Schizophrenia in adults: Maintenance therapy and

side effect management

INTRODUCTION Schizophrenia is a psychiatric disorder characterized by symptoms

of 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 among the
top 10 causes of years lost to disability worldwide for both males and females [2].

Antipsychotic medications are the 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. However, 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 the maintenance phase of

treatment and the management of side effects of medication. Epidemiology,
pathogenesis, clinical manifestations, and diagnosis are discussed separately. First-
generation antipsychotics, second-generation antipsychotics, long-acting injectable
antipsychotics, and psychosocial interventions for schizophrenia are discussed
separately.

●(See "Schizophrenia in adults: Epidemiology and pathogenesis".)

●(See "Schizophrenia in adults: Clinical features, assessment, and diagnosis".)
●(See "Schizophrenia in adults: Pharmacotherapy with long-acting injectable
antipsychotic medication".)
●(See "First-generation antipsychotic medications: Pharmacology, administration,
and comparative side effects".)
●(See "Second-generation antipsychotic medications: Pharmacology,
administration, and side effects".)
●(See "Schizophrenia in adults: Psychosocial management".)
●(See "Schizophrenia in adults: Guidelines for prescribing clozapine".)
●(See "Co-occurring schizophrenia and substance use disorder: Epidemiology,
pathogenesis, clinical manifestations, course, assessment and diagnosis".)

GENERAL PRINCIPLES

Objectives of treatment — The goal of maintenance treatment of schizophrenia is to

minimize symptoms and functional impairments, minimize side effects of
pharmacotherapy, avoid relapses, and promote recovery that allows self-determination,
full integration into society, and pursuit of personal goals. (See 'Psychosocial
treatments' below and "Schizophrenia in adults: Psychosocial
management" and 'Medication adjustments' below.)
Multidisciplinary care — We recommend a multidisciplinary approach to maintenance
treatment of patients who have recovered from an acute psychotic episode of
schizophrenia. Comprehensive programs provide individualized treatment plans
including pharmacotherapy, case management, family intervention, and other
community outreach services.
Treatment programs offering multidisciplinary interventions have been associated with
lower rehospitalization rates, lower core illness symptoms, and improved interpersonal
and everyday living skills in patients recovering from a first episode of psychosis [3]. As
an example, a clinical trial randomized 34 community mental health centers in 21 states
in the United States to offer people with newly diagnosed, nonaffective psychosis either
standard care (181 patients) or a program of intensive treatment (computerized,
algorithm-assisted medication management; family psychoeducation; resiliency-focused
individual psychotherapy; and supported education/employment; 223 patients) [4]. After
two years, subjects receiving the intensive intervention had greater improvement in
quality of life, more involvement in school/work, and less psychopathology than the
subjects in the standard care group. In this study, rates of hospitalization did not differ
between groups.
Limited availability of these programs is the main barrier to broad implementation.
(See 'Psychosocial treatments' below.)
Patient education — Patient education is the first step in effective maintenance
treatment of patients with antipsychotic medication. To promote adherence to
medication regimens, we recommend educating all patients treated with antipsychotics
about their side effects (eg, extrapyramidal symptoms, tardive dyskinesia, sedation, dry
mouth) and the increased risk of recurrence of symptoms due to premature
discontinuation of medications.

Patient education is important because some patients may view side effects as a sign that
the medication is not working or is worsening their symptoms. Anticipation of side effects
may prevent patients from unilaterally discontinuing their medication.

