Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment

Authors
T. Scott Stroup, MD, MPH
Stephen Marder, MD
Section Editor
Murray B Stein, MD, MPH
Deputy Editor
Richard Hermann, MD
Disclosures: T. Scott Stroup, MD, MPH Research/Grant Support: Auspex [Tardive dyskinesia
(Dutetrabenazine)]. Other Financial Interest: Genentech [Schizophrenia (Bitopertin)]. Stephen
Marder, MD Grant/Research/Clinical Trial Support: Sunovion [Psychosis (Lurasidone)].
Consultant/Advisory Boards: Otsuka [Psychosis (Aripiprazole, brexpiprazole)]; Lundbeck
[Psychosis (Aripiprazole, brexpiprazole]; Pfizer [Psychosis (Ziprasidone)]. Murray B Stein, MD,
MPH Grant/Research/Clinical Trial Support: Janssen [social anxiety disorder].
Consultant/Advisory Boards: Janssen [anxiety and traumatic stress]; Tonix [anxiety and
traumatic stress]; Pfizer [anxiety and traumatic stress]. Richard Hermann, MD Nothing to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements
for references to be provided to support the content. Appropriately referenced content is required
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Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2015. | This topic last updated: Sep 26, 2014.
INTRODUCTION Schizophrenia is a psychiatric disorder involving chronic or recurrent
psychosis. It is commonly associated with impairments in social and occupational functioning
[1]. It is among the most disabling and economically catastrophic medical disorders, ranked by
the World Health Organization as one of the top ten illnesses contributing to the global burden of
disease [2].
Antipsychotic medications are first-line medication treatment for schizophrenia. They have been
shown in clinical trials to be effective in treating symptoms and behaviors associated with the
disorder. Antipsychotic medications have significant side effects; assessment and management of

these adverse effects are an important part of treatment. Evidence-based psychosocial

interventions in conjunction with pharmacotherapy can help patients achieve recovery.
This topic addresses the pharmacotherapy of schizophrenia in acute and maintenance phase
treatment. Discussed separately are the use of long-acting antipsychotics and management of
side effects during pharmacotherapy for schizophrenia; the epidemiology, pathogenesis, clinical
manifestations, and diagnosis of schizophrenia; psychosocial interventions for schizophrenia;
and common comorbid presentations of schizophrenia. (See "Pharmacotherapy for
schizophrenia: Long-acting injectable antipsychotic drugs" and "Pharmacotherapy for
schizophrenia: Side effect management" and "Schizophrenia: Epidemiology and
pathogenesis" and "Schizophrenia: Clinical manifestations, course, assessment, and
diagnosis" and "Psychosocial interventions for schizophrenia" and "Anxiety in
schizophrenia" and "Depression in schizophrenia" and "Co-occurring schizophrenia and
substance use disorder: Epidemiology, pathogenesis, clinical manifestations, and
diagnosis" and "Guidelines for prescribing clozapine in schizophrenia".)
ACUTE PHASE The focus of treatment in schizophrenia changes as individuals enter
different phases of the illness. An acute phase occurs when patients with a prior history of
schizophrenia have a psychotic relapse, or during the first episode of psychosis. At this time, the
focus is on reducing the severity of psychotic thoughts and behaviors. (See "Schizophrenia:
Clinical manifestations, course, assessment, and diagnosis", section on 'Clinical manifestations'.)
Pre-treatment assessment When feasible, patients who are started on an antipsychotic
medication should receive a baseline physical examination with a neurological exam. Particular
attention should be focused on factors that may be affected adversely by antipsychotic
medication: (See "Pharmacotherapy for schizophrenia: Side effect management".)
Body mass index (BMI)
Waist circumference
Heart rate
Blood pressure
Signs of a movement disorder:
Extrapyramidal symptoms (EPS): akathisia, parkinsonism, dystonias
Tardive dyskinesia: abnormal movements of the face, peri-oral areas, tongue, extremities
When feasible, laboratory evaluations should be initiated before starting an antipsychotic. With
the exception of patients treated with clozapine, the antipsychotic can usually be started before
the results of laboratory tests are available.

CBC, electrolytes, fasting glucose, lipid profile, liver, renal and thyroid function tests
White blood cell (WBC) count with differential for patients treated with clozapine
ECG for patients with a cardiac history or those being treated with antipsychotics that may
prolong the QT interval such as clozapine, thioridazine, iloperidone,ziprasidone.
Antipsychotic drug efficacy and selection Antipsychotic drugs are first-line treatment for
schizophrenia. Randomized trials have shown that antipsychotics reduce positive symptoms of
schizophrenia, such as hallucinations, delusions, and suspiciousness, compared to placebo [3].
Antipsychotics eliminate or reduce these symptoms to a tolerable level in about 70 percent of
patients with schizophrenia [4].
With the exception of clozapine, careful systematic reviews and meta-analyses have not found
convincing evidence that any of the antipsychotics are more effective than any other for acute
schizophrenia [5]. Clozapine is more effective for patients who do not respond fully to other
antipsychotics, but due to increased risk of agranulocytosis is reserved for those who do not
respond well to or cannot tolerate other antipsychotics. (See 'Treatment-resistant
schizophrenia' below.)
There are important differences among the antipsychotics in areas other than efficacy, including
side effects and available formulations (table 1 and table 2). As a result, the selection of an
antipsychotic is often based on these considerations. The selection may vary for select
populations including individuals in a first psychotic episode, individuals who are only partial
responders to antipsychotics, patients who are agitated, and individuals who are sensitive to
particular side effects such as weight gain, EPS, or sedation. (See 'Initial management of
refractory symptoms' below and 'Managing first episodes' below and 'Management of
agitation' below and"Pharmacotherapy for schizophrenia: Side effect management".)
Antipsychotic drug categories Antipsychotic medications are commonly grouped into two
categories, with second-generation (or atypical) applied toclozapine and all antipsychotics
first marketed after clozapine was approved in 1989, and first-generation applied to
antipsychotics marketed previously. Recent clinical research, however, has strongly suggested
that the distinction between first- and second-generation antipsychotics has questionable validity
and is confusing [5]. The pharmacologic properties, therapeutic effects, and adverse effects are
not distinct between and are heterogeneous within the groups. Nevertheless, the terms first- and
second-generation antipsychotic are still in widespread use. A valid distinction is that the newer
(second-generation) antipsychotics tend to cause fewer extrapyramidal side effects than the older
ones, particularly at the high end of approved dosage ranges.
Administration The dose of most antipsychotic drugs should be titrated from an initial dose to
the therapeutic range as quickly as tolerated. Quetiapine, clozapine, and iloperidone need to be
increased gradually before reaching a therapeutic dose. The timeframe for titration differs for

each drug and also depends on the individual patients tolerance of the drugs tendency to cause
sedation and hypotension. In most cases, patients can reach a therapeutic level in five or six days
with quetiapine and iloperidone, and two to three weeks with clozapine. Suggested dosing and
side effect profiles for each antipsychotic drug are shown in tables (table 1 and table 2).
Because identifying the appropriate dose range can be difficult in the pre-marketing phases of
drug development, the antipsychotic doses listed (table 2) deviate somewhat from those
approved by the US Food and Drug Administration, reflecting more recent research findings or
clinical experience. Examples include:
Haloperidol is effective and most useful at doses drastically below the FDA-specified
maximum of 100 mg/day. Optimal haloperidol dosages are usually below 10mg/day and almost
always below 20 mg/day.
Optimal dosages of risperidone are lower than the approved 16 mg/day; typically, a maximum
dose for risperidone is 6 to 8 mg/day.
Resolution of psychotic symptoms generally occurs over several days and may take as much as
four to six weeks. Clinicians should avoid the impulse to change the medication or dose
prematurely. Once the dose reaches the therapeutic range, the decision to increase the dose
should follow at least several days of treatment during which the individual shows little or no
improvement. Higher dosing should be accompanied by careful observation of the patient for
side effects. If patients fail to show improvement on doses above the usual therapeutic range, the
dose should be reduced.
As an example, a patient treated with risperidone can be started on 2 mg administered as a single
daily dose or 1 mg twice a day. If this dose is well tolerated (ie, minimal sedation, hypotension,
or akathisia) the dose can be increased to 3 mg on the second day and 4 mg on the third day.
Since 4 mg is in the therapeutic range for most patients, the clinician may then choose to
continue this dose for an additional two weeks before considering an increase. If the patient
shows only minimal or no improvement, the dose can be increased up to 8 mg daily with careful
monitoring for clinical response and side effects. Doses of risperidone above 8 mg daily are
associated with substantial risk of EPS.
Because of dose-related toxicities, antipsychotics should be used at the lowest dose that is
effective for an individual. The toxicities of antipsychotic drugs typically increase with higher
doses while therapeutic effects can reach a maximum. At high doses, the adverse effects of an
antipsychotic may surpass the marginal benefit of dosage increases. As a result, increasing the
dose of antipsychotic for a patient who is already experiencing significant EPS is unlikely to
result in additional symptom reduction [6-8].
Course of response When a patient with schizophrenia is administered an antipsychotic
medication, the initial response is often a side effect such as sedation, restlessness, or postural

hypotension. It is important to explain this to patients, or they may conclude that the medication
is ineffective or worsening their condition. Most patients who will improve on an antipsychotic
show the most rapid improvement in the first two weeks [9]. Although the rate of improvement
may slow after two weeks, patients will often continue to improve during subsequent weeks and
months.
During the first weeks of treatment, patients may first experience a decrease in the severity of
symptoms. As a result, the impact of symptoms on patient behavior may be reduced [10].
Hallucinations or delusions may be less frightening or the patient may find that they can distract
themselves by focusing their attention elsewhere [11]. Delusions that are based on
misinterpretations from an earlier time may linger, whereas the tendency to misinterpret new
information may be reduced.
INITIAL MANAGEMENT OF REFRACTORY SYMPTOMS Patients should be observed on
a stable dose of an antipsychotic for two to six weeks before concluding the drug is ineffective.
The duration of the trial will vary depending on a number of factors:
Although patients improve most rapidly during the first two weeks, they may continue to
improve for several weeks or even months on a stable dose [9].
However, recent evidence suggests that if patients show only a minimal response to an
antipsychotic drug during the first two weeks, it is unlikely that the individual will have a robust
response [12]. The 2009 Schizophrenia PORT recommends that trials last for two to six weeks.
This timeframe will be slightly longer for antipsychotics such as iloperidone and quetiapine,
which require slow titration.
Dose adjustments In cases of nonresponse or partial response, the antipsychotic dose can be
gradually increased toward the high end of the recommended range (table 2).
Most careful studies of doses above the recommended range have not found higher doses to be
more effective than the maximal recommended dose [13,14]. If used, trials of higher doses
should be time limited, with reassessment planned within three months. Unless clear evidence of
improvement is seen, high doses should not be continued [15].
A dose reduction can be helpful in cases where side effects, such as akathisia, parkinsonism,
sedation, or insomnia have obscured the benefit of a higher antipsychotic dose, or have been
mistaken for signs of ineffective treatment, such as agitation or negative symptoms.
Changing to another antipsychotic Switching antipsychotics can be helpful when a poor
response is related to side effects. As an example, in the large US effectiveness study of
antipsychotic treatment for schizophrenia, the Clinical Antipsychotic Trials in Intervention
Effectiveness (CATIE), patients who gained weight during the first phase of antipsychotic

