LAT for the Management of Schizophrenia

Prof. Hani Hamed Dessoki, M.D.Psychiatry Prof. Psychiatry

Acting Dean, Faculty of Applied Mental Health sciences

Beni Suef University

Supervisor of Psychiatry Department

El-Fayoum University

APA member

2017

DisclosureProf. Hani H. Dessoki, MD Psychiatry, has disclosed the following relevant financial relationships:

• Served as an advisor or consultant for: Lundbeck, Inc.; Hikma Pharmaceutical PLC; Apex Multi-Apex Pharma.

• Served as a speaker for: AstraZeneca Pharmaceuticals LP; Eli Lilly and Company; Janssen Pharmaceuticals Inc; Lundbeck, Inc.; Otsuka Pharmaceutical Co., Ltd.; Pfizer Inc.; Hikma Pharmaceutical PLC; Apex Multi-Apex Pharma, Mash Primeire For Pharmaceutical Industry.

• Some promotional data provided by Janssen.

Objectives

• Introduction• Biology of schizophrenia• Outcome & Relapse rate • Biology of relapse• When and why LAT• Take Home Message• Recent data

Stor

ies

of

Schi

zoph

reni

a

Schizophrenia Spectrum Disorders• The prevalences of schizophrenia and schizophrenia-related

personality disorders in the general population are 1% and 5%, respectively; the prevalence of both together is 6%.

• Approximately 20% of family members of an individual with schizophrenia have spectrum manifestations.

• Moreover, approximately 20% of persons with spectrum manifestations have symptoms that are severe enough to impair work function and may benefit from antipsychotic treatment

Response

Remission

Relapse

Emergent refractoriness

RECOVERY

ACUTE PSYCHOTIC EPISODE

Partial response

Autonomy

Independent living

Quality of life

Social and occupational functioning

Shaping a future for schizophrenia patients

Dopamine hypothesis of schizophrenia

Nigrostriatalpathway(part of extrapyramidal motor system)

Tuberoinfundibular pathway(inhibits prolactin release)

Mesocorticalpathway

Hypoactivity:negative symptoms,cognitive impairment

Hyperactivity:positive symptoms

Mesolimbicpathway

Adapted from: Inoue & Nakata. Jpn J Pharmacol 2001;86:376–38010

Differential effects of receptor blockade in key dopamine pathways (1)

• Excess dopamine is associated with positive symptoms• D2 receptor blockade in this pathway can help reduce

positive symptoms

Mesolimbic pathway

• Deficits in dopamine are associated with negative and cognitive symptoms

• The mesocortical pathway is rich in 5-HT2A receptors • Serotonin receptor antagonists increase dopamine levels

and alleviate negative and cognitive symptoms

Mesocortical pathway

D, dopamine; 5-HT, serotonergic

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 3rd edition. 2008

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• Forms part of the extrapyramidal system and mediates motor control

• Dopamine receptor antagonism causes movement disorders such as EPS

• 5-HT2A antagonists disinhibit dopamine release, and may alleviate EPS

Nigrostriatal pathway

• Dopamine activity inhibits prolactin release, whereas serotonin stimulates its release

• Blockade of D2 receptors increases prolactin release and may cause sexual side effects

• Balancing dopamine and 5-HT2A antagonism is critical

Tubero-infundibular pathway

EPS, extrapyramidal symptoms;TD, tardive dyskinesia; 5-HT, serotonergic; D, dopamine

Differential effects of receptor blockade in key dopamine pathways (2)

Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 3rd edition. 2008

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• In order to fully understand the properties of antipsychotics, it is imperative to examine the serotonin (5HT) pathways throughout the brain and how they modulate DA and glutamate circuits.

Key Serotonin Pathways

• 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is on glutamate).

Glutamate acts as accelerator on dopamine in mesocortical area, and act as a brake in mesolimbic area.

Basic Conclusion• Glutamate acts as accelerator on dop. in mesocortical area.• Glutamate acts as brake on dop. in mesolimbic area. • 5HT 1A acts as accelerator on dop. • 5HT2A acts as brake on dop. • 5HT 1A acts as brake on glutamate. • 5HT2A acts as accelerator on glutamate.

So, atypical antipsychotics (mainly serotonergic, can decrease dopamine in mesolimbic area by 2 mechanisms 1st: it’s brake effect on dopamine through 5HT2A, and the 2nd is it’s accelerator effect on glutamate which is brake on dopamine).

Future of Biology

• The availability of the very new resource of the sequenced human genome is challenging our field to take advantage of this critical genetic information.

• Tracing the genetic basis of the cerebral mechanisms that, might, express a particular genetic defect in psychosis or in a disease like schizophrenia will require specific information about, the human schizophrenic brain.

