluphenazine in the past and currently is being treated with
trifluoperazine 25 mg HS (decreased from 30 mg 1 month ago). C.M. also has been taking trihexyphenidyl 2 mg
TID for the past 5 years. Involuntary movements (including tongue protrusion, frequent blinking, and writhing
movements of her legs) were noted during a recent evaluation. What data in C.M.'s history are consistent with
TD?
The 9 years of antipsychotic treatment and the symptoms of tongue protrusion, blinking, and writhing leg
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radical scavengers (vitamin E) have all been used, with limited or inconsistent results.160,167,168 These agents may be
useful as adjunctive treatments when TD persists despite the use of atypical agents.
Anticholinergic Effects
Anticholinergic effects are more significant with low-potency typical antipsychotics, and with the atypical agents,
clozapine and olanzapine. Clinically, patients complain of constipation, urinary retention, and dry eyes, mouth, and
throat. Dry mouth and throat can cause several additional problems, including dental caries and weight gain if thirst
is satisfied with high-sugar drinks. Oral fungal infections can also occur if gum or liquids with high sugar content are
regularly consumed. The most serious complications from medications with anticholinergic properties are delirium and adynamic ileus.169,170 Interestingly, clozapine causes significant
hypersalivation despite its anticholinergic effects. The mechanism is unknown, but it may be caused by clozapine's
augmentation of the adrenergic receptors that control salivation.171 Drug therapy with benztropine, amitriptyline,
and clonidine may alleviate hypersalivation; however, these agents are not effective in all patients and when they
are beneficial tolerance may develop. Although anticholinergic effects are a minor problem with high-potency
typical agents, some patients may still have problems when anticholinergic antiparkinsonian agents are added to
treat EPS.
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have appeared in individuals with a QT interval >500 msec, discontinuation of the suspected offending agent has
been recommended if the interval consistently exceeds 500 msec. It is important to note that no patients in this
study had QTc intervals exceeding 500 msec or arrhythmias. Despite the fact that no increased risk of arrhythmia or
sudden death has been demonstrated with ziprasidone, caution is warranted in patients with some types of cardiac disease and with an uncontrolled electrolyte disturbance. The coprescription of ziprasidone with other
drugs that prolong the QT interval should be avoided. Under most clinical circumstances, however, ziprasidone may
be safely used without ECG monitoring or other special precautions.
Metabolic Effects
Hyperprolactinemia
Antipsychotic-induced hyperprolactinemia has come to the forefront because of differences found among the
atypical agents. Before the introduction of the atypical agents, prolactin elevation was unavoidable because all
typical antipsychotics elevate serum prolactin by blocking the tonic inhibitory actions of dopamine in the
tuberoinfundibular tract.174 Among the atypical agents, risperidone and, to a lesser extent, olanzapine produce a
dose-related increase in prolactin levels that is equal to or greater than that seen with typical antipsychotics.175,176
The remaining atypical agents have little impact on serum prolactin levels.175 Hyperprolactinemia is of clinical
importance because it may lead to galactorrhea, gynecomastia, amenorrhea, anovulation, impaired
spermatogenesis, decreased libido and sexual arousal, and anorgasmia.177 Interestingly the hyperprolactinemia is not
always associated with clinical symptoms. For example, Kleinberg et al.176 failed to find an association between
sexual dysfunction and risperidone-associated hyperprolactinemia. This may be a product of the multifactorial
nature of sexual dysfunction or methodologic limitations in data collection. Patients often do not spontaneously
report symptoms of sexual dysfunction and clinicians must remember to ask about these potential side effects.175
Weight Gain
Weight gain is emerging as one of the most significant concerns associated with the use of antipsychotics,
particularly among the atypical agents. The mechanism of antipsychotic-induced weight gain is unclear, but
antagonism of histamine H1 and serotonin 5-HT2C receptors has been implicated.178 A genetic predisposition exists for
weight gain; a mutation in the 5-HT2c receptor gene may increase risk for weight gain from atypical antipsychotics.