ANTIPSYCHOTIC THERAPY

Initial management of acute psychosis — Initial management of schizophrenia

involves the treatment and stabilization of acute psychosis. Selection and dosing of
antipsychotic therapy in the acute setting is discussed in detail elsewhere.
(See "Psychosis in adults: Initial management", section on 'Initial management'.)
Medication adjustments
Patient-specific considerations
Full response to pharmacologic therapy — If a patient has fully responded (ie, no
longer has clinically significant psychosis) to the antipsychotic initiated for an acute
psychotic episode, we continue that medication. We use the lowest effective dose.
Duration of antipsychotic therapy is discussed elsewhere. (See 'Duration of antipsychotic
therapy' below.)
Partial response or recurrence of symptoms — Some patients, despite having
symptomatic improvement with antipsychotic treatment, have persistent residual
symptoms (eg, incomplete or partial response). Other patients have full response to
antipsychotic treatment but have intermittent symptom recurrence. If the symptoms are
bothersome to the patient or impair functioning, we consider the treatment response
suboptimal.
Our first step in patients with incomplete response or intermittent symptom recurrence
is to assess medication adherence (see 'Nonadherence'below). For those with confirmed
adherence, next steps depend on whether the antipsychotic dose is within therapeutic
range.
●In patients who have been treated with subtherapeutic doses, we increase their
dose until either the patient responds, therapeutic range is reached, or side effects
limit further increases (table 1). (See 'Side effect management' below
and "Psychosis in adults: Initial management", section on 'Administration'.)
●In patients who have incomplete response or recurrent symptoms despite the
medication being in the therapeutic range for an adequate time period (ie, six
weeks), data informing the optimal approach are very limited [5]. If the symptoms
are bothersome to the patient, we generally suggest switching the medication.
•For individuals who have only tried one or two other standard antipsychotic
agents (ie, not clozapine) in the past, we try a different standard antipsychotic.
There are no specific agents that are preferred. As with initial selection of
antipsychotic therapy, the choice depends on medication side effects, the
patient's comorbidities, history of adherence, and patient preferences.
Additionally, if the patient has had a good response to a particular agent in the
past, that would be a reasonable choice to try again. Selection of antipsychotic
therapy and changing medications are discussed in detail elsewhere.
(See 'Implementation of medication changes' below and "Psychosis in adults:
Initial management", section on 'Selection'.)
•For individuals who have chronic symptoms that have not fully remitted
despite two or more prior medication trials with standard antipsychotic agents
and who are bothered by these symptoms or who have functional impairment,
we consider them to have treatment-resistant schizophrenia and evaluate them
for clozapine eligibility. Management of treatment-resistant patients is
discussed in detail elsewhere. (See 'Treatment-resistant schizophrenia' below.)
We generally do not recommend doses above the therapeutic range. Most studies of
antipsychotics dosed above the recommended range have found no clear benefit [6]. If
used, trials of higher doses should be limited to three months unless there is clear
evidence of benefit. (See "Psychosis in adults: Initial management", section on
'Administration'.)
We typically do not add a second antipsychotic agent in patients who have suboptimal
response because little empirical evidence supports this practice [7,8]. Although a
national cohort study of over 62,000 patients with schizophrenia in Finland suggested
that combination antipsychotic therapy was associated with a lower risk of hospitalization
compared with monotherapy overall, the only specific oral combination therapy that was
clearly associated with better outcomes than its separate components
was clozapine plus aripiprazole [8]. Thus, we generally reserve combining antipsychotic
agents to patients on clozapine in whom a therapeutic dose cannot be achieved. This is
discussed elsewhere. (See "Evaluation and management of treatment-resistant
schizophrenia", section on 'Augmentation with medication'.)
Persistent suicidality — In patients with schizophrenia who have persistent suicidal
ideation despite antipsychotic treatment, we suggest a trial of clozapine [9-11]. Clozapine
has been shown in a large randomized trial to reduce suicide attempts in patients with
schizophrenia and schizoaffective disorder at high risk for suicide [9] and the US Food
and Drug Administration approved it for this use. In this study, 980 patients with
schizophrenia or schizoaffective disorder (27 percent refractory to previous treatment
and high risk due to prior suicide attempts or current suicidal ideation) were randomly
assigned to either olanzapine or clozapine treatment [9]. Less suicidal behavior (attempts
or completed suicide) occurred in patients treated with clozapine (hazard ratio 0.76, 95%
CI 0.58-0.97). Further, in nationwide observational studies of patients with schizophrenia
in Finland (n >61,000) and Sweden (n >29,000), clozapine was the only antipsychotic
associated with a decreased risk of suicide attempt or completion compared with use of
no antipsychotic (hazard ratio 0.64, 95% CI 0.49-0.84 Finnish cohort; hazard ratio 0.66,
95% CI 0.43-0.99 Swedish cohort) [10]. Guidelines for clozapine prescribing, dosing,
monitoring, and side effect management are described separately. Management of
suicidal patients is described separately. (See "Schizophrenia in adults: Guidelines for
prescribing clozapine" and "Suicidal ideation and behavior in adults".)
Treatment-resistant schizophrenia — Patients with schizophrenia who do not benefit
adequately from two or more trials of standard antipsychotic medications despite
typically therapeutic doses and treatment durations (eg, six weeks) are considered to
have treatment-resistant schizophrenia. We usually evaluate these patients
for clozapine eligibility. Randomized trials have shown that clozapine has greater efficacy
compared with other antipsychotics in treating patients who have responded poorly to
prior antipsychotic trials [12-15]. However, due to its potential toxicity, it is reserved for
treatment-refractory cases or cases with high risk for suicide. In the United States,
clozapine is the only antipsychotic medication approved for this use. 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 "Evaluation and management of treatment-
resistant schizophrenia" and "Schizophrenia in adults: Guidelines for prescribing
clozapine".)
Nonadherence — In patients with poor response to medication or repeated relapses,
nonadherence should be considered. We recommend asking patients about their
medication adherence in a nonjudgmental fashion. In many cases, side effects may be
the cause of nonadherence and may need to be addressed. (See 'Side effect
management' below.)
We suggest using long-acting injectable (LAI) antipsychotics for patients with
schizophrenia when nonadherence is problematic or leads to frequent relapse. LAI
antipsychotics are administered at intervals from 2 to 12 weeks. As an
example, risperidone LAI can be administered at a starting dose of 25 mg every two
weeks up to a maximum of 50 mg every two weeks. Paliperidone 12-week LAI is another
option that can be administered at 12-week intervals after the patient has been
adequately treated for at least four months on the four-week version of LAI paliperidone.
(See "Schizophrenia in adults: Pharmacotherapy with long-acting injectable antipsychotic
medication".)

