- Author: Frances R Frankenburg,
MD; Chief Editor: Eduardo Dunayevich, MD
Background
Schizophrenia
is a severe, persistent, debilitating, and poorly understood psychiatric
disorder that probably comprises several separate illnesses. The hallmark
symptoms of schizophrenia are psychotic ones, such as auditory hallucinations
(voices) and delusions (fixed false beliefs). Impaired cognition or a
disturbance in information processing is a less vivid symptom that is highly
disruptive. People with schizophrenia have lower rates of employment, marriage,
and independent living than other people do.
Schizophrenia
is a clinical diagnosis. It must be differentiated from other psychiatric and
medical illnesses, as well as disorders such as heavy metal toxicity, adverse
effects of drugs, and vitamin deficiencies. (See DDx and Workup.)
Treatment
of schizophrenia requires an integration of medical, psychological, and
psychosocial inputs. The bulk of care occurs in an outpatient setting and
probably is best carried out by a multidisciplinary team. Psychosocial
rehabilitation is an essential part of treatment.
The
use of antipsychotic m edications, also known as neuroleptic medications or
major tranquilizers, is the mainstay of medical treatment for schizophrenia.
These medications diminish the positive symptoms of schizophrenia and prevent
relapses. Unfortunately, they are also associated with a number of adverse
effects. (See Treatment and Medication.)
Pathophysiology
Both
anatomic and neurotransmitter system abnormalities have been implicated in the
pathophysiology of schizophrenia.
Anatomic abnormalities
Neuroimaging
studies in patients with schizophrenia show abnormalities such as enlargement
of the ventricles, decreased brain volume in medial temporal areas, and changes
in the hippocampus.[1, 2, 3] These findings are of interest more for research purposes
than for clinical application.
Interest
has also focused on the various connections within the brain rather than on
localization in a single part of the brain. Magnetic resonance imaging (MRI)
studies show anatomic abnormalities in a network of neocortical and limbic
regions and interconnecting white matter tracts.[4] A
meta-analysis of studies using diffusion tensor imaging (DTI) to examine white
matter found that 2 networks of white-matter tracts are reduced in
schizophrenia.[5]
In
the Edinburgh High-Risk Study, brain imaging showed reductions in whole-brain
volume and in left and right prefrontal and temporal lobe volumes in 17 of 146
people who were at high genetic risk for schizophrenia. The changes in
prefrontal lobes were associated with increasing severity of psychotic
symptoms.[6]
In
a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients
with control subjects, Olabi et al found that schizophrenia was associated with
structural brain abnormalities that progressed over time. The abnormalities
identified included loss of whole-brain volume in both gray and white matter
and increases in lateral ventricular volume.[7]
Neurotransmitter system abnormalities
Abnormalities
of the dopaminergic system are thought to exist in schizophrenia; however,
there is little direct evidence to support this belief. The first clearly
effective antipsychotic drugs, chlorpromazine and reserpine, were structurally
different from each other, but they shared antidopaminergic properties. Drugs
that diminish the firing rates of mesolimbic dopamine D2 neurons are
antipsychotic, and drugs that stimulate these neurons (eg, amphetamines)
exacerbate psychotic symptoms.
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 defined below; see
Presentation.) Moreover, the newer antipsychotic drugs block both dopamine D2
and 5-hydroxytryptamine (5-HT) receptors.
Clozapine,
perhaps the most effective antipsychotic agent, is a particularly weak dopamine
D2 antagonist. Thus, other neurotransmitter systems, such as norepinephrine,
serotonin, and gamma-aminobutyric acid (GABA), are undoubtedly involved. Some
research focuses on the N -methyl-D-aspartate (NMDA) subclass of
glutamate receptors because NMDA antagonists, such as phencyclidine and
ketamine, can lead to psychotic symptoms in healthy subjects.[8]
Inflammation and immune function
Immune
system function is disturbed in schizophrenia.[9] Overactivation
of the immune system (eg, from prenatal infection or postnatal stress) may
result in overexpression of inflammatory cytokines and subsequent alteration of
brain structure and function. For example, schizophrenic patients have elevated
levels of proinflammatory cytokines that activate the kynurenine pathway, by
which tryptophan is metabolized into kynurenic and quinolinic acids; these
acids regulate NMDA receptor activity and may also be involved in dopamine
regulation.
Insulin
resistance and metabolic disturbances, which are common in the schizophrenic
population, have also been linked to inflammation. Thus, inflammation might be
related to both the psychopathology of schizophrenia and to metabolic
disturbances seen in patients with schizophrenia.[10]
Etiology
The
causes of schizophrenia are not known. Most likely, there are at least 2 sets
of risk factors, genetic and perinatal. Undefined socioenvironmental factors
may increase the risk of schizophrenia in international migrants or urban
populations of ethnic minorities.[11, 12, 13]
Genetics
The
risk of schizophrenia is elevated in biologic relatives of persons with
schizophrenia but not in adopted relatives.[14] The
risk of schizophrenia in first-degree relatives of persons with schizophrenia
is 10%. If both parents have schizophrenia, the risk of schizophrenia in their
child is 40%. Concordance for schizophrenia is about 10% for dizygotic twins
and 40-50% for monozygotic twins.
Genome-wide
association studies have identified many candidate genes, but the gene variants
that have been implicated so far account for only a small fraction of
schizophrenia cases, and these findings have not always been replicated in
different studies. The genes that have been found mostly change a gene’s
expression or a protein’s function in a small way. Interactions with the rest
of the genome and with the environment will doubtless prove to be important.
Loci
of particular interest include the following:
- The
catechol-O-methyltransferase (COMT) gene
- The RELN gene
- The gene for nitric oxide
synthase 1 adaptor, NOS1AP
The
COMT gene codes for the postsynaptic intracellular enzyme, COMT, which
is involved in the methylation and degradation of the catecholamine
neurotransmitters dopamine, epinephrine, and norepinephrine. The several
allelic variants of COMT affect its activity. The valine-valine variant
degrades dopamine faster than does the valine-methionine variant; subjects with
2 copies of the methionine allele were less likely to develop psychotic
symptoms with cannabis use than were other cannabis-using subjects without that
variant.[15]
The
RELN gene codes for 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
of schizophrenia, but only in women.[16]
The
NOS1AP gene codes for the enzyme nitric oxide synthetase, which is found
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 of linkage disequilibrium, researchers have identified a
single-nucleotide polymorphism associated with higher levels of expression of
this gene in postmortem brain samples from individuals with schizophrenia.[17]
Other
genetic changes involve the structure of the gene. For example, copy number
variants are deletions and duplications of segments of DNA; they can involve
genes or regulatory regions. These variants are usually inherited, but can
arise spontaneously. Copy number variants such as the deletions found at
1q21.1, 15q13.3, and 22q11.2 increase the risk of developing schizophrenia.[18, 19] At
most, however, these findings probably account for only a small part of the
heritability of schizophrenia.
In
addition, the effects of some of these copy number variants are not restricted
to schizophrenia. Other copy number variant disorders include autism,
intellectual disability, attention-deficit hyperactivity disorder, and
epilepsy.[20]
In
a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a
copy number variant at 1 of the following loci: 1q21.1, 15q11.2, 15q13.3,
16p11.2, 16p13.11, and 22q11.2. Clinically, these people had various neurologic
or psychiatric disorders, including developmental delay, intellectual
disability and autism-related disorders. Subjects also had congenital
anomalies.[21]
Many
studies have also looked for abnormalities in neurodevelopmental genes, in
accordance with the neurodevelopmental hypothesis of schizophrenia. Disruptions
in the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been
associated with schizophrenia, albeit with significant variability between
studies.[22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34] These findings also lend support to
the hypothesis that schizophrenia is a disease in which multiple rare genetic
variants lead to a common clinical outcome.
Some
people with schizophrenia have no family history of the disorder. These cases
may be the result of new mutations. De novo mutations in the exome, which is
the part of the chromosome that codes for proteins, seem to be more common in
patients with schizophrenia than would otherwise be expected.[35, 36]
As
can be seen, working out the details of these genetic factors is difficult.
Nonetheless, a meta-analysis of twin studies estimated that genetic factors
account for about four fifths of liability to schizophrenia.[37]
Perinatal factors
Women
who are malnourished or who have certain viral illnesses during their pregnancy
may be at greater risk of giving birth to children who later develop
schizophrenia.[38] For
example, children born to Dutch mothers who were malnourished during World War
II have a high rate of schizophrenia.
After
the 1957 influenza A2 epidemics in Japan, England, and Scandinavia, rates of
schizophrenia were higher among offspring of women who contracted influenza
during their second trimester. Women in California who were pregnant between
1959 and 1966 were more likely to have a child who developed schizophrenia if
they had influenza in the first trimester of their pregnancy.[39]
Obstetric
complications may be associated with a higher incidence of schizophrenia.
