Schizophrenia & Medicines Management · improvement in negative symptoms •Modest benefits at best with: –Clozapine –Amisulpride –Aripiprazole –Olanzapine –Quetiapine –Risperidone

Schizophrenia & Medicines Management Clinical Pharmacy Congress 2013

“L’imagination est plus important que le savoir” Albert Einstein

John Donoghue, Liverpool

“Schizophrenia is arguably the worst disease affecting mankind,

even AIDS not excepted”

Editorial. Where next with psychiatric illness? Nature 1988;336:95-96

“Schizophrenia is arguably the worst disease affecting mankind,

even AIDS not excepted”

Editorial. Where next with psychiatric illness? Nature 1988;336:95-96

Unmet need in schizophrenia

Agenda

Negative symptoms

Relapse prevention

Physical health

Prodrome

10 20 30 40 50 60 70 Age (years)

General course of schizophrenia B

Chronic disability

Remitting & relapsing chronic schizophrenia

1st psychotic episode

Residual

Life expectancy 20% less than

general population

Outcomes of public concern

VIOLENCE

VICTIMISATION

SCHIZOPHRENIA

SELF-HARM & SUICIDE

SUBSTANCE MISUSE

HOMELESSNESS UNEMPLOYMENT

Kooyman I, Dean K, Harvey S & Walsh E Outcomes of public concern in schizophrenia Br J Psychiatry 2007;191:29-36

Schizophrenia symptoms: 3 natural dimensions

Positive symptoms

Psychosis

• Hallucinations • Delusions

Thought disorders

• Formal thought disorder • Disorganised / bizarre behaviour • Disorganised speech • Inappropriate affect

Pull CB. Diagnosis of schizophrenia: a review. in Eds Maj M., Sartorius N. World Psychiatric Association Series “Evidence and Experience in Psychiatry, Volume 2: Schizophrenia.” Chichester, U.K., John Wiley & Sons Ltd., 1999.

Negative symptoms Negative

symptoms

Blanchard JJ, Kring AM, Horan WP, Gur R. Toward the next generation of negative symptom assessments: collaboration to advance negative symptom assessment in schizophrenia. Schiz Bull 2011;37:291-9

Impaired affective (emotional) experiences

Reduced pleasure (anhedonia) Reduction in the range and

intensity of both positive and negative emotions

Lack of interest in or motivation for productive activities

Lack of sense of purpose (apathy)

Lack of social drive Lack of interest in or desire for

social contact (asociality)

Diminution or absence of normal thoughts, behaviour and emotions

Impaired expression or communication

Reduced spontaneous speech and vocabulary

Limited vocal intonation Lack of facial expression

Reduced gestures

Negative symptoms Negative symptoms

Negative symptoms: important prognostic implications

At 5-year follow-up after 1st episode

• Negative symptoms correlate highly with social disability and low social status

• Positive symptoms – no prognostic implications

Häfner H, Maurer K, Löffler W et al. The ABC schizophrenia study: a preliminary overview of the results. Soc Psychiatry Psychiatr Epidemiol 1998;33:380-86

Symptom severity (PANSS scores) following a first episode of schizophrenia

Positive symptoms Negative symptoms

Baseline

3 months

1 year

2 years

Melle I, Larsen TK, Haahr U, et al. Prevention of negative symptom pathologies in first-episode schizophrenia: two-year effects of reducing the duration of untreated psychosis. Arch Gen Psychiatry 2008;65:634-40

Symptom patterns 90

46 39 36 39

% of patients with symptoms

1. Pull CB. Diagnosis of schizophrenia: a review. in Eds Maj M., Sartorius N. World Psychiatric Association Series “Evidence and Experience in Psychiatry, Volume 2: Schizophrenia.” Chichester, U.K., John Wiley & Sons Ltd., 1999.

