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To all of you, everyday heroes, struggling with this disease

List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I Bodén R, Sundström J, Lindström E, Wieselgren I-M, Lind-

ström L. (2009) Five-year outcome of first-episode psychosis before and after the implementation of a modified assertive community treatment programme. Social Psychiatry and Psy-chiatric Epidemiology, DOI 10.1007/s00127-009-0108-3

II Bodén R, Sundström J, Lindström E, Lindström L. (2009) As-sociation between symptomatic remission and functional out-come in first-episode schizophrenia. Schizophrenia Research, 107:232-237

III Bodén R, Lindström L, Haenni A, Sundström J. (2009) Bio-chemical risk factors for development of obesity in first-episode schizophrenia. Schizophrenia Research, 115:141-145

IV Bodén R, Lindström L, Rautaharju P, Sundström J. Relations of electrocardiographic signs of autonomic dysregulation to five-year outcome in first-episode schizophrenia. Submitted

Reprints were made with permission from the respective publishers.

Contents

Introduction ..................................................................................................... 9 Epidemiology ............................................................................................. 9 Risk factors ................................................................................................. 9 Mortality ................................................................................................... 10 History of the concept of schizophrenia ................................................... 10

DSM-IV diagnostic criteria for schizophrenia ..................................... 11

Longitudinal outcome studies ....................................................................... 13 Mental hospital discharge samples ........................................................... 13 Studies of the early phase of schizophrenia ............................................. 13

Definition of baseline .......................................................................... 14 Included diagnoses............................................................................... 14 Outcome measures ............................................................................... 14 Rating scales of symptoms and remission ........................................... 15 Predictors of outcome .......................................................................... 16

Aetiological theories about schizophrenia .................................................... 21 Neurodevelopmental hypothesis .............................................................. 21 Neurodegenerative hypothesis ................................................................. 21 Dopamine and other neurotransmitters .................................................... 22 Autonomic dysregulation ......................................................................... 22

Treatment of schizophrenia ........................................................................... 25 Antipsychotics .......................................................................................... 25 Assertive community treatment ................................................................ 25 Psychotherapy .......................................................................................... 26

Side effects of antipsychotic medication ...................................................... 27 Extrapyramidal side effects ...................................................................... 27 Metabolic side effects and obesity ........................................................... 27

Hypotheses and Aims ................................................................................... 31

Methods ........................................................................................................ 33 Local background ..................................................................................... 33 Study design ............................................................................................. 33 Setting ...................................................................................................... 34 Case-finding process ................................................................................ 34 Review of the psychiatric records ............................................................ 35 Five-year follow-up interview .................................................................. 35 Investigated predictors and outcome measures ........................................ 36

Psychiatric service changes and symptoms (Paper I) .......................... 36 Symptomatic remission and function (Paper II) .................................. 36 Biochemistry and obesity (Paper III) ................................................... 37 ECG measures and remission (Paper IV) ............................................ 37

Statistical analyses .................................................................................... 37 Ethical considerations .............................................................................. 38

Summary of results ....................................................................................... 39 Paper I ...................................................................................................... 39 Paper II ..................................................................................................... 39 Paper III .................................................................................................... 40 Paper IV ................................................................................................... 41

Discussion ..................................................................................................... 43 General strengths and limitations ............................................................. 43 Paper I ...................................................................................................... 43 Paper II ..................................................................................................... 44 Paper III .................................................................................................... 45 Paper IV ................................................................................................... 45 Future research ......................................................................................... 46

Conclusions ................................................................................................... 47

Sammanfattning på svenska .......................................................................... 49 Bakgrund .................................................................................................. 49 Frågeställningar och målsättning .............................................................. 49 Resultat ..................................................................................................... 50

Acknowledgements ....................................................................................... 51

References ..................................................................................................... 53

9

Introduction

Schizophrenia is a chronic, episodic psychotic disease that affects a broad range of the patient’s life (1). Furthermore, it is one of the world’s top 10 leading causes of disease-related disability (2). Long-term maintenance treatment with antipsychotic medication is often needed to control the symp-toms (3). Moreover, schizophrenia is a disease that affects not only the pa-tient, but also family members and society (4, 5).

Epidemiology The annual incidence of schizophrenia is between 8 and 40 per 100 000 in-habitants. Despite this wide interval of reported incidence throughout the world, the incidence has been regarded as relatively similar across continents (6-8). The point prevalence has been estimated to be about 0.5%, but with a considerable variation around the world (9).

Risk factors Schizophrenia is a highly heritable disease. Twin studies have revealed that about 80% of the liability to schizophrenia is contributed to heritability fac-tors (10). The genetic basis for schizophrenia is not yet fully understood. Nevertheless, there is evolving evidence that rare genetic aberrations with large effects each can increase the risk of schizophrenia, as well as poly-genetic variations of many genes with small effects each (11, 12). Another intriguing observation is that older paternal age increases the risk of schizo-phrenia in the offspring (13). Moreover, there are strong indications that schizophrenia and bipolar disorder share a common genetic cause, with a considerable cross-over in heritability between the two disorders (12, 14).

Urbanicity and migration are associated with higher incidence rates (15-17). Other environmental risk-factors associated with small effect increases of the risk of schizophrenia are cannabis use (18), season of birth (19), prenatal infection and famine (20) and obstetric and perinatal complications (21).

10

Mortality Patients suffering from schizophrenia have a 15 years shorter life expectancy compared with the general population (22). This increased mortality is mainly due to cardiovascular disease and suicide (22, 23); alarmingly, this excess mortality has been increasing in the past decades of the 20th century (24). For a long time, the suicide rate in schizophrenia has been cited to be 10% (25), but this notion has recently been challenged and instead a suicide rate of about half (i.e. 5%) has been estimated (26, 27).

History of the concept of schizophrenia At the turn of the 19th century, the concept of dementia praecox, and a dec-ade later, schizophrenia, was formed. In 1896, the German psychiatrist, Emil Kraepelin, formed the idea of a progressively dementing disease, dementia praecox, and thus defined the disease from its course (28). The Swiss psy-chiatrist, Eugen Bleuler, later developed the phenomenology further and opposed to defining dementia praecox from its course and instead proposed a new name, schizophrenia. In his textbook Dementia Praecox in 1911 Eugen Bleuler identified fundamental schizophrenic symptoms, which included thought disturbances, ambivalence, indifference and autism. The fundamen-tal symptoms were, according to Bleuler, closely associated with the pre-sumed underlying pathophysiology of schizophrenia. Hallucinations, delu-sions and catatonia were termed accessory symptoms and subordinate to the understanding of the causes of the disease. He also divided the patients with schizophrenia into different diagnostic subgroups (paranoid, hebephrenic and catatonic) and noted that the disease had a chronic, episodic course (29).

Fifty years later, Kurt Schneider proposed 10 “first-rank” symptoms sup-posedly discriminative of schizophrenia, which have been much debated since (30). These first-rank symptoms emphasise implausible delusion and hallucinations as especially important. In the early 1970s there was a big gap between European and American criteria regarding the diagnosis of schizo-phrenia: the American definition was far broader and included more of the affective and briefer psychoses compared with the more narrowly defined schizophrenia in Europe (31). These two ways of defining schizophrenia resulted in discrepancies in incidence and prevalence, making ecological comparisons difficult across the world.

In 1980, Tim Crow, a British psychiatrist, made an attempt to combine previous theories by postulating that schizophrenia may consist of two neu-ropathological processes: type 1, which impairs neurotransmitters balance (e.g., dopamine) with associated hallucinations and delusions responsive to antipsychotic treatment, and type 2, with loss of grey and white matter in the brain and associated with negative symptoms and treatment resistance and eventually leading to cognitive decline (32).

11

DSM-IV diagnostic criteria for schizophrenia In the Diagnostic and Statistical Manual released in 1980 (DSM-III), a more narrow definition of schizophrenia was presented that was influenced by Kraepelin’s onset and course description, Bleuler’s fundamental symptoms and Schneider’s first-rank symptoms. This definition was widely accepted throughout the world (33). The criteria for schizophrenia in the most recent edition from 1994 (DSM-IV) are outlined in Table 1 (34).