Children born in the winter months may be at greater risk for developing
schizophrenia.[40]
A
study in Finnish women by Clarke et al supports an interaction between genetic
and environmental influences on causation of schizophrenia. A review of the
9,596 women in Helsinki who received hospital treatment during pregnancy for an
upper urinary tract infection between 1947 and 1990 found no overall
significant increase in the risk of schizophrenia among their offspring but a
5-fold higher risk among the offspring of women who also had a family history
of psychosis.[41]
Clarke
et al estimated that among offspring of women with both prenatal pyelonephritis
and a positive family history of psychotic disorders, 38-46% of schizophrenia
cases resulted from the synergistic action of both risk factors.[41]
Epidemiology
The
lifetime prevalence of schizophrenia has generally been estimated to be
approximately 1% worldwide.[42] However,
a systematic review by Saha et al of 188 studies drawn from 46 countries found
a lifetime risk of 4.0 per 1000 population. Prevalence estimates from countries
considered least developed were significantly lower than those from countries
classed as emerging or developed.[43] Immigrants
to developed countries show increased rates of schizophrenia, with the risk
extending to the second generation.[11, 12, 13]
People
with schizophrenia have a 5% lifetime risk of suicide.[44] Mortality
is also increased because of medical illnesses, which result from a combination
of unhealthy lifestyles, side effects of medication, decreased health care, and
perhaps even some fundamental vulnerability to medical comorbidities.
To
date, no racial differences in the prevalence of schizophrenia have been
positively identified. Some research indicates that schizophrenia is diagnosed
more frequently in black people than in white people; this finding has been attributed
to cultural bias of practitioners. The prevalence of schizophrenia is about the
same in men and women. The onset of schizophrenia is later in women than in
men, and the clinical manifestations are less severe. This may be because of
the antidopaminergic influence of estrogen. The onset of schizophrenia usually
occurs in adolescence, and symptoms remit somewhat in older patients. The first
5-10 years of the illness can be stormy; they are usually followed by decades
of relative stability (though a return to baseline is unusual). Positive
symptoms are more likely to remit than cognitive and negative symptoms are (see
Presentation for a description of symptoms).
Prognosis
The
prognosis for patients with schizophrenia is guarded. Full recovery is unusual.
Early onset of illness, family history of schizophrenia, structural brain
abnormalities, and prominent cognitive symptoms are associated with a poor
prognosis. The prognosis is better for people living in low-income and
middle-income countries.[45]
Symptoms
usually follow a waxing and waning course. A patient’s pattern of symptoms may
change over years. Positive symptoms respond fairly well to antipsychotic
medication, but the other symptoms are quite persistent.
Because
of vocational difficulties, many patients with schizophrenia also have to cope
with the burdens of poverty. These include limited access to medical care,
which may lead to poor control of the disease; homelessness; and incarceration,
typically for minor offenses.
People
with schizophrenia have a 5% lifetime risk of suicide.[44] Other
factors that contribute to an increased mortality in people with schizophrenia
include lifestyle issues such as cigarette smoking, poor nutrition, and lack of
exercise, and perhaps poorer medical care and complications of medications. A
study from Britain shows that this “mortality gap” is increasing.[46]
Schizophrenia
is not well understood, and the available treatment is unacceptably poor.
Research is ongoing into the pathophysiology and treatment of this illness. It
is hoped that such efforts will eventually allow earlier intervention with
better pharmacologic agents, the goal being to achieve complete resolution of
all symptoms of the illness and continuation or resumption of a full and
meaningful life.
Patient Education
The
nature of schizophrenia makes it a potentially difficult illness for patients
to understand. Nevertheless, teaching the patient to understand the importance
of medication compliance and abstinence from alcohol and other drugs of abuse
is important.
Working
with the patient so that patient and family can learn to recognize early signs
of a decompensation (eg, insomnia or increased irritability) is helpful. A
review of 44 studies showed that education of patients about the nature of
their illness and treatment, when added to standard care, led to reductions in
rehospitalization and symptoms.[47] Education
may help with adherence to medication and may help the patient cope with the
illness better in other ways.
Social
skills training is helpful, but the effects are not long-lived. Such training,
like other sorts of problem-solving therapy, may have to be continued on an
indefinite basis, much as pharmacologic therapy is. People with schizophrenia
have also championed self-help recovery-based approaches to care, with an
emphasis on developing the personal strengths and resilience to combat this
illness.
Physical
illnesses in schizophrenia are common. The importance of a healthy lifestyle
and regular health care should be stressed. Counseling with respect to
sexuality, pregnancy, and sexually transmitted diseases is important for
patients with schizophrenia. Side effects of antipsychotic medications may
affect physical appearance; this, in turn, can affect self-esteem and
relationships with others.[48]
The
following resources may also be helpful:
History
Information
about the medical and psychiatric history of the family, details about
pregnancy and early childhood, history of travel, and history of medications
and substance abuse are all important. This information is helpful in ruling
out other causes of psychotic symptoms.
The
patient usually had an unexceptional childhood. In retrospect, family members
may describe the person with schizophrenia as a physically clumsy and
emotionally aloof child. The child may have been anxious and preferred to play
by himself or herself. The child may have been late to learn to walk and may
have been a bedwetter.[49, 50]
A
noticeable change in personality and a decrease in academic, social, and
interpersonal functioning often begin during mid-to-late adolescence. Usually,
1-2 years pass between the onset of these vague symptoms and the first visit to
a psychiatrist.[51] The
first psychotic episode usually occurs between the late teenage years and the
mid-30s.
The
symptoms of schizophrenia may be divided into the following 4 domains:
- Positive symptoms – These
include psychotic symptoms, such as hallucinations, which are usually
auditory; delusions; and disorganized speech and behavior
- Negative symptoms – These
include a decrease in emotional range, poverty of speech, loss of
interests and drive; the person with schizophrenia has tremendous inertia
- Cognitive symptoms – These
include neurocognitive deficits (eg, deficits in working memory and
attention and in executive functions, such as the ability to organize and
abstract); patients also find it difficult to understand nuances and
subtleties of interpersonal cues and relationships
- Mood symptoms – Schizophrenia
patients often seem cheerful or sad in a way that does not make sense to
others; they often are depressed
Physical Examination
Findings
on a general physical examination are usually not contributory. This
examination is necessary to rule out other illnesses.
A
neurologic examination is sometimes helpful before the initiation of
antipsychotic medications as a baseline, because these drugs can change the
findings. Some patients with schizophrenia have motor disturbances before
exposure to antipsychotic agents. Schizophrenia has been associated with left
and mixed handedness, minor physical anomalies, and soft neurologic signs.
Mental Status Examination
On
a detailed Mental Status Examination in a patient with schizophrenia, the following observations
may be made in the severely ill person:
- The patient may be dressed
oddly (eg, may be wearing heavy jackets in the summer)
- The patient may pay
insufficient attention to personal hygiene
- The patient may be unduly
suspicious of the examiner or be socially awkward
- The patient may express a
variety of odd beliefs or delusions
- The patient often has a flat
affect (ie, little range of expressed emotion)
- The patient may admit to
hallucinations or respond to auditory or visual stimuli that are not
apparent to the examiner
- The patient may show thought
blocking, in which long pauses occur before he or she answers a question
- The patient’s speech may be
difficult to follow because of the looseness of his or her associations;
the sequence of thoughts follows a logic that is clear to the patient but
not to the interviewer
- Conversation and initiation of
speech may be limited
- The patient has difficulty with
abstract thinking, demonstrated by inability to understand common proverbs
or idiosyncratic interpretation of them
- The speech may be
circumstantial (ie, the patient takes a long time and uses many words in
answering a question) or tangential (ie, the patient speaks at length but
never actually answers the question)
- The patient often shows poor
attention
·
The patient’s thoughts may be disorganized, stereotyped or perseverative
- The patient may make odd
movements (which may or may not be related to neuroleptic medication)
- The patient may have little
insight into his or her problems (the term for this is anosognosia)
- Patients may have thoughts
about hurting or harming themselves or others or may hear voices telling
them to commit some kind of violence; note that suicide is not uncommon in
people with schizophrenia, but violence towards others is uncommon (see
below)
- Orientation is usually intact
(ie, patients know who and where they are and what time it is)
Persons
with schizophrenia may display strange and poorly understood behaviors. These
include drinking water to the point of intoxication, staring at themselves in
the mirror, performing stereotyped activities, hoarding useless objects, and
mutilating themselves. Their wake-sleep cycle may be disturbed. They often
experience difficulty dealing with change.
Diagnostic Criteria
According
to the American Psychiatric Association’sDiagnostic and Statistical Manual of Mental Disorders, Text
Revision (DSM-IV-TR), to meet the criteria for diagnosis
of schizophrenia, in most cases the patient must have experienced at least 2 of
the following symptoms[52]
:
- Delusions
- Hallucinations
- Disorganized speech
- Disorganized or catatonic
behavior
- Negative symptoms
Only
1 symptom is required under the following circumstances:
- The delusions are bizarre
- Auditory hallucinations occur
in which the voices comment in an ongoing manner on the person’s behavior
- Two or more voices are talking
with each other
The
patient must experience at least 1 month of symptoms (or less if successfully
treated) during a 6-month period, with social or occupational deterioration
problems occurring over a significant amount of time. These problems must not
be attributable to another condition.
