Transcript Overcoming non-adherence – is it possible?

”Effectiveness of long-acting antipsychotics in
the treatment of schizophrenia”
José M. Olivares
Department of Psychiatry. EOXI Vigo
Instituto Biomédico Galicia Sur
Vigo (Spain)
Disclosures
• Have been involved in advisory boards of Eli
Lilly, Janssen-Cilag and AstraZeneca
• Have been the recipient of compensation
from Janssen-Cilag, Lundbeck, Otsuka,
AstraZeneca, Eli Lilly, Bristol-Myers Squibb,
Sanofi-Aventis and Pfizer.
J Clin Psychiatry 2001; 62(1): 6-7.
Results of efficacy studies (RCT) seem confusing due
to:
• Biased samples (selected patients)
• Inclusion and exclusion criteria.
• Low and/or fixed doses
• Statistics and Methodologies.
• Sponsoring by pharmaceutical companies
Heres, Davis, Maino, et al. Am J Psychiatry 163:2, February 2006
Populations in RCT are highly selected
• 420 SCH patients
consecutively
admitted who fulfilled
usual RCT inclusion
and exclusion criteria
Reproduced with permission of Dr Enric Álvarez. Departmento de Psiquiatría, Hospital Santa Creu i Sant Pau, Barcelona.
What is Effectiveness?
Treatment perspective
Efficacy
Tolerability
and
security
Effectiveness
Adherence
TIME TO DISCONTINUATION: Good variable to assess effectiveness
Lehman AF, et al. Am J Psychiatry. 2004;161(2 suppl):1-56.
Swartz MS, et al. Schizophr Bull. 2003;29(1):33-43.
Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.
What is Effectiveness?
Clinicians’ perspective
• Clinicians prefer outcome measures:
– With clinical significance
– With the goal of maximazing generalizability
– That address practical questions about risks, benefits
and costs in routine clinical practice.
• Quality of life and Social Functioning: good
constructs to assess Effectiveness
Kwon JS & Jung-Seok Ch. World Psychiatry. 2009 Feb; 8(1): 35–36.
High rates of acute response* to treatment
in first episode schizophrenia
n=118
CGI, Clinical Global Impression
SADS, Schedule for Affective Disorders and Schizophrenia
Dotted lines represent 95% confidence intervals for percent of patients responding
Robinson D.G. et al. Am J Psychiatry 1999;156:544-549
*Response:
”Much” or ”very much” improved on CGI
Mild or less on SADS psychosis items
Maintained for 8 consecutive weeks
9
What are the real outcomes?
• Treatment response is better in first episode
than in multi-episode patients1
• 7-year follow-up study:2
– 80% deteriorated
– Degree of deterioration significantly correlated with the number of relapses
• 15-year follow-up study:3
– Striking finding: one in six patients did not remit after each episode
• More time to response:4
– Increased times to treatment response in succeeding episodes
1. Robinson et al. Arch Gen Psychiatry 1999;56:241–247; 2. Curson et al. Br J Psychiatry 1985;146:474–480;
3. Wiersma et al. Schizophr Bull 1998;24:75–85; 4. Lieberman et al. Neuropsychopharmacology 1996;14(suppl 3):13S–21S
Relapse rate (95% CI)
First episode patients are at high risk
of relapse
100
90
80
70
60
50
40
30
20
10
0
82%
78%
54%
n=104
Risk of 1st
relapse over
24 months
n=104
Risk of 1st
relapse over
5 years
n=63
Risk of 2nd
relapse over
5 years
There is a high rate of relapse within 5 years
after a first episode
Robinson et al. Arch Gen Psychiatry 1999;56:241–247
Illness progression after relapse
•
A 15-year follow-up study examined the natural course of schizophrenia
after each of the first four psychotic episodes (82 patients)
Patients with persistence of positive and/or
negative symptoms
Mean duration of subsequent
psychotic episodes*
*First episode mean duration=20 months
Emsley et al. Schizophr Res 2013;148(1–3):117–121; Wiersma et al. Schizophr Bull 1998;24(1):75–85
