A multicenter study aboutneurobiology of suicidal behaviour

T. Bronisch, J. Brunner, B. Bondy, D. Rujescu, G. Bischof, I. Heuser, B. Müller-Oerlinghausen, B. Hawellek, W. Maier, M.L. Rao,

W.Felber, U. Lewitzka, M. Oehler, A. Brooks, F. Hohagen, E.Lauterbach

3rd International SymposiumResearch Net Depression

Tutzing 06.10.2003

1. Psychiatrische Klinik und Poliklinik derLMU München(Prof. Ackenheil, Prof. Bondy, Dr. Rujescu)

2. Max-Planck-Institut für Psychiatrie MPI-P München(Prof. Bronisch, Dr. Brunner)

3. Psychiatrische Klinik und Poliklinik der Universität Bonn(Prof. Maier, Prof. Rao, Prof. Rietschel, Dr.Hawellek)

4. Psychiatrische Klinik und Poliklinik der Freien UniversitätBerlin(Prof. Heuser. Prof. Müller-Oerlinnghausen)

5. Psychiatrische Klinik und Poliklinik desUniversitätsklinikums der TU Dresden(Prof. Felber, Prof. Oehler, Dr. Lewitzka)

6. Psychiatrische Klinik und Poliklinik der Universität Lübeck(Dr. Lauterbach, Prof. Hohagen, Dr. Ahrens, Prof. Broocks)

Centres

Patients:

Inclusion criteria: Drug-free for two weeks (exception: BZD)

Psychiatric disorders: – Affective disorders

– Personality disorders – Adjustment disorder with depressed mood – With or without suicidal ideation/suicide attpts

Exclusion criteria: Psychiatric diagnoses: – Organic Brain Syndrome – Addiction (two months prior to enrolment) – Schizophrenic Psychoses Major disorder of internal medicine Pregnancy, Breast-feeding

Assessment of psychopathology:

Diagnoses: Axis I: Clinical Interview according to DSM-IV (MINI)

Axis II: Clinical Interview (SCID II)

Suicidality: Suicide Intent Scale (SIS) (Beck 1974)Medical Damage Scale (MDS) (Beck 1975)Risk Rescue Scale (RRS) (Weisman 1972)Scale for Suicidal Ideation (SSI) (Beck 1974)Hopelessness Scale (BHS) (Beck 1974)Typology of Parasuicide (Felber 1998)

Depression: Observer's rating: HAM-D21 (Hamilton)Self rating: BDI (Beck Depression Scale)

Anxiety: Trait: STAI (Spielberger)State: HAM-A (Hamilton)

General psychopathology: BPRS

Aggressivity/Impulsivity: FAF (modified Buss Durkee)STAXI (Spielberger)BIRS (Barrat Impulsivity Rating Scale)IRS (Lecrubier Impulsivity Rating Scale)

Personality traits: TCI (Cloninger)

Neurobiological parameters —assessed and evaluated by the different centres:

Material Parameters Centres

CSF (and plasma) HPA system: MPI-P

CRH, ACTH, Cortisol Munich

AVP, Oxytocin Excitatory and inhibitory amino acids

5-HT system: 5-HIAA, 5-HT NA system: MHPG DA system: HVA

Blood (and platelets) 5-HT2A receptors (platelets) LMU Munich MAO-B (platelets) Berlintryptophan, other amino acids (plasma) Berlin5-HT concentration (platelets) Bonncholesterol, essential fatty acids (plasma) MPI-P Munich

Saliva cortisol Dresden

Molecular- and see subproject 5 LMU and pharmacogenetics Bonn

Tasks which have been successfully resolved I

•The whole project has been subdivided in four subprojects:

•1. Lithium Intervention Study

•2. Molecular Genetics

•3. Peripheral Parameter

•4. CSF

Applications to the Ethics Committees

LMU MPI-P Bonn Dresden Berlin LübeckMunich Munich

Lithium notInterventionStudy

approved applicable approved approved approved approved

MolecularGenetics approved approved approved approved approved approved

PeripheralParameters approved approved approved approved approved approved

CerebrospinalFluid approved approved approved approved approved not applicable

Summary: 24 possible applications, 22 applications, 22 approvals

Tasks which have been successfully resolved II

• all six centers met regularly• biological target variables has been defined• psychopathological target variables has been defined• psychopathological assessment instruments has been established• a case record form has been developed• laboratory tests had been selected and established in the different centers• logistics of the distribution of the specimens has been developed• laboratory personnel has been engaged in the different laboratories• analyses of the assessed parameters had been performed

• a data collection center has been established (Luebeck)

• three independent data banks has been established, which can be connected with each other:1. data bank for peripheral parameter2. data bank for the Lithium Intervention Study3. data bank for molecular genetics• a double data entry has been performed (30.09.2003)

Recruitment of patients:

(1) The majority of patients so far included were inpatients of the six centres participating in subproject 1.5 (neurobiology of suicidal behaviour).