Classification of Schizophrenia
Schizophrenia
can be divided into the following types on the basis of the symptom pattern:
- Paranoid schizophrenia – This
is characterized by delusions and auditory hallucinations but relatively
normal intellectual functioning and affect. Delusions of persecution or
grandeur are common
- Disorganized schizophrenia –
This involves both speech and behavior, as well as flattened or
inappropriate emotions
- Catatonic schizophrenia – This
is characterized by disturbances of movement that may render the person
incapable of caring for himself or herself
- Undifferentiated schizophrenia
Residual
schizophrenia is the term used to describe the illness of a person who has a
history of at least 1 episode of schizophrenia but who currently has rather
mild symptoms. Patients with residual schizophrenia may progress to complete
remission or continue in this state for years without experiencing any further
psychotic episodes.
Diagnostic Considerations
Other
problems to be considered in the differential diagnosis of schizophrenia
include the following:
- Other psychiatric illnesses
- Anatomic lesions
- Metabolic illnesses
- Endocrine disorders
- Infectious illnesses
- Miscellaneous disorders
- Vitamin deficiency
Other
psychiatric illnesses
Schizophrenia
and bipolar affective
disorder (manic-depressive illness) may be
difficult to distinguish from each other. Patients with manic-depressive
illness predominantly have disturbances in their affect or mood. Psychotic
symptoms may be prominent during a mania or depression.
In
classic manic-depressive illness, the psychotic symptoms are congruent with
mania or depression, and the person has periods of euthymia (normal mood) with
no psychotic symptoms between the episodes. However, some patients have periods
of psychotic symptoms in the absence of depression or mania. In these cases,
the diagnosis of schizoaffective disorder is applied.
In
delusional disorder, the person has a variety of paranoid beliefs, but these
beliefs are not bizarre and are not accompanied by any other symptoms of
schizophrenia. For example, a person who is functioning well at work but
becomes unreasonably convinced that his or her spouse is having an affair has a
delusional disorder rather than schizophrenia.
Schizotypal
personality disorder is characterized by a pervasive pattern of discomfort in
close relationships with others, along with the presence of odd thoughts and
behaviors. The oddness in this disorder is not as extreme as that observed in
schizophrenia.
In
schizoid personality disorder, the person has difficulty and lack of interest
in forming close relationships with others and prefers solitary activities. No
other symptoms of schizophrenia are present.
In
paranoid personality disorder, the person is distrustful and suspicious of
others. No actual delusions or other symptoms of schizophrenia are present.
Anatomic
lesions
In
rare cases, brain tumors may be confused with a psychotic illness. Because
brain tumors are potentially lethal but treatable, it is important to consider
brain imaging studies for every person with a new onset of a psychotic illness
or, perhaps, a marked change in symptoms.
Subdural
hematomas can manifest as changes in mental status. Intracranial bleeds should
be considered in patients who report head trauma or who, for whatever reason,
are not able to provide a clear history. Brain imaging may be appropriate in
these cases.
Idiopathic
calcification of the basal ganglia is a rare disorder that tends to present as
psychosis in patients who become symptomatic early in adulthood; those
presenting later in life typically present with dementia and a motor system
disorder. Schizophrenialike symptoms may precede the onset of intellectual
deterioration and extrapyramidal motor disturbances.[53]
Metabolic
illnesses
Wilson disease,
also known as hepatolenticular degeneration, is a disorder of the metabolism of
copper. It is an autosomal recessive illness, the gene for which has been
located on chromosome 13. The first symptoms are often vague changes in
behavior during adolescence, which are followed by the appearance of odd movements.
The
diagnosis can be indicated by the laboratory findings of increased urinary
levels of copper and low serum levels of copper and ceruloplasmin or by the
detection of Kayser-Fleischer rings (copper deposits around the cornea) with or
without a slit-lamp examination. The diagnosis is usually confirmed by finding
increased hepatic copper at biopsy.
Not
all patients with Wilson disease have low serum ceruloplasmin or
Kayser-Fleischer rings, the 2 findings most commonly associated with this
disorder. Because the treatment of this disease is burdensome, some experts
recommend liver biopsy so that a tissue diagnosis may be made before chelating
therapy is started. This is an important diagnosis to make because of the
existence of a very specific treatment.
Porphyria
is a disorder of heme biosynthesis that can present as psychiatric symptoms.
Patients may have a family history of psychosis. The psychiatric symptoms may
be associated with electrolyte changes, peripheral neuropathy, and episodic
severe abdominal pain. Abnormally high levels of porphyrins in a 24-hour urine
collection confirm the diagnosis.
Patients
with hypoxemia or electrolyte disturbances may present with confusion and
psychotic symptoms. Hypoglycemia can produce confusion and irritability and may
be mistaken for psychosis.
Delirium
from whatever cause (eg, metabolic or endocrine disorders) is an important
condition to consider, especially in the elderly or hospitalized patient.
Although patients with delirium may have a wide range of neuropsychiatric
abnormalities, the clinical hallmarks are decreased attention span and a
waxing-and-waning type of confusion.
Endocrine
disorders
Infrequently,
thyroid illness may be confused with schizophrenia. Severe hypothyroidism or
hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is
usually associated with depression, which if severe may be accompanied by
psychotic symptoms. A hyperthyroid person is typically depressed, anxious, and
irritable.
Both
adrenocortical insufficiency (Addison disease)
and hypercortisolism (Cushing syndrome) may result in mental status changes. However, both
disorders also produce physical signs and symptoms that can suggest the
diagnosis. In addition, most patients with Cushing syndrome will have a history
of long-term steroid therapy for a medical illness.
Hypoparathyroidism
or hyperparathyroidism can on occasion be associated with vague mental status
changes. These are related to abnormalities in serum calcium concentrations.
Infectious
illnesses
Many
infectious illnesses, such as influenza, Lyme disease, hepatitis C, and any of
the encephalitides (particularly those caused by the herpes viruses), can cause
mental status changes such as depression, anxiety, irritability, or psychosis.
Elderly people with pneumonias or urinary tract infections may become confused
or frankly psychotic.
The
infectious illnesses of particular interest are the following:
- Neurosyphilis
- HIV infection
- Cerebral abscess
- Creutzfeldt-Jakob disease (CJD)
Neurosyphilis
Neurosyphilis
can be divided into the following 3 categories:
- Meningovascular syphilis
- Tabes dorsalis
- General paresis
Patients
with general paresis may present with behavioral changes, psychosis or
dementia. The diagnosis can be suggested by a history of exposure, personality
changes, and pupillary changes such as the Argyll Robertson pupil.
The
Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests
are nontreponemal tests that use antigens to detect antibodies to Treponema
pallidum. Antibodies decline during the disease, and so these tests have a
high false-negative rate. If neurosyphilis is strongly suspected, more specific
treponemal tests, such as the fluorescent-treponemal antibody absorption test
(FTA-ABS), can be useful.
HIV
infection
HIV
penetrates the blood-brain barrier early in the course of the infection and
thus can cause a number of mental status changes, particularly dementia or
other neuropsychological impairment. In addition, patients with HIV are at risk
for opportunistic infections, such as neurosyphilis, toxoplasmosis,
cryptococcal meningitis, progressive multifocal leukoencephalopathy,
cytomegalovirus encephalopathy, and tuberculous meningitis, all of which can
lead to mental status changes.
Persons
infected with HIV are also at risk for primary central nervous system lymphoma
and have vague symptoms such as confusion and memory loss. Many drugs used to
treat HIV may cause mental status changes. Finally, persons infected with HIV
are at risk for nutritional deficiencies that also contribute to mental status
changes.
Cerebral
abscess
Patients
with cerebral abscesses rarely have psychotic symptoms, but brain imaging
should be considered to rule out this treatable possibility. Immunosuppressed
persons and people living in or traveling in underdeveloped countries are
particularly at risk.
Creutzfeldt-Jakob
disease
Prions
cause the rare CJD, one of the transmissible spongiform encephalopathies. The
disease usually occurs in people older than 50 years and is marked by rapid
deterioration, dementia, abnormal electroencephalographic complexes, and
myoclonic jerks.
A
variant of this illness, vCJD, is the human form of bovine spongiform
encephalopathy (so-called mad cow disease). Fewer than 200 cases of vCJD have
occurred worldwide, and as of 2003, only 2 cases had occurred in the United
States. Unlike CJD, vCJD seems to affect people aged 20-40 years. It lasts much
longer than CJD and begins with behavioral changes. In several cases, the
patient was diagnosed with schizophrenia before the diagnosis of vCJD was made.
