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Redefining suicidal behaviour – Rating scales and biomarkers

Lindqvist, Daniel LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:116.
Abstract (Swedish)
Popular Abstract in Swedish

Introduktion

I Sverige dör i genomsnitt 4 personer i självmord dagligen vilket gör detta till en av de absolut vanligaste dödsorsakerna bland unga människor. Varje självmord föregås av ofattbart mänskligt lidande och innebär en tragedi för de anhöriga. Antalet självmordsförsök som kommer till vårdens kännedom är cirka 9000 varje år, men det finns ett stort mörkertal. Bakom denna statistik döljer sig ofta långvarigt psykiskt illabefinnande, ett stort lidande för de anhöriga samt höga kostnader för samhället. Att bedöma självmordsrisk är således en av de viktigaste uppgifterna inom sjukvården, tillika en av de svåraste. Denna bedömning baseras till stor del på läkarens “kliniska blick” och... (More)
Popular Abstract in Swedish

Introduktion

I Sverige dör i genomsnitt 4 personer i självmord dagligen vilket gör detta till en av de absolut vanligaste dödsorsakerna bland unga människor. Varje självmord föregås av ofattbart mänskligt lidande och innebär en tragedi för de anhöriga. Antalet självmordsförsök som kommer till vårdens kännedom är cirka 9000 varje år, men det finns ett stort mörkertal. Bakom denna statistik döljer sig ofta långvarigt psykiskt illabefinnande, ett stort lidande för de anhöriga samt höga kostnader för samhället. Att bedöma självmordsrisk är således en av de viktigaste uppgifterna inom sjukvården, tillika en av de svåraste. Denna bedömning baseras till stor del på läkarens “kliniska blick” och varierande grad av erfarenhet, vilket kan leda till felbedömningar med ibland deletära följder. Mot bakgrund av detta är det viktigt att öka kunskapen kring vad självmordsbeteende beror på, inte minst för att utveckla nya, objektiva bedömningsmetoder och bättre behandlingar.



Material och metoder

Genom att mäta biologiska ämnen hos självmordsbenägna patienter och studera hur dessa förhåller sig till psykiatriska symptom kan man erhålla ny, viktig kunskap om bakgrundsmekanismerna till självmord. Denna avhandling består av en serie studier i vilka patienter som har gjort självmordsförsök deltagit. Patienternas symptom och självmordstankar har utvärderats med hjälp av skattningsskalor. Biologiska undersökningar, inklusive lumbalpunktioner med insamlande av spinalvätska, har också genomförts i samband med att patienterna vårdats på psykiatrisk avdelning och varit fria från psykiatriska mediciner. Genom att analysera substanser i spinalvätska kan man få en bättre bild av biologiska förhållanden i hjärnan jämfört med motsvarande analyser i blod.



Resultat

Deprimerade patienter med hög självmordsavsikt (baserat på patientens egna beskrivningar samt omständigheterna kring självmordsförsöket) uppvisade låga blodnivåer av stresshormonet kortisol efter att ha blivit förbehandlade med en kvällsdos av en analog till kortisol (dexametason). Vi fann även att kortisol var sänkt i salivprover hos personer flera år efter ett självmordsförsök. Man kunde se särskilt låga värden hos dem som hade gjort upprepade självmordsförsök och hade svåra psykiatriska symptom.

Genom att mäta s.k. cytokiner (immunsystemets “budbärare”) i spinalvätska fann vi tecken på inflammatorisk aktivitet i centrala nervsystemet hos självmordsnära patienter. Den mest uttalade inflammationen återfanns hos de patienter som genomfört våldsamma självmordsförsök (ex. hängning) och hos de patienter som hade diagnosen egentlig depression.

I spinalvätska har vi även analyserat kynurensyra som är en nedbrytningsprodukt av aminosyran tryptofan. Bildningen av kynurensyra ökar i samband med inflammation och denna substans kan därefter påverka nervsignalerna i hjärnan. Vi såg ingen tydlig skillnad i kynurensyra mellan självmordsnära patienter och friska individer, men i en undergrupp av patienter med diagnosen egentlig depression fann vi höga nivåer.

Slutligen studerade vi hur olika biomarkörer i spinalvätska är kopplade till varandra med hjälp av den statistiska metoden faktoranalys. Vi fann en faktor (bestående av ett inflammatoriskt ämne samt nedbrytningsprodukter av signalsubstanserna serotonin och dopamin) som var starkt kopplat till våldsamma självmordsförsök och risken för att dö i självmord i framtiden.



Diskussion

Studierna visar att självmordsnära patienter har ett nedreglerat stressystem. En möjlig förklaring till detta är att patienterna har varit utsatta för långvarigt psykiskt lidande ackompanjerat av en initial ökning av stresshormon. Detta tillstånd kan i förlängningen har lett till en slags “utbrändhet” av stressystemet med låga nivåer av stresshormon som följd.

Vi såg även förhöjda nivåer av cytokiner i spinalvätskan hos självmordsnära patienter. Detta är unika resultat som talar för att inflammation i hjärnan är en bidragande orsak till självmordsbeteende och depressiva symptom.

Hos suicidförsökspatienter med diagnosen depression, men ej hos självmordsnära patienter i allmänhet, såg man höga nivåer av kynurensyra, vilket talar för att denna substans är involverad i utvecklingen av depression snarare än självmordsbeteende i sig.

Resultaten från faktoranalysen är intressanta då de antyder att det finns kopplingar mellan olika biologiska system i hjärnan som kan vara relaterade till uppkomsten av självmordsbeteende och risk att dö i självmord i framtiden.

Sammanfattningsvis stödjer våra fynd att det finns avvikelser i hjärnans signalsubstanser samt i stress- och immunsystemen hos självmordsnära patienter. Resultaten innebär ny och viktig kunskap som i framtiden kan leda till förbättrade metoder inom diagnostik och behandling. Exempelvis finns det skäl att tro att antiinflammatoriska läkemedel kan ha en plats i behandlingen av deprimerade och självmordsnära patienter. Detta ämnar vi testa i framtida studier. Dessutom kan våra resultat bidra till utvecklingen av så kallade biomarkörer inom psykiatrin. Biologisk testning, exempelvis genom att mäta inflammatoriska ämnen i blod eller spinalvätska, skulle kunna fungera som ett stöd i läkarens bedömning av självmordsrisk eller depressionsdjup. (Less)
Abstract
Risk assessment of suicidal behaviour is one of the most important tasks in clinical psychiatry and a major determinant of subsequent care and treatment selections. To date, suicide risk assessment is based solely on clinical evaluations, which inevitably leads to subjective interpretations and decisions by the psychiatrist. In order to find more robust instruments in the evaluation of suicidality it is important to search for objective correlates of different aspects of suicidal behavior. The main aim of the present thesis was to investigate neurobiological and clinical characteristics in a group of suicide attempters in order to gain a further understanding of the mechanisms underlying suicidal behavior.

The patients, who were... (More)
Risk assessment of suicidal behaviour is one of the most important tasks in clinical psychiatry and a major determinant of subsequent care and treatment selections. To date, suicide risk assessment is based solely on clinical evaluations, which inevitably leads to subjective interpretations and decisions by the psychiatrist. In order to find more robust instruments in the evaluation of suicidality it is important to search for objective correlates of different aspects of suicidal behavior. The main aim of the present thesis was to investigate neurobiological and clinical characteristics in a group of suicide attempters in order to gain a further understanding of the mechanisms underlying suicidal behavior.

The patients, who were all treated at a psychiatric ward of the Lund University Hospital after a suicide attempt, participated in a research program including clinical and biochemical investigations, as well as expert and self -ratings. While free of psychotropic medications, the patients underwent lumbar punctures and Dexamethasone Suppression Tests (DST). Diagnostic interviews and ratings of different aspects of psychopathology were carried out at the psychiatric ward. A subset of the patients participated in a clinical follow-up approximately 12 years after the suicide attempt, this time in an outpatient setting. Salivary samples were collected in conjunction with the follow-up.