No genetic tests exist to predict which patients will gain weight from the atypical antipsychotics.179,180 Another
theory is the potential decreased signaling of two serotonin receptors, 2A and 2C, increased calorie intake and
appetite, and/or decreased metabolic rate.180,181 The higher the binding affinity to the histaminergic receptor, the
more that agent is likely to be associated weight gain.180 Among the atypical agents, weight gain is most common
with clozapine and olanzapine, lowest with ziprasidone and aripiprazole, and intermediate with risperidone and
quetiapine.182 In a meta-analysis, Allison et al.183 found that the estimated weight gain at 10 weeks of therapy was
greater with clozapine (4.45 kg) and olanzapine (4.15 kg) relative to risperidone (2.1 kg) and ziprasidone (0.04 kg),
as illustrated in Figure 78-3. Moderate short-term weight gain has been demonstrated with quetiapine and is minimal
with aripiprazole.98,184 Similarly, clozapine and olanzapine have the largest associated weight gain with long-term
treatment.184 The weight gain observed with clozapine and olanzapine is not dose dependent and plateaus 6 to 12
months after treatment initiation.185,186 However, other authors suggest that antipsychotic-associated weight gain
plateaus within the first several months of treatment with risperidone, quetiapine, and ziprasidone can continue
over several years for clozapine and olanzapine.175 The issue of weight gain has important clinical implications in
light of the link with impaired glucose tolerance and type II diabetes, hyperlipidemia, and increased
mortality.58,187,188,189,190 Patients who had no weight gain due to atypical antipsychotics can still develop diabetes
mellitus. In a case review of 45 patients who developed or had worsening of their diabetes, nearly 50% had no
weight gain. Atypical antipsychotics may impair insulin sensitivity or glucose regulation independent of weight gain,
although the true reason for diabetes is still unknown.179,181
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Cardiovascular disease is the leading cause of death among patients with schizophrenia.191 On average, patients with schizophrenia live 20% shorter than the general population. They commit suicide up to 20 times more than the
general population; and patients with schizophrenia specifically aged 25 to 44 years old, are three times more likely
to die compared with the general population. This number has continued to increase as patients are no longer
institutionalized.179
23. L.A., a 45-year-old woman with chronic paranoid schizophrenia, had been managed successfully with
Figure 78-3 Comparison of weight change among antipsychotics. (Adapted from reference 183.)
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Table 78-13 Monitoring Protocol for Atypical Antipsychoticsa
� Baseline Week 4 Week 8 Week 12 Quarterly Annually Every 5 years
Personal/Family history X � � � � X �
Weight (BMI) X X X X X � �
Waist circumference X � � � � X �
Blood pressure X � � X � X �
Fasting plasma glucose X � � X � X �
Fasting lipids profile X � � X � � X
aMore frequent assessments may be warranted based on clinical status.
Compiled from references 219 and 220.
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Thioridazine is recognized as the most common cause of antipsychotic-induced sexual dysfunction.212 Sexual side
effects such as diminished libido, impaired arousal, and erectile and orgasmic dysfunction, however, have also been
reported with both other typical agents and atypical agents.175 The causes of antipsychotic-induced sexual
dysfunction are related to a number of factors including hyperprolactinemia via dopamine blockade, α-adrenergic
blockade, and anticholinergic and sedative effects.213 Impaired sexual function has also been observed in untreated
patients with schizophrenia, making the distinction between drug-induced and disease-induced symptoms
difficult.214 K.J.'s sexual dysfunction likely is related to the thioridazine because the symptoms resolved after he
stopped the medication. Lowering the dose of thioridazine or converting him to another antipsychotic with less
influence on sexual function may be helpful, although no reliable evidence is available to indicate which drugs are
least likely to cause sexual dysfunction.
Predictors of Medication Response As a general rule, antipsychotic agents should be initiated and titrated over the first few days to an average
effective “target” therapeutic dose unless the patient's physiological status or history indicates that this dose may
result in unacceptable adverse events.215 After 1 week on the “target” dose, a modest dosage increase (within the
recognized therapeutic range) may be considered if minimal or no improvement has been observed. In instances in
which symptoms improve after the dose is increased, it may be difficult to know whether the response resulted from
the dose change or from additional days on the drug. The duration of a therapeutic trial is 3 to 8 weeks in patients
with little to no response, and 5 to 12 weeks in patients with a partial response.166,215 Dosing recommendations for
the antipsychotics are provided in Table 78-10.
Factors to Consider When Evaluating a Poor Response A large proportion of patients with schizophrenia do not have an adequate response to antipsychotic therapy.