Miscellaneous
disorders
Multiple
sclerosis is notoriously difficult to diagnose in its early stages. The
physical symptoms may be overlooked, and psychological symptoms may
occasionally be an early feature.
Huntington
disease is a neurodegenerative disorder marked by neuronal loss throughout the
brain, especially in the striatum. This is an autosomal dominant disorder, the
gene for which has been located on chromosome 4. A family history is essential
to making the diagnosis, but it can be misleading. The maternity and paternity
of a patient are not always what they are represented to be, and causes of
death are often misreported.
The
occurrence of choreoathetoid movements well before exposure to antipsychotic
agents is suggestive of Huntington disease. About three-fourths of patients
with Huntington disease initially present with psychiatric symptoms, and most
need inpatient psychiatric care at some point in their illness.
Dementia
with Lewy bodies is the second most common type of dementia, after Alzheimer
disease. Patients present with fluctuating mental status and prominent
psychiatric symptoms, including depression and visual hallucinations. This is
an important disorder to diagnose because these patients are reported to do
poorly when treated with antipsychotic drugs.
Lipid
storage disorders include metachromatic leukodystrophy, adrenoleukodystrophy,
GM2 gangliosidosis, and ceroid lipofuscinosis. These illnesses usually occur in
childhood but may occasionally come to medical attention during adolescence.
Patients may present with psychiatric symptoms such as cognitive deterioration
and changes in personality. Patients may be diagnosed with schizophrenia until
the neurologic symptoms of these illnesses become more prominent.[54]
Malignancies
(typically, bronchial oat-cell carcinoma) can occasionally lead to dramatic
mental status changes early in their course and before they have been diagnosed
or metastasized to the brain. The etiology is not clear. Various paraneoplastic
neurologic syndromes have been described, including subacute cerebellar
degeneration, encephalopathy with brainstem involvement, diffuse
encephalopathies with mental symptoms, and limbic encephalopathy.
Patients
with a seizure or ictal disorder, especially temporal lobe epilepsy, may
occasionally display odd behavior before, during, or after a seizure. Aura and
ictal symptoms can include hallucinations, disturbances of memory, or affective
and cognitive changes. Ictal and postictal phenomena can include complex motor
abnormalities.
Patients
with systemic lupus
erythematosus, typically young women, may present
with psychiatric symptoms, such as psychosis or cognitive deficit, in
association with unexplained fever or joint pain. The diagnosis can be
suggested by the physical findings of malar flush and the laboratory findings
of anemia, renal dysfunction, elevated erythrocyte sedimentation rate (ESR),
and, most specifically, elevated antinuclear antibody (ANA) levels.
Presenting
features of systemic vasculitides (eg, polyarteritis nodosa, Churg-Strauss
syndrome, Wegener granulomatosis, and Behçet disease) may include personality
changes. Other symptoms, such as weight loss and fever, usually occur. Magnetic
resonance imaging (MRI) shows characteristic lesions of vasculitis.
Heavy
metal toxicity may cause changes in personality, thinking, or mood.
Occupational exposure is the usual source of heavy metal toxicity, but cases
have also resulted from ingestion of herbal medications contaminated with heavy
metals.
Many
medications have been associated with mental status changes, especially the
following:
- Corticosteroids (psychosis or
mania)
- Levodopa (hallucinations or
insomnia)
- Antidepressants (mania)
- Interferon alfa (depression)
- Beta blockers, including those
in eye drops (depression)
Substance
abuse (eg, abuse of alcohol, cocaine, opiates, psychostimulants, or
hallucinogens) not uncommonly leads to disturbed perceptions, thought, mood,
and behavior. The anabolic steroids used by body builders and athletes can lead
to psychotic symptoms.[55] Anticholinergic
medications can lead to delirium, especially if abused.
Vitamin
deficiency
Thiamine
deficiency can occur in people who rely on alcohol for calories or patients
with advanced malignancies or malabsorption syndromes. Acute and severe
thiamine depletion can lead to Wernicke encephalopathy, marked by oculomotor
disturbances, ataxia, and confabulation. If this condition is left untreated,
Korsakoff psychosis may develop. Wernicke encephalopathy is a common and
underdiagnosed cause of chronic cognitive impairment in people with alcoholism.[56]
Deficiency
of vitamin B-12, folate, or both may produce depression or dementia. Very
rarely, these deficiencies may result in delusional thinking.
Differential Diagnoses
Approach Considerations
Schizophrenia
is not associated with any characteristic laboratory results. The following
blood tests should be performed on all patients, both at the beginning of the
illness and periodically afterwards:
- Complete blood count (CBC)
- Liver, thyroid, and renal
function tests
- Electrolyte, glucose, vitamin
B12, serum methylmalonic acid, folate, and calcium levels
Other
tests to consider, if the history provides any reason for suspicion (see
Differentials), are as follows:
- HIV
- Rapid plasma reagin (RPR); if a
strong suspicion of neurosyphilis exists, specific treponemal tests may be
helpful
- Ceruloplasmin; if a strong
suspicion of Wilson disease exists, consider a liver biopsy (or multiple
biopsies)
- Antinuclear antibody (ANA) for
systemic lupus erythematosus
- Urine for culture and
sensitivity or drugs of abuse
- AM cortisol for adrenal
disorders
- 24-hour urine collections for
porphyrins, copper, or heavy metals
- Pregnancy testing, if the
patient is a woman of childbearing age
- Lyme disease
- Brain imaging to rule out
subdural hematomas, vasculitis, cerebral abscesses, and tumors
- Chest x-ray for pulmonary
illness or occult malignancy
- Dexamethasone suppression test
and adrenocorticotropic hormone (ACTH) stimulation test for
hypercortisolism and hypocortisolism, respectively
- Electroencephalography (EEG)
Neuropsychological
testing may be considered; determination of the patient’s cognitive weaknesses
and strengths can be helpful in treatment planning. Common findings in patients
with schizophrenia are as follows:
- Poor executive functioning (ie,
poor planning, organizing, or initiation of activities)
- Impaired memory
- Difficulty in abstraction and
recognizing social cues
- Easy distractibility
Approach Considerations
Treatment
of schizophrenia requires integration of medical, psychological, and
psychosocial inputs. The bulk of care occurs in an outpatient setting and
probably is best carried out by a multidisciplinary team, which should include
a psychopharmacologist, a counselor or therapist, a social worker, a nurse, a
vocational counselor, and a case manager. Clinical pharmacists and internists
can be valuable members of the team.
It
is vital not to neglect the medical care of the person with schizophrenia.
Obesity, diabetes, cardiovascular disease, and lung diseases are prevalent in
schizophrenia, and the person with schizophrenia often does not receive
adequate medical care for such conditions.[57]
The
use of antipsychotic medications, also known as neuroleptic medications or
major tranquilizers, is the mainstay of medical treatment for schizophrenia.
These medications diminish the positive symptoms of schizophrenia and prevent
relapses. Approximately 80% of patients relapse within 1 year if antipsychotic
medications are stopped, whereas only 20% relapse if treated. Children,
pregnant or breastfeeding women, and elderly patients present special
challenges. In all of these cases, medications must be used with particular
caution.
The
choice of which drug to use for treatment of a patient with schizophrenia
depends on many issues, including effectiveness, cost, side-effect burden,
method of delivery, availability, and tolerability. Pharmaceutical companies
have sponsored many studies comparing antipsychotic drugs with one another, but
little consensus has been reached. In the absence of clinical or
pharmacogenetic predictors of treatment response, the current treatment
approach is largely one of trial and error across sequential medication
choices.
Although
treatment is primarily provided on an outpatient basis, patients with
schizophrenia may require hospitalization for exacerbation of symptoms. This
may result from medication noncompliance, substance abuse, medication adverse
effects or toxicity, medical illness, psychosocial stress, or the waxing and
waning of the illness itself. Hospitalizations are usually brief and for the
purposes of crisis management or symptom stabilization.
Admission
to the hospital is stressful for anyone, but for someone with schizophrenia,
who can find change difficult and who is suffering an exacerbation of his or
her symptoms, it can be particularly frightening. The role of the inpatient
staff, particularly the psychiatric nurse, is to assess the cause for the
hospitalization; monitor response to therapy; and provide education, support,
reassurance, and encouragement.
Treatment
of patients with schizophrenia, particularly during a psychotic episode, may
raise the issue of informed consent. Consent is a legal term and should be used
with respect to specific tasks. A person who is delusional in some but not all
areas of life may still have the capacity to make medical and financial
decisions for himself or herself.
Insurance concerns
In
the United States, patients with schizophrenia who are unable to work may be
eligible for governmental programs, such as Medicare and Medicaid. These
programs pay the cost of medical care. Unfortunately, if individuals begin to
work and earn a sufficient salary, they are at risk of losing these benefits.
This is particularly awkward because they may be working in a job that provides
minimal or no health benefits. This situation is complicated and must be
monitored closely by professionals with a good understanding of health
benefits.