(2) Additional patients could be recruited as in- and outpatients of the lithium-intervention study (subproject 1.2).

.

We intend to match suicidal and non-suicidal patients for diagnoses, age, sex and seasonality. For matched pairs comparisons, a high sample size will be necessary

Minimum sample size of 42 for both patient groups.

Recruitment of Patients and Controls

Recruitment Period: January 1st 2001 – April 30st2003

CentresMolecular

Genetics

Peripheral

Parameters

Cerebrospinal

Fluid

LMU Munich 21 21 (7 SA) 3

MPI-P Munich 32 32 (16 SA) 32

Univ. Bonn 51 27 7

Univ. Dresden 49 8 (SA) 2

Univ. Berlin 30 8 n. a.

Univ. Lübeck 30 7 (4 SA) n. a.

Total 213 103 (67 SA) 44

SA = Suicide Attempt

ResultsRecruitment of patients and controls

(recruitment period: January 1, 2001 —April 30, 2003)

Molecular Peripheral CSFGenetics Parameters

Recruited 213 103 (67 SA) 44

Participation in the different Subprojects

Subprojects Patients N

NeurobiologyLithium

Pharmacogenetics

16

NeurobiologyLithium

5

NeurobiologyPharmacogenetics

43

Neurobiology 39

Total 103

Scientific results and publicationsThe existing literature has been reviewed with critical reference tomethodological and conceptual deficits by the research groups of Prof . Bronisch(Brunner et al. 1999, 2001a and 2002a) and Prof . Müller-Oerlinghausen (Müller-Oerlinghausen and Roggenbach 2002, Franke et al. 2002).

The center LMU ( Bondy et al. 2000 a) found a higher frequency of the shortallele of the 5-HT promoter region ( 5-HTTLPR) in suicide victims. The samegroup could not replicate a polymorphism of the 5-HT 2A receptor in suicidevictims and patients with suicidal ideation (Bondy et al. 2000 b).

The research group of Müller -Oerlinghausen and the group of the Charitésurprisingly showed that no statistical correlation exists between Vmax of the 5-HT transporter in platelets and the 44-bp polymorphism and the 17bp variablenumber of tandem repeat (Kaiser et al. 2002).

Brunner et al. (2001 a) found lower CRH concentrations in the CSF of suicideattempters as compared to psychiatric controls. A preliminary study showed nodifferences in CSF AVP between depressed suicide attempters and psychiatricand neurological controls (Brunner et al.2002b).

Lower cholesterol concentrations in suicide attempters have been reported inclinical studies, however, cholesterol-lowering therapies do not increase the riskof suicide (Brunner et al. 2001 b, 2002c).

Publications of the First Results of the Muticentre Study

Brunner J et al. (2001) Decreased corticotropin releasing hormone (CRH) concentrations in the cerebrospinal fluid of eucortisolemic suicide attempters. Journal of Psychiatric Research 35: 1-9

Brunner et al. (2002) Vasopressin in CSF and serum in depressed suicide attempters: correlations with monoamine metabolites and dexamethasone CRH test. European Neuropsychopharmacology 12: 489-494

Brunner et al. (2003) Proteomics analysis of the CSF in unmedicated patients with major depressive disorder reveals alterations in suicide attempterssubmitted

Follow-up

The recruitment of the patients could not be finished within the first three years of funding between January 2000 to December 2002 because the approval of the applications to the local ethics committees resulted in a delay of one year, so that the recruitment of the neurobiological parameters started later than planned: at the beginning of 2001 instead of 2000.

Expected closing of the recruitment of patients according to the analysis of the matching process: December 2003.

2004: Data analysis, evaluation and publishing of the data.

Networking

Subproject 1.2: Lithium-intervention study

Subproject 5: Molecular- and pharmacogenetics