Transcript MORPHINE-INDUCED NEUROTOXICITY: POSSIBLE …

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.
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
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
Contribution by different non-communicable diseases
to disability-adjusted life-years worldwide in 2005
•Prince et al, Lancet, 2007
Schizophrenia is Heritable
Disorder
Autism
Schizophrenia
Type II DM
Rheumatoid Arthritis
Alcohol Dependence
Asthma
Major Depressive Disorder
Breast Cancer
Smoller, Sheidley, Tsuang 2007
Psychiatric Genetics: Application in Clinical Practice
Approx. h2
90%
80%
80%
60%
55%
48%
42%
27%
Schizophrenia:
Core Symptom Clusters
I. Positive symptoms
• Delusions
• Hallucinations
• Disorganization
II. Negative symptoms
• Blunted affect
• Alogia
• Avolition
• Anhedonia
Social/occupational dysfunction
Work/interpersonal relationships
Self-care
IV. Affective symptoms
• Dysphoria
• Suicidality
• Hopelessness
III. Cognitive symptoms
• Attention
• Memory
• Executive functions
(eg, abstraction)
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth ed. Text Revision.
Washington DC: American Psychiatric Association. 2000.
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 firstgeneration 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 Antidepressant
Treatment on Hippocampal Neurons
Hippocampus
CA1
sc
Dentate gyrus
CA3
Granule
cell
mf pathway
Stress
 Glucocorticoid
Antidepressant
treatment
Stress
 NE and 5-HT
 Glucocorticoid
 BDNF
 BDNF
Atrophy
or death
Increased
survival
and growth
Increased vulnerability as a result of
environmental and genetic factors
Derived from: Duman RS et al. Biol Psychiatry. 1999;46:1811–1191.
Decreased
neurogenesis
Antidepressant
treatment
 NE and 5-HT
Increased
neurogenesis
SAMe, Methylfolate and Omega-3 Fatty Acids
and 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 antiinflammatory 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)
Amantadine and Inflammation
• Treatment with amantadine (AMA), an N-methyl-Daspartate (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.
Riluzole Increases BDNF and Cell
Proliferation
Katoh-Semba et al FASEB J. 2002 Aug;16(10):1328-30.
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)
Cognitive Remediation
McGurk and Mueser, Am J Psychiatry, 2007
Cognitive Enhancement Therapy Prevents
Brain Volume Loss in Early-stage Schizophrenia
Eack, S. M. et al. Arch Gen Psychiatry 2010;67:674-682
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
Cumulative Relapse Rate (%)
Effects of Family Intervention on 2-Year
Cumulative Relapse Rates in Schizophrenia (12 Studies)
100
75
59
Standard care (n=203)
Single family treatment (n=231)
Multiple family group treatment (n=266)
Single and multiple family group treatment
(n=243)
50
29
25
0
McFarlane WR et al. J Marital Fam Ther. 2003;29(2):223
28
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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. 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.
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
Thank You!
“You must be the change you
want to see in the world.”
Mahatma Gandhi