Antipsychotic Drugs: Comparative Efficacy
The
first antipsychotic medications were dopamine D2 antagonists, including
chlorpromazine and haloperidol. Medications similar to these agents are known
as first-generation, typical, or conventional antipsychotics. Other
antipsychotics, beginning with clozapine, are known as second-generation,
atypical, or novel antipsychotics.
The
conventional antipsychotic agents are available in generic forms and are less
expensive than the newer agents. They are available in a variety of vehicles,
including liquid and intramuscular (IM) preparations. Most important, these
agents are also available as depot preparations. Of the second-generation
agents, risperidone is now available as a long-acting injection (Risperdal
Consta) that uses biodegradable polymers, and a long-acting olanzapine IM
injection also is available.
The
first-generation antipsychotic drugs tend to cause extrapyramidal adverse
effects and elevated prolactin levels. The second-generation drugs are more
likely to cause weight gain and abnormalities in glucose and lipid control; in
addition, they are more expensive than the first-generation drugs.
For
some years, it was believed that the newer antipsychotic drugs were more
effective, but that belief is now fading. An exception is clozapine, which
consistently outperforms the other antipsychotic drugs.
Phase
1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a
large nationwide trial that compared the first-generation antipsychotic
perphenazine with the second-generation drugs olanzapine, risperidone,
quetiapine, and ziprasidone, found that olanzapine was slightly better than the
other drugs but also was associated with significant weight gain. Surprisingly,
perphenazine performed about as well as the other 3 second-generation agents.[58]
In
a study from the United Kingdom, the Cost Utility of the Latest Antipsychotic
Drugs in Schizophrenia Study (CUtLASS), more than 200 patients who were about
to change antipsychotic medication were randomly assigned to either a
first-generation or second-generation agent. In this study, the
first-generation drugs seemed to perform slightly better than the newer ones.
Clozapine was the exception, in that it outperformed all of the other drugs.[59]
First-episode schizophrenia
In
the European First Episode Schizophrenia Trial (EUFEST), which studied treatment
discontinuance as the main outcome measure, patients were more likely to stop
low-dose haloperidol than to stop olanzapine, quetiapine, ziprasidone, or
amisulpride (not available in the United States); however, all medications were
associated with similar decreases in symptoms.[60] EUFEST
was a year-long open-label study conducted in nearly 500 patients in 13
European countries and Israel.
Similarly,
the randomized, double-blind Comparison of Atypicals for First Episode (CAFE)
study found few differences between olanzapine, quetiapine, and risperidone in
400 patients experiencing a first episode of psychosis, with all-cause
treatment discontinuance rates in the vicinity of 70% by week 52. Drowsiness
and weight gain were along the most common adverse events with all 3 drugs; in
addition, insomnia was seen with olanzapine, longer sleep time with quetiapine,
and menstrual irregularities in women with risperidone.[61]
The
Schizophrenia Patient Outcomes Research Team (PORT) of the University of
Maryland recommends that any antipsychotic medication, with the exceptions of
clozapine and olanzapine, can be used as first-line treatment for patients with
schizophrenia who are experiencing their first episode of acute positive
symptoms.[62]
PORT
notes that early treatment with antipsychotic drugs is associated with
significant symptom reduction and that first- and second-generation
antipsychotics may have equivalent significant short-term efficacy. However,
because of the adverse side-effect profile of clozapine and the significant
metabolic risks associated with olanzapine, PORT advises that neither drug
should be considered as a first-line treatment for first-episode schizophrenia.[62]
PORT
notes that both responsiveness to treatment and sensitivity to adverse effects
are greater in patients with first-episode schizophrenia than in those who have
had multiple episodes. Therefore, PORT recommends starting antipsychotic
treatment for the former at doses lower than those recommended for the latter.
An exception is quetiapine, which may not be effective in lower doses; in
addition, low doses of aripiprazole or ziprasidone have not been evaluated in
first-episode schizophrenia.[62]
The
National Institute of Mental Health (NIMH) has initiated a research project, Recovery After an Initial
Schizophrenia Episode (RAISE),
to determine whether coordinated and aggressive treatment in the earliest
stages of illness can prevent long-term disability from schizophrenia. The RAISE Early Treatment Program (ETP), an integrated program delivered in community clinics, will
be compared with the RAISE Connection program, a program offered in Baltimore
and Manhattan in partnership with state mental health programs.
Antipsychotic Drugs: Choice of Agent
There
is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the
most effective medication but is not recommended as first-line therapy. It has
a high burden of side effects and requires regular blood work. Clozapine has
not outperformed other medications in first-episode patients.[63, 64]
Numerous
guidelines or algorithms for the treatment of schizophrenia are available.
Treatment guidelines are recommendations that require clinical judgment in
their application and must be regularly updated on the basis of new evidence.[65]
Few
studies have examined the outcome of treatment using these algorithms. In a
study from Canada, Agid et al described the outcome of treatment among 244
patients with first-episode schizophrenia using a 2003 algorithm.[66] If
no response to the first antipsychotic was observed, a second antipsychotic was
used. Most patients were treated with olanzapine or risperidone.
Response
rates fell from about 75% in the first trial to less than 20% in the second
trial.[66] The
patients who did not respond to either trial were offered clozapine, and 75%
responded. Unanswered questions from this study include the respective roles of
first-generation and second-generation antipsychotic medications and the issue
of when clozapine should be used.
If
the patient has not responded to a medication, physicians can switch
medications or add another one. Using 2 or even 3 different antipsychotic
agents together is common, though the evidence base for this is not compelling
and it does increase the complexity of the medication regimen. Nonetheless, in
one large study the discontinuation of one of two antipsychotics was followed
by treatment discontinuation more often and more quickly than when both
antipsychotics were continued.[67] A
meta-analysis of 19 studies involving more than 1200 subjects found a modest
advantage for antipsychotic polypharmacy.[68]
Physicians
sometimes choose what seems to be a simpler option, which is to increase the
dose of the original medication. For example, quetiapine is sometimes
prescribed at higher than approved doses for patients with schizophrenia or
schizoaffective disorder. Honer et al found that dosages higher than 800 mg/day
did not show any advantage over dosages in the approved range.[69]
PORT
provided a detailed review addressing the choice of antipsychotic medications;
this review included recommendations and discussions regarding acute,
maintenance, first-episode, and targeted intermittent treatment, as well as
treatment of individual symptoms.[62]
Clozapine
Clozapine
is the oldest atypical antipsychotic agent and probably the most effective.[70] Because
it is associated with about a 1% risk of agranulocytosis, patients must undergo
white blood cell (WBC) count monitoring every week for the first 6 months[71] (the
period of greatest risk), then every 2 weeks for 6 months, and finally every 4
weeks, as long as the absolute neutrophil count (ANC) is normal. If the ANC
drops, a strict protocol of monitoring and possibly medication cessation must
then be followed.
Clozapine
is also associated with anticholinergic adverse effects, sedation, and
drooling.[71] Constipation
and cardiac side effects (cardiomyopathy and myocarditis) can be
life-threatening. However, approximately one third of patients who have not
responded to conventional antipsychotic agents do better on clozapine.
Violence, hostility, and suicidality may be diminished with the use of
clozapine.
Antipsychotic Drugs: Maximizing Compliance
Noncompliance
with or nonadherence to pharmacologic therapy is difficult to estimate but is
known to be common, and it is one of the reasons for the use of IM preparations
of antipsychotic medications. A regular routine of IM medication is preferred
by some patients, and it permits easier monitoring of medication adherence by
the clinician. IM medication is less widely used in the United States than in
Europe.
A
large trial that compared long-acting injectable risperidone to the
psychiatrist’s choice of oral antipsychotic agent found, somewhat to the
surprise of many, that injectable risperidone was not superior to the oral form
and was associated with more side effects.[72]
Adherence
is usually overestimated by both patient and physician. Nonadherence can be
partial or complete, but even partial adherence is associated with relapse.[73] In
the past, nonadherence was thought to be due at least in part to the side
effects of the conventional antipsychotic agents, such as akathisia.
Nevertheless, nonadherence remains a major clinical problem, even with
second-generation antipsychotic agents.
Family
members of people with schizophrenia, as well as clinicians providing care for
them, should encourage them to take their medication, while at the same time
respecting their autonomy. This is a difficult balance to achieve.
Antipsychotic Drugs: Adverse Effects
The
following are adverse effects typically associated with conventional
antipsychotic agents and with risperidone, a novel antipsychotic agent, at
dosages higher than 6 mg/day:
Akathisia
is a subjective sense of inner restlessness, mental unease, irritability, and
dysphoria. Dystonia consists of painful and frightening muscle cramps, which
affect the head and neck but may extend to the trunk and limbs. Dystonia
usually occurs within 12-48 hours of the beginning of treatment or an increase
in dose. Muscular young men are typically affected. Hyperprolactinemia is
associated with galactorrhea, amenorrhea, gynecomastia, impotence, and
osteoporosis.
