Active psychosis is dangerous to a person's safety;
disrupts capacity to function, life, and reputation; and if persistent
for too long can negatively affect prognosis (251). In contrast,
early treatment may result in a significant reduction in morbidity
and better quality of life for patients and families (252–256).
Approximately 25 studies have examined this phenomenon; about two-thirds
have shown a significant association between earlier treatment and better
outcome on one or more measures, and none has shown a significant
association between delayed treatment and better outcome
on any measure (257). Despite the benefits of early treatment, there
is usually a delay of 1–2 years between the onset of psychotic
symptoms and the time the patient first receives adequate psychiatric
treatment (252, 258–261). Thus, once psychosis is evident,
it should be treated immediately.
In some persons, particularly those with a family history
of schizophrenia or other factors influencing risk, prodromal symptoms
may be apparent before the development of a full schizophrenia syndrome.
Although empirical evidence on long-term outcome is limited, antipsychotic
medication treatment may also be helpful in some persons with prodromal
When a patient presents with a first episode of psychosis,
close observation and documentation of the signs and symptoms over
time are important because initial psychotic episodes can be polymorphic
and evolve into a variety of specific disorders (e.g., schizophreniform
disorder, bipolar disorder, schizoaffective disorder). There is
controversy over whether first-episode patients should be treated
as outpatients or in the hospital. Inpatient care offers both risks
and protections. On the one hand, the experience of a first psychiatric
hospitalization, especially in a closed setting with many chronically
ill patients, can be frightening and produce its own trauma (265).
On the other hand, the nature and severity of a first episode are
often unknown, unpredictable, and require more than "usual" surveillance.
A hospital setting also allows for careful monitoring of the psychotic
symptoms as well as any side effects, including acute dystonia,
akathisia, or neuroleptic malignant syndrome (266), that may arise
from treatment with antipsychotic medications.
Patients with first-episode psychosis are comparatively more
treatment responsive than patients with multiple episodes of psychosis
but, at the same time, are quite sensitive to side effects (267–270).
Up to the early 1990s, drug treatment for a first episode of psychosis
was limited to first-generation antipsychotic medications that could
cause severe sedation and extrapyramidal side effects. The second-generation
antipsychotic medications have less propensity to cause extrapyramidal
side effects, and patients are hence less likely to need concomitant
anticholinergic agents (271–273).
More than 70% of first-episode patients achieve a
full remission of psychotic signs and symptoms within 3–4
months, with 83% achieving stable remission at the end
of 1 year (274). Studies also reveal that first-episode patients
often respond to low doses of antipsychotic medications (275–279).
However, predictors of poor treatment response include male gender,
pre- or perinatal injury, more severe hallucinations and delusions,
attentional impairments, poor premorbid function, longer duration
of untreated psychosis (280), the development of extrapyramidal
side effects (281), and high levels of expressed emotion in the
patient's family (282–289).
Not uncommonly, symptoms of schizophrenia have their onset
before adulthood, and aspects of treatment may differ in children
and adolescents. For more information on treating children and adolescents,
readers are referred to the American Academy of Child and Adolescent
Psychiatry's Practice Parameter for the
Assessment and Treatment of Children and Adolescents With Schizophrenia (290).
Once remission of psychotic symptoms is achieved, a high priority
should be placed on minimizing risk of relapse, given its potential
clinical, social, and vocational costs. In particular, recurrent episodes
are associated with increasing risk of chronic residual symptoms
and evidence of anatomical neuroprogression (257, 280, 291–293).
Patients, their families, and treating clinicians often hope that
symptom remission indicates that the disease will not become chronic,
although this is true only for a minority (about 10%–20%)
of patients (46, 218, 294). Thus, clinicians should candidly discuss
the high risk of relapse and factors that may minimize relapse risk.
Although there is very little study of factors that act to maintain
recovery in remitted first-episode patients, evidence suggests that
antipsychotics are highly effective in prevention of relapse. In
patients for whom antipsychotics are prescribed, 1-year relapse
risk varies from 0% to 46%, with relapse rates
of patients who discontinue taking medication being up to five times
higher than rates for those who continue treatment (46, 210–213).
Since adherence to maintenance medication treatment likely influences
effectiveness, it may contribute to the varying relapse rates found
in these studies.
In arriving at a plan of treatment with remitted first-episode
patients, clinicians should engage patients in discussion of the
long-term potential risks of maintenance treatment with the prescribed antipsychotic
versus risks of relapse (e.g., effect of relapse on social and vocational
function, risk of dangerous behaviors with relapse, and risk of
developing chronic treatment-resistant symptoms). Prudent treatment
options that clinicians may discuss with remitted patients include
either 1) indefinite antipsychotic maintenance medication (295) or
2) medication discontinuation with close follow-up and a plan of
antipsychotic reinstitution with symptom recurrence. Medications
should never be stopped abruptly, as rebound psychosis
may result and may be misinterpreted as a reoccurrence.
In addition to maintenance antipsychotic medication, other potential
strategies to maintain recovery in remitted first-episode patients
include enhancing stress management and eliminating exposure to
cannabinoids and psychostimulants (296).
b) Subtypes and deficit symptoms
According to DSM-IV-TR, the classic subtypes of schizophrenia
are paranoid, disorganized, catatonic, undifferentiated, and residual.
There are at present no treatment strategies specific to the various
subtypes, with the exception of the use of benzodiazepines for catatonia.
The deficit/nondeficit categorization, or the deficit syndrome,
is also important to recognize, although there are also no specific
treatments (297). The negative symptoms of schizophrenia may be
classified as primary or secondary. Negative symptoms may be primary
and represent a core feature of schizophrenia, or they may be secondary to
positive psychotic symptoms (e.g., paranoid withdrawal), medication
side effects (e.g., dysphoria), depressive symptoms (e.g., anhedonia),
anxiety symptoms (e.g., social phobia), demoralization, or environmental
deprivation (e.g., in chronic institutionalization). Deficit schizophrenia
is heavily loaded with enduring primary negative symptoms such as
affective flattening, alogia, and avolition.