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).

Implementation of medication changes — Medication changes are usually in response

to incomplete or poor response, side effects limiting response to or titration of the
medication, or nonadherence to the medication.

We vary the method and rate of change of medications depending on the clinical
situation. For example:

●Incomplete or poor response – Continue the ineffective medication at its current

dose while titrating the second medication according to its suggested titration
schedule (table 2). Once the second medication has reached its target dose, the
first medication can be tapered every few days over one to two weeks.
●Side effects – Lower the first medication every few days over one to two weeks
while simultaneously titrating the second medication at a similar rate.
●Nonadherence – Begin second medication (eg, LAI antipsychotic) according to
usual dosing schedule. (See 'Nonadherence' above and "Schizophrenia in adults:
Pharmacotherapy with long-acting injectable antipsychotic medication".)
Duration of antipsychotic therapy — For patients with known or suspected
schizophrenia who have recovered from an acute first psychotic episode, we recommend
continuing antipsychotics for at least two to three years.

Whether to continue beyond this interval depends on the course and individual features.

●For those with a first episode of psychosis, we base the decision to continue
antipsychotic therapy on the symptom intensity, level of psychiatric disruption,
response to medications, and support. For those who had psychosis that was
extremely disruptive, difficult to control, or accompanied by violence or suicidal
ideation, we favor continuing antipsychotic therapy indefinitely. Otherwise, if it
seems that potential relapses can be readily controlled, we explore the possibility
of discontinuing medications after two to three years.
●For those who have had multiple episodes of psychosis in the past, we generally
recommend continuing antipsychotic therapy indefinitely. However, in patients
whose recurrent psychosis has been mild with clear warning signs, a trial of
antipsychotic discontinuation may be reasonable. We individualize this decision
weighing the potential risks and benefits of indefinite antipsychotic treatment,
keeping in mind that antipsychotic treatment may be the reason that recurrences
have been mild. We would not consider discontinuing antipsychotic treatment for
individuals whose recurrent psychosis has been associated with violence,
hospitalization, or other serious disruptions.
If the decision is to discontinue antipsychotic medication, we recommend a gradual
reduction in antipsychotic dose and weekly monitoring. We recommend restarting an
antipsychotic medication, typically the same medication they were on previously, at the
first signs of symptom recurrence.

Discontinuing antipsychotic medications is associated with a higher rate of relapse

[16,17]. A meta-analysis of 9145 patients with schizophrenia in 75 randomized trials of 7
to 12 months duration found that patients who continued on an antipsychotic
experienced a lower relapse rate compared with patients who were transitioned to
placebo (24 versus 61 percent; number needed to treat = 3; relative risk 0.38, 95% CI 0.32-
0.45) [16]. Systematic reviews and meta-analysis of randomized trials have found that
maintenance antipsychotic medication reduces the risk of relapse after a first episode of
psychosis in schizophrenia over a period of up to three years [18-22]. Findings are
equivocal for longer periods of treatment.
However, among those who are able to discontinue or reduce the dose of antipsychotic
medication, doing so may be associated with better long-term functioning. In a trial of
patients with schizophrenia who were randomly assigned to either dose
reduction/discontinuation or maintenance, at two years, twice as many patients relapsed
with the dose reduction strategy versus maintenance treatment (43 versus 21 percent)
[23]. At seven-year follow-up, however, patients in the dose reduction/discontinuation
strategy were found to have superior functional remission rates (eg, function across
domains including housekeeping, community integration, and vocational functioning)
versus those in the maintenance group (40 versus 18 percent) [24]. Additionally, patients
in the dose reduction strategy group had lower mean daily antipsychotic dose over the
prior two years than those in maintenance group (2.2 mg versus 3.6
mg, haloperidol equivalent dose).
Other trials also demonstrate that a fraction of patients with schizophrenia do not need
continuous antipsychotic treatment throughout their lifetimes; however, there are no
clear characteristics that can identify these individuals prospectively [25].
PSYCHOSOCIAL TREATMENTS We recommend comprehensive psychosocial
treatment as an adjunct to antipsychotic medications for all patients with schizophrenia.
Interventions include cognitive remediation and social skills training, cognitive-behavioral
therapy, and family-based interventions. Psychosocial interventions for psychosis and
schizophrenia are discussed in detail elsewhere. (See "Schizophrenia in adults:
Psychosocial management" and "Psychosis in adults: Initial management", section on
'Psychosocial interventions'.)
MONITORING Follow-up monitoring should include symptom assessment and
review of medications and side effects (table 3). Periodic laboratory testing is needed to
address possible metabolic effects of medications. Recommended monitoring and
frequency are discussed below.
Frequency of follow-up — Frequency of follow-up for patients whose acute symptoms
have stabilized depends on the level of residual symptoms, prior history of recurrence,
history of adherence to medications, and level of support available to the patient.
For most patients, we recommend weekly follow-up for the first three months of
treatment.

