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Pramipexole and Emotional Processing (PEP)

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ClinicalTrials.gov Identifier: NCT03681509
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
University of Oxford

Brief Summary:
The dopamine agonist pramipexole has recently been suggested as a potential novel antidepressant drug. While preliminary clinical data hint at its efficacy in treating depressive symptoms, our current understanding of its impact on neurocognitive processes is relatively limited. This is in part because mechanistic studies have largely focused on the effects of single-dose treatments. However, such acute administration of dopaminergic drugs likely has different cognitive effects than the more prolonged administration that is used clinically. This study therefore aims to explore and characterise the neurocognitive effects of more prolonged pramipexole treatment. Forty healthy volunteers will be randomly allocated to 12 to 15 days of treatment with either pramipexole or placebo. Study participants as well as researchers will be blinded as to which treatment is used. Before and after treatment all participants will perform a set of psychological tasks and questionnaires evaluating reward-based learning, emotional information processing, motivational vigour and subjective experience. Furthermore, functional magnetic resonance imaging (fMRI) will be used to compare neural activity during emotion and reward processing between the two treatment groups. We hypothesises that pramipexole might enhance reward sensitivity, motivational vigour, and pleasure experience and could induce positive biases in emotional information processing.

Condition or disease Intervention/treatment Phase
Emotions Motivation Reward Dopamine Drug: Pramipexole Drug: Placebo Not Applicable

Detailed Description:

Background:

The dopamine receptor agonist pramipexole has recently been suggested as a potential novel antidepressant drug. While preliminary clinical data hint at its efficacy in treating depressive symptoms, our current understanding of its impact on neurocognitive processes is relatively limited. This is in part because, so far, mechanistic studies have largely focused on the effects of single-dose treatments. However acute administration of dopaminergic drugs likely has different cognitive effects than the more prolonged administration that is used clinically.

Aim of study:

To explore and characterise the effects of a 12 to 15 day regime of pramipexole on behavioural and neural measures of reward learning, emotional information processing, motivational invigoration, and subjective experience.

Methods:

Using a double-blind, parallel-group design, forty healthy volunteers (male and female, aged 18 to 45 years) will be randomly allocated to a 12 to 15 day regime of either pramipexole (maximum daily dose of 1.0 mg pramipexole salt) or placebo. At baseline and after 12 to 15 days of treatment, a set of previously established cognitive tasks and questionnaires tapping into reward learning, emotional information processing, motivational invigoration and subjective experience will be administered. Furthermore, at 12 to 15 days of treatment, all participants will undergo functional magnetic resonance imaging to compare neural responses to reward- and emotion-related information.

Hypotheses:

Our working hypothesis is that pramipexole will enhance reward sensitivity, motivational invigoration and hedonic experience and might positively bias emotional information processing.

Implications:

This will be the first study to broadly explore and characterise the neurocognitive effects of pramipexole administered for a clinically relevant time period. The results of the study will add to our understanding of the cognitive mechanisms through which pramipexole could exert both its beneficial as well as its adverse clinical effects.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: The Effects of the Dopamine Receptor Agonist Pramipexole on Reward and Emotion Related Information Processing in Healthy Volunteers
Actual Study Start Date : September 1, 2018
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pramipexole
Maximum daily dose: 1.0 mg of pramipexole salt
Drug: Pramipexole
Pramipexole

Placebo Comparator: Placebo
Lactose
Drug: Placebo
Lactose placebo capsule




Primary Outcome Measures :
  1. Change in reward sensitivity on a reinforcement learning task between baseline and final day of assessment [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants are shown two distinct abstract shapes and have to choose one of them. On each trial, one of the two shapes is associated with a 'win' (resulting in a small monetary gain) and one with a 'loss' (resulting in a small monetary loss). The two outcomes are independent (knowing the location of the win provides no information about the location of the loss). During the task, the information content of the outcomes is manipulated independently by varying the volatility of their occurrence (three conditions: 'win volatile, loss volatile', 'win stable, loss volatile', 'win volatile, loss stable'). Using trial and error, participants have to learn the stimulus-outcome associations and use their knowledge to maximise monetary earnings. Choices are made via button-press. Choice, choice reaction time and pupillary dilation in response to outcome presentation are recorded. By fitting a computational model, reward sensitivity is estimated.


Secondary Outcome Measures :
  1. Change in performance in a facial expression recognition task [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants are presented with individual pictures of facial expressions of emotions. Each presented face displays one of six basic emotions (anger, disgust, fear, happiness, sadness, or surprise). Each emotional expression is presented at different levels of intensity which have been created by combining shape and texture features of the two extremes "neutral" (0%) and "full prototypical emotion" (100%) to varying degrees. Examples of neutral facial expressions are presented as well. Participants are instructed to correctly classify each facial expression as angry, disgusted, fearful, happy, sad, surprised or neutral both as quickly and as accurately as possible. Responses are made by pushing one out of seven labelled keys on a response box. Hit rates, false alarm rates, and reaction times for correct classifications are measured separately for each emotion.

