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Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression
© Knorr et al; licensee BioMed Central Ltd. 2009
- Received: 15 May 2009
- Accepted: 11 August 2009
- Published: 11 August 2009
Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention.
The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.
Local Ethics Committee: H-KF 307413
Danish Medicines Agency: 2612-3162.
Danish Data Agency: 2006-41-6737.
ClinicalTrials.gov: NCT 00386841
- Plasma Cortisol
- Emotional Intelligence
- Salivary Cortisol
- Iowa Gambling Task
Robins and Guze described five phases in the development of a valid classification of psychiatric illness: clinical description, laboratory studies, delimitation from other disorders, follow-up studies and family studies . Later, response to treatment was added as a sixth phase . Recently, the endophenotype concept has emerged as a strategic tool in neuropsychiatric research .
Endophenotypes are quantifiable components in the "genes-to-behaviours" pathways distinct from psychiatric symptoms . In parallel with the classification of psychiatric diseases, endophenotypes are validated by specificity, state independence, heritability, familial association, co-segregation, and biological and clinically plausibility .
Several possible endophenotypes have been proposed in affective disorders, including stress regulation, cognition, neuroticism, depression and anxiety symptoms . Pharmacological anti-depressants may have an effect on endophenotypes in healthy persons with a family history of depression. We hypothesized that treatment response could be added to the validation of possible endophenotypes for depression. However, a systematic search for randomized multiple-dose, placebo-controlled trials on the effect of selective serotonin reuptake inhibitors did not identify any trials in which healthy first-degree relatives of depressed patients received a selective serotonin re-uptake inhibitor for at least one week (unpublished data).
Possible endophenotypes for depression
Hypothalamus-pituitary-adreno-cortical (HPA) axis regulation
Impaired regulation of the HPA axis during an acute episode of depression is the most consistent laboratory finding [5–7]. The combined dexamethasone (DEX)-corticotrophine releasing hormone (CRH) test is a sensitive test for detecting altered HPA axis regulation . In this test, the stimulating effects of 100 μg CRH on corticotrophin (ACTH) and cortisol are examined under the suppressive action of 1.5 mg of dexamethasone. ACTH and cortisol in the combined DEX-CRH test demonstrated an exaggerated response in patients with depression compared to healthy controls with a family history of depression  and between healthy first-degree relatives of patients with depression compared to healthy controls without a family history of depression . Increased ACTH and cortisol in the combined DEX-CRH test therefore seems to be a promising biomarker for depression and a potential endophenotype for depression .
Alterations in cognitive functions are common and included in the diagnostic criteria for depression  and some patients experience cognitive dysfunction even in euthymic phases of the disease [12–16]. A high-risk study showed impairment of selective and sustained attention, executive function, language processing and working and declarative memory in subjects with a family history of depression as compared to participants without . Thus cognitive function may be a candidate endophenotype for affective disorders.
Neuroticism is a measure of an individual's tendency to experience negative emotions that are manifested at one extreme as anxiety, depression, and moodiness, and at another extreme, as emotional stability. Neuroticism is most frequently measured by questionnaires such as Eysenck Personality Questionnaire (EPQ)  and the revised NEO Personality Inventory (NEO-PI-R) . The heritability of neuroticism is well established . Studies of healthy first-degree relatives of patients with a depression point at neuroticism as an endophenotype for depression .
Other potential endophenotypes for depression
More than 90% of depressed patients complain about impairment of sleep quality, which has been suggested as a potential endophenotype for depression . The effect of antidepressants on sleep quality in healthy individuals with a family history of depression has not been investigated. Subjective measures of stress, aggression, pain, and quality of life are all factors known to improve with remission of depressive symptoms. Whether this is a direct effect of treatment with antidepressants or a consequence of improvement in depressive symptoms is unclear.
Proportion of possible endophenotypes for depression
Based on results from recent studies it is estimated that 30% of healthy persons with a family history of depression will exhibit at least two of the three possible endophenotypes: dysregulation of the HPA axis, cognition, and neuroticism . The prevalence of other possible endophenotypes is unknown.
The effect of antidepressants on endophenotypes for depression
Treatment with antidepressants in patients with an acute depression is associated with partial normalization of the HPA axis [24, 25], enhanced cognitive function , and reduction in the personality trait of neuroticism . In these trials it has not been possible to distinguish the treatment effect on the endophenotypes from the treatment effect on the disease, since remission of depressive symptoms is associated with partial normalization of the endophenotypes. It is not known whether the treatment responses on the disease symptoms are mediated through an effect on the endophenotypes or vice versa. Results of recent randomized, placebo-controlled trials suggest that antidepressants have an effect on psychological variables and behaviour in individuals without psychiatric illness [28–30], one of these studies did not mention the family history status of the included individuals  but in two of the studies [29, 30] healthy individuals with a family history of psychiatric illness were excluded.