If remission is achieved and continues at three months, we typically lower the frequency
of visits to once or twice per month for several months, then once per month. Frequency
of follow-up visits can be changed depending on clinical progress and availability of a
support system.

Psychiatric symptoms — We recommend assessment of psychiatric symptoms at each

visit. This is done primarily through clinical interview and mental status examination of
the patient. The interview should be performed in a private setting with minimal
distraction to establish or maintain rapport with the patient. While open-ended
questioning is often preferred, when necessary, we recommend direct questioning about
specific symptoms such as hallucinations, paranoia, mood changes, sleep disturbance,
suicidality, and homicidality. (See "Schizophrenia in adults: Clinical features, assessment,
and diagnosis", section on 'Clinical manifestations'.)

The mental status examination is a portion of the clinical interview that evaluates
cognitive domains including arousal, attention, language, and memory and can be useful
to detect underlying cognitive or behavioral abnormalities.

While there are no widely accepted clinical tools for measuring the severity of
schizophrenia symptoms, some clinical programs use the modified Colorado Symptom
Inventory for this purpose [26]. (See "The mental status examination in
adults" and "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic
evaluation", section on 'Diagnostic evaluation'.)
Movement and motor symptoms — All patients treated with antipsychotic medications
should be monitored for extrapyramidal symptoms (EPS), for example akathisia,
parkinsonism, and dystonia, as well as for tardive dyskinesia (TD) at each visit.
●Frequency – Patients starting an antipsychotic medication should be evaluated
for EPS weekly until the medication dose has been stable for at least two weeks.
Two weekly assessments should follow any change in antipsychotic, addition of an
antipsychotic, or significant antipsychotic dose increase [27].
We recommend checking for TD whenever assessing for EPS. Additionally, formal
documentation of TD (eg, using the Abnormal Involuntary Movement Scale (form
1)) is recommended at the following intervals:
•For patients at high risk of developing abnormal movements (eg, over 55 years
old, female, comorbid mood disorder or substance use disorder, on high
potency D2 blockers such as first-generation antipsychotics) – Every three
months.
•For all other patients – At least every 12 months.
●Assessment – Examination for EPS and TD should include inspection of normal
movements and abnormal involuntary movements of orofacial muscles and tongue
as well as extremities, including fingers and toes. Muscle tone can be checked by
passive flexion and extension of arms, legs, wrists, and ankles. While standing the
 patients can be observed for abnormal movements of the trunk. Gait should be
observed for arm swing, bradykinesia (slowing), and balance.
Some abnormalities may be severe, reported by the patient, and noted by brief
visual inspection. Other symptoms may be very mild, unreported by the patient,
and identified only by careful examination. We recommend asking about motor
symptoms including restlessness or pacing, inability to sit still, stiffness or slowness
of movements, tremor, or gait change, in addition to direct examination.
Findings can be suggestive of syndromes:
•Akathisia is suggested by a sensation of restlessness, frequent pacing, a
compelling urge to move, or an inability to sit still. (See 'Akathisia'below.)
•Parkinsonism is suggested by finding of masked facies, bradykinesia, tremor,
or rigidity. (See 'Parkinsonism' below.)
•Dystonia is a tonic contraction of a muscle or muscle group that is typically
disturbing to the patient and obvious to the examiner. (See 'Dystonia' below.)
•TD is characterized by the following features (see 'Tardive dyskinesia' below
and "Tardive dyskinesia: Etiology, risk factors, clinical features, and
diagnosis" and "Tardive dyskinesia: Prevention, treatment, and prognosis"):
-Sucking, smacking of lips
-Choreoathetoid movements of the tongue
-Facial grimacing
-Lateral jaw movements
-Choreiform or athetoid movements of the extremities and/or truncal
areas
Metabolic dysregulation — We recommend monitoring fasting glucose or hemoglobin
A1c, lipid profile, weight, and body mass index at regular intervals during the first year
and then annually thereafter if normal (table 4).
More frequent measurements may be necessary for individual patients with significant
baseline metabolic abnormalities, significant weight gain, or where there is clear
evidence of increased risk of insulin resistance [28]. In these cases, we recommend
consultation with a primary care clinician, internist, or endocrinologist. Monitoring for
metabolic abnormalities in patients taking an antipsychotic drug and/or patients with
severe mental illness is reviewed in greater detail separately. (See "Approach to
managing increased risk for cardiovascular disease in patients with severe mental
illness" and "Metabolic syndrome in patients with severe mental illness: Epidemiology,
contributing factors, pathogenesis, and clinical implications".)
Orthostatic changes and tachycardia — We recommend checking pulse and blood
pressure at each visit. Orthostatic blood pressure is checked if the patient reports
lightheadedness or has tachycardia (eg, greater than 100 beats per minute).
Antipsychotics with alpha-adrenergic blocking effects
(eg, clozapine, risperidone, paliperidone, iloperidone) can produce a dose-related
orthostatic hypotension and associated tachycardia. These effects are most pronounced
during the first days of treatment and occur most frequently with clozapine and
iloperidone.
Electrocardiogram — We recommend an electrocardiogram (ECG) prior to starting
antipsychotic medications, three months after starting the medication, and yearly
thereafter in all patients with baseline risk for QT prolongation. Additionally, we
recommend checking ECG at the same intervals in all patients treated with antipsychotic
medications associated with QT prolongation (table 3). (See 'Cardiovascular
effects' below.)
Other testing in select cases — In some individuals, for example, individuals with pre-
existing neutropenia, or in those who report galactorrhea or sexual dysfunction while on
medications, it may necessary to check prolactin level or complete blood count more
frequently. (See 'Other patient-specific considerations' below and 'Endocrinologic and
metabolic side effects' below.)