The prevalence of deficit states in first-episode schizophrenia
has been estimated to be between 4% and 10% (298).
Negative symptoms are already present in the prodromal phase (299–301),
and the prevalence increases with the length of the schizophrenic
illness (302–306). Male patients have been found to experience
more negative symptoms than female patients (307–309).
Patients with deficit schizophrenia are also found to have poorer
premorbid adjustment during childhood and early adolescence. They
exhibit more impairment in general cognitive abilities and have
problems in sequencing of complex motor acts, which suggests frontoparietal
Treatment of negative symptoms begins with assessing the patient
for factors that can cause the appearance of secondary negative
symptoms (311). The treatment of such secondary negative symptoms
consists of treating their cause, e.g., antipsychotics for primary
positive symptoms, antidepressants for depression, anxiolytics for
anxiety disorders, or antiparkinsonian agents or antipsychotic dose
reduction for extrapyramidal side effects. If negative symptoms
persist after such treatment, they are presumed to be primary negative symptoms
of the deficit state (312).
There are no treatments with proven efficacy for primary negative
symptoms. Clozapine was reported to be effective for negative symptoms
in earlier short-term trials (313), but subsequent longer-term studies
challenged such claims (314, 315), although clozapine treatment
was associated with significant improvement in social and occupational
functioning (314). The second-generation antipsychotic medications
have been reported to be useful against negative symptoms (316–322),
but this improvement may be accounted for by their having less propensity
to cause extrapyramidal side effects (323).
c) Substance use disorders
More than one-third of patients with schizophrenia spectrum
disorders also have a substance use disorder, and people with schizophrenia
show six times the risk of developing a substance use disorder than
do persons in the general population (324). Other research finds
that between 20% and 65% of people with schizophrenia
experience comorbid substance use disorders (325–328).
A recent Australian study found the 6-month and lifetime prevalence
of substance abuse or dependence among people with schizophrenia
to be 26.8% and 59.8%, respectively (329).
Substance abuse in schizophrenia has been associated with
male gender, single marital status, less education, earlier age
at onset of schizophrenia and at first hospital admission, frequent
and longer periods of hospitalization, more pronounced psychotic
symptoms, more severe cerebral gray matter volume deficits, and
negative consequences such as poor treatment adherence,
depressive symptoms, suicide, violence, legal problems, incarceration,
severe financial problems, family burden, housing instability, and
increased risk of HIV infection (327, 330–332) and hepatitis
infection, particularly hepatitis C infection (333). Substance abuse
has been associated with precipitation of schizophrenia at an earlier
age (334–340), and in some studies amphetamine abuse has
been associated with an earlier age of onset (341). Alcohol and
a variety of other substances have also been associated with symptom
relapses in schizophrenia (342). Nicotine, alcohol, cannabis,
and cocaine have been found to be the most commonly abused substances.
Patients may also abuse prescribed medications such as benzodiazepines
and antiparkinsonian agents.
The goals of treatment for patients with schizophrenia who
also have a substance use disorder are the same as those for treatment
of schizophrenia without comorbidity but with the addition of the goals
for treatment of substance use disorders, e.g., harm reduction,
abstinence, relapse prevention, and rehabilitation (343).
Evaluation of the patient with schizophrenia should always
include a comprehensive inquiry into possible substance use. Self-report
is often unreliable; corroborating evidence from all sources such as
family members, friends, community-based case managers, and treatment
personnel should be sought (330, 344). Screening instruments for
substance use disorders developed for the general population, such
as the Alcohol Use Disorders Identification Test (AUDIT) (345),
can be used, but screening instruments specifically for patients
with severe mental illnesses, such as the Dartmouth Assessment of
Lifestyle Instrument (346), have been developed and may have greater
sensitivity for detecting substance use disorders in people with
schizophrenia. Laboratory investigations such as urine and blood
toxicology for abused substances and liver function tests should
be carried out. Many patients with schizophrenia do not develop
the full physiological dependence syndrome associated with dependence
on alcohol or other substances (330). However, even use of low levels
of alcohol or other substances by patients with schizophrenia can
have untoward consequences. Psychiatrists should therefore attend
carefully to the presence of alcohol or other substance use and
be familiar with the potential negative consequences described earlier.
The rates of current substance use will likely be higher in acute
settings such as the emergency department, and thus the index of
suspicion and effort devoted to assessment of substance use should be
especially high in such settings.
Traditionally, patients with schizophrenia and comorbid substance
use disorders were treated in separate programs, either sequentially
or in parallel, for the two types of disorder. Since the mid-1980s,
a comprehensive integrated treatment model has been adopted to provide
continuous outpatient treatment interventions and support over long
periods of time (months to years), enabling patients to acquire
the skills they need to manage both illnesses and to pursue functional
goals. In this model, the same clinicians or teams of clinicians
provide treatment both for substance use disorders and for other
mental disorders. This form of treatment features assertive outreach,
case management, family interventions, housing, rehabilitation,
and pharmacotherapy. It also includes a stage-wise motivational
approach for patients who do not recognize the need for treatment
of substance use disorders and behavioral interventions for those
who are trying to attain or maintain abstinence. The interventions
have been associated with reduced substance use and attainment of remission (347–350).
Initially, many patients need interventions to build motivation
rather than to achieve abstinence. Special efforts are
made to help them recognize that their substance
use is interfering with their ability to pursue personal
goals and to nurture their desire to reduce and eliminate their
substance use (161, 349). Such efforts represent examples of interventions
during the second (persuasion) stage in a four-stage dual-diagnosis
treatment model based on readiness for change; the other treatment
stages are engagement, active treatment, and relapse prevention (351).
