Proton MRS Study of SSRI-Zolpidem Interactions
Condition: Depression
MeSH terms: Depression
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The primary goal of this single-blind, placebo-controlled, within-subjects, double-scan,
      one-visit neuroimaging study is to examine the effects of the hypnotic zolpidem (Ambien®) in
      individuals who are maintained on selective serotonin reuptake inhibitors (SSRIs) for the
      treatment of major depressive disorder. Specifically, levels of the brain chemical GABA will
      be examined in the anterior cingulate and thalamus, two brain regions that play important
      roles in mediating some of the effects of depression and sleep-related drugs, respectively.
      Depressed individuals typically have lower levels of GABA than the healthy population, and
      antidepressant treatment has been shown to help normalize this neurochemical in conjunction
      with improved mood. Given that individuals maintained on SSRIs often are prescribed
      sedative/hypnotics to treat concurrent insomnia, understanding a possible neurochemical
      interaction between them, whether beneficial or harmful, is important for informing
      evidence-based treatment strategies to treat the co-morbid patient. Zolpidem's effects on
      GABA in participants who are maintained on SSRIs will be compared to baseline GABA levels in
      these individuals (i.e., following placebo administration). Two separate scanning sessions
      lasting approximately 45-60 min each will take place within one single study visit in order
      to obtain these measurements using proton magnetic resonance spectroscopy (1H MRS). This type
      of neuroimaging is like an MRI in that it is non-invasive, but it permits us to obtain
      information about chemicals in the brain. A secondary goal of this study is to compare the
      subjective drug effects, or how individuals feel, following the intervention. These measures
      will be used to determine the existence of brain-behavior relationships in order to assess
      the extent to which modulating GABA with zolpidem has effects on mood states in depressed
      participants. Collectively, this study will contribute to our understanding of how these
      drugs exert their effects when one is administered in the presence of the other, and it will
      demonstrate that imaging is an important tool for informing us about how drug effects in the
      brain ultimately result in behavior.
    

Detailed description: 
      Sleep disturbances are a primary complaint in at least 35% of depressed patients, and upwards
      of one third of individuals taking selective serotonin reuptake inhibitors (SSRIs) to treat
      major depressive disorder (MDD) also take prescription sleep-aids. Several controlled trials
      have documented the effectiveness of combining hypnotics with antidepressants in order to
      improve disordered sleep in MDD, but it is unclear if benzodiazepines and related drugs can
      cause or worsen depression. A recent study in which nightly administration of the
      benzodiazepine-like hypnotic zolpidem (Ambien®) was added to the SSRI citalopram demonstrated
      that while depressive symptoms were not improved by the combination treatment, this regimen
      also did not worsen symptoms in a clinically significant manner. However, the adverse events
      reported from that trial---although limited---confirm a number of case reports documenting
      psychiatric incidents related to this drug combination, and these accounts suggest
      collectively that the potential exists for zolpidem-antidepressant interactions.

      Within the brain, SSRIs are believed to exert their actions primarily in cortical regions
      where they increase GABA levels. Conversely, we and others have shown that zolpidem and
      conventional benzodiazepines reduced GABA levels in the thalamus and occipital cortex,
      respectively. Moreover, the zolpidem-induced reduction in GABA was accompanied by increased
      self-reported ratings of generally unpleasant or aversive-like subjective feelings,
      suggesting a relationship between them may exist. A possible implication of this finding is
      that administration of benzodiazepine-like drugs during SSRI treatment may exacerbate
      negative affect or depressed mood states by countering the restorative effects of SSRIs on
      dysfunctional GABA in MDD. The present study begins to address this hypothesis by employing
      proton magnetic resonance spectroscopy (1H MRS) at a field strength of 4 Tesla to assess the
      effects of a therapeutic dose of zolpidem (10 mg) administered acutely to volunteers
      maintained on stable SSRI treatment for the treatment of MDD.

      The primary aim of the study outlined in this protocol is to investigate drug-induced changes
      in the 1H MRS-visible pool of GABA in single voxels located within the anterior cingulate and
      thalamus following acute administration of zolpidem relative to placebo in depressed
      volunteers. The secondary aim is to collect information regarding the subjective effects
      engendered by each of the interventions. This information, in conjunction with data showing
      how each treatment affects brain chemistry, will help us understand the neurobiological
      mechanisms that may contribute to alterations in mood states when this popular hypnotic is
      combined with stable SSRI treatment.

      A total of 20 depressed but otherwise healthy volunteers will be enrolled at McLean Hospital
      to participate in this 2-visit (1 screening visit, 1 study visit) single-blind,
      placebo-controlled study, double-scan study. Participants will be between 21 and 40 years of
      age, they can be either male or female, and there are no restrictions regarding ethnic
      background. Participants will be maintained on stable SSRI therapy for the treatment of MDD,
      but they will not meet DSM-IV criteria for other major psychiatric disorders (including any
      substance abuse and/or dependence). They cannot report a family history of alcoholism,
      medical conditions that could affect drug disposition, and they will not be taking any
      medications other than their SSRIs. Participants also cannot have any MRI scanning
      contraindications (including pregnancy). They must be able to provide informed consent.

      Volunteers will visit the laboratory for a screening visit during which s/he will sign the
      informed consent form, and undergo both physical and psychiatric exams, as well as a
      structural screening MRI. The second visit will involve pre-study assessments, a standard
      breakfast, questionnaire sets, drug treatment, two scanning sessions, and lunch. After a
      baseline period during which participants will answer computerized questionnaires, they will
      receive a study medication (10 mg zolpidem or placebo) and then answer the questionnaires.
      Just prior to beginning the approximately 45-min scanning session (45-min post-medication),
      participants will be transported to the 4T scanner in a wheelchair and be positioned within
      the scanner. A small blood sample will be taken after the scan. In the afternoon,
      participants will receive another treatment and then answer the questionnaires. Just prior to
      beginning the approximately 45-min scanning session (45-min post-medication), participants
      will be transported to the 4T scanner in a wheelchair and be positioned within the scanner. A
      second small blood sample will be taken after the scan. The scanning session will be followed
      by hourly questionnaire sets until the end of the 8-hr visit at which point participants will
      take a taxicab home.

      An exhaustive screening procedure ensures that participants entering the study have no
      contraindicating conditions. All procedures are performed by experts specifically trained in
      their respective areas to minimize risks, discomfort, and adverse events. Participants are
      well informed of the potential risks of the study. The informed consent form is detailed and
      explicit. Participants are provided with unlimited time to read the consent and study
      personnel review it in detail before participants sign. In addition, participants have the
      opportunity to ask questions before, during, and after consent and at any time during the
      study. Participants can earn up to a total of $250 for completing the study.
    

Intervention name(s): Zolpidem; Placebo
Intervention type(s): Drug; Other
Other intervention name(s): Ambien
Intervention MeSH terms: Zolpidem
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Basic Science