Relationships between altered prefrontal cortical dopamine, norepinephrine and some cognitive impairments of schizophrenia supports and approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine. Atomoxetine, a selective norepinephrine re-uptake inhibitor, produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine. Given this, we are evaluating atomoxetine's cognitive effects in a pilot placebo controlled trial in patients with schizophrenia. Moreover, an fMRI investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine.
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Treatment
- Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Study Primary Completion Date: April 2007
Participants carrying a diagnosis of schizophrenia and receiving treatment with one of the following antipsychotic medications are eleigible for participation: risperidone, olanzapine, quetiapine, aripirazole. Following consent, participants will be observed for 4 weeks to ensure stability of their symptoms. Following this, there will be baseline assessments of symptom severity, cognitive ability, functional ability and an fMRI scan. Following this, participants will be randomly assigned to receive treatment with 40 mg of atomoxetine or placebo daily during a double-blind parallel designed four week treatment period, following which the dose of atomoxetine will be increased to 40 mg twice day (or matching placebo) for an additional 4 weeks. The cognitive assessment battery and MRI will be repeated following 8 weeks of treatment.
- Drug: Atomoxetine
- Dose escalation from 40 mg to 50 mg of Atomoxetine active treatment.
Arms, Groups and Cohorts
- Active Comparator: Atomoxetine
- Atomoxetine 40 mg compounded into capsules.
- Placebo Comparator: Placebo
- Inactive matching compounding of placebo capsules
Clinical Trial Outcome Measures
- Composite score on the Brief Assessment of Cognition in Schizophrenia
- Time Frame: 8 weeks
- Cognitive performance as measured by the BACS
- Brain activation measured by functional magnetic resonance imaging
- Time Frame: 8 weeks
- Differences between changes in brain oxygenation level dependent imaging measures between placebo and Atomoxetine
Participating in This Clinical Trial
1. Subjects will be males and females between the ages of 18 and 65 2. In good general medical health 3. For patient subjects, a DSM-IV diagnosis of schizophrenia, any subtype 4. Currently in remission or with stable, unchanging residual symptoms 5. Receiving treatment with olanzapine, aripiprazole, risperidone, or quetiapine as their antipsychotic medication at a stable dose for a minimum of eight weeks. 6. Able to complete neurocognitive tests 7. Able to give informed consent. All subjects will be required to have at least an 8th grade reading level and/or a full-scale IQ of at least 85 as assessed by the Wide Range Achievement Test (WRAT). Exclusion Criteria:
1. Recent history (within previous year) of serious suicide, homicide, or physical violence, or current suicidal or homicidal thoughts 2. Any axis I DSM-IV diagnosis in addition to schizophrenia or schizoaffective disorder except substance abuse in remission 3. History of severe head trauma, neurological disorder, or medical illness which may contribute to the subjects' psychiatric symptoms or cognitive impairment 4. Medical illness which requires taking any medication that has CNS activity which is known to impair cognition. 5. Untreated or unstable hypertension. 6. Coronary artery disease. 7. Receiving concomitant anticholinergic drugs, antidepressants or mood stabilizers. If patient subjects are receiving benzodiazepines, they must be short or intermediate acting (e.g. alprazolam, lorazepam) and must be held 48 hours prior to cognitive testing 8. Unable to give informed consent 9. History of developmental disorder or less than an eighth
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: 65 Years
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Research Foundation for Mental Hygiene, Inc.
- Eli Lilly and Company
- Provider of Information About this Clinical Study
- Principal Investigator: Joseph Friedman, Principal Investigator – Research Foundation for Mental Hygiene, Inc.
- Overall Official(s)
- Joseph I Friedman, MD, Principal Investigator, Pilgrim Psychiatric Center
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711.
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