Research Projects - Mood Disorders Research Group

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Personalized medicine and pharmacotherapy in treatment-resistant depression

Treatment resistance to antidepressants is rather the rule than the exception if full remission is set as the aim of clinical therapies. We have shown in previous works that standardization based on treatment algorithms is effective in improving treatment outcomes. However response predictors that guide the choice between different treatment escalation strategies are lacking. We hypothesize that the combination of standardization (tactics of treatment) and personalization (strategies of treatment) is key in optimizing the treatment of depression. We therefore investigate response predictors, particularly focussed on lithium augmentation as a highly evidence based second step strategy in TRD but is only effective in 40 to 50% of patients. Can we identify these patients before the initiation of treatment?

Neurobiology of emotion processing and social cognition in mood disorders

We use psychophysics, clinical testing, fMRI, genetic and epigenetic testing, and hormonal studies to address the following research questions:

  • What is the neural correlate of distinct aspects (emotion regulation, self-referential procssing, affect recognition, emotional memory) of emotion processing?
  • Which alterations of emotion processing can be found in individuals with major depressive disorder, bipolar disorders, Borderline personality disorder, and alcohol use disorder? Are these alterations also present during remission of symptoms? Are these alterations also present in first-degress relatives?
  • What is the neural correlate of non-pathological aggressive behavior?
  • What is the impact of personality traits and disorders on emotion processing?
  • What is the function of subjective (phenomenal) experience of emotions?
  • What is the neural correlate of empathy? Which alterations can be found in mood disorders?
  • What is the neural correlate of maternal affect recognition of the own child? What alterations can be found in mood disorders?
  • How do emotions influence decision making and behavior?
  • What is the neural correlate of mindfulness and mindwandering?
  • What are the neurobiological correlates of (successful) psychotherapeutic and pharmacological interventions? Can neurobiological markers be used to improve treatment (e.g., through personalization)? Can neurobiological markers be used to predict treatment outcome?

Transgenerational effects of maternal early-life stress, major depression and Borderline personality disorder on child well-being

Results of previous research as well as the experience of health care professionals indicate that mothers who were exposed to highly stressful experiences during childhood often have difficulties in reacting properly to the emotional needs of their own children. Similarly, maternal major depression and maternal Borderline personality disorder (often found in individuals that have experienced early-life stress) may impact on mother-child interaction. Through this, stress and strain might be transmitted to children. A better understanding of this intergenerational transmission of stressful experiences is necessary to efficiently use prevention and intervention programs. How do mothers who have experienced early-life stress, major depression or Borderline personality disorder interact with their own children? How do the mothers react to the emotions and needs of their children? Is it possible to detect the (neuro-)biological correlates that underlie maternal sensitivity or the capacity to regulate one’s own emotions in conflict situations with the child? Answers to these questions may not only shed light on the way mother and child interact but might also demonstrate how interaction is influenced by hormonal, neural, and (epi-)genetic factors.  
The goal of our research project is to understand intergenerational transmission of these highly demanding experiences and to test for the effectiveness of intervention programs.

Early detection and intervention for bipolar disorder (BipoLife)

Bipolar disorders are severe, recurrent affective disorders that are among the leading causes of disability in working age adults. Despite their high lifetime prevalence of 4-5%, bipolar disorders are often misdiagnosed leading to inappropriate or delayed treatments that have devastating socio-economic, professional and familial consequences. Typically, bipolar disorders evolve from an asymptomatic at-risk stage to the emergence of prodromal symptoms in adolescence or early adulthood, leading to a first episode and eventually to an unpredictable and relapsing course throughout the lifespan. The high suicide risk and severe medical comorbidity contribute to a reduced life expectancy of about ten years.


Bipolar disorders deserve a high priority in the research agenda to gain understanding of underlying pathogenic mechanisms, reduce the diagnostic delay, and improve treatment strategies. Therefore, for the first time in Germany, a group of eight academic centers, specialized in the care and research of bipolar disorders, forms an alliance with nationwide patient and caregiver support groups organized within the German Association for Bipolar Disorders. The overall aim of this BMBF-funded consortium is (1) to build a comprehensive network to optimize and develop innovative diagnostic procedures and therapeutic interventions, and (2) to integrate translational research efforts into clinical practice. The proposed work focuses on important unmet needs in the prevention, diagnostic assessment and therapeutic intervention in three critical populations: (1) individuals at high risk to develop bipolar disorders, (2) patients at early stage bipolar disorder, and (3) patients with difficult-to-treat bipolar disorders including those with an unstable, highly relapsing course, depression and suicidal behavior.