Table 1. DSM-IV Diagnostic Criteria of Schizophrenia

A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of timeduring a 1-month period (or less if successfully treated):

1. delusions 2. hallucinations 3. disorganized speech (e.g., derailment or incoherence) 4. grossly disorganized or catatonic behaviour 5. negative symptoms, i.e., affective flattening, alogia, or avolition

Note: Only one criterion A symptom is required if delusions are bizarreor hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts or two or more voices are conversing witheach other. B. Social/occupational dysfunction C. Duration: At least 6 months and must include at least 1 month of symptoms (or less if successfully treated) that meet criterion A D. Schizoaffective and mood disorder exclusion E. Substance/general medical condition exclusion: F. Relationship to a pervasive developmental disorder: Additional diagnosis of schizophrenia is made only if prominent delusions orhallucinations are also present for at least a month

13

Longitudinal outcome studies

It is important to bear in mind the above described history of different diag-nostic boundaries when considering outcome studies in schizophrenia. The outcome of a disease is of course dependent on which patients are included in the definition of the disease.

Mental hospital discharge samples Throughout the 20th century, many long-term follow-up studies have been performed on patients discharged from mental hospitals. When trying to compare these studies over time, it seems as though the outcome of schizo-phrenia has improved between the 1920s and 1970s (35). This improvement is largely attributed to new treatments, especially antipsychotic medication.

Results from more recent mental hospital follow-up studies in the 1960s to 1980s, as reviewed by McGlashan, revealed consistently that the course of schizophrenia mostly is chronic but not progressive along the entire course, but tends to plateau 5-10 years after first admission to hospital (36). This meta-analysis also found that schizophrenia is associated with increased risk of physical illness and mortality. Moreover, the outcome of schizophrenia is not only worse than that of other major mental diseases but also heterogene-ous, much of which can be linked to sample characteristics. The heterogene-ity of the phase of the disease is regarded as the major obstacle when trying to compare these kinds of studies.

From Manfred Bleuler’s unique 20-year follow-up of a population of pa-tients with schizophrenia (some of them treated by his father Eugene Bleuler), comes the often-cited prognostic distribution: 25% have severe chronic schizophrenia, 25% moderately severe, 30% mild and 20% recover (37).

Studies of the early phase of schizophrenia To create homogenous samples of patients with schizophrenia regarding dis-ease phase studies of the early phase have become the gold standard to inves-tigate outcome and its predictors. Another reason for studying prognostic factors in first-episode samples is that information about prognosis is proba-bly clinically most interesting in the beginning of the course of the disease.

14

Definition of baseline A crucial issue when defining illness stage is how to define the time of onset of the disease (38). Schizophrenia often has an insidious onset of the psy-chotic symptoms and a long period of prodromal symptoms not specific to schizophrenia, such as withdrawal from social contacts, decline in job or school performance, pondering and sleep disturbances (39). To operational-ise a fixed starting point many first-episode studies have set first admission to hospital as baseline, but as the number of inpatient beds has gradually decreased during the 1970s and thereafter, this threshold became more and more exclusive. This exclusivity was because a significant proportion of the patients were not admitted or because they had a prolonged period of outpa-tient treatment before first admission (40). Thus, in recent decades first con-tact with mental health care has more often been set as the baseline.

Included diagnoses Another important question in first-episode studies is which diagnoses are included in the sample. There are different trajectories for a patient present-ing for the first time to mental health care with psychotic symptoms. If there has been a short duration of the psychotic symptoms and they resolve com-pletely within a month, this could be a brief psychosis; however, if there has been affective symptoms simultaneously, this could be an affective psycho-sis (manic or depressive) or perhaps a drug-induced psychosis if drug abuse is confirmed. However, if the symptoms persist and all the other criteria in Table 1 are met, this could be a development of first schizophreniform dis-order (1 to 6 months) and finally schizophrenia (>6 months). The bottom line is that the earlier the mental health system gets in contact with a patient with psychosis, the more time is needed before a definitive diagnosis can be de-termined (41). Yet, to obtain baseline measures of all patients with first-episode schizophrenia, all patients with first-episode psychosis must be in-cluded, and then as time goes on sort out those with first-episode schizo-phrenia. Thus, there is generally a better outcome reported in first-episode psychosis samples than in first-episode schizophrenia samples because schizophrenia, in general, has a poorer prognosis than brief psychosis and affective psychoses (40).

Outcome measures How good or poor outcome is defined is the next methodological issue that affects the results. Some authors have regarded being discharged from hospi-tal or decreased delusional thinking a good outcome, whereas others have set the threshold higher to total absence of psychotic symptoms (42). Outcome can also be considered in other areas than symptoms: for example, function-

15

ing in daily life, work, social activities and quality of life (QoL) (43). In Manfred Bleuler’s 20-year follow-up the definition of a mild end state of schizophrenic illness included that the patients should be able to maintain a conversation about other topics than their delusions and hallucinations and performing some useful work and living outside the institution or on a quiet ward (37). The array of definitions of outcome has further decreased the opportunity of comparison between different settings and increased the het-erogeneity in findings about the course of schizophrenia (44). Recently, however, a condensed and operational definition of symptomatic remission has been proposed after many years of consensus work, although its relation to functional outcome has not been established (42).

Rating scales of symptoms and remission There are many available rating scales for symptoms in schizophrenia. The newly proposed definition of remission is based on eight core symptoms in schizophrenia and can be measured with several of the available scales (42). One of the most widely used rating scales in schizophrenia research is the Positive and Negative Syndrome Scale (PANSS) (45), consisting of 30 items that are rated on a seven-point scale ranging from absent to severe, and grouped into positive, negative and general psychopathology (Table 2).

Table 2. PANSS items and remission items

Positive and negative items General psychopathology

P1 Delusions* G1 Somatic concern P2 Conceptual disorganization* G2 Anxiety P3 Hallucinatory behaviour * G3 Guilt feelings P4 Excitement G4 Tension P5 Grandiosity G5 Mannerisms & posturing*P6 Suspiciousness/persecution G6 Depression P7 Hostility G7 Motor retardation G8 UncooperativenessN1 Blunted affect* G9 Unusual thought content* N2 Emotional withdrawal G10 Disorientation N3 Poor rapport G11 Poor attention N4 Passive/apathetic social withdrawal* G12 Lack of judgment & insightN5 Difficulty in abstract thinking G13 Disturbance of volition N6 Lack of spontaneity & flow of conversation* G14 Poor impulse controlN7 Stereotyped thinking G15 Preoccupation G16 Active social avoidance*Included in the definition of remission

16

Predictors of outcome The identification of predictors of outcome is important in establishing a prognosis to inform patients and peers, to tailor secondary preventive strate-gies and treatment and to enhance the understanding of the pathophysiology of the disease. In older studies of prevalent samples of patients with schizo-phrenia several predictors of schizophrenia outcome have been noted. These predictors comprise family history, schizoid personality, premorbid function in the social, work and cognitive domains, illness onset and symptom con-stellations (36). In a review of first-admission studies conducted in the late 1980s Ram et al concluded that duration of illness prior to first hospitalisa-tion seemed to be an additional important predictor, although methodologi-cal differences in case definition, sampling and risk factors limited the pos-sibility to identify definite prognostic variables (41). However, in the 1990s prospective first-episode studies with a more rigid methodology also empha-sised duration of untreated psychosis (DUP) as an important predictor of outcome (46). DUP is the time from first psychotic symptom to the time of initiation of treatment.

The observation that a longer DUP was associated with poor outcome and the observation of the plateau effect of the progress of schizophrenia were the basis for the formulation of the “critical period hypothesis” and early inter-vention (47). This concept is based on the idea that the disease process is detrimental in some way and that the treatments we have can stop this process — the sooner the better (48). However, the empirical support for lasting ef-fects of early intervention in clinical practice remains weak (49, 50).

