Diagnosis and Management Considerations in Acute and Maintenance Treatment of Schizophrenia

Dr. Harvey is Professor of Psychiatry, Mount Sinai School of Medicine

Dr. Buckley is Professor and Chair of Psychiatry, Medical College of Georgia

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

This activity has been peer reviewed and approved by Eric Hollander, MD, chair at Mount Sinai School of Medicine. Review Date: September 5, 2006.

Statement of Need

Schizophrenia is among the world’s top 10 causes of long-term disability, affecting ~1% of the United States population, with similar rates across countries, cultural groups, and genders. The course of illness is generally chronic with acute psychotic exacerbations that may require frequent hospitalization. Predictors of frequent relapse include poor compliance with antipsychotic drug treatment, severe residual psychopathology, comorbid substance abuse, and poor relationships between patients, families, and care providers.

Newer atypical antipsychotics have become the treatment of choice for schizophrenia. Maintenance treatment with antipsychotics can dramatically reduce the rate of relapse for patients with schizophrenia. Factors contributing to the rate of noncompliance include medication side effects, severity of psychotic symptoms, impaired cognition, and inadequate understanding of the role of medication for preventing relapse.

An important educational need exists to refine the diagnostic and treatment strategies of physicians in order to increase compliance and remission rates in patients with early psychosis. Clinicians need to accurately diagnose patients in the first episode and be aware of the newest agents and treatment options to optimize outcome and response.

Learning Objectives

• Describe the importance of early and accurate diagnosis of patients with schizophrenia in the acute care setting to limit rehospitalization.
• Assess the latest treatment information on the acute care and maintenance treatment of schizophrenia.
• Explain the newest treatment strategies to enhance safety and compliance.

Target Audience

This activity will benefit psychiatrists, hospital staff physicians, and office-based “attending” physicians from the community.

Funding/Support

This activity is supported by an unrestricted educational grant from Janssen, L.P.

Faculty Disclosures

Dr. Harvey is a consultant to Abbott, AstraZeneca, Janssen, Memory, Merck, Pfizer, and sanofi-aventis; is on the advisory boards of Eli Lilly and Forest; and receives grant support from Bristol-Myers Squibb.

Dr. Buckley is a consultant to Abbott, Alamo, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, and Pfizer; receives grant/research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, National Institute of Mental Health, Pfizer, and Solvay; and receives honoraria/expenses from Abbott, Alamo, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer.

Peer Reviewers

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

David L. Ginsberg, MD, is on the speaker’s bureaus of and receives honoraria from AstraZeneca and Bristol-Myers Squibb.

To Receive Credit for this Activity

Read this article, reflect on the information presented, and then complete the CME quiz found here: www.mssmtv.org/psychweekly. To obtain credit you should score 70% or better. The estimated time to complete this activity is 1 hour.

Release Date: October 1, 2006

Termination Date: October 1, 2008

Introduction

Schizophrenia as an illness concept has been controversial since its first definitions in the late 1800s. For example, Kraepelin defined dementia praecox as an illness entity with an early onset, a deteriorating course with dementia-like symptoms, and profound cognitive and functional impairments. Bleuler disagreed about the issues of onset age and invariably poor outcome, but agreed on the centrality of cognitive, functional, and emotional changes in the illness.

As in all DSM diagnoses, the criteria for schizophrenia are multidimensional, including the presence of active illness, a specified duration of symptoms, and exclusions of alternative causes of the symptoms. The symptoms used to define schizophrenia are the same as those noted by Kraepelin and Bleuler and, interestingly, the controversies are still the same as well

Important Features of Current Criteria

The most important feature of the current criteria is the specification of active illness, which includes the presence of at least two symptoms of illness (Table 1), unless either the delusions or hallucinations are “characteristic” in nature. In that case a single symptom satisfies the active illness criteria. Characteristic delusions are those that are completely impossible and are designated as “bizarre.” These include delusions of being controlled, of having thoughts either inserted or removed, or monitored in ways that are impossible, such as with two-communication from the television. Characteristic hallucinations are those that involve hearing voices spoken directly to the subject, hearing voices commenting on the subject’s thoughts, actions, or appearance, or hearing two or more voices conversing with each other.

Another important feature of the current criteria is that deterioration in functioning from previous levels of at least 6 months is required in order to substantiate the diagnosis.

One of the most important aspects of schizophrenia is the presence of substantial functional disability. The majority of patients have deficits in social functioning, the ability to live independently, and the ability to obtain and sustain employment. This disability leads to substantial indirect cost of the illness, because many individuals with schizophrenia never develop the adaptive skills that are required to succeed in independent life.

A primary determinant of functional disability is impairment in cognitive functions.¹ While most of the classical cognitive ability domains are impaired in schizophrenia, including attention, memory, problem solving, and language skills, the greatest relative deficits appear to be in episodic memory (the ability to learn information with exposure and practice and to recall it after a delay) and, to a lesser extent, attention and working memory (the ability to maintain and manipulate information in short term storage) skills. As noted above, these impairments in cognitive functioning have been noted since the earliest definitions of the illness over 100 years ago.

