PSYCHOGENETICS GROUP
COMPARATIVE GENOMICS CENTRE

Mail Address: Comparative Genomics Centre,
Molecular Sciences Bldg 21, James Cook University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6731 Fax:  61-7-4781 5945

CONTENTS:

RESEARCH OVERVIEW:

The Psychogenetics Group is working to determine genetic and immunological factors contributing to cognitive dysfunction, depression and response to antidepressant treatment by using both cellular and genetic techniques. In current projects we study the pharmacogenetics in the treatment of depression, immunology in depression and immunological factors related to cognitive performance in humans and mice.
This group focuses on the relationships between genetics, immunology and cognitive aspects of mood disorders and neurodegeneration of the CNS.

Genetics of Depression

Worldwide, mental disorders are highly prevalent and disabling psychiatric conditions. No causal therapeutic approach has been established yet. Moreover, the biological basis of affective disorders is only partly understood. The contribution of genetic factors to the development of mental disorders ranges between 50-80%. Psychiatric disorders do not follow monogenetic transmission as the heredity of these disorders is of polygenetic nature. Contrary to monogenetic disorders such as Chorea Huntington, several genes influence the development of mental disorders. Little scientific knowledge has been obtained on how gene-environment interaction as well as gene-gene interaction modify and contribute to the onset and course of mental illnesses. Among mental and physical illnesses depression represents the leading cause of disability.
Genetic factors have been suggested to influence the individual response to antidepressant treatment. Preclinical studies support a pivotal role of candidate genes implicated in the dopaminergic system: In the Flinders Sensitive Line rat model of depression, decreased availability of extracellular dopamine in the nucleus accumbens was found to be reversible by treatment with serotonergic antidepressants accompanied by improvements in depressive-like behavior. Also, augmentation of antidepressant treatment with dopamine agonists such as bupropion, pramipexole and ropinirole resulted in significant reduction in the number and severity of depressive symptoms. The catechol-O-methyltransferase (COMT) plays a pivotal role in the degradation of dopamine and therefore serves as a promising candidate gene in pharmacogenetic studies of antidepressant action. In pharmacological studies, the COMT inhibitor tolcapone has proven to reverse an anhedonic state in a rat model of depression and to reduce symptom severity in the treatment of Major Depression. Two previous pharmacogenetic studies, however, reported a negative effect of the lower activity COMT 158met/met genotype on antidepressant treatment response in Major Depression. In the present study, the influence of the COMT val158met polymorphism on clinical response to antidepressants was investigated in a sample of Caucasian patients with Major Depression by means of a novel approach analyzing the intra-individual rather than the averaged course of therapy response, in an attempt to follow the recently published ACNP task force guidelines on response and remission in Major Depressive Disorder and therefore to possibly further clarify the role of COMT gene variation in antidepressant treatment response. Since biochemical and pharmacological studies provide support for decreased availability of norepinephrine and dopamine as a detrimental factor in the pathomechanism of depression as well as response to pharmacological antidepressive treatment, higher COMT activity as conferred by the COMT 158val allele leading to decreased norepinephrine and dopamine availability was hypothesized to have a negative effect on antidepressant drug response in depression. Our results strongly point towards a negative influence of the higher activity COMT 158val/val genotype on antidepressant treatment response during the first six weeks of pharmacological treatment in Major Depression, possibly conferred by consecutively decreased dopamine availability.
Our future work addresses other genes of the serotonergic and dopaminergic systems related to treatment response on depression.
 