First-episode cohorts Although it is still inconclusive if early intervention can prevent the devel-opment of chronicity in schizophrenia, the rapidly growing number of longi-tudinal first-episode cohorts to study early intervention has become an Eldo-rado for the study of prognostic factors of schizophrenia. Some of the predic-tors of outcome that hitherto have been identified are presented in Table 3. The outcome measures predicted range from treatment response, relapse, to remission and global function. Although the predictors in Table 3 are nu-merous, the effects of each one are weak, with most odds ratios (ORs) rang-ing from 1.1 to 2.2, except for discontinuation of antipsychotics with a more substantial effect with ORs of about 5.

17

Table 3. Predictors of outcome

Predictor category Outcome

Pre-morbid factors Obstetric complications (51) response*Sex (51-54) response, remission, global functionSocial function and marital status (52-57) remission, social function, ADLSchool/work function (52-54, 56) remission, global function Onset, symptoms and co-morbidity Age of onset (52) remissionPositive symptoms (51, 54) response, global functionNegative symptoms (54, 58) social & global function, Cognitive dysfunction (51, 57, 58) response, social & global functionInsight (59) readmissionAlcohol abuse or dependence (60, 61) response, chronicity Neurobiological measurements Lateral ventricular enlargement (62, 63) responseEnlarged pituitary (64) responseDysrythmic EEG (65) remissionNeurological soft signs (55) remissionAutonomic imbalance (hyperarousal) (66) social function, work, negative symptomsEarly treatment factors DUP (52, 55, 56, 67) remissionEarly treatment response (55, 67) remissionDiscontinuation antipsychotics (57, 68, 69) readmission, social function, ADLDrug-induced Parkinsonism (51) response *Response in this table= response to antipsychotic treatment DUP= duration of untreated psychosis ADL= activities of daily living

Some of the important more recent prospective first-episode cohorts are

outlined in Table 4. Many of these projects are still running and adding to our knowledge of the early phase of schizophrenia. As can be seen, there is a drawback when attempting to include the acutely psychotic patients at base-line, mainly because this renders attrition already from the beginning, which, in combination with follow-up attrition, severely impairs the generalisability of the findings.

Tabl

e 4.

Pro

spec

tive

first

-epi

sode

coh

orts

Coh

ort

City

, C

ount

ry

Yea

rs

Dia

gnos

es,

base

line

N

Att

ritio

n ba

selin

e A

ttri

tion

follo

w-u

p Su

ffol

k (7

0, 7

1)

Lim

itatio

ns: N

on-r

epre

sent

ativ

e sa

mpl

e (7

1), h

igh

dose

s (72

)

New

Yor

k,

USA

19

89-1

991

Schi

zoph

reni

a 1st

-adm

issi

on

96

28%

25

%,

4 ye

ars

PEPP

(73,

74)

Li

mita

tions

: No

com

paris

on g

roup

fo

r tre

atm

ent o

utco

me

Ont

ario

, C

anad

a 19

97-2

003

Non

-aff

ectiv

e ps

ycho

sis

1st-a

dmis

sion

159

Not

repo

rted

38%

, 2

year

s

Opu

s (75

-80)

St

reng

th: R

CT

Mul

ticen

tre,

Den

mar

k 19

97-1

998

Non

-aff

ectiv

e ps

ycho

sis

1st-c

onta

ct

562

10-3

7%

45%

, 5

year

s

EPPI

C (8

1)

Li

mita

tions

: diff

eren

t cat

chm

ent

area

s, on

ly E

nglis

h-sp

eaki

ng p

atie

nts

Mel

bour

ne

Aus

tralia

19

95-1

996

Non

-aff

ectiv

e ps

ycho

sis

1st-a

dmis

sion

250

48%

25

%,

1 ye

ar

LEO

(82)

St

reng

th: R

CT

Li

mita

tions

: Sho

rt fo

llow

-up

Lond

on,

Engl

and

2000

-200

1 N

on-a

ffec

tive

psyc

hosi

s 1st

-con

tact

144

Not

repo

rted

9%;

18 m

onth

s

Not

tingh

am (8

3)

Lim

itatio

ns: H

isto

rical

com

paris

on

Engl

and

1992

-199

4 N

on-a

ffec

tive

psyc

hosi

s 1st

-con

tact

112

1% (!

) 19

%,

3 ye

ars

Hill

side

(68)

Lim

itatio

ns: O

nly

Engl

ish-

spea

king

, no

invo

lunt

ary

treat

ed p

atie

nts

New

Yor

k,

USA

19

87-1

996

Schi

zoph

reni

a 1st

-adm

issi

on

219

62%

12

%,

1 ye

ar

Can

tabr

ia (8

4)

Stre

ngth

s: R

epre

sent

ativ

enes

s Sp

ain

1989

-199

0 Sc

hizo

phre

nia

1st-c

onta

ct

86

0% (!

) 12

%,

3 ye

ars

Bor

deau

x (8

5)

Li

mita

tions

: Non

-rep

rese

ntat

ive,

not

in

clud

ing

all i

npat

ient

serv

ices

Fran

ce

2001

-200

2 N

on-a

ffec

tive

psyc

hosi

s 1st

-adm

issi

on

65

11%

8%

, 2

year

s

MA

P (8

6)

Li

mita

tions

: Con

side

rabl

e ba

selin

e at

tritio

n

Van

couv

er,

Can

ada

1982

-198

4 N

on-a

ffec

tive

psyc

hosi

s 1st

-con

tact

318

45%

29

%,

5 ye

ars

EPP

(87)

Lim

itatio

ns: O

nly

Engl

ish-

spea

king

pa

tient

s, no

t all

patie

nts r

efer

red

Cal

gary

, C

anad

a Si

nce

1996

N

on-a

ffec

tive

psyc

hosi

s 1st

-con

tact

278

Not

repo

rted

28%

, 1

year

Dub

lin (8

8)

Lim

itatio

ns: B

asel

ine

attri

tion

Irel

and

1995

-199

9 A

ll ps

ycho

ses

166

30%

20

%,

4 ye

ars

TIPS

(89)

Lim

itatio

ns: L

ong

inde

x ho

spita

lisa-

tion,

no

com

paris

on g

roup

Nor

way

, D

enm

ark

1997

-200

0 N

on-a

ffec

tive

psyc

hosi

s 1st

-adm

issi

on

301

29%

15

%,

1 ye

ar

The

Para

chut

e Pr

ojec

t (53

) Li

mita

tions

: Onl

y Sw

edis

h-sp

eaki

ng

17 c

entra

, Sw

eden

19

96-1

997

Schi

zoph

reni

a,

1st-c

onta

ct

175

31%

13

%,

5 ye

ars

21

Aetiological theories about schizophrenia

A descriptive diagnosis, such as schizophrenia, with no biomarkers con-nected to a causal explanation of the disease is predestined to be surrounded by a plethora of presumed aetiological theories. Moreover, the concept of schizophrenia probably includes several different diseases, making it diffi-cult to even pose the question of the cause of schizophrenia (90). However, the following chapter will try to describe some of the important prevailing theories of the aetiology underlying this enigmatic disease.

Neurodevelopmental hypothesis The neurodevelopmental hypothesis suggests that events during early life cause schizophrenia through an interaction between genetic and environ-mental factors during early periods of brain development. These disruptions in early life are clinically silent until after puberty when maturational events in the brain lead to a psychotic episode (91). Observations in patients with schizophrenia supporting this view are higher frequencies of minor physical abnormalities (92, 93), aberrant dermatoglyphics (94), neurological soft signs already in childhood (95) and delayed development in childhood, in-cluding motor abnormalities (96).

Neurodegenerative hypothesis The Kraepelinean concept of dementia praecox as a progressive brain dis-ease has been renewed by brain imaging studies exhibiting a progressive loss of grey and white matter in the brains of patients with schizophrenia (97). One argument against this view has been that no obvious cognitive decline has been observed in longitudinal studies (98). Thus, some people now argue for a synthesis of the two concepts: schizophrenia may be both a develop-mental and progressive brain disease (99, 100).

