Early detection and intervention in psychosis.

Early detection and intervention in psychosis. - (BORA)

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Dissertation for the degree philosophiae doctor (PhD)
at the University of Bergen
Dissertation date: © Copyright Wenche ten Velden Hegelstad
Materialet i denne publikasjonen er omfattet av åndverkslovens bestemmelser.
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1.1 Psychosis
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1.2 A brief history of early intervention and psychosis
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1.3 First episode psychosis (FEP)
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23
1.4 Course and Outcome
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28
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29
+),.! 0+0$!#!*!.(,+,1(0%+*?(/+%*+.353$!.!1*!),(+5)!*0/!!)/
(+3B
1.6 Criteria of recovery
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30
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31
2. Duration of untreated psychosis and prevention
strategies
2.1 Duration of Untreated Psychosis (DUP)
+*/%/0/+"0$!!)!.#!*!+",/5$+0%/5),0+)/* 0$!/0.0+"0.!0)!*0?
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2.2 International DUP findings
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32
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33
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2.3 Programmes to reduce DUP: Early Detection
.(5%*0!.2!*0%+**!2%!3! /$2%*#03+ %/0%*#1%/$(!!(!)!*0/A.(5?
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37
2.4 Factors influencing DUP
(+*#%* %0!/0.!0)!*0 !(5?* /!2!.("0+./+*0.%10%*#$2!!!*
/1##!/0! ".+)/01 5"%* %*#/B('+"%*/%#$0%*0+*!! "+.0.!0)!*0+*0$!
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*(0!.5!./?0$!%//1!+" !(5/%*0$!/+D((! I,0$35/0+.!J$2!!!*
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(B?\Z[[PB!.!%2! /0%#)+10,/5$+/%/,,!./0+,(5.+(!+0$.!#. %*#
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38
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2.5 Prevention strategies in psychosis
2.5.1 Primary prevention
.%).5,.!2!*0%+*+"*5 %/!/!+.%((*!//O %/!/!)!*%*#+.#*%
5/"1*0%+** %((*!//.!"!..%*#0+/1&!0%2!+),(%*0P%/%)! 0.! 1%*#
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,/5$+/%/.%/'"0+./ +!/*+05!03..*0,.%).5,.!2!*0%+*B.+,+/! %+(+#%("0+.//+".%*(1 !)0!.*(%*"(1!*6 1.%*#,.!#**5O! *%'!0
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O**+*!0(B?\ZZ\P?!..*0*!1.+ !2!(+,)!*0(,.+!//!/ 1.%*#,1!.05
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40
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41
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42
2.6 Reducing DUP: Combining different levels of prevention
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43
3. Objectives, hypotheses and methods
3.1 Objectives and research questions
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44
3.2 Hypotheses
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3.3 Methods
3.3.1 Design
Longitudinal DUP study
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45
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48
Table 4. Characteristics at inclusion of patients with and without 10-year
follow-up
Measure
Age
GAF
Symptom
GAF
Function
PANSS
components
Positive
Negative
Cognitive
Depressive
Excitative
Gender
(male)*
Alcohol abuse
Drug abuse
Core
schizophrenia
NoED
Follow-up at 10
No follow-up
years (N=73)
at 10 years
(N=67)
Mean
SD
Mean SD
31.2
10.3
30.9
10.7
27.1
7.6
27.1
6.1
ED
Follow-up at 10 No follow-up at
years (N=101) 10 years
(N=40)
Mean
SD
Mean SD
26.3
7.8
25.8
7.3
30.5
6.3
32.1
6.5
29.1
10.6
28.4
8.8
33.3
10.3
34.5
9.2
16.3
21.9
7.9
13.3
10.6
N
41
3.8
8.9
3.3
4.2
4.9
%
56
16.4
22.6
7.9
13.5
11.1
N
38
4.4
10.6
3.3
4.1
4.8
%
56
14.4
18.9
6.8
11.0
8.7
N
56
4.4
7.1
3.3
3.7
3.9
%
55
14.2
18.0
6.4
11.1
8.6
N
31
3.7
6.3
2.8
3.8
3.1
%
77
9
9
41
12
12
56
15
15
42
22
22
63
13
30
65
13
30
64
8
11
27
20
28
68
Median
Range
Ran
ge
0416
Media Range
n
18
01196
Media Ran Median
n
ge
DUP**
13
0-520 22
04
966
ED followed up group < ED no follow-up group, p <0.05
ED followed up group < ED no follow-up group, p <0.01
49
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50
3.4 The Early Detection intervention
3.4.1 The TIPS information campaigns
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56
3.4.2 Detection teams
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+*/%/0! +"0$.!!,/5$%0.%*1./!/3%0$
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57
3.4.3 Treatment protocol
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3.5 Assessments
.%*! )!*0($!(0$,!./+**!(O(%*%(,/5$+(+#%/0?,/5$%0.%/0?+.
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58
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59
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60
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3.5.1 Reliability
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64
4. Short summary of papers
4.1 Variation in Duration of Untreated Psychosis in an 18year perspective
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4.2 Long-Term Follow-up of the TIPS Early Detection in Psychosis
Study: Effects on Ten-Year Outcome
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4.3 Early Detection, early symptom progression and symptomatic
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5. Results
5.1 Longitudinal DUP-study
5.1.1 Sample characteristics across TIPS phases
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5.1.2 DUP did not remain at stable low levels during periods with
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1993-1994 pilot phase: Median: 26 weeks; range 0-936 weeks
1997-1998 TIPS 1: Median: 6 weeks; range 0-416 weeks
1999-2000 TIPS 1: Median: 8 weeks; range 0-364 weeks
2002-2004 TIPS 2, No information campaigns: Median: 15 weeks; range 0-2080 weeks
2005-2006 TIPS 3, Full ED programme: Median: 14 weeks; range 0-520 weeks
2007-2008 TIPS 4 Full ED programme: Median: 25 weeks; range 0-1530 weeks
2009-2010 TIPS 4 Full ED programme: Median: 8 weeks; range 0-1300 weeks
71
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Longitudinal symptom patterns
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5.2.2 The ED-area has higher rates of recovery at ten-year followup.
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5.3 Ten-year prediction of non-remission
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80
Table 10. Baseline characteristics of ten-year non-remitted and remitted patients.
Symptomatic non-remission (N=87) Symptomatic remission (N=87)
Analysis
Being from ED area
Male gender
Core schizophrenia
N (%)
48(55)
54 (62)
56 (64)
N (%)
53 (61)
43 (49)
50 (58)
OR
.83
1.92
1.29
95% CI
.46-1.52
.92-3.97
.7-2.37
Chi2
.35
2.82
.66
p
.56
.09
.42
Drug abuse
24 (28)
15(17)
1.92
.92-3.97
3.1
.08
Mean (SD)
28.0 (9.4)
Mean (SD)
28.7 (9.1)
T
-0.51
Df
172
p
.61
1.1(1.2)
0.7(1.5)
1.8 (1.3)
0.5(1.3)
0.8 (1.0)
0.8 (1.4)
1.6 (1.0)
0.7 (1.3)
1.57
-0.73
1.48
-1.07
169
169
169
169
.12
.47
.14
.29
16.2(4.2)
21.2 (8.7)
7.3(3.3)
11.4 (3.8)
9.3 (4.5)
28.6 (7.5)
31.0 (10.8)
27.4 (19.8)
14.2 (4.1)
19.1 (7.2)
7.2 (3.4)
12.5 (4.2)
9.6 (4.3)
29.7 (6.5)
32.0 (10.5)
17.1 (16.4)
3.12
1.73
0.26
-1.91
-0.33
-1.04
-.61
3.73
172
172
172
172
172
172
172
166
.002
.09
.80
.06
.75
.30
.55
.000
21.6 (23.9)
7.3 (16.7)
4.56
154
.000
44.8 (13.5)
44.2 (13.8)
0.27
172
.79
46.7 (13.9)
39.3 (19.5)
2.84
168
.005
39.8 (16.1)
38.5 (17.0)
0.49
172
.63
39.5 (19.4)
30.2 (22.8)
2.89
171
.004
17.2 (18.2)
14.6 (14.4)
1.03
172
.31
13.1 (19.2)
7.3 (15.2)
2.19
171
.03
N (%)
32 (37)
N (%)
15 (17)
OR
4.3
95% CI
2.0-9.2
Chi2
15.4
p
.000
25 (29)
12 (13.8)
2.5
1.2-5.4
5.8
.016
Median (Range)
Median (Range)
Mann-Whitney U
Z
p
Age
PAS score
Childhood social
Social change
Childhood academic
Academic change
PANSS component
Positive
Negative
Cognitive
Depressive
Excitative
GAF symptom
GAF function
Weeks in psychosis, total,
first year
Weeks in psychosis, total,
second year
Weeks in psychotherapy,
first year
Weeks in psychotherapy,
second year
Weeks on antipsychotics,
first year
Weeks on antipsychotics,
second year
Weeks as inpatient
first year
Weeks as inpatient second
year
One relapse or more first
year
Continuously psychotic
first year
DUP (weeks)
8 (0-520)
4 (0-416)
3009.5
-2.3
.02
Weeks to first remission
13 (1- >520)
9 (1-401)
3289.5
-1.5
.14
81
6. Dicussion
6.1 Variation in DUP
6.1.1 Decreasing salience of psychiatric information
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!+)!(!//!),$/%/! B
6.1.2 Expanded focus of information campaigns may have led to
expanded population
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6.2 Information campaigns were associated with DUP
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6.3 No symptom differences at ten years
6.3.1 Selective attrition
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84
6.3.2 Relatively short NoED DUP
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6.4 Higher recovery rates in ED
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6.5.1 Negative and positive illness trajectories
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comparison
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7.4 Circumstances
7.4.1 Spin-off effects of ED: confounders or moderators?
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7.4.2 Degree of urbanicity
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7.4.3 Selection bias
Sociodemographic differences at inclusion
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$!.!"1/!./)'!1,/1/0*0%(#.+1,+",0%!*0/3$+)3!'*+3(%00(!+10B
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Bias on symptom levels
% *+0$2!,.!D* ,+/0D!4,!.%)!*0+10+)!)!/1.!)!*0/+*0$!/)!
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/%0! !*0!. 0$! /01 5 0$!5 $2! (.! 5 !!* !4,+/! 0+ 0$! !4,!.%)!*0( "0+.?
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7.4.4 Autonomous change within the subjects over time
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7.4.5 Retest-effect
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(%*%(!2(10%+*/* +/!.20%+*/B!+*/% !..!0!/0D!""!0,.+(!)/0+*+0
!0$.!0%*0$!D++),.%/+*B
7.4.6 Measurements at one time point may differ from
measurements on the next
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7.4.7 Statistical regression
$%/ +1./ 3$!* /1&!0/ .! .!.1%0! 0+ * !4,!.%)!*0 +* 0$! /%/ +" 0$!%.
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+B " 0$%/ * ! +*/% !.! 0+ ! * !40.!)! +10+)!? +*! 3+1( !4,!0
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7.4.8 Dropout.
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* %/0+.00$!.!/1(0/+"0$!!4,!.%)!*0B
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102
8. Ethical considerations
.(5 !0!0%+*+" %/!/!+.%((*!//%*#!*!.(?* ,/5$+/%/%*,.0%1(.?.%/!/
!0$%(-1!/0%+*/O./!** ,&+. /)+!*?[cc`PB+)!+"0$!)%*+*!/3%((!
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8.1 False positives
"(/!,+/%0%2!+1./3$!*,!./+* +!/*+0"1("%(.%0!.%"+.+* %0%+*3$%(!
/.!!*%*#,.+! 1.!%* %0! 0$0$!+./$! % B$%/)5+1.3$!*
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/5),0+)/B$!.%/'+""(/!*!#0%2!/)5!#.!0!.0$*0$!.%/'+""(/!
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8.2 Stigmatisation
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!0!0%+*(! 0+1*3*0! * 1*3..*0! /0%#)0%/0%+*F
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+" !2!(+,%*#*50$%*#0$00$!,!./+* +!/*H0(.! 5!4,!.%!*!B0$!.?+*!
