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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!