  2. Change in performance in an emotional categorisation task [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants are presented with positive and negative personality descriptors and are asked to classify the valence of each word. These words describe either extremely agreeable/positive characteristics (e.g. "cheerful", "honest", "optimistic") or extremely disagreeable/negative characteristics (e.g. "domineering", "untidy", "hostile") and are presented individually in the centre of the screen. Participants are instructed to imagine themselves overhearing someone describing them with each of the words and to indicate as quickly and accurately as possible whether they would like or dislike to be described with each of the words. Responses are made by pressing a correspondingly labelled key on a button box. Reaction times for correct classifications are measured separately for positive and negative words.

  3. Change in performance in an emotional faces dot probe task [ Time Frame: Completed at day 12 to 15 of treatment ]
    Pictures of positive and negative emotional stimuli (happy and fearful facial expressions) are presented individually together with a matched neutral stimulus (neutral face). On each trial, one stimulus is shown above and the other below a central fixation point. Subsequently, a probe appears behind one of the stimuli and participants have to correctly classify the probe as quickly and as accurately as possible. Stimuli can be masked (i.e. presented very briefly and followed by a jumbled face) or unmasked (i.e. presented for a longer period without a subsequent masking stimulus). Reaction times for correct responses are recorded and vigilance scores are calculated for masked and unmasked positive and negative stimuli by subtracting reaction time data from trials when the probe appeared in the same position as the emotional stimulus (congruent trials) from trials when the probe appeared in the opposite position to the emotional stimulus (incongruent trials).

  4. Change in performance in an emotional recall task [ Time Frame: Completed at day 12 to 15 of treatment ]
    Following a delay period after the emotional categorization task (about 15 min), emotional recall memory is assessed. Participants are asked to recall and write down as many words as possible from the emotional categorization task. Numbers of correctly and incorrectly recalled positive and negative words are measured.

  5. Amygdala BOLD signal in response to positive and negative emotional faces [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants are presented with pictures of positive and negative facial expressions of emotions during functional magnetic resonance imaging. Participants are asked to correctly identify the gender of each face. BOLD signal in the amygdala in response to positive and negative emotional stimuli is measured.

  6. Change in performance in a probabilistic instrumental learning task [ Time Frame: Completed at day 12 to 15 of treatment ]
    In each trial, participants are presented with one out of two pairs of symbols. One pair of symbols is a 'win' condition in which one symbol (the 'correct' one) has a 70% chance to win a small monetary reward and a 30% chance to win nothing, while the other symbol (the 'wrong' one) has a 30% chance to win and a 70% chance to win nothing. The other pair of symbols is a 'loss' condition in which one symbol (the 'correct' one) has a 70% chance to lose nothing and a 30% chance to lose a small monetary reward, while the other symbol (the 'wrong' one) has a 70% chance to lose and a 30% chance to lose nothing. Participants are asked to choose one symbol in each pair such that they maximise their payoff. Participants have to learn the stimulus-outcome associations by trial and error such that they consistently choose the symbol with the high-probability win and low-probability loss. Responses are made via button press. Choice, reaction time, and payoff are measured.

  7. Change in performance in a motivational vigour task [ Time Frame: Completed at day 12 to 15 of treatment ]
    On each trial, participants are asked to fixate on the center of a computer screen. Following that, they are presented with a cue that provides information about how reward will be determined in that trial. Reward is determined according to one of the following four conditions: (a) 'performance-based reward' (fastest 50% of trials rewarded), (b) 'random reward' (50% small monetary reward and 50% no reward, regardless of performance), (c) 'guaranteed reward' (a fixed small monetary reward, regardless of performance), (d) 'guaranteed absence of reward' (no reward, regardless of performance). Subsequently, a target appears on either the left or the right side of the screen and participants have to move their eyes as quickly as possible towards the target. Participants are then informed about their speed and reward for the task. Saccade velocity and pupillary dilation in response to outcome are recorded.

  8. Subjective taste experience [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants are provided with standardized samples of different taste qualities (sweet, sour, bitter, salty) at four different concentrations. Participants are asked to correctly identify the taste quality of each sample and indicate on a visual analogue perceived pleasantness and disgustingness of each sample.

  9. Change in subjective experience of pleasure [ Time Frame: Completed at day 12 to 15 of treatment ]
    Snaith-Hamilton Pleasure Scale, standard questionnaire to assess subjective experience of pleasure

  10. BOLD signal in the ventral striatum, orbitofrontal cortex and anterior cingulate cortex in response to positive and negative outcomes in a probabilistic instrumental learning task [ Time Frame: Completed at day 12 to 15 of treatment ]
    Participants perform the same probabilistic instrumental learning task mentioned above while fMRI is conducted. BOLD signal in the ventral striatum and prefrontal cortex in response to positive and negative outcomes is measured.


Other Outcome Measures:
  1. Change in subjective mood and energy [ Time Frame: Completed at day 12 to 15 of treatment ]
    Zersen's Befindlichkeits-Skala

  2. Change in positive and negative affect [ Time Frame: Completed at day 12 to 15 of treatment ]
    Positive and Negative Affect Schedule

  3. Change in subjective anxiety [ Time Frame: Completed at day 12 to 15 of treatment ]
    State-Trait Anxiety Inventory

  4. Change in subclinical depressive symptoms [ Time Frame: Completed at day 12 to 15 of treatment ]
    Beck Depression Inventory

  5. Change in happiness levels [ Time Frame: Completed at day 12 to 15 of treatment ]
    Oxford Happiness Questionnaire

  6. Change in subjective experience of pleasure 2 [ Time Frame: Completed at day 12 to 15 of treatment ]
    Temporal Experience of Pleasure Scale

  7. Assessment of drug-induced side effects [ Time Frame: Completed at day 12 to 15 of treatment ]
    Side effect questionnaire

  8. Change in impulsive compulsive symptoms [ Time Frame: Completed at day 12 to 15 of treatment ]
    Adapted Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease Rating Scale



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or female
  • Age: 18 to 45 years
  • Good physical and mental health
  • Participant is willing and able to give informed consent for participation in the study
  • Sufficient knowledge of English language to understand and complete study tasks
  • Willingness to refrain from driving, cycling, or operating heavy machinery if necessary while taking part in the study
  • Willingness to refrain from drinking while taking part in the study.

Exclusion Criteria:

  • Current or past psychiatric disorder (e.g. depression, bipolar disorder etc.)
  • First-degree relative with a diagnosis of schizophrenia-spectrum or other psychotic disorder, or bipolar disorder
  • BMI not between 18 and 30
  • History of unexplained hallucinations or impulse control problems (e.g. pathological gambling)
  • Any severe medical condition not stabilized at the time of the experiment (e.g. cardiovascular disease, epilepsy, asthma etc.)
  • Severe heart or blood vessel disease
  • Postural hypotension
  • Any history of seizures
  • Lactose intolerance
  • Any current or past physical illness that has the potential to significantly affect mental functioning (e.g. epilepsy, hypothyroidism, Parkinson's disease, multiple sclerosis etc.)
  • Pregnant, or lactating woman
  • Sexually active woman who does not use any medically accepted method of contraception
  • Current or previous intake (last three months) of any medication that has a significant potential to affect mental functioning (e.g. benzodiazepines, antidepressants, neuroleptics etc.)
  • Any intake of recreational drugs in the last 3 months (e.g. marijuana, ecstasy etc.)
  • Regular alcohol consumption of more than 14 units a week or excessive alcohol consumption up to three days before the experiment
  • Regular smoker (> 5 cigarettes per day)
  • Excessive caffeine user (> 6 caffeinated drinks per day)
  • History of recurrent rashes or history of allergic reactions to relevant substances (pramipexole treatment, placebo treatment, taste samples)
  • Previous participation in a study using the same or similar tasks
  • Any contraindication to magnetic resonance imaging (e.g. metallic implant, severe claustrophobia)
  • Current participation in another study
  • In the researcher's opinion participation in the study could be harmful or severely distressing to the participant (e.g. intolerance of side effects) or the participant is not able to follow instructions or complete study tasks

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03681509


Contacts
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Contact: Alexander Kaltenboeck, Dr.med.univ. +44 1865 618260 alexander.kaltenboeck@psych.ox.ac.uk
Contact: Michael Browning, MB.BS +44 1865 618316 michael.browning@psych.ox.ac.uk

Locations
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United Kingdom
Dept of Psychiatry, University of Oxford Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7JX
Contact: Michael Browning, MB.BS    +44 (0)1865 6183161    michael.browning@psych.ox.ac.uk   
Principal Investigator: Michael Browning, MB.BS         
Sponsors and Collaborators
University of Oxford
Investigators
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Principal Investigator: Michael Browning, MB.BS University of Oxford

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03681509     History of Changes
Other Study ID Numbers: MS IDREC R07790
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Oxford:
Pramipexole

Additional relevant MeSH terms:
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Pramipexole
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents