Schizophrenia and Bipolar Disorder

Part 2: Recent Advances in the Treatment of Schizophrenia

First published in Psychiatry Weekly, January 28, 2008 

This is the second of a three-part series covering recent advances in diagnosis and treatment of schizophrenia and bipolar disorder. This second feature focuses on the development of new treatment strategies for schizophrenia and the importance of acute clinical investigation of their outcomes.

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)™. 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, Professor of Psychiatry and Chair at Mount Sinai School of Medicine. Review Date: December 19, 2007

Statement of Need

Although their mechanism of action is not well understood, antipsychotics present highly varying degrees of efficacy and adverse event profiles. Physicians should encourage not only strong treatment adherence, but should take steps to inform patients’ families of the importance of strong social support. This will ensure that, while treating positive symptoms of the patient’s illness, patients will be able to benefit from gains in parts of their lives that can be adversely affected by symptoms of schizophrenia, such as job performance.

Cognitive deficits are widely associated with schizophrenia and may cause the greatest impairment of all schizophrenia symptoms. Much treatment research is exploring how to address this problem, which, if answered, may lead to more successful treatment of nicotine addiction in this population; current estimates of tobacco use are as high as 80%.

The CATIE study, controversial as it may be, at least suggests that no single medication is universally efficacious in the treatment of schizophrenia. Therefore, a comprehensive evaluation of each patient’s unique treatment regimen is essential in order to provide maximum symptomatic improvement.

Learning Objectives

• Assess the role of community and social support in schizophrenia treatment.
• Explore recent advances in the understanding and treatment of reduced cognitive function in this population.
• Discuss the importance of flexible, customized pharmacotherapy in this population.

Target Audience

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

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Eli Lilly and Company.

Faculty Disclosure

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

Peer Reviewer

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

To Receive Credit for this Activity

Read this poster, reflect on the information presented, and then complete the CME quiz found in the accompanying brochure or online (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: January 28, 2008

Termination Date: January 28, 2010

Treatment

In schizophrenia, as in bipolar disorder, medications are the bedrock of treatment. However, medications are only partially effective, and their mechanism of action is still poorly understood.

Antipsychotics work in a variety of ways—so far researchers have yet to identify an antipsychotic that does not have appreciable binding to dopamine. Binding to D2 receptors is important, but by no means the full story. One of the most powerful agents, clozapine, binds very weakly to dopamine receptors. Aripiprazole, one of the newest drugs available, finetunes the dopamine system instead of blocking it.¹ Some agents bind very strongly, some bind weakly, some strike a balance between dopamine and serotonin, and others function like a blunderbuss, binding to many neurotransmitters with little discernment. Despite showing some efficacy in many cases, there is no single defined mechanism by which these antipsychotic medications work.

Medications are only one facet of successful schizophrenia treatment. It is extremely important that people with serious mental illness receive the highest level of social support, not only from family, but from friends, colleagues, and the community in general.² It is important that the patient’s family receive guidance and support from clinicians, as well. This not only enables them to better assist the patient in daily interactions, but also helps to deal with the stress that accompanies severe mental illness in the family.³ Establishing this support base is of particular importance in enabling patients to successfully return to work. While current treatment approaches for schizophrenia are generally effective in terms of treating positive symptoms, they are far less successful in establishing community support and enabling patients to return to leading generally productive lives.⁴

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A strong relationship between caregiver and patient has been shown to produce positive influence on the career and work performance in schizophrenia patients,⁸ and vocational rehabilitation programs and psychosocial therapy, specifically targeted toward improving social and job functioning, has shown some promise,^9,10 particularly in removing barriers to job seeking, although patient readiness and effort to return to the work force is still a major factor.¹¹

For patients with more severe illness, who would generally end up in a public inpatient facility, Assertive Community Treatment (ACT) is sometimes an option. In ACT, the patient’s care is managed by a multi-disciplinary team (comprising at least a psychiatrist, nurse, psychologist, and social worker) and is tailored specifically to meet the patient’s individual needs. Care is made available 24 hours a day, and support is provided to family as well. The cost of this focused, interdisciplinary treatment is high, but it has been shown relatively effective at rehabilitating schizophrenia patients and reducing relapse rates.¹²

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It is generally recognized that, while other symptoms may play a small role, it is cognitive deficits, such as impaired memory and the inability to concentrate, that most severely impact a schizophrenia patient’s ability to find and maintain employment.¹⁴ Accordingly, there has been a good deal of interest in treatments geared toward cognitive enhancement. Several psychosocial and cognitive behavioral therapies have attempted to target cognitive functioning, generally with limited success.^15,16 Recent evidence has suggested that the very high prevalence of tobacco use among schizophrenia patients—up to 80%—may be partially explained by the positive effect of nicotine on cognitive functioning.^17,18 The 5-HT2 antagonist properties of nicotine temporarily offset the suppression of cognitive functioning caused by some medications, which may be useful knowledge for the development of medications to improve functioning in this population.