Studies show that treatment programs with these characteristics
can be effective in reducing substance use and in decreasing the
frequency and severity of psychotic decompensations (332,
352–354). Collaboration with family members is often helpful
for both the patients and the family members (64, 171,
In practice, treatment of substance use disorders is commonly
conducted by means of a group therapy approach, usually after patients
have achieved stabilization of their schizophrenic symptoms. The
therapeutic approach should be an integrated one that takes into
account patients' cognitive deficits and limited tolerance
for stress. Generally, groups should emphasize support, psychoeducation,
and skills training (344, 352, 357). The length and frequency of
group sessions should be regulated according to the attention span and
interactive tolerance of the patients. Therapists should be active
in keeping the group structured and focused and should limit the
amount of stress by avoiding the direct confrontation of patients that
is common to traditional treatment programs for persons with substance
use disorders. Patients should understand that they have two complex
chronic disorders that together lead to a poorer prognosis than
each would have separately. Patients who have not yet attained complete
abstinence should be accepted into treatment, with abstinence as
a treatment goal (344, 352, 358). Patients who do not view abstinence
as a treatment goal may still be successfully engaged in treatment
that is aimed at achieving abstinence (359). Community-based self-help
and support groups such as Alcoholics Anonymous or Narcotics Anonymous
can be important in the recovery of patients with substance use
disorders. Such connections are, however, more effective once patients
are actively pursuing abstinence (349).
Antipsychotic medications remain the mainstay of pharmacological
treatment for patients with comorbid substance use disorders. They
are used in the usual doses, but patients should be informed that
side effects such as sedation and incoordination can be aggravated
when combining antipsychotic medication with alcohol or other substances.
First-generation antipsychotic medications and clozapine also have
the potential to lower the seizure threshold and infrequently may
precipitate seizures during alcohol or benzodiazepine withdrawal.
Dysphoria associated with first-generation antipsychotic
medications may precipitate or worsen the substance use (360). On
the other hand, studies have demonstrated that clozapine use is
associated with reductions in the use of nicotine, alcohol, cannabis,
and cocaine (361–363). In some clinical trials, second-generation
antipsychotics such as risperidone and olanzapine have also been
shown to be effective for reducing craving in cocaine dependence (364).
There is suggestive evidence from a case series of 30 patients
with schizophrenia and other severe mental illnesses and alcoholism
that disulfiram in moderate doses can be used safely and is associated with
clinical benefits in alcohol outcomes over 1–3 years (365).
However, for patients with schizophrenia who abuse alcohol, disulfiram
may pose some risk since it can precipitate psychosis at high doses (358, 366). It also has harmful physical effects when taken with alcohol,
and thus it is recommended only for patients who are motivated and
who have previously shown good judgment, treatment adherence, and
Depressive symptoms are common in all phases of schizophrenia (367).
The proportion of patients with schizophrenia who also manifest
depression ranges from 7% to 75% (368). Depression
may occur in the prodromal phase (300, 301), in the first episode (369–371),
during the early course (372, 373), and after remission, and it
may be superimposed on the symptoms of residual schizophrenia ("postpsychotic
depression") (374) or may occur in a prodrome to a psychotic
When patients with schizophrenia present with depressive features,
important differential diagnostic possibilities need to be considered (368, 380). These include side effects of antipsychotic medications (including
medication-induced dysphoria, akinesia, and akathisia), demoralization,
and the primary negative symptoms of schizophrenia. Concurrent abuse
or the sudden withdrawal of substances such as cannabis, cocaine,
narcotics, alcohol, nicotine, and caffeine can also lead to depression.
When the depressive symptoms are present at a syndromal level during
the acute phase of the schizophrenic illness, the possibility of
schizoaffective disorder should be considered.
Depressive symptoms that occur during the acute psychotic
phase usually improve as the patient recovers from the psychosis.
There is also evidence to suggest that depressive symptoms are reduced by
antipsychotic treatment, with comparison trials finding that second-generation
antipsychotics may have greater efficacy for depressive symptoms
than first-generation antipsychotics (381, 382). However, there
is also evidence to suggest that this apparent antidepressant effect
may be related to the lower likelihood of neurological side effects
with second-generation antipsychotics (222, 368, 383, 384). The
approach hence is first to treat the psychosis.
If antipsychotic medication-induced dysphoria is suspected,
then antipsychotic dose reduction may be effective. Alternatively,
the clinician may switch the patient's medication to an
antipsychotic with a lower risk of inducing extrapyramidal symptoms
(Table 4). There is no evidence that medications that treat the
motor symptoms of extrapyramidal side effects (e.g., benztropine,
amantadine) (Table 5) are effective for the treatment of neuroleptic-induced
Antidepressants are added as an adjunct to antipsychotics
when the depressive symptoms meet the syndromal criteria for major
depressive disorder, are severe and causing significant distress
(e.g., when accompanied by suicidal ideation), or are interfering
with function. Tricyclic antidepressants have been extensively
studied in the treatment of postpsychotic depression (103, 385).
Antidepressants, including the selective serotonin reuptake inhibitors
(SSRIs) and dual reuptake inhibitors, have also been found to be
useful in the treatment of depression in schizophrenia (368, 384).
However, very few studies have examined the effects of antidepressants
in patients treated with second-generation antipsychotic medications,
making it difficult to evaluate the current utility of adjunctive
antidepressant agents. When prescribed, antidepressants are used
in the same doses that are used for treatment of major depressive
disorder. There are, however, potential pharmacokinetic interactions
with certain antipsychotic medications; for example, the SSRIs (such
as fluoxetine, paroxetine, and fluvoxamine) are inhibitors of cytochrome
P450 enzymes and thereby increase antipsychotic plasma
levels. Similarly, the blood levels of some antidepressants may
be elevated by the concomitant administration of antipsychotic medications.
Suicide is the leading cause of premature death among persons
with schizophrenia (386, 387). Compared to the general population,
persons with schizophrenia are nine times more likely to die by
suicide (388). Up to 30% of patients with schizophrenia
attempt suicide (389), and between 4% and 10% die
by suicide (390–394). The estimated rate of suicidal behavior
among persons with schizophrenia is between 20% and 40% (395, 396).