SIDE EFFECT MANAGEMENT

Extrapyramidal symptoms — Extrapyramidal symptoms (EPS) include akathisia,

parkinsonism, and dystonia. While all antipsychotics can cause EPS, they tend to be more
common in first-generation antipsychotics (FGAs) than second-generation antipsychotics
(table 3) [29]. (See 'Medication adjustments' above and "First-generation antipsychotic
medications: Pharmacology, administration, and comparative side effects" and "Second-
generation antipsychotic medications: Pharmacology, administration, and side effects".)
Akathisia — Akathisia is the most common form of EPS. It usually presents as motor
restlessness with a compelling urge to move or an inability to sit still. Individuals with
milder akathisia may describe a subjective feeling of restlessness but not show restless
motor behavior.
In patients whose akathisia is intolerable or affects their response to medication we
generally suggest cautious reduction of the antipsychotic dose while closely monitoring
the patient for exacerbation of psychotic symptoms. In some instances, it may be
necessary to address the akathisia pharmacologically rather than lowering the
antipsychotic. As examples, when the psychosis was difficult to control or has required
several ineffective trials, or when the medications have not yet had time to take effect.
The treatment of akathisia in adults receiving antipsychotic medication is in the
associated algorithm (algorithm 1).

We suggest individualized treatment depending on the clinical presentation.

●In patients whose akathisia is improved on the lower dose of antipsychotic, we

recommend continuing that lower dose of antipsychotic medication.
●In patients with recurrent psychosis on the lower dose, we increase the dose back
to prior level to stabilize symptoms. When psychotic symptoms are stable, we
suggest switching to another antipsychotic with less propensity to cause EPS (table
3).
●In patients whose akathisia is unimproved on the lower dose, we suggest
switching to another antipsychotic with lower propensity to cause akathisia (table
3).

If the above options are tried without success or contraindicated (ie, in patients who
cannot have antipsychotic lowered or changed), we suggest treatment of akathisia with
medication.
Our preferred choices are propranolol and benztropine. We typically use propranolol to
avoid the anticholinergic effects of benztropine. We further individualize the choice based
on potential adverse effects and underlying comorbidities. As examples:
●In patients with chronic obstructive pulmonary disease, heart failure, or asthma,
we suggest avoiding beta blockers (ie, propranolol).
●In patients with glaucoma or cognitive concerns, we suggest
avoiding benztropine.
In small clinical trials, propranolol and benztropine have shown evidence of efficacy in
the treatment of akathisia [30-34]. Doses and monitoring are:
●Propranolol – Propranolol should be started to 10 mg orally twice daily. If
symptoms do not improve, dosing can be increased weekly to maximum dose of 40
to 60 mg twice daily. Blood pressure should be monitored with the use of
propranolol. Fatigue and light-headedness are common.
●Benztropine – Benztropine should be started at 1 mg twice daily and increased up
to 3 mg twice daily depending on response. Patients receiving benztropine should
be monitored for anticholinergic effects including dry mouth, constipation, urinary
retention, blurry vision, and cognitive impairment.
Benzodiazepines are another effective option for reducing akathisia; however, some
studies have suggested an increased risk of mortality with benzodiazepine use in
schizophrenia [34-36]. Additionally, they are associated with sedation, withdrawal
seizures, a potential for addiction, and tolerance. Thus, if used (eg, if there are no other
alternatives), patients should receive the lowest dose that reduces
akathisia. Lorazepam can be started at 0.5 mg orally twice daily and, if clinically
warranted, increased by 0.5 mg twice daily to a dose of 3 mg twice daily. We do not
recommend total daily doses above 6 mg.
Parkinsonism — Symptoms of secondary parkinsonism include masked facies, cogwheel
rigidity, tremor, and bradykinesia. These symptoms may range from severe (eg, noted by
brief visual inspection of patient) to very mild and unreported by the patient (eg, detected
only by careful examination). In severe cases, parkinsonism may significantly impair the
patient's quality of life and increase the risk of falls. In these cases, we suggest treatment
of the secondary parkinsonism as described below.

