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APA Guideline for Treating Adults With Schizophrenia

The Editors, Medscape Mental Health

Medscape Psychiatry & Mental Health eJournal. 1997;2(3) 

Abstract & Introduction

In April, the American Psychiatric Association (APA) released a comprehensive treatment guideline for treating adults who have
been diagnosed with schizophrenia. Titled "The Practice Guideline for the Treatment of Patients With Schizophrenia," it
highlights the latest research, stresses the value of such new medications as sertindole, quetiapine, and olanzapine as well as
clozapine and risperidone in treating the disorder, and recommends a range of psychiatric and rehabilitation approaches. More
than 91 researchers and clinicians and more than 15 professional and consumer associations reviewed and commented on the
Guideline, which was developed under the guidance of the APA Work Group on Schizophrenia. The Work Group, chaired by
Marvin I. Herz, MD, included Robert P. Liberman, MD; Jeffrey A. Lieberman, MD; Stephen R. Marder, MD; Thomas H.
McGlashan, MD; Richard J. Wyatt, MD; and Philip Wand, MD, consultant.

Schizophrenia is a chronic and disabling mental illness that affects men and women in equal numbers. The disease is
characterized by 3 types of symptoms: positive symptoms, which include delusions and hallucinations; disorganized thought and
speech; and negative or deficit symptoms, which include reduced thought and speech, flattened affect, and decreased initiation
of goal-directed behavior. The alterations in psychological processes--perception (hallucinations), reality (delusions), thought,
feeling (flat or inappropriate affect), behavior, attention, concentration, motivation, and judgment--lead to such functional
impairments as learning problems, self-care deficits, and impaired working and interpersonal relationships. (See Table I,
Diagnostic Criteria for Schizophrenia.)

The peak age of onset of schizophrenia in men is in the early 20s; in women, the illness peaks in the late 20s to early 30s. Risk
factors include having a first-degree relative or more than 1 relative with schizophrenia, being unmarried, living in an urban
center in an industrialized nation, having had a fetal history of in utero problems (eg, Rh incompatibility), being born in winter,
being in a lower socioeconomic class, and having recently experienced a stressful life event.

Treating Schizophrenia in the Acute Phase

The acute phase of schizophrenia is the florid psychotic phase, during which the patient exhibits acute symptoms--for example,
severe delusions and/or hallucinations (positive symptoms), disorganized thinking and speech, more profound negative,
withdrawal symptoms like flattened affect, reduced productivity (alogia), and decreased initiation of goal-directed behavior
(avolition). The acute phase may be preceded by a prodromal phase, characterized by social withdrawal, deterioration in
hygiene and grooming, unusual behavior, and/or angry outbursts during a period of several days or weeks before the acute
phase.

According to the APA Guideline, the goal of treatment during the acute phase is to "prevent harm, control disturbed behavior,
suppress symptoms, effect a rapid return to the best level of functioning, develop an alliance with the patient and family,
formulate short- and long-term treatment goals, and connect the patient with appropriate maintenance and follow-up care in the
community."

Treatment Strategy in the Acute Phase

The APA Guideline stresses the importance of the initial work-up and the use of antipsychotic medications.

Treatment begins with a thorough initial work-up to rule out conditions that may mimic schizophrenia, to identify any comorbid
conditions that can complicate diagnosis and/or treatment, to establish a baseline for monitoring the course of illness and
response to treatment, and to initiate any routine medical care required--for example, to manage a chronic illness that may have
been neglected by the patient.

While interviewing the patient is vital, the patient's symptoms during the acute phase may impede his ability to provide a reliable
history of medical and psychiatric problems and their treatment. To the extent possible, interview family and others with close
relationships to the patient, and review any available health care records to ascertain a complete psychiatric and medical history.

In the mental status exam, pay particular attention to suicidal ideation or intent, the presence of command hallucinations, and the
potential for violence or harm to self or others. As the APA Guideline points out, "Suicide is the leading cause of premature death
[1]
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[1]
among patients with schizophrenia. " Up to 55% of patients with schizophrenia attempt suicide, and an estimated 10% succeed
in killing themselves.[2] Besides the high risk of suicide, schizophrenia is associated with other life-threatening conditions related
to uncontrollable violent behavior.

