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Treatment Principles
Schizophrenia
Treatment (reduce symptoms and prevent relapse)
• Medications
• Psychosocial interventions (e.g. cognitive behavioral
therapy)
Rehabilitation (enhance adaptive skills)
• Social skills training
Supports (environmental changes)
• Supported housing
• Supported employment
Costs and unintended adverse consequences
• Side effects
• Direct and indirect costs
• Discrimination
• Related health risks
Tandon R et al. J Psychiatr Pract. 2006;12(6):348–363.
Reduces disease burden
Treatment and other services
Treatment should be optimized for each individual in order to improve the outcome
Adds to
treatment
burden
RECOVERY
Health and wellness
• Vocational and/or
educational functioning
• Independent living
• Better physical health
• Instrumental competence
• Social integration
• Improved quality of life
Psychosocial interventions should be tailored to the goals, needs, abilities and
circumstances of individuals
Vocational
training and
support
Integrated
substance use
programme
Patient has:
- Family members
available
- Ongoing treatment,
monitoring of
recovery, and
support
Family
psychoeducation
- Dysphoria and/or
depression
- Stress and
relapse prevention
Ability and
interest in
working
Substance
use issues
Cognitive behavioral
therapy (CBT)
Patient needs help with:
Patient
Medication
treatment
adherence and
relapse prevention
Psychoeducation
Canadian Psychiatric Association. Can J Psychiatry. 2005;50(13 Suppl 1):7S–57S.
[CPA Guidelines].
Social
interaction
skills
Social skills training
Consumer
involvement
(empowerment) in
setting rehabilitation
goals
Peer support, self-help
and recovery
Continuous maintenance treatment may decrease deterioration in symptoms
during the second year following diagnosis
Survival analysis for clinical deterioration* for patients receiving maintenance
antipsychotic treatment versus intermittent treatment:
Maintenance treatment is more
effective than targeted intermittent
treatment in preventing relapse
*Increase from baseline in the sum of PANSS positive and negative scores ≥25% or ≥10 points (if baseline value ≤40) or a CGI-C score ≥6.
CGI-C=Clinical Global Impression-Change scale; PANSS=Positive and Negative Syndrome Scale
Gaebel W, et al. J Clin Psychiatry. 2011;72(2):205–218.
Only a small proportion of patients with schizophrenia achieve recovery
In a 3-year observational study, adults with schizophrenia (N=6642) achieved:
33%
Long-lasting symptomatic remission*
27%
Long-lasting adequate quality of life†
13%
Long-lasting functional remission‡
4%
Recovery, defined as all 3 of the above
0
10
20
30
Patients, %
40
50
Employment, independent living, social activity, and medication adherence were
important predictors of recovery
CGI-SCH=Clinical Global Impression-Schizophrenia scale. *Defined as <4 in the CGI-SCH positive, negative, cognitive, and overall severity
score, plus no inpatient admission for ≥24 months. †Defined as ≥70 on the EuroQoL5 dimensions visual analogue scale (EQ-5D VAS) for ≥24
months. ‡Defined as employed/student, plus independent living, plus active social interactions for ≥24 months.
Novick D, et al. Schizophr Res. 2009;108(1–3):223–230.
60
How do medication side effects exacerbate
functional impairment?
Take home points
• Treatment side effects (such as EPS, activating, sedating,
sexual/endocrine, cardiovascular or metabolic side effects) can impose a
significant burden on patients, with activating and sedating side effects
among the most ‘bothersome’
• Antipsychotic-induced sedation may impair functional capacity and quality
of life, and impact caregiver burden
• Activating side effects (i.e., akathisia, anxiety, insomnia, agitation,
restlessness) may also may impair functional capacity and quality of life,
and impact caregiver burden
Side effects of treatments for schizophrenia can impose a
significant burden on patients
In a study of 1,825 participants with psychosis:
77%
reported
medication
side effects1
61%
reported
impairment in
their daily life as a
result of medication
side effects1
30%
reported
moderate or
severe
impairment1
Side effects impair ability to interact with others, reducing quality of life2
If not addressed, antipsychotic side effects can cause long-term distress and contribute to
chronic health complications3
A small shift in functional status may have marked effects on an individual’s quality of life2
1. Morgan VA, et al. Aust N Z J Psychiatry. 2012;46(8):73552. 2. Awad AG , et al. Acta
Psychiatr Scand Suppl. 1994;380:27–32. 3. Barnes TR, et al. J Psychopharmacol.