treatment frequently lost weight when they were changed to ziprasidone, an antipsychotic that is
not associated with weight gain [16].
Switching antipsychotics is less clearly beneficial when the initial medication lacked
effectiveness. Most studies have shown that poor responders to one antipsychotic are likely to be
poor responders to another antipsychotic except when the second agent is clozapine.
(See 'Treatment-resistant schizophrenia' below.)
As an example, an analysis of patients who were on olanzapine, quetiapine, or risperidone prior
to the CATIE trial showed that the patients on olanzapine or risperidone who were randomly
assigned to continue the same antipsychotic had better outcomes than patients who were
randomly assigned to change antipsychotics [17]. (See'Administration' below.)
Administration Two basic strategies for changing antipsychotics are [18,19]:
A standard cross-titration for a stable patient: Simultaneous taper of the current medication with
titration of the replacement drug in three to four steps over several days to several weeks.
For patients at higher risk of relapse, the current medication is maintained at its full dose as the
new medication is increased. Once the second drug has reached its target dose, the first
medication may be gradually decreased and discontinued. In most cases this change can be
managed in one to two weeks.
Discontinuation of antipsychotic medications is generally well tolerated, except for clozapine,
for which both cholinergic rebound and withdrawal-emergent movement disorders have been
reported [20-22]. A slow taper of clozapine over one to two weeks is
recommended. Chlorpromazine and thioridazine can also cause cholinergic rebound and should
be reduced over a week or more.
Adding a second antipsychotic Clinicians often add a second antipsychotic when patients
have a suboptimal response to a single drug. Little empirical evidence supports this practice [23].
Although some randomized trials indicated that augmentation of clozapine with another
antipsychotic may have some benefit, a meta-analysis of this practice found the supporting
evidence to be weak [24].
TREATMENT-RESISTANT SCHIZOPHRENIA Patients with schizophrenia who respond
inadequately to an initial antipsychotic, dose adjustments, or a change in antipsychotics are
classified as having treatment-resistant schizophrenia. The efficacy of interventions for
treatment-resistant schizophrenia, including clozapine, is discussed separately. Guidelines for
clozapine prescribing, dosing, monitoring, and side-effect management are described separately.
(See "Treatment-resistant schizophrenia" and "Guidelines for prescribing clozapine in
schizophrenia".)

CLOZAPINE FOR SUICIDALITY IN SCHIZOPHRENIA Clozapine has been shown in

randomized trials to reduce suicide attempts in patients with schizophrenia and schizoaffective
disorder at high risk for suicide [25]. A patient with schizophrenia who has persistent suicidal
ideation warranting clinician concern may benefit from a trial of clozapine. Guidelines for
clozapine prescribing, dosing, monitoring, and side-effect management are described separately.
Management of suicidal patients is described separately. (See "Guidelines for prescribing
clozapine in schizophrenia" and "Suicidal ideation and behavior in adults".)
MANAGEMENT OF AGITATION Clinical management of the acutely agitated patient with
schizophrenia is a common objective on inpatient units and other settings. Agitation can be
defined as a state characterized by motor restlessness, excitement, and mental tension.
Causes Treatment of agitation in patients with schizophrenia should be guided by the cause,
which can include extrapyramidal symptoms (EPS), substance use, or psychosis.
Extrapyramidal symptoms Akathisia can be difficult to distinguish from psychotic agitation
when patients are unable to describe the experience of restlessness [26]. Akathisia can be treated
with a benzodiazepine; eg, lorazepam can be started at 0.5 mg orally twice daily and
incrementally increased to a maximum of 6 to 10mg/day.
Substance use Up to half of individuals with schizophrenia have a comorbid substance use
disorder [27]. Use of stimulants such as phencyclidine (PCP), methamphetamine, and cocaine
can cause agitation, as can withdrawal from alcohol or benzodiazepines. Agitation from
substance use or withdrawal can be diagnosed by a history, physical exam, and toxicology.
(See 'Pharmacotherapy for comorbid disorders' below and "Co-occurring schizophrenia and
substance use disorder: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
Psychosis Psychotic symptoms of schizophrenia, such as frightening delusions,
suspiciousness, and command hallucinations can cause patients to become agitated. The agitation
associated with psychosis can be treated with an antipsychotic or an antipsychotic combined with
a benzodiazepine. The selection of a drug and the route of administration depend on a number of
considerations including the urgency of calming the patient and the cooperativeness of the
patient [28]. As noted below, the choice of an antipsychotic depends on the formulation selected.
It is important to note that the treatment goal is to induce a calmer state, which can often be
accomplished without inducing sedation.
Treatment Although antipsychotic medications can take days to weeks before having a robust
antipsychotic effect, they generally have a calming effect within minutes for agitated patients.
The route of administration influences time to onset, as described below (table 3). (See "Firstgeneration antipsychotic medications: Pharmacology, administration, and comparative side
effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and
comparative side effects".)