Common Comorbidities

Common comorbidities in schizophrenia include substance abuse and obesity (Table 2). While obesity may be partially treatment related, the typical social class of people with schizophrenia leads to a poor diet and nutritional problems. Smoking is very common in schizophrenia and this may be influenced by genetically transmitted deficiencies in receptors for the nicotinic cholinergic receptor system.

Course of Illness

The course of schizophrenia is marked by several different phases of illness. These include the premorbid period, a prodromal period where normal functioning is altered, and the psychotic phase. After the first episode of psychosis, recovery is usually incomplete and relapse is very common (Figure 1).

At the time of the first episode, the signature of both clinical symptoms and cognitive impairments is consistent with that seen in more chronic patients.² See Figure 2 for a comparison of the level of impairments in treatment naïve and previously treated patients. While a good treatment response of the diagnostic symptoms of the illness is seen in as many as 90% of patients, this response is often disproportionately greater than the rate of functional recovery. As many as 50% of people with schizophrenia are experiencing a disability within 6 months of their first treatment and as many as 95% of patients relapse within 5 years. Full functional recovery is quite rare and fewer than 20% of patients have both sustained remission of their symptoms and achievement of success in vocational and social functioning.³

Genetic Factors

Etiological factors have proven complex to identify. Genetics are clearly involved, as the familial risk rates are much higher than the general population and susceptibility genes have recently been identified (Table 3). However, the risk rate for schizophrenia is much less within family members than would be predicted with strictly Mendelian patterns of heritability. For instance, if both parents have schizophrenia the risk is about 40%, similar to having a monozygotic twin with the illness and the risk for children and siblings of people with schizophrenia appears to be about 10% to 15%. Therefore, there is reason to suspect that a combination of pre- and perinatal stress, combined with genetic risk, confers maximum vulnerability to the development of the illness. In terms of specific susceptibility genes, there is evidence for familial alterations in the functioning of the genes that are related to receptor sensitivity and density for the cortical a-7 nicotinic receptor. Further, there is evidence substantial down regulation of genes that are responsible for maintenance of white matter integrity.

Neurodegeneration and Deterioration

The general course of schizophrenia shows some evidence of deterioration. Patients show evidence of modest but consistent enlargement of their cortical ventricles and reduced latency to clinical response following successive exacerbations.³ While there is limited evidence suggestive of cognitive or functional decline over the middle of the lifespan, the evidence of consistent ventricular enlargement, found across samples with large variation in age and clinical status at the time of the first assessment, suggests that there are progressive neurobiological processes active across the lifespan course of the illness.

Finally, while postmortem specimens that would suggest that typical neurodegenerative influences are no more common than in the general population, there is some evidence of neurodegeneration. Cellular architecture appears altered and the density of certain cortical layers in reduced. The arrangement of white matter appears altered as well, with these tracts less well “bundled” than in healthy individuals.

Prognosis and Treatment

Antipsychotic medications are the mainstay of treatment for schizophrenia. A host of new, second-generation antipsychotics (SGAs, Table 1) have increasingly replaced first-generation medications, largely because of lower risk of inducing motor side effects. These newer drugs are not without their own side effects, however. Most notably they are associated with a heightened risk of weight gain and metabolic disturbances-including diabetes.

The CATIE Study and Beyond

In an effort to evaluate the relative merits of current medications, the National Institute of Mental Health commissioned the largest ever treatment study in schizophrenia, the CATIE study.^5-7 The study had three phases (Figure 1), with patients being able to receive care for up to 18 months in this carefully conducted study. The results provide some guidance as to how each different drug will fit within the therapeutic armamentarium. For a summary of the results of Phases I and II of the CATIE study, see the Appendix.

The CATIE study does not address directly the tremendous amount of polypharmacy in clinical practice. Important areas to be further studied include effective augmentation strategies, duration, and sequence of treatment choices at various stages of the illness.⁸ For instance, the presentation of the first episode of psychosis is perplexing and highly stressful for patients and families alike. Here, the clinician is faced with several options on how to initiate treatment in a first-episode patient. However, this same variety brings doubts on which medication to start in a first-episode patient. In addition, there is particular interest in trying to identify and treat patients in the prodromal phase, before florid psychosis emerges. This approach is still in its infancy and in the research arena, although preliminary studies are showing promise.⁹

Additionally, there are indications from pharmacogenetic studies that efficacy for the domains of symptoms and reduced re-hospitalization may be predicted through genetic analysis. Moreover, there is also evidence that the side-effect profiles of SGAs and their propensity to cause weight gain, glucose and lipid abnormalities may be predicted by pharmacogenetic analysis in this patient population.¹⁰ This is an encouraging approach, particularly if improved “patient-to-drug” matching results in better treatment compliance overall.¹¹

Goals of Acute and Maintenance Treatment

Patients may require hospitalization for injurious behavior, deterioration in symptoms, and/or bizzare behavior. Several SGAs are available in different formulations (oral tablet, dissolvable waifer, liquid, or intramuscular) which helps with choice of medication toward the clinical scenario. The goal of acute care is stabilization and treatment planing so that there will be a successful transition to maintenance treatment.