Understanding mindfulness

In this project, we develop instruments to quantify mindfulness deficits in patients with mood, borderline and addictive disorders. Behavioral tests are complemented by fMRI investigations to better understand the neurobiology of mindfulness and mindfulness deficits.

Chronostress

The project Chronostress studies the impact of biological and social rhythms on mental health and well-being.

Empathy in depression - a behavioral study

Major depressive disorder (MDD) and alexithymia have both been associated with deficits in empathy. Moreover alexithymia and MDD are assumed to be strongly associated. However, the exact nature of these empathy deficits remain unclear. We address the question whether depression and alexithymia show dissociable and interacting effects on empathy. For this purpose we comprehensively study the effects of depression and alexithymia on different components of cognitive and emotional components of trait and state empathy.

Research Outpatient Clinic

In our Research Outpatient Clinic, we evaluate the safety and efficacy of novel approaches to treat mood disorders.

Antidepressant and lithium augmentation study (ALIA)

This pharmacogenetic study aims at identifying genetic response predictors of lithium augmentation treatment in patients with treatment-resistant depression (TRD) and improving our understanding of the neurobiology of lithium augmentation. We are particularly interested in response-modulating factors along the neurochemical pathways of intracellular lithium effects. To our knowledge the ALIA study has collected the largest DNA sample of excellently characterized patients with TRD.

Study coordination: Dr. med. Pichit Buspavanich

Principal investigator: Dr. med. Roland Ricken

Tranylcypromine versus lithium augmentation study (TRAVEL study)

The Travel study is a prospective randomized study comparing the efficacy of tranylcypromine and lithium augmentation in treatment-resistant depression.

Study coordination: Dr. med. Pichit Buspavanich

Principal investigator: Dr. med. Roland Ricken

Early detection of bipolar disorders (BipoLife A1, BMBF-funded)

Bipolar disorders are severe, recurrent affective disorders that are among the leading causes of disability in working age adults. Despite their high lifetime prevalence of 4-5%, bipolar disorders are often misdiagnosed leading to inappropriate or delayed treatments that have devastating socio-economic, professional and familial consequences. Typically, bipolar disorders evolve from an asymptomatic at-risk stage to the emergence of prodromal symptoms in adolescence or early adulthood, leading to a first episode and eventually to an unpredictable and relapsing course throughout the lifespan. The high suicide risk and severe medical comorbidity contribute to a reduced life expectancy of about ten years.

Bipolar disorders deserve a high priority in the research agenda to gain understanding of underlying pathogenic mechanisms, reduce the diagnostic delay, and improve treatment strategies. Therefore, for the first time in Germany, a group of eight academic centers, specialized in the care and research of bipolar disorders, forms an alliance with nationwide patient and caregiver support groups organized within the German Association for Bipolar Disorders. The overall aim of this BMBF-funded consortium is (1) to build a comprehensive network to optimize and develop innovative diagnostic procedures and therapeutic interventions, and (2) to integrate translational research efforts into clinical practice. The proposed work focuses on important unmet needs in the prevention, diagnostic assessment and therapeutic intervention in three critical populations: (1) individuals at high risk to develop bipolar disorders, (2) patients at early stage bipolar disorder, and (3) patients with difficult-to-treat bipolar disorders including those with an unstable, highly relapsing course, depression and suicidal behavior.

In sub-project A1, currently used diagnostic tools will be applied in risk groups and a representative cohort. Predictive power of risk factors/constellations and potential resilience factors will be determined. Biomarkers will be incorporated to test whether they empower clinical/psychometric assessment. At-risk subjects will be classified and treatment guidance is provided. Decisions, efficacy and tolerability/safety are assessed. The refined model will be provided for research and clinical initiatives.

Psychotherapy for young patients with bipolar disorders (BipoLife A2, BMBF-funded)

Bipolar disorders are severe, recurrent affective disorders that are among the leading causes of disability in working age adults. Despite their high lifetime prevalence of 4-5%, bipolar disorders are often misdiagnosed leading to inappropriate or delayed treatments that have devastating socio-economic, professional and familial consequences. Typically, bipolar disorders evolve from an asymptomatic at-risk stage to the emergence of prodromal symptoms in adolescence or early adulthood, leading to a first episode and eventually to an unpredictable and relapsing course throughout the lifespan. The high suicide risk and severe medical comorbidity contribute to a reduced life expectancy of about ten years.

Bipolar disorders deserve a high priority in the research agenda to gain understanding of underlying pathogenic mechanisms, reduce the diagnostic delay, and improve treatment strategies. Therefore, for the first time in Germany, a group of eight academic centers, specialized in the care and research of bipolar disorders, forms an alliance with nationwide patient and caregiver support groups organized within the German Association for Bipolar Disorders. The overall aim of this BMBF-funded consortium is (1) to build a comprehensive network to optimize and develop innovative diagnostic procedures and therapeutic interventions, and (2) to integrate translational research efforts into clinical practice. The proposed work focuses on important unmet needs in the prevention, diagnostic assessment and therapeutic intervention in three critical populations: (1) individuals at high risk to develop bipolar disorders, (2) patients at early stage bipolar disorder, and (3) patients with difficult-to-treat bipolar disorders including those with an unstable, highly relapsing course, depression and suicidal behavior.

Sub-project A2 aims at testing three groups of hypotheses, regarding whether the addition of a specific, innovative psychotherapy (SPEC) to psychiatric care in young bipolar patients in early stage of their disease
Primary: (1) reduces rate of relapse (development of new affective episode), missed days at
work/school, days spent in hospitals, and health costs;
Secondary: (2) improves medical treatment compliance and social functioning; (3) normalizes
neurobiological functioning; (a) normalizes alterations in neural networks associated with emotion regulation and social cognition, i.e., reverses enhanced activation in the amygdala, attenuated activation in the medial prefrontal cortex; b) pre-treatment neural alterations in these systems will predict post-treatment outcome of SPEC, with the greatest improvement in SPEC for patients with the most pronounced neural alterations prior to treatment.

SPEC – specific psychotherapy experimental condition – is a new, innovative cognitive
behavioral intervention [5, 18, 25, 28] with four modules in a new format:
(1) psychoeducation and mood/activity diary; (2) structure of everyday life, sleep, social rhythm, interpersonal skills; (3) meta-cognitive skills; (4) emotion regulation skills. The training takes place over 6 months (t1, t2) and is delivered in 6 full day (ca. 8 hours) workshops in small groups (5-7 subjects).

Smartphone-based ambulatory assessment of early warning signs in the long-term treatment of bipolar disorders (BipoLife A3, BMBF-funded)

Bipolar disorders are severe, recurrent affective disorders that are among the leading causes of disability in working age adults. Despite their high lifetime prevalence of 4-5%, bipolar disorders are often misdiagnosed leading to inappropriate or delayed treatments that have devastating socio-economic, professional and familial consequences. Typically, bipolar disorders evolve from an asymptomatic at-risk stage to the emergence of prodromal symptoms in adolescence or early adulthood, leading to a first episode and eventually to an unpredictable and relapsing course throughout the lifespan. The high suicide risk and severe medical comorbidity contribute to a reduced life expectancy of about ten years.

Bipolar disorders deserve a high priority in the research agenda to gain understanding of underlying pathogenic mechanisms, reduce the diagnostic delay, and improve treatment strategies. Therefore, for the first time in Germany, a group of eight academic centers, specialized in the care and research of bipolar disorders, forms an alliance with nationwide patient and caregiver support groups organized within the German Association for Bipolar Disorders. The overall aim of this BMBF-funded consortium is (1) to build a comprehensive network to optimize and develop innovative diagnostic procedures and therapeutic interventions, and (2) to integrate translational research efforts into clinical practice. The proposed work focuses on important unmet needs in the prevention, diagnostic assessment and therapeutic intervention in three critical populations: (1) individuals at high risk to develop bipolar disorders, (2) patients at early stage bipolar disorder, and (3) patients with difficult-to-treat bipolar disorders including those with an unstable, highly relapsing course, depression and suicidal behavior.

Sub-project A3 aims at testing the hypothesis that time to new episode is significantly longer in the Smartphone-Based Ambulatory Assessment group, including personalized real-time data-driven therapeutic interventions (SBAA+) compared to the Smartphone-Based Ambulatory Assessment group, excluding personalized real-time data-driven therapeutic interventions (SBAA).