Standard oral formulations: Although many clinicians tend to favor sedating antipsychotics for
agitated patients, non-sedating agents can also be effective for reducing agitation. Risperidone 1
to 2 mg or olanzapine 5 to 10 mg will usually be effective in these circumstances.
Oral rapidly dissolving formulations: Oral rapidly dissolving formulations are available
for risperidone, olanzapine, asenapine, and aripiprazole. These formulations are helpful when a
patient is willing to take a pill by mouth, but either cannot or does not swallow it. Dosing for
these formulations is the same as for standard oral formulations, eg, risperidone 1 to 2 mg or
olanzapine 5 to 10 mg.
Short-acting intramuscular (IM) injectable formulations
(eg, haloperidol, olanzapine, aripiprazole, and ziprasidone): Olanzapine 5 or 10 mg administered
intramuscularly is a good choice under most circumstances. IM haloperidol is effective but
should be given with benztropine or diphenhydramine to reduce the risk of severe EPS including
dystonias.
A combination of haloperidol 5 mg, lorazepam 2 mg, and benztropine 1 mg given
intramuscularly can be effective to treat severe agitation in schizophrenia.
We advise against the use of IM chlorpromazine, which can induce severe postural hypotension.
Akathisia from any IM antipsychotic can contribute to agitation.
Injectable IM antipsychotics have two potential advantages over oral antipsychotics. First, they
can be administered safely to uncooperative individuals. Second, patients reach an effective
plasma concentration sooner than with oral formulations. For example, patients may experience a
calming effect within 10 to 30 minutes following IM administration. Calming effects may take
30 to 60 minutes following oral administration.
Although repeat administration of an oral or intramuscular antipsychotic is common when the
prior dose does not sufficiently reduce agitation, the overall antipsychotic dose should be limited,
because these medications can cause significant side effects such as hypotension, EPS, and
sedation, particularly at high doses over a brief period of time [9]. Maximum antipsychotic doses
are shown in a table (table 3).
To limit the amount of antipsychotic used, most physicians either start with a combination of an
antipsychotic and benzodiazepine or use a benzodiazepine when patients fail to respond to one or
two doses of an antipsychotic for agitation. Lorazepam can be administered as 1 to 2 mg orally
or 0.5 to 1 mg intramuscularly for calming.
MANAGING FIRST EPISODES Patients in a first psychotic episode tend to have higher
response rates than patients who have experienced multiple psychotic episodes. These
individuals also respond to lower antipsychotic doses [29]. At the same time, younger patients
and first episode patients have a greater vulnerability to side effects such as weight gain and

