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Course, Natural History and
Prognosis
Schizophrenia
Schizophrenia is a heterogeneous disease with many dimensions
Negative symptoms
Positive
symptoms
Disorganization
Dimensions underlying
pathophysiology and
treatment response
Motor
symptoms
Cognitive
deficits
Mood
symptoms
Tandon R et al. Schizophr Res. 2009;110(1-3):1–23.
Schizophrenia progression may lead to functional decline
The majority of patients with schizophrenia experience recurring psychotic relapses, and clinical deterioration may
occur in the context of these relapses:
Mild
The longer the period
of untreated psychosis,
the worse the prognosis
Premorbid
Childhood
Prodromal
Adolescence to
early adulthood
Number of
relapses may be
related to greater
deterioration
Prodromal
Psychotic
Critical years
Illness-driven decline in
functioning plateaus
Residual
Symptoms, level of functioning
Clinical deterioration begins here and
occurs throughout the first
5–10 years before the first episode
Severe
Remainder of life
Patients may not recover from subsequent psychotic episodes as quickly or as fully as they did from previous episodes, and
may experience greater degrees of residual symptomology and disability
Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884–897.
Typical Course of Schizophrenia
Prodromal Phase
Marked decrease
in function
Acute Phase
(≈1 to 6 months)
Psychotic
symptoms
begin
Recuperative/
Recovery
(several months)
Positive
symptoms;
negative symptoms
and impaired
functioning remain
Residual
(several months
or more)
Some positive
symptoms;
negative
symptoms persist
Some patients will remain chronically symptomatic despite adequate treatment over many years.
American Psychiatric Association. Practice Guideline for the Treatment of Patients
With Schizophrenia. 2nd ed. Arlington, VA: American Psychiatric Association;
2004.
Relapses, characterized by acute psychotic exacerbation, can have a negative
impact on psychosocial functioning
In addition to the risk of self-harm and harm to others, relapse may have
serious psychosocial implications:
Cause distress to patients
and families
Jeopardize friendships and
relationships
Disrupt education or
employment
Diminish personal
autonomy
Contribute to
stigma
Add to the economic burden of
treating schizophrenia
x
Emsley R, et al. Schizophr Res. 2013;148(1–3):117–121.
Relapse and treatment – Emergent adverse effects have substantial impact on
patient quality of life
Relapse has the highest impact on quality of life (lowest
utility value) of the various health states measured:
Stable schizophrenia
0.92
Stable schizophrenia with weight…
0.83
Stable schizophrenia with…
0.82
Stable schizophrenia with diabetes
0.77
Stable schizophrenia with EPS
Relapse
0.72
0.60
Mean utility score*
EPS=extrapyramidal symptoms. *A time trade-off instrument was used to determine the importance of each health state.
Higher scores represent the highest utility to the patient. Health state descriptions for each of the schizophrenia-related
symptoms, adverse events, and relapse were developed using a combination of a literature review, patient interviews,
and feedback, as well as feedback from volunteers to form the basis of the utility elicitation.
Briggs A, et al. Health Qual Life Outcomes. 2008;6:105.
Many patients experience symptoms that are not fully controlled with treatment
According to physician ratings, 47–60% of patients experiencing positive symptoms that are not fully controlled
following treatment and over 70% of patients experience only some, little or no control of negative symptoms,
Negative symptoms
Little or no control
Positive symptoms
Only some control
Social withdrawal
(n=3,491)
Disordered
thought (n=3,857)
Impoverished
thought (n=2,525)
Bizarre behaviour
(n=1,684)
Blunted affect
(n=2,487)
Delusions
(n=4,746)
Apathy/avolition
(n=1,737)
Hallucinations
(n=3,845)
Anhedonia
(n=1,549)
Agitation
(n=1883)
Lethargy/fatigue
(n=897)
Aggression
(n=1,413)
0
10
20
30
40
50
60
70
80
90 100
Percentage of patients with symptoms that
are not fully controlled
Physicians rated the level of
control with current treatment of
each of the five most important
symptoms in that patient. Rating
categories were “generally well
controlled,” “some control” and
“little or no control”.
0
10
30
40
50
60
70
80
90 100
Percentage of patients with symptoms that
are not fully controlled
n-values indicate the number of patients with that leading symptom, out of a total cohort of 6,523 patients
Lecrubier Y, et al. Eur Psychiatry. 2007;22(6):371–379.
20
Symptoms that are not fully controlled are significantly associated
with impaired global functioning
Residual symptoms in remitted patients
with a schizophrenia spectrum disorder
after acute inpatient treatment were
highly prevalent (94%)
Only 6% of patients in remission did not
have a residual symptom at discharge
from hospital
GAF mean score
Patients in remission with residual symptoms featured significantly worse
global functioning compared with the group without residual symptoms1
Global functioning
82
80
78
76
74
72
70
68
66
64
79.7
P=0.0003
69.6
Patients without residual
symptoms (n=14)
Patients with residual
symptoms (n=222)
GAF, Global Assessment of Functioning
Patients with a diagnosis of schizophrenia, schizophreniform disorder, delusional disorder, or schizoaffective disorder.
Residual symptoms were defined as the presence of any symptom, indicated by a PANSS item score >1 (at least borderline mentally ill), at the time of remission.
Remission was defined using the consensus criteria by Andreasen2 as a PANSS score of ≤ 3 on each of the following items: delusions (P1), unusual thought
contents (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerism/posturing (G5), blunted affect (N1), social withdrawal (N4) and lack of
spontaneity (N6)
1. Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):107–16.
2. Andreasen et al. Am J Psychiatry 2005;162(3):441–449
Disorganization, a common residual symptom,1 is associated with impaired
community functioning
Correlation (r) with Life
Skills Profile Dimension
Disorganization is a reliable predictor of several aspects of community functioning: 2
0
-0.07
-0.1
-0.2
-0.3
-0.4
-0.25
-0.31
-0.37
*
**
-0.5
* p<0.05. **p<0.01. Scales were scored so that higher scores indicated better community functioning.
Disorganization was defined using the PANSS P2 item (conceptual disorganization).
Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):107–16.
Norman RM, et al. Am J Psychiatry. 1999;156(3):400–5.
-0.37
**
-0.47
***
Positive symptoms of schizophrenia are inversely correlated with
ability to function
Positive symptoms impair functional capacity and are associated with reductions in
real-world performance measures via a correlation with depression:
Positive
symptoms
Functional
capacity
-0.27*
-0.21*
Depression
0.28*
-0.13
-0.20*
*p<0.05. N=78
Interpersonal Skills Prediction Model fit: ²=8.22, df=9, p=0.52; comparative fit index=0.99.
Community Activities Prediction Model fit: ²=10.37, df=9, p=0.32; comparative fit
index=0.99
Work Skills Prediction Model fit: ²=10.08, df=10, p=0.43; comparative fit index=0.99.
Bowie CR, et al. Am J Psychiatry. 2006;163(3):418–25.
Interpersonal
skills
Community
activities
Work skills
Primary negative symptoms of schizophrenia can impact
domains of functioning directly1
Even in those with positive symptoms that respond or remit, patients may
remain functionally impaired because of negative symptoms and cognitive
deficits2
r = –0.42***
Primary negative
symptoms
Interpersonal
relations
(social)
Use of common objects
and activities
r = –0.24***
r = –0.30***
***p<0.001
(recreational)
Instrumental role
functioning
(vocational)
Primary negative symptoms were assessed using the negative symptom factor score from the Positive and Negative
Syndrome Scale (PANSS). Functional status was assessed using the Heinrichs–Carpenter Quality of Life Scale (QLS).
1. Fervaha G, et al. Eur Psychiatry. 2014;29(7):449–55. 2. Lehman AF, et al. [APA Practice
Guidelines] 2010.
Take home points
• Functioning is complex and multifactorial, and a variety of factors
contribute to functional impairment in patients with schizophrenia
• Symptoms that are not fully controlled are significantly associated with
impaired global functioning
• Current treatment guidelines include optimizing functioning and quality of
life as important treatment goals
Schizophrenia Is a Progressive and Cyclical Disease Characterized
by Multiple Psychotic Relapses
Following a relapse, patients often fail to recover to the same degree1
Premorbid
Prodromal
Onset
Healthy
Deterioration
Chronic/residual
Worsening
Severity of
Signs and
Symptoms
Birth
10
20
30
Age, years2
40
50
60
Although the majority of patients with schizophrenia exhibit a severe pattern of deterioration,
different degrees of severity and temporal sequences do occur1
1
2
Lieberman JA et al. Biol Psychiatry. 2001;50(11):884-897.
Lewis DA, Lieberman JA. Neuron. 2000;28(2):325-334.
Early, Continuous Treatment of Schizophrenia Improves Treatment Outcomes
Symptom Remission
and Recovery Categories
Patients Meeting Criteria for
Any 6 Months, %
Patients Meeting Criteria for
All 12 Months, %
No hospitalizations
100
83
Symptom remission*
36
22
Disorganization symptoms
93
82
Reality distortion
65
48
Negative symptoms
55
40
Good functional outcome†
25
7
Social functioning
60
40
Work functioning
38
10
10
1
Recovery‡
* Symptom remission criteria that include 3 symptom groups: reality distortion (positive), negative
symptoms, and disorganization rated as mild or less for a duration of 6 months.
† Combined social and work functioning used to define good functional outcome.
‡ Requires no hospitalizations, good or adequate social and work functioning, and symptom ratings of mild
or less for a period of 1 year.
Ventura J et al. Schizophr Res. 2011;132(1):18-23.
Poor Treatment Outcomes Early in the Course of Schizophrenia Led to
Measurable Neurological Damage
Adapted from Lieberman J et al. Biol Psychiatry. 2001;49(6):487-499.
A Variety of Symptom Clusters Contribute to Functional Impairment
Positive symptoms1,2
Delusions
Disorganized thought
Disorganized speech
Hallucinations
Lack of insight2
Functional impairment2
Negative symptoms1
Flat or blunted affect
and emotion
Poverty of speech (alogia)
Inability to experience pleasure
(anhedonia)
Lack of desire to form relationships
(asociality)
Lack of motivation (avolition)
1
Ability to work
Coping with self care
Establishing social
relationships
Cognitive impairment1
Episodic memory
Inappropriate affect
Executive function
Working memory
Tandon R et al. Schizophr Res. 2009;110(1-3):1-23.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
Washington, DC: American Psychiatric Association; 2000.
2
Some Patients With Schizophrenia May Achieve Recovery
With Effective Treatment
In a 3-year observational study, adults with schizophrenia (N=6642) achieved1:
Long-lasting symptomatic remission*
27%
Long-lasting adequate quality of life †
Long-lasting functional remission ‡
13%
4%
Achieved recovery, defined as all 3 of the above
0
10
20
33%
30
40
Patients, %

Employment, independent living, social activity, and medication adherence
were all significantly associated with achieving recovery1
62% of patients at the end of a 10-year follow-up study were rated as having a “poor outcome”2
• Poor outcome was defined as substantial historical and recent mental illness and
unemployment or an unnatural cause of death
* 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.
CGI-SCH=Clinical Global Impression-Schizophrenia scale.
1 Novick D et al. Schizophr Res. 2009;108(1-3):223-230.
2 White C et al. Psychol Med. 2009;39(9):1447-1456.
Patients With Schizophrenia Who Achieved Symptomatic Remission Had
Significantly Better Personal and Social Functioning
80
70
MEAN TOTAL SCORE
60
P=0.001
67.1
P<0.001
Patients in remission (n=23)
Patients not in remission (n=53)
65.9
51.9
51
50
40
30
20
10
0
GAF Score
GAF=Global Assessment of Functioning scale; PSP=Personal and Social
Performance scale.
Brissos S et al. Schizophr Res. 2011;129(2-3):133-136.
PSP Total Score
Patients With Schizophrenia Who Achieved Symptomatic Remission Had
Significantly Better Self-Reported Quality of Life
80
Mean WHOQOL Score
70
60
P=0.009
P=0.013
P=0.023
70.4
68.7
56.4
59.8
P=0.009
65.7
62.5
50.5
54.4
50
40
30
20
10
0
Physical Domain
Psychological Domain
WHOQOL=World Health Organization Quality of Life measure.
Brissos S et al. Schizophr Res. 2011;129(2-3):133-136.
Social Domain
Environmental Domain
Patients in remission
(n=23)
Patients not in remission
(n=53)
Symptomatic Remission in Schizophrenia Led to Significantly Better Insight
and Fewer Depressive Symptoms
Patients in remission
(n=23)
Patients not in
remission (n=53)
P=0.003
Mean PANSS™ Item
G12 Score (Insight)
3.0
2.5
2.0
1.5
1.0
2.0
2.5
P=0.013
3.0
Mean PANSS™ Item
G6 Score (Depression)
3.5
Patients in remission
(n=23)
Patients not in
remission (n=53)
1.5
1.0
0.5
0.5
0
PANSS™=Positive and Negative Syndrome Scale; a trademark of Multi-Health
Systems, Inc.
Brissos S et al. Schizophr Res. 2011;129(2-3):133-136.
2.0
2.0
0
1.0
Excess mortality in severe mental illness1
• Serious mental illness (including schizophrenia) confers:
• 20–25 year reduction of life expectancy
• 40% excess mortality through suicide
• 60% excess mortality due to ‘natural causes’ including2:
•
•
•
•
Cardiovascular diseases
Digestive diseases
Infectious diseases
Respiratory diseases
1. Tiihonen J, et al. Lancet 2009;374:620–7.
2. Saha S et al. Arch Gen Psychiatry. 2007;64(10):1123-1131.
Schizophrenia: A broad range of symptoms
Positive symptoms
Excess or distortion of normal
functions2
Negative symptoms
Decline in or loss of normal
functions2
Cognitive symptoms
Key component of schizophrenia3
•
•
•
•
Delusions1
Hallucinations1
Disorganised thought/speech1
Grossly disorganised or catatonic behaviour1
•
•
•
•
•
Alogia1 (Poverty of speech )
Avolition1 (Lack of motivation )
Anhedonia1 (Inability to experience pleasure)
Asociality1 (Lack of desire to form relationships)
Diminished emotional expression1
•
•
•
•
•
•
•
Attention1
Episodic memory1
Executive functions (including language function) 1
Working memory1
Processing speed1
Inappropriate Affect1
Inhibitory capacity1
Mood symptoms, e.g., depression, anxiety, anger, hostility, aggression are common1
Catatonia: Motor abnormalities Repetitive, complex gestures. Usually of the fingers or hands . Excitable, wild flailing of limbs.
1. APA. 2013; 2. APA. 2000;
3. Wilk et al. Neuropsychology 2005;19(6):778–786;
Relapse is common in schizophrenia
Cumulative relapse rate
(%)
Cumulative relapse rates in schizophrenia, by year
following recovery from the first episode1
1
90
80
70
60
50
40
30
20
10
0
First relapse
(104 patients at risk of relapse)
2
3
4
5 Years after recovery from
previous episode
1. Robinson et al. Arch Gen Psychiatry 1999;56:241–247;
2. Csernansky & Schuchart. CNS Drugs 2002;16(7):473–484;
3. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30;
4. Lewis & Lieberman. Neuron 2000;28:325–344;
5. Levander et al. Acta Psychiatr Scand 2001;104(Suppl 408):65–74;
6. Briggs et al. Health Qual Life Outcomes 2008;6:105
About 82% of patients with schizophrenia or
schizoaffective disorder experienced ≥1
relapse over 5 years1
Relapse can cause:
• Rehospitalisation2
• Slow and incomplete recovery3
• Treatment-resistant illness3
• Persistent symptoms4
• Progressive cognitive decline5
• Increasing difficulty to regain previous
level of functioning3
• Reduced quality of life6
Multiple factors increase the risk of relapse
• The risk of relapse following treatment for first-episode psychosis was significantly
increased by:1,2
• Non-adherence to medication
• Treatment resistance
• Persistent substance use
• Carers’ criticism
• Poorer pre-morbid adjustment
Improving medication adherence, and relapse prevention, are key components
of the management of schizophrenia1,3
Findings from a systematic review and meta-analysis of 29 longitudinal studies1,2
1. Emsley et al. BMC Psychiatry 2013;13:50;
2. Alvarez-Jimenez et al. Schizophr Res 2012;139(1–3):116–128;
3. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30
Relapses negatively affect the disease trajectory and outcome
• 82% of the patients relapse within 5 years following recovery from the first
psychotic episode1
• Relapses lead to:
• Slow or incomplete remission/recovery2
• Treatment-resistant illness and increased difficulty regaining previous
level of functioning2
• Only 7% - 9% of patients, who have failed to respond adequately to 2
adequate antipsychotic treatments, will improve to subsequent
treatments3
1. Robinson et al. Arch Gen Psychiatry 1999;56:241–247.
2. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30.
3. Kinon et al. Psychopharmacol. Bull, 29, 309-314.
Brain imaging and relapse
• 5-year longitudinal study of MRI whole brain scans1
• 96 patients with schizophrenia and 113 matched healthy controls
• Excessive decreases in grey matter density occurred in the left superior
frontal area, left
superior temporal gyrus, right caudate nucleus, and right thalamus as
compared to healthy individuals1,2
• Number of hospitalisations was significantly associated with a larger
decrease in grey matter1,2
Suggests an association between number of relapses
and degree of morphological brain change2
1. van Haren et al. Neuropsychopharmacology 2007;32(10):2057–2066;
2. Emsley et al. Schizophr Res 2013;148(1–3):117–121
Days to remission after each relapse
140
130
Days to remission
120
100
76.5
80
60
47
40
20
0
First
Lieberman et al, J Clin Psychiatry1996;57:5–9.
Second
Third
Impact of Relapse on Patients
With Schizophrenia
Short- and Long-term Consequences of Relapse
Are Substantial to Patients
Increased risk
of recurrent psychotic
episodes
Cumulative
deterioration
in functioning
Short-term
Interruptions in
antipsychotic therapy
Long-term
Hospitalizations
Nasrallah HA, Lasser R. J Psychopharmacol. 2006;20(6 suppl):57-61.
Diminished ability to
maintain
employment or
relationships
Relapse May Reduce Patient Response to Medication
Following relapse, 14 of 97 (14.4%) patients who initially responded favorably to
antipsychotic therapy failed to respond to medication again
Prior to relapse (n=14)
Mean Change in PANSS™ Following
32 Weeks of Medication
20
Following relapse (n=14)
10
7
0
-10
-20
-18.2
PANSS™=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc.
Emsley R et al. Schizophr Res. 2012;138(1):29-34.
Relapse Can Decrease Patient Functioning
59
P<0.05
57.8
58
57
Score
56
55
54
53
52.6
52
51
50
GAF
GAF=Global Assessment of Functioning.
Almond S et al. Br J Psychiatry. 2004;184:346-351.
Relapse (n=77)
No relapse (n=68)
Impact of Early Intervention
for Patients With Schizophrenia
Shorter Duration of Psychosis Led to Improved Outcomes in Patients With
First-Episode Schizophrenia
100
82.1%
Patients With Favorable
Course of Illness, %2
Patients Relapsed
Within 1 Year, %1
75
50
41.4%
30
50.0%
25
28.9%
P=0.025
15
8.6%
0
0
DUI
<44 Days
DUI
44-365 Days
DUI
>365 Days
DUI=duration of untreated illness; DUP=duration of untreated psychosis.
1 Owens DC et al. Br J Psychiatry. 2010;196(4):296-301.
2 Primavera D et al. Ann Gen Psychiatry. 2012;11(1):21
DUP ≤1 Year
(n=45)
DUP >1 Year
(n=35)
Patients With First-Episode Schizophrenia Are
at an Increased Risk of Nonadherence
Only 45% of all patients with first-episode schizophrenia continue their initial
medication for longer than 30 days1
Patients with first-episode schizophrenia who discontinued antipsychotic
therapy had a nearly 5-fold increase in the risk of relapse2
1
2
Tiihonen J et al. Am J Psychiatry. 2011;168(6):603-609.