There has also been a particular interest in whether existing medications might enhance cognitive functioning. When atypical antipsychotics were introduced, reports surfaced that detailed encouraging, but modest, cognitive benefits. Later research, however, has produced little evidence for a pervasive and robust effect.¹⁹

Researchers are now looking into using a variety of different medications, such as those prescribed for Alzheimer’s, to treat the cognitive deficits associated with schizophrenia.²⁰ It is important to note, however, that none of these medications have been FDA-approved for this indication.

There is also increased interest in drugs with more selective targets. For instance, the glutamate system and D1 receptors.^21,22 The federal government has funded investigators in an important initiative treating cognition in schizophrenia as a core outcome measure, and these investigators are developing and field testing new metrics and novel compounds.²³ Some of the compounds being tested now are quite novel and require equally novel ways of testing them.

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Treatment Response

The results of the CATIE (Clinical Antipsychotic Trials for Intervention Effectiveness) study have been hotly debated, not just by academics but also in the public policy field.²⁶ Perhaps the most unifying conclusion is the reaffirmation that treatment of schizophrenia is highly individualized. Two treatments may match up quite well, but does not necessarily imply that a particular patient on drug A would not experience better outcome on drug B.²⁷ Inevitably, the clinician must match the symptom profile of each patient with susceptibility to adverse events and the tolerability profile of the medication, while simultaneously evaluating the current understanding of the robustness of the treatment effect for each class of medications. Further, each medication or combination must be given a reasonable trial period with attention given to dosing.

In spite of all our efforts to optimize treatment, many patients do not do well; negative treatment response is pervasive.²⁸ Before determining that a medication is ineffective for a patient, the clinician must confirm that the patient is demonstrating compliance with treatment. Noncompliance with treatment is strongly associated with substance use, which complicates prognosis and may lead a clinician to erroneously deem the patient’s condition as treatment refractory.^29,30 It is also essential to make certain the patient is adhering to recommended dosing of medication. With many of the newer medications, information is not yet available on proper dosing for patients who exhibit signs of treatment refractory illness.

Switching medications, although often a necessary element of treatment, further complicates the picture. Many patients may not spend enough time on one medicine to experience the full benefit, and it is very difficult to determine whether someone is truly refractory or not. In such cases, the medication that has shown the most promise is clozapine. Clozapine, however, has a substantial and high risk side effect profile, so there may be a tendency for clinicians to under-prescribe this drug,³¹ even though both the CATIE study and the Cost Utility of the Latest Antipsychotics in Severe Schizophrenia study suggest that it may have a more robust effect on refractory patients.³²

Future Research

Clearly, the clinician decision-making about treatment of schizophrenia still remains complex and more art than science. Much of the research that may one day drive new treatment approaches is focused on theories of the etiology and pathophysiology of schizophrenia. Researchers are now moving forward into genome research, searching for associations between particular candidate genes that may be relevant for neurotransmitter metabolism and examining how these genes are expressed in relation to particular aspects of the illness.^33,34

Also, researchers can now use imaging procedures to measure the amount of dopamine in the synaptic cleft between brain cells and to explore complex interactions between dopamine and other neurotransmitters.³⁵ Time will tell just how much these novel approaches will translate into the clinical realm.

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

References

1. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 2001;50(11):873-883.

2. Scott JE, Dixon LB. Psychological interventions for schizophrenia. Schizophr Bull. 1995;21(4):621-630.

3. Dixon LB, Lehman AF. Family interventions for schizophrenia. Schizophr Bull. 1995;21(4):631-643.

4. McGurk SR. The effects of clozapine on cognitive functioning in schizophrenia. J Clin Psychiatry. 1999;60 Suppl 12:24-29.

5. Perkins DO, Johnson JL, Hamer RM, et al. Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophr Res. 2006;83(1):53-63.

6. Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63(10):892-909.

7. Buckley PF, Wirshing DA, Pierre J, Bushen P, Resnick S, Wishing SC. Lack of insight and treatment adherence in schizophrenia. CNS Drugs. 2007;21:129-141.