extrapyramidal side effects (EPS) [30]. Since many first episode patients are also reluctant to
take an antipsychotic, it is important to minimize adverse effects.
The Schizophrenia Patient Outcomes Research Team (PORT) recommended treating first
episodes with antipsychotics other than clozapine or olanzapine. Both of these medications are
associated with more weight gain, insulin resistance and dyslipidemia than other antipsychotics
[3]. In addition, clozapine can cause agranulocytosis.
The Schizophrenia PORT recommended that first-episode patients receive antipsychotic doses in
the lower half of the recommended dose range [3]. As examples, a first-episode patient would be
treated with 1 to 3 mg of risperidone or 10 mg of aripiprazole daily. An exception to this
recommendation should be made for quetiapine, which may require titration to 500 to 600 mg
daily.
MAINTENANCE TREATMENT Patients with schizophrenia who have recovered from an
acute psychotic episode will usually reach a stable or maintenance phase in which psychotic
symptoms are reasonably well controlled. The goal of maintenance antipsychotic treatment of
schizophrenia is to minimize symptoms and functional impairments, avoid relapses, and promote
recovery that allows self-determination, full integration into society, and pursuit of personal
goals.
Efficacy For patients with schizophrenia who have recovered from an acute psychotic
episode, we suggest that antipsychotic medication should be continued indefinitely, even for
patients who have achieved remission from a first psychotic episode. This suggestion is in
accordance with the recommendation of the Schizophrenia PORT [3]. The lowest effective dose
that achieves therapeutic goals should be used. Patients should participate in the clinical
decision-making regarding the duration of antipsychotic drug treatment.
Multiple randomized trials have found that maintenance antipsychotic medication reduces the
risk of relapse over a period of up to two years. A meta-analysis of 6493 patients with
schizophrenia in 65 randomized trials of 7 to 12 months duration found that patients who
continued on an antipsychotic experienced a lower relapse rate compared to patients withdrawn
from an antipsychotic and receiving placebo (27 versus 64 percent; number needed to treat to
benefit = 3, 95% CI 23) [31]. Other studies of up to two years have found similar results [32].
A seven-year follow-up assessment of patients randomly assigned to either a dose reduction
strategy or to maintenance antipsychotic treatment found results that conflict with the studies of
up to two years. Two reports that follow describe an intervention and follow-up assessment of
patients who experienced a first episode of psychosis and subsequently met criteria for remission
prior to enrollment in the trial [33,34].
The initial trial randomly assigned 128 patients to continue maintenance treatment or to a dose
reduction strategy [33]. After two years, patients assigned to the dose reduction strategy had a

higher rate of relapse, without offsetting advantages, compared to patients continuing on

maintenance treatment.
A subsequent assessment at seven years follow-up included 103 of the 128 patients (81 percent)
who participated in the trial [34]. Patients who had originally been assigned to the dose reduction
strategy experienced a higher rate of recovery (ie, symptomatic and functional remission)
compared to patients originally assigned to maintenance treatment.
More studies of longer term outcomes of maintenance treatment versus dose reduction are
needed before we would suggest an approach other than indefinite continuation of maintenance
treatment for patients with schizophrenia following an acute episode of psychosis.
As these trials demonstrate, some people with schizophrenia do well without continuous
antipsychotic treatment; however, they are not identifiable prospectively [35].
Other considerations regarding selection of antipsychotic medication for maintenance treatment
mirror those for pharmacotherapy during the acute phase. (See'Antipsychotic drug efficacy and
selection' above.)
Medication adherence Long-acting injectable antipsychotics may be useful for patients with
schizophrenia who experience frequent relapses due to non-adherence to antipsychotic
medications. They also may be helpful for patients who will not take oral antipsychotics
regularly. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic
drugs".)
Other strategies to promote better adherence to antipsychotics include simplifying medication
regimens (eg, fewer medications, fewer pills, fewer daily doses) and active engagement of
patients in treatment planning (ie, shared decision making).
Treatment of cognitive impairment Improving cognitive impairment has increasingly become
an objective of treatment for schizophrenia. Preliminary studies suggest that antipsychotic
medication may improve cognition when received early in the course of schizophrenia [36,37].
Studies of patients with chronic schizophrenia have generally found less improvement in
cognition during antipsychotic treatment [37-40]. Trials of other medications (including nmethyl-d-aspartate (NMDA) glutamatergic receptor agonists, glycine, D-serine, ampakine
CX516, D-cycloserine, donepezil, rivastigmine, and galantamine) have failed to show significant
benefit [41-49].
Pharmacotherapy for comorbid disorders Depressive disorders and anxiety disorders can be
challenging to diagnose in patients with schizophrenia. A primary comorbid disorder needs to be
distinguished from symptoms of schizophrenia, antipsychotic drug side effects, and other clinical
presentations. Properly diagnosed, however, these syndromes can respond to antidepressant and

