SCHIZOPHRENIA (e-medicine)

Background
Schizophrenia is a severe, persistent, debilitating, and poorly understood psychiatric disorder that
probably consists oI several separate illnesses. The hallmark symptoms oI schizophrenia are
psychotic symptoms, such as auditory hallucinations (voices) and delusions (Iixed Ialse belieIs).
Impaired cognition or a disturbance in inIormation processing is a less vivid symptom that is
highly disruptive. People with schizophrenia have lower rates oI employment, marriage, and
independent living compared with other people.
Case study
John P is a 25-year-old male with the diagnosis oI schizophrenia. He was a healthy child, but his
parents report that he was a bedwetter and seemed slower to develop than his brothers and
sisters. A maternal uncle has also been diagnosed with schizophrenia.
John had 2 brieI hospitalizations in his late teens that were precipitated by anger at his boss,
depression, and voices in his head. He Iound the hospital stays unhelpIul. He was treated with
haloperidol, which gave him dystonic symptoms; he was then treated with olanzapine and gained
20 pounds and developed diabetes mellitus.
John smokes marijuana and tobacco Irequently to calm himselI; he also drinks vodka.
John's parents support him Iinancially. His brothers are sisters are angry and Irightened oI him
and have nothing to do with him. They are particularly upset by his lack oI interest in the outside
world. John lives in a boarding home and works in a sheltered workshop with diIIiculty.
John sees a psychiatrist Ior 15 minutes every 2 months but sometimes misses his appointment.
He has a social worker whom he sees oIten. The psychiatrist would like to switch him to long-
acting injectable antipsychotic treatment, but John is aIraid oI injections and isn't sure that he
needs medication. He usually misses his appointments with his primary care physician.
Pathophysiology
Neuroimaging studies have demonstrated anatomical abnormalities, such as enlargement oI the
ventricles and decreased brain volume in medial temporal areas.
|1|
These Iindings are oI greater
research interest than clinical use.
The hippocampus is a small, cortical, supposedly seahorse-shaped part oI the brain, curled within
the medial border oI the temporal lobe. The hippocampus is Iunctionally part oI the limbic
system, where emotions are processed. The hippocampus is where we Iorm declarative or
episodic memories (memories oI Iacts or events). The hippocampus is aIIected in Alzheimer
disease, the preeminent disease oI memory problems.
The hippocampus is also one oI the many parts oI the brain aIIected in schizophrenia.
Disturbances in declarative memory are common in schizophrenia, although not as marked as in
Alzheimer disease. Changes in the hippocampus, such as volume loss, change in perIusion, and
change in contour, observed in brains Irom patients with schizophrenia (including nonmedicated
patients) and relatives may be related to the cognitive problems oI schizophrenia.
|2|

Mattai et al studied a group oI children with schizophrenia and their healthy siblings and
controls.
|3|
The average age at the beginning oI the study was 12 years. The hippocampal volume
oI the ill children was less than that oI their siblings and controls and steadily decreased over 12
years oI Iollow up, although not at an increasing rate. The children with schizophrenia were
administered antipsychotic medications. The authors concluded that the hippocampal volume
deIicit was more likely due to the illness itselI rather than the use oI antipsychotic medication.
Interest has also Iocused on the various connections within the brain rather than localization in
one part oI the brain. Indeed, neuropsychological studies show impaired inIormation processing
in schizophrenia, and MRI studies show anatomic abnormalities in a network oI neocortical and
limbic regions and interconnecting white matter tracts.
|4|
A meta-analysis oI studies using
diIIusion tensor imaging to examine white matter Iound that 2 networks oI white matter tracts
are reduced in schizophrenia.
|5|

Other studies reveal less speciIic changes. In the Edinburgh High-Risk Study, researchers
examined brain images oI people at high genetic risk Ior schizophrenia. Seventeen oI 146 people
had reductions in whole brain volume and leIt and right preIrontal and temporal lobes. The
changes in preIrontal lobes were associated with increasing psychotic symptoms.
|6|

In a meta-analysis oI 27 longitudinal structural MRI studies oI patients with schizophrenia
compared with controls, the authors Iound that schizophrenia was associated with loss oI whole
brain volume in both gray and white matter and an increase in ventricular volume over time.
|7|

The Iirst clearly eIIective antipsychotic drugs, chlorpromazine and reserpine, were structurally
diIIerent Irom each other, but they shared antidopaminergic properties. Drugs that diminish the
Iiring rates oI mesolimbic dopamine D2 neurons are antipsychotic, and drugs that stimulate these
neurons (eg, amphetamines) exacerbate psychotic symptoms. ThereIore, abnormalities oI the
dopaminergic system are thought to exist in schizophrenia; however, little direct evidence
supports this. This theory has recently undergone considerable reIinement.
Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and
hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may
coexist. (Negative and positive symptoms are deIined below.) Moreover, the newer antipsychotic
drugs block both dopamine D2 and 5-hydroxytryptamine (5-HT) receptors.
Clozapine, perhaps the most eIIective antipsychotic agent, is a particularly weak dopamine D2
antagonist. Undoubtedly, other neurotransmitter systems, such as norepinephrine, serotonin, and
gamma-aminobutyric acid (GABA), are involved. Some research Iocuses on the N -methyl-D-
aspartate (NMDA) subclass oI glutamate receptors because NMDA antagonists, such as
phencyclidine hydrochloride and ketamine, can lead to psychotic symptoms in healthy
subjects.
|8|

Epidemiology
Frequency
International
The prevalence oI schizophrenia is approximately 1 worldwide.
Mortality/Morbidity
People with schizophrenia have a 10 liIetime risk oI suicide. Mortality is also increased
because oI medical illnesses, due to a combination oI unhealthy liIestyles, side eIIects oI
medication, and decreased health care.
Race
No known racial diIIerences exist in the prevalence oI schizophrenia. Some research indicates
that schizophrenia is diagnosed more Irequently in black people than in white people. This
Iinding has been attributed to cultural bias oI practitioners.
Sex
The prevalence oI schizophrenia is about the same in men and women. The onset oI
schizophrenia is later and the symptomatology is less severe in women than in men. This may be
because oI the antidopaminergic inIluence oI estrogen.
Age
The onset oI schizophrenia usually occurs in adolescence, and symptoms remit somewhat in
older patients. Most oI the deterioration that occurs in patients with schizophrenia occurs in the
Iirst 5-10 years oI the illness and is usually Iollowed by decades oI relative stability, although a
return to baseline is unusual. Positive symptoms are more likely to remit than cognitive and
negative symptoms.
History
InIormation about the medical and psychiatric history oI the Iamily, details about pregnancy and
early childhood, history oI travel, and history oI medications and substance abuse are all
important. This inIormation is helpIul in ruling out other causes oI psychotic symptoms.
The patient usually had an unexceptional childhood but began to experience a noticeable change
in personality and a decrease in academic, social, and interpersonal Iunctioning during mid-to-
late adolescence. In retrospect, Iamily members may describe the person with schizophrenia as a
physically clumsy and emotionally alooI child. The child may have been anxious and preIerred
to play by himselI or herselI. The child may have been late to learn to walk and may have been a
bedwetter.
|9, 10|

Usually, 1-2 years pass between the onset oI these vague symptoms and the Iirst visit to a
psychiatrist.
|11|