2. Bobes J, Arango C, Garcia-Garcia M, Rejas J; CLAMORS Study Collaborative Group. Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study. J Clin Psychiatry 2010;71:280-6 Copyright © John Donoghue 2013

Dopamine Hypothesis of Schizophrenia

• Nigrostriatal pathway

• DA activity normal

• Mesocortical pathway (1)

DL-PFC

• Negative symptoms

• Cognitive impairment

• DA activity LOW

• Mesolimbic pathway

• Positive symptoms

• DA activity HIGH

• Mesocortical pathway (2)

VM-PFC

• Negative symptoms

• Affective symptoms

• DA activity LOW

Pre-frontal cortex

Dorso-lateral-PFC

Ventro-medial-PFC

Striatum

Brain stem

Key Dopamine Pathways

NA = Nucleus Accumbens

a. Nigrostriatal pathway Motor function & movement

Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010

Pre-frontal cortex

Dorso-lateral-PFC

Ventro-medial-PFC

Striatum

Brain stem

b. Mesolimbic pathway Reward / pleasure Delusions & hallucinations

Pre-frontal cortex

Dorso-lateral-PFC

Ventro-medial-PFC

Striatum

Brain stem

a. Nigrostriatal pathway b. Mesolimbic pathway c. Mesocortical pathway

Glutamate hypothesis of schizophrenia

• Glutamate is the primary excitatory neurotransmitter

• Negative symptoms respond poorly to DA blockade

• Glutamate pathways regulate DA release

• Phencylidine (PCP) & ketamine mimic psychosis by blocking

glutamate receptors (N-methyl-D-aspartate; NMDA)

• Neuroimaging studies have found evidence of NMDA

receptor hypofunction

• Most of the identified schizophrenia susceptibility genes

affect NMDA receptor activity

Pre-frontal cortex

Dorso-lateral-PFC

Ventro-medial-PFC

Brain stem

Role of Glutamate in the Mesolimbic Pathway

Descending cortical-brainstem glutamate projection: Inhibits mesolimbic DA release

GABA interneuron

Pre-frontal cortex

Dorso-lateral-PFC

Ventro-medial-PFC Brain stem

Tegmentum

Role of Glutamate in the Mesocortical Pathway

Descending cortical-brainstem glutamate projection: Excites mesocortical DA pathway & acts as DA neuron accelerator

Treatment of Negative Symptoms

• To date no pharmacological treatment has demonstrated a consistent clinically important improvement in negative symptoms

• Modest benefits at best with:

– Clozapine

– Amisulpride

– Aripiprazole

– Olanzapine

– Quetiapine

– Risperidone

Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatrica Scand 2007;115:93-100

Standards for negative symptom trials

Patient Type

Clinically stable patients whose

negative symptoms persist despite antipsychotic

treatment.

Trial design

Double-blind,

randomised,

placebo-controlled,

parallel groups;

test treatment is

co-medication with

second generation

antipsychotic

Study duration

≥ 12 weeks “preliminary”

6 months

“registration”

Outcome measures

PANSS or SANS

(SANS preferred)

Meaningful effect

Cohen’s D ≥ 0.5

Kirkpatrick B, Fenton WS, Carpenter WT, Jr., Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32:214-219. Laughren T, Levin R. Food and Drug Administration commentary on methodological issues in negative symptom trials. Schizophr Bull 2011; 37:255-256. Marder SR, Daniel DG, Alphs L, Awad AG, Keefe RS. Methodological issues in negative symptom trials. Schizophr Bull 2011; 37:250-254. Copyright © John Donoghue 2013

Systematic reviews: adjunctive antidepressants

for negative symptoms of schizophrenia

Rummel C, Kissling W, Leucht S. Antidepressants as add-on treatment to antipsychotics for people with schizophrenia and pronounced negative symptoms: a systematic review of randomized trials. Schizophr Res. 2005;80(1):85-97

Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD005581

Sepehry AA, Potvin S, Elie R, Stip E. Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiatry. 2007;68(4):604-10

Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatr 2010;197:174-179

Phan SV, Kreys TJ. Adjunct mirtazapine for negative symptoms of schizophrenia. Pharmacotherapy 2011;31(10):1017-30

Antidepressants superior to placebo

Mirtazapine superior to placebo

SSRIs superior to placebo in ‘chronic’ patients

Antidepressants & standards for negative symptom trials

Patient Type

Clinically stable patients whose

negative symptoms persist despite antipsychotic

treatment.

Trial design

Double-blind,

randomised,

placebo-controlled,

parallel groups;

test treatment is

co-medication with

second generation

antipsychotic

Study duration

≥ 12 weeks “preliminary”

6 months

“registration”

Outcome measures

PANSS or SANS

(SANS preferred)

Meaningful effect

Cohen’s D ≥ 0.5

Kirkpatrick B, Fenton WS, Carpenter WT, Jr., Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32:214-219. Laughren T, Levin R. Food and Drug Administration commentary on methodological issues in negative symptom trials. Schizophr Bull 2011; 37:255-256. Marder SR, Daniel DG, Alphs L, Awad AG, Keefe RS. Methodological issues in negative symptom trials. Schizophr Bull 2011; 37:250-254.

19% 84%

Treatment in Phase III trials: Bitopertin Glycine re-uptake inhibitor

Agenda

Negative symptoms

Relapse prevention

Physical health

Antipsychotic induced

Iatrogenic disease in schizophrenia

Parkinsonism

Akathisia

Dystonia

Tardive dyskinesia Hyperprolactinaemia

Sexual dysfunction

Osteoporosis

Breast cancer

Obesity

Type 2 diabetes

Dyslipidaemia

Hypertension

Standardised Mortality Ratio (SMR) is high

– All causes of death: 2.98

– Cardiovascular disease: 2.01

SMR = (observed number of deaths / expected number of deaths)

Growing awareness of need to improve physical health in severe mental illness

• Life expectancy for individuals with schizophrenia is 20% less than that of the general population

• Increased morbidity – Medical illnesses

– Psychiatric comorbidities

• CV morbidity & mortality is a growing concern

• Decreased access to care

• Poverty

• Limited insight

Barnett AH et al. J Psychopharmacol OnlineFirst, published on April 19, 2007 as doi:10.1177/0269881106075509

• Health professionals in secondary

care should ensure that people with

schizophrenia receive physical

healthcare from primary care

• Physical health should be monitored

at least once a year

• Follow various NICE Guidelines for

cardiovascular disease

– Obesity

– Type 2 Diabetes

– Dyslipidaemia

– Hypertension

Challenges to maintaining

cardiovascular health in SMI

Correll CU. Balancing Efficacy and Safety

in Treatment with Antipsychotics CNS Spectr. 2007;12:10(Suppl 17):12-20,35

• Control blood glucose levels

• Metformin

• Educate patients – Give dietary advice

• Manage blood pressure

• Assess & monitor cardiovascular risk

Other diabetes care issues:

Address modifiable risk factors • Weight

– Diet • eatwell.gov.uk/healthydiet

• www.5aday.nhs.uk

– Exercise

• 30 minutes, moderate intensity, 5 days a week

• Alcohol consumption

• Smoking cessation

Medicines that cause weight gain & obesity????

• Lifestyle change – Diet

• Sodium intake

• Caffeine intake

– Exercise

– Alcohol

– Smoking

– Relaxation

• Assess cardiovascular risk

• Pharmacotherapy • Thiazide

• Ca-channel blocker

• ACE inhibitor

Patients with schizophrenia have complex cardiovascular needs

Obesity Hypertension

Dyslipidaemia Diabetes

Assess risk

Lifestyle advice Manage comorbidities

Address risk factors

Control glucose levels

Prescribe: Metformin Antithrombotic Statin Antihypertensive etc

Of all the pharmacologic strategies, choice of psychotropic medication may have the greatest influence on weight gain and associated metabolic disturbance.

There is good evidence for a range of weight-gain liability among antipsychotic medications.

Agenda

Negative symptoms

Relapse prevention

Physical health

Revolving door = vicious cycle

Delay in treating first

episode

Treatment response but subsequent poor

adherence to treatment

Relapse & need to re-establish treatment

Progression to chronic illness and/or treatment resistance

Poor adherence in schizophrenia: a large and persistent problem

Lacro JP, Dunn LB, Dolder CR et al. Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63:892-909

Make a note of this number!