In summary, no trial has investigated the effects of antidepressants on possible endophenotypes in healthy individuals with a family history of depression.
A recent systematic review and meta-analysis of pharmacogenetic studies of antidepressant response suggests that polymorphisms in genes such as 5-HTTLPR, STin2, HTR1A, HTR2A, TPH1, and BDNF may modulate antidepressant response , but the association between gene polymorphisms and the effect of an antidepressant treatment on the putative endophenotypes for depression has not been explored.
With the AGENDA trial (A ssociations between G ene-polymorphisms, E ndophenotypes for D epression and A ntidepressive Intervention) we want to test the hypothesis that potential endophenotypes for depression are affected by intervention with an antidepressant in healthy first-degree relatives of patients with the diagnosis of depression.
The study is conducted at the Department of Psychiatry, Rigshospitalet, Copenhagen University Hospital, Denmark as part of the Centre for Pharmacogenomics, University of Copenhagen. The trial has a d ata m onitoring and s afety c ommittee (DMSC) that is independent of the investigators conducting the trial.
Participants are recruited as healthy first-degree relatives of patients with a diagnosis of depression given at discharge from psychiatric hospital in- or out-patient contact . These patients participated in ongoing studies at the psychiatric department of Rigshospitalet, University of Copenhagen, Denmark. Individuals meeting the inclusion criteria and none of the exclusion criteria are enrolled in the trial (Appendix 1). The exclusion criteria were chosen partly for safety reasons and partly to decrease the risk of results being confounded by factors known to substantially affect the HPA-axis, thus interfering the primary outcome measure. Women taking birth control pills were instructed to discontinue these 6 weeks prior to entering the trial. All women were carefully instructed to use double barrier birth control methods and pregnancy tests were performed both before and after the intervention.
The participants are randomized to receive either escitalopram or placebo by oral administration as a single dose of 10 mg each evening as self-medication at home for four weeks. On completion of four weeks of double-blind intervention (or early discontinuation from the trial) participants entered a five-day blinded down-titration period to nil medication. Escitalopram 10 mg was selected because of its specific serotonergic selectivity  and because of the favourable adverse reaction profile , thus facilitating blinding. The dose of escitalopram 10 mg for four weeks was estimated to have a sufficient effect, since effect on depressive symptoms in patients with a major depression is observed within one to four weeks as compared with placebo . The validity of the results depends on a high compliance and high completion in the trial. This was sought obtained by weekly telephone control calls to the enrolled participants to insure adherence to the protocol and to record adverse events. Escitalopram and placebo tablets were identical in appearance, colour, smell, and solubility allowing for blinding of treatment assignment. H. Lundbeck A/S provided identically appearing blister packages containing escitalopram or placebo. An independent pharmacist then packed, sealed and numbered the drug packages according to a randomization list provided and concealed by the Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Rigshospitalet.
Randomization into one of the two intervention groups is done immediately after it has been established that the participant fulfils all the inclusion criteria and none of the exclusion criteria. Randomization is stratified by age (18 – 31 years and 32 – 60 years) and sex in order to get an equal distribution in the intervention groups, knowing that the response to the DEX-CRH test is sensitive to these factors. Participants are randomized in a 1-to-1 ratio to receive escitalopram 10 mg or placebo. The Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Rigshospitalet performs the centralised randomization, and only the IT Manager of the CTU will know the block size used for stratification. The sponsor-investigator (UK) provides information of the participants to the CTU during the entry assessment as soon as participation in the study has been decided. CTU performs the computer-generated randomization to ensure adequate allocation concealment and adequate generation of the allocation sequence . The number of the allocated treatment is communicated to UK, both by phone and email.
All study personnel and participants are blinded to the packaging of the study drug, and blinding is maintained throughout monitoring, follow-up, data management, assessment of outcomes and data analyses. The randomization code will not be broken until all the data has been analysed and conclusions drawn. At the assessment after four weeks intervention, every participant, the sponsor-investigator (UK), and the neuropsychological testers will make a guess as to which intervention the participant has received. When the trial is finished, inter-rater reliability between the actual intervention and the guesses will be estimated to assess the degree to which blinding has been successful.
Outcomes are assessed at entry and after four weeks intervention by assessors who are all blinded to the randomization group.
Depression has a wide range of possible features that can be measured and tested as possible endophenotypes . Since no prior trial has investigated the effect of SSRI on healthy first-degree relatives of patients with depression, we have chosen to include many outcomes since the nature of this trial is predominantly exploratory, i.e., hypothesis generating, and only partly hypothesis testing. When available, previously developed and validated scales and instruments were used in order to facilitate appropriate comparisons with data obtained in previous studies.
During selection of the primary outcome, it was stressed that the outcome should be objective and of clinical importance. Further, blinding should be possible at all levels of assessment and analyses. The measurement of change in plasma cortisol in the DEX-CRH test from entry before to four weeks during intervention fulfils these criteria. Plasma cortisol will be estimated as the total area under the curve (AUC-total) from administration of CRH at 15.00 hours to the last plasma cortisol measure at 18.00 hours. The DEX-CRH test is performed according to international standards with a few minor modifications ; thus plasma cortisol, plasma ACTH and salivary cortisol are measured at the same time points.
Secondary outcomes include changes in scores from baseline to four weeks on: 1) cognitive functions are measured with a broad battery of neuropsychological tests with relevance in relation to depression, evaluating memory, attention, visuomotor speed, visuo-constructional abilities, decision making, logical thinking, executive functions, verbal fluency, social and moral cognition, recognition of emotions and emotional intelligence [37–54], 2) neuroticism as measured by the NEO-PI-R  and EPQ .
Tertiary outcomes include changes in scores from baseline to four weeks on: 1) mood as measured by the Hamilton rating scale for depression (HAM-D17)  and the Hamilton rating scale for anxiety (HAM-A14 , 2) participants subjective perception of pain on a visual analogue scale modified from Klepstad , 3) sleep on a visual analogue scale for sleep quality, sleep items from the HAMD-17 and supplementary questions on sleep characteristics, 4) aggression by The Buss-Perry Aggression Questionnaire , 5) depressive symptoms by the Beck Depression Inventory (BDI-21) , 6) quality of life by the WHO Quality of Life questionnaire , 7) a global measure of stress by the Cohen Perceived Stress Scale , and 8) salivary cortisol assessed by Salivettes during an ordinary day in the participants usual environment at the following time points: awakening, awakening + 15 min., awakening + 30 min., awakening + 45 min., awakening + 60 min., 12:00, 18:00 and at 23:00 . Further, side-effects are assessed at four weeks by the UKU Side Effect Rating Scale .
Blood samples are stored in a bio bank for further analyses. Among others we intend to genotype for the 5-HTTLPR-short/long-promoter variant, and the catechol-O-methyltransferase (COMT), and to test whether these genotypes will be associated with the response to escitalopram on the potential endophenotypes for depression. Further, messenger RNA for the glucocorticoid receptor will be analysed and associated to the effect of escitalopram.
Participants are subjected to almost identical sequences of assessments at entry and after four weeks of intervention (Appendix 2). The first part of the assessment is a telephone interview, and the individuals who are not excluded at that time point, are scheduled to meet at the clinic at two different days before and following four weeks of intervention with escitalopram or placebo. At the first day of examination the participants are interviewed to evaluate fulfilment of inclusion and exclusion criteria including the Schedules for Clinical Assessment in Neuropsychiatry (SCAN)  and various socio-demographics.
A high-risk study performed by Modell et al.  found that healthy high-risk probands of patients with a diagnosis of depression examined by the DEX-CRH test present with a cortisol AUC-total (mean ± SEM) of 15,064 ± 3,947 nmol × min/L. Further, Modell et al reported that cortisol AUC-total (mean ± SEM) in healthy individuals with no family history of depression was 7,773 ± 1,071 nmol × min/L. A clinically relevant effect of escitalopram on the cortisol AUC-total (mean ± SEM) was thus estimated to be the difference in cortisol AUC-total (mean ± SEM) of high-risk probands of patients with the diagnosis of depression and that of healthy individuals with no family history of depression. Accordingly, the relevant difference we aim to detect or reject is 15,064 – 7,773 = 7,291 nmol × min/L. Given a standard deviation (SD) = SEM × √14 = 3,947 × 3.7 = 14,768 nmol × min/L provides a power of the trial at a minimum of 60% (1 - β = 0.60), β being the risk of overlooking a difference in the cortisol AUC-total. However, the power in the trial may be higher, considering the use of analysis of covariance (ANCOVA) of the change from entry to after four weeks of intervention in AUC total during the DEX-CRH test. Based on these calculations we aim for a full data set of 80 participants to be able to conclude in relation to the primary outcome measure.
All data analyses will be carried out according to a pre-established analysis plan. The main null-hypothesis to be tested is that there is no difference between the two intervention arms with regard to the plasma cortisol AUC-total in the DEX-CRH test. All randomized participants will be analysed, including those with missing data on AUC.
Covariates in the statistical models for the AGENDA trial.
AUC-total plasma cortisol
Body Mass Index, entry
Number of daily cigarettes
Years of education
In the case of missing data according to the primary outcome, analyses will be performed both on complete data sets, as well as data sets on all participants completed by multiple imputation (MI) of missing data by MI-analysis (SASS version 9.1 or NORM version 1) based on age, sex, body mass index, HAMD, neuroticism before and after the intervention, years of education, and AUC-total for cortisol, and ACTH and salivary cortisol before and after the intervention. In the case of discrepancy between these results, the result from the MI procedure is regarded as the result in the trial. P < 0.05 will be regarded as statistically significant.