The physical exam should include a thorough neurologic exam, plus urine and serum screening for alcohol, other drugs that may
be abused, and level of antipsychotic medications if currently prescribed. In addition, such basic lab tests as CBC; serum
electrolytes; glucose, liver, renal, and thyroid function; and HIV and syphilis testing are needed to establish baselines, as well as
to identify any illnesses that may mimic schizophrenia or are comorbid with schizophrenia and require modification of treatment
plan.

While the initial assessment is crucial, pharmacologic treatment generally should not be delayed because of an incomplete
assessment. "Given the relative safety of most antipsychotic medications," the APA Guideline recommends that the psychiatrist
"begin treatment with an appropriate medication, even in states where involuntary use of medication must be approved by a
court, and perform the necessary evaluations as they become possible."

The treatment venue should be the least restrictive setting that is safe and allows effective treatment. The APA recommends that
the patient be hospitalized if he poses a serious threat of harm to himself or others, needs constant supervision, is unable to
care for himself, or if he has a coexisting medical or psychiatric problem that would make outpatient treatment unsafe or
ineffective. Even if a patient is not dangerous, hospitalization is recommended for first-episode patients so that they can be
carefully assessed and monitored for the effects and side effects of treatment.[3]

A highly structured environment that can be used to remove the patient from stress and can reduce stimulation is crucial in the
psychosocial management. Another key psychosocial intervention in the acute phase is to educate the patient about the nature
of his illness as well as the effects and side effects of medications, and to enlist the patient's participation, to the extent that he is
able, in adjusting the medications and other treatment used to control symptoms.

The APA Guideline notes that "antipsychotic medications are indicated for nearly all acute psychotic episodes in patients with
schizophrenia." (See Table II, Evidence of Efficacy: Highlights of Antipsychotic Research Findings.) In selecting specific
medication, the APA recommends taking into consideration the drug's potential side effects, the intended route, and the patient's
preference and past response to antipsychotics.

The most common side effects associated with conventional antipsychotics are sedation, anticholinergic and antiadrenergic
effects, and neurological side effects. Nearly all patients experience sedation early in treatment with conventional antipsychotics,
but the symptom can often be managed by lowering the dose, consolidating divided doses into a once-a-day bedtime dose, or
prescribing a less sedating antipsychotic. Between 10% and 50% of patients taking conventional antipsychotics develop
anticholinergic or antiadrenergic side effects. In some cases, patients have mild and tolerable side effects such as transient dry
mouth, blurred vision, or constipation. More serious anticholinergic side effects can include central anticholinergic toxicity leading
to impaired cognition, delirium, and hallucination.[4-7]

About 60% of patients treated with conventional antipsychotics develop clinically significant acute or chronic extrapyramidal (EP)
side effects at some point in treatment.[8-10] Acute EP side effects usually develop within the first days or weeks after a
conventional antipsychotic is started; they are dose-dependent and reversible when the drug is reduced or discontinued.

Other side effects associated with conventional antipsychotics include weight gain[11]; eye problems such as pigmentary
retinopathies and corneal opacities; hematologic effects such as benign leukemia; erectile dysfunction in men; and increased
prolactin levels, which cause nipple secretion in 1%-5% of all patients and menstrual irregularities, such as oligomenorrhea, in
20% of women.

New atypical antipsychotics cause fewer EP symptoms than do the conventional antipsychotics. In addition, olanzapine,
sertindole, and quetiapine are associated with little or no rise in prolactin levels, making them useful for women who develop
irregular menses or galactorrhea while taking conventional antipsychotics.

In selecting an antipsychotic, it is important to examine the side effects of the medications in light of any existing medical
problems. For example, in a patient with preexisting parkinsonian symptoms, high-potency conventional antipsychotics may
worsen the tremor and rigidity. However, high-potency antipsychotics might be appropriate for a patient with a preexisting
cardiovascular disorder, such as orthostatic hypotension, since high-potency antipsychotics have fewer cardiotoxic effects than
low-potency antipsychotics. Low-potency antipsychotics with the most pronounced anticholinergic effects--for example,
thioridazine--should be avoided if possible in patients who have prostatic hypertrophy or other conditions that could contribute to
urinary retention or glaucoma, or in those who are taking another anticholinergic drug.