Illness progression after relapse
Increased time to treatment response in successive episodes
•
•
70 patients with first-episode schizophrenia were treated according to a specific
protocol and followed-up over 5 years
If patients relapsed they were placed back onto their original treatment
Time to remission in patients who had
two episodes (n=22)
p=0.06
Emsley et al. Schizophr Res 2013;148(1–3):117–121;
Lieberman et al. Neuropsychopharmacology 1996;14(3 Suppl):13S–21S
Time to remission in patients who had
three episodes (n=6)
p=0.001
13
Excessive decrease in superior
frontal grey matter density in patients
Grey matter decrease and the number of
hospitalizations in schizophrenia patients
0.05
0
-0.05
-0.1
-0.15
n=92
p=0.03
-0.2
0
1
2
3
4
5
6
7
Number of hospitalizations
during scan-interval
van Haren et al. Neuropsychopharmacology 2007;32:2057–2066
8
Relapse duration and brain tissue loss in
schizophrenia: A prospective longitudinal MRI study
Plot of Duration of Relapse By Interscan Interval in a
Longitudinal Study of 202 Schizophrenia Patientsa
•
•
•
202 patients with first-episode
schizophrenia
MRI data (N=659 scans) over an
average of 7 years
Relapse duration was related to
significant decreases in both
general (e.g.,total cerebral
volume) and regional (e.g.,frontal)
brain measures)
aScatterplot
depicts the pattern of symptomatic relapse in schizophrenia patients during the longitudinal follow-up period. Duration of relapse is
plotted against each interscan interval (years). Early phases of the illness are characterized by multiple relapses of shorter durations.
Andreasen et al. Am J Psychiatry 2013 Apr 5. [Epub ahead of print]
Animal (rat) model for the progressive pathophysiology
of schizophrenia – haloperidol induces apoptosis
#p<0.01
vs. vehicle + saline; *p<0.01 vs. vehicle + METH; mPFC=medial prefrontal cortex
Abekawa et al. Schizophr Res 2011;125(1):77–87
Haloperidol
+ saline
Aripiprazole
+ saline
Aripiprazole
+ METH
Haloperidol
+ METH
Mean
Single animal
(left or right side)
Vehicle
+ METH
However, repeated administration of
haloperidol without METH induces
apoptosis
– Neurotoxic effect
Extent of apoptosis
Vehicle
+ saline
•
Repeated administration of
methamphetamine (METH) increases
extracellular glutamate in the mPFC
– Induces apoptosis (TUNELpositive cells)
– Repeated administration of
aripiprazole (3.0 mg/kg) or
haloperidol (0.1 mg/kg) with
METH markedly attenuates the
induction of apoptosis
– Neuroprotective effect
Concentration of TUNEL-positive
cells in the mPFC (cells/mm2)
•
Implications of relapse
Cause distress to
patients and their
families
Jeopardise
friendships and
relationships
Disrupt education
or employment
Diminish personal
autonomy
Contribute to
stigma
Increase cost of
care
Increased risk of
self-harm
Illness can become
more resistant to
treatment
Family burden
Potential
neurobiological
sequelae
1. Emsley et al. Schizophr Res 2013;148(1–3):117–121; 2. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30;
3. Ascher-Svanum et al. BMC Psychiatry 2010;10:2
Preventing relapse in schizophrenia
 Preventing relapse is a key goal highlighted in many
international clinical guidelines1–3
 Medication discontinuation is one of the top predictors of
relapse in schizophrenia4
 Treatment discontinuation increases the relapse
risk five-fold4
 The chance of relapse is decreased if pharmacotherapy
continues uninterrupted5
 Other risk factors include:3
 Substance abuse, residual symptoms, poor insight
Relapse prevention strategies should ensure periods of nonadherence to medication are minimized3