22

Dopamine and other neurotransmitters Dopamine dysregulation has been identified as having a central role leading to the symptoms observed in schizophrenia. The evidence is based on the observation that stimulation of D2 receptors in the brain produces psychotic symptoms and the dopamine-antagonising medications reduce these psy-chotic symptoms (101). Striatal excess and frontal lack of dopamine are thought to explain positive and negative symptoms in schizophrenia (102). Another neurotransmitter that is thought to play an important role in the causal pathway is glutamate and the corresponding N-methyl-D-aspartate (NMDA) receptor. In low doses NMDA receptor antagonists can induce negative and cognitive symptoms seen in schizophrenia. Furthermore, NMDA receptor activating agents may reduce negative symptoms when added to regular antidopaminergic treatment (103).

Autonomic dysregulation Already in beginning of the 20th century, signs of autonomic dysregulation were observed in patients with schizophrenia with discrepancies between blood pressure and pulse frequency, oscillating body temperature and non-adaptive sweating (29, 104). Over the following century, there has been an abundance of reports of autonomic dysregulation from various bodily func-tions controlled by the autonomic nervous system, including pupil function (105, 106), sweat glands (107-109), vascular baroreceptors (105), heart rate control and repolarisation disturbances (110-114). Autonomic dysregulation has been hypothesised as one mediating factor that precipitates and leads to a psychotic episode and that contributes to the increased risk of cardiovascular disease in schizophrenia (107, 110, 115).

Despite the numerous reports of disturbances in various functions con-trolled by the autonomic nervous system, it is only electrodermal activity (sweat gland regulation) that so far has been evaluated as a prognostic tool in schizophrenia. The results are somewhat inconsistent: electrodermal non-responding to external stimuli in male patients with schizophrenia was asso-ciated with poor functional 2-year outcome (108), whereas female patients with electrodermal non-responding was associated with good functional 2-year outcome (109). However these samples were mixed regarding disease stage. Moreover, the samples were too small to differentiate the analyses between chronic and first-episode patients. In a recent study with a sample of only patients in their early phase of schizophrenia (after initial stabilisation of acute psychosis) both hyperarousal and hyperresponsiveness at baseline were associated with more negative symptoms and poor functional outcome 1 year later (66).

23

Heart rate variability studies suggest a lower parasympathetic activity in schizophrenia (110, 116), an activity that seems to be related to the degree of symptoms (112, 117, 118).

Moreover, autonomic cardiac dysregulation is evident in attenuated form in first-degree relatives (119), raising the question of whether autonomic dysregulation is perhaps both state and trait phenomena of schizophrenia. Despite the numerous reports of autonomic dysregulation in schizophrenia and the obvious advantages of electrocardiogram (ECG) measurements be-ing cheap, easily obtained and widely used, there have not been any studies on ECG measures and their association with longitudinal outcome.

25

Treatment of schizophrenia

Antipsychotics Before the introduction of antipsychotics in the 1950s, the majority of pa-tients with schizophrenia were dwelling in mental hospitals. Because of the new pharmacological option to control psychotic symptoms, a dramatic change took place in psychiatric hospitals: some of the patients that had pre-viously been in mental hospitals for years with severely disturbing and ag-gressive behaviour could now be discharged and live in the community (120). The dopamine-2 receptor antagonists, also called antipsychotics, are still the only effective therapeutic pharmacological agents currently available to treat psychotic symptoms (121). Clozapine is more effective for treat-ment-resistant positive symptoms and suicidality (122, 123). Olanzapine may also be somewhat more efficacious but otherwise there is similar effi-cacy on positive symptoms (hallucinations, delusion, and agitation) among the other available antipsychotics (124-126). Antipsychotics have a limited efficacy on negative and cognitive symptoms, but because high doses of dopamine-2 blockade can produce negative and cognitive symptoms; claims of efficacy for these symptoms should be evaluated with close scrutiny of the dosing of the comparator drug (127).

Assertive community treatment As a response to the deinstitutionalisation in the early 1970s, a team-based approach called Assertive Community Treatment (ACT), a service-delivery model, was formed as a means of delivering care for severe mentally ill peo-ple living in the community. ACT has proven to be an evidence-based treat-ment in the sense of making the patients keep in contact with mental health services, reduce hospital admissions and improve accommodation status, employment and patient satisfaction. However, the effects of ACT on mental state and social functioning are still conflicting (128). In samples of patients with first-episode psychosis the large Danish OPUS study and two smaller randomised controlled trials found some support for the short-term efficacy of services with ACT (80, 129, 130). The long-term effectiveness of this treatment approach for first-episode psychosis in a naturalistic setting has not been established, however (81).

26

Psychotherapy Some studies report benefits from family treatment and cognitive behaviour therapy for patients with schizophrenia as add on treatment (131, 132). However, Lynch et al observed no effect of cognitive behavioural therapy on symptoms or relapse in schizophrenia in a recent comprehensive meta-analysis (133).

27

Side effects of antipsychotic medication

While most patients with schizophrenia are relying on long-term mainte-nance antipsychotic medication to control their symptoms, it becomes utterly important monitoring both symptoms and side effects longitudinally and optimise treatment to maximise antipsychotic effects and minimise the bur-den of the side effects. Patients with first-episode schizophrenia are also more prone to experience side effects (134). The most common or serious side effects are extrapyramidal symptoms, metabolic, sedation, hyperprolac-tinemia, heart rhythm abnormalities and neuroleptic malignant syndrome.

Extrapyramidal side effects The general concern with the older antipsychotics has been the extrapyrami-dal side effects (EPS): akathisia (inner restlessness), parkinsonism (rigidity, tremor, hypokinesia), dystonia (muscle cramps) and tardive dyskinesia (in-voluntary movements, often in facial muscles) (135). The newer antipsychot-ics were introduced with high expectations that they would not be associated with EPS. Nevertheless, in non-commercially funded, large quasi-experimental, long-term studies the newer antipsychotics have been found to be associated with considerable levels of EPS (125, 126). Moreover, parkin-sonism and dyskinesia have been observed in populations of patients with schizophrenia that have never been exposed to antipsychotic medication, indicating that these motor symptoms partly are intrinsic aspects of the ill-ness (136, 137).

Metabolic side effects and obesity The introduction of the new antipsychotics with a different receptor binding profile has somewhat changed the focus of side effect concerns. With per-haps somewhat lower propensity for EPS, the newer antipsychotics have, on the other hand, been associated with considerably higher frequencies of me-tabolic side effects (125, 126). The metabolic side effects include weight gain, hyperlipidemia and impaired glucose tolerance (138, 139).

The weight gain observed with some commonly prescribed antipsychotics in the two landmark studies CATIE (patients with chronic schizophrenia in

28

the USA) and EUFEST (first-episode patients in Europe) are depicted in Figure 1 and Figure 2, respectively (125, 126). In the CATIE study the mean age was 41 years and mean baseline body mass index (BMI) 30; in the EUFEST study the mean age was 26 years and the mean baseline BMI 22. As can be seen in the figures, a substantial proportion of the patients experi-enced a clinically significant weight gain. In addition, first-episode and leaner patients seem to have a greater risk of weight gain that is due to antip-sychotic medication. However, there is also some evidence that the risk of developing obesity is an intrinsic feature of schizophrenia, regardless of antipsychotic medication and lifestyle factors (140).

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29

Already in the beginning of the 20th century Eugene Bleuler observed that patients with schizophrenia with a rapid weight gain during acute psychosis had a poor prognosis. Moreover, he noted that many patients exhibited con-siderable weight gain after the psychotic episode, sometimes more than 25 kg, and that the weight gain was not parallel to food intake (29). This obser-vation was also made by Emil Kraepelin a decade earlier in patients with dementia praecox (28).