Robinson D et al. Arch Gen Psychiatry. 1999;56(3):241-247.
Continuous Maintenance Treatment Led to Decreased Deterioration in
Symptoms During the Second Year Following Diagnosis
* 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, a trademark of Multi-Health Systems, Inc.;
Gaebel W et al; for the German Study Group on First-Episode Schizophrenia. J Clin Psychiatry. 2011;72(2):205-218.
Supportive Relationships Can Improve Long-term
Adherence and Reduce Relapse Risk in Patients
With Schizophrenia
Family Involvement and Better Patient Insight May Improve Patient Adherence
• Patients with early-episode schizophrenia who were significantly more
adherent 6 months after hospital discharge:
• Were more aware of their illness and need for medication
• Had more positive perceptions of doctor–patient trust in the therapeutic alliance
• Had better perceived family involvement in treatment and had more positive family attitudes
toward medication
• Had more positive attitudes toward medication
Baloush-Kleinman V et al. Schizophr Res. 2011;130(1-3):176-181.
Instrumental Family Support* Predicts Higher Medication Usage
in Patients With Schizophrenia
• A logistic regression analysis was conducted to assess if family factors,
including the independent dimensions of expressed emotion (EE) and
family support variables, would predict usage of psychiatric medications
• Higher levels of instrumental family support were associated with greater
likelihood of medication usage
• Only family instrumental support significantly predicted medication usage
(odds ratio = 4.8, P=0.05)
* Instrumental support was operationalized as the total number of statements that
illustrated family caregiver ‘‘task-oriented’’ assistance, such as completion of
errands; eg, ‘‘I helped him fill out an employment application.’’
Ramírez García JI et al. Soc Psychiatry Psychiatr Epidemiol. 2006;41(8):624-631.
Family-Supervised Treatment Led to Significant
Improvement in Symptoms and Functioning
PANSS™ total score
GAF score
105
65
Intervention
(n=55)
Treatement as
usual (n=55)
100
55
50
Intervention
(n=55)
Treatment as
usual (n=55)
45
Mean PANSS™ Score
Mean GAF Score
60
95
90
85
80
75
70
65
P=0.003
P=0.008
60
40
0
3
6
9
12
0
Months
Intervention involved supervised treatment in outpatients for schizophrenia (STOPS).
GAF=global assessment of functioning; PANSS™=Positive and Negative Syndrome Scale,
a trademark of Multi-Health Systems, Inc.
Farooq S et al. Br J Psychiatry. 2011;199(6):467-472.
3
6
Months
9
12
The Value of a Support System
In a post hoc analysis of data from the CATIE trial, 89% of patients with a supportive
family improved, compared with only 39% of those lacking a supportive family
With support system
n=27
Without support system
n=23
No change
or worsening
11%
No change
or worsening
61%
Improved
89%
Patients with a supportive family were about twice as likely
to remain in treatment for the duration of the study
CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness.
Glick ID et al. J Clin Psychopharmacol. 2011;31(1):82-85.
Improved
39%
Involving Patients in Their Own Care Increases Knowledge About Their Disease
Patients who were provided information about treatment options and asked to write
down medication preferences perceived a higher level of treatment involvement and
demonstrated significantly more knowledge
18
P=0.03
Knowledge
Before Discharge*
Perceived Involvement
COMRADE
85
80
75
P=0.01
16
14
12
70
10
65
Intervention
(n=49)
Control
(n=58)
Intervention
(n=49)
* Knowledge was assessed with a 7-item questionnaire about the patient’s disease and its treatment.
COMRADE=Combined Outcome Measure for Risk Communication and Treatment Decision
Making Effectiveness.
Hamann J et al. Acta Psychiatr Scand. 2006;114(4):265-273.
Control
(n=58)
Simple Techniques Improve the Communication Between Patients and Clinicians
300
1.5
250
Mean Number of Clinician
Statements of Empathy
Mean Number of Patient
Statements Contributing to Dialogue
P<0.05
200
150
100
50
P<0.03
1
0.5
0
0
Intervention
(n=24)
Control
(n=26)
Steinwachs DM et al. Psychiatr Serv. 2011;62(11):1296-1302.
Intervention
(n=24)
Control
(n=26)
A Strong Therapeutic Alliance and High Patient Insight Was Significantly
Correlated With Adherence to Medication
Medication Adherence Rating Scale (MARS)
Total Score
Medication
Adherence Behavior
Attitude Toward
Taking Medication
Negative Side Effects
SUMD subscore
(patient insight)
−0.54*
−0.46†
−0.45†
−0.19
4PAS
(therapeutic alliance)
0.66*
0.45†
0.52*
0.48†
Patient insight and therapeutic alliance were significantly correlated
with medication adherence (P<0.0001)
* P<0.001.
† P<0.01.