Inadequate response may be caused by inadequate dosing, poor adherence, or true resistance to antipsychotic
treatment.216 Some of these factors can be addressed. In some patients, the therapeutic antipsychotic dose cannot
be reached because of intolerable side effects. As mentioned, a therapeutic trial of 3 to 12 weeks at an optimal
dosage may be necessary to determine the full benefit from an antipsychotic agent. Nonadherence with medications
is a common obstacle in the management of schizophrenia, even in supervised settings. Blood level monitoring may
be helpful to identify nonadherent patients as well as those in whom a pharmacokinetic factor may account for a
poor response (e.g., poor drug bioavailability, rapid metabolizer, concomitant use of a metabolism-inducing agent). Therapeutic ranges of some antipsychotics are provided in
Table 78-9.
A single definition of treatment resistance does not exist, but factors to consider in this definition include chronic or
repeated hospitalizations, persistent positive symptoms, lack of improvement in negative symptoms, and
breakthrough symptoms despite adherence to treatment.216 Guidelines for determining treatment resistance have
been proposed and include at least two prior drug trials of 4 to 6 weeks duration at 400 to 600 mg chlorpromazine
(or equivalent, i.e., 8–12 mg of risperidone) with no clinical improvement, >5 years without a sustained period of
good social or occupational functioning, and persistent psychotic symptoms.216,217
Several strategies have been proposed if a change in antipsychotic medication is necessitated by side effects or
insufficient efficacy.140 These include an abrupt switch (abrupt cessation of the current drug, with abrupt
introduction of the new one at the expected therapeutic dose), a gradual switch (slow downward adjustment of the
dosage of the current medication, with slow upward adjustment of the dosage of the new drug) or an overlapping
switch (abrupt introduction of the new medication overlapping with the current medication, followed by downward
adjustment of the dosage of the previous medication). None of these strategies has been demonstrated to be
superior to another in terms of efficacy or safety, and the switch strategy depends on the clinical presentation.
31. M.S., a 24-year-old man, was brought to the ED by the police because voices told him to strike his mother.
His medical workup and urine drug screen were negative. M.S. has a diagnosis of schizophrenia,
undifferentiated type, and has been hospitalized four times in the last 2 years secondary to poor adherence to
his prescribed medication. He has had the same presentation on all previous hospitalizations. During his last
hospitalization, M.S. was stabilized on thiothixene (Navane) 20 mg orally at bedtime without any signs of
adverse effects. How can IM depot therapy decrease readmissions, and how do we determine if M.S. is a good
candidate for IM depot therapy?
M.S.'s history suggests that he is a good candidate for depot therapy. He responds to typical antipsychotics, but
relapses owing to nonadherence. He should be able to tolerate higher potency antipsychotics because he has
tolerated moderate doses of thiothixene. The patient should also be asked whether he is willing to take injections
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Clozapine can be started in an outpatient setting if patients are carefully monitored for tolerability, especially
orthostasis. The starting dose is 12.5 to 25 mg once or twice a day with increases of 25 to 50 mg/day until a target
dose is reached. Clozapine is given in divided doses. The optimal dose has not been specifically delineated although
an initial target of 300 to 450 mg/day is reasonable based on clinical experience. The maximum daily dose is 900
mg, but titration should proceed slowly to such high doses, and only after adequate trials at lower doses. Response
is based on improvement of individual target symptoms and can be monitored by psychometric rating scales (Table
78-11). In addition, the overall ability of a patient to function and care for oneself during clozapine therapy also
should be considered.228 Most patients improve significantly during the first 6 weeks, but some take longer. Although
the exact length of an appropriate trial is unclear, 12 weeks is adequate for most clients; however, improvement may continue for 6 to 12 months after initiating therapy.58,229,230
Clozapine has been issued five blackbox warnings from the FDA. These included agranulocytosis, seizures,
myocarditis, increased mortality in elderly patients with dementia-related psychosis, and other adverse
cardiovascular and respiratory effects.231 The risk of seizures is dose dependent. The risk of fatal myocarditis is most
frequent in the first month of treatment with clozapine. Other adverse cardiovascular and respiratory effects
indicates orthostatic hypotension that may or may not be accompanied by syncope. Rarely, collapse with respiratory
or cardiac arrest may occur. This is why it is essential to start patients on 12.5 mg once or twice daily, whether it is
initiation of treatment, or the patient has been off of clozapine for 2 or more days.231
Clozapine causes agranulocytosis in approximately 1% of patients; therefore, baseline and weekly CBCs are required
during treatment. Clozapine is automatically discontinued if a patient is noncompliant with the blood work. After 6
months of continuous, stable treatment, patients can be changed to biweekly WBC monitoring if their WBC counts
are acceptable (≥3,500 mm3 and the absolute neutrophil count [ANC] is ≥2,000 mm3). After an additional 6 months
on a continuous, stable regimen, the patient may be changed to WBC monitoring every 4 weeks.231 If a patient takes
clozapine for <6 months with no problems, but stops the drug for <1 month, WBC monitoring can restart where it
was left off for a total of 6 months. If the break is >1 month, then an additional 6 months of weekly testing are
needed.
If baseline laboratory work is within normal limits and an informed consent is obtained, J.H. can start on clozapine
25 mg at bedtime. His clozapine dose should be increased by 25 to 50 mg every day until the dose is 300 mg/day,
the minimum dose at which most patients respond. The doses should be split and given as 150 mg twice a day.
Subsequently, clozapine should be increased incrementally according to the guidelines described. If J.H. has no
response to 300 mg after 4 to 8 weeks (based on a reduction in Brief Psychiatric Rating Scale scores and global
improvement), then the dose can be increased to 450 mg (150 mg TID). If response still is inadequate, then the dose
can be increased slowly to a maximum of 900 mg/day. Careful monitoring for orthostasis, hyperthermia, and
oversedation is needed, especially during early titration. Serum concentration monitoring can also help to guide dose
increases.
Clozapine may also cause sialorrhea, or hypersalivation. This is most often worst at night, and may lead to social
withdrawal, choking, or aspiration pneumonia.232 The incidence ranges from 31% of patients (premarket studies) to
up to 80% in several clinical trials.233 Several case reports have indicated that the scopolamine patch (1.5 mg/72
hour), ipratropium sublingual spray (0.03% or 0.06% given 2 sprays up to three times daily), atropine 1% ophthalmic
solution (2 drops swish and swallow twice daily), botulinum toxin (150 IU injected into each parotid gland), and
guanfacine (1 mg every morning) are effective in reducing, if not eliminating, sialorrhea.232,233,234,235,236 Other
medications commonly used are clonidine, anticholinergics (biperiden, benztropine, and diphenhydramine),
amitriptyline, terazosin, and propranolol.235,237
36. Four weeks after starting clozapine, J.H.'s WBC count drops to 4,000/mm3 from a baseline of 6,800/mm3.
Two weeks later, he has a WBC count of 2,100/mm3 and an ANC of 980/mm3. What action, if any, should be
taken?
[SI unit: WBC count, 4.0 and 2.1 × 109/L, respectively]
The hematologic adverse effect profile for clozapine is very different from that of other antipsychotic agents. The
incidence of clozapine-induced agranulocytosis is at least 10 to 20 times greater than the incidence with typical
antipsychotic medications.221 The incidence increases with age and is higher among women.238 Analysis of data from
150,409 patients followed by the Clozaril National Registry found agranulocytosis in 585 patients resulting in 19
deaths.238 The risk of agranulocytosis is greatest early in treatment with most cases appearing during the first 3
months of treatment. After 6 months, the risk for agranulocytosis decreases substantially but may occur in rare
instances up to 5 years into treatment.228,231 Trends in the weekly tests showing a continual decline in WBC count,
even if it remains >3,000/mm3, require careful attention. Guidelines for responding to reduction in WBC are
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Clozapine should be discontinued immediately, J.H. should be hospitalized, and hematology and infectious disease specialists should manage his care. Granulocyte colony-stimulating factor has been used successfully to manage
clozapine-induced agranulocytosis.239 Clozapine should not be reinstituted in J.H. because he has a very low ANC.