2011;25(5):567–6203.
Side effects can be classified into different groups
Anxiety
Activating
Agitation
Sedation
Restlessness
Insomnia
Somnolence
Fatigue
Akathisia
Parkinsonism
Extrapyramidal
symptoms
Dystonia
Hypersomnia
Sedating
Cardiac arrhythmias
Antipsychoticinduced side
effects1–4
Cardiovascular
QT interval prolongation
Dyskinesia
Hyperglycaemia
Sexual
dysfunction
Hyperlipidaemia
Sexual / endocrine
Metabolic
Weight gain
Hyperprolactinemia
Metabolic
syndrome
Diabetes
mellitus
1. Jibson MD. Second-generation antipsychotic medications: pharmacology, administration, and comparative side effects.
In: UpToDate, Stephen Marder (Ed), UpToDate, Waltham, MA. Accessed March 13, 2015. 2. Lehman AF, et al. [APA
Practice Guidelines] 2010. 3. Lieberman JA, et al. N Engl J Med. 2005;353(12):1209–23. 4. Kane JM, et al. Schizophr Res.
2016 pii: S0920-9964(16)30162–1. 5. Cheng-Shannon J et al. J Child Adolesc Psychopharmacol. 2004;14(3):372-94
There are multiple clinical benefits of a low risk of extrapyramidal symptoms
Reduced
negative
symptomsb
Enhanced
complianced
Reduced
extrapyramidal
symptoms
Less impaired
cognitionb
Less
dysphoriac
Lower tardive
dyskinesia
riskb
Fewer motor
side effectsa
Strength of evidence: avery strong, almost certain; bmoderately strong, probable; cmild to moderate, possible; dsome suggestion, little or no hard data.
Note: all antipsychotic drugs carry a significant risk for extrapyramidal symptoms for which active management is recommended.
While all of the drugs in the class have been shown to contribute to the these side effects, each drug has its own specific risk profile.
Tandon R, Jibson MD. Ann Clin Psychiatry. 2002;14(2):123–9.
Akathisia is associated with emotional symptoms and cognitive impairment
Reduced self-esteem1
Mental control3
Anxiety2
Obsessive–compulsive3
Emotional
symptoms
Associate learning3
Cognitive
impairment
Selective attention2
Somatization3
Discrimination2
Depression3
Perception2
Paranoid ideation3
Severe subjective distress3
Coping responses2
1. Hofer A, et al. J Clin Psychiatry. 2004;65(7):932–9. 2. Kim JH, Byun HJ. J Clin Pharm Ther. 2007;32:461–467.
3. Kim et al. Compr Psychiatry. 2002;43(6):456–462.
Some antipsychotics are associated with high rates of sedating side effects,
which can worsen outcomes
Antipsychotic-induced sedating side effects have been associated with:
Reduced cognitive
performance and functional
capacity1
Risk of unintentional
injury3
Medication non-adherence2
Concerns over the safety of
dependants,4 particularly as
women are more sensitive to
sedative effects5
For agitated patients, sedating side effects and true antipsychotic effects are sometimes
incorrectly thought to be the same6
• Sedation may be considered necessary for controlling positive symptoms; however, selecting a less
sedating antipsychotic for patients who experience excessive sleeping can improve outcomes7
1. Loebel AD et al. CNS Spectr 2014;19(2):197–205. 2. DiBonaventura M et al. BMC Psychiatry 2012;12:20. 3. Said Q et al. Pharmacoepidemiol
Drug Saf 2008;17(4):354–364. 4. Seeman MV. Psychiatr Q 2012;83(1):83–89; 5. Lindberg N et al. Int Clin Psychopharmacol 2002;17(4):177–
184. 6. Miller DD. Curr Psychiatr. 2007;1;6(8):38. 7. Miller DD, et al. Prim Care Companion J Clin Psychiatry. 2004; 6(suppl 2): 3–7.