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8.3 Informed consent
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104
8.4 It’s unethical not to intervene
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105
9. References
%*#0+*?B?*/0.%#0?B?
%*#0+*?B?\ZZ^B1.0%+*+"1*0.!0! ,/5$+/%/A%),0+*\D5!.+10+)!B/5$+(! ]Ô\P?\aaDb^B
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10. Appendices
10.1 Table I. Long-term outcome studies in psychosis.
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ADMP: Association for methodology and Documentation in Psychiatry; a rating scale
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144
10.3 Letter by Dr. Amos to the editor of the American
Journal of Psychiatry and response by TIPS group
LETTERS TO THE EDITOR
develops enhanced colonic inflammatory responses in adulthood (3). This would set the stage so that when the perinatally
BPA-exposed female rat becomes pregnant, the pregnancy
may be marked by enhanced inflammation. Paradoxically,
estrogenic exposure may have anti-inflammatory effects in the
exposed adult, but inappropriate estrogen exposure may have
pro-inflammatory effects in the perinatally exposed offspring.
These effects were observed at levels of BPA exposure previously believed to be too low for observed adverse effects in
humans (3).
I have proposed elsewhere an estrogenic endocrine disruption theory of schizophrenia, in which inappropriate
dosage, timing, or duration of prenatal estrogen exposure
causes schizophrenia (4, 5). Within this theoretical framework, inappropriate estrogen exposure occurring in the brain
could also be occurring in the colon so that an association
of celiac disease or some other inflammation and schizophrenia may be observable not from a genetic link per se
but rather a transgenerational effect of prenatal estrogen
exposure.
References
1. Karlsson H, Blomström A, Wicks S, Yang S, Yolken RH, Dalman C:
Maternal antibodies to dietary antigens and risk for nonaffective
psychosis in offspring. Am J Psychiatry 2012; 169:625–632
2. Rubio-Tapia A, Murray JA: Celiac disease. Curr Opin Gastroenterol
2010; 26:116–122
3. Braniste V, Jouault A, Gaultier E, Polizzi A, Buisson-Brenac C,
Leveque M, Martin PG, Theodorou V, Fioramonti J, Houdeau E:
Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats.
Proc Natl Acad Sci USA 2010; 107:448–453
4. Brown JS Jr: Association of increased prenatal estrogen with risk
factors for schizophrenia. Schizophr Bull 2011; 37:946–949
5. Brown JS Jr: Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an
endocrine-disruption theory of schizophrenia. Schizophr Bull
2009; 35:256–278
JAMES S. BROWN, JR., M.D., M.P.H.
Richmond, Va.
The author reports no financial relationships with commercial interests.
This letter (doi: 10.1176/appi.ajp.2012.12060735) was accepted
for publication in June 2012.
Alternative Interpretation for the Early
Detection of Psychosis Study
To the Editor: In the April issue, the Treatment and Intervention in Psychosis (TIPS) early-detection study reports
10-year results in a manner that overstates the impact of
reducing the duration of untreated psychosis (1). The authors
dismissed a 50% increase in hospitalization in the treatment
group after 5 years as the result of regional policy differences. They did not describe the policy differences or analyze
the effects of this impressive confound on the small difference
in symptoms, instead claiming to have demonstrated “positive
effects on clinical and functional status” (2, 3). They omit
hospitalization results altogether at 10 years, despite this being
by far the most impressive result at 5 years (1).
992
ajp.psychiatryonline.org
Perhaps because at 5 years the researchers reported a
nonsignificant advantage in remission for the control group
(2), at 10 years they introduce a new recovery metric, based
largely on work function, which showed a significant advantage for the treatment group (1). Although they acknowledge
a significant attrition bias by 10 years, they do not report that
at 5 years there was no difference in work function, or suggest
how reducing the duration of untreated psychosis at baseline would not improve work function at 5 years but double
work function at 10 years.
The authors reported that the control group achieved
independent living significantly more often at the 10-year
mark, but dismiss this evidence of worse function in the
treatment group, suggesting that independent living is not
evidence of recovery because it is not included in the new
metric. They do not analyze the possibility that failure to
achieve independent living is evidence of poor function (1).
