Schizophrenia & Medicines Management · improvement in negative symptoms •Modest benefits at best...
Transcript of Schizophrenia & Medicines Management · improvement in negative symptoms •Modest benefits at best...
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
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Copyright © John Donoghue 2013
Unmet need in schizophrenia
Agenda
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Negative symptoms
Relapse prevention
Physical health
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Prodrome
10 20 30 40 50 60 70 Age (years)
Psy
cho
pat
ho
logy
, Fu
nct
ion
& o
utc
om
e
General course of schizophrenia B
ette
r
Chronic disability
Remitting & relapsing chronic schizophrenia
1st psychotic episode
Residual
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Wo
rse
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
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Schizophrenia symptoms: 3 natural dimensions
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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
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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
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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
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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
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Symptom severity (PANSS scores) following a first episode of schizophrenia
0
5
10
15
20
25
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
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Symptom patterns 90
50
15 20
46 39 36 39
0
10
20
30
40
50
60
70
80
90
100
10
1
1
1 1
2
2 2
2
% 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
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• Mesolimbic pathway
• Positive symptoms
• DA activity HIGH
• Mesocortical pathway (2)
VM-PFC
• Negative symptoms
• Affective symptoms
• DA activity LOW
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Pre-frontal cortex
Dorso-lateral-PFC
Ventro-medial-PFC
Striatum
Brain stem
Key Dopamine Pathways
NA
NA = Nucleus Accumbens
a. Nigrostriatal pathway Motor function & movement
a
Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010
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Pre-frontal cortex
Dorso-lateral-PFC
Ventro-medial-PFC
Striatum
Brain stem
NA
NA = Nucleus Accumbens
a
b. Mesolimbic pathway Reward / pleasure Delusions & hallucinations
b
Key Dopamine Pathways
Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010
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Pre-frontal cortex
Dorso-lateral-PFC
Ventro-medial-PFC
Striatum
Brain stem
NA
NA = Nucleus Accumbens
a
b
a. Nigrostriatal pathway b. Mesolimbic pathway c. Mesocortical pathway
c
Key Dopamine Pathways
Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010
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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
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Pre-frontal cortex
Dorso-lateral-PFC
Ventro-medial-PFC
Brain stem
NA
NA = Nucleus Accumbens
Role of Glutamate in the Mesolimbic Pathway
Descending cortical-brainstem glutamate projection: Inhibits mesolimbic DA release
GABA interneuron
Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010
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Pre-frontal cortex
Dorso-lateral-PFC
Ventro-medial-PFC Brain stem
Based on: Stahl SM, Mignon L Antipsychotics: Treating Psychosis, Mania & Depression (2nd Edn) Cambridge University Press 2010
Tegmentum
Role of Glutamate in the Mesocortical Pathway
Descending cortical-brainstem glutamate projection: Excites mesocortical DA pathway & acts as DA neuron accelerator
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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
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Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatrica Scand 2007;115:93-100
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Standards for negative symptom trials
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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
size
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
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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
Antidepressants superior to placebo
Antidepressants superior to placebo
Mirtazapine superior to placebo
SSRIs superior to placebo in ‘chronic’ patients
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Antidepressants & standards for negative symptom trials
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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
size
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.
41%
31%
19% 84%
25%
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Treatment in Phase III trials: Bitopertin Glycine re-uptake inhibitor
Unmet need in schizophrenia
Agenda
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Negative symptoms
Relapse prevention
Physical health
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Antipsychotic induced
Iatrogenic disease in schizophrenia
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Parkinsonism
Akathisia
Dystonia
Tardive dyskinesia Hyperprolactinaemia
Sexual dysfunction
Osteoporosis
Breast cancer
Obesity
Type 2 diabetes
Dyslipidaemia
Hypertension
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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)
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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
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• 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
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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
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• Control blood glucose levels
• Metformin
• Educate patients – Give dietary advice
• Manage blood pressure
• Assess & monitor cardiovascular risk
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Other diabetes care issues:
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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????
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• Lifestyle change – Diet
• Sodium intake
• Caffeine intake
– Exercise
– Alcohol
– Smoking
– Relaxation
• Assess cardiovascular risk
• Pharmacotherapy • Thiazide
• Ca-channel blocker
• ACE inhibitor
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Patients with schizophrenia have complex cardiovascular needs
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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.
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Unmet need in schizophrenia
Agenda
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Negative symptoms
Relapse prevention
Physical health
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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
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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
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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
82
78
86
1st relapse 2nd relapse 3rd relapse
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• 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
53
16
Medication discontinued
Medication maintained
Make a note of this number!
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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
5
10
15
20
25
30
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
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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
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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
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A strategy for preventing relapse
Individualise treatment
Engage patient by improving
communication & information
Medicines management
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Involving patients in individualising treatment
Involve patient in treatment decisions
Provide accessible & meaningful information
Take patient
concerns seriously
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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
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Individualising antipsychotic medication
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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?
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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
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NHS Constitution:
information about any proposed treatment, including
any significant risks
any alternative treatments
the risks involved in doing nothing
http://www.nhs.uk 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 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
Copyright © John Donoghue 2013
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
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Unmet need in schizophrenia
Food for thought . . .
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Negative symptoms
Relapse prevention
Physical health
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www.mentalmeds.co.uk 54
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