1. NICE Schizophrenia Guidelines CG82, March 2009; 2. APA Practice Guidelines, 2004.
http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2ePG_05-15-06; 3. Barnes et al. J Psychopharmacol. 2011
Feb 3 [Epub ahead of print]; 4. Robinson et al. Arch Gen Psychiatry 1999;56:241–247; 5. Kane. J Clin Psychiatry 2007;68(suppl 14):27–30
Relapse after antipsychotic discontinuation in
remitted subjects after 24-month treatment
Survival function
Complete Censored
Cumulative proportion surviving
1.2
1.1
94% relapse rate
Median time to
relapse = 15 wks
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
n=33
10
20
30
40
50
60
70
80
Survival time (weeks)
Patients with recent onset psychosis who achieved remission relapsed after stopping
treatment with RLAI, therefore, treatment continuation should be considered
RLAI, risperidone long-acting injectable
Emsley et al. Eur Neuropsychopharmacol 2009;19(suppl 3):S486
Relapse cannot be predicted
Mean PANNS score
100
Total PANSS score
90
80
70
60
50
40
30
20
10
0
8
7
n=26
6
5
4
3
2
1
0
Months before relapse
PANSS, Positive and Negative Syndrome Scale
Emsley et al. Eur Neuropsychopharmacol 2009;19(suppl 3):S486
Why is adherence still a challenge
in patient care?
• Non-adherence is more common than
treatment refusal or discontinuation
• Medications with improved safety and
tolerability profiles have not improved
adherence rates
• HCPs focus on difficult-to-treat patients
on maintenance therapy
– Patients who openly refuse or repeatedly discontinue treatment
HCP, healthcare practitioner
Masand et al. Prim Care Companion J Clin Psychiatry 2009;11:147–154
Rates of non-adherence to treatment in
schizophrenia are high
• In study of 34,128 patients, 61% had adherence
difficulties† at some point over 4-year period
following initial diagnosis1
– ~18% had consistently poor adherence
– 43% were inconsistently adherent
– 39% had consistently good adherence
†Determined
using medication possession ratio
1.
Valenstein et al. J Clin Psychiatry 2006;67:1542–1550
Antipsychotic discontinuation after a
first hospitalization for schizophrenia
• Nationwide cohort study conducted 2000–2007 in Finland (n=2588)
Collected a prescription during the
first 30 days after discharge
Continued their initial treatment for
30 days or longer
Tiihonen et al. Am J Psychiatry 2011;168:603–609
Comparison of Atypicals in First-Episode
psychosis (CAFE): randomized 52-week trial
All-cause treatment discontinuation
All-cause
Patient decision
Side effects
Inadequate
therapeutic effect
Olanzapine
Quetiapine
Risperidone
Administrative
0
20
40
Discontinuation (%)
60
80
Broad inclusion and minimal exclusion criteria used to enrol patients similar to those
seeking treatment in clinical practice
n=400
McEvoy et al. Am J Psychiatry 2007;164:1050–1060
Adherence challenges affect almost
all patients*
Continuous therapy
ANY ‘no therapy’ days †
100
5.2%
94.8%
7.1%
350
92.9%
300
250
60
Days
Patients (%)
80
Mean number of days
with ‘no therapy’
40
200
150
110.2
125.0
SGA
n=349
FGA
n=326
100
20
50
0
0
SGA
n=349
FGA
n=326
*Based on availability of medication in a 1-year naturalistic study
†’No therapy’ defined as days in which medication was not available. Patients were considered to be receiving
therapy on days when medication was available and COULD have been taken
Mahmoud et al. Clin Drug Invest 2004;24:275–286
Partial Adherence and Nonadherence Led
to Increased Hospitalization
Time spent hospitalized
Rate of hospitalization
*
Time, days
*
Rate, %
*
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.
*
Even 1–10 days therapy missed per year leads
to an increased risk of hospitalization
Californian Medicaid assessment (n>4000 patients)
p<0.001
Risk of hospitalization
4
3
p<0.001
p=0.0042
2
1
0
n=327
0 days
n=1710
n=1166
1–10 days
11–30 days
Missed therapy over 1 year
n=1122
30+ days
p values given with 0 days as the referent
Weiden et al. Psychiatric Services 2004;55:886–891
Real-World Studies Favour Use of LAIs
RCT studies: good adherent samples?