Our first treatment intervention is a cautious reduction in antipsychotic dose with close
monitoring of the patient for exacerbation of psychotic symptoms.

●In patients whose parkinsonism is improved with lower dose of antipsychotic, we

continue the lower dose while monitoring for symptoms and side effects.
●In patients with recurrent psychotic symptoms on a lower dose of antipsychotic,
we increase the medication back to its prior dose to stabilize symptoms. When
psychosis is stable we suggest switching to another antipsychotic with lower
propensity to cause parkinsonism (table 3). In patients who are highly sensitive to
parkinsonism, clozapine should be considered.
●In patients whose parkinsonism is unimproved despite lower dose of
antipsychotic, we suggest switching to another antipsychotic with lower propensity
to cause parkinsonism (table 3).
If the above options are tried without success or contraindicated (ie, in patients who
cannot have antipsychotic lowered or changed), we suggest treatment of antipsychotic
induced parkinsonism with medications although there is little high-quality evidence
supporting the effectiveness of these approaches [37-39]. Choice of medication is based
on age of patient, medical comorbidity, current medications, and prior history of
treatment for EPS.
Benztropine is our preferred choice for treating antipsychotic induced parkinsonism. We
suggest starting at 1 mg twice daily and titrating to 3 mg twice daily if needed. Doses of 1
to 2 mg/day are often effective. Benztropine is an anticholinergic medication that can
lead to dry mouth, constipation, blurry vision, urinary retention, and cognitive
impairment. These effects may be more severe in patients over 70 years old and in
patients on other medications with anticholinergic properties.
If benztropine is ineffective or in patients in which it is not preferred (eg, cognitive
concerns, anticholinergic sensitivities), we suggest the N-methyl-D-aspartate-receptor
antagonist, amantadine. Amantadine may be given as immediate release 100 mg orally
two to three times daily [40]. Once daily forms are available as well for increased
adherence. Side effects include hypotension and mild agitation. (See "Initial
pharmacologic treatment of Parkinson disease", section on 'Amantadine'.)
Other agents that are less commonly used in the treatment of antipsychotic-induced
parkinsonism include diphenhydramine, levodopa, and trihexyphenidyl.
Diphenhydramine, an antihistamine, may be given at a dose of 25 to 50 mg orally every
six hours. It is less commonly used due to its shorter half-life and sedative properties.
Trihexyphenidyl has anticholinergic properties similar to benztropine and is used based
on cost and availability.
We advise against using the dopamine agonist levodopa in patients with active psychosis.
It has been shown in observational studies to have minimal benefit in the treatment of
drug-induced parkinsonism and adverse reactions may include psychosis and agitation
[39]. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Nonergot
dopamine agonists'.)
Prophylactic use of antiparkinsonian agents is not recommended to prevent
antipsychotic-induced parkinsonism. However, it may be useful in patients treated with
high doses (eg, greater than haloperidol 10 mg/day or the equivalent dose of other
antipsychotics) of high-potency first-generation antipsychotics, or in those patients with
known sensitivity to EPS [41,42].
Dystonia — Dystonia is an involuntary contraction of major muscle groups that is highly
disturbing to the patient. Some types of dystonia, for example laryngospasm, may be life
threatening. Antipsychotic-induced dystonia is usually rapid in onset and is characterized
by torticollis, retrocollis, oculogyric crisis, and opisthotonos. Risk factors for dystonia
include young age, male sex, use of cocaine, and a history of acute dystonic reaction.
For treatment of acute dystonia secondary to antipsychotic, use we recommend
treatment with diphenhydramine or benztropine, as described below. We prefer
diphenhydramine.
●Diphenhydramine – We suggest a dose of 50 mg intravenously (IV) or
intramuscularly (IM) acutely followed by 50 mg orally every four to six hours. Milder
cases may be treated with 50 mg orally two to three times daily.
 ●Benztropine – We suggest a dose of 1 to 2 mg IM or IV acutely followed by 1 to 2
mg orally daily. Milder cases may be treated with oral benztropine 1 to 2 mg once
or twice daily.
The emergence of a dystonia should lead to reevaluation of the patient's antipsychotic
regimen. After acute dystonia we suggest continuing the daily dose
of benztropine or diphenhydramine and changing to an antipsychotic with less
propensity to cause EPS (table 3).
Prophylactic treatment with an anticholinergic agent such as benztropine is
recommended to prevent an acute dystonic reaction in patients who receive
intramuscular haloperidol (eg, in the treatment of acute agitation or psychosis).
This is particularly important in patients with little prior exposure to
antipsychotics. As an example, intramuscular haloperidol 5 or 10 mg can be
accompanied by intramuscular benztropine 1 or 2 mg.
Tardive dyskinesia — Tardive dyskinesia (TD) is a syndrome consisting of characteristic
involuntary movements occurring most often after chronic treatment with antipsychotic
medications or another dopamine receptor blocking agent. TD syndromes are more
common after sustained exposure to antipsychotic medications; however, they may
appear as early as one to six months after initiation of these agents. TD may initially
worsen or reappear after lowering or discontinuing medication. (See "Tardive dyskinesia:
Etiology, risk factors, clinical features, and diagnosis", section on 'Risk factors'.)
When patients develop TD, clinicians should re-evaluate the current medication
treatment. Prevention and treatment of TD are discussed in detail elsewhere.
(See "Tardive dyskinesia: Prevention, treatment, and prognosis", section on 'Initial
management'.)
Neuroleptic malignant syndrome — Neuroleptic malignant syndrome (NMS) is a life-
threatening syndrome that is characterized by a tetrad of clinical features (fever, rigidity,
mental status changes, autonomic instability) and can occur in patients taking
antipsychotic or other dopamine-blocking agents [43]. Incidence rates range from 0.02
percent to 3 percent. Treatment of NMS involves withdrawal of medication and intensive
management for cardiovascular support, control of hyperthermia, fluids, and restoration
of electrolyte balance. (See "Neuroleptic malignant syndrome".)
Endocrinologic and metabolic side effects — Most antipsychotic medications are
known to cause metabolic side effects including weight gain, hyperlipidemia,
hyperglycemia, and hypertension (table 3). These side effects are risk factors for
cardiovascular disease. Additionally, they are primary contributors to the early and
increased mortality experienced by patients who have severe mental illness or are on
antipsychotic medication [44].