4PAS=4-Point Ordinal Alliance Scale; SUMD=Scale to Assess Unawareness of
Mental Disorder.
Misdrahi D et al. Nord J Psychiatry. 2012;66(1):49-54.
High Prevalence of Nonadherence to Medication
Among Patients With Schizophrenia
Rates of Medication Nonadherence in Chronic Nonpsychiatric
Conditions and Schizophrenia
Nonpsychiatric conditions
Schizophrenia
100
75
Nonadherent Patients,* %2
Nonadherent Patients,* %1
100
63%
49%
45%
50
35%
28%
32%
39%
25
75
50
25
0
0
Hypertension
Hypothyroidism
Hypercholesterolemia
Gout
Type 2 diabetes
Seizure disorders
Osteoporosis
N=706,032.1
* Defined as having a medication possession ratio (MPR) <80% during a 1-year study.
1 Briesacher BA et al. Pharmacotherapy. 2008;28(4):437-443.
2 Byerly M et al. Psychiatry Res. 2005;133(2-3):129-133.
60%
Few Patients With Schizophrenia Take Their Medication as Prescribed
24%
Nonadherent
41%
Partially adherent
Excess fillers
16%
Adherent
19%
MPR=medication possession ratio.
Gilmer TP et al. Am J Psychiatry. 2004;161(4):692-699.
Clinicians Overestimated Patient Adherence to Medication
Adherent
Adherent
52%
≤6
≤5
100
90
80
70
60
50
40
30
20
10
0
0%
0%
0%
0%
≤4
≤3
≤2
≤1
Clinician Rating Scale Score
(Measure of Adherence)
MEMS=medication event monitoring system.
Byerly M et al. Psychiatry Res. 2005;133(2-3):129-133.
Nonadherent
72%
60%
Patients, %
84%
Patients, %
100
90
80
70
60
50
40
30
20
10
0
Nonadherent
48%
20%
12%
4%
<90%
<80%
<70%
<50%
<30%
Actual Daily Adherence
Based on MEMS
<10%
Clinicians Overestimate Medication Usage in Their Patients With Schizophrenia
What portion of patients take >80% of their doses?
50
43%
Patients, %
40
30
Proportion of patients
based on the literature*
Proportion of their
own patients†
28%
20
10
0
N=47.
* Please indicate the proportion of patients with schizophrenia you believe to be
adherent, based on your reading of the treatment literature.
† What proportion of your patients with schizophrenia are adherent?
Kane JM et al; Expert Consensus Panel for Optimizing Pharmacologic Treatment
of Psychotic Disorders. J Clin Psychiatry. 2003;64(suppl 12):52-94.
Risk Factors for Nonadherence
in Patients With Schizophrenia
Adherence Is a Multidimensional Phenomenon
The 5 Dimensions of
Adherence
Health care system/
HCT factors
Disease-related
factors
Social/economic
factors
Treatment-related
factors
Patient-related factors
HCT=health care team.
Adherence to long-term therapies: evidence for action. World Health Organization
Web site. Published 2003. Accessed March 6, 2013.
Cognitive deficits
Co-occurring
substance abuse
Partial or lack
of efficacy
Unresolved
symptoms: negative
and/or positive
Belief medications
are no longer needed
Attitude toward
medication
Velligan DI et al; Expert Consensus Panel on Adherence Problems in Serious and
Persistent Mental Illness. J Clin Psychiatry. 2009;70(suppl 4):1-48.
Practical problems:
transportation,
financial situation
Homelessness
Lack of daily routines
Stigma toward
mental illness
and medication
Social
Fear of potential side
effects
Complexity of
regimen
Environmental
Poor insight
Treatment
Patient
Specific Factors Influence Adherence
Lack of social support
Therapeutic alliance
Beliefs of significant
others toward mental
illness and
medication
Barriers to Medication Adherence in Patients With Schizophrenia
Difficulty with Regimen
Lack of trust in Provider
Denial of Illness
Afraid of Medication
Lack of Social Support
Memory Problems
“Other” Barriers (Homelessness, Substance Abuse)
Adverse Drug Reactions
Stigma
0
10
20
30
40
Patients Reporting Barriers, %
Hudson TJ et al. J Clin Psychiatry. 2004;65:211-216.
50
60
Predictors for Nonadherence in First-Episode Patients With Schizophrenia
60 First-episode patients with schizophrenia or schizophreniform disorder were assessed over a 4-year period. After 6
months, adherence was assessed using the Compliance Interview, and nonadherence was defined as 0% to 74% adherence
over the preceding 3 months. 20 Patients (33%) were nonadherent with medication
Predictors of Nonadherence
Total positive symptom
score (P<0.01)
Alcohol misuse
(P=0.01)
Lack of insight
(P=0.04)
Drug misuse
(P=0.04)
Kamali M et al. Eur Psychiatry. 2006;21(1):29-33.