All the data of each participant is kept in a Case Record File, which fulfils the Danish law for medical doctors' obligation to keep patient records. In order to maintain blinding, the result of serum escitalopram concentration at end of the intervention is sent to the CTU, that keeps it in a locked safety box until the practical part and the data analyses of the trial are finished. Participants are not registered in The Danish Psychiatric Central Research Register or in any local hospital registers.
Procedures for breaking the code for randomization has been established for the case of severe adverse reactions, which can be related to the intervention or if a serious adverse events occur. It is the decision of UK and LK to request emergency breaks, and the CTU can be contacted at any time regarding the practical procedure. The participants can at all times reach UK by mobile phone. An independent data monitoring and safety committee has been established to further ensure the safety of the participants, should the need for considering early stopping occur.
Current trial status
Enrolment started July 2007 and is ongoing until July 2009. Status in May 2009 is that 390 eligible persons have been screened and that 77 of these have been randomized (Figure 1) and the dataset is complete for 64 participants regarding the primary outcome measure.
The regional ethics committee for the greater Copenhagen area has approved the protocol (H-KF-307413) as has The Danish Data Protection Agency (2006-41-6737) and The Danish Medicines Agency (2612-3162). The trial has the EudraCT number 2006-001750-28 and is registered at ClinicalTrials.gov as NCT 00386841. Both positive, neutral, and negative findings from the trial will be published in accordance with the CONSORT guidelines . The trial is conducted and monitored in accordance with the International Conference on Harmonization for Good Clinical Practice guidelines  and the Declaration of Helsinki 2002 http://www.wma.net/e/policy/b3.htm.
Information about the trial is presented to potential participants both verbally and in written form in quiet surroundings, and the participants were given permission to bring a relative or friend. It is made clear that participation is voluntary and that the participant can withdraw the given consent at any time without consequence for future treatment possibilities. Participants receive a copy of their rights. All participating healthy volunteers sign a written informed consent. The participants are paid up to 9,000 Danish crowns for full participation (equal to about one weeks pay) and are further compensated for any travel expenses. When the randomization code is broken the participants will receive a letter with information on whether they received escitalopram or placebo and the major results of the trial.
The AGENDA trial is the first trial investigating whether an antidepressant has an effect on potential endophenotypes in healthy first-degree relatives of patients with a diagnosis of depression. This represents a new strategy to validate potential endophenotypes for depression, which may cast light on the pathophysiology of depression. The trial is fully investigator initiated and controlled to secure unbiased assessment of the effect of escitalopram on endophenotypes of healthy first-degree relatives of patients with depression. The AGENDA trial has received non-restricted grants from non-profit and for-profit organizations.
Further knowledge of endophenotypes may increase the validity of the diagnosis of depression in the future and may eventually improve our possibilities to reclassify depression. The principle of testing the effect of a psychotropic drug on possible endophenotypes for a given disorder could be used to test putative endophenotypes for other disorders as well.
Further outcome assessments
We plan to assess the effect of escitalopram versus placebo on a number of other outcomes in healthy participants with a family history of depression. These assessments include:
A: Investigation of the association between inflammation and depression. A flow-cytometric profile with focus on activated and non-activated t-cell subsets measured before and after intervention. Furthermore inflammatory variables and proinflammatory genepolymorphisms are measured.
B. Magnetic Resonance Imaging (MRI) of hippocampus volume. Studies of patients with unipolar depression suggest a decreased volume of hippocampus in MR scans . Decreased volume of hippocampus is a possible endophenotype for depression and the effect of SSRI on hippocampal volume has not been established in healthy individuals with a family history of depression. Functional MRI including Face Emotion – Gender Discrimination Task  and Flanker Go-No go Risk paradigm  is conducted in a subpopulation of participants in the AGENDA trial.
Appendix 1. Criteria for inclusion and exclusion in the AGENDA trial
Healthy individual of both sexes. Women should preferable be in day 1–13 of her menstrual cycle at the time of randomization.
Offspring or sibling of an ethnic Dane, with a history of psychiatric in- or outpatient care with the diagnosis of depression and who later had the diagnosis verified in a SCAN interview at the Department of Psychiatry Rigshospitalet, Denmark 2004–2009.
Aged 18 – 60 years.
Born in Denmark.
European parents and grandparents.
Able and willing to sign informed consent.
Somatical illness or other handicap, which make participation in the trial impossible.
Daily intake of drugs interfering with corticosteroids or escitalopram, including birth control pills or any kind of corticosteroids.
Hypersensitivity to escitalopram, dexamethasone, or human corticotrophin-releasing hormone.
Former medical or psychological treatment for diseases in the affective or schizophrenic spectrum.
Abuse of alcohol or psychotropic medication.
For women: pregnancy or breastfeeding.
