recent advances in schizophrenia management · schizophrenia or schizoaffective disorder...
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Recent Advances in Schizophrenia Management
Matcheri S. Keshavan, MDStanley Cobb Professor of Psychiatry, Harvard Medical School, Vice Chair of Public Psychiatry Beth Israel Deaconess Medical Center and Massachusetts Mental Health Center
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Issues We’ll Touch Upon
Burden of disease and unmet therapeutic needs in schizophrenia
Current understanding on schizophrenia neurobiology and how it relates to treatment
Review safety and efficacy of available antipsychotics Identifying and managing nonadherence Future trends in schizophrenia
Schizophrenia: Burden of Disease and Unmet Treatment Needs
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Pharmacologic Treatment of Any Disease
Know the disease that you are treating• Nature; treatment targets; treatment goals
Know the treatments at your disposal• What they do; how they compare; costs
Principles of treatment• Measurement-based; targeted; individualized
Tandon R, et al. Schizophr Res. 2009;110(1-3):1-23.
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Prevalence of Schizophrenia
Tandon R, et al. Schizophr Res. 2008;102(1-3):1-18.
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Schizophrenia: Economic Burden (2013)
Cloutier M, et al. J Clin Psychiatry. 2016;77(6):764-771.
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Schizophrenia: Heterogeneous Disease with Many Dimensions
Tandon R, et al. Schizophr Res. 2009;110(1-3):1-23.
Orbitofrontal Cortex
Prefrontal Cortex
Medial prefrontal, amygdala
N. accumbens,reward circuits
Mesolimbic,hippocampus
Thalamus,basalganglia
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Psychosis Begins in Adolescence, but Cognitive Deficits Begin EarlierEffect sizes from 4 meta-analyses on cross-sectional IQ impairment in individuals with
psychosis or at risk for psychosis compared to controls (Cohen’s d).
PRE=premorbid; PRO-C=prodrome converter; FE=first episode; CSZ=chronic schizophrenia.Liu, Keshavan and seidman. Schizophr Bull. 2015;41(4):801-816.
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Unmet Needs in Schizophrenia
Cognitive impairments Negative symptoms Treatment-resistant positive symptoms Side effects Treatment nonadherence
Neurobiology of Schizophrenia: Current Understanding
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NMDA receptor hypofunction
Mesencephalic DA nuclei
GABAInter-neurons Increased
Mesolimbic DA
PSYCHOSIS
NEGATIVE/Cognitive symptoms
InefficientGlu activity
The emerging model of the brain chemical “imbalance”in schizophrenia.
1212Keshavan et al prog Neurobiol 2015
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NMDA receptor
hypofunction
Reduced GABA
inhibitoryactivity
Increasedexcitatoryglutamat-
ergicactivity
Increased phasic
DA activity
Decreased Tonic
DA activity
Cognitive deficits
Negative symptoms
Positive symptoms
Gen
etic
fact
ors
Envi
ronm
enta
l /D
evel
opm
enta
lIn
sults
/ str
ess
HPA axis overactivity
Affective symptoms
Increased oxidative
stress
Brain Inflammation?
ReducedGamma
oscillations
Epig
enet
icfa
ctor
s
An impaired balance between excitatory and inhibitory circuitsmay underlie at least part of the pathophysiology of schizophrenia.Keshavan et al Schiz Res 2013
Management of Schizophrenia: Current Pharmacotherapy
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Clinical Nature of Schizophrenia: What We Know Chronic, remitting and relapsing disease with incomplete remissions Multiple symptom dimensions
• Different time course, neurobiology, & patterns of treatment response
Distinct natural course of illness• Distinct stages with evolution of pathology• Begins premorbidly and progresses through prodrome to
psychosis • Much of the decline occurs early in the illness• Functional impairment and social dysfunction peaks within
3 to 5 years of psychotic phase
Tandon R, et al. Schizophr Res. 2010;122(1-3):1-23.
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Toward measurement-based care: Diagnosis-Specific Severity Assessment:Symptom Domains
Hallucinations Delusions Disorganized speech Abnormal psychomotor
behavior (catatonia) Negative symptoms Impaired cognition Depression Mania
0 = Not Present 1 = Equivocal 2 = Present, but mild3 = Present and moderate 4 = Present and severe
Tandon R, et al. Schizophr Res. 2013;150(1):3-10.
