Atomoxetine as an Adjunct to Novel Antipsychotic Medication in the Treatment of Cognitive Deficits of Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia; Cognition Disorders; Cognitive Dysfunction
Study type: Interventional

Summary: 
      The purpose of this study is to:

        -  To examine wether adjunctive atomoxetine is more effective thank placebo for
           neuropsychological measures of reaction time, motor speed, psychomotor speed, sustained
           attention, learning and memory, working memory, and executive functioning. To determine
           the effect size of atomoxetine on these neuropsychological measures for follow-up
           studies.

        -  To determine if atomoxetine has short-term benefits for improving weight gain and other
           metabolic abnormalities associated with antipsychotics.
    

Detailed description: 
      Participants with schizophrenia or schizoaffective disorder who are competent to participate
      in the informed consent process and provide written informed consent will be enrolled into
      the study. Participants will undergo a psychiatric evaluation, which will include the
      ascertainment of demographic information, past psychiatric and treatment history, and
      Structured Clinical Interview for DSM-IV (SCID; First et al, 1997) diagnostic interviews. A
      best estimate diagnostic approach will be utilized in which information from the SCID is
      supplemented by information from family informants, previous psychiatrists, and medical
      records to generate a diagnosis.

      Clinical Assessments: The symptom assessments will include the Brief Psychiatric Rating Scale
      (BPRS; Overall and Gorham, 1961); Scale for the Assessment of Negative Symptoms (SANS;
      Andreasen, 1982); and Clinical Global Impression Scale (CGI; Guy, 1976). i) BPRS: the four
      positive symptom items - conceptual disorganization, suspiciousness, hallucinatory behavior,
      and unusual thought content - will be used to measure positive psychotic symptoms. These four
      items have been have been used to assess positive symptoms in previous studies (Kane et al,
      1988; Buchanan et al, 1998). The BPRS Anxiety/Depression Factor, consisting of the somatic
      concern, anxiety, guilt feelings, and depression items, will be used to assess dysphoria
      (Guy, 1976). The BPRS hostility and uncooperativeness items will be used to assess hostility.
      We are not including the suspiciousness item, which is traditionally part of the BPRS
      Hostility Factor (Guy, 1976), because we have included this item with the other positive
      symptom items. ii) SANS: the SANS total score, minus the global items, inappropriate affect,
      poverty of content of speech, and attention items, will be used to measure negative symptoms.
      The inappropriate affect, poverty of content of speech, and attention items are excluded as
      lacking construct validity and because factor analytic study results suggest that these items
      are not closely related to negative symptoms (Buchanan and Carpenter, 1994). iii) CGI: the
      CGI severity of illness item will be used to assess global changes.

      Safety Assessments: The safety assessments will include the Simpson-Angus Extrapyramidal
      Symptom Rating Scale (SAS; Simpson and Angus, 1970); Abnormal Involuntary Movement Scale
      (AIMS) (Guy, 1976); Barnes Akathisia Scale (BAS; Barnes, 1989) and Side Effect Checklist
      (SEC). i) SAS: a modified 11-item version of the SAS will be used to assess EPS. ii) AIMS: is
      a 12-item scale, with 7 items designed to assess abnormal facial, oral, extremity, and trunk
      movements; 3 global judgement items; and 2 current dental status items. iii) BAS : is a 4
      item scale assessing objective and subjective symptoms of akathisia. iv) SEC: is designed to
      assess vital signs and commonly occurring antipsychotic side effects. v) Changes in total
      body weight, body mass index, lipid profile, and serum glucose.

      Neurocognitive Assessments: The following neuropsychological tests will be administered: (1)
      reaction time, processing speed and efficiency, working memory-Digit Symbol, Number
      Sequencing, Letter Number Sequencing, Mental Arithmetic, Grooved Pegboard, Simple Reaction
      Time, Complex Reaction Time, Delayed Match to Sample from the Automated Neuropsychological
      Assessment Metric; (2) sustained attention and resistance to distractibility-Gordon's
      Continuous Performance Test; (3) learning and memory-California Verbal Learning Test and
      Brief Visual Memory Test; (4) executive functioning- Planning Test and Phonemic Fluency.

      2-Week Stabilization Phase: In the 2-week stabilization phase, participants will undergo
      baseline symptom, medical, safety, and neurocognitive assessments. The participants will
      undergo a physical examination; an EKG; and laboratory tests of major organ functions (i.e.,
      CBC, liver function tests, electrolytes, glucose, BUN/Creatinine, Urinanalysis (UA), and
      thyroid functions). A baseline antipsychotic level will be collected. All women will have a
      pregnancy test.