Appendix 2. Assessments of prognostic factors and outcome measures in the AGENDA trial
Socio-demographics, family history of psychiatric illness, Kendler's questionnaire for lifetime events in a brief Danish version , Schedules for Clinical Assessment in Neuropsychiatry, version 2.1, The Structured Clinical Interview for DSM – IV Axis II Personality Disorders , birth weight, height, current weight, waist-hip ratio and Edinburgh Inventory for handedness . For women a pregnancy test is performed.
At entry and at four weeks of intervention the following variables are assessed
The Combined Dexamethasone Corticotrophine-releasing Hormone Test (DEX-CRH) salivary cortisol, plasma cortisol and plasma-ACTH are measured every 15 minutes from 14:00 – 18:00 hours .
The Danish Adult Reading Test , Familiar faces , Trail Making A and B , Stroop test , Boston naming , Block Designs , Cambridge Cognitive Examination , Rey Auditory Verbal Learning Test , Rey-Osterrieth Complex Figure , verbal fluency for animals and letter "s" , Symbol Digit Modalities Test , Iowa Gambling Task , Letter-number sequencing , recognition of facial emotions , moral judgement [51, 52], Mayer-Salovey-Caruso Emotional Intelligence Test .
Rating scales of mood
Depressive symptoms, quality of life, perceived stress, subjective evaluations of aggression, sleep and pain
Buss-Perry Aggression Questionnaire , Beck Depression Inventory, 42-items , Side Effect Self Rating Scale by UKU-SERS-Pat , WHO Quality of Life , Cohen's Perceived Stress Scale  and Klepstad Visual Analogue Scale for pain, modified . Sleep is evaluated by Hamilton Depression Scale and additional questions of number of night sleep hours, subjective quality of sleep on a visual analogue scale and number of interruptions of sleep.
Saliva samples by Salivettes for measurements of cortisol are obtained at the clinic and during a day in the participant's usual environment.
We thank the patients who gave us permission to contact their relatives and Camilla Bock and Jens Bukh for facilitating the contact. We thank the participants in the trial for their collaboration. Further we thank H. Lundbeck A/S for free supply of the study drug and placebo, and The Lundbeck Foundation, The Eli Larsen Foundation, The Jeppe Juhl Foundation, The Geert Jørgensen Foundation and The Ivan Nielsen Foundation for unrestricted economical support. The members of the DMSC, Jørgen Hilden and Per Bech, are thanked for their contribution.
- Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry. 1970, 126: 983-987.View ArticlePubMedGoogle Scholar
- Kendell RE: Clinical validity. Psychol Med. 1989, 19: 45-55. 10.1017/S0033291700011016.View ArticlePubMedGoogle Scholar
- Gould TD, Gottesman II: Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 2006, 5: 113-119. 10.1111/j.1601-183X.2005.00186.x.View ArticlePubMedGoogle Scholar
- Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK: Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry. 2006, 60: 93-105. 10.1016/j.biopsych.2005.11.006.View ArticlePubMedGoogle Scholar
- Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000, 23: 477-501. 10.1016/S0893-133X(00)00159-7.View ArticlePubMedGoogle Scholar
- Pariante CM, Papadopoulos AS, Poon L, Cleare AJ, Checkley SA, English J: Four days of citalopram increase suppression of cortisol secretion by prednisolone in healthy volunteers. Psychopharmacology (Berl). 2004, 177: 200-206. 10.1007/s00213-004-1925-4.View ArticleGoogle Scholar
- Raison CL, Miller AH: When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003, 160: 1554-1565. 10.1176/appi.ajp.160.9.1554.View ArticlePubMedGoogle Scholar
- Ising M, Kunzel HE, Binder EB, Nickel T, Modell S, Holsboer F: The combined dexamethasone/CRH test as a potential surrogate marker in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005, 29: 1085-1093. 10.1016/j.pnpbp.2005.03.014.View ArticlePubMedGoogle Scholar
- Modell S, Lauer CJ, Schreiber W, Huber J, Krieg JC, Holsboer F: Hormonal response pattern in the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology. 1998, 18: 253-262. 10.1016/S0893-133X(97)00144-9.View ArticlePubMedGoogle Scholar
- Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern N: Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression – a potential biomarker?. Biol Psychiatry. 2007, 62: 47-54. 10.1016/j.biopsych.2006.07.039.View ArticlePubMedGoogle Scholar