Outcomes in schizophrenia

• Long-term clinical outcomes are variable. Approximately 10–15% of patients will not experience further episodes

• The majority of patients display exacerbations and experience clinical deterioration

• From the outset, 10–15% of patients remain chronically, severely psychotic

Long-term clinical outcomes are

variable1

• Associated with clinical deterioration2

• High level of distress and burden for carers3

Early in the disease course,

patients respond well to treatment

but frequently relapse2

1. APA Practice Guidelines, 2004. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2ePG_05-15-06; 2. Robinson et al. Arch Gen Psychiatry 1999;56:241–247;

3. Awad & Voruganti. Pharmacoeconomics 2008;26:149–16219

Recovery in schizophrenia

This review concluded that 42% of patients had a good outcome

13.5% of patients met recovery criteria

Recovery may be treatment-related or spontaneous

20Jääskeläinen et al. Schizophr Bull 2012. Nov 20 [Epub ahead of print]

• Jääskeläinen et al meta-analysis of 50 studies• Primary aims were to:

• Identify the proportion of individuals with schizophrenia and related psychoses who met recovery criteria

• Examine which factors were associated with recovery

Risk and protective factors for relapse among Individuals with Schizophrenia

• People with schizophrenia and their caregivers perceived non adherence to antipsychotic medication as a leading risk factor of relapse; other risks included poor family support, stressful life events and substance use.

• Family support, adherence to antipsychotic medication, employment and religion were viewed as protective factors.

• Participants suggested strengthening mental health psycho-education sessions and community home visits conducted by mental health nurses to help reduce relapse.

BMC Psychaitry,2014

The Nature of Relapse in Schizophrenia

• Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse.

• Many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs.

• The response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients.

BMC Psychiatry2013, 13:50

Is relapse associated with disease progression?

• Active psychosis may affect the brain in a more fundamental way. It has been suggested that psychosis may be neurotoxic and that acute psychotic exacerbations represent active periods of a morbid process that leads to disease progression and to impairment of treatment response.

Is relapse associated with disease progression?

• Treatment response has been observed to be better in first-episode schizophrenia than in chronic multi-episode schizophrenia .

• A study utilizing the neuroleptic threshold principle found that first-episode patients required lower doses of haloperidol to achieve optimal clinical response than multi-episode patients.

Neurobiology of Relapse in Schizophrenia

• The dopamine hypothesis of schizophrenia has been central to our understanding of neurobiological mechanisms underpinning the illness, and dopamine D2 receptor blockade remains a necessary and sufficient component for antipsychotic action.

• Therefore relapse, characterized by acute psychotic exacerbation, would be associated with striatal dopamine hyperfunction, likely as elevation of presynaptic dopamine synthesis.

Neurobiology of Relapse in Schizophrenia

• Cortical and limbic striatal (nucleus accumbens) dopamine release is regulated by a glutamate-GABA-glutamate loop located on pyramidal cells of the frontal cortex.

• Cortical hypoglutamatergia in turn compromises dopamine release in the ventral tegmentum leading to meso-limbic hyperdopaminergic and meso-cortical hypodopaminergia that we observe as positive or negative symptoms, respectively.

Neurobiology of Relapse in Schizophrenia

• Mesolimbic dopaminergic supersensitivity after chronic antipsychotic treatment could explain the emergence of antipsychotic treatment failure.

• The kindling phenomenon has also been linked to increased excitatory glutamatergic activity combined with a relative loss of inhibitory GABA’ergic tone

Relapse Prevention• 5y, Relapse rate 82% (16% 54% 63% 75% 82%).

• after discharge, 8% stop taking antipsychotics • relapse rate of 3.5% of patients/month with good adherence.• Atypical vs Conventional (23% Vs 15%). • Strongest Predictors of Relapse is Adherence/ length of treatment

Decreasing relapse: • Wishful thinking • Integrated strategy approach

• Oral Vs Injectables

Clinical impact of treatment-related adverse events

• The patient’s subjective experience of treatment-related adverse events contributes to their assessment of a drug

• In clinical practice, patients should be informed of common side effects prior to treatment

• Individual tolerability is unpredictable; close monitoring is required

• Different side effects affect patients differently; sometimes related to gender, age and physical condition

Adapted from Hamer & Haddad. Br J Psychiatry 2007;191:s64–s70; Marder et al. Schizophr Bull 2002;28:5‒16

Pooradherence

Relapse

Chronicsymptoms

Reducedqualityof life

Stigma

Physicalmorbidityand mortality

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SGA

FGA

FGA, first-generation antipsychotic; SGA, second-generation antipsychotic

Adverseevents

Under-treatment with FGAs: EPS are most disturbing

Under-treatment with SGAs: sexual side effects, weight gain and sedation can be problematic

High inter-individual variation

Taylor et al. The Maudsley Prescribing Guidelines in Psychiatry. 11th edition; Chichester: Wiley-Blackwell; 2012

FGA, first-generation antipsychotic; EPS, extrapyramidal symptoms; SGA, second-generation antipsychotic

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Impact of side effects on subjective well-being

Guidelines recommend offering early intervention services

• Urgently refer all people with first-episode psychosis to a local community-based secondary mental health service

Offer early intervention services to all patients with a first psychotic episode1

• Pharmacological, psychological, social, occupational and educational services

Early intervention services should aim to provide a full range of:1

• Encourage patients to collaborate on the selection and adjustment of treatment

Develop a therapeutic alliance with the patient and their family during acute phases of illness2

1. Barnes. J Psychopharmacol 2011;25:567–620;2. APA Practice Guidelines, 2004. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?

file=Schizophrenia2ePG_05-15-0632

Guidelines for the use and management of LAI AP in serious mental illness 1

French Society for Biological Psychiatry

• Key points

– LAI antipsychotics should be considered and systematically proposed to any patients for whom maintenance antipsychotic treatment is indicated

– It is recommended to deliver to each patient specific information concerning the advantages and inconveniences of the LAI formulation, in the framework of shared decision-making.

1. Llorca et al (2013)

History of LAIs

• Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment.

• LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 2007.

Clinical pearls

• Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method.

• Peak-related adverse effects typically are not contraindications, although they may prompt you to start at a lower dose.

Benefits of LAT Antipsychotic 1

• Controlled administration :– Early identification of non adherence– Improved adherence– Clear attribution of cause of relapse or non response

• Regular interactions between patient and healthcare provider

• Improved interaction with family1. Kane JM and Garcia-Ribera (2009)

Objectives for LAI development:

◎Early onset of efficacy ◎Constant drug release over weeks/months◎Good tolerability

◎ At injection site, weight gain, EPMS, low drug-drug-interaction…

◎Convenience/ handling◎ Prefilled syringe ◎ Storage at room temperature ◎ gluteal and deltoid injection available

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Opinions of patients with schizophrenia regarding LAI

• Survey in which 206 French schizophrenia patients were interviewed 1

– Ninety-five percent had been treated with more than one form of dosage

• Injections were being preferred by 47% of patients• Oral tablets were being preferred by 35% of patients• Drops were being preferred by 7% of patients

• 51% considered injectable therapy to be more effective than other medication

• 70% felt better supported in their illness by the regular contact with the caregivers

1. Caroli et al (2012)

Attitudes of Psychiatrists and Nurses

• Recently, a survey of 891 European psychiatrists and nurses revealed that 96% preferred LAI medications to oral treatment for patients with chronic schizophrenia, whereas only 40% preferred them for first-episode patients [Geerts et al. 2013].

Cost-effectiveness of LAI AP treatment

• Finally, increase in medication adherence with the use of LAI APs may eventually induce a reduction in the pharmaceutical costs of schizophrenia treatment by a decrease in hospital stays that compensate their higher costs, especially SGAs [Niaz and Haddad, 2010].

• Treatment with LAIs may be also more cost-effective than oral medication, and may reduce the suicide risk and the greater propensity to violence observed at least in a subset of persons with psychotic illnesses and comorbid substance/alcohol use disorders [Ravasio et al. 2009; Reichart and Kissling, 2013].

Paliperidone Palmitate Receptor Profile

Paliperidone palmitate – Key attributes Paliperidone palmitate1

Formulation Aqueous-based suspension

Treatment initiation Initiation injections on Day 1 and Day 8; no oral supplementation required

Maintenance dosing Once-monthly injectionAdministration Deltoid and gluteal IM

Dosage range 25, 50, 75, 100 and 150 mg eq.

How supplied No reconstitution required;prefilled syringes

Storage No refrigeration requiredNeedle supplied or recommended

1 inch (25mm) 23G or 1½inch (38mm) 22G needle (depending on patient weight and injection site)

Post-injection monitoring No*

1. Proposed Xeplion® EU SmPC; 2. Alphs et al. Curr Drug Saf. 2011; 6:43–45

LAI, long-acting injectable; RLAI, risperidone long-acting injectable; IM, intramuscular; UTW, ultra thin wall; TW, thin wall

* No cases of PDSS were identified in an analysis of completed trials2

• Broad dose range• 50, 75, 100, 150 mg (~ 25, 37.5, 50, 75 mg Risperidone LAI)

• Small volume of injection• 0.5, 0.75, 1.0, 1.5 mL

• Deltoid and gluteal administration• Deltoid quicker steady state (see later)• Greater patient choice

Paliperidone – dosing & indication

Deltoid administration – higher Cmax and AUCτ, but similar tmax and AUC∞

1. Xeplion® EU SmPC; 2. Cleton et al. Poster no. PI-75 presented at ASCPT: Orlando, April 2–5, 2008

Paliperidone – Deltoid vs Gluteal profile

*Recommended monthly dose**Some patients may benefit from lower or higher doses based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper range†A switch from gluteal to deltoid (and vice versa) should be considered in the event of injection site pain (if discomfort is not well tolerated).It is also recommended to alternate between left and right sides

INITIATION REGIMEN MAINTENANCE REGIMEN(1 month after 2nd initiation dose)

Day 1 Day 8 +/- 2 days

150 mg eq. Deltoid

100 mg eq. Deltoid

1 month later +/- 7 days

1 month later+/- 7 days

Dose range**

25–150 mg eq.Deltoid/gluteal†

Dose range**

25–150 mg eq.Deltoid/gluteal†

75 mg eq. (recommended*)

Deltoid/gluteal†

75 mg eq. (recommended*)

Deltoid/gluteal†

Xeplion® EU SmPC; Gopal et al. Curr Med Res Opin 2010;26:377–387

Paliperidone – Adminsration

Risperdal Consta Xeplion® 2 weekly injection Monthly injection

Requires cold storage No cold chain3 weeks delay Fast Onset

Oral Supplementation No oral Supplementation3 available doses 4 available doses19 Steps to Inject Inject and go

Xeplion®: Product summary

ROLE OF PSYCHOSOCIAL INTERVENTIONS

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What are the goals of integrated care?

• Reduce the symptoms experienced by patients1,2

• Reduce periods in hospitals3

• Reduce the risk of relapse4

• Preserve patients’ long-term functioning3

• Improve quality of life5

• Improve neurological and social cognition6

• Help patients to develop larger social networks7

• Help patients to find and retain competitive employment and live independently8,9

Good management of schizophrenia can:

1. Emsley et al. Int Clin Psychopharmacol 2008;23:325–331; 2. Emsley et al. J Clin Psychopharmacol 2008;28:210–213; 3. Peuskens et al. Curr Med Res Opin 2010;26:501–509; 4. Kane. N Engl J Med 1996;334:34–41; 5. Ascher-Svanum et al. J Clin

Psychiatry 2006;67:1114–1123; 6. Roder et al. Schizophr Bull 2011;37(suppl 2):S71–S79; 7. Tempier et al. Psychiatr Serv 2012;63:216–222; 8. Twamley et al. J Nerv Ment Dis 2005;193:596–601; 9. Burns et al. Lancet 2007;370:1146–115248

Take Home Messages

• Adherence is an issue in long term treatment of schizophrenia and is frequently underestimated

• LAT has a demonstrated efficacy for relapse prevention and long term treatment of schizophrenia

• LAT is an option to be proposed to all patients with schizophrenia needing a maintenance treatment even in the early phase of illness

• Patients’ perspective is neutral or positive on LAT

Recent Data• FDA Approves New Three-Month Long-Acting Antipsychotic Invega Trinza

(Trevicta)•

The FDA has approved Invega Trinza (paliperidone palmitate), a long-acting atypical antipsychotic intended to treat schizophrenia, from Janssen Pharmaceuticals Inc. 

The approval of the injectable antipsychotic, which remains active in the body for three months, was based on results from a two-year maintenance trial with 506 patients diagnosed with schizophrenia. Theanalysis, published March 29 in JAMA Psychiatry, showed that patients who were administered Invega Trinza were statistically less likely to relapse than those who were administered placebo. The most common adverse effects of the medication included injection-site reactions, weight gain, upper respiratory tract infections, and extrapyramidal symptoms. 

Invega Trinza was approved under the FDA's priority review process, a fast track for drugs thought to represent a significant advance in medical care. It is being marketed by Janssen. 

For more information about psychotropic medications in the pipeline, see thePsychiatric News article "Candidates, Innovation Missing From Psychotropic Drug Pipeline." 

Scientists find chemical pathway responsible for schizophrenia symptoms

• Recent studies have suggested that kynurenic acid (KYNA) plays a key role in the pathophysiology of schizophrenia. People with schizophrenia have been shown to possess higher levels of KYNA than healthy individuals.

• KYNA helps to metabolize tryptophan - an essential amino acid that, in turn, helps the body to produce the "happiness" neurotransmitter serotonin, and the vitamin niacin.

• Additionally, KYNA decreases glutamate - a nonessential amino acid widely recognized as the most important neurotransmitter for healthy brain functioning.

Biological Psychiatry, 2016

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