Biomarkers from the stress-, immune-, and the monoaminergic systems were analyzed in cerebrospinal fluid (CSF), saliva and blood, and subsequently analyzed in relation to different aspects of suicidal behaviour and psychiatric symptoms.

The most salient findings were that:

1. Low post-DST cortisol levels were associated with high suicidal intent among patients with Major Depressive Disorder (MDD).

2. Low salivary cortisol levels were found in suicide attempters approximately years after the index suicide attempt. Low salivary cortisol was associated with repetition of suicidal behaviour and severe psychiatric symptoms.

3. Suicide attempters had significantly higher CSF levels of pro- inflammatory cytokine Interleukin (IL)-6 compared to healthy individuals, and the highest levels were found in violent suicide attempters and patients with MDD.

4. Levels of CSF-Kynurenic acid (Kyna), an end-metabolite of tryptophan through the kynurenine-pathway, did not significantly differ between

suicide attempters and controls. High Kyna levels were, however, associated with high IL-6 levels and a diagnosis of MDD.

5. By using Principal component analysis (PCA) we found that a combination of IL-6, 5-Hydroxyindoleacetic acid (serotonin metabolite), and Homovanillic acid (dopamine metabolite) was associated with severe suicidal behaviour and risk for future completed suicide.

We found that suicide attempters display elevated levels of the proinflammatory cytokine IL-6 in CSF. We therefore suggest that neuroinflammation may be involved in the pathophysiology of suicidal behaviour. The results from the PCA further confirm that IL-6 seems to play an important role for suicidal behaviour, an effect perhaps mediated via the monoaminergic system.

In addition, our results suggest that low Hypothalamic-Pituitary-Adrenal (HPA)- axis activity is associated with more severe forms of suicidal behaviour in our sample of patients. This might be due to long-term stress resulting in an “HPA- axis burnout”. We propose a neurobiological model for suicidal behaviour linking long-term stress with HPA-axis burnout, which in turn might lead to a shift towards immune activation. We further suggest a dynamic relationship between the immune system and monoamines, where an acute immune response may result in increased monoamine turnover whereas long-lasting, low-grade inflammation, in contrast, may lead to a monoamine depletion.