The Iirst psychotic episode usually occurs between the late teenage years and mid 30s.
The symptoms oI schizophrenia may be divided into the Iollowing 4 domains:
1. Positive symptoms: These include psychotic symptoms, such as hallucinations, which are
usually auditory; delusions; and disorganized speech and behavior.
2. Negative symptoms: These include a decrease in emotional range, poverty oI speech, loss
oI interests, and loss oI drive. The person with schizophrenia has tremendous inertia.
3. Cognitive symptoms: These include neurocognitive deIicits, such as deIicits in working
memory and attention and executive Iunctions such as the ability to organize and abstract.
Patients also have diIIiculty understanding nuances and subtleties oI interpersonal cues
and relationships. A new initiative Irom the National Institutes oI Mental Health, known
as Measurement and Treatment Research to Improve Cognition in Schizophrenia
(MATRICS), is a collaboration between various programs to develop tools Ior measuring
cognition in clinical trials and aiding drug development that is targeted at these
symptoms.
4. Mood symptoms: Schizophrenia patients oIten seem cheerIul or sad in a way that does
not make sense to others. They oIten are depressed.
Physical
indings on a general physical examination are usually not contributory. This examination is
necessary to rule out other illnesses.
A neurologic examination is sometimes helpIul beIore the initiation oI antipsychotic medications
because these drugs can change the Iindings. Some patients with schizophrenia have motor
disturbances beIore exposure to antipsychotic agents. Schizophrenia has been associated with leIt
and mixed handedness, minor physical anomalies, and soIt neurological signs.
Mental Status Examination
Patients with schizophrenia may show a repertoire oI strange and poorly understood behaviors
that are rarely observed in others. These include water drinking to the point oI intoxication,
staring at oneselI in the mirror, stereotyped behaviors, hoarding useless objects, selI-mutilation,
and a disturbed wake-sleep cycle. They oIten experience diIIiculty dealing with change.
On a detailed Mental Status Examination in the oIIice, the Iollowing observations are oIten made
when talking with a person with schizophrenia:
O The person may be dressed oddly, such as wearing heavy jackets in the summer. The
person may pay insuIIicient attention to personal hygiene.
O The person may be unduly suspicious oI the examiner or be socially awkward.
O The person may admit to a variety oI odd belieIs or delusions.
O He or she oIten has a Ilat aIIect, meaning that they have little range oI expressed emotion.
O The person may admit to hallucinations or respond to auditory or visual stimuli not
apparent to the examiner.
O The person may show thought blocking in which long pauses occur beIore he or she
answers a question.
O The person's speech may be diIIicult to Iollow, because oI the looseness oI his or her
associations. This means that the sequence oI thoughts Iollows a logic that is clear to the
patient but not to the interviewer.
O Conversation and initiation oI speech may be limited.
O Schizophrenia patients may demonstrate their diIIiculty in abstract thinking by not being
able to understand common proverbs. Or, the patient may give an idiosyncratic
interpretation.
O The speech oI a person with schizophrenia can be circumstantial, meaning that the person
takes a long time and uses a lot oI words in answering a question, or tangential, meaning
the person speaks at length but never actually answers the question.
O The patient oIten shows poor attention, disorganized thinking, and stereotyped or
perseverative thinking.
O The patient may make odd movements (which may or may not be related to neuroleptic
medication).
O The person has little insight into his or her problems (the term Ior this is anosognosia).
O The person may have thoughts about hurting or harming themselves or others or may
hear voices telling them to commit some kind oI violence. (Note that suicide in
schizophrenia is not uncommon; violence towards others is. Both oI these issues are
discussed in greater detail below.)
O Attention is intact. (This is important in distinguishing psychosis Irom delirium.)
O Orientation (knowing their own identity, where he or she is, and what the time is) is
usually intact.
According to the American Psychiatric Association'sDiagnostic and Statistical Manual of
Mental Disorders (DSM-IJ-TR), the patient must have experienced at least 2 oI the Iollowing
symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or
negative symptoms. Only 1 symptom is required iI the delusions are bizarre or iI auditory
hallucinations occur in which the voices comment in an ongoing manner on the person's
behavior, or iI 2 or more voices are talking with each other. The patient must experience at least
1 month oI symptoms (or less iI successIully treated) during a 6-month period, and social or
occupational deterioration problems occur over a signiIicant amount oI time. These problems
must not be attributable to another condition Ior the diagnosis oI schizophrenia to be made.
|12|

Causes
The causes oI schizophrenia are not known. Most likely, at least 2 groups oI risk Iactors exist:
genetic and perinatal.
enetic
The risk oI schizophrenia is elevated in biological relatives oI patients but not in adopted
relatives.
|13|

The risk oI schizophrenia in Iirst-degree relatives oI people with schizophrenia is 10.
II both parents have schizophrenia, the risk oI schizophrenia in their child is 40.
Concordance Ior schizophrenia is about 10 Ior dizygotic twins and 40-50 Ior monozygotic
twins.
The gene variants that have been implicated so Iar are responsible Ior only a small Iraction oI
schizophrenia, and these Iindings have not always been replicated in diIIerent studies. The genes
that have been Iound mostly change a gene`s expression or a protein`s Iunction in a small way.
Interactions with the rest oI the genome and with environment will doubtless prove to be
important.
Some loci oI particular interest are the Iollowing:
O The catechol-O-methyltransIerase (COMT) gene codes Ior the postsynaptic intracellular
enzyme, COMT, which is involved in the methylation and degradation oI the
catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several
allelic variants oI COMT aIIect its activity. The valine-valine variant degrades dopamine
Iaster than does the valine-methionine variant; subjects with 2 copies oI the methionine
allele were less likely to develop psychotic symptoms iI they used cannabis than other
cannabis-using subjects.
|14|

O The RELN gene codes Ior the protein reelin, which plays a role in brain development and
GABAergic activity. In an international study using a genome-wide association scan, a
common variant in this gene increased the risk oI schizophrenia, but only in women.
|15|

O A Canadian group has looked at the gene Ior nitric oxide synthase 1 adaptor, known as
NOS1AP. This gene codes Ior the enzyme nitric oxide synthetase, which is Iound in high
concentration in inhibitory neurons in the brain. Nitric oxide acts as an intracellular
messenger. Using a newly developed statistical technique, the posterior probability oI
linkage disequilibrium, the authors identiIied a single nucleotide polymorphism
associated with higher levels oI expression oI this gene in postmortem brain samples.
|16|

Other genetic changes involve the structure oI the gene. or example, copy number variants are
deletions and duplications oI segments oI DNA. Copy number variants can involve genes or
regulatory regions. These variants are usually inherited, but can spontaneously arise. Copy
number variants, such as deletions Iound at 22q11.2, 1q21.1, and 15q13.3 increase the risk oI
patients developing schizophrenia.
|17|
Some copy number variants include autism, intellectual
disability, attention-deIicit hyperactivity disorder, and epilepsy.
|18|
These Iindings account Ior
only a very small part oI the heritability oI schizophrenia.
Many people with schizophrenia have no Iamily history oI the disorder. This may be due to the
occurrence oI new mutations in the patient. De novo mutations in the exome, which is the part oI
the chromosome that codes Ior proteins, seem to be more common in patients with schizophrenia
than is otherwise expected.
|19, 20|

Perinatal
Women who are malnourished or who have certain viral illnesses during their pregnancy may be
at greater risk oI giving birth to children who later develop schizophrenia.
Children born to Dutch mothers who were malnourished during World War II have a high
incidence oI schizophrenia.
The 1957 inIluenza A2 epidemics in Japan, England, and Scandinavia resulted in an increase in
schizophrenia in the oIIspring oI women who developed this Ilu during their second trimester.
Women in CaliIornia who were pregnant between 1959 and 1966 were more likely to have
children who developed schizophrenia iI they had Ilu in the Iirst trimester oI their pregnancy.
|21|

Obstetric complications may be associated with a higher incidence oI schizophrenia.
Children born in the winter months may be at greater risk Ior developing schizophrenia.
|22|

A study in innish women by Clarke et al supports an interaction between genetic and
environmental inIluences on causation oI schizophrenia. A review oI the 9,596 women in
Helsinki who received hospital treatment during pregnancy Ior an upper urinary tract inIection
between 1947 and 1990 Iound no overall signiIicant increase in the risk oI schizophrenia among
their oIIspring but a 5-Iold higher risk among the oIIspring oI women who also had a Iamily
history oI psychosis. Clarke et al estimated that, among oIIspring oI women with both prenatal
pyelonephritis and a positive Iamily history oI psychotic disorders, 38-46 oI schizophrenia
cases resulted Irom the synergistic action oI both risk Iactors.
|23|

Laboratory Studies
No characteristic laboratory results are Iound in schizophrenia. The Iollowing blood work should
be perIormed on all patients, at the beginning oI the illness and periodically aIterwards:
O Complete blood count
O iver, thyroid, and renal Iunction tests
O Electrolytes, glucose, B12, serum methylmalonic acid, Iolate, and calcium level
O II the patient's history provides any reason Ior suspicion, check HIV; RPR;
ceruloplasmin; ANA; urine Ior culture and sensitivity and/or drugs oI abuse; a.m.
cortisol, and 24-hour urine collections Ior porphyrins, copper, or heavy metals.
O II the patient is a woman oI childbearing age, a pregnancy test is important.
O II a strong suspicion oI neurosyphilis exists, speciIic treponemal tests may be helpIul.
O Consider testing Ior yme disease.
Imaging Studies
O Brain imaging is indicated to rule out subdural hematomas, vasculitis, cerebral abscesses,
and tumors.
O A chest x-ray should be done iI pulmonary illness or occult malignancy is suspected.
Other Tests
O Neuropsychological testing in patients with schizophrenia oIten shows poor executive
Iunctioning, meaning diIIiculty in inIormation processing, impaired memory, diIIiculty in
abstraction and recognizing social cues, and easy distractibility. Determination oI the
patient's cognitive weaknesses and strengths can be helpIul in treatment planning.
O II indicated, an electroencephalogram can be useIul.
O Dexamethasone suppression test and adrenocorticotropic hormone (ACTH) stimulation
tests are used to establish the diagnosis oI hypercortisolism and hypocortisolism,
respectively.
Procedures
O II a strong suspicion oI Wilson disease exists, consider a liver biopsy (or multiple
biopsies) to conIirm the diagnosis.
Medical Care
The use oI antipsychotic medications, also known as neuroleptic medication or major
tranquilizers, is the mainstay oI treatment Ior schizophrenia. These medications have repeatedly
been shown to diminish the positive symptoms oI schizophrenia and prevent relapses.
Approximately 80 oI patients relapse within 1 year iI antipsychotic medications are stopped,
while only 20 relapse iI treated.
The Iirst antipsychotic medications were dopamine 2 antagonists, such as chlorpromazine and
haloperidol. Medications that are similar to these are known as Iirst-generation, typical, or
conventional antipsychotics. Other antipsychotics, beginning with clozapine, are known as
second-generation, atypical, or novel antipsychotics. The Iirst-generation antipsychotic drugs
tend to cause extrapyramidal adverse eIIects and elevated prolactin levels. The second-
generation drugs are more likely to cause weight gain and abnormalities in glucose and lipid
control.
The choice oI which drug to use in schizophrenia depends on numerous issues, such as
eIIectiveness, cost, side-eIIect burden, method oI delivery, availability, and tolerability. Many
studies are Iunded by pharmaceutical companies and compare antipsychotic drugs to one
another. ittle consensus has been reached.
or some years it was believed that the newer drugs were more eIIective, but that belieI is now
Iading. The exception is clozapine, which consistently outperIorms the other antipsychotic drugs.
An inIluential study has been the Clinical Antipsychotic Trials oI Intervention EIIectiveness
(CATIE). This is a large study Iunded by the Iederal government to examine the eIIectiveness oI
several diIIerent antipsychotic drugs in more than 1400 patients. By multiple measures,
perphenazine, a Iirst-generation drug, was almost or about as good as the second-generation
drugs.
|28|

In a study Irom the United Kingdom, the Cost Utility oI the atest Antipsychotic Drugs in
Schizophrenia Study (CUtASS), more than 200 patients who were about to change
antipsychotic medication were randomly assigned to either a Iirst-generation or second-
generation agent. In this study, the Iirst-generation drugs seemed to perIorm slightly better than
the newer ones. Clozapine was the exception, in that it outperIormed all oI the other drugs.
|29|

