Effects of Atomoxetine on Cognitive Function in Schizophrenia
Condition: Schizophrenia; Cognition; Smoking
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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 [1].
      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 [5].

      Atomoxetine (Strattera™) 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 [6]. In contrast, atomoxetine was not found to
      increase extracellular DA in subcortical areas [6]. 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.
    

Intervention name(s): Atomoxetine (Strattera™)
Intervention type(s): Drug
Intervention MeSH terms: Atomoxetine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Schizophrenia; Prefrontal Cortical Function; Smoking; Cognition; Positive and Negative Symptoms; Tobacco; Cigarette Smoking; Dopamine