anxiolytic medications [50]. (See "Depression in schizophrenia" and "Anxiety in

schizophrenia".)
Substance abuse and dependence occur at a high prevalence in schizophrenia [51]. The
combination of a severe mental illness and a substance use disorder (SUD), commonly described
as dual diagnosis, is associated with increased morbidity, poorer functioning, decreased
adherence to medication, and higher rates of relapse compared to either disorder individually
[52]. Integrated treatment strategies for dual diagnosis that include pharmacotherapy have been
developed for individuals with schizophrenia and SUDs. (See "Co-occurring schizophrenia and
substance use disorder: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
The Basics and Beyond the Basics. The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
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are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Schizophrenia (The Basics)")
SUMMARY AND RECOMMENDATIONS
Patients treated with an antipsychotic for schizophrenia should be assessed prior to treatment if
possible and at regular intervals for: (See 'Pre-treatment assessment' above.)
Signs of a movement disorder including extrapyramidal symptoms and tardive dyskinesia
Symptoms of metabolic syndrome including measurements of body mass index, waist
circumference, hemoglobin A1c, serum lipids, and blood pressure
ECG for patients with a history of cardiac disease or when starting an antipsychotic that
prolongs the QT interval
We recommend antipsychotic medication as first-line medication treatment for acute and
maintenance phase treatment for schizophrenia (Grade 1A). (See'Antipsychotic drug efficacy and
selection' above.)
For patients with schizophrenia who have recovered from an acute psychotic episode, we
suggest that antipsychotic medication should be continued indefinitely at the lowest effective

dose that achieves therapeutic goals (Grade 2C). This approach is suggested even for patients
who have achieved remission from a first psychotic episode. (See 'Maintenance
treatment' above.)
The selection of which antipsychotic medication to use for an individual patient with
schizophrenia should be made based on patient clinical factors and the side effect profiles of
antipsychotic drugs. With the exception of clozapine for patients with refractory symptoms, there
is not convincing evidence to favor one antipsychotic over the others based on efficacy.
(See 'Antipsychotic drug efficacy and selection' above.)
Because olanzapine is associated with significant weight gain and metabolic adverse effects,
leading guidelines state that it should not be used as a first-line agent for first-episode patients,
but should be considered for patients who fail treatment with a first-line agent.
Other strategies for the patient with schizophrenia who has not adequately responded to an
antipsychotic drug include:
Changing to another antipsychotic has been shown to be an effective strategy for addressing
side effect problems but is not clearly associated with improved efficacy, with the exception
of clozapine. (See 'Changing to another antipsychotic' above.)
Clozapine. (See "Treatment-resistant schizophrenia", section on 'Clozapine' and "Guidelines for
prescribing clozapine in schizophrenia".)
Adding a second antipsychotic medication has not been proven efficacious in randomized trials.
For patients with psychotic symptoms that do not respond to two trials of antipsychotic
monotherapy, a trial of clozapine is strongly recommended before combining two antipsychotics.
(See 'Adding a second antipsychotic' above.)
Hospitalized patients with schizophrenia may require treatment for agitation. If agitation is
associated with psychotic symptoms of schizophrenia, it can be treated with a standard oral
formulation, rapid dissolving, or intramuscularly injected antipsychotic, depending on the level
of patient participation. Other causes of agitation should be ruled out, including akathisia and
substance abuse or withdrawal. (See 'Management of agitation' above.)
Long-acting injectable (LAI) antipsychotic medication may be useful for patients with
schizophrenia when non-adherence to oral antipsychotics leads to frequent relapse. LAI
antipsychotics are administered at two to four week intervals. As an
example, fluphenazine decanoate can be administered at a dose between 6.25 to 50 mg
intramuscularly every two weeks. Extrapyramidal symptoms can be prominent at higher doses.
(See 'Medication adherence' above and "Pharmacotherapy for schizophrenia: Long-acting
injectable antipsychotic drugs".)
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