Patients With Schizophrenia Are Commonly Unaware of Signs and Symptoms
Associated With Their Disease
Patients Unaware of Signs and Symptoms, %
Hallucinations
Delusions
Thought Disorder
Blunt Affect
Anhedonia
Asociality
0
10
20
30
40
50
60
57.4% of patients with schizophrenia showed a moderate to severe lack of awareness
of having a mental disorder
Amador XF et al. Arch Gen Psychiatry. 1994;51(10):826-836.
Poor Insight Was Associated With Nonadherence
60
P<0.001
Patients Demonstrating
Poor Insight, %,*
52.8%
P<0.001
53.9%
P<0.001
43.8%
40
30.7%
27.7%
20
12.9%
0
Lack of Insight into Having
a Mental Disorder
Lack of Insight into Effects of
Medication
* Poor insight was defined as a score ≥3 on each of the respective dimensions of
the SUMD scale.
SAIQ=Self-Appraisal of Illness Questionnaire; SUMD=Scale to Assess
Unawareness of Mental Disease.
Dassa D et al. Aust N Z J Psychiatry. 2010;44(10):921-928.
Lack of Insight
into Consequences
of Mental Disorder
Adherent (n=202)
Nonadherent (n=89)
Poor Insight Was Associated With Nonadherence
5
Adherent (n=26)
Nonadherent (n=32)
GAS
4
P<0.01
P<0.05
3
2.7
2.4
2
1.5
1.7
1
0
Lack of Feeling of Illness
GAS=Global Assessment Scale.
Bartkó G et al. Acta Psychiatr Scand. 1988;77(1):74-76.
Lack of Insight Into Illness
Poor Insight in Schizophrenia Is a Well-Established
Risk Factor for Relapse and Rehospitalization
16
16
P=0.013
8.8
8
8.1
4
0
0
Nonrelapsed (n=116)
10.2
8
4
Relapsed (n=120)
P=0.001
12
10.3
Mean BIS
Mean BIS
12
Rehospitalized (n=84)
Not rehospitalized (n=152)
The rate of relapse in patients with the best insight scores was 39% of the rate among
patients with the worst insight scores
BIS=Birchwood Insight Scale, rated from 0 to 16.
Drake RJ et al. J Clin Psychiatry. 2007;68(1):81-86.
Insight Varies Over Time
Model of the etiology and implications of insight components over time
Awareness of
need for
treatment
Attitudes
toward
illness
Awareness of
consequences
Reasoning biases
Relabeling of
symptoms as
mental illness
Neuropsychologica
l deficits
Awareness of
symptoms
Lincoln TM et al. Schizophr Bull. 2007;33(6):1324-1342.
Higher likelihood of
treatment adherence and
recovery
Depression, functional
strategies
Time
Attitudes
toward
treatment
Implications
Etiology
Societal, cultural,
and religious
norms;
prior experiences;
mood
Lower likelihood of
dysfunctional coping strategies
and acting on symptoms
Consequences of Nonadherence to
Antipsychotics in Patients With Schizophrenia
Poor Adherence Negatively Impacts Patient Outcomes
Hospitalizations
• Hospitalizations were higher among those who did not adhere to
antipsychotics (17.1% vs 29.6%; P<0.05)1
Length of stay
• Partially adherent patients had more total days hospitalized
vs adherent patients (32.0 vs 8.8 days; P<0.05)1
Number of suicide attempts
• Suicide attempts were more frequent among patients who
did not adhere to antipsychotic treatment (1% vs 0%; P=0.004)2
Number of episodes
• Nonadherent patients had a higher rate of >4 annualized episodes vs
adherent patients (23% vs 10%; P<0.001)2
Recovery*
• Adherent patients are more likely to achieve recovery
(OR: 2.25; CI, 1.45-3.51)3
Relapse rate
• Nonadherent patients are more likely to relapse vs adherent patients
(OR: 10.27; CI, 2.59-40.67)4
* Defined as simultaneously achieving long-lasting symptomatic and functional remission and an
adequate quality of life for a minimum period of 24 months and maintained until the 36-month visit.
CI=confidence interval; OR=odds ratio.
1
Ascher-Svanum H et al. BMC Res Notes. 2009;2:6.
Schizophr Res. 2009;108(1-3):223-230.
4
2
Ahn J et al. Value Health. 2008;11(1):48-56.
Morken G et al. BMC Psychiatry. 2008;8:32.
3
Novick D et al.
Nonadherent Patients With First-Episode Psychosis Were More Likely to Relapse
1.0
Adherence (n=92)
Nonadherence (n=48)
Fraction Survival
(Patients Not Relapsed)
0.8
0.6
0.4
0.2
0.0
0
12
24
Months
Caseiro O et al. J Psychiatr Res. 2012;46(8):1099-1105.
36
Nonadherence Predicts Relapse in Patients With Recent-Onset Schizophrenia
Proportion Not Relapsed
1.0
0.9
Adherent (n=65)
0.8
Nonadherent* (n=35)
0.7
0.6
0.5
0.4
0.3
0.2
0
31
151
271
391
511
Days in Study
Missing as little as 25% of the prescribed dosage over a period of ≥2 weeks significantly
raised the risk of psychotic symptom return
* Nonadherence was defined as adherence with <50% of the prescribed medication dose for at least 2 weeks. All sources of
information were considered in categorizing medication adherence. Typically, patient self-report and clinician judgments were
available at each rating point, pill counts were available every 1–2 weeks, and plasma levels were assayed every 4 weeks.
Subotnik KL et al. Am J Psychiatry. 2011;168(3):286–292.
Nonadherence Led to Worsened Symptoms and Decreased Functioning in
Patients With Schizophrenia
Measure
Mean (SD)
Adherent*
(n=381)
Nonadherent*
(n=201)
P Value
Total
-26.84 (19.66)
-22.57 (21.20)
0.002
Positive factor
-10.61 (8.07)
-8.70 (8.75)
0.002
Negative factor
-5.59 (5.65)
-4.79 (6.13)
0.058
Disorganized thought factor
-4.41 (4.13)
-3.84 (4.01)
0.035
Hostility factor
-2.60 (3.04)
-1.87 (3.61)
<0.001
Depression factor
-3.62 (3.43)
-3.23 (3.57)
0.017
-1.14 (1.05)
-0.96 (1.13)
0.05
12.14 (13.57)
9.54 (12.20)
0.036
-5.0 (6.91)
-4.29 (7.93)
0.004
8.55 (18.81)
6.06 (18.19)
0.15
PANSS™ score
CGI-S score
GAF score
MADRS total score
QLS total score
* Medication nonadherence was defined as not taking the full dose of medication as prescribed and was determined based on a daily pill count for each
patient.
CGI-S=Clinical Global Impression-Severity of Illness scale; GAF=Global Assessment of Functioning; MADRS=Montgomery-Åsberg Depression Rating
Scale; PANSS™=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc.; QLS=Quality of Life scale; SD=standard deviation.
Lindenmayer JP et al. J Clin Psychiatry. 2009;70(7):990-996.
Nonadherence to Antipsychotics and Relapse
Are Associated With a High Health Care Burden
Annual health care costs are 2 to 3 times higher for patients who have had
a recent relapse1,2
Adherence to antipsychotic therapy could save a Medicaid system
$106 million in inpatient costs3
Loss of neuroleptic efficacy accounted for ~60% of hospitalization costs,
while nonadherence was predicted to account for ~40%4
1
2
3
4
Hong J et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(5):835-841.
Ascher-Svanum H et al. BMC Psychiatry. 2010;10:2.
Marcus SC, Olfson M. Schizophr Bull. 2008;34(1):173-180.
Weiden PJ, Olfson M. Schizophr Bull. 1995;21(3):419-249.
Hospitalization Costs due to Patient Nonadherence
Gilmer et al,
2004
Variables
Svarstad et al,
2001
0≤MPR≤0.49
0.5≤MPR≤0.79
Refill gap
≥3 months
US population in 2005, millions
296.4
296.4
296.4
Prevalence rate of schizophrenia
0.01
0.01
0.01
Nonadherence rate
0.24
0.16
0.19
Hospitalization rate for nonadherent patients
0.35
0.24
0.33
$3413
$2689
$3421
0.14
0.14
0.19
Annual hospitalization costs for adherent patients
$1025
$1025
$1799
Hospital costs per day in 2005
$1658
$1658
$1658
Hospital costs per day in the study year of the corresponding studies
$1096
$1096
$528
Subtotal, millions
$1122
$357
$1392
Nonadherence measure and cut-off level
Annual hospitalization costs for nonadherent patients
Hospitalization rate for adherent patients
Total, millions
MPR=medication possession ratio.
Sun SX et al. Curr Med Res Opin. 2007;23(10):2305-2312.
$1479
$1392
Nonadherent Patients Were More Likely to Be Hospitalized
Psychiatric Hospitalization Rate %
40
35
34.9%*
30
24.8%*
24.1%*
25
20
13.5%
15
10
5
0
Nonadherent
* P<0.001 compared to adherent patients.
Gilmer TP et al. Am J Psychiatr. 2004;161(4):692-699.
Partially Adherent
Adherent
Excess Medication Filler
Partial Adherence and Nonadherence Led to Increased Hospitalization
Adherent
(n=1758)
32.0
Nonadherent
(n=216)
Adherent was defined as an MPR ≥80%, partially adherent was defined as an
MPR ≥60% and <80%, and nonadherent was defined as an MPR <60%.
* P<0.05 vs adherent.
MPR=medication possession ratio.
Ascher-Svanum H et al. BMC Res Notes. 2009;2:6.
17.6
*
8.8
Time, days
Partially
adherent
(n=36)
*
*
17.1
Rate %
*
Time spent hospitalized
29.6
30.6
Rate of hospitalization
Adherent
(n=1758)
Partially
adherent
(n=36)
Nonadherent
(n=216)
Nonadherent Patients Were More Likely to Be Hospitalized
25
22%
P<0.001
Patients Hospitalized, %
20
15
14%
10
5
0
Nonadherent
Nonadherent was defined as an MPR <70%.
MPR=medication possession ratio.
Weiden PJ et al. Psychiatr Serv. 2004;55(8):886-891.
Adherent