The goals of long-term treatment are to maintain stabilization, prevent relapse, improve functional performance, and promote recovery. While medications are the bedrock of maintenance treatment, people need a host of other supports and services. Continuous antipsychotic therapy is recommended, although in practice there is a lot of switching of medications (as exemplified by the results of the CATIE study) and this is also often interrupted by either partial or complete medication noncompliance.

Improving Patient Outcomes

Compliance is complex issue,¹² involving illness-related factors, person (attitudinal) related factors, and more general (health system) factors (Table 3). Achieving optimum mediation compliance is important in schizophrenia, where failure to take antipsychotics has been repeatedly shown to be associated with an overwhelmingly higher risk of hospitalization. In addressing this need, there are now several novel approaches (using web-based, hand-held, and related technologies) to improving medication compliance.¹³ Less technical approaches such as skills training or cognitive-behavioral therapy (so-called “compliance therapy”) have also shown to be effective interventions to enhance medication compliance in patients with schizophrenia.¹⁴

The combination of new medications and effective rehabilitative and cognitive remediation interventions has the potential to improve patient outcomes significantly beyond what was expected previously. Patients with persistent symptoms and impairments in social competence can show benefit from social skills training. Importantly, supported employment programs show potential toward increasing the ability of patients with schizophrenia to obtain competitive employment. The use of computer-based cognitive remediation strategies for schizophrenia is also gaining ground.

Family members are strong advocates to positively impact the outcomes of schizophrenia and in planning for healthcare services. With the goal of promoting integrated and more effective mental health care, family members have joined together with other organizations to find more inclusive policy and practice approaches toward reducing the stigma against schizophrenia.

Additionally, patients who are recovering from mental illness disease are playing an ever-increasing role in public health policy and patient care in schizophrenia. The recovery philosophy which recognizes the unique contributions of those who have experienced mental illness is now a guiding approach for systems transformation and—in particular with the emergence of Peer Support Specialists—a fundamental direction for mental health care delivery in many states.¹⁵ Recovery is an unprecedented, concerted effort to change public opinion and to achieve integration and superior services at all levels for persons with mental illness. Although still at a nascent stage that is awaiting more widespread acceptance by clinicians, the introduction of Peer Support Services represent an innovation in mental health care.

To take the free, online CME post-test, go to www.mssmtv.org/psychweekly.

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

2. Harvey PD, Green MF, Keefe RSE, Velligan D. Cognitive function in schizophrenia: Its role in the definition and evaluation of effective treatments for the illness. J Clin Psychiatry. 2004;65:361-372.

3. Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological deficits in neuroleptic naive patients with first- episode schizophrenia. Arch Gen Psychiatry. 1994;51:124-131.

4. Robinson DG, Woerner MG, McMenamin M, et al. Symptomatic and functional improvement from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161:473-479.

5. O’Tuathaig CMP, Babovic D, O’Meara G, et al. Susceptibility genes for schizophrenia: characterization of mutant mouse models at the level of phenotypic behavior. Neurosci Behav Rev. 2006. In press.

6. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005:353:1209-1223.

7. Stroup TS, Lieberman JA, McEvoy JP, et al for the CATIE investigators. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006;163:611-622.

8. McEvoy JP, Lieberman JA, Stroup TS, et al for the CATIE investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610.

9. Buckley PF. So which drug do I choose next? Curr Psychiatry. 2006. In press.

10. Narasimhan M, Buckley PF. Early interventions when symptoms suggest a psychotic prodrome: implications from research to clinical practice. Curr Psychiatry. 2005;4:32-46.

11. Miller DD, Ellingrod VL, Holman TL, Buckley PF, Arndt SV. Weight gain associated with the -759 C/T polymorphism of the 5HT2C receptor and clozapine. Am J Med Genet. 2005;133B(1):97-100.

12. Hwang R, Shinkai T, Deluca V, et al, Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment. Eur Neuropsychopharmacol. 2006;16:248-259.

13. Ascher-Svanum, Faries DE, Zhu B, et al. Medication adherence and long-term functional outcomes in schizophrenia in usual care. J Clin Psychiatry. 2006;67:453-460.

14. Velligan DI, Lam YW, Glahn DC, et al. Defining and assessing adherence to oral antipsychotics: a review of the literature. Schizophr Bull. 2006. In press.

15. Turkington D, Kingdon D, Weiden PJ. Cognitive behavior therapy for schizophrenia. Am J Psychiatry. 2006;163:365-373.

16. Liberman, R, Kopelowicz A. Recovery from schizophrenia: a concept in search of research. Psychiatr Serv. 2005;56:735-742.

To take the free, online CME post-test, go to www.mssmtv.org/psychweekly.