Immunology of Depression

It has been postulated that depression is caused by release of pro-inflammatory cytokines associated with an activation of the immune system. Cytokines are small ubiquitous pleiotropic molecules that are expressed and secreted in response to a variety of stimuli. These molecules exert a multitude of functions, including a yet ill-defined influence on the function of the central and peripheral nervous systems. Alterations in the levels of circulating cytokines have been linked to a variety of disease states such as depression involving the central nervous system [2]. Scientific evidence for the link between systemic inflammation and depression is reported from animal and human studies. More specific, the hypothesis of an inflammation induced depression has been based on the observation in animals that the administration of lipopolysaccharides (LPS) or the proinflammatory cytokine interleukin-1 (IL-1) induced a behavioral pattern that is known as sickness behavior (e.g., agitation, restlessness, loss of appetite and weight, sleep disturbances). Since there are many similarities between sickness behavior and symptoms of depression, it has been suggested that cytokines could induce depression. In the literature this is meanwhile described as the cytokine hypothesis of depression. Human studies extend the accumulating evidence for a cytokine-induced depression. Researcher found higher incidence of immune abnormalities in depressed patients than in the general population. Furthermore, depression and depression-like neuropsychiatric symptoms are common side effects of interferon and cytokine (i.e. IL-2) therapy in man. Depressed patients display elevated concentrations of inflammatory markers, such as prostaglandins and complement [8]. Specifically, cytokines such as IL-1 beta, interleukin-6 (IL-6) and the IFN's have been reported to be increased in the plasma of depressed patients. Moreover, increased serum levels of the pro-inflammatory cytokines (IL-8, TNF-alpha) have been observed among diagnostic subgroups of mood disorders, such as acute mania or bipolar depression. Other studies also defined a diagnostic role of the cytokines IL-1-beta, IL-2, IL-10, IFN-gamma which seem to play an important role in melancholic vs. non-melancholic types of depression. The following two examples of pathophysiological mechanisms explain how cytokines induce depression:
a) Pro-inflammatory cytokines such as IL-1 beta modulate central monoamine function by activating the serotonin-transporter thereby increasing the reuptake of serotonin from the synaptic cleft, subsequently inducing a deficit of serotonin in the central nervous system which boosts depression.
b) Clinical studies have shown that the increase in acute phase proteins which are elevated by IL-6 and IL-1-beta in the periphery, are associated with a decrease in plasma tryptophan, the precursor of serotonin. Thus, a reduction in serum tryptophan associated with elevated acute phase proteins, and an enhanced reuptake of serotonin from the synaptic cleft, may contribute to a malfunction of the serotonergic system which is causally associated with depression.
Antidepressants are effective agents for the treatment of depression and it has been discussed that antidepressant also have anti-inflammatory properties. Recent research in rats and mice reported a reduction of the inflammatory activity in the central nervous system (CNS) through antidepressants which partly accounts for their antidepressive effect. As a mode of action in humans and rats/mice, researchers suggest an anti-inflammatory effect of antidepressants through the involvement of the pituitary-adrenal axis in the CNS via serotonin, a monoamine relevant for the aetiology and treatment of depression. Congruently, antidepressants are found to reverse cytokine-induced major depression by antagonising the following pathophysiological mechanisms:
a) Antidepressants reduce the release of pro-inflammatory cytokines from activated macrophages and thereby facilitate the feedback inhibition of the HPA axis; this results in a reduction in the release of glucocorticoids from the adrenal glands.
b) Many antidepressants have the ability to increase the release of endogenous cytokine antagonists such as interleukin -1 receptor antagonist and interleukin-10.
c) Different classes of antidepressants may act as cyclooxygenase inhibitors which, by lowering the concentration of inflammatory prostaglandins in the brain, reduce the detrimental impact of the inflammatory changes on neurotransmitter function.
d) Antidepressants attenuate the adverse effects of glucocorticoids and pro-inflammatory cytokines on central neurotransmission.
Our current work concentrates on the identification of specific cytokines linked to the diagnoses of depression in clinical samples and samples of the general population as well as in mice models of depression. In addition, we work on the identification of genotypes of cytokines predicting treatment outcome in major depression in clinical samples.
Biology of Cognitive Performance

The relationship between cytokine levels and cognitive functioning in the elderly has been investigated in both general and dementia specific populations. Some cytokines, such as IL-1beta, IL-6 and TNF-α, have been associated with cognitive decline and dementia in several population studies. Other pro-inflammatory cytokines, such as TNF-alpha and IL-1beta have been associated with Alzheimer’s disease in cohorts referred to specialists centres Results, however, have not been consistent for all cytokines across these studies and critical methodological aspects of cognitive assessment, such as the use of the mini mental state examination (MMSE) to measure cognitive function rather than specific and extensive cognitive tests, have been discussed recently. The MMSE while being easy to apply lacks the sensitivity and specificity provided by a more detailed assessments of cognitive function. It has been proposed to apply a detailed cognitive assessment tool for the study of the relationship between cytokines and cognitive functioning, since the assessment with global cognitive measures such as the MMSE or Short Portable Mental Status Questionnaire may be not sensitive enough to identify possible focal neuropsychological cytokine influences. In a large community-based study in the elderly using a detailed cognitive test battery and examining a wide range of cytokines we found that elevated cytokine IL-8 levels were consistently linked with poorer performance in the memory, cognitive speed and motor function domains, but not with MMSE scores.

