Effects of Atomoxetine on Cognitive Function in Schizophrenia
Information source: Yale University
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Schizophrenia; Cognition; Smoking
Intervention: Atomoxetine (Stratteraâ¢) (Drug)
Phase: Phase 2
Sponsored by: Yale University
Official(s) and/or principal investigator(s):
Kristi A Sacco, Psy.D., Principal Investigator, Affiliation: Yale School of Medicine
The purpose of this study is to examine the effects of atomoxetine (Strattera™) on prefrontal
cognitive functioning in persons with schizophrenia. Secondarily, the effects of atomoxetine
on positive and negative symptoms and on cigarette smoking consumption in persons with
schizophrenia will be examined.
Official title: Effects of Atomoxetine on Cognitive Function in Schizophrenia
Study design: Treatment, Randomized, Double-Blind, Dose Comparison, Parallel Assignment, Safety/Efficacy Study
Primary outcome: To examine the effects of atomoxetine (Stratteraâ¢) on prefrontal cognitive functioning in persons with schizophrenia.
Secondary outcome: To examine the effects of atomoxetine on positive and negative symptoms and on cigarette smoking consumption in persons with schizophrenia.
Schizophrenia occurs in approximately 1% of the general population. Hallmark symptoms of
schizophrenia include positive and negative symptoms, as well as deficits in various aspects
of cognitive function, with particular reference to neuropsychological tasks related to the
prefrontal cortex (PFC). A leading theory with respect to these deficits in prefrontal
cortical functioning is that there is dysregulation (with overall hypofunction) of
mesocortical dopamine (DA) projections from the VTA to the prefrontal cortex (PFC) in persons
with schizophrenia, thus diminishing abilities on tasks mediated by these cortical areas .
Further, it is thought that the high rates of smoking in schizophrenia (58-88%) as compared
to a non-psychiatric population (~25%) may be due in part to the tendency of schizophrenic
patients to remediate these neurocognitive deficits by cigarette smoking, as nicotine has
been shown to improve selected cognitive deficits in persons with this illness [2-4], and in
fact such cognitive deficits may be a vulnerability factor predisposing these patients to
initiate and maintain smoking .
Atomoxetine (Stratteraâ¢) which has efficacy in treating children and adults with Attention
Deficit Hyperactivity Disorder (ADHD). It increases extracellular levels of both NE and DA
in the PFC by blocking the NE transporter (NET), where it has been shown that DA is
predominately taken up non-selectively by NET . In contrast, atomoxetine was not found to
increase extracellular DA in subcortical areas . It can be theorized that atomoxetine may
selectively increase DA in the PFC (versus subcortical areas) by inhibition of NETs in the
PFC. Accordingly, since persons with schizophrenia are thought to have a deficit of DA in the
PFC, and excessive subcortical DA function, a NET inhibitor such as atomoxetine may increase
DA-dependent PFC-mediated neurocognitive functioning, and reduce negative symptoms associated
with this disorder, without worsening positive symptoms of schizophrenia. Atomoxetine has
been shown to be safe and effective for ADHD treatment in both children and adults (Eiland,
2004). Little is known about Atomoxetine's effects in treating other psychiatric disorders,
however, it has been hypothesized that this medication may have efficacy for cognitive
remediation in the schizophrenic population (Friedman, 2004).
In order to more fully understand the effects of this medication, a double-blind,
placebo-controlled clinical trial is proposed in which sixty (60) participants with
schizophrenia who are cigarette smokers would be randomized in a double-blind manner to one
of three doses of atomoxetine [0. 0 mg/day (n=20) , 40. 0 mg/day (n=20), or 80. 0 mg/day
(n=20)]. Doses were chosen in accordance with the FDA suggested dosing, including a schedule
of initiation starting with 40. 0mg/day and a target recommended dose of 80. 0mg/day which may
be reached within a three day period. The highest recommended dose is 100 mg/day. These
doses were ultimately selected for this study because they are doses that are believed to be
well-tolerated by patients, doses that may be achieved within the two-week period of this
study, and two doses that fit with our intention to study the dose-dependent effects of this
medication. Safety and effectiveness for these doses has been determined for patients 18
years of age and older with ADD, the population that has been studied using Atomoxetine.
Should we discover that our patients with schizophrenia do not tolerate these doses well
through extensive monitoring of their physiological and clinical symptoms, or that the
maximum dose of 80. 0 mg/day cannot be reached during this time period, smaller doses will be
considered and the appropriate amendments will be submitted.
Participants would be assessed across three cognitive testing sessions over a two-week period
including baseline assessments Day 1 (prior to medication administration), on Day 8 (after
one week of medication), and again on Day 15 (after two weeks of medication). No data
currently exists in the literature regarding specific improvements in neurocognitive
performance in schizophrenia with atomoxetine, although it has been hypothesized that this
medication may be specifically helpful in schizophrenia. Therefore we believe this will be
one of the first studies of its kind. We hypothesize that atomoxetine will dose-dependently
improve deficits in PFC-related cognitive performance in persons with schizophrenia. We
secondarily hypothesize that schizophrenic smokers will demonstrate a reduction in negative
symptoms and daily cigarette consumption with atomoxetine as compared to placebo.
Minimum age: 18 Years.
Maximum age: 59 Years.
- Between ages 18 and 59;
- SCID-I for DSM-IV diagnosis of schizophrenia or schizoaffective disorder, and nicotine
- Smoking at least 15 cigarettes per day, and have expired breath CO level >10 ppm,
- Be in stable remission from active psychiatric symptomatology, (as judged by trained
clinical staff in the PRISM research program) and be on a stable dose of psychiatric
medication(s) for the past 3 months
- No current abuse or dependence of alcohol or other substances of abuse within the past
- Full scale IQ > 80,
- Presence of definable cognitive deficits of interest including VSWM, CPT, and WCST
(e. g. at least one standard deviation below average).
- Able to give informed consent for participation.
- Meet DSM-IV criteria for other major Axis I disorders besides those specified for each
- Current abuse or dependence of alcohol or substances within the last 3 months, and
subjects who are methadone maintained will be excluded.
- Full scale IQ < 80.
- Unable to give informed consent.
- Patients who are pregnant or planning on becoming pregnant will not be included in
- Patients on paroxetine, fluoxetine, and quinidine will be excluded from this study.
- Are deemed medically unsafe to take atomoxetine, as judged by the study physician.
Contraindications to the use of atomoxetine include hypersensitivity to atomoxetine,
concurrent use of monoamine oxidase inhibitors (atomoxetine should be avoided during
therapy with or within 2 weeks of discontinuing an MAO inhibitor), and patients with
narrow angle glaucoma. Precautions would include concomitant administration with CYP
2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) (which would necessitate a dose
adjustment with atomoxetine), liver disease (enhanced risk of toxicity; empiric dose
reduction is suggested based on clinical response; the drug should be avoided in acute
hepatic failure), patients with hypertension, tachycardia, or other cardiovascular or
cerebrovascular disease, patients with or at risk of hypotension , patients with
urinary retention or bladder dysfunction.
Locations and Contacts
Connecticut Mental Health Center, SAC-115, New Haven, Connecticut 06519, United States
Starting date: August 2005
Ending date: September 2007
Last updated: December 11, 2007