- Ravnkilde B, Videbech P, Clemmensen K, Egander A, Rasmussen NA, Rosenberg R: Cognitive deficits in major depression. Scand J Psychol. 2002, 43: 239-251. 10.1111/1467-9450.00292.View ArticlePubMedGoogle Scholar
- Paelecke-Habermann Y, Pohl J, Leplow B: Attention and executive functions in remitted major depression patients. J Affect Disord. 2005, 89: 125-135. 10.1016/j.jad.2005.09.006.View ArticlePubMedGoogle Scholar
- Weiland-Fiedler P, Erickson K, Waldeck T, Luckenbaugh DA, Pike D, Bonne O: Evidence for continuing neuropsychological impairments in depression. J Affect Disord. 2004, 82: 253-258. 10.1016/j.jad.2003.10.009.View ArticlePubMedGoogle Scholar
- Kessing LV: Cognitive impairment in the euthymic phase of affective disorder. Psychol Med. 1998, 28: 1027-1038. 10.1017/S0033291798006862.View ArticlePubMedGoogle Scholar
- Clark L, Sarna A, Goodwin GM: Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry. 2005, 162: 1980-1982. 10.1176/appi.ajp.162.10.1980.View ArticlePubMedGoogle Scholar
- Savitz JB, Solms M, Ramesar RS: Neurocognitive function as an endophenotype for genetic studies of bipolar affective disorder. Neuromolecular Med. 2005, 7: 275-286. 10.1385/NMM:7:4:275.View ArticlePubMedGoogle Scholar
- Christensen MV, Kyvik KO, Kessing LV: Cognitive function in unaffected twins discordant for affective disorder. Psychol Med. 2006, 36: 1119-1129. 10.1017/S0033291706007896.View ArticlePubMedGoogle Scholar
- Eysenck HJ, Eysenck SGB: The Manual of the Eysenck Personality Questionnaie. 1975, London: Hodder and StoughtonGoogle Scholar
- Costa PT, McCrae RR: Stability and change in personality assessment: the revised NEO Personality Inventory in the year 2000. J Pers Assess. 1997, 68: 86-94. 10.1207/s15327752jpa6801_7.View ArticlePubMedGoogle Scholar
- Kirk KM, Birley AJ, Statham DJ, Haddon B, Lake RI, Andrews JG: Anxiety and depression in twin and sib pairs extremely discordant and concordant for neuroticism: prodromus to a linkage study. Twin Res. 2000, 3: 299-309. 10.1375/136905200320565274.View ArticlePubMedGoogle Scholar
- Vinberg M, Mortensen EL, Kyvik KO, Kessing LV: Personality traits in unaffected twins discordant for affective disorder. Acta Psychiatr Scand. 2007, 115: 442-450. 10.1111/j.1600-0447.2006.00909.x.View ArticlePubMedGoogle Scholar
- Hasler G, Drevets WC, Manji HK, Charney DS: Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004, 29: 1765-1781. 10.1038/sj.npp.1300506.View ArticlePubMedGoogle Scholar
- Krieg JC, Lauer CJ, Schreiber W, Modell S, Holsboer F: Neuroendocrine, polysomnographic and psychometric observations in healthy subjects at high familial risk for affective disorders: the current state of the 'Munich vulnerability study'. J Affect Disord. 2001, 62: 33-37. 10.1016/S0165-0327(00)00348-7.View ArticlePubMedGoogle Scholar
- Holsboer-Trachsler E, Stohler R, Hatzinger M: Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res. 1991, 38: 163-171. 10.1016/0165-1781(91)90041-M.View ArticlePubMedGoogle Scholar
- Binder EB, Kunzel HE, Nickel T, Kern N, Pfennig A, Majer M: HPA-axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients. Psychoneuroendocrinology. 2009, 34: 99-109. 10.1016/j.psyneuen.2008.08.018.View ArticlePubMedGoogle Scholar
- Burt DB, Zembar MJ, Niederehe G: Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity. Psychol Bull. 1995, 117: 285-305. 10.1037/0033-2909.117.2.285.View ArticlePubMedGoogle Scholar
- Quilty LC, Meusel LA, Bagby RM: Neuroticism as a mediator of treatment response to SSRIs in major depressive disorder. J Affect Disord. 2008, 111: 67-73. 10.1016/j.jad.2008.02.006.View ArticlePubMedGoogle Scholar
- Tse WS, Bond AJ: Serotonergic intervention affects both social dominance and affiliative behaviour. Psychopharmacology (Berl). 2002, 161: 324-330. 10.1007/s00213-002-1049-7.View ArticleGoogle Scholar
- Knutson B, Wolkowitz OM, Cole SW, Chan T, Moore EA, Johnson RC: Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry. 1998, 155: 373-379.View ArticlePubMedGoogle Scholar
- Gelfin Y, Gorfine M, Lerer B: Effect of clinical doses of fluoxetine on psychological variables in healthy volunteers. Am J Psychiatry. 1998, 155: 290-292.PubMedGoogle Scholar
- Kato M, Serretti A: Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2008,Google Scholar
- Bock C, Bukh JD, Vinberg M, Gether U, Kessing LV: Do stressful life events predict medical treatment outcome in first episode of depression?. Soc Psychiatry Psychiatr Epidemiol. 2009,Google Scholar
- Owens MJ, Knight DL, Nemeroff CB: Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001, 50: 345-350. 10.1016/S0006-3223(01)01145-3.View ArticlePubMedGoogle Scholar
- Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R: Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009, 373: 746-58. 10.1016/S0140-6736(09)60046-5.View ArticlePubMedGoogle Scholar
- Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG: Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008, 336: 601-605. 10.1136/bmj.39465.451748.AD.View ArticlePubMedPubMed CentralGoogle Scholar
- Mossner R, Mikova O, Koutsilieri E, Saoud M, Ehlis AC, Muller N: Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression. World J Biol Psychiatry. 2007, 8: 141-174. 10.1080/15622970701263303.View ArticlePubMedGoogle Scholar
- Nelson HE, O'Connell A: Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex. 1978, 14: 234-244.View ArticlePubMedGoogle Scholar
- Waldemar G, Bruhn P, Kristensen M, Johnsen A, Paulson OB, Lassen NA: Heterogeneity of neocortical cerebral blood flow deficits in dementia of the Alzheimer type: a [99mTc]-d, l-HMPAO SPECT study. J Neurol Neurosurg Psychiatry. 1994, 57: 285-295. 10.1136/jnnp.57.3.285.View ArticlePubMedPubMed CentralGoogle Scholar
- Reitan RM: Trail Making Test. Manual for Administration and Scoring. 2920 South 4th Avenue, South Tucson, Arizona 85713-4819, Reitan Neuropsychology Laboratory. 1992Google Scholar
- Kaplan E, Goodglass H, Weintraub S: Boston Naming Test, Philadelphia. 1983, 2Google Scholar
- Gade A, Mortensen EL, Bruhn P: "Chronic painter's syndrome". A reanalysis of psychological test data in a group of diagnosed cases, based on comparisons with matched controls. Acta Neurol Scand. 1988, 77: 293-306. 10.1111/j.1600-0404.1988.tb05913.x.View ArticlePubMedGoogle Scholar
- Buschke H, Sliwinski MJ, Kuslansky G, Lipton RB: Diagnosis of early dementia by the Double Memory Test: encoding specificity improves diagnostic sensitivity and specificity. Neurology. 1997, 48: 989-997.View ArticlePubMedGoogle Scholar
- Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S: CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry. 1986, 149: 698-709. 10.1192/bjp.149.6.698.View ArticlePubMedGoogle Scholar
- Hawkins KA, Dean D, Pearlson GD: Alternative forms of the Rey Auditory Verbal Learning Test: a review. Behav Neurol. 2004, 15: 99-107.View ArticlePubMedGoogle Scholar
- Akshoofmoff N, Stiles J: Developmental trends in visuospatial analysis and planning: Copying a complex figure. Neuropsychology. 1995, 9: 364-377. 10.1037/0894-4126.96.36.1994.View ArticleGoogle Scholar
- Yaretsky A, Arzi T, Ben-Nun Y: Word fluency in aging and dementia: principles of relatedness in the generative naming process. Arch Gerontol Geriatr. 1999, 29: 57-60. 10.1016/S0167-4943(99)00023-0.View ArticlePubMedGoogle Scholar
- Sheridan LK, Fitzgerald HE, Adams KM, Nigg JT, Martel MM, Puttler LI: Normative Symbol Digit Modalities Test performance in a community-based sample. Arch Clin Neuropsychol. 2006, 21: 23-28. 10.1016/j.acn.2005.07.003.View ArticlePubMedGoogle Scholar
- Bechara A, Damasio H, Tranel D, Damasio AR: The Iowa Gambling Task and the somatic marker hypothesis: some questions and answers. Trends Cogn Sci. 2005, 9: 159-162. 10.1016/j.tics.2005.02.002.View ArticlePubMedGoogle Scholar
- Haut MW, Kuwabara H, Leach S, Arias RG: Neural activation during performance of number-letter sequencing. Appl Neuropsychol. 2000, 7: 237-242. 10.1207/S15324826AN0704_5.View ArticlePubMedGoogle Scholar
- Donais P: O'Sullivan and Guilford's Four Factor Test of Social Intelligence as predictors of counselor effectiveness: An exploratory study. Dissertation Abstacts International. 2006, 40: 3115-Google Scholar
- Mendez MF, Anderson E, Shapira JS: An investigation of moral judgement in frontotemporal dementia. Cogn Behav Neurol. 2005, 18: 193-197. 10.1097/01.wnn.0000191292.17964.bb.View ArticlePubMedGoogle Scholar
- Greene JD, Sommerville RB, Nystrom LE, Darley JM, Cohen JD: An fMRI investigation of emotional engagement in moral judgment. Science. 2001, 293: 2105-2108. 10.1126/science.1062872.View ArticlePubMedGoogle Scholar
- Lopes PN, Brackett MA, Nezlek JB, Schutz A, Sellin I, Salovey P: Emotional intelligence and social interaction. Pers Soc Psychol Bull. 2004, 30: 1018-1034. 10.1177/0146167204264762.View ArticlePubMedGoogle Scholar