      8-Week Double-Blind Treatment Phase: Participants will be randomly assigned to atomoxetine or
      placebo using a permuted block randomization system. Treatment assignment order is random
      within each block, and the total number of participants assigned to each treatment are equal.
      The block sizes will vary in random sequence between 2 and 4. Thus, it will be difficult to
      ascertain the next treatment assignment, even if a participant becomes unblinded, while the
      imbalance of numbers between the treatment groups is kept within tight limits. The central
      unblinded pharmacist will be notified of the treatment assignment, and will inform unblinded
      pharmacists at the other sites about which study medication to dispense. Separate emergency
      unblinding envelopes for each participant will be kept in a locked cabinet at each dispensing
      pharmacy. In addition, an emergency unblinding tool will allow specific, designated staff
      (i.e., the P.I. and Co-P.I.) to log onto the randomization data base through the MPRC
      computer network and request treatment assignment for a specific participant. An electronic
      audit trail will be kept of all such unblinding requests. All unused unblinding envelopes
      must be returned unopened to the central pharmacy at the end of the study. Participants will
      receive biweekly BPRS, SANS, SAS, BAS, AIMS, Side effect, and vital sign assessments.
      Neurocognitive assessments will be performed at week 0 and week 8 or endpoint. Laboratory
      tests, antipsychotic levels, and the EKG will be repeated at 8 weeks.

      Medication Titration Schedule: The target atomoxetine dose for this study is 80 mg/day. The
      following titration schedule will be used: Week 1-2: atomoxetine 40 mg/day; Week 3-8:
      atomoxetine 80 mg/day. This titration schedule serves to enhance tolerability and minimize
      side effects. Participants randomized to placebo will receive an equal number of placebo
      tablets during the titration schedule.

      Concomitant Medications: Participants in the study will be allowed to continue on their
      medication regimen that they were taking prior to the trial. This will allow the results to
      be more generalizable. Patients must be stabilized on a single second generation
      antipsychotic, excluding clozapine, at an unchanged dose for at least 4 weeks prior to
      randomization. All participants must be on a stable dose of all other psychotropic
      medications for at least 4 weeks prior to randomization. No medication changes or changes in
      dose will be permitted during the study period.

      Because of atomoxetine's noradrenergic activity and it's modest ability to cause increases in
      blood pressure, participants on drugs that have the potential for vasopressor effects, such
      as venlafaxine or monoamine oxidase inhibitors, will be excluded.

      Participants will be allowed as needed (PRN) benztropine (1-6mg/day) for extrapyrmidal
      symptoms, lorazepam (1-6 mg/day) for anxiety, agitation or akathisia, and chloral hydrate for
      sleep (500-1000 mg/day). To minimize the effects of the PRN medications on test results,
      participants will not receive any of the above PRN medications 12 hours prior to
      neurocognitive testing. Additionally, participants requesting the use of benztopine or any
      antiparkinson agent will first be assessed with a movement rating scale to document the
      presence of EPS prior to receiving the antiparkinson agent and will not have received any
      antiparkinson agent within 12 hours prior to the movement assessment. Participants requiring
      routine use of benztropine and lorazepam will be excluded or withdrawn from the study.

      Maintenance of the Blind: For outpatients, study medication will be dispensed on a biweekly
      basis. They will be given two extra days of medication in case of a missed appointment.
      Inpatient subjects will receive their study medication daily from either the Spring Grove
      Hospital Center TRU or the Perry Point VAMHC central pharmacy. An unblinded pharmacist at
      each site will dispense all study medications. The blind will be broken only if a medical
      emergency requires this information. If this occurs, the participant will be withdrawn from
      the study.

      All raters, investigators and other staff will be blind to treatment assignment except for
      the pharmacist. The pharmacist does not participate in assessing any of the primary symptom
      or side effect dependent variables and conveys no information about treatment assignment to
      participants or staff except in a medical emergency.

      Compliance: Participants receiving 75% of their assigned medication will be considered
      compliant. The 75% criterion ensures that participants will receive adequate treatment to
      evaluate the comparative efficacy of atomoxetine and placebo. Outpatient compliance will be
      monitored through weekly pill counts and subject interviews. Medications will be dispensed on
      a weekly basis and will only be dispensed after compliance is assessed and all assessments
      are completed. Inpatient compliance will be monitored through inpatient medication records.
      If a participant is observed to have a compliance problem, then this will be discussed with
      the participant and a plan formulated to bring the participant back within the compliance
      parameter. For outpatients, the plan may include contacting the participant's caretaker or
      scheduling increased clinic visits. These monitoring procedures have been used in other MPRC
      studies and have resulted in high levels of compliance. Compliance patterns will be carefully
      monitored in each treatment group and will be described as part of any presentation of study
      results.
    

Intervention name(s): Atomoxetine
Intervention type(s): Drug
Intervention MeSH terms: Atomoxetine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment