American Academy of Sleep Medicine. http://www.aasmnet.org/
American Sleep Apnea Association. http://www.sleepapnea.org/
National Sleep Foundation. http://www.sleepfoundation.org/
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Schizophrenia is a persistent, heterogeneous syndrome, which includes
both positive and negative symptoms. Together, these symptom clusters
can have variable effects on patient quality of life, functional recovery,
and prognosis. Prodromalsymptoms preceding the first episode of
psychosis may go unnoticed for many months. Onset of an initial
psychotic episode can be an acute or insidious process that causes a
significant impact on function and ability to perform activities of daily
Treatment goals will vary based upon the stage of the patient. During an
acute phase, stabilization and safety are primary. During a stable phase,
maintaining stability and improving functional recovery are the main
goals. Treatment modalities should include both pharmacologic and
Many factors need to be considered in selecting an appropriate
medication regimen for a patient with schizophrenia. Patient factors
such as comorbidities, target symptoms, adherence history, personal and
family history of medication response, and others need to be assessed.
Medication-related factors include efficacy, safety profile,
pharmacokinetics and drug interactions, and economic considerations.
Adverse effects of antipsychotics are varied. They may include acute
and chronic extrapyramidal movement disorders, metabolic disturbances
such as weight gain and alterations in serum glucose and lipids, and
other adverse effects such as sedation and orthostasis. Monitoring and
appropriate interventions for adverse effects should be ongoing
throughout allstages of illness to ensure continued safety and avoid
Tables 85-4, 85-5, 85-6, 85-7,
Patients who do not respond to an adequate antipsychotic trialshould be
assessed for adherence. Long-acting injectable antipsychotics may be
an option to help maintain adherence. Clozapine is the treatment of
choice in patients who are refractory to at least two adequate trials of
antipsychotic medications. However, clozapine does require strict
adherence to blood monitoring due to the risk of agranulocytosis and
carries a significant adverse effect burden.
Treatment of female patients of childbearing age may require special Case 85-1 (Question 34)
consideration. Untreated psychosis can result in poor self-care for the
mother and inadequate prenatal care. There is also the concern for
substance use, dangerous behaviors, and even suicide. Therefore, the
risks and benefits of ongoing antipsychotic treatment should be carefully
weighed by both the patient and the treatment team.
Early recognition of symptoms of first-episode psychosis (FEP) and
referral to appropriate multidisciplinary, comprehensive treatment
services are crucial to long-term functional recovery. This population is
highly sensitive to adverse effects. Antipsychotics should be titrated to
the minimum effective dose to decrease duration of untreated psychosis
and improve long-term prognosis.
Schizophrenia is a psychiatric illness that can lead to lifelong effects on a patient’s
functioning. Manifesting primarily as a thought disorder, patients often have problems
with perception, maintaining contact with reality, thought processing, and behavior.
These symptoms can lead to a variety of impairments across many domains, including
social, occupational, and emotional. Due to these symptoms, patients may require
hospitalizations to help maintain or restore functionality. Treatment of schizophrenia
encompasses multiple modalities, all targeted on improving a patient’s symptoms and
functioning, decreasing hospitalizations, and preventing morbidity and mortality.
Schizophrenia is a heterogeneous, genetically linked “spectrum” disorder that affects
It is the ninth leading cause of disability in the world,
found in all cultures and races. While often incorrectly assumed to be more common
in men, there is no gender difference in the incidence of the illness. However, the
onset of schizophrenia tends to occur between the ages of 18 to 25 in males and from
26 to 45 years old in females, and usually persists for a lifetime.
severe symptoms are generally seen in males versus females.
The economic burden of this devastating disease and its treatment is enormous.
one estimate from 2002, US costs for schizophrenia totaled $62.7 billion. This
included $30.3 billion in direct healthcare costs (of which medications accounted for
$5.0 billion) and $32.4 billion in indirect costs, such as lost productivity and other
costs incurred to the healthcare system.
3 Although progress has been made in treating
the symptoms of schizophrenia and restoring moderate levels of functioning, there is
as of yet no cure. As many patients present with an early age of onset, the lifetime
burden of illness can be great. Many patients will need repeated hospitalizations and,
when not hospitalized, will require significant outpatient services and treatment.
Additionally, many patients require supportive living situations, either in facilities
designed for these services or with family members, increasing the financial burden
Multiple neurotransmitter and physiologic mechanisms have been hypothesized to
explain the complex etiology of schizophrenia. Many theories on the role aberrant
neurotransmitter systems play in schizophrenia are derived from the pharmacologic
actions of the medications used to treat the illness in addition to direct analysis from
biologic samples. Findings on neurologic scans and other measurements of
neuroanatomy are also not consistent across patients to allow for these methods to be
reliably employed in making a diagnosis of schizophrenia. Genetic markers have
schizophrenia will be presented.
Genetic and Environmental Risk Factors
A genetic component to schizophrenia has been hypothesized since the observation
that family members of patients are more prone to develop schizophrenia than the
general population. Rates of schizophrenia among family members vary (anywhere
from 2% to 50%) based upon the relationship to the patient with schizophrenia.
Children born to parents who both have schizophrenia are affected in 40% to 60% of
cases. Siblings of patients with schizophrenia, including dizygotic twins, are also
affected in 10% to 15% of cases. However, monozygotic twins develop
schizophrenia approximately 50% of the time if their twin also has the illness.
Second- and third-degree relatives of patients more closely approximate the general
population, but still develop the illness approximately 2% to 5% of the time. Many
genes are thought to play a role in schizophrenia, but no gene has been found to be
universal across patients. This finding suggests multiple genes may be involved in the
etiology of schizophrenia. Although a genetic role appears to exist, it does not
explain how all patients develop the illness. Approximately two-thirds of patients
have no known familial history of the illness; therefore, other factors must play a role
1 Certain environmental exposures in early development are
associated with development of schizophrenia. Maternal infections, in particular
influenza, stress, and malnutrition during the first and second trimesters, have shown
a link to the child developing schizophrenia. Fetal or infant hypoxia during delivery
or in the first few months of life has been shown to double the risk of schizophrenia.
Childhood trauma and substance abuse have also been linked to the development of
The actual nature of the pathophysiology of schizophrenia is both unknown and
complex. It may be more appropriate to conceptualize it as a syndrome that may
involve many different underlying disease mechanisms.
deviations in brain structure and physiology have been noted, such as decreased gray
matter volume, whole-brain volume, and enlarged ventricle size,
focus on antagonism of presupposed increased activity at dopamine-2 (D2
The potency of typical antipsychotic medications has correlated with their
antagonism of these receptors, although some atypical antipsychotics, such as
clozapine, are extremely effective with a lesser degree of D2
The initial dopamine hypothesis of schizophrenia theorized that positive symptoms of
schizophrenia (e.g., conceptual disorganization and hallucinations) result from
abnormally increased activity in the mesolimbic dopamine neurons and that negative
and affective symptoms of schizophrenia result from subnormal mesocortical
11 This remains a clinically useful, albeit simplistic,
conceptual framework because many dopamine agonists tend to increase positive
symptoms and oppose the effects of antipsychotics. The relation of negative
symptoms to dopamine neurotransmission is even more complex. Some suggest that
decreased dopamine in frontal areas is linked to negative symptoms and increased
dopaminergic neurotransmission in striatal areas results in positive symptoms.
explain the efficacy and lack of movement adverse effects, prolactin elevation, or
secondary negative symptoms of antipsychotics such as clozapine and quetiapine, one
theory proposes that they have a faster dissociation from the D2
It has also been suggested that 65% of D2
predicted response and 78% predicted extrapyramidal adverse effects.
More recent thinking suggests involvement of glutamate and GABA, which are
intertwined with the disturbances in dopaminergic neurotransmission.
speculation that glutamate was involved in the pathophysiology of schizophrenia
started in the 1980s, the demonstration that N-methyl-D-aspartate (NMDA) receptor
antagonists best replicated all the major schizophrenic
symptoms such as the positive, negative, and cognitive ones in healthy subjects lent
credence to the “NMDA receptor hypofunction hypothesis.” Because negative
symptoms and cognitive deficits are not treated by D2
worsened by dopamine agonists, a theory that involves early disruption of glutamine
transmission in schizophrenia is an appealing hypothesis. Also, unlike subcortical
dopaminergic dysfunction, pathologic brain changes such as widespread dendritic
and spine dysplasia along with cortical atrophy could possibly relate to NMDA
16 Excitatory neurotransmission in the brain is predominantly
glutamatergic, and glutamate dysfunction could possibly relate to dopamine
dysfunction both in its prodrome and later on in the course of the illness.
schizophrenia, it can be considered that dopaminergic changes are a final end
mechanism where antipsychotics work in which increased mesocortical dopamine
turnover and overactive mesolimbic dopaminergic over activity result from other
preceding neurotransmitter changes.
Gradual progressive NMDA receptor hypofunction would also be consistent with
the altered neuroanatomy of schizophrenia.
schizophrenia has been noted since the 1920s, and there are more recent findings to
believe that there are changes in brain structure with reductions in the volume of
certain areas of the brain as well as changes in connectivity.
cerebral ventricles is a typical finding in schizophrenia, and reduced dendritic spine
density in cerebral cortical pyramidal neurons where NMDA subtypes of glutamate
receptors are present has been noted.
19 Some of these neuroanatomic differences
include impaired white matter integrity as well as reduced volume of gray matter in
inferior parietal, prefrontal, superior, and medial temporal, thalamic, and striatal
20 There are also a number of studies suggesting the importance of these white
matter abnormalities in schizophrenia to dysconnectivity between functional tracts.
Historical Concept of Schizophrenia
Schizophrenia was first characterized as “dementia praecox” by early psychiatrists
Arnold Pick and Emil Kraepelin in the late 19th century,
Bleuler as a “disintegration of psychic functions.”
23 Historically, schizophrenia has
been a disease characterized by progressive deterioration of the brain. Although
modern findings seem to corroborate this viewpoint, few patients with schizophrenia
show the progressive incremental loss of function that is characteristic of
24 The demonstrated effectiveness of dopamine receptor
antagonists in the treatment schizophrenia
resulted in the disorder being
conceptualized as a heterogeneous syndrome characterized by D2
26 predominately in mesolimbic regions of the brain.
Diagnosis and Differential Diagnosis
The diagnosis of schizophrenia in the recently introduced DSM-5 requires that an
individual has at least two persistent symptoms such as delusions, hallucinations,
disorganized speech, or behavior over a 6-month period.
subtypes of schizophrenia, such as paranoid or undifferentiated, have been removed.
These distinctions were not clinically useful because patients often displayed
characteristic symptoms from each subtype at various times in their illness, or even
27 Patients presenting with either manic or depressive symptoms
concomitantly with their typically schizophrenic ones are still diagnosed as having
schizoaffective disorder (Table 85-1).
Numerous disorders are characterized by psychosis during exacerbation (Table
85-2). Schizophrenia differs in its presentation from bipolar disorder in that there are
prominent signs of conceptual disorganization and hallucinations. Prominent
“negative” symptoms such as apathy, avolition, poverty of speech, and emotional
blunting may also be present. Schizoaffective disorder, bipolar type, may pertain to
patients who present with both positive schizophrenic symptoms and either mania or
depression. It is not uncommon for patients with schizophrenia to suffer from
secondary depression at various times during the course of their illness as well.
Suicide in these patients is not uncommon.
DSM-5 Criteria for Schizophrenia
successfully treated). At least one of these must be 1, 2, or 3:
Disorganized speech (e.g., frequent derailment or incoherence)
Grossly disorganized or catatonic behavior
Negative symptoms (i.e., restricted affect or avolition)
academic, or occupational functioning).
present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective Disorder and Mood Disorder Exclusion
total duration of the active and residual periods of the illness.
E. Substance or General Medical Condition Exclusion
F. Relationship to a Neurodevelopmental Disorder
symptoms of schizophrenia, also are present for at least 1 month (or less if successfully treated).
Arlington, VA: American Psychiatric Publishing; 2013:87–122, with permission (Copyright 2013).
Differential Diagnosis for Schizophrenia
Alcohol (or other sedative-hypnotics)
Amphetamine (or other stimulant)
Lysergic acid diethylamide (LSD)
Anticholinergics (especially in overdose)
Major depressive or bipolar disorder with psychotic features
Schizophreniform disorder and brief psychotic disorder
Paranoid, Schizoid, or Schizotypal personality disorder
Obsessive-compulsive disorder and body dysmorphic disorder
Post-traumatic stress disorder
Autism spectrum disorder or communication disorders
Arlington, VA: American Psychiatric Publishing; 2013:87–122, with permission.
In new-onset psychosis, the treating clinician should be careful to rule out drug-
induced (i.e., amphetamines, cocaine, “k2” synthetic cannabinoids, anticholinergics,
LSD, phencyclidine) causes. Corticosteroids may induce a manic type of psychosis,
whereas anabolic steroids may provoke a more aggressive type of psychotic
presentation. Obtaining a toxicology screen may be prudent. A patient can have a
brief psychotic disorder that comes on suddenly, last for up to one month, and remit
with no recurrence of symptoms. A patient presenting with signs and symptoms of
schizophrenia between one to 6 months is said to have a schizophreniform disorder.
Furthermore, depression can present with mood congruent auditory hallucinations
(often deprecatory) and delusions. Finally, patients with cluster A personality
disorders can show some isolated symptoms such as paranoia or blunted affect, but
do not meet full criteria of schizophrenia.
The symptoms of schizophrenia are generally organized into two main domains:
positive and negative (Table 85-3). Positive symptoms are usually what the public
perceives when thinking about schizophrenia: hallucinations, delusions, and
disorganization. Hallucinations can affect any of the five senses, but auditory are the
most common. Delusions are fixed false beliefs that are persistent despite evidence
to the contrary. Delusional subtypes include persecutory, erotomanic (e.g., delusion
of love), delusions of grandeur (having special abilities), or somatic (i.e., delusion of
being pregnant in context of negative pregnancy tests). Disorganization can manifest
in the patient’s speech, thought patterns, or behaviors. Some examples of
disorganized speech can include made-up words (neologisms), rhyming words (clang
speech), speaking words in a sentence in incorrect order (word salad), and repeating
words said to them (echolalia). Examples of disorganized behaviors can include
repeating the same activity needlessly (perseveration), repeating someone else’s
actions (echopraxia), dressing oddly for the setting or season of the year (wearing
winter clothes in summer), or other odd behaviors based upon the setting the patient
is in. Negative symptoms of schizophrenia include apathy, avolition, blunted affect,
31 A decreased ability to experience pleasure (known as
anhedonia) and social withdrawal can lead to significant functional impairment, even
when positive symptoms are relatively absent in a patient. During acute episodes,
positive symptoms may predominate, whereas over the long term it may be negative
symptoms that are more troubling and disabling to a patient. A third domain of
cognitive symptoms can also present in schizophrenia. Symptoms include concrete
thinking, inattention, problems with memory, learning and executive function, as well
as conceptual disorganization.
32 When these cognitive symptoms are combined with
negative symptoms over the patient’s lifespan, significant impairment in function may
result. Comorbid depression is also common in schizophrenia
28,34,35 and symptoms can be predictive of relapse.
may be overlooked in the face of overwhelming positive symptoms, or confused with
Positive and Negative Symptoms of Schizophrenia
Hallucinations (auditory, visual, or other senses) Diminished emotional expression (body language)
Delusions (persecutory, paranoid, grandiose, etc.) Avolition/psychomotor retardation
Disorganized thinking/speech Alogia (decreased speech)
Grossly disorganized or abnormal motor behavior
Anhedonia (decreased ability to feel pleasure)
Unusual behavior Asociality (lack of socialization)
Combativeness, agitation, and hostility Affective flattening
roommate has accompanied her with the security officers.
semesters, but she thought it was just from an online video game they had been playing. Once, she
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