Systematic review of adherence • 39 studies from 1980 onwards

– 10 retrospective, 15 cross-sectional, 14 prospective

• Mean duration of illness 9-24 years

• Range of adherence measures

• “Taking medication as prescribed at least 75% of the time”

49.5% of patients non-adherent

1st episode schizophrenia: Poor adherence leads to high relapse rates

• 5-year follow-up study after initial recovery from first episode of schizophrenia or schizoaffective disorder

• Discontinuation of antipsychotic medication increased risk of relapse almost 5-fold

Robinson D, Woerner MG, Alvir JMJ et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder Arch Gen Psychiatry 1999;56:241-47

Cumulative rates (%) of relapse over 5 years follow-up

1st relapse 2nd relapse 3rd relapse

• Pooled analysis of 66 studies with 4365 patients with chronic schizophrenia

• Relapse rates over 10 month period

• Number needed to harm for antipsychotic withdrawal

NNH = 3 (95% CI 2-3)

Chronic schizophrenia: Poor adherence leads to high relapse rates

Gilbert PL, Harris MJ, McAdams LA, Jeste DV. Neuroleptic withdrawal in schizophrenic patients: a review of the literature. Archives of General Psychiatry 1995;52:173-88

% of patients relapsing

Medication discontinued

Medication maintained

Make a note of this number!

What would be predicted annual relapse / admission rates? If: 50% of patients don’t take treatment regularly and Relapse rates in these patients are about 50% in 1st year 0

Hospital admission

Self-harm Suicide attempt

Civil detention in

past 12 months

Care programme

approach

12 months

24 months

Schizophrenia: 2-year Outcomes in UK

% of patients (N=1,015)

Hunter R, Cameron R, Norrie J. Using patient-reported outcomes in schizophrenia: The Scottish Schizophrenia Outcomes Study Psychiatric Services 2009;60:240-245

Adherence is influenced by multiple factors

General Complexity of treatment

Duration of treatment

Lack of support

Clinician / Service Poor therapeutic relationship

Poor explanation / communication

Inadequate follow-up

Illness Severity of illness

Depression / psychosis

Cognitive impairment

Mitchell AJ, Selmes T Why don’t patients take their medicines? Reasons and solutions in psychiatry. Advances in Psychiatric Treatment 2007;13:336-346

Patient Concerns about side effects

Few perceived benefits

Stigma

Daily routine

Concerns about dependence

Lack of involvement

Necessity / Concerns model for understanding adherence

= poor adherence = adherence

Necessity = understanding and accepting necessity of treatment Concerns = concerns about accepting treatment

Necessity

Concerns Necessity

Concerns

A strategy for preventing relapse

Individualise treatment

Engage patient by improving

communication & information

Medicines management

Involving patients in individualising treatment

Involve patient in treatment decisions

Provide accessible & meaningful information

Take patient

concerns seriously

Reaching agreement on necessity & concerns

• Benefits of treatment vs no treatment

• How likely is it to work?

• How does it compare with other options?

– Side effects

• Risks associated with poor adherence to treatment

Individualising antipsychotic medication

Antipsychotic dose form: Oral or depot?

Which side-effects do patients want to avoid the most?

Which antipsychotics are least likely to cause

these side-effects?

5 tests for patient information

• It must be intuitive and easily understood

• It must be evidence-based

• It must address issues that are important to patients

• Both patients and health professionals must be involved in its development locally

• It should be accessible and easily available during all patient-facing interactions

Donoghue JM www.mentalmeds.co.uk/patient-information.php

NHS Constitution:

information about any proposed treatment, including

any significant risks

any alternative treatments

the risks involved in doing nothing

http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Mania%20and%20Bipolar%20Disorder&medicine=Zyprexa&preparation=Zyprexa%2015mg%20tablets Accessed 01.02.2013 Copyright © John Donoghue 2013

http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Mania%20and%20Bipolar%20Disorder&medicine=Zyprexa&preparation=Zyprexa%2015mg%20tablets Accessed 01.02.2013

Easily understood and intuitive

Evidence-based

Address issues that are important to patients

Patients and health professionals involved

Easy to use during patient-facing interactions

A strategy for preventing relapse

Individualise antipsychotic

treatment

Avoid complex treatment regimens

Ensure patient understands

treatment regimen

Engage patient by improving

communication & information

Medicines management

Adjust to daily routine

Ensure easy access

to repeat prescription

Consider depot

antipsychotic

Food for thought . . .

Negative symptoms

Relapse prevention

Physical health

www.mentalmeds.co.uk 54

Schizophrenia & Medicines Management · improvement in negative symptoms •Modest benefits at best with: –Clozapine –Amisulpride –Aripiprazole –Olanzapine –Quetiapine –Risperidone

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