Antipsychotic-induced sedation may impair functional capacity and quality of life
Decreased utility and quality of life2
Change from baseline in Epworth Sleepiness Scale: Item analysis1
Quetiapine XR 600mg/day
Placebo
0.25
0.20
**
0.15
0.10
0.05
**
*
*
0.00
Improvement
LS mean change from baseline (LOCF)
Decreased functional capacity1
**
-0.05
-0.10
-0.15
-0.20
-0.25
Sitting
& reading
Watching
TV
Sitting inactive in
public place
Passenger in a
car for an hour
without a break
Afternoon resting
Common situations assessed in ESS. **P<0.01 (versus placebo); *P<0.05 (versus placebo)
1. Loebel AD, et al. CNS Spectr.2 014;19(2):197–205.
2. Millier A, et al. J Med Econ. 2014;17(12):853–861.
Dozing when
talking to
someone
Sitting quietly after In a car while
lunch without stopped for traffic
alcohol
Sedation can have a severe impact on many aspects of patient life
Long-term sedation may prevent patients from gaining improvement from
psychosocial training, psychiatric rehabilitation and other treatments1
Persistent sedation can interfere with social, academic, recreational and vocational
functioning, and with quality of life, often leading to treatment dissatisfaction2–6
Sedation/cognition side effects (e.g., sedation, difficulty thinking/ concentrating,
sleepiness, dizziness) are associated with medication non-adherence7
1. Miller DD. Curr Psychiatr. 2007;1;6(8):38. 2. Kane JM, Sharif ZA. J Clin Psychiatry. 2008;69(suppl 1):18–31.
3. Lehman AF, et al. [APA Practice Guidelines] 2010. 4. Loebel AD, et al. CNS Spectr. 2014;19(2):197–205. 5.
Millier A, et al. J Med Econ. 2014;17(12):853–61. 6. Said Q, et al. Pharmacoepidemiol Drug Saf.
2008;17(4):354–64. 7. DiBonaventura M, et al. BMC Psychiatry. 2012;12:20.
Sedation impacts both patient functioning and caregiver burden
Patient
Caregiver
No energy
They do not want to get out of
bed or participate in activities
Constantly feel tired
Cannot think
clearly
Effects of patient sedation can
increase caregiver burden
Patients may also have impaired cognitive
and motor performance and increased risk
of injury
Impacts on patient’s
quality of life
Persistent
sedation or
somnolence
Functional impairments
in vocational, academic,
social and recreational
activities
Kane JM, Sharif ZA. J Clin Psychiatry. 2008;69)s Suppl. 1):18–31.
Dissatisfaction
with medication
Discontinues
treatment/becomes
non-adherent
Activating and sedating effects are among the most ‘bothersome’ antipsychotic
side effects
Percentage of patients reporting
the side effect as ‘at least
moderately bothersome’
Activating***†
Sedating*†
35
30
Prolactin/endocrine*
GI
32.2
28.2
28.4
25.8
25.1
25
22.2
20
15
Metabolic**
20.6
16.0
13.1
17.8
16.2
86.2% of patients
with schizophrenia
reported the
presence of any
medication
side effect in this
cross-sectional
study (N=876)
12.6
10.2
10
5
0
4.7
1.4
0.8
*p<0.05, **p<0.01, ***p<0.001 for
the association with a lower
likelihood of adherence; †study
authors grouped activating side
effects under the category
‘EPS/agitation’ and sedating side
effects under the category
'sedation/cognition’.
EPS=extrapyramidal symptoms;
GI=gastrointestinal.
DiBonaventura M, et al. BMC
Psychiatry. 2012;12:20.
Gastrointestinal side-effects can occur with antipsychotics
•
Dyspepsia
•
Vomiting
•
Nausea
•
Esophageal dysmotility
•
Hypersalivation
•
Dry mouth
•
Constipation
Gastrointestinal side-effects associated with antipsychotics1
In a retrospective study of 273 patients with
schizophrenia, over a period of 22 months:2
36.3% had at least 1 pharmacological intervention for
constipation
63.7%
1. MHRA Antipsychotics learning module 2015. Available at
http://www.mhra.gov.uk/antipsychotics-learningmodule/con155606?useSecondary=&showpage=8 Last accessed July
2016. 2. De Hert M et al. BMC Gastroenterol. 2011:8;11:17.
Are medication side effects a necessary
compromise for continued symptom control?
