Mood Disorders


Introduction

In our research program we study the course and treatment of mood disorders, with specific focus on transdiagnostic factors such as anhedonia, arousal (stress) and cognitive functions.

In several projects we study the impact of stress, cognition and emotions (life events and trauma) on course and treatment response of depression. Our focus is on specific mechanisms through which these treatments exert their acute, prophylactic and preventive effects using a variety of biological treatments and/or neuromodulation.
Moreover, investigating the neurobiological background of stress and vulnerability including (epi)genetic, neuroendocrine, metabolomics, and brain circuitry factors, with a special interest in the GABA (i.e. glutamate) and Dopaminergic systems.
Traumatic stress, especially during early life, is a major risk factor for the development of mood disorders. Moreover, stress has persistent effects on brain structure and functionality.


Research Projects:

Schema-ECT study


G. van Wingen (PI), D.S. Scheepens, MD, PhD student

A randomized controlled trial is used to determine schema-ECT efficacy. Neuroimaging and blood biomarkers will be associated with changes in clinical variables.
Electroconvulsive therapy (ECT) is often considered a last treatment option for otherwise treatment resistant depression. Unfortunately, approximately 50% of patients do not respond sufficiently (Heijnen et al., 2010). Furthermore, of the patients who respond initially, 40-80% relapse within half a year (Sackeim et al., 2001). We hypothesize that suboptimal efficacy of ECT could be due to insufficient modulation of negative cognitive schemas, which are relative stable representations of prior knowledge and experiences. These negative schemas distort the perception of new experiences in a maladaptive manner, and focus one’s thoughts on negative aspects of oneself. Cognitive theories of depression hold that these negative schemas play an important role in the development, maintenance and recurrence of depression (Beck and Clark, 1988).
We recently found that memories can be weakened by applying ECT shortly after reactivation of a memory (Kroes et al., 2013). This suggests that reactivation of negative schemas just prior to ECT may also weaken those schemas. According to the cognitive theory of depression this will lead to the recovery from depression and will additionally reduce the risk to relapse, but this has not yet been investigated. Here, we aim to investigate the efficacy of “schema-ECT” and hypothesize that repeated reactivation of depressive schemas prior to ECT weakens negative schemas, increases the efficacy of the ECT course, and reduces the relapse rate after the reduction of the ECT session frequency or discontinuing ECT. In addition to our main aim, we will investigate whether the clinical response to ECT response is associated with changes in neurobiological biomarkers using neuroimaging scans and blood samples obtained from the venous catheter, and whether these biomarkers at baseline can predict treatment response.

van Waarde JA, Scholte HS, van Oudheusden LJ, Verwey B, Denys D, van Wingen GA. Mol Psychiatry. 2015 May;20(5):609-14. doi: 10.1038/mp.2014.78. Epub 2014 Aug 5



The effectiveness of Deep Brain Stimulation (DBS) of the Nucleus Accumbens as a treatment for therapy resistant depressive patients
Prof. D. Denys (PI), I. Bergfeld, PhD student
Major depressive disorder (MDD) is a psychiatric illness characterized by a disorder of mood, but is also associated with several neuropsychological deficits. Additionally, some of the treatment options for the disorder are linked with further cognitive decline, most notably electroconvulsive therapy (ECT). At present ECT is the “treatment-of-choice” for treatment-refractory (TR) MDD patients, who have failed to respond to different therapies (medication and/or psychotherapy).
In recent years a new neurosurgical treatment option for TR MDD has emerged in the form of deep brain stimulation (DBS). Different targeting sites have proposed as a potential target, e.g. subgenual cingulate region (Brodmann area 25) and the nucleus accumbens (N.Acc.). For this project the latter has been chosen, because DBS of this site has shown to have a positive result on mood in obsessive-compulsive patients. N.Acc. DBS has also shown promising results in lifting depression in a small group of MDD patients.
The study will compare the neuropsychological outcomes of patients treated with N.Acc DBS to those treated with ECT or medication.

Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, Visser I, Figee M, de Kwaasteniet BP, Horst F, Schene AH, van den Munckhof P, Beute G, Schuurman R, Denys D. Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.JAMA Psychiatry. 2016 May 1;73(5):456-64.

Helius Study: Mental Health

Prof. E. Derks (PI), A. Lok, MD, PhD
The HELIUS study is a prospective cohort study (n=23.000) on health and health care among an urban multi-ethnic population. The aim of the HELIUS study is to gain insight in the biological, psychological and social causes of the unequal burden of disease across ethnic groups, and ultimately enable the improvement of health care and prevention strategies. The study is being carried out in Amsterdam, the Netherlands, and is an initiative of the Academic Medical Center (AMC) and the Public Health Service of Amsterdam (GGD Amsterdam).
The study focusses on three primary research areas:

  • Cardiovascular diseases (including diabetes)
  • Mental health (depression and trauma)
  • Infectious diseases

Baseline data collection took place in 2011-2015. Participants of Turkish, Moroccan, South-Asian Surinamese, African Surinamese, Ghanaian and Dutch origin were included in the study. Data were collected through a questionnaire/interview and a physical examination. Biological samples were obtained during study visits. We are planning to invite participants for repeated measurements in the near future.
For more information on the study design and data collection, also see:

K Stronks, MB Snijder, RJ Peters, M Prins, AH Schene, AH Zwinderman. The impact of ethnicity on health in a Western society: the HELIUS study. BMC Public Health 2013;13:402.



A randomised controlled trial of oral S-ketamine as add-on medication for patients with treatment-resistant major depressive disorder
Prof. D. Denys (PI), prof. R. Schoevers (UMCG), A. Lok, MD PhD, M. Figee, MD PhD, J. Strous, PhD student

The study aims to examine the efficacy of oral S-ketamine augmentation in patients with TRD treated with regular antidepressants in a double-blind randomised controlled trial. Secondary questions involve the effects of oral S-ketamine on sleep, memory, pain, anxiety, quality of life and consumption of medical care, as well as a detailed assessment of possible side effects caused by the ketamine treatment. Brain activation parameters and MDD-related biomarkers in blood and urine will be assessed to develop a better understanding of the mechanisms of action and metabolism. Furthermore, the study will also investigate the duration of antidepressant effects after discontinuation of S-ketamine add-on treatment.
Start September 2016

DELTA (neuro-imaging) study
Prof. W. van den Brink (PI), prof. A.H. Schene, R.J.T. Mocking, PhD student, C. Figuroa, PhD student
In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35–65 years) with ≥2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination.
Diagnostic Imaging of Affective Disorders using Emotion Processing (DIADE)


Prof. W. van den Brink (PI), prof. A.H. Schene, M. Rive, PhD student

This project concerns the diagnosis of major depressive disorder (MDD) and bipolar disorder (BD). Early differentiation of MDD and BD is very important, but questionnaires or interviews do not adequately differentiate between these disorders. We investigate the value of fMRI as additional diagnostic instrument, by directly comparing emotion regulation processes in unmedicated MDD and BD patients versus HC.

Rive MM, Mocking RJ, Koeter MW, van Wingen G, de Wit SJ, van den Heuvel OA, Veltman DJ, Ruhé HG, Schene AH. State-Dependent Differences in Emotion Regulation Between Unmedicated Bipolar Disorder and Major Depressive Disorder. JAMA Psychiatry. 2015 Jul;72(7):687-96. doi: 10.1001/jamapsychiatry.2015.0161.