Some risk factors for suicide in schizophrenia are the same
as those for the general population, including being male, white,
single, socially isolated, and unemployed; having a positive family history
of suicide; previous suicide attempts; having a substance use disorder;
being depressed or hopeless; and having a significant recent adverse
life event. Specific risk factors for suicide among persons with
schizophrenia are young age, high socioeconomic status background,
high IQ with a high level of premorbid scholastic achievement, high
aspirations and expectations, an early age at onset of illness/first
hospitalization, a chronic and deteriorating course with many relapses,
and greater insight into the illness (391, 397–401). A
change in the environment, such as a hospital admission and discharge,
may trigger suicidal behavior (402, 403). Suicide is more common
within the first 6 years of the initial hospitalization and also
during periods of remission after 5–10 years of illness.
Other risk factors include severe depressive and psychotic symptoms,
with an increase in the patient's paranoid behavior (395,
404–406). Suicidal ideation has also been shown to be predictive
of suicide over the subsequent 2–4 weeks (407). As patients
do not often report suicidal ideation spontaneously, clinicians
are encouraged to ask patients about suicidal ideas whenever there
is suggestion that they could be present (e.g., in the presence
of depression or severe stress). Treatment-related factors associated
with suicide include inadequate antipsychotic treatment, nonadherence
to the medication regimen, and lack of response to medication (408).
In several case reports, suicide has also been noted among patients
with akathisia (409, 410).
Despite identification of these risk factors, it is not possible
to predict whether an individual patient will attempt suicide or
will die by suicide. Suicide thus must be considered at all stages
of the illness, and suicide risk must be assessed initially and
regularly as part of each patient's psychiatric evaluation.
The patient's desire to die may be more important than
the lethality of the methods used (403). Additional information
may be obtained from close family members and treating therapists. Patients
should be admitted to a secure inpatient unit if they are judged
to be at substantial risk for suicide.
It is important to maximize the treatment of both psychosis
and depression. There is suggestive evidence that both first- and
second-generation antipsychotic medications may reduce the risk
of suicide (411). However, clozapine is the most extensively studied
and has been shown to have the greatest therapeutic effect on suicidal
behavior, possibly reducing the suicide rate by as much as 75%–85% (55,
398, 399, 412). For these reasons, clozapine should be preferentially
considered for patients with a history of chronic and persistent
suicidal ideation or behaviors.
During the initial hospitalization, suicide precautions should
be instituted, and the patient must be closely monitored to prevent
escape. There should also be minimal use of ward transfers. Suicide risk
should be examined carefully before a patient is granted any privileges
and again before the patient is finally discharged from the hospital.
The patient and the patient's family members should be
advised to look for warning signs and to initiate specific contingency
plans if suicidal ideation recurs. In outpatients, the frequency
of visits should be higher after a recent discharge from the hospital
and may need to be increased in times of personal crisis, significant
environmental changes, heightened distress, or deepening depression
during the course of illness.
For additional information, readers are directed to APA's Practice
Guideline for the Assessment and Treatment of Patients With Suicidal
Behaviors (56) (included in this volume).
Although only a minority of patients with schizophrenia are
violent, evidence does suggest that schizophrenia is associated
with an increase in the risk of aggressive behavior (413–419).
Sociodemographic risk factors for aggression in schizophrenia are
male gender; being poor, unskilled, uneducated, or unmarried; and
having a history of prior arrests or a prior history of violence (420).
The risk for aggressive behavior increases with comorbid alcohol
abuse, substance abuse, antisocial personality, or neurological
impairment (421–427). Violent patients with schizophrenia
have more positive symptoms and bizarre behaviors and may act on
their delusions, especially if the delusions are distressing and
the patient can find evidence to support them (428–430).
Patients who experience command hallucinations to harm others are
also more likely to be violent (431).
Identifying risk factors for violence and assessment of dangerousness
are parts of a standard psychiatric evaluation, which should be
conducted in an environment that is safe for both the patient and
clinician (432). It is important to determine if use of alcohol
or other substances, including use of amphetamines or other stimulants,
is causing or contributing to aggressive behavior. Severe akathisia
associated with prescribed medications may also cause or contribute
to aggressive behavior. It is important to inquire about thoughts
of violence and determine the persons to whom these thoughts are
directed. Parents, for example, are frequent targets of violence
when it occurs (433). When a patient is found to pose a serious
threat to others (e.g., having homicidal ideation with imminent
plans), the psychiatrist should consider hospitalizing the patient
and must exercise his or her own best judgment, in accord with the
legal requirements of the jurisdiction, to protect those people
from foreseeable harm (54, 434).
If the patient is acutely aggressive, the clinician can try
to calm the patient by distraction or "talking down" techniques.
If restraint or seclusion is needed, it should be done with adequate
numbers of well-trained professional staff (70). When sedation is
indicated and the patient is unwilling to accept oral medication,
intramuscular injection of a first-generation antipsychotic agent
(5 mg of haloperidol) (75) or second-generation agent (e.g., ziprasidone) (76–79) can
be given, with or without a concomitant dose of 1–2 mg
of oral or intramuscular lorazepam (72–74). Other medications,
such as 5 mg i.m. of droperidol, can be used in selected clinical
situations of extreme emergency or in highly agitated patients (80, 435). However, if droperidol is used, its potential for cardiac
rhythm disturbances must be considered, as indicated in its labeling
by a black-box warning for QTc prolongation. After seclusion, restraint, or
sedation, the mental status and vital signs of the patient should
be monitored regularly. Release from seclusion or restraint can
proceed in a graded fashion, as risk of harm to self or others diminishes (432).
Limit setting and behavioral approaches have been employed
for the management of persistently violent patients (432, 436).
Antipsychotic medications remain the mainstay of management (421, 437), with good evidence for clozapine in particular (438–440).
Other agents have been used, including mood stabilizers (lithium,
valproate), SSRIs (such as citalopram), benzodiazepines,
and -adrenergic blocking agents
(propranolol, nadolol), but empirical evidence is lacking.
It is common for patients with schizophrenia in the community
to stop taking their medications. Patients who are more likely to
be violent with psychotic relapses are of particular concern and
may be primary candidates for mandatory outpatient treatment programs (441) (see
Section II.A.3, "Developing a Therapeutic Alliance and
Promoting Treatment Adherence").
g) Psychosis-induced polydipsia
Polydipsia is compulsive water drinking, usually in excess
of 3 liters per day. It can be complicated by water intoxication,
i.e., severe hyponatremia (serum sodium <120 mmol/liter),
which is potentially fatal, as the associated cerebral edema can
result in delirium, seizures, coma, and death. About 20%–25% of
chronically ill inpatients have primary polydipsia, and as many
as 10% have a history of water intoxication (442–445).
The pathophysiology of the water imbalance is still unclear.
It occurs most commonly in the most severely ill patients with schizophrenia
and thus has been termed "psychosis-induced polydipsia." Polydipsia
and water intoxication are associated with long hospitalization,
high doses of antipsychotic medications, moderate doses of anticholinergic
medications, and heavy smoking (442, 444). Development of hyponatremia
has also been associated with use of diuretics, SSRIs and venlafaxine (446, 447), tricyclic antidepressants, and calcium antagonists (448).
Polydipsia has also been known to occur prior to the introduction
of antipsychotic medications (449).
The approach to psychosis-induced polydipsia is to control
both the psychosis and water intake after excluding possible underlying
medical causes of polydipsia, such as diabetes mellitus, diabetes insipidus,
chronic renal failure, malignancy, pulmonary disease, hypocalcemia,
and hypokalemia. Acute management involves water restriction
and sodium replacement to prevent seizures. Clozapine appears to
be effective, albeit in studies with small sample sizes (450–452).
The second-generation antipsychotics have also been examined for
their role in the long-term management of the condition (453, 454).
Various other medications, including demeclocycline (455, 456),
naltrexone (457), enalapril (458), clonidine (458, 459), and propranolol (460),
have also been used in some case studies.
2. Demographic and psychosocial variables
By current estimates, as many as 800,000 Americans are homeless
on any given night; an estimated one-fourth of these people have
serious mental illnesses, and more than one-half have an alcohol and/or
drug problem (461). Schizophrenia is a risk factor for homelessness,
as is infectious disease, alcohol and other substance use, depression,
and social isolation (462, 463). Comprehensive reviews have suggested
that the rate of schizophrenia in homeless persons has ranged from
2% to 45%. Methodologically superior studies have
produced estimates of 4%–16%, with a
weighted average prevalence of 11% (464). Factors that
have been noted to contribute to the magnitude of homelessness among
patients with schizophrenia include deinstitutionalization (465),
limitations of public funding, problems in service integration,
and lack of low-cost housing (466). Substance use disorders contribute
substantially to homelessness among patients with schizophrenia.
Many housing programs do not accept patients with schizophrenia
who use alcohol or other substances, and treatment for substance
use disorders is often lacking for these individuals (466). In addition,
the illness of schizophrenia may directly predispose persons to
housing difficulties through withdrawal, disorganization, and disruptive
Homeless mentally ill persons are likely to have multiple
impairments. Most lack basic health care, income, and any social
support network. Only slightly more than one-half of the homeless
persons with schizophrenia have been found to be currently receiving
psychiatric treatment (464). Homeless persons with schizophrenia
have been found to have elevated rates of victimization (468) and
to have mortality rates that are three to four times higher than
the expected rate (469). Further, a large study of mentally ill
homeless veterans found that a majority of homeless veterans contacted
through a national outreach program did not receive medical services
within 6 months of program entry (470). Medical treatment is thus
a great challenge for this population.
Given the level of need of this population, services should
include provision of appropriate housing, access to medical services,
treatment of substance use disorders, income support and benefits,
and rehabilitation and employment assistance (466). Such services
must be comprehensive, continuous, accessible, and individualized (467).
A number of controlled studies have demonstrated the effectiveness
of such treatment models for reducing homelessness and improving
psychiatric outcomes (164, 471). The Center for Mental Health Services
conducted a multisite 5-year demonstration program called Access
to Community Care and Effective Services and Supports (ACCESS) to
test the effect of the integration of fragmented services in treating
homeless persons with serious mental illness. This study involved
18 sites in nine states from 1993 to 1998, and treatment outcomes
were studied at both the system and patient levels. All project
sites conducted extensive outreach efforts to engage homeless persons
and provided a comprehensive range of services, including mental
health treatment, medications, substance use disorder treatment
or referral, job placement, housing support, social support, and
primary health care. Patients served in the ACCESS program showed
improved housing stability and reductions in substance use and minor
criminal incidents, as well as increased use of psychiatric outpatient
care, although integration of treatment did not influence these
outcomes. The provision of direct community services and outreach
appeared to be most important.
Clinical care of homeless mentally ill patients involves three
basic stages: 1) engagement, 2) intensive care, and 3) ongoing rehabilitation (472).
In introducing services into the community, psychiatrists must be
prepared to work with homeless patients in nonclinical environments,
including streets, shelters, subways, bus terminals, and other public
spaces. In discussing outreach to homeless patients with schizophrenia,
Goldfinger (467) stressed the importance of engagement. Homeless
patients with schizophrenia are often fearful and distrustful of
the mental health system, and they can require a combination of
patience, persistence, and understanding. Depending on the needs
and wants of a particular patient, the provision of food, clothing,
medical attention, or simply company can be indispensable in developing a
therapeutic relationship. As noted by Goldfinger (467), such provisions
document one's concern, demonstrate one's reliability,
and acknowledge the importance of the needs of the homeless person
with schizophrenia. To engage the homeless person with schizophrenia,
active outreach is usually necessary and is often performed by case
managers. In particular, street outreach to homeless persons with
serious mental illness is justified, as they have been found to
be more severely impaired, to have more basic service needs, to
be less motivated to seek treatment, and to take longer
to engage than those contacted in other settings. The ACCESS program
found that patients engaged from the street showed improvement on
nearly all outcome measures that was equivalent to that of enrolled
patients who were contacted in shelters and other service agencies (473).
Despite appropriate outreach efforts, some homeless persons
with mental illness are so impaired that they remain unable to recognize
their basic needs or avoid personal dangers. One program developed
to address the treatment needs of this population was the Homeless
Emergency Liaison Project (Project HELP), in which a mobile treatment
team arranged for involuntary psychiatric emergency department evaluation
of high-risk homeless patients (474). Involuntary hospitalization
resulted from 93% of such evaluations, and 80% of
all patients received the diagnosis of schizophrenia. At 2-year
follow-up of 298 patients initially evaluated during the project,
only 12% were found to be back living on the streets.