References
1. Hegelstad WTV, Larsen TK, Auestad B, Evensen J, Haahr U, Joa I,
Johannesen JO, Langeveld J, Melle I, Opjordsmoen S, Rossberg JI,
Rund BR, Simonsen E, Sundet K, Vaglum P, Friis S, McGlashan T:
Long-term follow-up of the TIPS early detection in psychosis study:
effects on 10-year outcome. Am J Psychiatry 2012; 169:374–380
2. Larsen TK, Melle I, Auestad B, Haahr U, Joa I, Johannessen JO,
Opjordsmoen S, Rund BR, Rossberg JI, Simonsen E, Vaglum P, Friis
S, McGlashan TH: Early detection of psychosis: positive effects on
5-year outcome. Psychol Med 2011; 41:1461–1469
3. Amos A: Early detection of psychosis: positive effects on 5-year
outcome? (letter). Psychol Med 2012; 42:669–670
ANDREW AMOS, B.ARTS (HONS), M.B.B.S.
Brisbane, Australia
The author reports no financial relationships with commercial interests.
This letter (doi: 10.1176/appi.ajp.2012.12050578) was accepted
for publication in June 2012.
Response to Amos Letter
To the Editor: Dr. Amos raises several points of criticism
regarding the TIPS study and our interpretation of the data, as
he did previously (1) in response to abstracts from our group.
We thank the Journal for the opportunity to respond.
First, Dr. Amos points out that patients from the health
care area practicing early detection had significantly higher
rates of hospitalization at the 5-year follow-up, and he is
critical of the fact that we did not thoroughly investigate this
possible confounder. This is a valid concern; however, he
seems to miss the point that it is the group of patients not in
symptom remission (a prerequisite of recovery) who received
more inpatient care in the early-detection area. For recovered
patients, there was no difference between early and usual
detection. Knowing that more hospital time did not lead to
better recovery, hospitalization cannot be a confounder.
Second, Dr. Amos questions the finding that while there
apparently were no differences in work function at the 5-year
follow-up, the early-detection patients had double the chance
of full-time employment at 10 years. He goes on to imply that
we might have chosen a new measure of “recovery” out of
convenience, having made sure that this measure would yield
us more favorable results. At 5 years, we used “working at least
Am J Psychiatry 169:9, September 2012
145
LETTERS TO THE EDITOR
20 hours per week” as the employment outcome (2). At the
10-year follow-up, using a new measure of recovery chosen
before data collection and on the basis of recent developments in the field, we looked only at full-time employment.
This is a stricter measure and was significantly higher for
early detection patients. However, nonrecovered patients had
poor working capacity both in early and usual-detection
areas, both at 5 and 10 years.
Third, Dr. Amos addresses the finding that more patients
from the usual-detection area were living independently.
However, living independently is a necessary but not sufficient element in recovery. In fact, as reported in our 10-year
follow-up in the April issue, only 17.9% of the patients living
independently in the usual-detection area were fully recovered with both symptom remission and full-time employment,
compared with 48.4% for early-detection patients. This seems
to indicate that living independently does not automatically
imply better health and function.
All in all, as we have noted elsewhere (3), we agree that
early detection cannot and should not be presented as a
“cure for all.” Nevertheless, our data show that early detection does seem to have long-standing positive associations
with outcome measures for a large group of patients, and it
improves the chances of recovery. However, for a considerable group of patients, we were not able to demonstrate a longterm effect.
References
1. Amos AJ: Selective bias in early detection for psychosis. Aust N Z J
Psychiatry (in press)
2. Larsen TK, Melle I, Auestad B, Haahr U, Joa I, Johannessen JO,
Opjordsmoen S, Rund BR, Rossberg JI, Simonsen E, Vaglum P,
Friis S, McGlashan T: Early detection of psychosis: positive effects
on 5-year outcome. Psychol Med 2011; 41:1461–1469
3. Friis S, Barder H, Evensen J, Haahr U, Hegelstad WtV, Joa I,
Johannessen JO, Langeveld J, Larsen TK, Melle I, Opjordsmoen S,
Rund BR, Røssberg JI, Simonsen E, Sundet K, Vaglum P, McGlashan T: The TIPS study and bias: replies to Dr. Amos. Aust N Z J
Psychiatry (in press)
WENCHE TEN VELDEN HEGELSTAD, M.SC.
TOR K. LARSEN, M.D. PH.D.
JAN O. JOHANNESEN, M.D. PH.D.
Stavanger, Norway
INGRID MELLE, M.D. PH.D.
Oslo, Norway
ERIK SIMONSEN, M.D. PH.D.
Roskilde, Denmark
SVEIN FRIIS, M.D. PH.D.
Oslo, Norway
THOMAS MCGLASHAN, M.D.
New Haven, Conn.
The authors’ disclosures accompany the original article.
This reply (doi: 10.1176/appi.ajp.2012.12050578r) was accepted for publication in June 2012.
Bilateral Pallidal Necrosis and Cardiac Toxicity
in a Patient With Venlafaxine and Bupropion
Overdose
To the Editor: The new generation of antidepressants is
generally thought to be safer than traditional antidepressants.
Am J Psychiatry 169:9, September 2012
Although combining antidepressants is recommended for
the treatment of refractory depression, the toxicity of drug
overdose from more than one antidepressant is seldom
addressed.
Case Report
A 30-year-old woman was sent to the emergency department 1 hour after ingesting venlafaxine and bupropion
in a suicide attempt. The exact dose was uncertain, but
according to the metabolites of venlafaxine, bupropion,
and benzodiazepine found in her urine, it is probable that
she consumed a 1-month prescription of 150 mg venlafaxine,
300 mg bupropion, and 3 mg lorazepam that was prescribed
3 days earlier.
She had clear consciousness initially, but generalized
myoclonus soon occurred. A fever (40.6°C) and tachycardia (100–170 bpm) developed with normal blood pressure (122/91 mmHg), respiratory rate (16/min), and O 2
saturation (SpO 2 =95%). An ECG demonstrated prolonged
QRS complex with a deep, slurred S wave on lead I and
an R wave on lead aVR. Sodium bicarbonate was then
administrated.
One hour later, the patient became drowsy and confused
and she suffered respiratory distress. Her blood pressure
decreased (94/36 mmHg), tachycardia increased (200 bpm),
and SpO2 decreased (49%). Endotracheal intubation was
performed within 5 minutes, and her SpO 2 and blood
pressure returned to normal. After sodium bicarbonate
treatment, the patient recovered from the changes seen
on the ECG. However, leukocytosis (10.27×109 /L), elevated
creatine kinase (520 U/L) and creatinin (1.5 mg/dL) levels,
and changes in vital signs suggested serotonin syndrome.
Cyprohepadine was provided with supportive treatment;
intravenous lorazepam was also given continuously for
agitated behavior. Fever and disturbed consciousness
ameliorated within 2 days, but creatine kinase and alanine
transaminase levels continued to increase, peaking at
107,895 U/L and 2,453 U/L around 43 and 102 hours,
respectively, after overdose. The patient was extubated 7
days later.
One week after extubation, purposeful involuntary movement and akathisia were noted after discontinuing lorazepam. Suspecting benzodiazepine withdrawal, lorazepam
was resumed with pramipexole, 0.75mg/day, until the
akathisia subsided 2 weeks later. The choreoathetosis
remained, with frontal releasing signs (i.e., Luria test,
glabellar reflex) and impaired recent memory, language,
and executive function. An MRI scan revealed bilateral
pallidal necrosis 7 weeks after admission (Figure 1 and
Figure 2).
Discussion
A limited number of reports of antidepressant overdoserelated bilateral pallidal necrosis have been published. Szólics
et al. (1) reported similar pallidal necrosis with multiple
functional changes and extrapyramidal symptoms after fluoxetine overdose, implying a complex relationship between
serotonin and the nigrastriatal dopaminergic system. The
bilateral pallidal necrosis in our patient could have been
caused by transient hypoxia, but the toxicity of venlafaxine
and/or bupropion could not be excluded. It is therefore
worth being cautious when prescribing venlafaxine concomitantly with bupropion for patients at high risk of deliberate
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993
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