First-episode patients seem to be more susceptible to gaining weight, even when treated with assumed weight-neutral antipsychotics such as ziprasidone (125, 141). These findings raise the question of whether the risk factors in developing obesity should be explored beyond the field of exposure to antip-sychotics. Except for the different antipsychotics, known predictors associ-ated with an increased risk of weight gain in first-episode samples include lower age, more negative symptoms and lower BMI at baseline (142, 143).

Obesity is a major risk factor for cardiovascular disease in the general population (144) and patients with schizophrenia have an increased risk of dying from cardiovascular disease (23). Other adverse effects of obesity in schizophrenia are poor QoL (145) and non-adherence to treatment leading to worse outcome (146). Thus, studies of early risk factors in the development of obesity in schizophrenia are urgently needed to enable more efficient tai-loring of early preventive interventions (147).

31

Hypotheses and Aims

1. The overall aim of this study was to collect an epidemiologically repre-sentative semi-historical (archival assessments and investigations) cohort of first-episode non-affective psychosis patients and through a compre-hensive 5-year follow-up explore a wide array of predictors of various aspects of long-term outcome.

2. The aim of the first study was to investigate all consecutive patients with a non-affective first-episode psychosis within the psychiatric services in Uppsala County, as well as to compare the two cohorts treated 3 years before and 3 years after the service change. Our hypothesis was that the implementation of a modified ACT programme would be followed by improvement in symptomatic and functional 5-year outcome.

3. In the second study the aim was to investigate the relations of symptom remission to a broad functional outcome, including subjective satisfac-tion with life in a 5-year follow-up of a subsample of the above cohort consisting of patients with first-episode schizophrenia spectrum disorder. We hypothesised that remission would be associated with better func-tional outcome and subjective satisfaction with life, and that other fac-tors than the ones included in the definition of remission may be impor-tant predictors of functional outcome.

4. The aim of study III was to explore routine blood chemistry variables as predictors of developing obesity and weight gain over 5 years in first-episode schizophrenia.

5. The aim of study IV, the final study in this thesis, was to investigate whether routine ECG measures reflecting cardiac autonomic balance (such as altered heart rate, repolarisation and left ventricular hypertrophy early in the schizophrenic disease) can predict remission status 5 years later. Our hypothesis was that the degree of autonomic dysregulation is associated with the symptomatic outcome of first-episode schizophrenia.

33

Methods

Local background Uppsala University Hospital has a long tradition of prospective first-episode schizophrenia studies (148, 149). In the early 1990s one ward at the Univer-sity Hospital was assigned to admit and examine all patients with a first-episode psychosis according to a protocol that included clinical interviews with the patients and their parents, siblings, friends and spouse, a psychiatric evaluation (including DUP), social evaluation (educational level, occupa-tional status and frequency of social activities), somatic assessment (somatic status, blood biochemistry, ECG, weight, height and electroencephalogra-phy) and neurocognitive testing. After this initial inpatient phase, the pa-tients were referred to one of three sectorised clinics with eight community-based teams serving all psychiatric patients living in that part of the county, irrespective of diagnosis.

In 1998, the psychiatric treatment organisation was changed and a modi-fied ACT (mACT) model was implemented, where seven multidisciplinary teams were established with specialisation in outpatient treatment of schizo-phrenia. The modifications of ACT according to the Dartmouth criteria were (150): no 24-h coverage by the teams and no specialist in substance abuse treatment within the teams. The goal was to have close co-operation with the vocational and residential help organisations in the community and to ensure optimal multidimensional rehabilitation. One of the seven teams was special-ised in the treatment of young adults with early non-affective psychosis. However, the algorithm for the initial examination of the patients remained unchanged.

Study design This study was designed as a semi-historical cohort study in order to maxi-mise inclusion of all consecutive patients because asking actively psychotic patients about research participation at baseline can render severe attrition already from start. Thus, we used historical data (from patient charts such as ECGs, blood biochemistry, DUP) and then made a prospective follow-up.

34

Setting The study was performed in a geographically defined area (Uppsala County in Sweden), which consists of a semi-rural and semi-urban region with 290 000 inhabitants. All patients with psychosis were treated within the same organisation of psychiatric care — care that is state financed in Swe-den. Homelessness is rare in Sweden in the general population (151). Em-ployment ratios and the proportion of high alcohol consumption in the gen-eral population were virtually stable during the study period (152, 153).

Case-finding process To identify all patients with first-episode psychosis we searched the elec-tronic psychiatric health care registers of Uppsala County with the period set to 1995-2000. These registers contain information on which health care fa-cility has been attended, date and diagnosis of each outpatient visit to a psy-chiatrist, admissions and discharges from inpatient care. Forensic psychiatric patients are also found in these registers and, according to Swedish legisla-tion, patients with psychotic disorders cannot be imprisoned. The set of search criteria used was all non-affective psychosis diagnoses with DSM-IV codes: 295.1-295.9, 297.1, 298.8 and 298.9 (i.e. schizophrenia, schizophreni-form disorder, schizoaffective disorder, delusional disorder, brief psychosis and psychotic disorders not otherwise specified). In 1998, the local register in Uppsala changed to ICD-10 and from this point we used the search crite-ria of the corresponding ICD-10 diagnoses with the codes F20-F29.

All medical records were then manually evaluated if the case in the regis-ter was a first episode of non-affective psychosis. Patients were included if they were between 16 and 59 years old. If organic causes or severe drug abuse was identified as a main cause of psychosis, the patient was excluded. We identified 167 patients in the register search. After a review of the medi-cal records of the first year of illness, 13 patients were found to have an af-fective psychosis and 6 patients had a personality disorder (with no clear psychotic symptoms found in the psychiatric records). In addition, two pa-tients had severe drug abuse and two had an organic cause of their psychosis. This yielded a final sample of 144 patients with a first episode of non-affective psychosis. Of these 144 patients, 124 had a schizophrenia spectrum disorder (schizophrenia, schizophreniform or schizoaffective disorder). Baseline was defined as the date of first contact with a mental health service with psychotic symptoms recorded in the patients’ medical record. A flow-chart of attrition in the different papers is displayed in Figure 3.

35

All consecutive, first-episode psychosis through registers:

n=167

•Affective psychosis (n=13)•Personality disorder (n=6)•Drug induced psychosis (n=2)•Organic cause (n=2)

Review medical records 1st year

Original cohort:n=144

All non-affective first-episode psychosis

Schizophrenia spectrum:n=124

•Psychosis NOS (n=9)•Brief psychosis (n=11)

•Lost to follow-up (n=5)•Declined (n=9)•No complete PANSS (n=34)

•No baseline ECG (n=61)•No 5-year PANSS (n=18)•Lost to follow-up (n=7)

•No baseline weight (n=33)•No 5-year weight (n=28)•No blood test (n=4)

•Lost to follow-up (n=8)•Declined (n=14)•Missing data (n=1)

Paper I: n=121 Paper III: n=38 Paper IV: n=59Paper II: n=76

Figure 3. Flow-chart of the attrition in the four studies

Review of the psychiatric records The first year of illness was reviewed with a structured reassessment using a checklist composed of DSM-IV diagnostic criteria. Confirmation of the di-agnosis and a baseline GAF rating, based on information in the medical re-cords, were carried out by the principal author (RB) with consensus agree-ment by two of the co-authors of Paper I (EL and I-MW), who are both ex-perienced psychiatrists. Baseline sociodemographic variables, DUP, weight and height measures, ECGs, blood chemistry data and treatment exposure during the first year were extracted from the psychiatric records.

Five-year follow-up interview A follow-up interview was conducted 5 years after the patients’ first presenta-tion to mental health care. Patients were traced by using their personal identi-fication number to locate their current address. The patients were first sent a letter and then contacted by phone. The follow-up face-to-face interview was conducted in one or sometimes two sessions. The assessments consisted of the Positive and Negative Syndrome Scale (PANSS) (45), the Alcohol Use Disorders Identification Test (AUDIT) (154, 155), the Subjective Satisfaction

36

With Life (SSWL) scale (156), the Global Assessment of Functioning (GAF) scale (34) and a life-time re-diagnosis according to DSM-IV.