Strategies for preventing and treating metabolic side effects of antipsychotic drugs
include:

●Changing the antipsychotic regimen

●Lifestyle interventions including diet changes and exercise to reduce weight and
metabolic risk factors
 ●Treatingother metabolic risk factors such as hypertension, dyslipidemia,
hyperglycemia, diabetes, and tobacco use

Prevention and treatment of metabolic syndromes are presented in detail elsewhere.

●(See "Approach to managing increased risk for cardiovascular disease in patients

with severe mental illness".)
●(See "Modifiable risk factors for cardiovascular disease in patients with severe
mental illness".)
●(See "Lifestyle interventions for obesity and overweight patients with severe
mental illness".)
●(See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary
prevention of cardiovascular disease".)
●(See "Initial management of hyperglycemia in adults with type 2 diabetes
mellitus".)
Cardiovascular effects
●QT prolongation – In patients who develop prolonged QT syndrome during
treatment with antipsychotic medications, we recommend consultation with a
cardiologist and changing to another antipsychotic medication with lower
propensity to cause QT prolongation (table 3). (See "Acquired long QT syndrome:
Clinical manifestations, diagnosis, and management" and "Psychosis in adults:
Initial management", section on 'Cardiovascular risk factors'.)
●Orthostatic hypotension and tachycardia – In individuals at risk for orthostatic
hypotension, such as older adult or frail patients, we recommend starting at the
lowest possible dose of the prescribed medication and titrating slowly (table 3). As
an example, quetiapine can be started at 25 mg per day and increased by 25 mg
per day to the acute therapeutic dose range of 150 to 750 mg depending on clinical
response. If orthostatic hypotension develops, we recommend carefully lowering
the dose of the antipsychotic medication. If this is not effective or contraindicated,
we recommend changing to another antipsychotic with less propensity to cause
orthostasis.
Treatment strategies for tachycardia include reducing the dose of antipsychotic
medication and avoiding anticholinergic medications. For symptomatic patients, we
recommend referral to a cardiologist.
●Myocarditis and cardiomyopathy – These have been reported in patients treated
with clozapine. (See "Schizophrenia in adults: Guidelines for prescribing clozapine",
section on 'Myocarditis/cardiomyopathy'.)
Other treatment-emergent side effects and their treatment
●Anticholinergic-related side effects – These side effects include tachycardia, dry
mouth, urinary hesitancy, constipation, visual changes, and cognitive impairment.
In patients with problematic anticholinergic side effects, we recommend lowering
medication dosing as the first treatment. If this is ineffective, we recommend
changing to a medication with less anticholinergic effect. Anticholinergic effects are
seen with clozapine, chlorpromazine, olanzapine, and, to a lesser extent,
with quetiapine, iloperidone, and loxapine (table 3). These side effects tend to be
worse in older patients.
●Sedation – We recommend giving antipsychotic medications with high propensity
to cause sedation at night. Sedation is usually most severe during the first few
weeks of treatment and can be minimized by titrating medications slowly. Although
all antipsychotics medications can cause sedation, it is most strongly associated
with chlorpromazine, olanzapine, clozapine, and quetiapine (table 3).
●Agranulocytosis – Leukopenia, neutropenia, and agranulocytosis have been well
documented with clozapine but have been reported with other antipsychotics as
well [45]. In the United States and other countries, regulations require routine
monitoring of clozapine patients for neutropenia and discontinuation of the drug
in severe cases. Monitoring guidelines are discussed in detail separately.
(See "Schizophrenia in adults: Guidelines for prescribing clozapine", section on
'Monitoring'.)
For patients taking other antipsychotics who develop drug-induced neutropenia,
we recommend prompt withdrawal of the antipsychotic and consultation with a
primary care provider or hematologist.
We then carefully consider the need for continued antipsychotic treatment. If an
antipsychotic is still indicated, then we carefully reintroduce a different
antipsychotic.
For patients who have previously experienced a drug-induced neutropenia or who
