Matters PRACTICE PRACTICE Matters

OCTOBER, 2002 VOL. 7 ISSUE 1

EFFECTIVE

TREATMENT

FOR

SCHIZOPHRENIA

A publication of the Management Decision and Research Center

A program within the Department of Veterans Affairs Health Services Research and Development Service

• Schizophrenia affects 1% of the US population,

or more than 2 million Americans.1

• The annual cost of treating schizophrenia exceeds

$30 billion nationwide.

• While there are effective pharmacologic

treatments for schizophrenia, almost 50% of

patients in the US with this disorder do not

remain in treatment over time.

• Veterans with schizophrenia occupy more hospital

beds at any given time than veterans with any

other illness, and the most severely ill may

comprise at least 10% of homeless veterans

receiving VA healthcare.

• Moderate doses of antipsychotic medications are

required to treat acute schizophrenia and prevent

relapse in stabilized patients.

• Research indicates that clozapine may be the

most effective antipsychotic for the treatment of

refractory patients.

• Research suggests the need for improving

adherence to evidence-based guidelines for

treating schizophrenia in VA.
2 PRACTICE Matters

BACKGROUND

Schizophrenia is a severe psychiatric disorder

that is characterized by psychotic symptoms such

as hallucinations and delusions, and impairments

in social and vocational adjustment. It affects more

than 2 million people in the United States and with

25% of hospital bed days devoted to patients with

schizophrenia, the yearly cost of this disorder

exceeds $30 billion.1,2,3

In 2001, the VA provided care to more than

98,000 veterans with schizophrenia at a cost of

$1.7 billion.4

 Veterans with schizophrenia occupy

more hospital beds at any given time than veterans

with any other illness. In addition, even when

stabilized in the community, many veterans with

chronic schizophrenia function poorly. Many are

chronically or periodically unemployed, some are

isolated in the community, and the most severely

ill may comprise at least 10% of homeless veterans

receiving VA health care. Even those patients who

have been stabilized may have persistent psychotic

symptoms that can interfere with their community

adjustment.

While there are effective pharmacologic

therapies for schizophrenia, studies show that

almost 50% of patients with schizophrenia who

are discharged from hospitals do not remain in

treatment over time.

TREATMENT AND

AVAILABLE THERAPIES

Treatment Recommendations

During the past decade, research has

contributed to substantial improvements in the

pharmacological and psychosocial treatments of

schizophrenia. The Schizophrenia Patient

Outcomes Research Team, or PORT,5

 examined the

research evidence for a variety of treatments and

found that there was sufficient evidence to make a

series of treatment recommendations that include:

• the use of antipsychotic medications for the

treatment of acute schizophrenia and the

prevention of relapse in stabilized patients;

• the use of moderate antipsychotic doses;

• clozapine for the treatment of refractory patients;

• the use of adjunctive medications for depression

and anxiety;

• family psychosocial treatment for patients who

have ongoing contact with their families or nonfamily caregivers;

• supportive individual and group psychotherapies;

• assertive community treatment for patients who

are high utilizers of service; and

• vocational rehabilitation.

Consensus on Prescribing Antipsychotics

A number of groups including VA, PORT, the

American Psychiatric Association, the New York

Office of Mental Health, and the Texas Department

of Mental Health and Mental Retardation have

reviewed the evidence and made recommendations

for treating schizophrenia with antipsychotic

medication. The recommendations from these

groups are similar, but not always the same. The

Mental Health QUERI and representatives from

three Mental Illness Research Education and

Clinical Centers (MIRECCs) recently participated

in a consensus meeting that included experts who

were working to revise the recommendations of all

of the above groups. The goal of the meeting was

to determine whether they could reach a consensus

on a number of controversial issues using the

available evidence.

The results of the meeting were summarized in

a special issue of the Schizophrenia Bulletin that was

published in Spring 2002.6

 Following are a number

of selected issues on which the group was able to

reach a consensus based on the current evidence.

• Second-generation antipsychotics (SGAs) — with

the exception of clozapine and ziprasidone —

should be selected before first-generation

(conventional) agents for patients experiencing

a first episode of schizophrenia, or for those

patients where there is no available history

concerning response to antipsychotics.

• Conventional antipsychotics may be appropriate

selections for: 1) Individuals who have a history

of responding well to a conventional

antipsychotic without experiencing

extrapyramidal side effects; 2) Individuals

who have a history of a better response to

conventional agents than to second-generation
PRACTICE Matters 3

antipsychotics; and 3) Patients who have

responded better to a long-acting injectable

antipsychotic when compared to an oral

antipsychotic.

• Clozapine appears to be the most effective

antipsychotic for treatment-refractory

patients. For this reason, patients should

not be considered partial responders or nonresponders until they have had an adequate

trial with clozapine. However, clinicians

should assess a patient’s response to at least

one second-generation antipsychotic before

beginning clozapine.