In addition, information was collected on education, employment status, accommodation, height, weight and current medication. If a patient declined being interviewed, but consented to participation, a phone interview or mail interview and/or review of the current psychiatric records was performed, including AUDIT, SSWL, education, employment status, accommodation and height and weight. The principal author (RB) conducted 80% of the interviews while five trained MDs conducted the remaining 20% of the interviews.

Investigated predictors and outcome measures Psychiatric service changes and symptoms (Paper I) First, we explored how the predictor of first presentation to mental health services and having initial treatment during 3 years before or during 3 years after the implementation of mACT in 1998 was associated with a broad ar-ray of outcome measures at the 5-year follow-up.

The two co-primary endpoints were poor outcome regarding positive and negative symptoms at the 5-year follow-up, defined as having a rating of >4 on any positive or negative subscale item. Secondary outcome measures were dichotomised and defined as poor according to the following: GAF <40, AUDIT >7, use of illicit drugs, any domain on SSWL <2, being home-less or living in a sheltered or supervised accommodation, not working or studying at all the previous year, or having committed suicide.

Symptomatic remission and function (Paper II) Remission of core schizophrenia symptoms was the main predictor in the second paper. Other psychopathology factors were also tested and included excited, depression and anxiety factors, negative symptoms, lack of judge-ment and insight. Additionally, comorbid alcohol use or obesity and pre-treatment factors, such as educational level, premorbid occupational function and DUP were investigated.

A composite outcome measure labelled “good function” was created and defined as: living independently (not sheltered living or homeless), in com-petitive work or studying at least 50% during the past year and meeting friends at least once a month. All three criteria had to be met to be rated as having good function.

37

Biochemistry and obesity (Paper III) In the third paper the following routine biochemistry variables were explored as predictors: haemoglobin, red blood cell count, hematocrit, white blood cell count, platelet count, alkaline phosphatase, alanine aminotransferase, �-glutamyltransferase, thyroid-stimulating hormone, albumin, calcium, so-dium, potassium and creatinine.

The presence of obesity at the 5-year follow-up was the primary outcome measure. Obesity was defined as having a BMI �30, which is in accordance with the WHO definition (157). As a secondary outcome, -BMI was con-sidered, defined as the difference between the 5-year follow-up BMI and baseline BMI.

ECG measures and remission (Paper IV) In the last paper 10 ECG variables were selected to reflect autonomic regula-tion: heart rate, repolarisation disturbances (various QT and T-wave meas-ures) and left ventricular hypertrophy measures (Cornell and Sokolov-Lyon voltage).

The outcome measure was symptomatic remission at the 5-year follow-up. Remission was defined as a score of “3=mild” or less on all of the previ-ously described eight items from the PANSS.

Statistical analyses All continuous variables were tested for normality. Skewed variables were transformed with a natural logarithm to promote normality. If non-normally distributed variables contained values of zero, they were dichotomised with median as cut off to maximise power. Non-linear associations between the independent and dependent variables were investigated with multivariable regression-penalised spline.

In the first paper we analysed the dichotomised variables one by one in sepa-rate logistic regression models with exposure group (non-mACT and mACT) serving as the main independent variable. We considered one unadjusted model and one adjusted for a baseline propensity score (including all baseline vari-ables) and use of antipsychotic medication at the 5-year follow-up.

In the second paper we also investigated the predictors one by one in separate analyses as independent variables in logistic regression models. In this paper good function was the dependent variable. C-statistics (area under the receiver-operating characteristics curves, ROC) was calculated from those models to analyse the discriminatory capacity of symptomatic remis-sion for good function.

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In Paper III logistic regression with obesity status as the dependent vari-able was used to investigate relations of the independent variables to the primary outcome variable. For the secondary outcome, linear regression models with BMI as the dependent variable were used.

In the last paper logistic regression models were applied to investigate the relations of the 10 ECG variables to the dependent variable, i.e. non-remission. Data were analysed using the software packages SPSS 15.0-16.0 (SPSS Inc., Chicago, IL, USA) and Stata 10.0-10.1 (StataCorp; College Sta-tion, TX).

Ethical considerations Asking patients with schizophrenia about participation in research can be a sensitive and difficult issue, not only because schizophrenia is often a dis-ease with fluctuations in insight, suspiciousness and delusions but also be-cause many patients with schizophrenia have been subjected to involuntary treatment. Additionally, all patients, whichever diagnosis, are in a subordi-nate position in relation to the healthcare system.

If the patients still had an ongoing treatment for the time of the follow-up assessment, they were first asked by their primary staff member if they al-lowed someone from the research team to contact them for information about the research programme. Then the patients were contacted by phone and received information about the nature of the research project and that their participation would consist of an interview that would last about 1-1.5 hours. The patients were also given written information about the project and at the time of the interview there was an initial reassurance that the patients had understood the information and that they consented to participation.

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Summary of results

Paper I In contrast to our hypothesis, patients in the mACT group had a borderline significant increased risk of having a poor 5-year outcome regarding positive psychotic symptoms (adjusted OR 3.21, 95% confidence interval [CI] 0.97 to 10.63). Concerning negative symptoms, there was no difference (adjusted OR 1.65, 95% CI 0.48 to 5.66), nor were there any differences in any of the secondary outcome measures: global assessment of functioning, hazardous alcohol use, use of illicit drugs, not working or in education, independent living, subjective satisfaction with life or suicide.

Results were similar in subgroup analyses, but in the subgroup of patients with a schizophrenia spectrum diagnosis the mACT group had a higher risk of having poor outcome on positive psychotic symptoms with an OR of 3.67 and a 95% CI of 1.07 to 12.56, adjusted for the baseline data propensity score and use of antipsychotics at the 5-year follow-up.

Paper II The proportion of patients having good function was significantly higher among remitters than non-remitters in all domains (Figure 4). Subjective satisfaction with life was also rated higher among remitters (Figure 5). In comparison with non-remission, symptomatic remission was strongly asso-ciated with good function (OR 13.2, 95% CI 4.3 to 40.3). A DUP of 3 months or less as compared with a longer duration was associated with hav-ing good function at the 5-year follow-up independently of remission status. The discriminatory capacity of symptomatic remission for having good func-tion vs. not was acceptable (c-statistic=0.78), which was significantly im-proved to an excellent discriminatory capacity by adding DUP less than 3 months vs. not adding DUP to the model (c-statistic=0.83, p=0.04).

Having insight was significantly associated with good function, but the association was attenuated after adjusting for remission status.

40

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Paper III The proportion of obese patients was more than twice as high at the 5-year follow-up compared with baseline (Figure 6). The mean change of BMI over 5 years (-BMI) was a 4.1 kg/m2 increase (4.5 SD). The greatest BMI in-crease was observed among the patients who had a normal to low BMI at baseline; in contrast, the patients who were obese at baseline experienced a median BMI decrease (Figure 7).

Development of obesity among those who were not obese at baseline was predicted by baseline haemoglobin levels (odds ratio per standard deviation [OR/SD] 3.3, 95% CI 1.4 to 7.5), red blood cell count (OR/SD 2.6, 95% CI 1.2 to 5.5), hematocrit (OR/SD 2.8, 95% CI 1.3 to 5.9), �-glutamyltransferase (OR/SD 2.8, 95% CI 1.2-6.3) and creatinine (OR/SD 3.1, 95% CI 1.2 to 8.0). Sodium level was borderline significantly associated with subsequent obesity (OR/SD 2.1, 95% CI 1.0-4.6). Adjusting for baseline BMI attenuated the asso-ciations for �-glutamyltransferase and creatinine.

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Figure 7. Differences in body mass index (-BMI) between 5-year follow-up and baseline in three classes of baseline body mass index (BMI). Box limits represent the interquartile ranges, line in box represents the median, and whiskers represent the range.