have a pre-existing low white blood cell count or low absolute neutrophil count
(ANC; eg, individuals with Duffy-null associated neutrophil count [DANC]), we
recommend monitoring ANC at baseline, after two weeks, and after three to six
months. If recurrence of neutropenia is documented, we recommend prompt
withdrawal of the antipsychotic and further consultation with primary care provider
or hematologist. (See "Schizophrenia in adults: Guidelines for prescribing
clozapine", section on 'Duffy-null associated neutrophil count
(DANC)' and "Schizophrenia in adults: Guidelines for prescribing clozapine", section
on 'Neutropenia' and "Approach to the adult with unexplained neutropenia",
section on 'Normal variants <1500/microL'.)
Restarting an antipsychotic after recurrent antipsychotic-induced neutropenia
prompts careful assessment of benefits and risks, and must be done with ongoing
consultation with a primary care provider or hematologist.
●Symptoms of hyperprolactinemia – All FGAs can elevate plasma prolactin.
Among second-generation antipsychotics, risperidone and paliperidone are most
likely to elevate plasma prolactin (table 3). This elevation can lead to galactorrhea,
menstrual disturbances, and sexual dysfunction in females and gynecomastia and
sexual dysfunction in males. In patients reporting these symptoms, we recommend
prolactin level to clarify diagnosis and treatment. Patients with elevated prolactin
levels with the symptoms described above should be referred to their primary care
clinician for further evaluation. (See "Causes of hyperprolactinemia", section on
'Drug induced' and "Clinical manifestations and evaluation of hyperprolactinemia",
section on 'Clinical presentation' and "Management of hyperprolactinemia".)
 ●Seizures – Most antipsychotics cause a dose-related reduction in the seizure
threshold. If a patient experiences new-onset seizures, antipsychotic drugs should
not be assumed to be the etiology, as these rarely cause seizures in a patient not
otherwise prone to epilepsy. Usual procedures for evaluation of new-onset seizures
should be followed. (See "Evaluation and management of the first seizure in
adults".)
The risk of seizures is greatest with clozapine, which has an adjusted hazard ratio
of greater than 3 [46]. As a result, patients with seizure disorders who are on
clozapine should be carefully monitored in conjunction with their neurologist.
(See "Schizophrenia in adults: Guidelines for prescribing clozapine", section on
'Seizures' and "Overview of the management of epilepsy in adults", section on
'Maximizing the likelihood of a successful outcome'.)
●Visual disturbances – Pigmentary retinopathies and corneal opacities have been
described with chronic administration of chlorpromazine and thioridazine. Cataract
development with quetiapine has been reported from preclinical evidence in
beagles [27]. The clinical relevance of this finding in beagles is unclear.
Nevertheless, all patients should have routine eye examinations, which are
generally recommended every two years for adults. (See "Second-generation
antipsychotic medications: Pharmacology, administration, and side effects", section
on 'Cataracts'.)
●Cholestatic jaundice – This has been described with chlorpromazine and, rarely,
with other FGAs. In most cases, discontinuation of the offending drug is the only
treatment required [47].

OTHER PATIENT-SPECIFIC CONSIDERATIONS

Comorbid psychiatric disorders — Comorbid depressive disorders and anxiety

disorders can lead to increased morbidity, poor functioning, higher relapse rates, and
lower quality of life in patients with schizophrenia. Comorbid disorders may be difficult to
distinguish from symptoms of schizophrenia or antipsychotic drug side effects. Properly
diagnosed, however, these syndromes can respond to antidepressant and anxiolytic
medications [48]. Treatment of comorbid disorders in schizophrenia is discussed
elsewhere. (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)
Substance use disorders (SUDs) are highly prevalent in patients with schizophrenia [49].
The combination of a severe mental illness and a SUD is commonly described as "dual
diagnosis." Dual diagnosis is associated with increased morbidity, poor functioning,
decreased adherence to medication, and higher rates of relapse compared to either
disorder individually [50]. 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, course, assessment and diagnosis".)