There is sufficient evidence to conclude that

SGA’s are less likely to cause tardive dyskinesia

(abnormal involuntary movements) than

conventional agents. Other recommendations

focused on the appropriate monitoring of patients

receiving different antipsychotic medications, the

duration of an adequate drug trial, and the selectio

of an antipsychotic for different populations.

Treating Refractory Patients

There is a substantial body of evidence

indicating that patients with schizophrenia should

not be considered treatment refractory until they

have received a trial of clozapine. This finding is

reinforced by a VA Cooperative study, which foun

that clozapine was more effective than haloperidol

in veterans with treatment refractory

schizophrenia.7

 Although treatment refractory

illness is relatively common in schizophrenia, only

2.9% of veterans with schizophrenia received

clozapine in FY 2001.4

 There was also wide

variability in clozapine prescribing among facilities

and VISNs, with one network prescribing clozapin

to only 0.8% of veterans with schizophrenia.

Moreover, this lack of access to clozapine existed

in sites that treated substantial populations of

patients with schizophrenia. Since nearly all

treatment guidelines recommend the use of

clozapine for patients who are treatment refractory

it is clear that many clinicians are failing to adhere

to recommended evidence-based practices.

Many factors probably contribute to the

underutilization of clozapine. Because clozapine

is associated with a risk of agranulocytosis

(pronounced reduction in white blood cells),

patients who receive it require weekly neutrophil

n

d

e

,

counts for the first six months, followed by counts

every two weeks. In addition, clozapine is

associated with other undesirable side effects such

as weight gain, seizures, orthostatic hypotension,

and sedation. The VA also requires that – in order

to use the drug – each facility develop a Clozapine

Treatment Team, and new prescriptions for

clozapine must be approved by the Clozapine

Treatment Team and the National Clozaril

Coordinating Center. It is also possible that

clinicians are inexperienced with prescribing

clozapine and, thus, are uncomfortable prescribing

it. Because of these factors, clinicians may find it

easier to prescribe alternative drugs.

Advances in Clinical Research

The Program for Assertive Community

Treatment (or PACT model treatment) has been

found to be cost effective for patients who are

heavy users of clinical services.8 PACT programs

usually include a high staff-to-patient ratio, a

multidisciplinary team that provides a broad range

of services in community settings, and the

availability of services around the clock. The

implementation of these programs has permitted

severely ill patients, who were frequently

hospitalized for long periods, to remain in the

community. The VA implemented its own form

of the PACT model treatment (originally Intensive

Psychiatric Community Care), currently termed

VA Practice Matters is a publication for VA decision

makers and practitioners that summarizes the results

of important research to help inform policy and to

promote the application of research for improved

health care delivery and decision making within VA.

It is produced by HSR&D’s Information Dissemination Program in collaboration with topic experts

in the field. For more information or to provide us

with your suggestions, please contact:

Information Dissemination Program

Management Decision and Research Center (152-M)

VA Boston Health Care System

150 South Huntington Avenue

Boston, MA 02130

Phone: (617) 278-4433

FAX: (617) 278-4438

Email: geraldine.mcglynn@med.va.gov

VA Practice Matters is also available on the

VA HSR&D internet at

www.hsrd.research.va.gov/publications/practice_matters/
PRACTICE Matters 4

Mental Health Intensive Community Management

(MHICM).

Gaps in Current Practice

Despite the wealth of research supporting the

above mentioned treatment modalities, multiple

studies indicate that a substantial proportion of

patients with schizophrenia — including veterans —

are not benefiting from these advances. For

example, even though, as mentioned earlier,

clozapine appears to be the most effective

antipsychotic for the treatment of refractory

patients, there is wide variability in clozapine

prescribing among VISNs. There is also evidence

that veterans are not benefiting from advances in

clinical research, such as the PACT model of

treatment. Further, PORT investigators surveyed

actual practice in a number of settings and found

that there was reasonable compliance with most of

the recommendations that focused on

pharmacotherapy, but poor compliance with

recommendations for psychosocial treatments.5

A recent survey by the VA’s Committee on Care of

Severely Chronically Mentally Ill also found that

only a small fraction of veterans who were

candidates for MHICM had access to these

programs.

In a study from the Mental Health QUERI,

Owen et al. looked at prescribing practices in

a population that included veterans with

schizophrenia.9 Findings show that only 52%

were treated with antipsychotic doses within the

range recommended by the Schizophrenia PORT.

Moreover, Leslie and Rosenheck examined

prescribing practices at all VA facilities and found

that 13% of patients were prescribed antipsychotic

doses greater than the PORT recommended range,

with substantial variation among facilities.10

CLINICAL OPINION

The treatment of schizophrenia has become

more complicated, but has also improved. Until

1990, the prescribing of antipsychotics was

relatively straightforward: all of the antipsychotics

were equally effective, and side effect concerns

focused on neurological adverse effects such as

Parkinsonism and tardive dyskinesia. Neurological

side effects are a minor concern with the second

generation of antipsychotics that include clozapine,

risperidone, olanzapine, quetiapine, and

ziprasidone. However, these newer agents are

associated with new concerns about side effects that

include weight gain, vulnerability to diabetes,

hyperlipidemia, and cardiac arrhythmias.