Our findings may in the long run have important clinical implications. For example, we are planning to start a treatment study in which suicidal patients will receive anti-inflammatory agents added to their regular medicine. We hope that this combination will improve their psychiatric symptoms and that this will show in blood and CSF samples. Another potential clinical implication is the use of biomarkers in psychiatry. Suicide risk assessment is one clinical situation in which biomarkers would be useful as a tool in the clinical evaluation. Indeed, inflammatory markers such as IL-6 are candidates for this purpose, although further studies are warranted in order to identify biomarkers with sufficient sensitivity and specificity to be used in the clinic. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Van Heeringen, Cornelis, Unit for Suicide Research, University of Gent, Belgium
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neurobiology, Suicide, attempted, Principal component analysis, Chemokines, Cytokines, Hypothalamic-Pituitary-Adrenal-Axis, Hydroxyindoleacetic Acid
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:116
pages
104 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2010-12-11 09:00
ISSN
1652-8220
ISBN
978-91-86671-32-7
language
English
LU publication?
yes
id
1dc03554-b56e-4d3d-bc78-1b4a7e25bff5 (old id 1718668)
date added to LUP
2010-11-22 14:02:02
date last changed
2018-05-29 12:12:21
@phdthesis{1dc03554-b56e-4d3d-bc78-1b4a7e25bff5,
  abstract     = {Risk assessment of suicidal behaviour is one of the most important tasks in clinical psychiatry and a major determinant of subsequent care and treatment selections. To date, suicide risk assessment is based solely on clinical evaluations, which inevitably leads to subjective interpretations and decisions by the psychiatrist. In order to find more robust instruments in the evaluation of suicidality it is important to search for objective correlates of different aspects of suicidal behavior. The main aim of the present thesis was to investigate neurobiological and clinical characteristics in a group of suicide attempters in order to gain a further understanding of the mechanisms underlying suicidal behavior.<br/><br>
The patients, who were all treated at a psychiatric ward of the Lund University Hospital after a suicide attempt, participated in a research program including clinical and biochemical investigations, as well as expert and self -ratings. While free of psychotropic medications, the patients underwent lumbar punctures and Dexamethasone Suppression Tests (DST). Diagnostic interviews and ratings of different aspects of psychopathology were carried out at the psychiatric ward. A subset of the patients participated in a clinical follow-up approximately 12 years after the suicide attempt, this time in an outpatient setting. Salivary samples were collected in conjunction with the follow-up.<br/><br>
Biomarkers from the stress-, immune-, and the monoaminergic systems were analyzed in cerebrospinal fluid (CSF), saliva and blood, and subsequently analyzed in relation to different aspects of suicidal behaviour and psychiatric symptoms.<br/><br>
The most salient findings were that:<br/><br>
1. Low post-DST cortisol levels were associated with high suicidal intent among patients with Major Depressive Disorder (MDD).<br/><br>
2. Low salivary cortisol levels were found in suicide attempters approximately years after the index suicide attempt. Low salivary cortisol was associated with repetition of suicidal behaviour and severe psychiatric symptoms.<br/><br>
3. Suicide attempters had significantly higher CSF levels of pro- inflammatory cytokine Interleukin (IL)-6 compared to healthy individuals, and the highest levels were found in violent suicide attempters and patients with MDD.<br/><br>
4. Levels of CSF-Kynurenic acid (Kyna), an end-metabolite of tryptophan through the kynurenine-pathway, did not significantly differ between	<br/><br>
suicide attempters and controls. High Kyna levels were, however, associated with high IL-6 levels and a diagnosis of MDD.<br/><br>
5. By using Principal component analysis (PCA) we found that a combination of IL-6, 5-Hydroxyindoleacetic acid (serotonin metabolite), and Homovanillic acid (dopamine metabolite) was associated with severe suicidal behaviour and risk for future completed suicide.<br/><br>
We found that suicide attempters display elevated levels of the proinflammatory cytokine IL-6 in CSF. We therefore suggest that neuroinflammation may be involved in the pathophysiology of suicidal behaviour. The results from the PCA further confirm that IL-6 seems to play an important role for suicidal behaviour, an effect perhaps mediated via the monoaminergic system.<br/><br>
In addition, our results suggest that low Hypothalamic-Pituitary-Adrenal (HPA)- axis activity is associated with more severe forms of suicidal behaviour in our sample of patients. This might be due to long-term stress resulting in an “HPA- axis burnout”. We propose a neurobiological model for suicidal behaviour linking long-term stress with HPA-axis burnout, which in turn might lead to a shift towards immune activation. We further suggest a dynamic relationship between the immune system and monoamines, where an acute immune response may result in increased monoamine turnover whereas long-lasting, low-grade inflammation, in contrast, may lead to a monoamine depletion.<br/><br>
Our findings may in the long run have important clinical implications. For example, we are planning to start a treatment study in which suicidal patients will receive anti-inflammatory agents added to their regular medicine. We hope that this combination will improve their psychiatric symptoms and that this will show in blood and CSF samples. Another potential clinical implication is the use of biomarkers in psychiatry. Suicide risk assessment is one clinical situation in which biomarkers would be useful as a tool in the clinical evaluation. Indeed, inflammatory markers such as IL-6 are candidates for this purpose, although further studies are warranted in order to identify biomarkers with sufficient sensitivity and specificity to be used in the clinic.},
  author       = {Lindqvist, Daniel},
  isbn         = {978-91-86671-32-7},
  issn         = {1652-8220},
  keyword      = {Neurobiology,Suicide,attempted,Principal component analysis,Chemokines,Cytokines,Hypothalamic-Pituitary-Adrenal-Axis,Hydroxyindoleacetic Acid},
  language     = {eng},
  pages        = {104},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Redefining suicidal behaviour – Rating scales and biomarkers},
  volume       = {2010:116},
  year         = {2010},
}