Social cognition, inhibition and emotion regulation in chronically aggressive men

This project aims at identifying psychological and neurobiological mechanisms of aggressive behavior in men that do not meet diagnostic criteria for psychiatric disorders according to DSM.

Clinical database for patients with bipolar disorders

To improve our understanding of the development and course of bipolar disorders, we document the long term course of the disorder in our cohort. The database includes clinical data (with particular focus on personality and temperament traits) and genetic material.

Meta-cognitive training in bipolar disorders

In this study, we establish and evaluation meta-cognitive training for patients with bipolar disorders.

Cognitive behavioral therapy for individuals at risk to develop bipolar disorders (Early CBT, DFG-funded)

In this DFG-funded multi-center study, we evaluate the efficacy of a specialized group training to prevent the developement of bipolar disorders.

A change of perspective: Mentalization-based parental counseling program

Parents with mental illness, a history of early abuse and socio-economic problems are known
to be at risk of maltreating their children. To date, parenting programs have not been
sufficiently effective in protecting children and have not reached high-risk groups of parents.
In this BMBF-funded research consortium we aim at utilizing mentalization-based intervention programs to break the transgenerational cycle of abuse by protecting children of mentally ill parents.
In a randomized controlled trial we will test the effectiveness of a mentalization-based parental counseling program implemented in routine psychiatric hospital care and thus at a particularly opportune time to reach severely mentally ill parents. This clinical trial will be accompanied by investigation of the clinical relevance of psychological and biological factors as mediators of response to interventions.
We expect that mentalization-based programs will improve parenting attitudes. Improvement will be mediated by increasing parent’s theory of mind and empathy as well as optimizing parent-child synchrony.

Drug and alternative reward cue reactivity and cognitive control in humans with substance use disorders: Psychological and neurobiological correlates and non-pharmacological interventions

A bias towards drug rewards at the expense of alternative rewards is considered a key factor contributing to the consumption of drugs and to relapse following detoxification. At the psychological level, this bias is characterized by increased craving (desire) for drug and reduced craving for alternative rewards. At the neural level, this bias is reflected by sensitization of the mesocorticolimbic reward system (including the ventral striatum, medial prefrontal cortex, and amygdala) towards drug and desensitization towards alternative reward cues. Reduced cognitive control is considered another key factor contributing to the consumption of drugs. At the neural level, reduced cognitive control is reflected in structural and functional alterations of the prefrontal control network, including the dorsolateral, ventrolateral, dorsomedial prefrontal brain regions and the anterior cingulate. Regaining control over drug consumption may to be linked both (1) to the modification of drug and alternative reward processing and (2) to improved cognitive control.
Several research projects of our group investigate how reward processing and cognitive control are altered in substance use disorder and how these alterations may be modified through non-pharmacological interventions.

Publications:

Stuke, Gutwinski S, Wiers C, Schmidt T, Gröpper S, Parnack J, Gawron C, Hindi Attar C, Sprengel S, Walter H, Heinz A & Bermpohl F (2016) To drink or not to drink: Harmful drinking is associated with hyperactivation of reward areas rather than hypoactivation of control areas in men. J Psychiatry Neurosci. 41(3):24-36

Wiers C, Kühn S, Javadi A, Korucuoglu O, Wiers R, Walter H, Gallinat J & Bermpohl F (2013) Automatic approach bias towards smoking cues is present in smokers but not in ex-smokers. Psychopharmacology 229(1):187-197

Wiers C, Shumay E, Volkow N, Frieling H, Kotsiari A, Lindenmeyer J, Walter H & Bermpohl F (2015a) Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism. Transl Psychiatry 5:648

Wiers C, Stelzel C, Gladwin T, Park S, Pawelczack S, Gawron C, Stuke H, Heinz A, Wiers R, Rinck M, Lindenmeyer J, Walter H & Bermpohl (2015b) Effects of Cognitive Bias Modification Training on Neural Alcohol Cue Reactivity in Alcohol-Dependence. American Journal of Psychiatry 172(4):335-343

Wiers C, Volkow N, Shokri-Kojori E, Tomasi D, Wang G & Baler R (2017) Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: Studies with positron emission tomography. Neuropharmacology 122:175-188