Moreover, these newer antipsychotics may differ in

their effectiveness. Clozapine appears to be more

effective for severely ill, treatment refractory

patients than other antipsychotics, and there are

indications that other second-generation agents are

more effective for the neurocognitive impairments

associated with schizophrenia. As a result, clinicians

who manage schizophrenia have switched most

patients to the second generation of antipsychotics.

In 2001, more than 77.4% of veterans with

schizophrenia were prescribed a second–generation

antipsychotic, reflecting an upward trend in recent

years.4

 This change is reinforced by treatment

guidelines, including those being developed by the

VA, as well as the Texas Medication Algorithm

Project.11

This change in antipsychotic prescribing should

also be associated with changes in the monitoring

of patients. At a time when neurological side effects

were the most serious concern, the VA selected

tardive dyskinesia (TD) monitoring with the

Abnormal Involuntary Movement Scale (AIMS) as

a performance measure. Although yearly monitoring

for TD is still an appropriate practice, TD is

probably less of a problem than other side effects.

For example, weight gain is a very serious concern

for patients with schizophrenia. A meta-analysis of

controlled trials found that during a 10-week

period, patients receiving clozapine gained an

average of 4.45 kg and patients receiving olanzapine

gained 4.15 kg.12 Both quetiapine and risperidone

were also associated with some weight gain. Other

continued on page 5

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PRACTICE Matters 5

continued from page 4

reports have suggested that newer antipsychotics

may also be associated with an increased risk for

Type 2 diabetes and hyperlipidemias.13 Since

individuals with schizophrenia have a greater

likelihood of both obesity and diabetes, monitoring

for these adverse consequences of drug treatment

should probably be performed.

 14, 15

Clinicians – and clinical managers in large

health care organizations such as the VA – should

consider focusing on weight and glucose

monitoring for all patients with schizophrenia.

The level of monitoring was recently considered by

a consensus conference organized by the Mental

Health QUERI and others, which recommended

that patients have their weight monitored at every

visit and that patients have their blood glucose

monitored prior to starting an antipsychotic, as

well as yearly.6

 More careful monitoring may be

appropriate if patients are receiving olanzapine or

clozapine – which have been associated with new

cases of diabetes, or if patients are obese or have a

family history of diabetes.

The issue of monitoring is an important

concern since there is evidence that psychiatrists

in public mental health settings, such as the VA

and community mental health centers, often fail to

monitor side effects in patients with schizophrenia.16

Moreover, in settings like the VA, clinicians carry

high caseloads – often more than 500 patients –

which can result in very brief sessions with

individual patients. Given this clinical reality, the

VA and other health care organizations should

assure that patients with schizophrenia are seen

by a primary care provider at least yearly. New

approaches, including collaborative care models

with care coordinators, have been proposed to

address the tendency of some specialists to fail to

perform important routine monitoring.

Stephen R. Marder, MD

Director, VISN 22 MIRECC

Clinical Coordinator, Mental Health QUERI

VA Greater Los Angeles Health Care System

RECOMMENDATIONS

• Individuals with schizophrenia should be treated

with antipsychotics that are prescribed within the

recommended dose range for an adequate length

of time.

• Second-generation antipsychotics (SGAs) should

be selected before first-generation (conventional)

agents for patients experiencing a first episode of

schizophrenia.

• All patients with schizophrenia should have their

weight monitored at every visit and their blood

glucose monitored before starting an

antipsychotic, and then yearly.

• Clozapine should be considered for patients who

continue to be symptomatic on their current

antipsychotic medication. However, clinicians

should assess a patient’s response to at least one

second-generation antipsychotic before

beginning clozapine.

• There should be increased availability and access

to Mental Health Intensive Community

Management (MHICM) programs for veterans

who are heavy users of clinical services.

ACKNOWLEDGEMENTS

This issue of VA Practice Matters on the

Effective Treatment for Schizophrenia was written

by: Richard Owen, MD, Director of HSR&D’s

Center for Mental Healthcare and Outcomes

Research, and Research Coordinator for the

Mental Health Quality Enhancement Research

Initiative (MH QUERI), and Stephen Marder, MD,

Clinical Coordinator for MH QUERI. Laurent S.

Lehmann, MD, Chief Consultant for Mental

Health, Veterans Health Administration; Frederic

C. Blow, PhD, SMITREC Director, HSR&D

Center for Practice Management and Outcomes

Research, Ann Arbor, MI; and John G. Demakis,

MD, HSR&D Director, reviewed the issue and

provided comments. The issue was edited by

Geraldine McGlynn, MEd and Diane Hanks, MA,

of VA’s Management Decision and Research Center.
6 PRACTICE Matters

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1999;156:1686-96.

13. Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics

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