Little research has been carried out on the association between genotypes of cytokines and cognitive performance in humans. A study among newborns reported a relation between specific IL-6 genotypes and cognitive function showing that the IL-6-572 C-allele (CC/GC genotypes) is associated with impaired cognitive development among children. Further evidence for a role of IL-6 was found in an animal study examining cognitive function in transgenic mice not expressing IL-6 (IL-6 KO). Compared to wild type (WT) genotype IL-6 KO mice showed better performance in various cognitive tests, suggesting a possible involvement of IL-6 in memory processes addition, the interleukin-1α -889 *1 allele has been associated with cognitive decline in patients with Alzheimer’s disease. Reports on the relation between TNF-alpha genotypes and cognition are still lacking.
Applying a dominant model of inheritance we found that the combined CT/TT genotype of the IL-1beta-(1418C>T) polymorphism was related to poorer memory performance. We also observed an association between TNF-alpha-(308G>A) polymorphism and cognitive speed, indicating a better performance for the combined GA/AA genotype of the dominant model. These results remained highly significant after adjustment for common confounders of cognitive performance and after Bonferroni correction for multiple testing.
 
Further investigations on the research topic that cognitive performance is related to systemic inflammation and immune alterations is carried out in mice models by our group. We objectively assess behaviour and cognitive performance in wildtype and immunological altered mice. We recently found that i.e. gld-mice performed significantly poorer in the novel object recognition task as compared to wildtype mice. Other models of immune-modified mice are tested applying various objectively assessable cognitive and behavioural tests. These results will be used in the context of the development of new treatment strategies in cognitive dysfunction in depression and cognitive decline.
  
STAFF:

Group Head:

Research Staff  
SELECTED PUBLICATIONS:

1.    Dannlowski U, Ohrmann P, Bauer J, Kugel H, Baune BT, Hohoff, C, Kersting A, Arolt V, Heindel W, Deckert J, Suslow T (2006) Serotonergic genes modulate amygdale activity in major depression. Genes, Brain, Behaviour (in press)

2.    Baune BT, Caliskan S, Todder D (2006) Effects of adjunctive antidepressant therapy with quetiapine on clinical outcome, quality of sleep and daytime motor activity in patients with treatment resistant depression. Human Psychopharmacology (in press)

3.    Baune BT, Ponath G, Golledge J, Varga G, Rothermundt M, Berger K (2006) Association between IL-8 cytokine and cognitive performance in an elderly general population – the MEMO study. Neurobiology of Aging (in press)

4.    Baune BT, Adrian I, Jacobi F (2006) Medical disorders affect health outcome and general functioning depending on comorbid major depression in the general population. Journal of Psychosomatic Research (in press)

5.    Todder D, Caliskan S, Baune BT (2006) Locomotor activity and quality of sleep in Quetiapine treated patients with depression. J Clin Psychopharmacology 26(6):638-642

6.    Stich H*, Baune BT*, Caniato R, Krämer A (2006) Association between preschool attendance and developmental impairments in preschool children in a six-year retrospective survey. BMC Public Health 6:260 
    * contributed equally
7.    Baune BT, Caliskan S, Todder D (2006) A case series of the development of rest-activity rhythm and quality of sleep in patients hospitalized for treatment of uni- or bipolar depression: a potential role for quetiapine. International Journal of Psychiatry in Clinical Practice 10(4):269-275

8.    Hihn H, Baune BT, Michael N, Markowitsch H, Arolt V, Pfleiderer B (2006) Memory performance in severely depressed patients treated by electroconvulsive therapy. J of ECT 22(3):189-195

9.    Baune BT, Suslow T, Arolt V, Berger K (2006) The relationship between psychological dimensions of depressive symptoms and cognitive functioning in the elderly - The MEMO-Study. Journal of Psychiatric Research Aug 1; [Epub ahead of print]

10.    Baune BT, Adrian I, Arolt V, Berger K (2006) The association between major depression, bipolar disorders, dysthymia and cardiovascular diseases in the general adult population. Psychother Psychosom 75:319-326

11.    Schilling, M, Brueckner C, Arolt V, Baune BT (2006) A case of masked multiple sclerosis by depression and diabetic neuropathy. Psychosomatics, 47(4):361-3

12.    Baune BT, Hay P (2006) Suicide rates and antidepressant prescribing: A casual or causal relationship? PLoS Med, 3(6):e220

13.    Baune BT, Suslow T, Engelien A, Arolt V, Berger K (2006) The association between depressive mood and cognitive performance in an elderly general population - The MEMO Study. Dement Geriatr Cogn Disord. 22(2):142-149
   
14.    Baune BT, Aljeesh YI (2006) The association of psychological stress and health related quality of life among patients with stroke and hypertension in Gaza Strip. Annals of General Psychiatry, 5(1):6