Paper IV Higher heart rate at baseline was associated with a higher risk of being in non-remission 5 years later (OR 2.2, 95% CI 1.0-4.8, per SD). Among the ECG variables reflecting repolarisation, T-wave amplitudes above the median in leads V1 or V5 were associated with higher risks of non-remission, OR 4.8 (95% CI 1.2-19.1) and 5.2 (95% CI 1.2-21.6), respectively. An ST60 ampli-tude from lead V5 above the median was also associated with a higher risk of non-remission (OR 6.4, 95% CI 1.5-27.2). Adjusting models for heart rate did not materially change the results, except from T-axis and QRS-T axis that became borderline statistically significant.

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Discussion

General strengths and limitations The strengths of this study are that we included all patients in a defined catchment area and used a fairly long follow-up time. One limitation is that we used archival naturalistic data from the patients’ psychiatric records for the investigated predictors (e.g., height, weight, routine measures of blood biochemistry and routine ECG recordings). Thus, the external conditions were not strictly standardised and held constant: for instance, the same time of day, duration of fasting and resting time before recordings. On the other hand, these measures are cheap, easy to obtain, already widely used in clini-cal practice, and because this is a naturalistic study, it is a more fair reflec-tion of clinical reality, not suffering from the initial baseline attrition as “tra-ditional” cohort studies. Because the clinical investigation was formalised and held constant during the study period, the available baseline predictors were numerous. Unfortunately, we did not have comprehensive baseline symptom ratings, precluding the opportunity to explore the independent con-tribution of the predictors to the prognosis. Another limitation is the small sample sizes, which precludes controlling for a variety of different possible confounders.

Paper I The main result in this paper was that we could not support our hypothesis that the implementation of mACT would be followed by a more beneficial 5-year outcome of first-episode psychosis. This result differs from other recent studies of ACT for first-episode psychosis (77, 78, 130). Because we de-signed this study as a before and after comparison, it is not possible to draw any definitive conclusions on causality of the findings. On the other hand, naturalistic studies can give more knowledge about the “real world” effec-tiveness of a certain intervention.

Contrary to our expectations, there was even a borderline significant in-creased risk of having poor outcome of positive psychotic symptoms after the implementation of mACT. Because antipsychotics are mainly known to have an effect on positive symptoms, these outcome differences may be due to a confounder co-varying with drug treatment adherence (158). A greater

44

proportion of the patients in the mACT group had hazardous alcohol use after 5 years, which may partly explain the results regarding positive symp-toms. More patients in the mACT group were prescribed a second-generation antipsychotic as first antipsychotic and at the 5-year follow-up. There is no substantial difference in efficacy between first and second gen-eration antipsychotics concerning positive psychotic symptoms, but there is some evidence for better short-term tolerability in the latter (134). Thus, this could not explain the present findings. One possibility is that the doses used have decreased over time (when using the second-generation antipsychotics) and hence it may be that too low doses have been used in recent years.

Paper II Core symptoms of schizophrenia seem to have an important limiting effect on function and life satisfaction in the early course of the illness. This posi-tion is consistent with the results from studies on chronic samples (159, 160).

Our finding that there is no independent association between depressive and anxiety symptoms and good function concurs with a recent Dutch study on a chronic sample (161).

Insight was associated with both good function and remission in the pre-sent study. This finding is in accord with a Canadian study that reported correlations between insight and positive and negative symptoms at four consecutive measuring times during the first year of psychotic illness (162). Insight has previously been shown to predict good functioning, but this could be due to the relation to remission (163). Because lack of insight and judgement had a trend towards an independent association with good func-tion in our study, we calculated c-statistics to evaluate the discriminatory capacity of good function for this single item. The c-statistics was 0.75, which can be compared to 0.78 for remission (severity criterion). Having insight vs. not having insight was also associated with a higher mean on the three subscales of the SSWL scale.

One of the limitations with this study is that the interviewers were not blinded to the patient’s functional outcome when rating the symptoms. This limitation could perhaps bias the results towards a stronger association be-tween symptoms and function in that the interviewers might tend to rate symptoms lower if the patient had a good function. However, the SSWL is a self-report measure and not subject to this possible bias. Moreover, the SSWL had a concordant tendency in the results as the other functional measures.

45

Paper III The pattern of biochemistry predictors of obesity may indicate that the more dehydrated the patient is at baseline, the higher the risk of developing obesity over a 5-year period. Previous studies have reported that patients with schizo-phrenia have lower fractions of body water compared with healthy controls, measured with bioelectrical impedance analysis (164, 165). Further, dehydra-tion has been observed in a Japanese sample of patients with acute psychosis (166). Dehydration in the acute psychotic phase may be predictive of poor response to antipsychotics, which, in turn, eventually leads to treatment with clozapine, the most weight-gain prone antipsychotic (167).

Another possible mechanism is based on the notion that treatment-naïve patients with first-episode schizophrenia have been reported to have im-paired glucose tolerance (168). In the general population haemoglobin and hematocrit have been proposed as surrogate markers for insulin resistance (169, 170), which, in turn, is predictive of the development of obesity (171). Furthermore, �-glutamyltransferase has also been suggested as a predictor of metabolic syndrome and type II diabetes in the general population (172).

A third possible interpretation could be an altered autonomic tone, which has been associated with schizophrenia and with prediction of obesity in the general population (114, 173). Interestingly, both increased pituitary vol-umes (64, 174) and basal hypothalamic-pituitary–adrenal axis hyperactivity with increased ACTH and cortisol levels have recently been reported in pa-tients with schizophrenia (175). Sympathetic dominance can cause both de-hydration and insulin resistance and may be a possible link explaining the predictive capacity of these biochemical markers.

Paper IV One possible explanation of our observations in the last paper is that auto-nomic dysregulation with sympathetic dominance at baseline is related to subsequent non-remission. How this altered balance in the autonomic nerv-ous system is affecting the prognosis is not obvious; but if cardiac sympa-thetic dominance is a reflection of the same phenomenon as overarousal in EDA measures, then the recently observed association between overarousal and negative symptoms and subsequent poor outcome supports our hypothe-sis and observations (66). The lack of activation in medial prefrontal cortex observed in patients with schizophrenia might be the correlate in the central nervous system affecting the inhibitory control over autonomic function in amygdale (176).

A recent study of relatives of patients with schizophrenia found that auto-nomic cardiac dysfunction was also evident among the relatives, although with attenuated strength (119). Thus, autonomic dysregulation may be partly

46

a state and partly a trait phenomenon. The possible state part of the autonom-ic dysregulation may, however, not be specific to schizophrenia alone, i.e. cardiac autonomic dysregulation has also been reported in several other mental diseases, such as major depression and panic disorder (177, 178).

Future research Based on the results of these studies, some directions for future research can be proposed. First, because the findings of biochemical risk factors in the development of obesity in schizophrenia and that ECG measures of auto-nomic balance can predict remission are rather unique, the first step would to replicate the findings in other study populations and settings. Preferably, such a replication would be done in larger samples so that the differential effect of the studied risk factors can be clarified. Because most pharmaceuti-cal trials include the biochemical measures used in paper III and the ECG recordings used in paper IV as part of the safety routines, it should be feasi-ble to perform these analyses on existing datasets.

The observed biochemical risk factors would be of worth to associate with other measures of insulin resistance (insulin and glucose levels), dehy-dration (bioimpedance) and measures of autonomic tone (from, e.g., ECGs, EDA or cortisol curves). In addition, moderating effects of these predictors on the effect sizes of the weight-gaining effect of various antipsychotics should be investigated.

It would also be worthwhile to explore whether the observed ECG aberra-tions in our study are present even before onset (archival ECGs?) or in first-degree relatives or other mental illnesses.

The relation of ECG predictors to treatment response or tolerability and if there is a differential effect of different antipsychotics would be particularly important to study. Early biomarkers to guide treatment choices (both re-garding side effects and effect) would be a significant improvement in the clinical management of schizophrenia.