Selecting a medication to treat schizophrenia in the acute phase often requires looking beyond the acute phase. For example, if
the patient is a candidate for a long-acting depot medication like haloperidol or fluphenazine, he should be treated during an
acute episode with the oral form of the depot medication. However, the depot form of a medication generally is not
recommended to treat an acute psychotic episode because it takes months to reach a stable steady state, and the drugs are
eliminated slowly, which gives the clinician little control over the dose and makes it impossible to titrate the dose to control the
side effects and therapeutic effects. If the patient is agitated and a short-acting agent is needed, a medication that has an IM

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form is preferred. If the patient is on a depot form and has an acute exacerbation, the depot medication may be supplemented
with an oral form.

The initial dose should be high enough to be effective, but low enough to minimize risk of side effects. If a high-potency
antipsychotic is to be used, the APA Guideline notes that the effective daily dose is likely to be in the range of 5-20mg
haloperidol or 300-1000mg chlorpromazine equivalents. For risperidone, the daily dose range is usually 4-6mg; for olanzapine
10-20mg; and for sertindole 20-24mg; the optimal dose for quetiapine has not yet been established. (See Table III, Antipsychotic
Drugs.) Many factors affect the dose selection. (See Table IV, Drug Dosing Guidelines.) Gender is one such factor: Even after
body weight is taken into consideration, women generally require lower doses of antipsychotics than do men.[12]

The APA Guideline advises monitoring the patient's symptoms for response at the initial dose for at least 3 weeks, unless the
patient has uncomfortable side effects. Do not prematurely escalate the dose in a patient who appears to be responding slowly,
advises the APA Guideline. Rapid neuroleptization lacks effectiveness and is associated with a high risk of adverse effects.
Titrate the dose by monitoring a patient's response using symptom rating scales[13]--for example, the Scale for the Assessment
of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), and the Brief Psychiatric Rating Scale
(BPRS).

If the patient seems not to be responding, measure the plasma level of the antipsychotic to determine whether the dose is too
low to reach an adequate plasma level, or conversely, too high, which can result in side effects such as akathisia or akinesia--
both sometimes confused with schizophrenia symptoms. The plasma level also can be useful in evaluating whether other
medications (eg, the anticonvulsant carbamazepine, which lowers blood levels of antipsychotics by affecting hepatic enzymes)
or medical condition (eg, a hepatic or renal disorder) is altering the pharmacokinetics of the drug. Finally, the plasma level can
help in determining whether the patient is taking the medication as prescribed or if noncompliance is the problem.

If a low plasma level suggests that the patient is not complying, administering the medication in an intramuscular form or in a
liquid form under direct supervision may help, advises the APA Guideline. Also, review with the patient the intended effect of the
medication and be sure that any uncomfortable side effects are effectively managed so that side effects do not become a reason
for the patient to resist taking the medication.

If the patient is taking the antipsychotic as prescribed and has an adequate plasma level but is not responding, alter the
treatment: If the patient can tolerate a higher dose, raise the dose for specific period--for example, 2 weeks. If the patient does
not respond to the higher dose, switch to a different class of antipsychotic.

After the patient has tried at least 2 antipsychotics from different classes and the symptoms still are out of control or the patient
has intolerable side effects, consider a trial of clozapine. Note that clozapine is contraindicated for a patient who has history of
blood dyscrasias or cardiac arrhythmia, or who is unable to cooperate with weekly serum monitoring for agranulocytosis. (See
Table V, Agranulocytosis Monitoring Guidelines.) Most patients respond to clozapine within 6 weeks; others take longer to
respond, but 12 weeks is usually adequate to evaluate whether a patient is likely to respond. The APA Guideline notes that
some researchers suggest a clinical trial of clozapine for least 6 months,[14] while others say the trial should not exceed 2-4
months.[15]

Adjunctive medications, such as lithium, carbamazepine, valproic acid, and benzodiazepines, are best used to enhance the
effect of antipsychotics or treat comorbid conditions. For example, benzodiazepines may be useful in treating for acute anxiety
and agitation. Lorazepam or oral clonazepam, combined with a high-potency antipsychotic, have been found to be safer and
more effective in managing excitement and motor agitation than are large doses of antipsychotics. Antidepressants may be
added to the antipsychotics used to treat schizophrenic patients who have persistent depressive symptoms.