However, it should be noted that agranulocytosis can be reversible upon discontinuation of clozapine, in most cases,
with no persisting hematologic sequelae.238
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Table 78-14 Guidelines for Response to Clozapine-Induced White Blood Cell Abnormalities
Do Not Initiate Clozapine
Initial WBC count <3,500/mm3
Initial ANC <2,000/mm3
History of myeloproliferative disorder
History of agranulocytosis or granulocytopenia related to clozapine
WBC <2,000/mm3 and/or ANC <1,000/mm3
Discontinue clozapine immediately
Do not rechallenge patient
Monitor WBC and differential: until normal and for at least 4 weeks:
—Daily until WBC > 3,000/mm3 and ANC > 1,500/mm3
—Twice weekly until WBC > 3,500/mm3 and ANC > 2,000/mm3
—Weekly after WBC > 3,500/mm3
Consider bone marrow aspiration
Protective isolation initiated if deficient granulopoiesis
WBC 2,000–3,000/mm3 or ANC 1,000–1,500/mm3
Discontinue clozapine
Monitor WBC and differential:
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� Evaluating whether the lowest effective dose is used in maintenance therapy
� Children, elderly, and medically compromised patients with potentially altered pharmacokinetics
It is unnecessary and not cost effective to obtain serum concentrations for antipsychotic drugs that do not have
defined therapeutic ranges. Most studies describe haloperidol's therapeutic range to be between 4 and 12
ng/mL.241,242 The recommended ranges for fluphenazine and thiothixene are 0.2 to 2.8 ng/mL and 2 to 15 ng/mL,
respectively.243,244,245 Evaluation of clozapine trials suggest an optimal range of 350 to 420 ng/mL.246,247 Greater
response rates were observed in olanzapine-treated patients whose plasma concentrations were >23.2 ng/mL in
blood samples collected 12 hours after the dose.248 Samples should be collected 5 to 7 days after a fixed dose and 10
to 12 hours after the last dose for oral preparations. Two to three months should elapse before samples are
collected in patients taking depot preparations.240
E.H. has received an adequate trial of haloperidol and has moderate antipsychotic-induced parkinsonism. To prevent
exposure to higher than necessary doses, a serum haloperidol concentration is warranted before increasing the dose.
The target serum concentration should be between 4 and 12 ng/mL.
Treatment Adherence Poor adherence with prescribed antipsychotic therapy is a significant problem in the long-term management of
schizophrenia. Comprehensive reviews suggest that deviation (primarily underuse) from prescribed regimens occurs
in about 50% of patients with schizophrenia.249,250 Recent advances in medication treatments with atypical agents
have produced fewer side effects, which some studies have shown has increased adherence.251,252 During any phase
of illness, nonadherence with maintenance antipsychotic therapy places patients at risk for exacerbation of
psychosis, increased clinic and emergency room visits, and rehospitalization.253,254 Nonadherence to prescribed
regimens can also compromise patients' daily functioning and quality of life. Long-acting depot antipsychotics should
be strongly considered for patients who have a history of nonadherence. In addition to assured medication delivery,
another benefit of depot preparations is avoidance of potential bioavailability problems. Clinicians should suspect
poor absorption if serum concentrations are much lower than expected for a given oral dose; however, factors such
as nonadherence or drug–drug interactions must also be ruled out. Disadvantages of long-acting depot formulations
include the time required to reach optimal dosing and the inability to immediately withdraw the drug if unpleasant
side effects develop.58,255 Because of this, patients should be converted to a depot form after confirmation that the
oral dosage form is safe and effective.
Considerations in specific populations
Pregnancy 39. D.M., a 26-year-old woman, has a 6-year history of chronic undifferentiated schizophrenia that has been
treated with chlorpromazine 400 mg HS. She is psychiatrically stable and was last hospitalized 2 years ago.
When D.M. decompensates, she isolates herself, is unable to care for herself, does not eat properly, and does
not maintain her grooming and hygiene. She just found out that she is 8 weeks pregnant. Should her
chlorpromazine be continued and what are the risks if the medication is continued?
Most of the available evidence regarding the use of antipsychotics during pregnancy has focused on typical
antipsychotics. Among the typical antipsychotics, pooled results of large retrospective and small prospective
controlled studies suggest an increased risk of congenital anomalies in patients treated with low-potency
phenothiazines, particularly when treated during the first trimester.256 Guidelines have recommended that the use
of antipsychotic medication during the first trimester should be minimized or avoided if possible, especially between
weeks 6 and 10.58 If an antipsychotic is necessary during this period, high-potency typical antipsychotics may be safer.58 In addition to their teratogenic effects, there are other reasons to avoid low-potency
antipsychotics. Low-potency agents can worsen constipation and cause orthostatic hypotension and uteroplacental
insufficiency. Guidelines have also recommended that medications should be tapered 1 week before delivery to
minimize neonatal complications such as dystonia, withdrawal dyskinesias, temperature dysregulation, and
irritability.58
Medication management should balance the needs of D.M. against those of her unborn child. D.M.'s schizophrenia has
been stable for 2 years. Chlorpromazine should be discontinued because it is a low-potency phenothiazine and D.M.
is currently in her first trimester. Because she is a danger to herself when ill, it is critical that treatment be initiated
at the first evidence of decompensation. D.M. should be monitored by her clinician, family members, and
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