Take home points
• A key challenge for physicians is to choose an antipsychotic that
effectively controls symptoms, while minimizing side effects
• The limitations of current treatments can lead to a frustrating experience
for everyone impacted
• Treatment of schizophrenia needs a rational approach with minimal
tolerability issues to optimize patient functioning
Selecting suitable treatments for schizophrenia can pose a dilemma for psychiatrists
In selecting treatments for schizophrenia, physicians consider variables related to the:1,2
Patient
Illness
Medication
Environment
An ‘ideal’ medication is one that can:2
 treat psychosis
 lead to symptom resolution
 lead to remission
 overcome treatment resistance
 effectively prevent against relapse
 have a benign side-effect profile
(with minimal sedation and akathisia)
 have efficacy for symptoms of anxiety and depression
1. Kane JM, et al. Dialogues Clin Neurosci. 2010;12(3):345–357. 2. Correll CU. J
Clin Psychiatry. 2011;72(suppl. 1):9–13. 3. Abidi S, et al. Can J Psychiatry.
2003;48(11):749‒755. 4. Leucht S, et al Lancet. 2013;382(9896):951‒962. 5. Ucok
et al. World Psychiatry. 2008;7(1):58‒62. 6. Barnes TR, et al. J Psychopharmacol.
2011;25(2):567‒620.
The long-term nature of side effects, including
metabolic, endocrine and cardiac complications,
can pose a dilemma for physicians in providing
effective treatment while avoiding side effects3
Physicians have to consider how side effects interact
with the patient’s health and lifestyle
(e.g., age, weight, cardiovascular health, coprescribed medications, previously experienced
side effects)4–6
Guidelines for good practice are measurement-based and individualized
Ongoing, careful monitoring is critical1
• Reliable and repeated assessment of the efficacy of treatment
using defined treatment targets1,2
– Using standard rating scales like BPRS and PANSS will facilitate this goal
• Careful assessment of possible adverse effects of treatment1,3
– Protocols for health monitoring1
• Ongoing collaboration with patient in decision-making1
Standard protocols should be customized in response to
individual vulnerabilities/needs and specific agent1
1. Canadian Psychiatric Association. Can J Psychiatry. 2005;50(13;s uppl 1):7S–57S. [CPA Guidelines]. 2. Lehman AF,
et al. [APA Practice Guidelines] 2010. 3. Hasan A, et al. World J Biol Psychiatry. 2013;14(1):2–44 [WFSBP guidelines].
Shared decision-making and patient centered care lead to better
health outcomes
Shared decision-making is a process in which clinicians and patients work together to make decisions
about care and treatment based on both clinical evidence and the patient’s informed preferences 1
A central part of shared decision-making is the recognition that patients and clinicians bring different,
but equally important, knowledge and expertise to the process: 1,2
Social circumstances
Diagnosis
Disease etiology
Prognosis
Treatment options
Clinician's
expertise
Outcome probabilities
Patient’s
expertise
Attitude to risk
Values
Preferences
Experience of illness
When patients are involved in decisions about health and care, the decisions are better, health
and health outcomes improve, and resources are allocated more efficiently1
1. Foot C et al. The Kings Fund, 2014; 2. Coulter & Collins. The King’s Fund, 2011
Efficacy for positive and negative symptoms are higher priorities than
tolerability for physicians when choosing a treatment
Most common reasons for selecting an antipsychotic reported by 872 European and US physicians
Effect on positive symptoms
91
Effect on negative symptoms
62
Well tolerated
47
Patient acceptibility
46
Reduced risk of EPS/parkinsonism
45
Reduced agitation
40
Effect on mood/affective symptoms
37
Familiarity with drug
35
Reduced aggression
34
Reduced risk of tardive dyskinesia
33
Improved compliance
31
Complete symptom control
28
0
Percentage of patients (n=6,523)
Lecrubier Y, et al. Eur Psychiatry. 2007;22(6):371–379.
10
20
30
40
50
60
70
80
90
100
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Based on clinical circumstances,
choose medication from the
following:
Acute
phase
Yes
Group 1: First-generation antipsychotics
Group 2: Risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole
Group 3: Clozapine
Group 4: Long-acting injectable antipsychotics
Good response without intolerable side effects?
For intolerable side effects: choose a
different medication from Group 1 or 2
No
For inadequate therapeutic response: choose
a different medication from Group 1, 2 or 3
For patients who continue to respond inadequately: choose a
different medication from Group 1, 2, or 3.
Consider ECT for patients with persistent severe psychosis,
catatonia, and/or suicidal ideation
Stabilization phase
Yes
Good response without intolerable side effects?
No
Continue acute-phase medication treatment
For intolerable side effects:
choose a different medication
from
Group 1 or 2
Adapted from Lehman AF, et al. [APA Practice Guidelines] 2010.
For residual or intercurrent
symptoms: consider a different
medication from Group 2 or 3 or
appropriate adjunctive medication
For treatment nonadherence:
consider a different medication
from Group 4
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Institute non-drug measures: safety, seclusion. Obtain medication response history. Determine route of
drug administration
Oral administration not appropriate or refused by patient?
Acute
phase
No
Yes
Consider starting or increasing
regular oral second-generation
(except clozapine) medication or
first-generation medication if
history of positive response (liquid
if available)
Yes
Treatment with one of the following:
• Haloperidol and lorazepam
• Other mid- to high-potency antipsychotic with lorazepam
• Zuclopenthixol acetate
• In intensive care unit or medical setting, haloperidol and
lorazepam
• Olanzapine injectable
Response
No
Yes
Response
Repeat above after waiting time specified. Repeat to a maximum of
20 mg haloperidol or equivalent, 8 mg lorazepam and 20 mg
olanzapine per 24-hour period
Adapted from: Canadian Psychiatric Association. Can J Psychiatry. 2005;50(13)(suppl 1):7S–57S. [CPA Guidelines].
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Stabilization
phase
Before treatment: clarify diagnosis, perform a clinical examination and obtain baseline values if available
Pharmacotherapy: administer an SGA (except clozapine) or an oral FGA previously effective and tolerated.
Assess over 4–8 weeks
Ye
Good response without intolerable side effects?
s
Ineffective or partial therapeutic response:
Not tolerated or side effects: Try
No
augmentation OR another SGA (except
Try augmentation OR another SGA (except
clozapine). Assess over 4–8 weeks
clozapine). Assess over 4–8 weeks
Good response without intolerable side effects?
Continue with
oral therapy or
switch to longacting injectable
depot (if
available) to
improve
medication
adherence
Yes
No
Continue with oral therapy or switch to long-acting
injectable depot (if available) to improve medication
adherence
Try a third SGA (assess over 4–8 weeks) OR consider
optimization OR change to clozapine. Assess over 4–6
months
Good response without intolerable side effects?
Continue treatment
Adapted from: Canadian Psychiatric Association. Can J Psychiatry. 2005;50(13)(suppl 1):7S–57S. [CPA Guidelines].
Yes
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Acute relapse
Multiple-episode patients should receive prompt
antipsychotic treatment. Antipsychotic selection should
consider:
First episode of
schizophrenia
Choose first-line treatment from firstgeneration (FGA) and second-generation (SGA)
antipsychotic
All established FGAs
and SGAs can be used
• Lower end of the standard dose range
• SGAs should be favored in first-episode patients
Side effects (e.g.,
cardiovascular, motor
and metabolic)
Patient’s experience
with certain drugs
and the individual
side effect profile
Switching to another antipsychotic drug
Stabilization and
stable phase
• Conduct a treatment trial with the optimal dose for each patient for at
least 2 weeks (but not longer than 8 weeks) unless there is unacceptable
tolerance or contraindication
Maintenance treatment
• Should be carried forward with
the antipsychotic that led to the
best response and had the best
side effect profile
First-episode patient
Continuous antipsychotic for at least 1 year
Continuous antipsychotic for at least 2–5 years
Multi-episode
patient
Adapted from 1. Hasan A, et al. [WFSBP Guidelines for Biological Treatment of Schizophrenia, Part
1]; World J Biol Psychiatry 2012;13(5):318–378. and Hasan A, et al. [WFSBP Guidelines for
Biological Treatment of Schizophrenia, Part 2]; World J Biol Psychiatry 2013;14(1):2–44.
Indefinite continuation of antipsychotic for patients
with a history of serious suicide attempts or violent,
aggressive behavior
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Psychiatric and physical assessment,
allowing an antipsychotic drug-free
assessment phase
First-episode
non-affective psychosis
Non-adherence
• Discuss reasons with patient
and carers and optimize
treatment, give compliance
therapy
• Side effects: try another
antipsychotic
• Consider trial of depot
medication
• Improved adherence: go on
with treatment or switch to
other antipsychotic if no
response
Start antipsychotic treatment
• Use a low dose and increase slowly
• Consider amisulpride, aripiprazole,
quetiapine, risperidone,
ziprasidone
Insufficient response after 3 weeks:
• Increase dose over next 2–3 weeks and
optimize psychosocial interventions
Non-response After 6–8 weeks:
• Cross-over switch to another SGA including
olanzapine
Non response to second antipsychotic trial
• Review reasons for failure (e.g. adherence)
• Consider switch to clozapine
• If not possible, consider add-on or trial of low
dose typical antipsychotic or mood stabilizer or
other antipsychotic combination therapy
Adapted from Galletly C, et al. Aust N Z J Psychiatry. 2016;50(5):410-72.[RANZCP
Guidelines]
Add benzodiazepine as per
symptoms:
• Agitation/depression –
e.g. diazepam
• Anxiety – e.g. lorazepam
• Sleep disturbance –
e.g. temazepam
Response
• Continue treatment for at
least 2–5 years
• If incomplete remission or
treatment resistance,
consider long-term
treatment
• If discontinuing, stop
gradually over at least 3–6
months with close follow-up
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Acute phase
Assess:
• Adherence to medication and recent stressors
• Comorbid substance use
• Side effects
Cognitive behavioral therapy directed at persistent
symptoms of psychosis
Treatment
unsuccessful
• Depression
• Complications of polypharmacy
• Quality of the social environment
Adequate sequential trials of two antipsychotic
medications
• At least 6 weeks of chlorpromazine equivalents
• At least one second-generation antipsychotic agent
Treatment unsuccessful
Good adherence
Consider clozapine
Symptoms persist despite
adequate trial of clozapine
Continue clozapine and prescribe adjunctive
medication
Adapted from Galletly C, et al. Aust N Z J Psychiatry. 2016;50(5):410-72.[RANZCP
Guidelines]
Poor or uncertain adherence
Consider the use of longacting injectable antipsychotic
medication
Reinstate the previous regimen that was most effective and
well tolerated and prescribe adjunctive medication
The limitations of current treatments can lead to a frustrating
experience for everyone affected
Severe persistent or unremitted schizophrenia
Treatment resistance clearly demonstrated
Persistence of symptoms
due to poor response to
treatment
Recovery plan
• Negotiate and agree upon
with the patient
• Review regularly
Concordant
with
Treatment plan
Seek second opinion
Clozapine is the treatment of choice
• Should be offered within 6–12 months of demonstrating
treatment resistance
Review regularly to identify modifiable
illness or lifestyle risk factors
Optimize management
Adapted from Galletly C, et al. Aust N Z J Psychiatry. 2016;50(5):410-72.[RANZCP
Guidelines]
The limitations of current treatments can lead to a frustrating
experience for everyone affected
First episode psychosis
Oral antipsychotic medication
+
Psychological interventions
(family intervention and individual CBT)
The choice of antipsychotic medication could consider:
• Views of the carer
• Benefits and possible side effects of each drug, including metabolic, cardiovascular, and hormonal
Before starting antipsychotic medication:
• Undertake and record the recommended baseline investigations (e.g. weight and glycosylated hemoglobin)
• Consider offering an electrocardiogram (e.g. if there is a personal history of cardiovascular disease)
• Discuss and record the side effects that the person is most willing to tolerate
At the start of treatment:
• Give a dose at the lower end of the licensed range and slowly titrate upwards
• Carry out a trial of the medication at optimum dosage for 4–6 weeks
• Monitor and record the recommended parameters (e.g. response to treatment and side effects)
throughout treatment and titration
Kuipers E, et al. NICE Guideline. 2014
The limitations of current treatments can lead to a frustrating
experience for everyone affected
No adequate response to pharmacological or
psychological treatment
No adequate response
(despite sequential use of
adequate doses of at least
two different antipsychotic
drugs with at least one
being a non-clozapine
second-generation
antipsychotic)
Offer clozapine