In the acute phase, a trial of 8-20 ECT treatments, in addition to continuing antipsychotics, may be indicated for catatonic
schizophrenia, treatment-resistant schizophrenia, or severe depression that cannot be managed with medications.

Treatment During the Stabilization Phase of Schizophrenia

The stabilization phase covers the first 6 months or more after the onset of an acute phase, during which acute psychotic
symptoms decrease in severity.

The treatment goals during the stabilization phase are to minimize stress and provide support to prevent relapse, enhance the
patient's adaptation to life in the community, facilitate continued reduction of symptoms, and consolidate remission.

During the stabilization phase, monitor the patient for at least 6 months on the same medications at the same dose used in acute
phase. Prematurely lowering the dose or discontinuing medication can lead to relapse.

Less structure and direction is needed in the stabilization phase than in the acute phase. This is the time to reinforce patient
education about the course and treatment of illness. Teach aspects of medication self-management, including the benefits of
maintaining antipsychotics to lower the risk of relapse; approaches for managing drug side effects; and symptom self-
management techniques, such as recognizing early warning signs of relapse, developing a relapse-prevention plan, and
avoiding illicit substances and alcohol. Continuity in the treatment plan, from the acute phase through the stabilization phase, is
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critical. If the patient is hospitalized, for example, arrange for him to visit the outpatient residence, clinic, or psychiatrist's office
where treatment will be continued.

Schizophrenia in the Stable Phase

The stable phase of schizophrenia is the period during which psychotic symptoms are less severe and may even be absent.
Some patients have nonpsychotic symptoms like anxiety, tension, depression, or insomnia during the stable phase; others have
symptoms that persist in an attenuated, nonpsychotic form--for example, circumstantiality rather than looseness, illusions rather
than hallucinations, and overevaluated ideas rather than delusions.

According to the APA Guideline, the overall goal of the stable phase is "to optimize functioning and minimize the risk and
consequences of relapse." This goal includes monitoring the patient's progress to ensure that he is maintaining or improving his
level of functioning and quality of life; treating relapses or exacerbations of symptoms to return the patient to optimal functioning;
and monitoring for adverse effects, including tardive dyskinesia, at least every 6 months. The APA Guideline recommends at
least 1 year of maintenance treatment with antipsychotic medications to lower the risk of relapse. In the first year after recovery
from an initial acute psychotic episode, the relapse rate among untreated patients reaches 40%-60%.[16,17]

Treatment Issues and Strategy in the Stable Phase

Frequency of evaluation varies according to the nature of the treatments and fluctuations of the illness--for example, patients on
depot treatment must be monitored at least every month, those on clozapine must be evaluated every week, and those going
through stressful life events may need daily assessments. Besides using symptom-rating scales to monitor the psychopathology
and course of illness, standardized instruments, such as the Abnormal Involuntary Movement Scale (AIMS),[18] should be used
to monitor for tardive dyskinesia (TD) in patients who are receiving long-term antipsychotic therapy.

In the stable phase, the patient needs to be helped to consolidate his treatment gains, suggests the APA Guideline. During the
stable phase, the patient can benefit from reeducation in basic living skills, social skills training, cognitive rehabilitation, and
beginning vocational rehabilitation.

If the patient has few or no positive or deficit symptoms and is able to tolerate more than minimal stress, complex individual
and/or group therapy may be appropriate. On the other hand, if the patient has marked deficits, treatment should continue to be
structured and supportive.

It may be appropriate to adjust the antipsychotic medication dose during the stable phase to optimize patient functioning. If the
dose is too low, the patient will not be able to sustain gains from rehabilitation. If the dose is too high, EP side effects--especially
akinesia or akathisia--can impair the patient's functioning in the community and reduce compliance with the medication regimen.
During the stable phase, subtle akinesia can appear as decreased spontaneous movement, diminished conversation, apathy,
and disinclination to initiate any activity,[19] making it particularly difficult to distinguish from the negative impairments of
schizophrenia or the symptoms of depression.

When antipsychotics are actively suppressing psychotic symptoms, discontinuing treatment or reducing the dose too low
produces almost immediate worsening of symptoms; for these patients, the maintenance dose must be carefully titrated
according to symptoms. If, however, the stable phase represents a true remission, the antipsychotics are prophylactic. In this
case, if the medication is stopped, a patient may continue to do well for weeks or months and then relapse.

According to the Guideline, "stable patients who do not have positive symptoms may be candidates for dose reductions." As
long as the patient remains stable, the dose may be reduced to one fifth of the usual maintenance dose.[20] Precautions during
dose reduction include gradual reduction over several months, more frequent visits, and use of such early intervention strategies
as teaching patient and family to recognize signs of relapse and developing an action plan to follow if signs appear.

Two groups of patients are candidates for a trial without medication: First are patients who have had only 1 episode of positive
symptoms and no symptoms in the 1 year of maintenance therapy; second are patients who have had multiple episodes and
remained stable for 5 years with no positive symptoms. Patients who have had a history of serious suicide attempts or violent,
aggressive behavior are generally not candidates for discontinuing medications; they need to continue antipsychotics indefinitely.

During the stable phase, it is particularly important to teach the patient and family to recognize prodromal symptoms or early
signs of exacerbation. During prodromal episodes, early intervention using supportive therapy and higher medication doses may
reduce the risk of relapse.

Clinical Factors Complicating Treatment

Treatment can be complicated by a variety of psychiatric, psychosocial, and medical factors. For example, psychiatric features
that can have an impact on treatment include whether an acute episode is the patient's first episode or a relapse: If a patient has

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never before taken an antipsychotic, it is important that he be hospitalized so that his response can be carefully monitored,
whereas a patient who relapses and is in a structured, supportive environment may be able to remain in community treatment as
long as he is no danger to himself or others. Comorbid substance abuse or dependence complicates treatment both because the
symptoms may resemble those of a functional psychosis and because of drug-drug interactions. Administering an antipsychotic
in the presence of a central nervous system (CNS) depressant like alcohol can produce profound sedation; in contrast, seizures
can be precipitated by administering an antipsychotic during withdrawal from a CNS depressant like alcohol or benzodiazepine.

Among the psychosocial variables are gender, age, and culture. Men, for example, tend to have more negative symptoms, a
poorer response to neuroleptics, and a poorer course of illness, overall, than women.[21] A key factor with age is whether the
older patient has late-onset schizophrenia--that is, symptoms beginning after 45 years of age--or had early-onset schizophrenia
and grew older. Late-onset schizophrenia is typically of the paranoid type, occurs more often in women, and usually responds to
lower doses of antipsychotic medications than early-onset schizophrenia.[22] On the other hand, patients with early-onset
schizophrenia tend to have fewer positive symptoms and more negative or deficit symptoms as they move into middle-age or
later life.[23]

Studies have also documented the impact of various cultural factors. For example, African Americans are more likely than other
groups to be misdiagnosed as schizophrenic when an affective disorder or organic brain syndrome is present.[24] Asian-
Americans tend to have higher serum levels of haloperidol after oral administration, requiring lower doses.[24] Patients of
Ashkenazi Jewish descent have been reported to be at higher than average risk of clozapine-induced agranulocytosis.[25]

Conclusion: Directions for Future Research

Research into the diagnosis and management of schizophrenia has multiplied exponentially, offering greater options as well as
greater complexity in the treatment of schizophrenia. From the 1930s when treatment research focused mainly on
electroconvulsive therapy, to the 1960s when research on neuroleptics marked the dawning of medications to manage the
illness, and on to the 1990s, researchers have steadily added to the databank needed to understand and effectively treat
schizophrenia. Yet the basic pathophysiology of schizophrenia remains to be fully elucidated. Once researchers are able to
uncover such pathophysiologic mysteries as the genetic link to the disease, the functions of neurotransmitters, and the
processes underlying symptom clusters, clinicians will be able to exercise far greater precision in diagnosing and predicting the
course of schizophrenia. The future may also hold the means to effectively treat schizophrenia and, perhaps, even prevent it
from becoming the chronic, debilitating illness it is today.

Schizophrenia. A comprehensive resource for information on schizophrenia. Information provided includes: treatment,
research, stories of recovery, medication, and more. Provided by Internet Mental Health.

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