15.    Vennemann M, Berger K, Richter D, Baune BT (2006) Evidence of a systematic underreporting of suicide rates in Germany. Journal of the German Medical Association, 103, A1222-1226

16.    Baune BT, Mikolajczyk R, Stich H, Krämer A (2006) Body weight, Body Mass Index, overweight and obesity in consecutive cohorts of school beginners in a community in Lower Bavaria 1997-2002. GMS Med Inform Biom Epidemiol 2(1):Doc03

17.    Baune BT, Eckardstein Av, Berger K (2006) Lack of association between iron metabolism and depressive mood in an elderly general population. International Psychogeriatrics, 18(3):437-44

18.    Baune BT, Mikolajczyk RT, Reymann G, Duesterhaus A, Fleck S, Kratz H, Sundermann U (2005) A 6-month assessment of the alcohol-related clinical burden at emergency rooms (ERs) in 11 acute care hospitals of an urban area. BMC Health Service Research 5:73

19.    Stuppe M, Baune BT, Westermann H, Scherbaum N, Reker, M, Aljeesh YI, Driessen M (2005) Qualified treatment in patients with addictive disorders - clinical challenges and structural implications in a day hospital. Krankenhauspsychiatrie 16; 174-177

20.    Hohoff C, MacDonald J, Baune BT, Cook E, Deckert J, de Wit H (2005) Interindividual variation in anxiety response to amphetamine: Possible role for adenosine A(2A) receptor gene variants. Am J Med Genet B Neuropsychiatr Genet. Nov 5; 139(1):42-4;

21.    Baune BT, Aljeesh YI, Adrian I (2005) Predictors of quality of life among hypertensive patients with and without stroke. Journal of the Islamic University of Gaza (Natural Science Series) 13(2):91- 107

22.    Baune BT, Aljeesh YI, Bender R (2005) Factors of non-compliance with the therapeutic regimen among hypertensive men and women: a case-control study to investigate risk factors of stroke in Gaza Strip. European Journal of Epidemiology 20(5):411-419

23.    Baune BT, Berger K (2005) The influence of depressive mood on activities of daily living and health care utilization in the elderly – The MEMO-Study on the KORA Platform Augsburg. Gesundheitswesen Aug 67 Suppl 1: 176-9

24.    Scherbaum N*, Baune BT*, Mikolajczyk R, Kuhlmann T, Reymann G, Reker M (2005) Prevalence, risk factors and evaluation of screening strategies for syphilis infection among drug addicts. BMC Infectious Disease, 5:33
* contributed equally

25.    Will B, Zeeb H, Baune BT (2005) Overweight and obesity at school entry among migrant and German children: cross-sectional study. BMC-Public Health, 5:45

26.    Baune BT, Arolt V (2005) Psychiatric Epidemiology and Public Health Medicine: Principles of Mental Health Service Research. Nervenarzt; May, 76(5):633-46

27.    Baune BT, Will B, Zeeb H (2005) Comparative health assessment among migrants and Germans: combined results of a school health examination and a health survey among parents. Journal of Public Health; 13(3):153-159

28.    Keller A, Baune BT (2005) Impact of social factors on health status and help seeking behaviour among migrants and Germans. Journal of Public Health; 13:22-29

29.    Baune BT, Aljeesh Y, Bender R (2004) The impact of non-compliance with the therapeutic regimen on the development of stroke among hypertensive men and women in Gaza, Palestine. Saudi Medical Journal. Vol. 25 (11): 1683-1688

30.    Kremer G, Baune BT, Driessen M, Wienberg G (2004) Alcohol-Related Interventions in General Hospitals in Germany: Public Health and Consultation-Liaison Psychiatry Perspectives (Review). Adv Psychosom Med. 26:118-27

31.    Zeeb H*, Baune BT*, Vollmer W, Cremer D, Krämer A (2004) Health status and health care of adult migrants – a survey along the medical pre-school examination of children. Gesundheitswesen 66, 76-84
* contributed equally

LINKS:

Autoimmunity Research Group, Medical Genomics Rseearch Group, James Cook University, Key words: Immunology, immune, immunogenetics, disease, risk, vaccine, Genetics, Genomics, Phenomics, Proteinomics, Gene, Autoimmune diabetes, Type 1 diabetes mellitus, childhood diabetes, lupus, systemic lupus erythematosus, haemolytic anaemia, hemolytic anemia, Coombs' test, antinuclear antibodies, renal failure, glomerulonephritis, gastritis, type A gastritis, pernicious anemia, immunology, popular science, biology.