No adequate response at
an optimized dose
Kuipers E, et al. NICE Guideline. 2014
Consider the following before
adding a second antipsychotic
• Review the diagnosis
• Establish that there has been
adherence to antipsychotic
medication, prescribed at an
adequate dose and for the
correct duration
• Review engagement with and
use of psychological treatments
• Consider other causes of nonresponse, such as comorbid
substance misuse (including
alcohol), the concurrent use of
other prescribed medication, or
physical illness
Add a second antipsychotic
augment treatment with
clozapine
• May need up to 8–10
weeks to assess
• Choose a drug that does
not compound the
common side effects of
clozapine
If family
intervention has
been undertaken
Suggest CBT
If CBT has been
undertaken
Suggest family
intervention
Treatment of schizophrenia needs a rational approach with minimal tolerability
issues to optimize patient functioning
APA guidelines recommend choosing a
medication that offers good clinical
response without intolerable side
effects1
NICE guidelines recommend regular
monitoring of side effects based on the
side-effect profile of the prescribed
antipsychotic2
Patients who experience serious side effects may decide that the adverse effects
outweigh the benefits of medication1
Antipsychotics that minimize EPS, cardiovascular risk, and activating and sedating
adverse effects may optimize the physical health and social functioning of
patients with schizophrenia
1. Lehman AF, et al. [APA Practice Guidelines] 2010. 2. Kuipers E, et al. NICE
Guideline. 2014
Medication side effects can impair workplace performance and act as
a barrier to entering or returning to work
In a focus group of patients with schizophrenia, stigma of side effects was most felt in employment and
occupation and had led to some reducing their dose or skipping regular medication 1*
Flight of ideas
Lack of
concentration
‘Lazy’
‘Pretending’
Tiredness
Muscle rigidity and
clumsiness
‘Addiction
problems’
Ridicule
Consequence of schizophrenia
Perception by others
Treatment side effects, symptoms and risk of relapse may make entering or returning to work difficult2
The onset of schizophrenia during the teens
and early twenties can interrupt:
• Education
• Early careers
• Transition to independent living
Employers and colleagues may be wary of
working with someone with schizophrenia due
to negative misconceptions of their ability
and/or nature
1. Novak L, Švab V. Psychiatr Danub. 2009;21(1):99–102. 2. Steadman K, et al. Working
with Schizophrenia: Employment, recovery and inclusion in Germany. The Work
Foundation. 2015.
Negative feelings towards medication are associated with lower
scores in both affect and self-esteem
Multiple linear regression analysis of various factors on quality of life
Lancashire
QoL subscale
General life
satisfaction
Affect
Self-esteem
•
Independent variable
Direction of
effect
Partial
correlation*
P-value
Work
↑
0.33
0.005
Cognitive symptoms (PANSS)
↑
0.41
<0.001
Depression/anxiety (PANSS)
↓
–0.23
0.045
Parkinsonism
↓
–0.27
0.021
Work
↑
0.42
<0.001
Negative feelings and effects (DAI)
↓
–0.33
0.003
Depression/anxiety (PANSS)
↓
–0.34
0.003
Parkinsonism
↓
–0.36
<0.001
Negative feelings and effects (DAI)
↓
–0.25
0.026
*Partial
correlation of independent variable with the dependent (quality of life) variable, adjusting for other independent variables
in the model. DAI, Drug Attitude Inventory; PANSS, Positive and Negative Syndrome Scale, QOL, quality of life; ↑ higher values
of independent variable were associated with higher QoL scores; ↓ higher values of independent variable were associated with
lower QoL scores
Hofer A, et al. J Clin Psychiatry. 2004;65(7):932–939.
Side effects of antipsychotic medications are significantly associated with
lower adherence
Adjusted odds ratios for the impact of each side effect on complete adherence (N=876):
Restlessness/feeling jittery
Insomnia (difficulty sleeping)
Activating†
Tremors
Agitation
Difficulty thinking or concentrating
Sleepiness
Sedating†
Sedation
Dizziness
Decreased interest in sex
Prolactin/
endocrine
Sexual dysfunction
Difficult or painful menstrual periods
Male breast enlargement or secretions
Weight gain
Metabolic
Increase in blood glucose level
Nausea/vomiting
GI
Constipation
0.00
0.50
1.00
1.50
2.00
2.50
Odds ratios based on multivariable logistic regression with adherence as dependent variable. Adherence defined as a score of zero on the Morisky
Medication. Adherence Scale. 95% Confidence Intervals are indicated. †study authors grouped activating side effects under the category ‘EPS/agitation’
and sedating side effects under the category 'sedation/cognition’.
DiBonaventura M, et al. BMC Psychiatry. 2012;12:20.
