This study will evaluate whether Atomoxetine improves cognition in healthy volunteers as
well as patients with schizophrenia. Atomoxetine is a drug that has been FDA approved for
Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter
dopamine in the frontal cortex of the brain.
Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of
cognitive function. For example, COMT inhibitors such as tolcapone can improve working
memory/executive function. Similarly, modafinil, a catecholaminergic agonist with NA
reuptake blocking properties, was also shown to improve delay-dependent working memory in
mice. Differences in the response between individuals might be related to a number of
factors, including variations in the genes. The recent finding that a polymorphism in the
catechol-O-methyl-transferase (COMT) gene, which produces a change in enzyme activity,
accounts for 4% of the variance in performance of working memory tasks in humans suggest
that COMT genotype may predict response to COMT inhibitors or to other dopaminergic agonists
that increase catecholaminergic function in the frontal cortex. In the present
investigation our goal is to examine, in normal controls and patients with schizophrenia,
the effect of atomoxetine, a selective noradrenaline reuptake inhibitor that increases
extracellular levels of dopamine in the frontal cortex, on cognitive function. We predict
that both normal controls and patients with schizophrenia with the val/val genotype, which
present higher COMT activity and, thus, lower extracellular dopamine concentrations in the
frontal cortex, will have a significant improvement in working memory. Furthermore, in
conjunction with other NIMH imaging protocols, we would like to examine the
neurophysiological correlates related to working memory. We predict improved measures in
prefrontal efficiency in subjects and patients specifically with the val/val genotype. The
present protocol will provide new insights on the importance of this genetic polymorphism in
the regulation of aminergic-controlled cognitive function in normal individuals.
Furthermore, this protocol will test whether atomoxetine offers a new treatment, based on
genotype, for cognitive impairment in schizophrenia. An IND waiver will be requested for
the present study.
- INCLUSION CRITERIA:
- Prior participation under NIH protocol # 95-M-0150, or new normal volunteers or
schizophrenic patients that meet criteria for NIH protocol # 95-M-0150.
- No active Axis I or Axis II diagnosis in normal volunteers.
- Age range: 18-45 years.
- Normal EKG and blood pressure readings.
- Normal volunteers with an active Axis I or Axis II disorder or patients with an Axis
I diagnosis other than schizophrenia or schizoaffective disorder obtained either from
prior SCID interview in Protocol 95-M-0150 or through a screening interview will be
- Subjects with a history of cardiovascular disease, liver disease and other serious
medical illnesses, and untreated or uncontrolled hypertension will be excluded
because of the potential for drug-drug interaction or because of the potential
deleterious effect of the drug on the medical condition. An electrocardiogram, blood
pressure, pulse rate, toxicological screen, cell blood count and metabolic panel
including LFTs will be checked on all subjects prior to participation in the study.
Any subject with an electrocardiogram deemed abnormal by a cardiologist or with
sustained systolic blood pressure of 150 mmHg or above, diastolic blood pressure of
100 mmHg or above will be excluded from the study.
- Schizophrenic patients taking a COMT inhibitor, any illicit drugs of abuse, or MAO
inhibitors will be excluded. Patients taking paroxetine, fluoxetine, bupropion,
tricyclic antidepressants, albuterol, modafinil, stimulants or pressor agents will be
excluded from the study. No medication will be stopped in order to participate in the
- Normal control subjects taking any medication other than occasional NSAID or with
recent history of illicit drug or alcohol abuse will be excluded. Normal controls on
contraceptive medication will be excluded from the study.
- Pregnant women: Women of childbearing potential will undergo a urine pregnancy test
the day the study initiates and they will be screened by history for the possibility