8. Davis LW, Lysaker PH. Therapeutic alliance and improvements in work performance over time in patients with schizophrenia. J Nerv Ment Dis. 2007;195(4):353-357.

9. Lehman AF. Vocational rehabilitation in schizophrenia. Schizophr Bull. 1995;21(4):645-656.

10. Killackey EJ, Jackson HJ, Gleeson J, Hickie IB, McGorry PD. Exciting career opportunity beckons! Early intervention and vocational rehabilitation in first-episode psychosis: employing cautious optimism. Aust N Z J Psychiatry. 2006;40(11-12):951-962.

11. Liu KW, Hollis V, Warren S, Williamson DL. Supported-employment program processes and outcomes: experiences of people with schizophrenia. Am J Occup Ther. 2007;61(5):543-554.

12. Phillips SD, Burns BJ, Edgar ER, Mueser KT, Linkins KW, Rosenheck RA. et al. Moving assertive community treatment into standard practice. Psychiatr Serv. 2001;52(6):771-779.

13. ACT Model. http://www.actassociation.org/actModel. Date accessed: December 19, 2007.

14. Holthausen EA, Wiersma D, Cahn W, Kahn RS, et al. Predictive value of cognition for different domains of outcome in recent-onset schizophrenia. Psychiatry Res. 2007:149(1-3):71-80.

15. Bell M, Fiszdon J, Greig T, Wexler B, Bryson G. Neurocognitive enhancement therapy with work therapy in schizophrenia: 6-month follow-up of neuropsychological performance. J Rehabil Res Dev. 2007;44(5):761-770.

16. Granholm E, McQuaid JR, McClure FS, Link PC, et al. Randomized controlled trial of cognitive behavioral social skills training for older people with schizophrenia: 12-month follow-up. J Clin Psychiatry. 2007;68(5):730-737.

17. Levin ED, Rezvani AH. Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function. Biochem Pharmacol. 2007;74(8):1182-1191.

18. Prochaska JJ, Hall SM, Bero LA. Tobacco Use Among Individuals With Schizophrenia: What Role Has the Tobacco Industry Played? Schizophr Bull. 2007 Dec 10 [Epub ahead of print].

19. Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry. 2007;64(10):1115-1122.

20. Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new therapeutic target? Trends Pharmacol Sci. 2007;28(11):561-566.

21. Robbins MJ, Starr KR, Honey A, Soffin EM, et al. Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res. 2007 Jun 4;1152:215-227. Epub 2007 Mar 15.

22. Castner SA, Williams GV. Tuning the engine of cognition: a focus on NMDA/D1 receptor interactions in prefrontal cortex. Brain Cogn. 2007;63(2):94-122.

23. Buchanan RW, Davis M, Goff D, Green MF, et al. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull. 2005;31(1):5-19.

24. Moore TA, Buchanan RW, Buckley PF, Chiles JA, et al. The Texas medication algorithm project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psych. 2007;68(11):1751-1762.

25. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50(11):884-897.

26. Manschreck TC, Boshes RA. The CATIE Schizophrenia Trial: Results, Impact, Controversy. Harv Rev Psychiatry. 2007;15(5):245-258.

27. Swartz MS, Perkins DO, Stroup TS, Davis SM, et al. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428-436.

28. Kucukalic A, Džubur-Kulenovic A, Mehmedika-Suljic E. Relapse prevention in schizophrenia - new therapeutic challenges. Psychiatr Danub. 2007;19(4):362-366.

29. Valenstein M, Ganoczy D, McCarthy JF, Myra Kim H, et al. Antipsychotic adherence over time among patients receiving treatment for schizophrenia: a retrospective review. J Clin Psychiatry. 2006;67(10):1542-1550.

30. Tunis SL, Faries DE, Stensland MD, Hay DP. An examination of factors affecting persistence with initial antipsychotic treatment in patients with schizophrenia. Curr Med Res Opin. 2007;23(1):97-104.

31. Moore TA, Buchanan RW, Buckley PF, Chiles JA, et al. The Texas medication algorithm project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psych. 2007;68(11):1751-1762.

32. Tandon R, Carpenter WT, Davis JM. First- and second-generation antipsychotics: learning from CUtLASS and CATIE. Arch Gen Psychiatry. 2007;64(8):977-978.

33. Egan MF, Straub RE, Goldberg TE, Yakub I, et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci U S A. 2004;101(34):12604-12609.

34. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40-68; image 5.

35. Laruelle M, Frankle WG, Narendran R, Kegeles LS, Abi-Dargham A. Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther. 2005;27 Suppl A:S16-24.

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