3.00
3.50
Emotional and practical burdens of schizophrenia on families are
intertwined
The subjective burden of social stigma for relatives of patients includes feelings of
frustration, anxiety, low self-esteem and helplessness
Difficulties meeting
practical demands
Negative emotional
response
E.g., frustration
E.g., financial burden
E.g., anxiety
Patient symptoms
aggravated
Tsang HW, et al. Int J Rehabil Res. 2003;26(2):123–130.
Further attempts to e.g., find
employment are more difficult
Take home points
• A key challenge for physicians is to choose an antipsychotic that
effectively controls symptoms, while minimizing side effects
• The limitations of current treatments can lead to a frustrating experience
for everyone impacted
• Treatment of schizophrenia needs a rational approach with minimal
tolerability issues to optimize patient functioning
Can advances in the understanding of receptor
pharmacology avoid the current treatment
compromises?
Take home points
• Antipsychotics have a rich receptor pharmacology which contributes to
efficacy as well as side effects
• Level of sedation is affected by histamine H1 affinity and the amount of
drug reaching the H1 receptors
• Partial agonists often avoid the development of adverse effects associated
with overstimulation of receptors by full agonists
Antipsychotics have a rich receptor pharmacology, which contributes to
efficacy as well as side effects
Receptor1
Effects of blockade
Antipsychotics with a
stronger relative affinity for
a particular receptor system
over the D2 receptor are
likely to induce side effects
associated with the blockade
of that receptor system1
Antipsychotic, antimanic, antiagression
D2
ɑ1-adrenergic
(peripheral)
ɑ2-adrenergic
(peripheral)
EPS/akathisia, tardive dyskinesia, increased prolactin
Postural hypotension, dizziness, syncope
Antidepressant, increased alertness
Increased blood pressure
Anxiolytic, sleep induction, anti-EPS/akathisia
H1
Sedation, weight gain
Memory, cognition, anti-EPS/akathisia
M1 (central)
Dry mouth
M2-4 (peripheral)
Blurred vision, constipation, urinary retention, tachycardia, hypertension
5-HT1A (partial
agonism)
Anxiolytic, antidepressant, anti-EPS/akathisia
5-HT2A
Anti-EPS/akathisia, antipsychotic
5-HT2C
Increased appetite/weight(?)
Efficacy
1. Correll CU. Eur Psychiatry. 2010;25(suppl 2):S12–S21. 2. Stahl SM. CNS
Spectr. 2013;18(6):285‒288. 3. Leucht S et al. Lancet. 2013;382(9896):951‒962.
Side effects
Newer antipsychotics, which
act as partial agonists at
the D2 receptor, regulate
dopamine activity and
reduce the risk of
extrapyramidal symptoms
and prolactin elevation2,3
A key factor for D2 partial agonism is the determination of the optimal
level of intrinsic activity at the receptor
Too high:1
Too low:1
• Activity closer to that of an agonist
• Activity closer to that of an antagonist
• Potential lack of antipsychotic effect
• Potential increased risk of
extrapyramidal symptoms and raised
prolactin levels
• Side effects such as nausea, vomiting,
insomnia and motor effects
Advances in the understanding of receptor pharmacology support the
development of new agents that offer efficacy with improved tolerability profiles
Citrome L, et al. Expert Rev Neurother 2015;15(10):1219–1229.
Take home points
• Antipsychotics have a rich receptor pharmacology which contributes to
efficacy as well as side effects
• Level of sedation is affected by histamine H1 affinity and the amount of
drug reaching the H1 receptors
• Partial agonists often avoid the development of adverse effects associated
with overstimulation of receptors by full agonists
Summary
Summary
Optimal patient functioning and
improved quality of life are important
treatment goals at all stages of
schizophrenia management
The limitations of current
treatments, especially the
side-effect burden, and the
impact on different domains
of functioning can be
frustrating for everyone and
decrease quality of life
The side effects associated with
current treatments are often seen as a
necessary compromise for continued
symptom control
For references please see slide notes
Agents with different
pharmacological profiles may
avoid the current treatment
compromises, and help patients
with schizophrenia to function at
their optimal level
Functional impairment
may result from an
insufficient treatment
effect
Sedating or activating side effects can
prevent patients from functioning at their
optimal level and negatively impact their
quality of life