Cultural factors are known to affect the course, diagnosis,
and treatment of schizophrenia (475). There is a robust pattern
of evidence that race has a substantial effect on whether persons
with substantively similar symptoms receive a diagnosis of an affective
disorder or a schizophrenia spectrum psychotic disorder. Compared
with Caucasians, African Americans, especially men, are less likely
to receive a diagnosis of a mood disorder and more likely to receive
a diagnosis of schizophrenia (476–479). African Americans
with schizophrenia are also less likely to receive a diagnosis of
a comorbid affective or anxiety disorder (480, 481). While it is
possible that such differences may reflect actual illness variation
among racial/ethnic groups, there is growing evidence that
cultural differences in symptom and personal presentation, help
seeking, interpretation of symptoms and clinical judgments by (usually
Caucasian) clinicians, and treatment referral are likely causing
race-linked biases in diagnosis and therefore in treatment (e.g.,
see references 482–486). Additional possible causes or
contributors to this pattern of disparity include low levels of
cultural competence among clinicians, unbalanced research samples,
inaccurate or biased pathology assessment tools, and the failure
of researchers to control for socioeconomic status, education, and
urbanicity (487, 488). These remarkably consistent findings suggest
that clinicians should be mindful of the extent to which cultural
factors influence their diagnostic approach.
Once patients receive a diagnosis, substantial data suggest
that race affects the type of pharmacological treatment they receive.
For example, the Schizophrenia Patient Outcomes Research Team (PORT) (65) showed
that among patients for whom psychotropic medications at doses outside
the recommended range were prescribed, patients from racial/ethnic
minority groups (especially African Americans) were much
more likely than Caucasian patients to receive doses above recommended
levels. The same patients were also more likely to receive prophylactic
antiparkinsonian agents, suggesting increased rates of adverse
side effects related to higher doses. Prescription of higher doses
of antipsychotic medications to African American patients has also
been noted in several other reports (489–493).
However, in another PORT study, among patients with schizophrenia
who were also experiencing significant depression, Caucasian patients
were significantly more likely to receive adjunctive medications (494).
In addition, there is growing evidence that racial/ethnic
minority patients with psychotic disorders are less likely than
Caucasian patients to receive second-generation antipsychotics and
more likely to receive long-acting injectable agents (495–498).
Other research suggests that these gaps may be decreasing over time
but are still persistent and may be related to differential prescribing
patterns in private versus managed health care (496, 499).
There is clearly a need for more research to describe and
understand the differences in patterns of treatment by race and
ethnicity. Most of the published research focuses on African Americans; the
needs and treatments of other cultural groups also require attention.
The observed phenomena provide little guidance about whether the
care delivered is appropriate. In the meantime, the strength and
consistency of these findings suggest that clinicians should consider
the extent to which a patient's race and/or ethnicity
are playing a role in the treatment and should ensure that care
is being individualized and optimized.
To some extent, differences in drug dosing or side effect
risk may be related to genetically based differences in drug metabolism.
For example, the activity of the enzyme encoded by the CYP2D6 gene
is very low or absent in 5%–8% of Caucasians
but only 2%–5% of African Americans and Asians.
Low activity of the enzyme encoded by the CYP2D6 gene may dramatically
affect the metabolism of many drugs, increasing serum levels (500).
There is also suggestive evidence that up to one-third of African
Americans possess genetic polymorphisms of other enzymes that metabolize
psychotropic agents, resulting in altered metabolism and potential
for enhanced medication side effects. Ethnic factors may also confer
a susceptibility to medication side effects in certain persons.
For example, patients of Jewish descent have been noted to be at
greater risk for clozapine-induced agranulocytosis than other patients
with schizophrenia (501) and therefore may require close monitoring
during clozapine treatment.
There are numerous gender differences in the presentation
and course of schizophrenia (502–505). Men with schizophrenia
have been noted to have a younger age at onset, a poorer premorbid history,
more negative symptoms, a greater likelihood of having the deficit syndrome (306, 309), and a poorer overall course than women with schizophrenia (503, 506). Compared with men, women are more likely to have affective
symptoms, auditory hallucinations, and persecutory delusions, but
they have a better overall course and better outcomes than men,
as evidenced by better social and occupational functioning,
fewer hospitalizations, and less substance use and antisocial behavior (504, 505, 507). While such differences may be biologically mediated,
psychosocial factors, including family and societal expectations,
may also affect outcome. Haas and colleagues (507) noted that social
and occupational role demands may result in unrealistic family expectations
of men with schizophrenia, and this issue should be dealt with in
There are also gender differences in both response to and
adverse effects of treatments for schizophrenia. Most of this research
has been conducted with first-generation antipsychotic medications. Women
exhibit more rapid responses to antipsychotic medications and a
greater degree of improvement in both first-episode and multi-episode schizophrenia (504).
It has also been observed that even after body weight is considered,
women require lower antipsychotic doses (508, 509) than men, although
there is suggestive evidence that postmenopausal women may require
higher doses (504). Although women may show greater responsivity
to antipsychotics, they also experience more neurological side effects,
including acute dystonia, parkinsonism, akathisia, and tardive dyskinesia (504).
Women also develop higher serum prolactin levels in response to
both first-generation antipsychotics and risperidone, compared with
men (504), and therefore women may be more prone to the sexual side
effects of the medications. Finally, although studies of gender
differences in response to psychosocial treatments are sparse, there
is some evidence to suggest that social skills training may be more
effective for male patients, whereas inpatient family interventions
have shown greater success in families of female patients (504, 505).
Treatment of the pregnant or lactating patient with schizophrenia
must consider two issues: 1) risks of various psychotropic medications
to the fetus, newborn, and breast-fed infant, and 2) adequacy of
prenatal care. A general reference on medications in pregnancy and
lactation is the text by Briggs et al. (510).
