Schizophrenia Treatment The Next Ten Years

1. Schizophrenia Treatment The Next Ten Years David C. Henderson, MD Director, MGH Schizophrenia Clinical and Research Program Director, MGH Chester M. Pierce Division of Global Psychiatry Associate Professor of Psychiatry, Harvard Medical School

2. “”No health without mental health” WHO WHO mental health budget approximately 1.8% of total budget and no line item for child mental health.

3. Mental health has become a major international public health concern • "We believe that mental health is just as important as physical health, maybe even more so.“ Donna Shalala, former Secretary of the Department of Health and Human Services • "The challenge to humanity is to adopt new ways of thinking, new ways of acting, new ways of organizing itself in society in short, new ways of living.” Our Creative Diversity, UNESCO

4. Consequences of stigma BASAVARAJ He suffers from chronic schizophrenia. He was chained for 15 years at his home in Bangalore till Vidyakar (below left) brought him to Udavum Karangal five years ago. Now in his forties, he is on medication and seems far happier

5. Contribution by different non-communicable diseases to disability-adjusted life-years worldwide in 2005 • Prince et al, Lancet, 2007

6. Schizophrenia is Heritable Smoller, Sheidley, Tsuang 2007 Psychiatric Genetics: Application in Clinical Practice

7. I. Positive symptoms • Delusions • Hallucinations • Disorganization III. Cognitive symptoms • Attention • Memory • Executive functions(eg, abstraction) IV. Affective symptoms • Dysphoria • Suicidality • Hopelessness Schizophrenia: Core Symptom Clusters II. Negative symptoms • Blunted affect • Alogia • Avolition • Anhedonia Social/occupational dysfunctionWork/interpersonal relationshipsSelf-care American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth ed. Text Revision. Washington DC: American Psychiatric Association. 2000.

8. Challenges Over the Next Decade • Despite the increasing number of psychotropic drugs available the mechanisms of action are predominantly the same as the original prototypes developed in the 1950s. • There have been few innovative new compounds developed despite an array of theoretically viable biologic targets. • Although different modes of brain stimulation beyond ECT have been invented (VNS, R-TMS, DBS, DCS), their effectiveness has yet to be established, and their availability is limited. • the psychosocial therapies that have been proven effective are not widely available and inconsistently reimbursed. • The health care financing system and lack of cohesion in public and private health care systems have not met the clinical need and left many patients partially or completely untreated.

9. Numerous studies have demonstrated the dramatic efficacy of antipsychotic drugs in suppressing psychotic symptoms and preventing their recurrence, • Their inability to alleviate the negative and cognitive symptoms of the illness are limited. • In addition, with the exception of clozapine in treatment-resistant patients, the effectiveness of the newer second-generation APDs is not significantly greater than the older first-generation medications.

10. Many psychosocial treatments with established efficacy have been developed but are not readily available or adequately reimbursed • Assertive community treatment, • Cognitive Behavioral Therapy • Supported employment and housing, • Psychoeducation, • Social-skills training, • Cognitive remediation

11. Strategies • Develop treatments based on precedented mechanisms of action and targets (for example, D-2, 5-HT2A receptors). • Refinements of existing therapeutic mechanisms and improvement in the benefit to risk ratios of medications • Pursue novel targets for which there is a theoretical rationale but no proof of the therapeutic concept (for example, drugs targeting • glutamate receptors, • muscarinic and • nicotinic cholinergic receptors, • intracellular signaling proteins like PDE and AKT.

12. Approach • Improve the quality of mental health care by the application of existing knowledge. • Changes in clinical practices, services provided, and reimbursement methods would make a huge difference in the quality of care and outcomes of patients. • ? Greater use of clozapine and long-acting injectables • Broader availability and reimbursement of psychosocial services, and better integration of substance abuse and primary care with mental health services.

13. As risk genes for schizophrenia are identified and their biology elucidated, their products will provide potential targets for new drug development • COMT, DISC-1, neuregulin, proline dehydrogenase, RGS proteins • Through these investigative strategies, new treatments will be developed that may eventually lead to fully effective treatments and ultimately a cure for schizophrenia.

14. Actions of Stress and AntidepressantTreatment on Hippocampal Neurons Hippocampus CA1 sc Dentate gyrus Granule cell CA3 mf pathway Antidepressant treatment Stress Antidepressant treatment Stress Glucocorticoid  NE and 5-HT Glucocorticoid  NE and 5-HT  BDNF BDNF Increased survival and growth Atrophy or death Increased neurogenesis Decreased neurogenesis Increased vulnerability as a result of environmental and genetic factors Derived from: Duman RS et al. Biol Psychiatry. 1999;46:1811–1191.