- Sprengelmeyer R, Young AW, Calder AJ, Karnat A, Lange H, Homberg V: Loss of disgust. Perception of faces and emotions in Huntington's disease. Brain. 1996, 119 (Pt 5): 1647-1665. 10.1093/brain/119.5.1647.View ArticlePubMedGoogle Scholar
- Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960, 23: 56-62. 10.1136/jnnp.23.1.56.View ArticlePubMedPubMed CentralGoogle Scholar
- Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol. 1959, 32: 50-55.View ArticlePubMedGoogle Scholar
- Klepstad P, Loge JH, Borchgrevink PC, Mendoza TR, Cleeland CS, Kaasa S: The Norwegian brief pain inventory questionnaire: translation and validation in cancer pain patients. J Pain Symptom Manage. 2002, 24: 517-525. 10.1016/S0885-3924(02)00526-2.View ArticlePubMedGoogle Scholar
- Buss AH, Perry M: The aggression questionnaire. J Pers Soc Psychol. 1992, 63: 452-459. 10.1037/0022-35188.8.131.522.View ArticlePubMedGoogle Scholar
- Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory for measuring depression. Arch Gen Psychiatry. 1961, 4: 561-571.View ArticlePubMedGoogle Scholar
- Skevington SM, Lotfy M, O'Connell KA: The World Health Organization's WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res. 2004, 13: 299-310. 10.1023/B:QURE.0000018486.91360.00.View ArticlePubMedGoogle Scholar
- Cohen S, Kamarck T, Mermelstein R: A global measure of perceived stress. J Health Soc Behav. 1983, 24: 385-396. 10.2307/2136404.View ArticlePubMedGoogle Scholar
- Deshauer D, Duffy A, Meaney M, Sharma S, Grof P: Salivary cortisol secretion in remitted bipolar patients and offspring of bipolar parents. Bipolar Disord. 2006, 8: 345-349. 10.1111/j.1399-5618.2006.00338.x.View ArticlePubMedGoogle Scholar
- Lindstrom E, Lewander T, Malm U, Malt UF, Lublin H, Ahlfors UG: Patient-rated versus clinician-rated side effects of drug treatment in schizophrenia. Clinical validation of a self-rating version of the UKU Side Effect Rating Scale (UKU-SERS-Pat). Nord J Psychiatry. 2001, 55 (Suppl 44): 5-69.PubMedGoogle Scholar
- Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R: SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry. 1990, 47: 589-593.View ArticlePubMedGoogle Scholar
- Vickers AJ, Altman DG: Statistics notes: Analysing controlled trials with baseline and follow up measurements. BMJ. 2001, 323: 1123-1124. 10.1136/bmj.323.7321.1123.View ArticlePubMedPubMed CentralGoogle Scholar
- ICH Harmonised Tripartite Guideline for Good Clinical Practice (CPMP/ICH/135/95). 2006, http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf
- Moher D, Schulz KF, Altman D: The CONSORT Statement: revised recommendations for improving the quality of reports of parallel-group randomized trials 2001. Explore (NY). 2005, 1: 40-45.View ArticleGoogle Scholar
- Videbech P, Ravnkilde B: Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004, 161: 1957-1966. 10.1176/appi.ajp.161.11.1957.View ArticlePubMedGoogle Scholar
- Gorno-Tempini ML, Pradelli S, Serafini M, Pagnoni G, Baraldi P, Porro C: Explicit and incidental facial expression processing: an fMRI study. Neuroimage. 2001, 14: 465-473. 10.1006/nimg.2001.0811.View ArticlePubMedGoogle Scholar
- Vollm B, Richardson P, McKie S, Elliott R, Deakin JF, Anderson IM: Serotonergic modulation of neuronal responses to behavioural inhibition and reinforcing stimuli: an fMRI study in healthy volunteers. Eur J Neurosci. 2006, 23: 552-560. 10.1111/j.1460-9568.2005.04571.x.View ArticlePubMedGoogle Scholar
- Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC: Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry. 1995, 152: 833-842.View ArticlePubMedGoogle Scholar
- The Structured Clinical Interview for DSM – IV Axis II Personality Disorders (SCID – II). 1997, Wasington DC: American Psychiatric PressGoogle Scholar
- Oldfield RC: The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971, 9: 97-113. 10.1016/0028-3932(71)90067-4.View ArticlePubMedGoogle Scholar
- Golden CJFS: Stroop Color an Word Test, revised 2002 adult Manual for Clincal and Experimental Uses. Stoelting. 2002Google Scholar
- Norholm V, Bech P: The WHO Quality of Life (WHOQOL) Questionnaire: Danish validation study. Nord J Psychiatry. 2001, 55: 229-235. 10.1080/080394801681019075.View ArticlePubMedGoogle Scholar
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