Controlled studies of psychotropic drug risks during pregnancy
are, for obvious ethical reasons, not done. Knowledge of the risks
of these agents comes from animal studies and from uncontrolled exposures
in humans. Nonetheless, there is a body of information that can
help guide clinicians' and patients' decision
making about the use of psychotropic agents during pregnancy and
lactation. Risks do vary from drug to drug and from drug class to
drug class. In addition, two periods of high risk to the fetus or
newborn are identifiable: teratogenic risk is highest in the first
trimester, and withdrawal risk is highest at the time of birth.
Only with planned pregnancies is management of first trimester psychotropic
drug exposure under full control of the doctor and patient. Drug
withdrawal risk at the time of parturition may be more predictable
and manageable, depending on the drug(s) involved and the circumstances
There are substantial data on fetal exposure to first-generation
antipsychotic medications, with relatively little evidence of harmful
effects, especially with high-potency agents (511–513).
Much less information is available regarding fetal exposure to second-generation
antipsychotic medications. Koren et al. (514) found that pregnant
women with schizophrenia taking second-generation antipsychotic
medications were frequently obese and had inadequate intake of folic
acid, putting their offspring at increased risk for neural tube
defects. Such an outcome would be an indirect rather than a direct
effect of these medications. A limited number of reports of treatment
with olanzapine during pregnancy and lactation showed that olanzapine
did not appear to increase the risk of harm (515). A case report
of clozapine treatment during pregnancy described development of
gestational diabetes, possibly exacerbated by clozapine, but no
fetal abnormalities (516). Pregnancy can be a period of decreased
symptoms for women with schizophrenia, but relapses are frequent
in the postpartum period (517). Thus, the clinical risks of not
using antipsychotic medications may be somewhat less during pregnancy
but are greater thereafter.
Compared with antipsychotic medications, mood stabilizers
and benzodiazepines are much more closely associated with fetal
malformations and behavioral effects (511, 513, 518). Thus, their
risk/benefit ratio is different, and the need for their
continuation during pregnancy and breast-feeding requires strong
A number of studies have shown that pregnant women with schizophrenia
receive relatively poor prenatal care. These women have more obstetric
complications, and their offspring are more likely to have adverse
outcomes, such as low birth weight and stillbirth (519–522).
There are many contributing factors to the relatively poor prenatal
care and outcomes, such as low socioeconomic status, high rates
of smoking and substance use disorders, and obesity. For the clinician
treating a pregnant woman with schizophrenia, it is particularly
important to insist on early involvement of an obstetrician who
can help reduce the risks of the pregnancy and with whom risks and
benefits of pharmacological treatment options can be discussed.
f) Psychosocial stressors
A variety of psychosocial stressors can precipitate the initial
development or recurrence of symptoms in a vulnerable person (304,
523–526). Stressors include stressful life events (e.g.,
interpersonal loss, leaving home, military service), sociocultural
stress (e.g., poverty, homelessness, fragmented social network),
or a distressing emotional climate (e.g., hostile and critical attitudes
and overprotection by others in one's living situation
or high levels of expressed emotion) (282–289). While schizophrenia
can emerge or worsen in the absence of environmental influences,
attention to stressors frequently helps to prevent relapse and/or
maximize healthy functioning. Sometimes the stress is internal,
and knowledge of developmental vulnerabilities can assist in identifying
and assisting with this variety of stress. Treatment strategies
include preventing the development or accumulation of stressors
and helping the patient develop coping strategies that keep tension
levels within manageable bounds.
g) Schizophrenia in later life
With the overall increase in longevity, the number of older
patients with schizophrenia is expected to increase rapidly over
the next three decades (527). Among middle-aged and elderly persons
with schizophrenia, approximately 80% have early-onset
schizophrenia (528), with the remaining 20% including persons
with late-onset schizophrenia (onset after age 40) and very-late-onset
schizophrenia-like psychosis (onset after age 60) (DSM-IV, 529).
The rate of aging-associated cognitive decline in older patients
with schizophrenia is similar to that in age-comparable normal persons,
although, as with younger patients, they have greater overall cognitive
impairment (530, 531). The approach to the treatment of older persons
with schizophrenia is similar to that of younger patients (532) and
involves combining pharmacotherapies with psychosocial interventions.
Several age-related physiological changes may influence
the approach to pharmacotherapy. These physiological changes
include reduced cardiac output (and concomitant reduction in renal
and hepatic blood flow, relative to younger persons), reduced glomerular
filtration rate, possible reduction in hepatic metabolism, and increased
fat content. These changes may alter the absorption, distribution,
metabolism, and excretion of medications and may result in prolonged
drug effects and greater sensitivity to medications, in terms of
both therapeutic response and side effects (533). Age-related changes
in receptor-site activity may further influence response to drugs
in elderly patients. In general, recommended starting doses in older
patients are one-quarter to one-half of the usual adult starting
dose (529) (see Table 2).
The presence of concomitant medical illness or the use of
multiple medications frequently complicates the treatment of older
patients. In addition, age-related sensory deficits and cognitive impairment
may interfere with patients' adherence to prescribed medication
regimens. Elderly patients may unintentionally take incorrect doses
of medications or follow erroneous dosing schedules.
Several important considerations bear on the use of antipsychotics
in elderly patients. The cumulative annual incidence of tardive
dyskinesia with first-generation antipsychotic medications has been
found to be sixfold higher in later life than in younger adults
(i.e., about 30% in later life) (534). Other side effects
of particular concern in elderly patients include sedation, anticholinergic effects,
and postural hypotension. Second-generation antipsychotics are generally
recommended over first-generation agents because of their significantly
lower risk of inducing extrapyramidal symptoms and tardive dyskinesia
in older persons (534–538). However, the second-generation
agents have other clinically significant and common side effects (Table 4), most notably sedation and orthostatic hypotension. Elderly patients
with low cardiac output are especially vulnerable to hypotension
and cardiac arrhythmia. The anticholinergic side effects of antipsychotic
drugs in the presence of the age-related decrease in cholinergic
function can contribute to problems such as urinary retention,
confusion, and constipation or fecal impaction in the elderly patient.