NMS
is marked by fever, muscular rigidity, altered mental state, and autonomic
instability. Laboratory findings include increased creatine kinase levels and
myoglobinuria. Acute kidney injury may result. Mortality is significant. NMS is
thought to be less common in patients taking clozapine or other atypical
antipsychotic agents.
Parkinsonism
presents as tremor, bradykinesia, akinesia, and, sometimes, rigidity or
bradyphrenia (slowed thinking). This is particularly likely to occur in women
and elderly patients.
The
incidence of TD is as high as 70% in elderly patients. It presents as
involuntary and repetitive (but not rhythmic) movements of the mouth and face.
Chewing, sucking, grimacing, or pouting movements of the facial muscles may
occur. People may rock back and forth or tap their feet. Occasionally,
diaphragmatic dyskinesia exists, which leads to loud and irregular gasping or
“jerky” speech. The patient is often not aware of these movements.
Risk
factors for TD include older age, female sex, and negative symptoms. Logically,
duration of therapy and dosage would be risk factors, but this has not been
conclusively demonstrated to be the case. TD appears to be less common with the
novel antipsychotic drugs, but whether this is actually so will not be known
with certainty until many patients have been exposed to these drugs for several
years.
Physicians
should warn patients, especially those being treated with conventional
antipsychotic agents about the risk of TD. Regular examinations, using the
abnormal involuntary movement scale (AIMS), should be performed to document its
presence or absence.
Anticholinergic effects
Anticholinergic
side effects occur with most antipsychotics (though risperidone, aripiprazole,
and ziprasidone are relatively free of them). Such effects include the
following:
- Dry mouth
- Exacerbation of glaucoma
- Confusion
- Decreased memory
- Agitation
- Visual hallucinations
- Constipation
QT interval prolongation
The
QT interval is the interval between the beginning of the QRS complex and the
end of the T wave on an electrocardiogram (ECG). It reflects the time required
for the ventricles to depolarize and repolarize. The QT interval corrected for
heart rate is called the QTc. A prolonged QTc interval puts a person at risk
for torsades 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
failure, bradycardias, electrolyte imbalance (especially hypokalemia),
hypomagnesemia, and female gender.[74]
No
cases of torsades de pointes were reported in a large trial of more than 18,000
patients in 18 countries who were randomly assigned to receive either
ziprasidone or olanzapine, though the event is so rare that this finding is not
entirely surprising. No increase in nonsuicide mortality was reported. In
particular, no increase in cardiac mortality was found, which is somewhat
reassuring with respect to the cardiac safety of ziprasidone.[75]
Haloperidol
has only a small influence on the ECG. Nevertheless, this agent has been
implicated, albeit very rarely, in causing torsades de pointes.[76]
Clinicians
should be alert to the ability of antipsychotic medications to cause ECG
changes in patients with any of the above risk factors or in patients taking
other medications that can lengthen the QTc interval. Particular caution is
advised with regard to using these medications in patients who are elderly or
medically ill.
Altered glucose and lipid metabolism and weight gain
Altered
glucose and lipid metabolism, with or without weight gain, may occur with most
antipsychotic agents, as can weight gain itself.[77] Aripiprazole
and ziprasidone are the antipsychotic drugs least likely to lead to these
adverse effects, whereas olanzapine and clozapine are the drugs most likely to
do so. The newer agents asenapine, iloperidone, and lurasidone may also share a
lower liability for weight gain and metabolic disturbances.
The
mechanism of 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 self-esteem)
and with medical problems (eg, diabetes, coronary artery disease, and
arthritis). Some approaches to the problem of weight gain include educational
programs on nutrition and exercise, as well as cognitive behavioral therapy.
Various medications have been tried but with little success.
A
Danish study of the risk for diabetes with antipsychotics found that the rate
ratio (RR) for risk with first-generation antipsychotics was 1.53, whereas the
RR varied widely for second-generation antipsychotics (1.32; range, 1.17-1.57).
This study compared nearly 346,000 patient records where individuals purchased
antipsychotics and nearly 1.5 million unexposed individuals.[78]
Stroup
et al reported that patients experiencing cardiovascular or metabolic side
effects of an antipsychotic medication may fare better if they switch to a
different agent, provided that they are closely monitored.[79] This
study included 215 patients whose psychotic symptoms were stabilized on
olanzapine, quetiapine or risperidone. After 24 weeks, those who switched to
aripiprazole showed improvement with regard to cholesterol levels and other
metabolic factors, and they lost more weight than those who stayed on their
original medication.
Relapse
or worsening of psychotic symptoms occurred no more frequently in patients who
switched medications than in those who stayed on their original medication.[79] However,
patients who switched to aripiprazole were more likely to discontinue the
assigned medication; 43.9% of those who switched discontinued their medication,
versus 24.5% of those who stayed on their original medication.
It
is unclear whether weight-reducing drugs should be added to antipsychotic
therapy, although Wang et al found that the diabetes drug metformin (1000 mg
daily) was effective and safe in attenuating antipsychotic-induced weight gain
and insulin resistance.[80] This
randomized, placebo-controlled study was conducted in 72 patients with
first-episode schizophrenia who gained more than 7% of their predrug weight.
Miscellaneous adverse effects
All
antipsychotic agents may be associated with esophageal dysmotility, aspiration,
choking, and the subsequent risk of pneumonia. Orthostatic hypotension can be
problematic at the beginning of therapy, with dose increases, and in elderly
patients. This is related to alpha1 -blockade and seems to be
particularly severe with risperidone and clozapine.
Venous
thromboembolism may be associated with the use of antipsychotic drugs. Patients
treated with clozapine may be at particular risk for this complication;
however, the reasons for this possible association are not understood.[81, 82]
Neurotoxic effects
Some
studies have explored the potential neurotoxic effects of antipsychotic
medications; however, no clear conclusions have been reached. For example, Ho
et al performed structural brain imaging in more than 200 patients with
schizophrenia over 7 years and found that whereas patients treated with higher
doses of antipsychotic medications seemed to lose gray matter throughout their
brain (except the cerebellum), those treated with lower doses seemed to have a
small increase in white matter of the brain.[83]
The
clinical significance of these findings is unclear. It is not known whether
these changes are directly associated with any clinical symptoms and whether
they are reversible. It also is not known whether the higher medication doses
were in response to the gray matter loss or whether it was the other way
around.
Antipsychotic Drugs: Monitoring of Blood levels
Regular
measurement of blood medication levels in the blood would be helpful in schizophrenia,
for the following reasons:
- Patients may not always take
their medications, and checking drug levels can detect this noncompliance
- Patients may not always be the
best reporters of side effects, and monitoring medication levels can
occasionally help the clinician detect toxicity
- Smoking tobacco products
induces the liver enzyme CYP1A2 (though nicotine patches, nicotine
inhalers, and chewing tobacco do not), which metabolizes a number of
antipsychotic drugs, so that, for example, patients who stop smoking while
being treated with clozapine or olanzapine often experience increased
antipsychotic levels; a patient who has stopped smoking may have a variety
of complaints, and checking drug levels can help determine their etiology
For
most antipsychotic medications, however, clear dose-response curves have not
been established, and the reasons listed above are not compelling enough to
induce clinicians to monitor drug levels. In clinical practice, drug levels are
rarely monitored.
There
are 2 exceptions to this general statement. Plasma concentrations of
haloperidol are correlated to some degree with clinical effects. levels in the
range of 15-25 ng/mL are thought to be optimal. Plasma concentrations of
clozapine in the range of 300-400 ng/mL may be optimal.
Other Medications
Anticholinergic
agents (eg, benztropine, trihexyphenidyl, and diphenhydramine) or amantadine
are often used in conjunction with the conventional antipsychotic agents to
prevent dystonic movements or to treat extrapyramidal symptoms. Akathisia is
particularly difficult to treat, but it occasionally responds to an
anticholinergic agent, a benzodiazepine, or a beta blocker.
Many
patients with schizophrenia are treated with other psychotropic medications in
addition to antipsychotic agents. Polypharmacy in schizophrenia is supported by
very little rigorous evidence but is widely practiced nonetheless. Medications
often used include antidepressants, mood stabilizers, and anxiolytic agents.
Note that carbamazepine and clozapine should not be used together.
Benzodiazepines
are often used and are perceived as being quite safe. Nevertheless, they can be
addictive and can lead to falls, especially in the elderly. There has long been
a concern that they might increase mortality.[84]
Psychosocial Interventions
Psychosocial
treatment is essential for people with schizophrenia, in that medications alone
are insufficient. The best-studied psychosocial treatments are social skills
training, cognitive behavioral therapy, cognitive remediation, and social
cognition training.[85] PORT,
referred to above, also provides a detailed review of psychosocial
interventions.[86]
Psychosocial
treatments are currently oriented according to the recovery model. According to
this model, the goals of treatment for a person with schizophrenia are as
follows:
- To have few or stable symptoms
- Not to be hospitalized
- To manage his or her own funds
and medications
- To be either working or in
school at least half-time
Hope,
empowerment, choice, and community integration are emphasized in this treatment
approach.
A
large study from China demonstrated the benefits of medication plus
psychosocial intervention over medication alone.[87] In
the psychosocial intervention arm, each month patients and their families
received a day of 4 types of evidence-based interventions: psychoeducation,
family intervention, skills training, and cognitive-behavioral therapy. After a
year, the patients in the group receiving the extra interventions were more
compliant with their medications, had fewer rehospitalizations, and experienced
better quality of life.
Cognitive remediation
Cognitive
impairment, a core feature of schizophrenia, is less dramatic than other
symptoms of the disease (eg, hallucinations and 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 derived from principles of
neuropsychological rehabilitation. It is based, in part, on the ideas 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
different models of cognitive remediation are available. Some models emphasize
drill-based practicing of isolated cognitive skills with the aid of computers,
whereas others help people develop strategies for overcoming areas of weakness.
Other forms of this therapy are known as cognitive rehabilitation, cognitive
enhancement, or metacognitive therapy.
Cognitive
remediation works best when patients are stable. Improvement occurs across
numerous cognitive functions, and changes are found on brain imaging that
reflect these changes in brain functioning.
Cognitive
remediation techniques are time-intensive and labor-intensive. Because
cognitive deficits are multiple and vary from person to person, such techniques
seem to work best when specifically tailored to each patient. When combined
with other therapies, such as supported employment, cognitive remediation leads
to clinically relevant improvements.[88] These
effects are durable, lasting even after the training has stopped.[89]
In
a study by Grant et al, low-functioning patients with prominent negative
symptoms were assigned to either recovery-oriented cognitive behavioral therapy
or standard treatment; after 18 months, the authors found that both negative
and positive symptoms had decreased.[90] The
study was not blinded, and the treatment was delivered by enthusiastic doctoral
level therapists, which may limit the generalizability of these findings.
None
of the antipsychotic medications currently available are particularly effective
at addressing cognitive symptoms. A new initiative from NIMH, known as Measurement
and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), is a
collaboration between various programs to develop tools for measuring cognition
in clinical trials and aiding drug development that is targeted at these
symptoms.
Vocational rehabilitation
Most
patients with schizophrenia would like to work. Employment can improve income,
self-esteem and social status. However few people with the disorder are able to
maintain competitive employment.[91] Supported
employment programs currently thought to be most effective are those that offer
individualized, supported, and rapid job assignments and that are integrated
with other services. These programs are associated with higher rates of
employment but gains in other domains are surprisingly difficult to discern.[92]
Assertive community treatment
Assertive
community treatment is a form of case management that is typically used for
patients who have had multiple hospitalizations. The treatment involves active
outreach to patients. Case managers usually have a fairly small outpatient load
(about 10 patients) and are able to go into the community to work with their
clients. The managers coordinate and integrate care.
The
case managers, who may come from various disciplines, identify indications for
treatment, make referrals to appropriate services, and promote engagement with
interventions. This form of treatment is expensive but may be associated with
better clinical and social outcomes and lower hospitalization rates.
Family intervention
Schizophrenia
affects the person’s whole family, and the family’s responses can affect the
trajectory of the person’s illness. Familial “high expressed emotion” (hostile
overinvolvement and intrusiveness) leads to more frequent relapses. Some
studies have found that family therapy or family interventions may prevent relapse,
reduce hospital admission, and improve medication compliance.[93]
Smoking Cessation
Most
patients with schizophrenia smoke. This may be a result of previous
conventional antipsychotic treatment, as nicotine may ameliorate some of the
adverse effects of these drugs. Smoking may also be related to the boredom
associated with hospitalizations, the peer pressure from other patients to
smoke, or the anomie associated with unemployment.
Whatever
the cause of the high incidence of smoking, the health risks from smoking are
well known, and all schizophrenic patients should be encouraged to stop
smoking.
Diet and Activity
Many
psychotropic medications can cause weight gain and changes in glucose or lipid
metabolism. Occasionally, a person with schizophrenia develops odd food
preferences. Finally, many persons with schizophrenia have limited funds, do
not cook for themselves, and live in areas where fast food outlets are
abundant. Therefore, nutritional counseling is difficult but important.
Because
many psychotropic medications are associated with weight gain, persons with
schizophrenia should be encouraged to be as physically active as possible.
Alternative Housing
In
the United States, many people with schizophrenia do not live with their
families. Because they do not always have the skills needed for independent
living, a system of alternative housing arrangements has emerged. At their most
basic, such arrangements may consist of boarding houses or single-room
occupancy (SRO) hotels with no supervision. Patients with schizophrenia often
have difficulty finding housing; therefore, working with associations that may
provide housing assistance is important.
Many
organizations, often state-supported, provide communal-living settings with
24-hour supervision in halfway houses. Veterans Affairs (VA) facilities have
developed a sophisticated system of family care homes. Therapeutic halfway
houses also exist in which independence and social skills training are
encouraged.
In
the past, long-term inpatient units offered an alternative for patients whose
symptoms left them too disorganized to live in the community. These units were usually
found in state hospitals or VA hospitals but are now increasingly rare.
Complications
Substance abuse
Alcohol
and drug abuse (especially involving nicotine) are common in schizophrenia. The
reasons for this are not entirely clear. For some people, these drugs provide
relief from symptoms of the illness or the adverse effects of antipsychotic
drugs, and the drive for this relief is strong enough to allow even patients
who are impoverished and disorganized to find substances to abuse.[94]
Comorbid
substance abuse occurs in 20-70% of patients with schizophrenia, particularly
younger male patients, and is associated with increased hostility, crime,
violence, suicidality, noncompliance with medication, homelessness, poor
nutrition, and poverty. Drug use and abuse can also increase symptoms. For
example, cannabis use has been shown to correlate, in a bidirectional way, with
an adverse course of psychotic symptoms in persons with schizophrenia.[95]
Patients
who abuse substances may fare better in dual-diagnosis treatment programs, in
which principles from both the mental health field and the chemical dependency
field can be integrated.
Depression
Many
patients with schizophrenia report symptoms of depression. It is not clear
whether the depression is part of the schizophrenia, a reaction to the
schizophrenia, or a complication of treatment. Addressing this issue is
important because of the high rate of suicide in patients with schizophrenia.
The
research evidence for the use of antidepressant agents in schizophrenic
patients is mixed. Further complicating the situation are the findings that
antipsychotic agents, even the older conventional ones, may have antidepressant
properties.[96] One
meta-analysis suggested that the addition of antidepressants to antipsychotics
might help treat the negative symptoms of chronic schizophrenia, which can be
difficult to distinguish from depression.[97]
Anxiety
Anxiety
is common in patients with schizophrenia. It may be an aspect of schizophrenia
itself, a side effect of medication (eg, akathisia and obsessions/compulsions),
or a comorbid disorder. Anxiety may precede the onset of schizophrenia by
several years.[98]
Treatment
is keyed to the source of the anxiety. Antipsychotics usually relieve anxiety
that is part of an acute psychotic episode; only limited data are available on
treatment of comorbid anxiety disorders. Following treatment recommendations
for primary anxiety disorder would be reasonable in many cases; however,
fluvoxamine and other selective serotonin reuptake inhibitors should be used
cautiously in patients receiving clozapine; they can raise clozapine blood
levels. Benzodiazepines may be helpful but carry their own risks.[84, 99]
Violence
Most
people with schizophrenia are not violent, tending to be afraid of others
rather than threatening toward them. However, a few may act violently,
sometimes as a result of command hallucinations or delusions.[97] Because
the violent acts carried out by these few patients may be unpredictable and
bizarre, they are often highly publicized, and the intense publicity has the
unfortunate consequence of exacerbating the stigma of the disease.
Violence
may be associated with substance abuse. However, the rate of violence in
patients with schizophrenia who do not abuse substances is higher than that in
people without schizophrenia.[100, 101] Clozapine is sometimes recommended for treatment of patients
with schizophrenia who are violent.
Prevention
Many
have wondered whether patients with schizophrenia would have a better prognosis
if treatment could be started as early as possible. A study from Scandinavia
found that early detection and intervention in first-episode psychosis led to
higher recovery and employment rates at 10-year follow-up.[102]
The
North American Prodrome Longitudinal Study is exploring whether the incorporation of biologic measures
into prediction algorithms can provide more accurate identification of young
people who are at greatest risk for developing a psychotic disorder. The goal
of this study is to establish objective criteria that can be used to develop
preventive approaches.
There
are several studies of prodromal schizophrenia under way to inform early
intervention strategies. In the absence of highly reliable methods of
predicting schizophrenia, however, intervention during the prodromal stage
could result in the unnecessary administration of antipsychotic medication to
young people who are mistakenly identified as being at risk for schizophrenia.[103]
One
approach to this problem is to use psychological therapies rather than
pharmacotherapy. A German study of young people at risk for schizophrenia
showed that the use of a psychological intervention involving
cognitive-behavioral therapy, group skills training, cognitive remediation and
multifamily psychoeducation delayed the onset of psychosis for at least 2
years.[104]
Medication Summary
Antipsychotic
agents are the mainstay of medical treatment of schizophrenia. These
medications diminish the positive symptoms of schizophrenia and prevent
relapses. The second-generation (novel or atypical) antipsychotic drugs may be
more effective in treating negative symptoms and cognitive impairment.
Some
clinicians routinely perform electrocardiography (ECG) before beginning
treatment with antipsychotic medications. Because suicide is not uncommon in
patients with psychotic illnesses, clinicians should write prescriptions for
the lowest dosage that is consistent with good clinical care. Patients should
be urged to avoid substance abuse. All medications should be given at lower
dosages in children and elderly patients and used with great caution in women
who are pregnant or breastfeeding.
Antipsychotics
are not indicated for the control of agitation in dementia. In clinical
practice, however, these agents are often given for that purpose.
Antipsychotics, 1st Generation
Class Summary
First-generation
antipsychotics, also known as conventional or typical antipsychotics, are
strong dopamine D2 antagonists. However, each drug in this class has various
effects on other receptors, such as 5-HT2 serotonin, alpha1,
histaminic, and muscarinic receptors.
First-generation
antipsychotics have a high rate of extrapyramidal side effects, including
rigidity, bradykinesia, tremor, and akathisia. Tardive dyskinesia (TD;
involuntary moments in the face and extremities) is another side effect that
can occur with first-generation antipsychotics. However, first-generation
antipsychotics have large cost advantages over second-generation
antipsychotics.
Chlorpromazine,
which was the first conventional antipsychotic developed and is still in wide
use for treatment of schizophrenia, is a phenothiazine antipsychotic that is a
dopamine D2 receptor antagonist. Chlorpromazine is available in oral tablets,
syrup, and concentrate; as an injectable solution for intramuscular
administration; and in suppository form.
Extrapyramidal
symptoms from chlorpromazine include akathisia, TD, dystonia, and infrequently,
neuroleptic malignant syndrome (NMS). Common adverse effects include
anticholinergic effects, sedation, and weight gain.
Fluphenazine
is a high-potency typical antipsychotic that blocks postsynaptic dopaminergic
D1 and D2 receptors in the brain. It has some alpha-adrenergic and
anticholinergic effects and may depress the reticular activating system. It is
available in a depot formulation (fluphenazine decanoate). A short-acting
intramuscular (IM) injection is also available for acute agitation.
Fluphenazine is clinically comparable to haloperidol, a first-generation
antipsychotic with similar potency, route of administration, side effects, and
efficacy.
Haloperidol
is indicated for management of schizophrenia when no contraindications exist.
It is a D2 antagonist noted for high potency and low potential for causing
orthostasis. The drawback is the high potential for extrapyramidal symptoms or
dystonia. Haloperidol can interact with CYP3A4 and CYP2D6 inhibitors and
inducers. It also can interact with drugs that prolong QTc intervals.
Haloperidol is available in tablets, as a liquid concentrate, in IM and
intravenous (IV) forms, and in long-acting IM form for depot injection.
Perphenazine
is a phenothiazine antipsychotic that is indicated for the treatment of
schizophrenia and severe nausea and vomiting. It blocks postsynaptic
dopamineric receptors in the brain and exhibits alpha-adrenergic blocking
effects. It has slightly lower potency than haloperidol and it sometimes
classified as a midpotency drug. It is available in an oral formulation.
Thiothixene
is a dopamine D2 antagonist that also elicits anticholinergic and
alpha-blocking effects.
Trifluoperazine
is a piperazine phenothiazine agent. It elicits antagonist action on the
postsynaptic mesolimbic dopaminergic D2 receptors in the brain and also
decreases the release of hypothalamic and hypophyseal hormones.
Loxapine's
mechanism of action is unknown, but is theorized to antagonize central dopamine
D2 and serotonin 5-HT2a receptors. The inhaled dosage form is indicated for
acute treatment of agitation associated with schizophrenia or bipolar I
disorder in adults.
Antipsychotics,
2nd Generation
Class
Summary
Second-generation antipsychotics are
also known as atypical antipsychotics. These drugs, with the exception of
aripiprazole, are dopamine D2 antagonists. They are associated with lower rates
of extrapyramidal side effects and TD than the first-generation antipsychotics
are; however, they have higher rates of metabolic side effects and weight gain.
Aripiprazole is a partial agonist at
dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin
5-HT2A receptors, alpha1, and H1 receptors. It is available in tablets, orally
disintegrating tablets, and short-term IM injection (a long-acting depot
preparation is under development). The most common side effects include
headache, nausea, vomiting, insomnia, tremor, and constipation.
Oral aripiprazole is indicated for
acute and maintenance treatment of schizophrenia. It is also used for acute and
maintenance treatment of bipolar I disorder, adjunctive therapy for major
depressive disorder, and treatment of irritability associated with autistic
disorder.
Asenapine is indicated for acute and
maintenance treatment of schizophrenia. It is absorbed poorly in the
gastrointestinal (GI) tract and thus is available in a sublingual form. The
most common side effects include sedation, weight gain, dizziness,
extrapyramidal symptoms, and oral hypoesthesia.
The mechanism of action of asenapine
is unknown. The efficacy of this agent is thought to be mediated through a
combination of antagonist activity at dopamine D2 and serotonin 5-HT2
receptors.
Asenapine exhibits high affinity for
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 affinity for H2 receptors.
In vitro assays suggest antagonistic activity elicited at these receptors.
Clozapine is an antagonist at
adrenergic, cholinergic, histaminergic, and serotonergic receptors. It has some
dopamine D2 antagonism and high D4 affinity. It is indicated for treating
refractory schizophrenia and for reducing the risk of recurrent suicidal
behavior in schizophrenia or schizoaffective disorder.
Iloperidone is indicated for acute
treatment of schizophrenia. Its precise mechanism of action is unknown, but it
is known to antagonize dopamine D2 and serotonin 5-HT2 receptors. Side effects
include dizziness, orthostatic hypotension, tachycardia, weight gain, dry
mouth, and sedation. Iloperidone causes fewer extrapyramidal symptoms than
other antipsychotics do.
Lurasidone is an atypical
antipsychotic whose precise mechanism of action is unknown. Its efficacy
thought to involve mediation of central dopamine D2 and serotonin 5-HT2A
receptor antagonism. It is indicated for treatment of schizophrenia. This drug
has not been tested in children or adolescents.
A major route of metabolism for
lurasidone is via CYP3A4. Dose reduction is recommended in the presence of
moderate CYP3A4 inhibitors. Coadministration with strong CYP3A4 inducers is not
recommended.
Olanzapine is a selective
monoaminergic antagonist at the following receptors: serotonin, dopamine D1-4,
muscarinic, histamine H1, and alpha¬1-adrenergic. It is available in regular
tablet form, rapid-disintegrating tablets, short-acting injectable solution,
and long-acting injectable formulation. The most common side effects of
olanzapine include weight gain, sedation, akathisia, hypotension, dry mouth,
and constipation.
Paliperidone is the major active
metabolite of risperidone and was the first oral agent to allow once-daily
dosing. It is indicated for acute and maintenance treatment of schizophrenia.
Its mechanism of action not completely understood but is thought to involve
mediation of central antagonism of dopamine D2 and serotonin 5HT-2A receptors.
Paliperidone also elicits antagonist activity at adrenergic alpha1 and alpha2
receptors and histamine H1 receptors. Paliperidone is available in an osmotic
delivery capsule.
Quetiapine may act by antagonizing
dopamine and serotonin effects. It is used for treatment of schizophrenia.
Improvements over earlier antipsychotics include fewer anticholinergic effects
and less dystonia, parkinsonism, and TD. Quetiapine is available in
immediate-release and extended-release tablets. Major side effects include
sedation, orthostatic hypotension, akathisia, dry mouth, and weight gain.
Risperidone has both dopamine D2 and
serotonin 5-HT2 antagonism. It is available in tablets, oral disintegrating
tablets, and oral solution, as well as a long-acting form for IM injection that
uses microspheres made of biodegradable polymers. It has no anticholinergic
effects and little effect on muscarinic receptors. Primary side effects of
risperidone include mild sedation, hypotension, akathisia, increase in
prolactin, and weight gain.
Ziprasidone antagonizes dopamine D2,
serotonin 5-HT2, histamine H1, and alpha1-adrenergic receptors. It is available
in capsule and short-acting IM injection forms. It is indicated for treatment
and acute agitation in patients with schizophrenia. Ziprasidone appears to
cause less weight gain, hyperglycemia, and hyperlipidemia than other drugs in
its category do.
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