Schizophrenia Treatment The Next Ten Years

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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
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No health without mental health WHO

• WHO mental health budget approximately 1.8 of
  total budget and no line item for child mental
  health.

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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

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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

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Contribution by different non-communicable
diseases to disability-adjusted life-years
worldwide in 2005

• Prince et al, Lancet, 2007

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Schizophrenia is Heritable
Disorder Approx. h2
Autism 90
Schizophrenia 80
Type II DM 80
Rheumatoid Arthritis 60
Alcohol Dependence 55
Asthma 48
Major Depressive Disorder 42
Breast Cancer 27
Smoller, Sheidley, Tsuang 2007 Psychiatric
Genetics Application in Clinical Practice
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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.
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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.

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• 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.

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• 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

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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.

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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.

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• 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.

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Actions of Stress and AntidepressantTreatment on
Hippocampal Neurons
Hippocampus
CA1
sc
Dentate gyrus
Granule cell
CA3
mf pathway
Stress
Antidepressant treatment
Antidepressant treatment
Stress
? Glucocorticoid
? Glucocorticoid
? NE and 5-HT
? 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.
19994618111191.
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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-a
  and to increase the expression of the
  anti-inflammatory cytokine IL-10 (McClain et al,
  Alcohol 200227(3)185-92).
• In the mouse macrophage cell line RAW264.7, SAMe
  has been shown to reduce TNF-a mRNA levels and
  protein secretion by affecting the binding of
  methylated histone 3 to the TNF-a promoter (Ara
  et al, Hepatology 200847(5)1655-66.).
• Folic acid protects motor neurons against
  inflammation and apoptosis in SOD1 G93A
  transgenic mice (Zhang et al, Neuropharmacology.
  2008 Jun54(7)1112-9)
• A significant reduction with Omega-3 fatty acids
  (fish oil) in plasma concentrations of
  inflammatory biomarkers, including TNF-a and
  IL-6, has been observed in numerous studies (Wang
  et al, Nutrition. 2012 Jun28(6)623-9 Moertl et
  al, Am Heart J 2011161(5)915-9 Zhao et al, J
  Int Med Res 200937(6)1831-41 Papageorgiou et
  al, Eur J Clin Nutr 201165(4)514-9 Tartibian
  et al, Clin J Sport Med 201121(2)131-7)

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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-Dec61(6)1105-12.

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Riluzole Increases BDNF and Cell Proliferation
Katoh-Semba et al FASEB J. 2002
Aug16(10)1328-30.
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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 2009242753. Ponzini, Neurosci lett
  201250613640).
• Minocycline inhibits mitochondrial
  permeability-transition mediated cytochrome c
  release from the mitochondria (Kim and Suh. Behav
  Brain Res 200919616879)
• 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 200919616879)
• 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 Neuropsychopharmaco
  l Biol Psychiatry 20083216606.)
• 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 20091451122)

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Cognitive Remediation
McGurk and Mueser, Am J Psychiatry, 2007
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Cognitive Enhancement Therapy Prevents Brain
Volume Loss in Early-stage Schizophrenia
Eack, S. M. et al. Arch Gen Psychiatry
201067674-682
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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

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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.
200329(2)223
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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.
200580295-303 2. Bell MD et al. J Rehabil Res
Dev. 200542829-8383. Silverstein S et al.
Psychiatr Q. 19986995-105 4. Hogarty GE et
al. Psychiatr Serv. 2006571751-1757.
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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

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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

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Thank You!

• You must be the change you want to see in the
  world.
• Mahatma Gandhi