Effects of Quetiapine on Ultrastructural Hippocampal and Neurochemical Changes in Patients With Bipolar Disorder: Searching for Antidepressant and Mood Stabilising Neurophysiology

The aim of the study was to determine the pharmacological induced equivalents of neurogenesis and synaptic sprouting in the hippocampus, localized volume changes, changes in water content and neurochemical changes in the medial temporal regions.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: Seroquel

Detailed Description

Quetiapine is an antipsychotic that has mood stabilizing and antidepressant effects (Vieta, 2005). Animal studies showed that the expression of neurotrophins and the subsequent modulation of the neuroplastic processes, including neurogenesis in the hippocampus, play a key role in the mechanism of mood stabilizing (Kim et al., 2004) and antidepressant (Santarelli et al., 2003). Since atypical antipsychotics also have antidepressant and mood stabilizing effect, it is hypothesized that the common mechanism of action in all three pharmacological classes is neurogenesis and synaptic sprouting in the hippocampal region. Thus, the aim of this study was to test this hypothesis.

Quetiapine was associated with antidepressant and mood stabilizing effects in patients with bipolar disorder (Vieta, 2005). The evidence based on animal studies shows that administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor in the hippocampi. This may explain the improved cognitive symptoms in patients with schizophrenia and depression (Luo et al., 2005, Park et al, 2006).

The aim of the study was to determine the pharmacological induced equivalents of neurogenesis and synaptic sprouting in the hippocampus, localized volume changes, changes in water content and neurochemical changes in the medial temporal regions.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Aachen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age ranging 18 - 55 years old
• intelligence coefficient (IQ) of minimum 85 as estimated by MWT-B
• MRI compatibility
• for healthy volunteers - no DSM-IV diagnosis
• patients should have had a diagnosis of bipolar disorder in accordance with DSM-IV.

Exclusion Criteria:

• substances or alcohol abuse or dependence (except caffeine and nicotine) at enrollment;
• medical conditions that would affect absorption, distribution, metabolism or excretion of study treatment;
• unstable or inadequately treated medical illness (diabetes, angina, pectoris, hypertension);
• diabetes mellitus
• patients who in the opinion of the investigator pose a risk of suicide or danger to self or others,
• patients who known intolerance or lack of response to Quetiapine fumarate,
• patients who use of any of the cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, nelfinavir, ritonavir, fluvoxamine and saquinavir) in the 14 days preceding enrollment,
• patients who use of any of the cytochrome P450 inducers (phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort and glucocorticoids) in the 14 days preceding enrollment,
• current treatment of Quetiapine or use of mood stabilizer or antidepressant as co-medication throughout the study.
• lack of inform consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Healthy volunteers; MRI compatible, no present or past DSM-IV diagnosis
Active Comparator: patients with Bipolar Disorder; MRI compatible, presence of DSM-IV diagnosis for Bipolar Disorder	Drug: Seroquel; for 4 weeks, 300 - 800 mg per day in 2 doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anisotropy in hippocampal formation detected with Diffusion Tensor Imaging (DTI)	Detection of pharmacologically induced equivalents of neurogenesis and synaptic sprouting in the hippocampal region.	after 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety and tolerability of medical treatment	Observation of adverse events and tolerability assessed by vital signs and clinical chemistry	every time during the study
Detection of pharmacologically induced localised volume changes	Measurement with 3D MPRAGE (structural scan)	after 6 weeks
Detection of pharmacologically induced localised changes in water content	differentiation between neurogenesis/sprouting and mere water intake	after 6 weeks
Detection of pharmacologically induced neurochemical changes in the medial temporal regions (Glx and NAA, choline)	Measurement of glutamate and N-acetylaspartate in the medial temporal lobe with MRS	after 6 weeks
Detection of pharmacologically induced differential activation during an episodic memory task measured with fMRI.	Measurement of BOLD response using fMRI during an episodic memory test	after 6 weeks

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Study Director: Klaus Mathiak, Prof MD, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Aachen

Publications and helpful links

General Publications

• Basser PJ, Mattiello J, LeBihan D. Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B. 1994 Mar;103(3):247-54. doi: 10.1006/jmrb.1994.1037.
• Luo C, Xu H, Li XM. Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. Brain Res. 2005 Nov 23;1063(1):32-9. doi: 10.1016/j.brainres.2005.09.043. Epub 2005 Nov 4.
• Vieta E. Mood stabilization in the treatment of bipolar disorder: focus on quetiapine. Hum Psychopharmacol. 2005 Jun;20(4):225-36. doi: 10.1002/hup.689. Erratum In: Hum Psychopharmacol. 2005 Jul;20(5):375.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: March 2, 2012
• First Submitted That Met QC Criteria: March 9, 2012
• First Posted (Estimate): March 13, 2012

Study Record Updates

• Last Update Posted (Estimate): March 13, 2012
• Last Update Submitted That Met QC Criteria: March 9, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Bipolar Disorder; quetiapine; Magnetic Resonance Spectroscopy; hippocampus; Diffusion Tensor Imaging,; Volume Brain Morphometry; effect of quetiapine on hippocampal neurogenesis
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Bipolar and Related Disorders; Disease; Bipolar Disorder; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Quetiapine Fumarate
• Other Study ID Numbers: D1449L00030; 07-010 (Sponsor's Code); 2007-000479-40 (EudraCT Number); EK 024/07 (Other Identifier: Ethics Commettee Number)