2.2
As study design shifts toward real-world populations,
LAI formulations display significant advantages
Relapse
2.0
Hospitalization
1.4
All-cause discontinuation
Favors
oral
1.6
Overall
1.2
1.0
0.8
0.6
0.4
Favors
LAI
Adjusted Risk Ratio
1.8
RR=0.877
RR=0.622
RR=0.558
0.2
0
Randomized
Clinical Studies
Prospective
Studies
RCT
LAI=long-acting injectable; RCT=randomized controlled trial; RR=risk ratio.
Kirson N et al. Presented at: 52nd Annual Meeting of New Research Approaches for
Mental Health Interventions; May 29-June 1, 2012; Phoenix, AZ.
Real-world
Retrospective
Studies
LAIs reduce the risk of hospitalisation
in Finland
Cohort study of patients followed between 2000 and 2007 (n=2588)
Treatment
HR
p value
Haloperidol LAI
0.21
0.13
Clozapine
0.48
0.001
Olanzapine
0.54
<0.0001
Other antipsychotics
0.56
0.09
Risperidone LAI
0.57
Perphenazine LAI
0.59
Polypharmacy
0.92
Zuclopenthixol LAI
0.95
Risperidone oral
1.00
Perphenazine oral
1.11
Quetiapine
1.11
0.60
No treatment
1.63
<0.0001
Haloperidol oral
1.79
0.28
Zuclopenthixol oral
1.93
0.29
4 pooled LAI vs oral mother compounds
0.36
0.007
0.10
1.00
Favours LAI
0.09
0.11
0.62
0.92
0.76
10.00
Favours oral antipsychotics
Adjusted HR (95% CI)
CI, confidence interval; HR, hazard ratio; LAI, long-acting injectable
Tiihonen J et al. Am J Psychiatry 2011;168:603-9
Depot formulations vs. oral APS:
an old story
Proportion of patients
without relapse (%)
100
Fluphenazine decanoate (n=55)
Fluphenazine oral (n=50)
90
80
70
60
50
40
30
0
6
12
18
Months in community
24
Hogarty et al. Arch Gen Psychiatry 1979;36:1283–1294; Kane. J Clin Psych 2006;67(suppl 5):9–14
LAI Antipsychotics Increase Time to Medication
Discontinuation Compared to Oral Antipsychotics
Proportion
Time to discontinuation for any reason with typical antipsychotics*
in the first year after medication initiation
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time to Discontinuation for Any Reason With Typical
Antipsychotics* in the First Year After Medication Initiation
LAI (n=97)
Oral (n=202)
P<0.01
0
50
100
150
Days
200
250
300
350
In a 3-year observational study, patients with schizophrenia treated with LAI antipsychotics
demonstrated a significantly longer time to discontinuation
Data from the US Schizophrenia Care and Assessment Program, a large, prospective study of
treatment for schizophrenia, schizoaffective disorder, or schizophreniform disorders conducted July
1997 through September 2003 (n=2327).
*Includes fluphenazine and haloperidol.
LAI=long-acting injectable.
Zhu B et al. Psychiatr Serv. 2008:59(3):315-317.
