Download Pharmacological interventions in the isolation

Department of Pharmacology
Utrecht Institute for Pharmaceutical Sciences
Faculty of Science
Pharmacological intervention in the isolationinduced pup vocalization test
Lucianne Groenink
Assoc. Professor Psychopharmacology
Monika Verdouw, Brenda Bakker & Kimberley Wever (SYrcle)
Introduction
Anxiety disorders
15% of population
Complex set of risk factors
• Genetics
• Life events
Generalized anxiety
Differences between disorders
•
Core symptoms: Fear and worry
•
Divergent malfunctioning in same circuits
Panic disorder
(amygdala, CSTC loop)
•
Neurotransmitters (serotonin, GABA)
PTSD
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Introduction
Treatment of anxiety disorders
Cognitive behavioural therapy
Medication (similar for all disorders)
•
Selective serotonin re-uptake inhibitors (SSRIs)
•
Benzodiazepines
•
Partial serotonin1A receptor receptor agonist
•
other antidepressants
25% Non-responders
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Introduction
Measuring anxiety in animals
To determine anxiolytic-like action of novel compounds
Animals
Naive, healthy animals or Mimic aspects of disorder
Tests
Innate anxiety
Conditioned fear
Conflict behaviour
shock
Do these approaches differ in predictive value?
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Introduction
Isolation-induced vocalization test in guinea pig pups
Test detects SSRIs (treatment of choice)
Homology towards human receptor pharmacology
Straightforward test set-up
Housing in litters
Isolation and quantification of emitted calls
microphone
Birth
Injection
TEST
-30
0
5 min
Objective and aims
Systematically assess drug treatment effects
in the isolation-induced vocalization test in guinea pigs
Specific aims:
• Evaluate effect of drug intervention* on reducing vocalizations
• Characterize experimental characteristics that may affect test outcome
• Determine prevalence of reporting of measures to reduce bias
• Characterize if biases in publication are likely to occur
*
Preferably individual drugs, otherwise drug classes
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Methods
Search strategy*
1. Guinea pig
2. Vocalization
Selection Criteria*
1. Route of administration (systemic)
2. No prior treatment
Selection/extraction process*
1. Two independent reviewers
2. Email to authors
*details:
Groenink et al (in press) Eur J Pharmacol
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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SR results
Pharmacological intervention
Systematic review
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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SR results
Risk of Bias: reported quality is poor
32 papers
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis
Meta-analysis
19 papers, 54 vehicle-drug comparisons
Outcome measure: Total number of calls
15 papers, 43 vehicle-drug comparisons, 977 guinea pigs
•
Drugs hypothesized to reduce vocalization behaviour
•
Most effective dose, in case of dose-response study
•
SMD (baseline level, test duration)
Meta-analysis Pharmacological intervention
Outcome measure: Total number of calls
Clinically active drug classes have comparable effects
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis Pharmacological intervention
Outcome measure: Total number of calls
All experimental drug classes are found active in test
*
*
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Meta-analysis Pharmacological intervention
Outcome measure: Total number of calls
All experimental drug classes were found active in test, but
Tested and reported
inactive in clinical trials
*
*
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MA pharmacological intervention
Outcome measure: total number of calls
Summary
Predictive value?
•
Tests detects all clinically active anxiolytic drug classes
•
All experimental drug classes also suppressed vocalization behaviour
- some of which appeared inactive in clinical trials
Of note:
•
Inclusion in meta-analysis
•
Publication bias
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis Pharmacological intervention
Outcome measure: total number of vocalization
Characterization of publication bias
Publication bias seems to have occurred
Smaller studies with neutral or negative effects are lacking
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis experimental characteristics
Outcome measure: Total number of calls
Experimental characteristics*
Selecting pups with high pre-test vocalization levels not favourable
Subgroup analysis ≥ 3 papers and ≥ 3 experiments
*
For details: Groenink et al (in press) Eur J Pharmacol
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Conclusions
Summing up
Pharmacology
• All drug classes show comparable effects,
•
•
independent of mechanism of action
Test is highly sensitive
→ Moderate predictive value and/or publication bias
Suited as global screen to detect potential anxiolytic drug properties
Test characteristics
• strict vocalization inclusion criterion not associated with larger
treatment effects, relative to moderate selection criterion
Study quality
• Quality of reporting is poor & potential for bias high
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis Pharmacological intervention
Outcome measure: Total number of calls
Additional test results for nociceptin receptor agonists
(unpublished)
And the corresponding reference compound chlordiazepoxide
(unpublished)
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Meta-analysis Pharmacological intervention
Outcome measure: total number of calls
Subgroup analysis
Subgroup analysis pharmacological intervention
Subgroup analysis ≥ 3 papers and ≥ 3 experiments
Groenink et al| Pharmaceutical Sciences| Pharmacological intervention in the guinea pig pup vocalization test
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Meta-analysis Experimental characteristics
Outcome: total number of calls
All subgroups
Subgroup analysis experimental characteristics
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the guinea pig pup vocalization test
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