In some cases, elderly patients who are frail or poorly nourished
may benefit from medication-induced weight gain; however, weight
gain may also aggravate preexisting cardiovascular disease or osteoarthritis
in this population. Elevated prolactin levels may also compromise
bone-mineral density and increase osteoporosis.
Depression is not only common but also functionally disruptive
in older persons with schizophrenia (539). In such instances, an
antidepressant may need to be added to the treatment regimen. A
wide variety of antidepressants are commonly used, although no comprehensive
comparative trials in this population have been published. One small
study found citalopram to be both useful and relatively safe in
older patients with psychosis (540).
Psychosocial treatments are also recommended for a majority
of individuals. Psychosocial evaluation may reveal a precipitating
stress, such as a death in the family or a move to unfamiliar surroundings,
that may explain a sudden change in the elderly person's
behavior. Recent work has evaluated the benefits of integrated cognitive
behavioral and social skills training (CBSST) in groups of older
patients with schizophrenia (541). Results of a small randomized,
controlled pilot study comparing CBSST plus pharmacotherapy to pharmacotherapy
alone demonstrated the feasibility and acceptability by patients
of CBSST and some improvement in psychopathology with CBSST in older
patients with schizophrenia (541). Another pilot study showed the
usefulness of functional adaptation skills training (542) in improving
daily functioning in older patients with schizophrenia.
3. Concurrent general medical conditions
Patients with schizophrenia and related severe and persistent
mental illness suffer disproportionately from a variety of comorbidities,
including cardiovascular disease, respiratory disease, diabetes, infectious
diseases (e.g., HIV), and substance use disorders (including nicotine,
alcohol, and other substances) (543–554). A consequence
of this excess comorbidity is an increased non-suicide-related mortality
rate in this population (34, 388, 555). The increased frequencies
of the various comorbid conditions are determined by multiple factors, including
associations with schizophrenia itself (e.g., diabetes, smoking),
life style (e.g., smoking, substance use, obesity, lack of exercise),
environment (e.g., poverty, institutionalization), and medications
(e.g., extrapyramidal syndromes, tardive dyskinesia, hyperprolactinemia,
weight gain, hyperglycemia, hyperlipidemia, and cardiac arrhythmias).
Thus, treatment selection and clinical management of patients with
schizophrenia must consider the patient's past medical
history and general medical status of the patient in determining
the treatment plan. Patients should be evaluated in terms of their
medical history and baseline assessments and then monitored with
the relevant measures at appropriate intervals or when the patient's
medical condition warrants or when a change in medication that could
affect their medical condition is made, as indicated in Table 1.
In the event that the patient's comorbid medical condition
is affected adversely by a therapeutic agent (including an antipsychotic
drug), management strategies may include helping the patient tolerate
the adverse effect, treating the comorbid condition, or considering
a change in the psychotropic medication to an alternative with less
potential to induce side effects.
Patients with dementia and elderly patients are at very high
risk of tardive dyskinesia. In addition, patients with dementia,
Parkinson's disease, or other disorders associated with
structural brain pathology are at increased risk of worsening of
extrapyramidal side effects. Similarly, patients with psychosis
and mental retardation are at increased risk for extrapyramidal
side effects and tardive dyskinesia (556, 557). Thus, in these groups
of patients, second-generation antipsychotics and particularly those
with minimal or no risk of extrapyramidal effects (e.g., quetiapine)
are recommended (558, 559). Furthermore, when such patients are
treated with antipsychotic drugs, they must be monitored for side
effects, and the increased risk of extrapyramidal side effects and
tardive dyskinesia must be weighed against potential therapeutic
For patients with preexisting osteopenia or osteoporosis,
an antipsychotic with minimal to no effects on prolactin should
be prescribed. If a drug that increases prolactin is clinically
indicated, then the relative safety of the antipsychotic should
be discussed with the physician treating the bone demineralization.
Female patients with menstrual or fertility problems should be evaluated
for abnormalities in prolactin secretion, and non-prolactin-elevating
medications should be considered as indicated. In addition, for
women with breast cancer, antipsychotics with prolactin-elevating
effects should be avoided or prescribed only after consultation
with the patient's oncologist. In such instances, aripiprazole,
which partially suppresses prolactin release, may be specifically
indicated. However, in lactating mothers, suppression of prolactin
may be detrimental, and the potential for this effect should be
Obese patients and patients who have or may be at risk for
diabetes and cardiovascular disease should be assessed before beginning
treatment with antipsychotic drugs. Additional assessments are indicated
at appropriate intervals thereafter or when warranted by a change
in the patient's medical condition or medication regimen
(see Table 1). Treatment selection should weigh the expected benefits
of antipsychotic therapy against its potential to exacerbate
or contribute to the development of specific medical conditions.
Patients with prolonged QT syndrome, bradycardia, certain
electrolyte disturbances, heart failure, or recent myocardial infarction
and patients who are taking drugs that prolong the QT interval should not
be treated with an antipsychotic that could further prolong the
QT interval or increase the risk of the arrhythmia torsades de pointes.
These antipsychotics include thioridazine, droperidol, and ziprasidone.
Pimozide also may prolong the QT interval.
Medications with low affinity for -adrenergic receptors
should be prescribed for patients who are vulnerable
to orthostatic hypotension, including elderly patients, patients
with peripheral vascular disease or compromised cardiovascular status,
and other severely debilitated patients.
For patients with acute angle-closure glaucoma, severe constipation
(or at risk for fecal obstruction), history of a paralytic ileus,
urinary retention, prostate hypertrophy, or delirium/dementia, antipsychotics
with little or no antagonism for cholinergic receptors should be
Patients with severe dementia may be at increased risk of
stroke when treated with risperidone. Clinicians treating psychosis
in patients with dementia should refer to up-to-date FDA guidelines
when considering the safety of risperidone in this population.
Clozapine should not be prescribed for patients with neutropenia
(<1500/mm3) or low white
blood cell (WBC) count (<3000/mm3)
or a history of such sensitivities to prior medications.