15. SAMe, Methylfolate and Omega-3 Fatty Acidsand Inflammation • The anti-inflammatory effects of SAMe have been attributed to its ability to reduce the expression of the pro-inflammatory cytokine TNF-α and to increase the expression of the anti-inflammatory cytokine IL-10(McClain et al, Alcohol 2002;27(3):185-92). • In the mouse macrophage cell line RAW264.7, SAMe has been shown to reduce TNF-α mRNA levels and protein secretion by affecting the binding of methylated histone 3 to the TNF-α promoter(Ara et al, Hepatology 2008;47(5):1655-66.). • Folic acid protects motor neurons against inflammation and apoptosis in SOD1 G93A transgenic mice(Zhang et al, Neuropharmacology. 2008 Jun;54(7):1112-9) • A significant reduction with Omega-3 fatty acids (fish oil) in plasma concentrations of inflammatory biomarkers, including TNF-α and IL-6, has been observed in numerous studies(Wang et al, Nutrition. 2012 Jun;28(6):623-9; Moertl et al, Am Heart J 2011;161(5):915-9; Zhao et al, J Int Med Res 2009;37(6):1831-41; Papageorgiou et al, Eur J Clin Nutr 2011;65(4):514-9; Tartibian et al, Clin J Sport Med 2011;21(2):131-7)

16. Amantadine and Inflammation • Treatment with amantadine (AMA), an N-methyl-D-aspartate (NMDA) receptor antagonist reduces the production of the pro-inflammatory cytokines, specifically interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). • In addition, amantadine treatment increased the production of the negative immunoregulator, interleukin-10 (IL-10). • Furthermore, the combined treatment of amantadine with the SSRI fluoxetine, but not imipramine, had a stronger immunomodulatory effect on cytokine production than amantadine alone. Kubera et al, Pharmacol Rep. 2009 Nov-Dec;61(6):1105-12.

17. Riluzole Increases BDNF and Cell Proliferation Katoh-Semba et al FASEB J. 2002 Aug;16(10):1328-30.

18. Minocycline Effects on Inflammation and Neuronal Plasticity • The second-generation tetracycline antibiotic drug minocycline has powerfully anti-inflammatory and neuroprotective effects (Maes et al., Metab Brain Dis 2009;24:27–53.; Ponzini, Neurosci lett 2012;506:136–40). • Minocycline inhibits mitochondrial permeability-transition mediated cytochrome c release from the mitochondria (Kim and Suh. Behav Brain Res 2009;196:168–79) • Minocylcine inhibits caspase-1 and -3 expressions, and the suppression of microglial activation, involvement in some signal pathways, and metalloprotease activity inhibition (Kim and Suh. Behav Brain Res 2009;196:168–79) • Co-administration of minocycline synergized the antidepressant-like action of sub-threshold doses of desipramine (but not fluoxetine), mGluR1 antagonist EMQMGM, mGluR5 antagonist MTEP, and NMDA receptor antagonist dizocilpine (Molina-Hernandez et al., Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1660–6.) • Minocycline attenuated lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines, and that this drug prevented LPSinduced development of depressive-like behaviors in mice (O'Gonnor et al., Mol Psychiatry 2009;14:511–22)

19. Cognitive Remediation McGurk and Mueser, Am J Psychiatry, 2007

20. Cognitive Enhancement Therapy Prevents Brain Volume Loss in Early-stage Schizophrenia Eack, S. M. et al. Arch Gen Psychiatry 2010;67:674-682

21. Integration of Mental Health in Primary Care System • SMI has worst outcomes compared to general population in several chronic diseases such as obesity, diabetes and cardiovascular disease • Poorer outcomes even when utilizing primary health care system • Best Models • New approaches with changes in Health Care- Massachusetts leading the way

22. Standard care (n=203) Single family treatment (n=231) Multiple family group treatment (n=266) Single and multiple family group treatment (n=243) Family Psychoeducation Research Effects of Family Intervention on 2-Year Cumulative Relapse Rates in Schizophrenia (12 Studies) 100 75 59 Cumulative Relapse Rate (%) 50 29 28 26 25 0 McFarlane WR et al. J Marital Fam Ther. 2003;29(2):223

23. Psychosocial Approaches to Specific Targets • Facial affect recognition can be enhanced with special training1 • Cognitive training can improve working memory2 • Attention can be improved with specialized training3 • Cognitive Enhancement Therapy (CET) improved neurocognition and processing speed4 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838;3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757.

24. Prevention • Identify at risk individuals (such as children of individuals with schizophrenia) • Implement preventive strategies including the use of vitamins, agents that reduce inflammation and promote neurogenisis • Utilize existing psychosocial such as cognitive enhancement therapies that prevent brain volume loss

25. Conclusions • Compounds that increase brain energy metabolism may be useful augmentation strategies in TRD • Medications and nutraceuticals with antiinflammatory properties have shown promise in the treatment of MDD • Agents that increase neurogenesis and neuronal plasticity may be protective • New service delivery models need to be implemented to address both mental health and physical health • Prevention, Prevention, Prevention

26. Thank You! “You must be the change you want to see in the world.” Mahatma Gandhi