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Conclusions

1. The implementation of the mACT programme was not followed by any long-term clinical benefits and was even accompanied by worse outcome regarding positive symptoms for the subgroup of schizophrenia spectrum disorders.

2. The recently proposed definition of remission of schizophrenia has an acceptable discriminatory capacity for good function; moreover, when adding DUP of 3 months or less, the discriminatory capacity proved ex-cellent. Remission is also related to higher subjective satisfaction with life. Thus, symptomatic remission could be a feasible intermediate treatment goal for patients with first-episode schizophrenia. Insight was also associated with good function, suggesting it should be investigated as a possible clinical predictor of functioning in future studies.

3. Easily available routine biochemistry markers can be useful in predicting development of obesity in first-episode schizophrenia. The mechanisms underlying the observed associations are unknown, but the predictors identified in this study may be consistent with dehydration, insulin resis-tance or dominance of the sympathetic nervous system.

4. Routine 12-lead ECG measures in the early phase of schizophrenia are related to subsequent symptomatic remission status. Our observations indicate that it is an altered cardiac autonomic regulation (with both the sympathetic and vagal systems involved) that may be associated with an increased risk of not being in remission 5 years later.

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Sammanfattning på svenska

Bakgrund Kunskapen kring prognostiska faktorer, sjukdomsorsaker och optimal orga-nisation av vården vid schizofreni är ofullständig trots över hundra års inten-siv schizofreniforskning. Genom åren har en mängd olika utfallsmått använts i olika studier, vilket har försvårat jämförelser dem emellan. Dock är det känt att schizofreni är kopplat till överdödlighet i hjärt-kärlsjukdom, ökad förekomst av fetma, annan metabol sjuklighet och obalans i autonoma nerv-systemet. Det är även vedertaget att antipsykotiska läkemedel är hörnstenen i behandlingen av schizofreni. När det sedan gäller att organisera psykosvår-den effektivt, verkar Assertive Community Treatment (ACT) vara ett lovan-de alternativ. Det bygger på ett multidisciplinärt omhändertagande med teamarbete och uppsökande verksamhet. Dock är långtidseffekterna inte klarlagda och särskilt inte i vilken mån det kan ersätta slutenvårdsbehand-ling. Den tidiga fasen av psykossjukdom och schizofreni är optimal för stu-dier av prognostiska markörer och tidiga behandlingsinsatser, då man har noterat att symtom och funktionsnivå tenderar att nå en platånivå inom de första fem åren av sjukdom.

Frågeställningar och målsättning Ett mål med denna femårsuppföljning har varit att epidemiologiskt beskriva en totalpopulation av förstagångsvårdade patienter med icke-affektiv psykos, i Uppsala läns landsting mellan åren 1995-2000. Därtill har målet varit att utvärdera femårsutfallet avseende symtom och funktion för dem som insjuk-nat och behandlats tre år före och tre år efter efter omorganisationen till en modifierad form av ACT år 1998. Ett annat mål var att undersöka ett nylan-serat remissionsbegrepp för schizofreni och dess relation till funktion och livstillfredsställelse. Ytterligare mål med studien var att undersöka om rutin-biokemiska markörer kan prognosticera viktuppgång och fetmautveckling under de fem första åren. Slutligen undersöktes även om enkla EKG-mått på obalans i autonoma nervsystemet kan förutsäga sannolikheten att vara i sym-tomatisk remission fem år efter första sjukvårdskontakten.

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Resultat Under åren 1995 till och med 2000 vårdades 144 patienter i Uppsala Län för första gången för en icke-affektiv psykossjukdom. Det gick inte att observera någon klinisk fördel i femårsutfallet för patienterna efter införandet av en modifierad ACT. Samtidigt noterades att mängden tillgängliga slutenvårds-bäddar mer än halverats under tidsperioden som studerades.

Remission av kärnsymtomen vid schizofreni var starkt kopplat till god funktion och högre självskattad livstillfredsställelse, men även sjukdomsin-sikt var lika starkt kopplat till god funktion. Symtomatisk remission av schi-zofreni ter sig således som ett kliniskt relevant delmål.

Viktuppgången under de första fem åren av schizofrenisjukdom var avse-värd med en BMI-ökning på 4,1 kg/m2 i medeltal. Flera rutinbiokemiska blodprover (Hb, EPK, EVF, �-GT och kreatinin) visade sig ha ett prognos-tiskt värde för fetmautveckling. Dessutom observerades att ju lägre BMI patienterna hade från början desto större risk för en stor viktuppgång.

EKG-mått vid första psykosinsjuknandet som tyder på obalans i autono-ma nervsystemet såsom hög hjärtfrekvens, höga T-vågor och ST-sträckor kan delvis prognosticera symtomatisk remission av schizofrenisjukdomen fem år senare.

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Acknowledgements

These studies were carried out at the Department of Psychiatry, Ulleråker, Uppsala University Hospital. This thesis was financially supported by unre-stricted grants from Söderström-Königska Foundation, the Swedish Psychia-try Foundation, Bror Gadelius Memorial Foundation and the Märtha and Nicke Nasvell Foundation.

Many people working in psychiatric clinics and academia have been in-volved in making these studies possible. I would like to express my gratitude to everyone of you, and especially to:

Johan Sundström and Leif Lindström, my supervisors: Johan, some peo-ple can move a mountain, but you could produce a researcher out of a rock. Leif, in times of loss at our department you have injected new life and ex-perience into this project.

Ing-Marie Wieselgren, for initially being my supervisor, mentor and ini-tiator of this project. Without your inspiring enthusiasm in which everything is possible I would never have dared to start this project.

Eva Lindström, my second supervisor, for your unreserved support and being my clinical role model.

Arvo Haenni, co-author, for informative and inspirational discussions. Pentti Rautaharju, co-author, for transatlantic, translational research co-

operation, for your vast electrocardiographic knowledge and open mind. Björn Nilsson, my fellow (former) PhD student and clinical supervisor,

one of the most well-read persons I know. It is never boring having a discus-sion with you, which we have had quite a few over gallons of coffee. I hope we will keep on discussing in the future.

Ida Svedberg, Per Melander, psychiatrists to be, for your time and effort during different periods of this project and for helping me locate patients and perform interviews.

Johan Reutfors, friend and PhD student at Karolinska Institute, in the joint field of schizophrenia epidemiology, for your critical and sharp analyses paired with the ability see the world from new and unexpected angles. Hope-fully, we may pursue research collaboration in the near future!

A special thank to some of the senior researchers at the department: Lisa Ekselius for your wisdom and warm heart and Mia Ramklint for being an inspiring clinical researcher in psychiatry. Christina Hultman, for construc-tive criticism and creative input, always with kind and inspiring words. Tom

52

Lundin, Tommy Levander and Anders Fredriksson for giving feedback on the manuscripts and during seminars.

Urban Ösby Karolinska Institute for your thoughts and comments on the drafted thesis.

Åsa Hagberg, Björn Milesson-Fors, my former heads of the psychosis clinic, for allowing time to perform research.

Lottie Söder, Lena Bohlin, for all your administrative help and in keeping the department running smoothly and efficiently.

Anna Blomgren, Annica Lundberg and all archive personnel for your ad-ministrative help with the psychiatric records.

Eva Thorell and Marianne Andersson for excellent librarian support. Leslie Shaps, for finding my errors in writing and helping me to improve

my command of English. Hans Arinell, for statistical support. All the psychiatric team personnel. All other colleagues and PhD students at the Department of Psychiatry,

Uppsala University Hospital Special thanks to all the patients participating in the studies. My parents, Christina and Per-Göran, for support and love, my beloved

sister, Anna, and brother, Henrik, and their families, and my big warm fam-ily-in-law that have generously incorporated me into their spirit of together-ness within their family. All my dear friends, you are too many and too pre-cious to single out here.

My wife Maria for your never-ending energy, love and robust capacity to always help me to re-navigate towards the really important values in life, and to my three boys and little baby girl for…just being. You are the earth and the sky.

53

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