Nicotinic Receptor Augmentation of SSRI Antidepressants
Condition: Depressive Disorder
MeSH terms: Depressive Disorder; Depression
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether the nicotinic receptor antagonist
      mecamylamine hydrochloride (Inversine) can augment SSRI-refractory major depression symptoms,
      quality of life and cigarette smoking outcomes. A total of n=60 SSRI-refractory patients who
      are on stable doses of an SSRI are being recruited into this 8-week double-blind, randomized,
      placebo-controlled trial.
    

Detailed description: 
      Mecamylamine for the Treatment of Depression in SSRI-Treated Partial Responders

      A. Purpose

        1. To compare the nicotinic receptor antagonist mecamylamine (MEC) to placebo for the
           treatment of depressive symptoms in nicotine-dependent, cigarette smokers and in
           non-smokers who are maintained on, and are partial responders to serotonin-selective
           reuptake inhibitors (SSRIs).

        2. To determine the effects of MEC versus placebo on cigarette smoking behavior in
           SSRI-maintained depressed smokers and non-smokers.

      B. Background The co-morbid rates of nicotine dependence in patients with major depression
      are estimated to be 50-60% [1-3]. Smokers with a history of major depression disorders have
      great difficulty quitting smoking compared to smokers without a history of major depression
      [2, 4]. Furthermore, smokers with a history of depression appear to be at substantial risk
      for the emergence of depressive symptom exacerbation, typically within one month after
      smoking cessation [2, 5-7], though this phenomenon has been recently questioned [8]. Recent
      estimates are that nearly 45% of all cigarettes consumed in the USA are by individuals with
      mental illness [10].

      These clinical relationships between tobacco use and depression do suggest some important
      effects of nicotine and nicotinic receptor mechanisms in major depressive disorder. Thus, it
      has been postulated that nicotine and cigarette smoking may exert antidepressant effects [4,
      5, 11, 12], presumably mediated through stimulation of nicotinic acetylcholine receptor
      (nAChR) systems. In fact, it has been shown in an open-label trial that nicotine patch could
      produce substantial antidepressant effects with 3 days of transdermal nicotine administration
      in non-smoking subjects with major depression [12].

      Based on the results of several studies, serotonin-selective reuptake inhibitors (SSRIs) have
      not shown promise as anti-smoking pharmacotherapies [5, 9]. However, bupropion and several
      SSRIs (including fluoxetine, sertraline, fluvoxamine and paroxetine) have been shown using in
      vitro studies to bind, at clinically relevant concentrations, to the non-competitive ion
      channel site of the high-affinity nAChR [11], the same site to which mecamylamine (MEC)
      binds. Since MEC has been shown to have mood-enhancing effects in a controlled smoking
      cessation study examining the combination of MEC and NTP [13], and recently to have
      mood-stabilizing properties in patients with bipolar symptoms [14], we speculate that the
      combination of MEC with an SSRI may have significant positive effects on both depressive
      symptoms and smoking. In on-going work at Yale using transgenic mice with deletion of the
      alpha 2-subunit of the nAChR, Picciotto and colleagues have demonstrated that the
      antidepressant effects of the tricyclic antidepressant amitriptyline in a learned
      helplessness model of depression are abolished in alpha 2-subunit knock-out mice (which lack
      functional high-affinity nAChRs containing the alpha 2-subunit) compared to the control
      background (C57B/L) mouse strain (M.R. Picciotto, Ph.D., personal communication). This
      finding suggests that the presence of functional nAChRs is necessary, but not sufficient, for
      generation of antidepressant responses to amitriptyline, an antidepressant that has also been
      shown to non-competitively inhibit high-affinity nAChRs [11]. Thus, since both SSRIs and MEC
      bind to nAChRs and since nAChRs may mediate the effects of most clinically effective of
      antidepressants, it is possible that the combination of MEC with an SSRI may serve to augment
      partial antidepressant responses to SSRIs, and reduce the drive to smoke in these patients,
      either primarily or secondarily.

      The current study proposes to evaluate the nicotinic receptor antagonist mecamylamine
      (Inversine®) in comparison to matching placebo, in the treatment of depressive symptoms in
      smokers and non-smokers with major depressive disorder. These subjects would be maintained on
      antidepressant treatment with serotonin-selective reuptake inhibitors, and continue to
      exhibit at least mild depressive symptoms (e.g. partial antidepressant responders). The
      primary outcome measure will be depressive symptoms at the end of the 12-week trial (e.g. a
      50% decrease in depressive symptoms) compared to baseline. Furthermore, we will compare the
      effects of mecamylamine versus placebo on smoking behavior in these SSRI-maintained partial
      responders.

      C. Specific Location of Study: The study will be conducted at the Program for Research in
      Smokers with Mental Illness (PRISM), Substance Abuse Center, Connecticut Mental Health Center
      (CMHC), New Haven, CT.

      D. Probable Duration of Project - (3/1/02-12/31/06)

      E. Research Plan and Data and Safety Monitoring Plan Study Medication: Mecamylamine
      hydrochloride has been on the market since 2000 and is FDA approved for the treatment of
      hypertension. Mecamylamine HCI is currently made by Targacept, Inc. We will purchase
      Mecamylamine study medication through local pharmacies and the CMHC pharmacist will make
      placebo capsules.

      Inclusion Criteria:

        1. Have a history of major depression based on SCID, and currently maintained on an SSRI
           antidepressant with no dose changes in the past three months.

        2. May have a history of bipolar disorder, with no evidence of manic or hypomanic episode
           in the past year and currently in depressive phase of Bipolar I or II disorder.