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Relapse is Common in Schizophrenia
Robinson D, et al. Arch Gen Psychiatry. 1999;56(3):241-247; Csernansky JG, et al. CNS Drugs. 2002;16(7):473-484; Kane JM. J Clin Psychiatry. 2007;68 Suppl 14:27-30; Lewis DA, et al. Neuron. 2000;28(2):325-334; Levander S, et al. Acta Psychiatr Scand Suppl. 2001;104(408):65-74; Briggs A, et al. Health Qual Life Outcomes. 2008;6:105.
About 82% of patients with schizophrenia or schizoaffective disorder experienced ≥1 relapse over 5 years
Relapse can cause:• Rehospitalization• Slow and incomplete recovery• Treatment-resistant illness• Persistent symptoms• Progressive cognitive decline• Increasing difficulty to regain
previous level of functioning• Reduced quality of life
Cumulative relapse rates in patients with schizophrenia, by year following recovery
from the first episode
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First-Generation Antipsychotics (FGAs)
Drug Dose Range Side Effects
HIGH-POTENCY High selectivity for D2
Haloperidol 6-20 mg/day EPS
Fluphenazine 6-20 mg/day EPS
MID-POTENCY Medium selectivity for D2
Perphenazine 8-64 mg/day Moderate-high EPS, mild sedation
Loxapine 30-100 mg/day Moderate EPS, moderate sedation
LOW-POTENCY Low selectivity for D2; H1, AChR, AR antagonism
Chlorpromazine 100-1000 mg/day
Sedation, anticholinergic side effects, hypotension
AChR=acetylcholine; AR=adrenergic; EPS=extrapyramidal symptoms; H1=histamine.Buchanan RW, et al. Schizophr Bull. 2010;36(1):71-93.
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Second-Generation Antipsychotics (SGAs)Drug Dose Range Side EffectsClozapine 25-900 mg/day Sedation, weight gain, agranulocytosis
Olanzapine 5-20 mg/day Sedation, weight gain, dyslipidemia
Risperidone 0.5-8 mg/day Sedation, weight gain, hyperprolactinemia
Paliperidone 3-6 mg/day Sedation, weight gain, hyperprolactinemia
Quetiapine 25-750 mg/day Sedation, weight gain, postural hypotension
Asenapine 10-20 mg/day Sedation, weight gain, EPS
Iloperidone 12-24 mg/day Sedation, moderate weight gain
Ziprasidone 40-160 mg/day, with food
Akathisia, QTc prolongation, minimal weight gain
Lurasidone 40-160 mg/day, with food
Akathisia, EPS, minimal weight gain
Freudenreich O, et al. Antipsychotic Drugs. In: Stern TA, et al (eds). Massachusetts General Hospital Clinical Psychiatry (2nd edition). Elsevier, 2016:475-488.
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Partial Agonist/Antagonist Antipsychotics
Drug Dose Range Side effects
Aripiprazole 10-30 mg/day Akathisia, activation, someweight gain, tremor
Brexpiprazole 2-4 mg/day Akathisia, insomnia, minimal weight gain
Cariprazine 3-6 mg/day Akathisia, EPS, insomnia, tremor, minimal weight gain
Kane JM, et al. J Clin Psychiatry. 2002;63:763-771; Kane JM, et al. Schizophr Res. 2016; 174:93-98; Citrome L. Clin Schizophr RelatPsychoses. 2016; 10:109-119.
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Treatment Selection with Antipsychotics
All antipsychotics are effective against psychotic symptoms
Clozapine is more effective than other agents in otherwise treatment-refractory patients
SGAs have lower risk of EPS and TD than FGAs Each medication has unique side effects Each medication has unique pharmacokinetics Individual patients may respond preferentially to
different medications
SGA=second-generation antipsychotic; FGA=first-generation antipsychotic; EPS=extrapyramidal symptoms; TD=tardive dyskinesia.Bruijnzeel D, et al. Asian J Psychiatr. 2014;11:3-7.
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Sedating Reduced cognitive performance
and functional capacity5
Risk of unintentional injury3
CardiovascularSuggested link to torsade de pointes, but risk is minimal7
Activating – akathisia
Cognition: selective attention, perception, discrimination, coping responses2Emotional symptoms: depression,
obsessive–compulsive, distress, paranoid ideation1
Sexual/endocrine Prolactin elevation can have
profound effects on reproductive health and sexual function8
Extrapyramidalsymptoms
Risk of tardive dyskinesia6
Cognitive dysfunction6
Negative symptoms6
Cardiometabolic – weight gain; hypertension
Secretive eating9
Difficulty establishing intimate relationships9
Lack of a sense of self-worth9
Antipsychotic agents cause range of side-effects- can profoundly impact patient’s life
1. Kim JH et al. Compr Psychiatry. 2002;43(6):456-462; 2. Kim JH, et al. J Clin Pharm Ther. 2007;32(5):461-467; 3. Said Q, et al. PharmacoepidemiolDrug Saf. 2008;17(4):354-364; 4. DiBonaventura M, et al. BMC Psychiatry. 2012;12:20; 5. Loebel AD, et al. CNS Spectr. 2014;19(2):197-205; 6. TandonR, et al. Ann Clin Psychiatry. 2002;14(2):123-129; 7. DeGrote et al. Psychol Res. 2017;7(5):287-296; 8. Bains & Shah. Adv Pharmacoepidemiol Drug Saf. 2012;1(2):1000109; 9. Usher K, et al. J Psychiatr Ment Health Nurs. 2013;20(9):801-806.
Side-Effects
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SGAs are Better than FGAs for Most
Tandon R, et al. Schizophr Res. 2010;122(1-3):1-23.
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Limitations of Antipsychotic Therapies
Incomplete efficacy Significant adverse effects
Poor treatment adherence• Leads to recurrent relapses with adverse consequences• Higher mortality• Worse functional ability• Worse quality of life
Keshavan MS, et al. Prog Neurobiol. 2017;152:3-20.
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The Best Treatment Today:Targeted, Measurement-Based, Individualized
Targeted• Define targets for AND with patient
Ongoing, careful monitoring is critical!• Reliable and repeated assessment of the efficacy of
treatment using defined treatment targets– Use standard rating scales: DSM-5 Scale, CGI, PANSS
• Careful assessment of adverse effects of treatment– Protocols for health monitoring
• Ongoing collaboration with patient in decision-making Standard protocols should be customized in response
to individual vulnerabilities/needs and specific agent
CGI=Clinical Global Impression; PANSS=Positive and Negative Syndrome Scale.Bruijnzeel D, et al. Asian J Psychiatr. 2014;11:3-7.
The Issue of Nonadherence: Identifying and Managing
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Medications Don’t Work When Patients Don’t Take Them! Consequences of poor adherence
• Increases likelihood of illness exacerbation• Impairs recovery• Associated with illness progression• Impairs functional recovery • Treatment costs are higher
Poor adherence leads to a 3-fold increase in risk of relapse and relapse prevention is CRITICAL.
Tandon R, et al. Schizophr Res. 2010;122(1-3):1-23.
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Antipsychotics Reduce Relapse Rates (70%)
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
Placebo
Antipsychotic
Estim
ated
Per
cent
of P
atie
nts W
ithou
t a R
elap
se
Days since Randomization
Log-rank test, P-value < 0.0001
Antipsychotics vs Placebo
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Methods to Improve Adherence
Adherence training (eg, motivational interviewing, CBT)
Hand-holding Patient-specific behavioral tailoring Reminder cues Simplify treatment regimens Encourage disease acceptance Patient/family psychoeducation Long-acting antipsychotic formulations
Bruijnzeel D, et al. Asian J Psychiatr. 2014;11:3-7.
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LAIs Have Less Relapses Than Oral Antipsychotics
Time to first psychotic exacerbation and/or relapse as a function of form of medication administration in 83 patients.Subotnik KL, et al. JAMA Psychiatry. 2015;72(8):822-829.
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Long-Acting Injectable AntipsychoticsDrug Dose (IM) & Frequency Notes
Haloperidol decanoate 50-300 mg Q4wks Overlap with PO
Fluphenazine decanoate 12.5-100 mg Q2-3wks Overlap with PO
Risperidone LA (Consta)Risperidone (Perseris)
25-50 mg Q2wks90-120 mg monthly
3 week overlap with PONo overlap with PO
Paliperidone palmitate(Sustenna)
39-234 mg Q4wks273-819 mg Q12wks
No overlap with PO Q12wks can be used after 4 months on Q4wks
Olanzapine pamoate 150 or 300 mg Q2wks405 mg Q4wks
No overlap with POMonitor for 3 hours post injection
Aripiprazole monohydrate (Maintena)
300, 400 mg Q4wks 2 week overlap with PO
Aripiprazole lauroxil 441, 662, 882 mg Q4wks882 mg Q6wks1064 mg Q8wks
3 week overlap with PO(One day alternative withAripiprazole initio inj+ single oral dose)
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LAI Antipsychotics: Advantages
No need for daily administration Guaranteed administration and transparency of adherence If a relapse occurs, it is due to other reasons beyond nonadherence Lower relapse rates Minimal GI absorption problems, circumventing first-pass metabolism More consistent bioavailability More predictable correlation between dosage and plasma levels Reduced peak-trough plasma levels Improved patients’ and physicians’ satisfaction Regular contact between the patient and mental healthcare team Improved patient outcomes
Brissos S, et al. Ther Adv Psychopharmacol. 2014;4(5):198-219; Salquerio M, et al. Int Clin Psychopharmacol. 2019;34(2):51-56.
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LAI Antipsychotics: Disadvantages
Slow dose titration Longer time to achieve steady state levels Less flexibility of dose adjustment Delayed disappearance of distressing and/or severe side effects Pain at the injection site can occur, and leakage into the
subcutaneous tissue and/or the skin may cause irritation and lesions (especially for oily LAI)
Perception of stigma
Brissos S, et al. Ther Adv Psychopharmacol. 2014;4(5):198-219.
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Current Recommendations: LAIs
LAIs should not be restricted to patients with adherence problems, but instead should be more widely prescribed
LAIs should systematically be offered to all patients through shared decision-making
Any patient for whom long-term treatment is indicated should be considered a candidate for an LAI
Even if patients initially refuse an LAI, it would be helpful to discuss it further to better understand the potential advantages
Kane JM, et al. Br J Psychiatry Suppl. 2009;52:S63-S67.
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Communication with Patient
Many psychiatrists believe that their patients who take oral antipsychotics would, if offered, refuse a recommendation for LAI antipsychotic medications
Research suggests that the offer of LAI therapy itself is often characterized by hesitation and reluctance and that this may hinder the acceptance rate
Patients might have accepted the offer of LAI therapy if it had been presented differently
A common reason for non-acceptance of LAI therapy may be that psychiatrists are ambivalent or unenthusiastic about this option even as they recommend it
Weiden PJ, et al. J Clin Psychiatry. 2015;76(6):684-690.
Novel Therapeutic Targets and Adjunctive Treatments
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Schizophrenia: New Drugs Lead the Way
Available at www.schizophrenia.com.
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cAMP/cGMPPhospho-diesterase
D-serineGlycine
Glutamate
Astrocyte
Pre-synapticneuron
Post-synapticneuron
mGluR5
GABAinterneuron Pyramidal
Glutamatergic neuron
Glutamine
AMPA
Calcium channels
Oxidative stress
Glutathione
GlyT1
1. GABA allosteric modulators2. NMDA agonists (glycine, D-serine)3. 5HT2 antagonists4. GlyT1 inhibitors5. A-7 nicotinic receptor agonists6. MGlu2/3 agonists7. Dopamine D1 agonists8. PDE 10 antagonists9. CB1 antagonists10. COMT agonists11. Ampakines12. Antioxidant (N-acetylcysteine)13. Anti-inflammatory agents
(celecoxib, minocycline)
CB1
COMT
1
2
3
4
5
12
2
3
56
78
9
1011
dopamine neuron
5
7
Inflammation(cytokines, antibodies)
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MANY WAYS TO TARGET THE SYNAPSE
Keshavan MS, et al. Prog Neurobiol. 2017;152:3-20.