Discontinuation rates on oral versus
Risperidone LAI: 24-month report from Spain
(e-STAR)
% patients remaining on treatment
100
95
90
86.1%
85
81.8%
80
76.7%
75
70
63.4%
65
60
RLAI patients (n=1345)
Oral patients (n=277)
55
50
0
90
180
270
380
450
540
630
720
Time on treatment (days)
Olivares JM et al. European Psychiatry (2009)
Paliperidone palmitate vs. oral APS
• Time to relapse* was significantly longer in the PP group compared to the oral AP group (p=0.0191,
HR [95% CI] 1.5 [1.1; 2.2])†
• The 85th percentile for time to relapse was 469 days in the PP group vs 249 days in the oral AP
group2
Proportion of patients not relapsing
1.0
By the end of the 24month treatment
phase, 52 (14.8%)
patients met relapse
criteria in the PP group
versus 76 (20.9%)
patients in the oral AP
group (p=0.0323)
Kaplan–Meier plot of time to relapse
Core ITT for efficacy population
0.9
0.8
Paliperidone palmitate (n=352)
Any oral AP (n=363)
0.7
0
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
237
216
233
212
230
207
225
201
221
198
0
0
Days
Patients in the treatment phase
PP
352
326
306
Oral AP 363
323
297
292
280
278
265
272
258
260
246
256
242
252
230
244
227
750
This represents a
29.4% relative risk
reduction in favour of
PP
*According to Csernansky criteria
†log-rank test
AP, antipsychotic; HR, hazard ratio;
TT, intent-to-treat;
PP, paliperidone palmitate;
Schreiner A et al. Poster presented at CINP, 22–26 June 2014, Vancouver, Canada, Poster LP-01-013)
Aripiprazol once monthly vs oral
Time to all-cause discontinuation
Proportion of patients
free of event
1.0
0.8
*
0.6
**
0.4
Aripiprazole once monthly 400 mg
0.2
Oral aripiprazole 10–30 mg/day
Aripiprazole once monthly 50 mg
0
0
14
28
42
56
70
84
98 112 126 140 154 168 182 196 210 224 238 252 266
Days from randomisation
Log-rank test:
* Aripiprazole once monthly 400 mg vs. oral aripiprazole 10–30 mg/day; p=0.0484
** Aripiprazole once monthly 400 mg vs. aripiprazole once monthly 50 mg; p<0.0001
a
Patients discontinued prior to or on Day 280 in Phase 3; ITT sample
Fleischhacker WW, et al. Br J Psychiatry. 2014 [Epub ahead of print].
Hospitalization Rates in patients switched
from Oral Antipsychotics to Aripiprazole
Once-Monthly: a Mirror Study
Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936
Study Design
Retrospective oral
SOC treatment
Prospective aripiprazole
once-monthly treatment
Start
Patient signs Phase B
informed
(n=433)
consent
(1st dose)
Month
-7
Month
-4
Month Month
-1
0
4th
dose
Month
3
Month
6
Extension Phase
Screening and
Oral
Conversion
Phase A
(1-4 weeks)
3-month
hospitalization data
(n=336)
6-month
hospitalization data
(n=433)
3-month
hospitalization data
(n=336)
6-month
hospitalization data
(n=433)
Pre-specified 1-month period
that patient must be stable
and an outpatient
SOC: standard-of-care.
Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936.
Total psychiatric hospitalization rates before and after
prospective treatment with aripiprazole once-monthly
Total psychiatric hospitalization rate
between retrospective period (Months –4 to –1)
and prospective period (Months 4 to 6) p<0.0001
Total psychiatric hospitalization rate
between retrospective 6-month period and
prospective 6-month period p<0.0001
Percentage of patients with
≥1psychiatric hospitalization
45
retrospective
38.1%
40
prospective
35
30
27.1%
25
20
15
8.8%
10
5
2.7%
0
Patients who completed 3 months
treatment on aripiprazole oncemonthly (n=336)
Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936.
All patients who entered Phase B
treatment with aripiprazole
once-monthly (n=433)
Aripiprazole once-monthly
vs. paliperidone palmitate
in a randomized, head-to-head
clinical study
Naber D, et al.
Presented at the 23rd European Congress of Psychiatry (EPA);
March 28-31, 2015, Vienna, Austria
Methods
• Phase 3b, multicenter, 28-week, randomized, open-label, raterblinded, parallel group study (NCT01795547)
• Direct comparison of the treatment effectiveness of two atypical
LAIs: AOM 400 and PP
– AOM 400: 400mg maintenance dose with reduction to 300mg
permitted based on the individual patient tolerability
– PP: flexible dosing of 50 to 150 mg/month (EU and Canada) or
equivalent 78 to 234 mg/month (US).
• Primary outcome: Heinrichs-Carpenter Quality-of-Life Scale (QLS)
• Key secondary outcome: Clinical Global Impression – Severity scale
(CGI-S)
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
40
Study design
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
Results
Patient disposition and exposure
• The treated patient population (n=281) was stable at
baseline
• 100/148 (67.6%) in the AOM 400 and 83/147 (56.5%) in
the PP group completed 28 weeks of treatment.
• The mean doses (±SE) at week 24 were 387.0±3.4 mg
for AOM 400 and 110.3±3.6 mg (EU and Canada) for
PP, equivalent to a mean of 172 mg (US). Doses were in
line with recommended monthly maintenance doses of
AOM 400 and PP.
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
42
Results
Significant improvements with AOM 400 compared to PP treatment on
Heinrichs-Carpenter Quality-of-Life Scale (QLS) total scores
*
*
*
Weeks
Least square mean [LSM] changes from baseline are analyzed with a mixed model for repeated measures, and *p<0.05 indicates significant
differences between treatments (AOM 400 vs PP). Error bars indicate standard error of the LSM
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
43
Results
Significant improvements with AOM 400 compared to PP treatment on
Clinical Global Impression – Severity scale (CGI-S) scores.
Weeks
**
*
*
*
**
**
Least square mean [LSM] changes from baseline are analyzed with a mixed model for repeated measures, and *p<0.05, **p<0.01 indicate
significant differences between treatments (AOM 400 vs PP). Error bars indicate standard error of the LSM.
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
44
Results
Treatment-emergent adverse events (TEAEs) occurring in ≥5% frequency in any group of any phase
Treatment phase:
Treatment group:
Oral conversion
LAI initiation
LAI continuation
AOM 400
(n=144)
PP
(n=137)
AOM 400
(n=132)
PP
(n=118)
AOM 400
(n=119)
PP
(n=109)
50 (34.7)
53 (38.7)
55 (41.7)
51 (43.2)
62 (52.1)
72 (66.1)
Patients with any SAE, n(%):
2 (1.4)
1 (0.7)
2 (1.5)
1 (0.8)
6 (5.0)
8 (7.3)
TEAE leading to discontinuation
6 (4.2)
10 (7.3)
4 (3.0)
6 (5.1)
6 (5.0)
13 (11.9)
2 (1.4)
8 (5.8)
0 (0.0)
0 (0.0)
0 (0.0)
1 (0.9)
11 (7.6)
11 (8.0)
19 (14.4)
2 (1.7)
2 (1.7)
1 (0.9)
Insomnia
11 (7.6)
4 (2.9)
4 (3.0)
8 (6.8)
3 (2.5)
6 (5.5)
Psychotic disorder
2 (1.4)
0 (0.0)
2 (1.5)
0 (0.0)
3 (2.5)
6 (5.5)
N/A
N/A
1 (0.8)
10 (8.5)
3 (2.5)
1 (0.9)
0 (0.0)
2 (1.5)
1 (0.8)
1 (0.8)
12 (10.1)
17 (15.6)
Patients with any TEAE, n(%):
Gastrointestinal disorders
Nausea
Injury, poisoning and procedural complications
Accidental overdosea
Psychiatric disorders
General disorders and administration site conditions
Injection site pain
Investigations
Weight increased
Results shown from the safety sample (all patients treated set, APTS).
AOM 400: aripiprazole once-monthly 400 mg, LAI: long-acting injectable , PP: paliperdone palmitate once-monthly, SAE: serious
adverse event, TEAE: treatment-emergent adverse event.
aDue to the switch between oral medication and LAI treatment, a number of patients took more tablets than planned. These were
reported as a TEAE (‘accidental overdose’) even when these occurrences were not SAEs and had no clinical relevance.
Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria
45
Conclusions
 Results of efficacy studies are difficult to generalize to routine
clinical practice.
 Effectiveness may be defined in different ways
 Efficacy and tolerability are not enough: adherence has
important implications for patient outcome, from the outset
of the disease
 The majority of schizophrenia patients are partially or nonadherent
 Continuous pharmacological treatment combined with
psychosocial treatments improve the possibility of achieving
functional recovery and getting a good quality of life.
 LAIs play a key role in the treatment of schizophrenia,
particularly within the first years after diagnosis.
 More effectiveness studies are needed, particularly head-tohead studies