        3. May have a history of depression with psychotic features with no current evidence of
           psychotic features in the past year and not currently treated with an antipsychotic
           medication.

        4. Current depressive symptoms will be assessed to be mild to moderate, and Beck Depression
           Inventory scores of 10-30.

        5. Capable of giving informed consent.

        6. For smoking subjects, meet DSM-IV criteria for nicotine dependence, smoking at least 15
           cigarettes/day, biochemically verified.

        7. For smoking subjects, no intention to quit smoking.

        8. Adults age 18-65.

      Exclusion Criteria:

        1. A history of alcohol or drug dependence or abuse in the six months prior to study entry.

        2. A history of schizophrenia or schizoaffective disorder, or currently treated with
           antipsychotic medications.

        3. A history of a manic or psychotic episode within the past year.

        4. Currently treated with antidepressants other than SSRIs.

        5. Presence of suicidal or homicidal ideation at the time of study entry, and/or evidence
           of significant impairment in functioning that would necessitate treatment of the subject
           in a non-outpatient setting.

        6. If female, currently pregnant (as assessed by urine pregnancy test at baseline and as
           appropriate thereafter), or planning to become pregnant during the course of the trial.
           7) Current history of glaucoma (open- and closed angle), prostatic hypertrophy, urethral
           obstruction, cerebral arteriosclerosis and pyloric stenosis..

      8) A history of hypotension (e.g. systolic blood pressure less than 90mm Hg). 9) A history of
      known contraindications to Mecamylamine (Inversine) 10) For smokers, currently taking
      bupropion (either Wellbutrin or Zyban preparations) or nicotine replacement therapies, or
      currently involved in smoking cessation behavioral therapies.

      Study Design:

      Subjects who have a history of major depression partially responsive to an SSRI and either
      dependent cigarette smokers (N=30) or non-smokers (N=30) will be recruited into this study.
      The study design is a 2 (smoking status) x 2 (study medication) configuration for 8 weeks.

      Treatments Groups:

      Smoker Subjects:

        1. Placebo (Placebo tablets, one po bid, N=15)

        2. Mecamylamine (10.0 mg/day as 5 mg po bid; N=15)

           Non-Smoker Subjects:

        3. Placebo (Placebo tablets, one po bid, N=15)

        4. Mecamylamine (10.0 mg/day; as 5.0 mg po bid, N=15)

      Subjects will begin MEC in Week 2 at 0.0/5.0 mg qd (2 tablets po qd), which will be increased
      to 0.0/5.0 mg po bid (2 tablets po bid) during Day 8 of the trial (Week 2). Study medications
      will be continued until the end of Week 8. If the subject finds the study medication,
      mecamylamine, to be helpful, this information can be shared with the subject's physician to
      enable a decision about whether mecamylamine should be continued after the study, since it is
      available by prescription from the subject's physician. Both smoker and non-smoker
      participants would receive supportive therapy intervention for the treatment.

      G. Economic Considerations:

      Subjects would be paid $25.00 for completion of baseline assessments and $25.00 for
      successful completion of the 8-week trial. Thus, subjects could earn up to $50.00 for their
      study participation.

      III. HUMAN SUBJECTS A. Subject Population, Recruitment: A total of 60 smoking (n=30) and
      non-smoking (n=30) subjects with current depressed and treated with a serotonin-selective
      reuptake inhibitor (SSRI) will be recruited.

      B. Source of Research Material: Study medication (Mecamylamine 2.5 mg) will be purchased from
      local pharmacies. Placebo medication will be prepared by CMHC pharmacist using encapsulation.

      C. Consent Procedures: Subjects will be recruited for participation and provided with a
      written consent form requiring their signature. Only subjects capable of giving informed
      consent and scoring 80% on post-consent test will be admitted into the study.

      D. Risks: The primary risks in this study are those associated with the study medication,
      mecamylamine. Side effects associated with mecamylamine include constipation, dry mouth,
      nausea and vomiting, orthostatic hypotension (dizziness when standing) and, very rarely,
      unusual muscle movements and seizures. In our experience, constipation appears to be the most
      common side effect.

      Because the study medication, mecamylamine, may cause a drop in blood pressure, we plan to
      monitor each subject's blood pressure (sitting and standing) on a weekly basis. If a subject
      develops a systolic blood pressure < 100mm Hg, we will plan to monitor blood pressure twice
      weekly. If a subject develops a systolic blood <90mm Hg, we will plan to discontinue study
      medication. Lastly, if a subject experiences a systolic blood pressure drop >10mm Hg, we will
      plan to monitor twice weekly or until the problems resolves.

      In addition, we will exclude potential subjects with a history of glaucoma, prostatic
      hypertrophy, urethral obstruction, cerebral arteriosclerosis, pyloric stenosis, and a history
      of hypersensitivity to mecamylamine. There is the rare chance that if a smoking subject quit
      smoking during this study, the subject could have a worsening of depressive symptoms.

      E. Protection of Subjects: All reports generated from the data obtained through this study
      will protect the confidentiality of the subjects who participate in this study. In case of a
      medical emergency, the medication group blinding can be broken by the principal investigator.
      If a depressed subject shows clinical deterioration, Dr. George and Ms. Vessicchio will
      determine: 1) whether subject can remain in the study, or; 2) whether a higher level of care
      is needed.

      G. Confidentiality: All reports generated from this study will not contain any identifying
      information about the participants.
    

Intervention name(s): Mecamylamine hydrochloride (Inversine)
Intervention type(s): Drug
Intervention MeSH terms: Mecamylamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: major depressive disorder,; serotonin selective reuptake inhibitor,; mecamylamine,; controlled trial,; cigarette smoking