Effect of Quetiapine on Brain Activity Patterns in Patients With Heightened Risk of Bipolar Disorder

Cognitive Control and Functional Connectivity During Resting State in Patients With Heightened Risk of Bipolar Disorder - a Quetiapine Challenge

Bipolar disorder (BPD) is often misdiagnosed as unipolar depression. This leads to inadequate treatment and can have negative impact on the course of the disease. There is now preliminary evidence that patients with unipolar and bipolar depression as well as healthy individuals with a heightened risk of BPD can be distinguished from each other based on their brain activity patterns and functional connectivity during resting state.

However, the impact of pharmacological treatment on these functional brain measures have not yet been clarified. For common antidepressants it has been shown that they seem to normalise aberrant brain activity patterns and functional connectivity. The problem is that some antidepressants can induce mania or accelerate pathological cycling in depressive patients with unrecognised BPD. Therefore, pharmacological drugs with mood-stabilising properties such as quetiapine are more and more prescribed. Although the effectiveness and tolerability have been proven, the neuronal effects of these adjunctive treatments are not clear. The aim of the study is thus to investigate the impact of quetiapine on measures of brain activity in depressive patients with a heightened risk of BPD. Moreover, the investigators want to examine whether the investigators can distinguish depressive patients with a heightened risk of BPD from depressive patients without a heightened risk of BPD using neuroimaging techniques, and whether these measures can predict the course of the disease.

Study Overview

• Status: Unknown
• Conditions: Depression; Bipolar Disorder
• Intervention / Treatment: Drug: Quetiapine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 54
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lina Winkler, M.Sc.; Email: liwinkler@ukaachen.de

Study Locations

• Germany
  • NRW
    • Aachen, NRW, Germany, 52074 Aachen
      • Clinic for psychiatry, psychotherapy and psychosomatic, RWTH Aachen University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• diagnosis of depressive episode (F32.X, F33.X) with duration less than < 6 months
• max. three previous episodes of illness
• no manic or hypomanic episodes in the past
• current treatment with one antidepressant
• MRI-compatibility
• unequivocal understanding of study information and autonomous consent
• for women: negative pregnancy test

• for risk-group:

  • 14 or more points on hypomania checklist (HCL-32)

  • additionally at least one of the following four risk factors:

    1. positive family history (i.e. first or second order relatives with BPD, schizoaffective or schizophrenic psychosis, mania or suicide attempt)
    2. initial manifestation before 30 years of age
    3. initial manifestation after childbirth
    4. suicide attempt in the past

Exclusion Criteria:

• additional diagnoses of psychiatric disorders (Organic, including symptomatic, mental disorders [F0X.X]; mental and behavioural disorders due to psychoactive substance use [F1X.X]; schizophrenia, schizotypal and delusional disorders [F2X.X]; mental retardation [F7X.X])
• chronic or acute physical disease
• individuals who are in a dependence- or work-relation with the sponsor
• limited or annulled legal capacity
• court or administrative order for hospitalisation
• for women: pregnancy, nursing period or unsafe contraceptive methods

• for the risk group:

  • clinical relevant changes in clinical chemistry, hematology, EEG or EKG
  • known contraindication for quetiapine (e.g. hypersensitivity to [active] ingredient[s], HIV-protease inhibitors, antimycotics, antibiotics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Quetiapine; 18 patients of the risk-group will receive quetiapine (Seroquel Prolong (c)) for 8 weeks in adjunction to their antidepressant standard therapy. Group allocation is randomised and double-blind. Dosages: 50mg (day 1-3), 100mg (day 4-6) and 150mg (from day 7 onwards). Administration: Quetiapine will be given once daily before bedtime, not together with a meal and swallowed as a whole.	Drug: Quetiapine; See information in arm description.; Other Names: Seroquel Prolong
Placebo Comparator: Placebo; 18 patients of the risk-group will receive placebo for 8 weeks in adjunction to their antidepressant standard therapy. Group allocation is randomised and double-blind. The placebo does not contain any psychoactive substance.	Drug: Placebo; See information in arm description.
No Intervention: Control-group; 18 depressive patients without a heightened risk for BPD will not receive any medication apart from their standard antidepressant therapy (control-group).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BOLD signal during a combined inhibition-reward-task	At baseline (day 0) the risk-group and control-group will be compared on BOLD signal (and behavioural data) during a combined inhibition-reward-task (neuronal correlate of cognitive control) (fMRI). These measures will be obtained once again at visit 4 (day 56) in the risk-group to evaluate the impact of quetiapine (i.e. change from baseline measure).	Baseline (Day 0)
Functional connectivity in the default mode network during resting state (rstfMRI)	At baseline (day 0) the risk-group and control-group will be compared on functional connectivity in the default mode network during resting state (rstfMRI).	Baseline (Day 0)
Structural differences in brain anatomy (MRI)	At baseline (day 0) the risk-group and control-group will be compared on structural differences in brain anatomy (MRI).	Baseline (Day 0)
Structural integrity of nerve fibres (DTI)	At baseline (day 0) the risk-group and control-group will be compared on structural integrity of nerve fibres (DTI).	Baseline (Day 0)
Effect of quetiapine on brain measures	After the quetiapine/ placebo intervention the risk-group will be compared whether there are changes from baseline in outcome measures 1 to 4.	Visit 4 (Day 56)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of quetiapine	Blood samples of the patients of the risk group will be obtained to analyse the plasma levels of quetiapine.	Visit 4 (Day 56)
Change over time in affect and psychopathology	All patients (risk-group and control group) will be assessed with questionnaires tapping affect and psychopathology (MADRS, YMRS, CGI, PANSS, BDI-II, Bf-S, SWN-K, EPS, BARS, C-SSRS, NGASR). These measures will be obtained at three different time points to evaluate the respective change over time.	Baseline (Day 0), Visit 4 (Day 56), Follow-up (after 1 year)
Personality	All patients (risk-group and control group) will be assessed with questionnaires of personality (TCI-R, BIS-15, RS-13).	Baseline (Day 0)

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Study Director: Frank Schneider, Univ.-Prof., University Hospital, Aachen

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Anticipated): May 1, 2017
• Study Completion (Anticipated): May 1, 2018

Study Registration Dates

• First Submitted: April 22, 2015
• First Submitted That Met QC Criteria: May 18, 2015
• First Posted (Estimate): May 21, 2015

Study Record Updates

• Last Update Posted (Estimate): May 21, 2015
• Last Update Submitted That Met QC Criteria: May 18, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Bipolar and Related Disorders; Bipolar Disorder; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Quetiapine Fumarate
• Other Study ID Numbers: EK018/15