Effects of Aripiprazole and Haloperidol on Mesolimbic System Functioning
Condition: Psychosis; Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      The main objective is to investigate if the brain activation signature of a typical
      antipsychotic agent is dissociable from a newer drug with a pharmacological profile that
      differs from both typical and atypical antipsychotics since it is a potent partial D2
      agonist. The method used to study this will be functional magnetic resonance imaging (fMRI).
    

Detailed description: 
      The advent of neuroimaging has opened a new window into the human brain. Here, we propose to
      investigate if the activation signature of a traditional antipsychotic agent is dissociable
      from a new drug with a unique pharmacological profile that differs from both typical and the
      more recent atypical antipsychotics. The introduction of aripiprazole is of interest because
      while clinically it has all the features of an atypical antipsychotic (antipsychotic effect
      with very low motor side effects) it differs from all other antipsychotics in that it is a
      partial D2 receptor agonist.

      Antipsychotic drugs can be classified as either typical or atypical. Typical antipsychotics,
      like haloperidol, are dopamine antagonists which are clinically efficacious when they occupy
      60-70% of the striatal dopamine D2 receptors, and extra pyramidal side (EPS) effects begin to
      show when D2 receptor occupancy (D2RO) is >80%. Atypicals, like the typicals, are
      efficacious; however, they are unique insofar as they have a low affinity for dopamine
      receptors, target other neurotransmitter systems (in particular the serotonergic system), and
      show low motor side effects. While most atypicals are dopamine antagonists, a new class of
      antipsychotics characterized as partial agonists have emerged. Aripiprazole is one of these
      novel partial agonists. It has the ability to act as an antagonist in the presence of high
      concentrations of dopamine and as an agonist in low concentrations. Animal models can be used
      to predict both the clinical efficacy of antipsychotics as well as to predict their
      propensity to induce EPS. What follows is a comparison of the behavior of the typical
      antagonist haloperidol and the novel partial antagonist aripiprazole in these models. Both
      haloperidol and aripiprazole show dose-dependent striatal D2 receptor occupancy (D2RO)
      (Natesan et al., 2006). In two measures of clinical efficacy, conditioned avoidance response
      (CAR) and amphetamine induced locomotion (AIL), haloperidol and aripiprazole behave
      differently. Haloperidol's ED50 for the inhibition of CAR and AIL corresponds to ~60% D2RO.
      Aripiprazole, however, shows dissociation between function and occupancy. While aripiprazole
      is similar to haloperidol in that it blocks AIL at ~60% D2RO, it differs in that a 23-fold
      higher dose, corresponding to an 86% D2RO is required to inhibit CAR. It has been suggested
      by Natesan et al., 2006 that this functional dissociation occurs as a result of
      aripiprazole's partial agonist property. If aripiprazole has approximately 20% in vivo
      intrinsic activity, this could raise the threshold for CAR inhibition from the ~60% D2RO seen
      in haloperidol to the ~85% D2RO seen in aripiprazole. A similar result to that in the CAR
      model is found in another measure of clinical efficacy - FOS expression in the shell of the
      nucleus accumbens (NAcc). While haloperidol induced FOS at a dose corresponding to ~60% D2RO,
      an ~80% D2RO was needed for aripiprazole. Despite the >80% D2RO required for aripiprazole to
      be efficacious in the CAR model, and induce FOS in the NAcc shell, catalepsy was not present.
      This is contrary to what is seen in the typicals, including haloperidol. It is also
      surprising, as aripiprazole D2ROs >80% induce FOS in the core of the NAcc and the
      dorsolateral striatum (a marker for catalepsy and extrapyramidal symptoms).

      It is well established that animals treated with low doses of antipsychotic drugs fail to
      acquire or perform avoidance responses to a conditioned stimulus (CS) that is associated to
      an aversive unconditioned stimulus (US), whereas their escape responses to that stimulus are
      not affected in aversive avoidance paradigms. This selective disruption of avoidance, but not
      escape responses, is a characteristic pharmacologic effect of all antipsychotics, including
      newer atypical ones. This feature has been effectively used to differentiate antipsychotic
      medication from other classes of psychotropic drugs to predict their clinical potencies and
      to identify potential drugs to be used as antipsychotics.

      More appetitive paradigms where animals have to work for rewarding stimuli (food, water, sex,
      brain stimulation) show a dramatic decrement in performance/pursuit when administered
      antipsychotics. This deficit can be reversed with dopamine agonists such as amphetamine and
      thus suggesting symmetrical effects of dopamine agonists and antagonists in these kinds of
      paradigms. While typical antipsychotics like haloperidol reduce impact of both appetitive and
      aversive CSs but not the US at doses producing >60% D2 occupancy, it has been reported that
      aripiprazole was effective at doses that gave rise to occupancies of >85%. This has to be
      examined in humans and functional Magnetic Resonance Imaging (fMRI) might be a tool specific
      and sensitive enough.

      fMRI is now a standard tool in human brain imaging and provides a good spatial resolution at
      the millimeter level with a second level temporal resolution. Event-related fMRI, wherein
      brain responses are recorded in response to specific events, are optimally suited for
      studying the neurobiology of phenomena such as classical conditioning in humans. In a
      previous event-related fMRI study from our group, using Pavlovian aversive conditioning, the
      ventral striatum was reliably and directly activated in three experiments. These results have
      been replicated in healthy controls, whereas patients with schizophrenia have shown a
      different activation pattern. The ventral striatum was activated in the anticipation of
      aversive events regardless of whether there was an opportunity to avoid the aversive stimulus
      (similar to the animal models described above) or not. Thus, our data suggested that the
      ventral striatum, a crucial element of the dopaminergic mesolimbic "reward" system, is
      directly activated in anticipation of aversive stimuli. Similar to other conditioning studies
      we also found robust activations of the anterior insula and anterior cingulate, both parts of
      the greater limbic cortex and projects to the ventral striatum. The anterior insula has been
      proposed to play a role in processing emotional relevant contexts such as disgust and pain
      whereas the anterior cingulate is involved in assessing motivational content of internal and
      external stimuli and regulating context dependent behavior. Both structures have extensive
      connections with the amygdala which is the substrate most commonly associated with fear.

      The field of pharmacological fMRI is emerging and some early studies have demonstrated the
      proof of principle that drugs can influence activations. The dopamine system has been the
      focus of several fMRI studies, most probably as a result of its innervations of key cortical
      and sub-cortical regions implicated in motor and neurocognitive functions, in addition to its
      implication in a range of psychiatric and neurological conditions. Early pharmacological fMRI
      studies suggest that this is a tool sensitive enough to pick up pharmacologically modulated
      activations in the brain. Pharmacological fMRI has a potential for testing transmitter models
      of disorder, predicting treatment response and supporting the development of novel compounds
      in neuropsychiatry.

      The main objective of this study is to investigate if the activation signature of a typical
      antipsychotic agent is dissociable from a new drug with a pharmacological profile that
      differs from both typical and the atypical antipsychotics since it is a potent partial D2
      agonist. For this purpose we will employ fMRI paradigms based on findings from previous
      research on animals and humans described above.
    

Intervention name(s): Aripiprazole; Haloperidol; Placebo sugar pill
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Dose: 5-10 mg depending on subject weight; Dose: 1-2 mg depending on subject weight; Dose: 1-2 pills depending on subject weight
Other intervention name(s): Abilify; Haldol
Intervention MeSH terms: Haloperidol; Aripiprazole; Haloperidol decanoate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Aripiprazole; Haloperidol; Ventral striatum; Reward; fMRI