In a large study Irom inland, researchers used a database to review the eIIectiveness oI
antipsychotic agents in the treatment oI 2600 people aIter their Iirst episode oI schizophrenia.
|30|
The study Iound that slightly less than halI oI patients continued treatment Ior longer than 30
days aIter discharge. With respect to rehospitalization, patients treated with depot haloperidol did
the best, Iollowed by those treated with clozapine. Patients treated with depot haloperidol,
perphenazine, or risperidone stayed on these medications longer than those treated with the oral
equivalents and had a lower rehospitalization rate.
These Iindings are diIIicult to translate to practice in the United States Ior a Iew reasons. Medical
care is delivered diIIerently in inland, with the cost oI antipsychotic medication Iully
reimbursed, according to the authors. The average age at admission was 38 years, which is much
older than is expected Ior the Iirst episode. inally, depot perphenazine and zuclopenthixol are
not available in the United States. Depot olanzapine was not used. However, the authors`
Iindings that patients who had their Iirst episode did best in terms oI avoiding more
hospitalizations when treated with depot haloperidol or clozapine are noteworthy.
The Iollowing adverse eIIects are those typically associated with conventional antipsychotic
agents or with risperidone, a novel antipsychotic agent, at doses greater than 6 mg/d.
O Akathisia is a subjective sense oI inner restlessness, mental unease, irritability, and
dysphoria.
O Dystonia is the occurrence oI painIul and Irightening muscle cramps that usually occur
within 12-48 hours oI the beginning oI treatment or an increase in dose. This typically
occurs in young muscular men. It aIIects the head and neck, but it may extend to the
trunk and limbs.
O Hyperprolactinemia (high levels oI prolactin) is associated with galactorrhea,
amenorrhea, gynecomastia, impotence, and osteoporosis.
O Neuroleptic malignant syndrome is marked by Iever, muscular rigidity, altered mental
state, and autonomic instability. aboratory Iindings include increased creatine kinase
and myoglobinuria. Acute renal Iailure may be present. A signiIicant mortality rate
exists. Rarely, neuroleptic malignant syndrome associated with clozapine and other
atypical antipsychotic agents has been reported.
O Parkinsonism presents with tremor, bradykinesia, akinesia, and, sometimes, rigidity or
bradyphrenia (slowed thinking). This occurs particularly in women and elderly patients.
O The incidence oI tardive dyskinesia (TD) is as high as 70 in elderly patients. It presents
as involuntary and repetitive (but not rhythmic) movements oI the mouth and Iace.
Chewing, sucking, grimacing, or pouting movements oI the Iacial muscles may occur.
People may rock back and Iorth or tap their Ieet. Occasionally, diaphragmatic dyskinesia
exists, which leads to loud and irregular gasping and/or "jerky" speech. The patient is
oIten not aware oI these movements. Risk Iactors Ior TD include age, Iemale sex, and
negative symptoms. Duration oI therapy and dose seem to be logical risk Iactors, but this
has not been demonstrated conclusively. TD is probably less common with the use oI
novel antipsychotic drugs but, until many patients have been exposed to these drugs Ior
several years, this will not be known with certainty.
The Iollowing adverse eIIects may occur with all antipsychotic agents, except as noted.
O Anticholinergic side eIIects include dry mouth, exacerbation oI glaucoma, conIusion,
decreased memory, agitation, visual hallucinations, and constipation. Risperidone,
aripiprazole, and ziprasidone are relatively Iree oI anticholinergic adverse eIIects.
O The QT interval is the electrocardiogram interval between the beginning oI the QRS
complex and the end oI the T wave. It reIlects the time required Ior the ventricles to
depolarize and repolarize. When the QT interval is corrected Ior heart rate, it is called
QTc. A prolonged QTc interval puts a person at risk Ior torsade de pointes, a malignant
arrhythmia associated with syncope and sudden death. QTc intervals are lengthened by
the conventional antipsychotic agents thioridazine, pimozide, and mesoridazine and, to a
lesser extent, by the novel antipsychotic agent ziprasidone. Risk is increased by
individual susceptibility, heart Iailure, bradycardias, electrolyte imbalance (especially
hypokalemia), hypomagnesemia, and Iemale gender.
|31|

O As oI 2003, no novel antipsychotic agents had been reported to lead to torsade de pointes.
O In a large simple trial, more than 18,000 patients in 18 countries were randomly assigned
to receive either ziprasidone or olanzapine. No cases oI torsade de pointes were reported,
although this event is so rare that this Iinding is not entirely surprising. No increase in
nonsuicide mortality was reported. In particular, no increase in cardiac mortality was
Iound, which is somewhat reassuring in terms oI the cardiac saIety oI ziprasidone.
|32|

O Haloperidol has only a small inIluence on the ECG but it has been implicated, although
very rarely, in causing torsades de pointes.
|33|

O All antipsychotic agents may be associated with esophageal dysmotility, aspiration, and
the subsequent risk oI pneumonia.
O Orthostatic hypotension can be problematic at the beginning oI therapy, with dose
increases, and in elderly patients. This is related to alpha1-blockade and is particularly
severe with risperidone and clozapine.
O Venous thromboembolism may be associated with the use oI antipsychotic drugs.
Patients treated with clozapine may be at particular risk Ior this complication. The
reasons Ior this possible association are not understood.
|34, 35|

O Altered glucose and lipid metabolism, with or without weight gain, may occur with most
antipsychotic agents, as can weight gain itselI.
|36|
Aripiprazole and ziprasidone are the
antipsychotic drugs least likely, and olanzapine and clozapine the most likely, to lead to
these adverse eIIects. The mechanism oI weight gain associated with psychotropic drugs
is not understood. Sensitivity to insulin may be increased, or increased leptin levels may
be present. Weight gain is associated both with psychological problems (eg, decreased
selI-esteem) and with medical problems (eg, diabetes, coronary artery disease, arthritis).
Some approaches to the problem oI weight gain include educational programs on
nutrition and exercise, and cognitive behavioral therapy. Various medications have been
tried but with little success.
O Kessing et al examined nearly 346,000 patient records where individuals purchased
antipsychotics and nearly 1.5 million unexposed individuals registered in Denmark to
compare risk Ior diabetes.
|37|
Treatment with antipsychotics has been associated with an
increased risk Ior diabetes. The rate ratio (RR) Ior risk with Iirst-generation
antipsychotics was 1.53, whereas the rate ratio varied widely Ior second-generation
antipsychotics (RR 1.32; range, 1.17-1.57).
The conventional antipsychotic agents are available in generic Iorms and are less expensive than
the newer agents. They are available in a variety oI vehicles, including liquid and intramuscular
preparations. Most importantly, they are also available as depot preparations. In other countries,
several diIIerent antipsychotic depot preparations exist, but, in the United States, only
haloperidol and Iluphenazine are available in depot Iorms. With respect to the newer agents,
risperidone is now available as a long-acting injection (Risperdal Consta) that uses biodegradable
polymers, and a long-acting olanzapine intramuscular injection also is available.
Therapeutic drug monitoring is the measurement oI medication levels in the blood to ensure that
the levels are in the therapeutic range. This is important in schizophrenia Ior several reasons.
O Patients may not always take their medications; checking the level can detect this.
O Patients may not always be the best reporters oI their side eIIects, and medication levels
can occasionally detect clinically silent toxicity.
O Smoking tobacco products induces the liver enzyme CYP1A2, which metabolizes a
number oI antipsychotic drugs. or example, patients who stop smoking while being
treated with clozapine or olanzapine oIten experience an increase in their antipsychotic
levels. (Nicotine patches and nicotine inhalers and chewing tobacco do not induce this
enzyme.)
However, many medications do not have clear dose-response curves established. Plasma
concentrations oI haloperidol are somewhat correlated with clinical eIIects. levels oI about 15-25
ng/m are thought to be optimal. Plasma concentrations oI clozapine oI around 300-400 ng/m
may be optimal.
O Anticholinergic agents (eg, benztropine, procyclidine, trihexyphenidyl, diphenhydramine)
or amantadine are oIten used in conjunction with the conventional antipsychotic agents to
prevent dystonic movements or to treat extrapyramidal symptoms. Akathisia is
particularly diIIicult to treat, but it occasionally responds to an anticholinergic agent, a
benzodiazepine, or a beta-blocker.
O Clozapine is the oldest atypical antipsychotic agent and probably the most eIIective.
|38|
It
is associated with about a 1 risk oI agranulocytosis, so patients must have weekly white
blood cell count monitoring Ior the Iirst 6 months
|39|
(the period oI greatest risk) and then
monitoring every 2 weeks Ior 6 months, and then every 4 weeks, as long as the absolute
neutrophil count (ANC) is normal. (II the ANC drops, then a strict protocol oI monitoring
and possibly medication cessation must be Iollowed). Clozapine is also associated with
anticholinergic adverse eIIects, sedation, and drooling.
|39|
Constipation and cardiac side
eIIects (cardiomyopathy and myocarditis) can be liIe threatening. However,
approximately one third oI patients who have not responded to conventional
antipsychotic agents do better on clozapine. Violence, substance abuse, smoking, and
suicidality are diminished with the use oI clozapine.
Many patients with schizophrenia are treated with other psychotropic medications in addition to
antipsychotic agents. Very little rigorous evidence Ior the use oI polypharmacy in schizophrenia
exists, but it is widely practiced. Medications oIten used include the antidepressants, mood
stabilizers, and anxiolytic agents. Note that carbamazepine and clozapine should not be used
together.
Using 2 or even 3 diIIerent antipsychotic agents together is also common. Recent reports suggest
that patients preIer this.
|40|
A recent meta-analysis oI 19 studies involving more than 1200
subiects also Iound an advantage Ior antipsychotic polypharmacy.
|41|
Some studies have
explored the potential neurotoxic eIIects oI antipsychotic medications; however, no clear
conclusions have been reached. or example, Ho et al perIormed structural brain imaging in
more than 200 patients with schizophrenia over 7 years. Those patients treated with higher doses
oI antipsychotic medications seemed to lose gray matter throughout their brain (except the
cerebellum); those treated with lower doses oI antipsychotic medications seemed to have a small
increase in white matter oI the brain.
|42|
The clinical signiIicance oI these Iindings is unclear.
Whether these changes are associated with any clinical symptoms directly or iI the changes are
reversible is unknown. Whether higher doses oI medication were in response to the gray matter
loss or the other way around is unclear.
Psychological interventions
Psychosocial treatment Ior the person with schizophrenia is essential, since medications alone
are insuIIicient. Psychosocial treatments are currently oriented according to the recovery model.
The goal oI treatment, according to this model, is Ior the person with schizophrenia to have Iew
or stable symptoms, not be hospitalized, manage his or her own Iunds and medications, and
either be in work or school at least halI-time. Hope, empowerment, choice, and community
integration are emphasized in this treatment approach.
The best studied psychosocial treatments are social skills training, cognitive behavioral therapy,
cognitive remediation, and social cognition training.
|43|

In one study Irom China, the authors randomly assigned over a thousand patients with
schizophrenia to either antipsychotic medication alone or medication with a psychosocial
intervention. The authors chose an interesting way oI delivering a psychosocial intervention.
Each month, the patients and their Iamilies received a day oI 4 types oI evidence-based
interventions: psychoeducation, Iamily, intervention, skills training, and cognitive behavior
therapy. AIter a year, the patients in the group receiving the extra interventions were more
compliant with their medications and had Iewer rehospitalizations and greater quality oI liIe.
|44|

Cognitive impairment, a core Ieature oI schizophrenia, is less dramatic than other symptoms (eg,
hallucinations, delusions) but can be more problematic with respect to work, social relationships,
and independent living. Cognitive impairment responds poorly to medication. Cognitive
remediation is a treatment modality that is based on principles oI neuropsychological
rehabilitation. It is based, in part, on the idea that the brain has some plasticity, and that brain
exercises can encourage neurons to grow and can develop the neurocircuitry underlying many
mental activities.
Numerous diIIerent models oI cognitive remediation are available. Some models emphasize drill
practice oI isolated cognitive skills with the aid oI computers, whereas others help people to
develop strategies to overcome areas oI weakness. Other Iorms oI this therapy are known as
cognitive rehabilitation, cognitive enhancement, or metacognitive therapy.
Cognitive remediation works best when patients are stable. People improve across numerous
cognitive Iunctions, and changes are Iound on brain imaging that reIlect these changes in brain
Iunctioning. These techniques are time-intensive and labor-intensive and seem to work best
when individualized to the particular person. This is because cognitive deIicits are multiple and
vary Irom person to person. When combined with other therapies, such as supported
employment, cognitive remediation leads to clinically relevant improvements.
|45|
These eIIects
are durable; the eIIects last even aIter the training has stopped.
|46|

In a study by Grant et al, low-Iunctioning patients with prominent negative symptoms were
assigned to recovery-oriented cognitive behavioral therapy or standard treatment. AIter 18
months, the authors Iound that both negative and positive symptoms had decreased. The study
was not blind, and the treatment was delivered by enthusiastic doctoral level therapists, which
may limit the generalizability oI these Iindings.
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Consultations
Social work
Social work: Schizophrenia aIIects the person's whole Iamily, and the Iamily`s responses can
aIIect the trajectory oI the person`s illness. amilial "high expressed emotion" (hostile over
involvement and intrusiveness) leads to more Irequent relapses. Some studies have Iound that
Iamily therapy or Iamily interventions may prevent relapse, reduce hospital admission, and
improve medication compliance.
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Vocational rehabilitation
ew patients with schizophrenia are able to maintain competitive employment. Supported
employment programs are associated with higher rates oI employment but not with increases in
global Iunctioning, selI-esteem, time out oI the hospital, or quality oI liIe.
iet
Many psychotropic medications are associated with weight gain and changes in glucose or lipid
metabolism. Occasionally the person with schizophrenia develops odd Iood preIerences. Many
persons with schizophrenia have limited Iunds, do not cook Ior themselves, and live in areas
where Iast Iood outlets are abundant. ThereIore, nutritional counseling is diIIicult but important.
Activity
Because many psychotropic medications are associated with weight gain, persons with
schizophrenia should be encouraged to be as physically active as possible.
O Most patients with schizophrenia smoke. This may be a result oI previous conventional
antipsychotic treatment because nicotine may ameliorate some oI the adverse eIIects oI
these drugs. Smoking may also be related to the boredom associated with
hospitalizations, the peer pressure Irom other patients to smoke, or the anomie associated
with unemployment. The health risks Irom smoking are well known, and patients should
be encouraged to stop smoking. Cessation oI tobacco smoking, however, may result in
the unexpected increase oI clozapine levels.
O Involving people outside the usual medical settings is also helpIul. The National Alliance
Ior the Mentally Ill (NAMI) is a helpIul advocacy group that is supportive Ior Iamily
members. NAMI also advocates Iunding and research. Patients with schizophrenia oIten
have diIIiculty Iinding housing; thereIore, working with associations that may provide
housing assistance is important.
Medication Summary
O The medications listed below diminish the positive symptoms oI schizophrenia and
prevent relapses. The newer, or atypical, antipsychotic drugs may be more eIIective in
treating negative symptoms and cognitive impairment.
O All medications should be used in lower doses with children and elderly patients and with
great caution in women who are pregnant or breastIeeding.
Antipsychotics
Class Summary
Mainstay oI treatment oI schizophrenia. Some clinicians routinely perIorm ECGs on patients
beIore beginning treatment with antipsychotic medication. Note that the use oI antipsychotic
medications Ior the treatment oI behavioral symptoms in elderly patients with dementia has
not been shown to be eIIective and is associated with an increased risk oI mortality. Because
suicide is not uncommon in patients with psychotic illnesses, the clinicians should write
prescriptions Ior the smallest quantity that is consistent with good clinical care. Patients
should be urged to avoid substance abuse.
Aripiprazole (Abilify) A partial agonist at dopamine D2 and serotonin 5-HT1A receptors
and an antagonist at serotonin 5-HT2A receptors. Also antagonizes alpha1 receptors.
Available as tab, orally disintegrating tab, or oral solution.
Clozapine (Clozaril) Antagonist at adrenergic, cholinergic, histaminergic and
serotonergic receptors. Has some D2 antagonism and high D4 aIIinity.
Olanzapine (Zyprexa) Olanzapine is a selective monoaminergic antagonist at the
Iollowing receptors: serotonin, D1-4, muscarinic, H1, and alpha1 adrenergic.
Paliperidone (Invega) Major active metabolite oI risperidone and Iirst oral agent
allowing once-daily dosing. Indicated Ior treatment oI acute schizophrenia. Mechanism oI
action not completely understood but thought to mediate central receptor antagonism oI
dopamine type 2 (D
2
) and serotonin type 2 (5HT
2A
). Also elicits antagonist activity at
adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Has no aIIinity Ior
cholinergic, muscarinic, or beta-adrenergic receptors. Available as extended-release drug
delivery system via osmotic pressure.
Risperidone (Risperdal) Has both D2 and serotonin 5HT2 antagonism. Now available in
long-acting Iorm using microspheres made oI biodegradable polymers.
"uetiapine (Seroquel) May act by antagonizing dopamine and serotonin eIIects. Newer
antipsychotic used Ior long-term management. Improvements over earlier antipsychotics
include Iewer anticholinergic eIIects and less dystonia, parkinsonism, and tardive dyskinesia.
Ziprasidone (eodon) Antipsychotic agent that antagonizes dopamine type-2, 5-HT2,
histamine H1, and alpha1-adrenergic receptors.
Iloperidone (Fanapt) Atypical antipsychotic agent indicated Ior acute treatment oI
schizophrenia. Precise mechanism oI action unknown. Antagonizes receptors Ior dopamine-2
and serotonin type 2 (5-HT2). Approved by DA in May 2009.
Asenapine (Saphris) Mechanism oI action unknown. EIIicacy thought to be mediated
through a combination oI antagonist activity at dopamine 2 and serotonin (5-HT2) receptors.
Exhibits high aIIinity Ior serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-
HT6, and 5-HT7 receptors; dopamine D2, D3, D4, and D1 receptors; alpha1- and alpha2-
adrenergic receptors; and histamine H1 receptors, with moderate aIIinity Ior H2 receptors. In
vitro assays suggest antagonistic activity elicited at these receptors. Indicated Ior acute
treatment oI schizophrenia.
The prescribing inIormation was updated in September 2011 to include data Irom 52 reports
oI type 1 hypersensitivity reactions.
Lurasidone (Latuda) Atypical antipsychotic. Precise mechanism unknown. Suggested
eIIicacy thought to be mediation oI central dopamine type-2 and serotonin type-2 (5HT-2A)
receptor antagonism. Indicated Ior schizophrenia.
Fluphenazine hydrochloride (Prolixin) High-potency typical antipsychotic that blocks
postsynaptic dopaminergic D1 and D2 receptors in the brain. Some alpha-adrenergic and
anticholinergic eIIects and may depress the reticular activating system.
Haloperidol (Haldol) Drug oI choice Ior patients with acute psychosis when no
contraindications exist. Haloperidol is a D2 antagonist. Butyrophenone noted Ior high
potency and low potential Ior causing orthostasis. The drawback is the high potential Ior
EPS/dystonia. Parenteral dosage Iorm may be admixed in same syringe with 2 mg oI
lorazepam Ior better anxiolytic eIIects.
Emergent Treatment of Scbizopbrenia
O AuLhor aul S CersLeln Mu Chlef LdlLor amela L uyne Mu more
Overview
It is essential in the emergency department (ED) not to conIuse the thought and behavioral
disturbances oI organically based acute delirium with any oI the psychotic disorders. The
avoidance oI this conIusion is the primary reason Ior "medical clearance" examinations and
drugs-oI-abuse screening. Because oI the variability oI symptom expression, diagnostic
requirements oI chronicity, and lack oI pathognomonic Ieatures, an ED diagnosis oI
schizophrenia should be provisional at best. As a diagnosis-by-exclusion, schizophrenia must be
distinguished Irom the numerous psychiatric and organic disorders that also can lead to psychotic
disturbances in thinking and behavior. Psychosis and schizophrenia are not equivalent, although
they are commonly mistaken as such. Psychosis is a disorder oI thinking and perception in which
inIormation processing and reality testing are impaired, resulting in an inability to distinguish
Iantasy Irom reality (delusions and hallucinations). Schizophrenia is one oI several psychiatric
disorders Ior which psychosis is a major Ieature. Other psychiatric disorders that can be mistaken
Ior schizophrenia include the Iollowing:
O lpolar dlsorder ln a manlc phase
O ueluslonal dlsorders
O rlef psychoLlc dlsorder
O Schlzophrenlform lllness schlzold and schlzoLypal personallLy dlsorder
O orderllne personallLy dlsorder
O osLLraumaLlc sLress dlsorder (1Su)
O 1ranslenL druglnduced psychosls alcohollc halluclnosls and drug or alcohol wlLhdrawal
syndromes
O Ma[or depresslon wlLh psychoLlc feaLures
O uellrlum and demenLla
The most common etiologies Ior severe mental status changes in the ED are organic, not
psychiatric. They include medications, drug intoxication, drug withdrawal syndromes, and
general medical illnesses causing delirium. Take a careIul medication history; many commonly
prescribed medicines can occasionally cause psychotic reactions. Medical clearance
examinations are medicolegally risky. These evaluations are typically brieI and rarely suIIicient
to rule out organic etiologies. Go to SchizoaIIective Disorder, Childhood-Onset Schizophrenia,
and SchizophreniIorm Disorder Ior complete inIormation on these topics.
Patient History
The onset oI schizophrenia is insidious in approximately one halI oI all patients. The prodromal
phase can begin years beIore the Iull-blown syndrome and is characterized by losses oI
Iunctioning in home, society, and occupation (eg, poor school or work perIormance,
deterioration oI hygiene and appearance, decreasing emotional connections with others,
behaviors that would have been odd Ior the individual in the past). A gradual onset indicates a
more severe and prolonged course oI illness. An abrupt onset oI hallucinations and delusional,
bizarre, or disorganized thinking in patients who previously Iunctioned normally may result in a
better intermediate and long-term outcome. Such patients arriving in a psychotic crisis that
requires immediate management may not have been diagnosed with psychiatric illness
previously. They oIten present diagnostic dilemmas involving organic versus psychiatric
etiology and primary psychotic versus aIIective disorder diagnosis. Treatment may be
complicated Iurther by the presence oI alcohol or drug intoxication. OIten, the history obtained
in the ED relates to a complication oI treatment (medication adverse eIIects) or a crisis arising
Irom socioeconomic Iactors secondary to schizophrenia (eg, poverty, homelessness, social
isolation, Iailure oI support systems). While the primary diagnosis oI schizophrenia rarely is
made in the ED, several historical Ieatures can be helpIul in distinguishing the illness Irom the
many medical and psychiatric conditions that can mimic it.
Two or more oI the Iollowing must have been present over the prior month Ior a signiIicant
period (unless treated with medication):
O ueluslons lzarre or llloglcal false bellefs whlch ofLen have a paranold grandlose persecuLory
or rellglous flavor false lnLerpreLaLlon of normal percepLlons
O alluclnaLlons 1yplcally audlLory (vlsual or LacLlle sLrongly suggesL an organlc eLlology) ofLen
lnvolvlng malevolenL or LaunLlng volces commenLlng on Lhe paLlenLs acLlons or characLer ofLen
wlLh a sexual flavor volces glvlng commands (le command halluclnaLlons) 2 or more volces
dlscusslng or argulng wlLh each oLher audlble LhoughLs LhoughL wlLhdrawal (feellng LhaL
LhoughLs are belng removed from head) LhoughL broadcasLlng or LhoughL lnLerference by an
ouLslde agenL
O ulsorganlzed speech 1angenLlal lncoherenL rambllng speech neologlsms (new word creaLlon)
loosenlng of assoclaLlons
O ehavlor Crossly dlsorganlzed or caLaLonlc
O -egaLlve sympLoms overLy of speech (le alogla) emoLlonal and/or soclal wlLhdrawal
blunLlng of affecL avollLlon
oss oI a previously held level oI occupational, social, or selI-care Iunctioning must have
occurred since the onset oI illness. Presence oI an aIIective disorder (eg, major depression,
bipolar disorder, schizoaIIective disorder) must be excluded; these conditions can be mistaken
Ior schizophrenia and have very diIIerent prognoses and therapies. Additionally, an organic
etiology (eg, drug intoxication, medical illness) must be ruled out.
One oI the Iollowing problems with antipsychotic medications commonly is the chieI complaint:
O AcuLe dysLonla (muscle rlgldlLy and spasm) oculogyrlc crlsls (blzarre and frlghLenlng upward
gaze paralysls and conLorLlon of faclal and neck musculaLure) akaLhlsla (dysphorlc sense of
moLor resLlessness)
O arklnsonlan sympLoms of sLlffness resLlng Lremor dlfflculLy wlLh galL and feellng sloweddown
O rLhosLaLlc hypoLenslon caused by alphaadrenerglc blockade
O ury mouLh faLlgue sedaLlon vlsual dlsLurbance lnhlblLed urlnaLlon and sexual dysfuncLlon
whlch can be adverse reacLlons Lo anLlpsychoLlc medlcaLlon or Lo anLlchollnerglc drugs Laken for
prophylaxls of dysLonla
Obtain the Iollowing inIormation when an acutely psychotic patient presents to the ED:
O 1he poLenLlal danger Lhe paLlenL presenLs Lo hlmself or herself or Lo oLhers
O rlor medlcal and psychlaLrlc records lncludlng pasL hosplLallzaLlons and medlcaLlon Lherapy
O ls or her basellne level of funcLlonlng
O CurrenL or recenL subsLance abuse
O CurrenL use of prescrlbed overLhecounLer (1C) and herbal medlcaLlons
O Compllance wlLh currenL psychlaLrlc medlcaLlons
A paranoid schizophrenic, in response to delusions and command hallucinations, can be
extremely dangerous and unpredictable. ind out about threats made to others, expressions oI
suicidal intent, and possession oI weapons at home or on the person.
Physical Examination
Depending on the reason Ior ED presentation, the patient with schizophrenia may present with
wildly agitated, combative, withdrawn, or severely catatonic behavior. Conversely, the patient
may appear rational, cooperative, and well controlled (perhaps with only some blunting oI
aIIect). The person also could be subtly odd, unkempt, or Irankly bizarre in manner, dress, and/or
aIIect. PerIorm a general physical examination on all patients, with attention to vital signs,
pupillary Iindings, hydration status, and mental status. A comprehensive physical examination
and laboratory evaluation is required when an organic etiology or drug intoxication may be
related to mental status changes. Pay particular attention to Iever, tachycardia (which, in
association with rigidity, can be a sign oI neuroleptic malignant syndrome), heatstroke
(antipsychotics inhibit sweating), and other medical illness. ook Ior signs oI dystonia, akathisia,
tremor, and muscle rigidity. Tardive dyskinesia is a common and oIten irreversible sequela oI
long-term (and sometimes brieI) antipsychotic use. It involves uncontrollable tongue thrusting,
lip smacking, and Iacial grimacing. Mental status testing should typically reveal clear sensorium
and orientation to person, place, and time. Assess attention, language, memory, constructions,
and executive Iunctions. Absence oI clear sensorium and/or orientation may indicate the
presence oI acute delirium, a medical condition.
ifferential iagnosis
Conditions to consider in the diIIerential diagnosis oI schizophrenia include the Iollowing:
O uellrlum demenLla and amnesla
O uepresslon
O LncephallLls
O -eurolepLlc mallgnanL syndrome
O anlc dlsorders
O ersonallLy dlsorders
O AceLamlnophen LoxlclLy
O alluclnogen LoxlclLy
O alluclnogenlc mushroom LoxlclLy
O -eurolepLlc agenL LoxlclLy
O hencyclldlne LoxlclLy
O SympaLhomlmeLlc LoxlclLy
Laboratory Studies
No speciIic laboratory Iindings are diagnostic oI schizophrenia. However, perIorming some
studies may be necessary to rule out possible organic etiologies Ior psychosis or to uncover
complications oI schizophrenia and its treatment. Blood levels oI certain psychiatric drugs,
speciIically lithium and the mood-stabilizing antiseizure medications (eg, valproic acid,
carbamazepine), can be used to conIirm compliance or rule out toxicity. Serum alcohol levels
and drugs-oI-abuse screening can be useIul when substance abuse is suspected. Interpreting the
results oI a Iingerstick blood glucose determination is a rapid and inexpensive method oI ruling
out a diabetic emergency masquerading as an exacerbation oI a psychotic illness; similarly,
measuring oxygen saturation levels can help to disclose hypoxia resulting in behavioral or
central nervous system (CNS) disturbance. Electrolyte measurements may reveal hyponatremia
secondary to water intoxication (ie, psychogenic polydipsia). This is common in undertreated or
reIractory schizophrenia. aboratory abnormalities observed in neuroleptic malignant syndrome
may include leukocytosis with leIt shiIt and elevated skeletal muscle creatinine kinase (CK) and
aldolase levels.
Other Studies
Computed tomography (CT) scanning, magnetic resonance imaging (MRI), and positron
emission tomography (PET) scanning can disclose abnormalities oI brain structure and Iunction
in schizophrenia. Although these studies are oI interest Ior research, they have limited clinical
relevance. Various psychological and neurobiologic tests, such as absence oI smooth eye-
tracking, may be helpIul in studying schizophrenia but are not useIul in the ED setting.
Prehospital Care
SaIe transport oI a patient with acute psychosis may require physical or chemical restraints. Be
Iamiliar with restraint and sedation protocols in your emergency medical service (EMS) area and
hospital.Know your state's regulations or statutes regarding involuntary transport, treatment, and
hospitalization oI psychiatric patients.Document your concerns regarding imminent risk to the
patient or others resulting Irom the patient's psychiatric condition. ile appropriate application
Ior involuntary transport/treatment when indicated.
Emergency epartment Care
Evolving Irom the eIIicacy oI modern antipsychotic medications and the subsequent widespread
budget cutting oI psychiatric services over the past 2 decades, deinstitutionalization oI patients
with schizophrenia has had a major impact on emergency medicine. Patients with schizophrenia
now are Irequent visitors to the ED, presenting with problems ranging Irom symptom
exacerbation to medication noncompliance, adverse eIIects to medications, and socioeconomic
crisis arising Irom substance abuse, poverty, homelessness, or a Iailed support system.
Depending on the reason Ior the patient's ED visit, care may be limited to diagnosis and
treatment oI an urgent or nonurgent medical complaint; a brieI medical evaluation Iollowed by
consultation with psychiatric, crisis, or social service personnel; evaluation and treatment oI an
adverse reaction to a psychiatric drug; or physical and chemical restraint oI a patient with acute
psychosis in coordination with a workup, when indicated, to rule out organic etiologies.
Remember that psychiatric and organic illness can coexist and interact at the same time in the
same patient. urthermore, acute psychiatric symptoms and diIIiculties obtaining a reliable
history Irom the patient can mask serious organic illness. A brieI medical clearance examination
is limited in useIulness and insuIIicient to rule out organic etiologies.
Use of restraints and involuntary commitment
ailure to talk down or intimidate (with a show oI Iorce) a severely agitated patient may require
physical restraint oI the patient, Iollowed by chemical restraint (ie, sedation). Proper physical
restraints and individuals trained in their application should be available at all times. Document
reasons Ior restraining a patient (mention patient/staII saIety and protection), the type oI restraint
used (eg, locked room vs 4-point leather), the maximum duration oI restraint, and reasons Ior
involuntary commitment
|3|
; Iollow all Consolidated Omnibus Budget Reconciliation Act
(COBRA) regulations when transIerring patients to another Iacility Ior psychiatric care. Be
Iamiliar with ED and hospital regulations, Health Insurance Portability and Accountability Act
(HIPAA) rules, regional statutes, and Emergency Medical Treatment and abor Act (EMTAA)
requirements regarding the use oI physical restraints, involuntary psychiatric commitment, and
transIer. Do not order "restrain prn." Give speciIic reasons Ior applying and removing restraints.
Personally ensure that restraints are applied saIely. Use the least restrictive measures that are
eIIective. The patient should be monitored continuously while restrained either physically or
chemically. Restraint and seclusion orders should be renewed at regular intervals not to exceed 4
hours. In most cases, chemical restraint (ie, sedation) is preIerable to physical restraint when
prolonged behavioral control is necessary or when the patient is severely combative. Any
physical restraint oI a combative patient can lead to serious injury or death (eg, Irom aspiration,
sudden cardiac death, rhabdomyolysis).
Tranquilization
Rapid tranquilization (chemical restraint) may be carried out as Iollows here. Typically, a
combination oI lorazepam 2 mg mixed in the same syringe with haloperidol 5 or 10 mg is
administered intramuscularly or intravenously. Benztropine (Cogentin), 1 mg, may be added to
counteract dystonia ("5-2-1"). Elderly patients typically require lower doses. Repeat doses can be
administered in 20-30 minutes as needed to control continued severe agitation. Haloperidol dose
can be doubled each time up to 20 mg iI prior dosing is inadequate Ior severe agitation. An
alternative to the haloperidol component is droperidol at the same dosages. Droperidol is more
sedating, Iaster in onset, and somewhat shorter acting. The downside is the black-box warning
about prolonged QT syndrome, which rarely occurs at higher doses than those typically utilized
Ior acute behavioral control. Cardiac monitoring is recommended, but some experts believe these
warnings to be overly cautious.
|1|
ollowing the black-box warning, most physicians continuing
to utilize droperidol Ior acute behavioral control reserve it Ior special situations requiring
somewhat Iaster onset and greater sedation than would be achieved with similar doses oI
haloperidol. Droperidol, thereIore, may be considered useIul, yet second-line to haloperidol in
the emergency department. In certain cases, sedation can be administered orally and may consist
oI lorazepam 2 mg plus haloperidol 2-5 mg or risperidone 2 mg PO (by mouth). An alternative is
Zyprexa Zydis, which is an oral, rapidly disintegrating tablet, 5-10 mg. II the patient has
haloperidol or droperidol sensitivity, ziprasidone 10-20 mg (administered intramuscularly) can
be substituted (20 mg is the typical dose). Exercise caution regarding prolonged QT syndrome
and multiple drug-drug interactions. Ziprasidone may be somewhat slower in onset than
haloperidol and droperidol but has excellent sedating qualities with less propensity Ior dystonia.
A single repeat dose oI 20 mg in 4 hours may be necessary (maximum 40 mg/d IM). A 10 mg
dosing can be repeated in 2 hours. Reduced pricing now makes ziprasidone an excellent Iirst-line
alternative to the older, conventional antipsychotics, especially in younger patients who are more
likely to develop dystonic reactions. orazepam alone is sometimes suIIicient Ior lesser degrees
oI agitation or anxiety and can be given sublingually Ior more rapid onset. The recommended
dose Ior anxiety and mild agitation is 1-2 mg administered orally or sublingually.
Consultations
Crisis liaison teams, typically made up oI clinical social workers, psychologists, and/or
psychiatric nurses, are available in many EDs 24 hours a day through the hospital or local
psychiatric agencies. Consulting with a psychiatrist by phone or physically in the ED may be
more diIIicult, but this should be done whenever it is necessary to correctly diagnose and/or
saIely treat a patient who is severely disturbed. Emergency clinicians always should examine
each patient personally, assessing their suicide risk or threat to others and documenting all
reasoning. The emergency clinician should speak directly with the crisis consultant and read his
or her evaluation notes. Then, based on the evaluation and the inIormation has been obtained, the
crisis consultant's disposition proposals should be conIirmed or modiIied.Ultimately, the
emergency clinician is medically and legally responsible Ior the patient until a psychiatrist or
other provider assumes the responsibility Ior care. The ultimate decision-making role must not be
abdicated to a consultant. Do not delay necessary sedation oI a patient with acute psychosis Ior
the diagnostic beneIit oI psychiatric crisis consultants not yet present in the ED. Treatment
delays can lead to injuries and can increase morbidity and worsen prognosis. In these situations,
the crisis consultant must rely on the presedation assessment.
Transfer
Psychiatric transIers Irom the ED to other hospitals are common because oI bed shortages and
insurance considerations. These transIers should be treated as medical transIers by documenting
the patient's stability, the reason Ior transIer, and other Iactors required to meet COBRA
obligations.Sedating patients with severe agitation and/or acute psychosis is essential to prevent
potential injury to the patient and staII en route.
Medication
Antipsychotic medications (previously reIerred to as neuroleptics or major tranquilizers) have
revolutionized the treatment oI and prognosis Ior schizophrenia. All block dopamine (especially
D2) receptors in the brain.
The newer, atypical agents also aIIect serotonin transmission. These newer agents (eg,
risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole) are less likely to
produce dystonia and tardive dyskinesia and are more likely to improve negative symptoms.
However, they are not more eIIective than traditional agents (eg, haloperidol, droperidol,
Iluphenazine), with the possible exception oI clozapine in the treatment-resistant patient. Some
newer agents cause serious weight gain and may raise the risk oI insulin resistance and diabetes
mellitus. Studies show a slightly increased death rate in elderly patients with dementia using
atypical agents. However, the risk was even higher with the older, conventional agents.
Benzodiazepines also have a role in schizophrenia, especially in the emergency care oI a patient
with acute psychosis.Anticholinergic medications (ie, benztropine, diphenhydramine) are used to
counteract the dystonic and parkinsonian adverse eIIects (extrapyramidal symptoms |EPS|) oI
the antipsychotics, particularly the higher-potency agents that are less sedating but more EPS-
producing. or Iurther inIormation, see the Practice Guideline Ior the Treatment oI Patients with
Schizophrenia.
|2|