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Raphe
5HT
VTADA
5 HT2a,2c
GLU
GABA
5 HT1a
Prefrontal cortex Serotonin (pimavanserin, Nuplazid)
Nasrallah HA, et al. Schizophr Res. 2019 Mar 2. [Epub ahead of print]; McGuire P, et al. Am J Psychiatry. 2018;175(3):225-231; Solmi M, et al. CNS Spectr. 2017;22(5):415-426; Conus P, et al. Schizophr Bull. 2018;44(2):317-327.
Potential Therapeutic Targets
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GLU Raphe
ACh
VTADA
GABA
Encenicline,ongoing studies
A7 nicotinic,M1 muscarinic
Prefrontal cortex Other potential pharmacological targets: Acetylcholine
Keefe R et al Neuropsychopharmacology 2015
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Other potential pharmacologicaltargets: Cannabinoid agonistsCannabidiol: mixed results
GLU
VTADA
GABA
Prefrontal cortex
CannabinoidsCBDRimonabant
CB1
CB1
McGuire P, et al. Am J Psychiatry. 2018;175(3):225-231.
McGuire, AJP 2018
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Inflammation
Oxidative stress
Glu
tam
ater
gic
dysf
unct
ion
Anti-inflammatory agentsMinocycline, metformin
Anti-oxidantsN-acetyl cysteine
GLU
GABA
Prefrontal cortex
VTADA
Solmi M, et al. CNS Spectr. 2017;22(5):415-426.; Conus P, Seidman L, Keshavan Met al. Schizophr Bull. 2018;44(2):317-327.
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Cognitive Remediation Can Reverse Gray Matter Deficits
Eack SM, et al. Arch Gen Psychiatry. 2010;67(7):674-682.
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ValbenazineIngrezza
a new medicinefor TD
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Stratified medicine (e.g. circuit based)
Precision medicine
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Circuit based treatments? Neuromodulation Can Improve Symptoms via Network Manipulation
Hypothesis: If network disconnectivity causes negative symptoms, modulating connectivity by repetitive transcranial magnetic stimulation (rTMS) should modulate symptom severity.
• Clinical characterization• fMRI Imaging
2x/Day rTMS targeted to cerebellar target ID’d in Connectomic study
Result: TMS induced increase in connectivity strongly and significantly correlates with improvement in negative symptoms (r=-0.809, p=0.003). Active rTMS resulted in a greater change in Cerebellar-DLPFC connectivity than sham rTMS, (p = .017).
Brady RO Jr, et al. Am J Psychiatry. 2019 Jan 30. [Epub ahead of print]
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Precision medicine approaches? Bodkin et al Glycine supplementation effective in patients with Glycine
decarboxylase gene copy number variant (Bodkin, Deb Levy et al BiolPsychiatry 2019
Kelly et al Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): Deanna Kelly et al J Psychiatry Neurosci. 2019
Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia. (Palmer et al SchizRes 2019
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Prevention is Possible at Several Stages
RecoveryPremorbidProdromal
Psychotic
Transitional
Secondaryprevention
Tertiary Prevention
Primary Prevention
Early detectionof riskParental supportFamily-centeredcare
CBT, family-centered careCognitive remediationAnti-inflammatory treatmentsAntioxidantsOmega-3 fatty acidsGABA modulators
Relapse preventionOptimal pharmacotherapyEarly detection of treatment resistanceAddressing comorbid mood, medical and substance use disordersCognitive rehabilitation, exerciseSupportive employment
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Summary While the neurobiology of schizophrenia is increasingly better understood,
many unmet therapeutic needs remain. All currently used antipsychotics impact dopaminergic function, are
effective in psychosis, but are limited by metabolic and/or extrapyramidal side effects, and treatment resistance in many patients.
Clozapine is an effective treatment for treatment-resistant schizophrenia, but is limited by substantive side effects.
Nonadherence is a common problem; long-acting injectable antipsychotics have an important role in management of nonadherence.
Best treatment practice today involves a targeted, individualized and measurement-based approach.
Novel treatments being investigated include drugs targeting non-dopaminergic mechanisms (such as glutamate, serotonin), neuromodulation and psychosocial approaches such as cognitive remediation.
Circuit-based and precision medicine based interventions are on the way
Thank You!