L16: Drugs for Anxiety and Depression Flashcards
What is major depressive disorder? (MDD)
- Common mental disorder, unmet medical need
- ~185 million people globally
- Includes:
–> depressed mood
–> reduced interest or pleasure in previously enjoyable activities
–> recurrent thoughts of death - Depression in adults ~30% higher during/since COVID-19 pandemic
stats about MDD
increase in depression diagnoses by 33% since 2013
- mainly in teens (63%) and millenials (47%)
- 2x more likely in women than males
- high comorbidity with other diseases (chronic, pain related, substance use) when diagnosed with depression
- loss of 10 years of healthy life
describe the MDD prevalence over incomes
increases in all incomes (low, low-middle, upper-middle, high income countries)
what are some biological mechanisms of MDD?
Symptoms? (3)
Mechanisms for MDD that involve predominantly central processes (3)
Mechanisms for MDD that involve both central and peripheral processes (4)
Central symptoms of MDD:
- emotional
- neurovegetative (fatigue, sleep, weight disturbances)
- neurocognitive
Mechanisms for MDD that involve predominantly central processes:
- neurotransmitter systems (serotonin, dopamine etc)
- neuroplasticity
- brain structure and function
Mechanisms for MDD that involve both central and peripheral processes:
- immune and inflammatory systems
- gut microbiota-brain axis
- hypthalamus-pitutary-ardenal axis
- (epi)genetics
Give context about SSRIs (Serotonin reuptake inhibitors)
what is it?
does it have side effects if so what?
- Many traditional antidepressants block serotonin reuptake at the synapse (selective serotonin re-uptake inhibitors, SSRIs)
- Many non-responders (people may not respond to the SSRIs), and side effects (nausea, headache, insomnia)
- Limitations to serotonin theory (that less serotonin = depression)
- adverse effects increased risk of suicidality in children and young adults aged 18–24
describe the 2017 drug for MDD, esketamine
- how fast does it act
- what does it directly effect
- how is it taken
- who mainly takes it
- what is a pro about it
- what is the target for the drug
- Rapid-acting (different mechanism than SSRIs which take a long time to work)
- Analogue of ketamine
- Affects neuroplasticity
- Nasal spray (not given by surgery like ketamine which has an unexpected side effect)
- Taken under medical supervision
- For treatment-resistant MDD (for people that don’t respond to SSRI)
- Less suicidal side effects than SSRIs
- Target: open channel of NMDA receptors, involved in neuron communication (different than serotonin receptor)
Describe the 2023 geprione drug for MDD
- how does it act as an agonist and antagonist
- what are the pharmacokinetics
- what is the clinical efficacy
- New about gepirone:
–> Agonist (turn on) at serotonin 1A receptor
—–> Gepirone AND many of its metabolites act as agonists on the serotonin 1A receptor
–> Antagonist (turns off) at serotonin 2A receptor - Extended-release (for pharmacokinetics – take it and it lasts a long time in you)
- Clinical efficacy: Reduced side effects (re: weight gain, sexual function) compared to traditional antidepressants
- Different target profile than SSRIs
–> Possibility of different (improved) side effects
Describe the preclinical study: forced swim test and geprione
- Developed in 1977, uses the idea of “giving up” in depression
- Mice swim in chilly water for 5 min, and sometimes “give up” swimming and float instead
- Traditionally used to test antidepressant drugs
–> gepirone improved depression in rodent models with forced swim test (1991) - Currently not a popular test
–> Challenges with animal to human translation
describe how countries react to using the forced swim test
UK and Australia
- pressure grows to ditch controversial forced swim test in rodent studies for depression
- UK: Researchers required to justify use of forced swim test (March 2024)
- Australia: will not fund research using forced swim test (Dec 2023)
what alternative behavioral tests might be used to test MDD
- Specific behaviours associated with mental health:
- Enjoyment of life
–> In mice: consumption of sugar water - Healthy sleep patterns
- Resilience to stress
–> In mice: interactions with a larger “bully” mouse – do you give up?
describe gepirones clinical trials and their eventual approval
- submitted the NDA first in may 2001 after clinical trials
- US requested additional clinical trial data
- Amended but declined again in 2007
- appealed, amended again, and finally approved in the USA for treatment of MDD in Sep 2023
why was it so difficult for the eventual approval of gepirone
- this drug may have worked better for some subtypes of depression more than others
- the clinical trial data was also challenging:
–> variability in the patient population
–> high placebo response rates
–> self-reported, subjective responses
MDD is very complex and not everyone will be a responder. everyone has different issues when it comes to MDD so its hard to create a generalizable drug
what is the chemical structure of psychedelics? where is it found?
- the chemicals are part of a family known as Substituted tryptamines (general double ring structure involved in all chemicals in that family)
- this family includes Psilocybin, Psilocin, and LSD ”acid” (lysergic acid diethylamide)
- Psilocybin is found in the psychedelic (“magic”) mushrooms
- body converts the inactive prodrug to the active form psilocin
describe the single dose psilocybin randomized clinical trial for MDD treatment
importance
objective
sample
doses
results
locations
key critical findings (2)
importance: psilocybin showed promise as treatment for MDD
objective: to evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD
Sample: 52 men and 52 women, mean age = 41 years
doses:
- 51 people got the psilocybin
- 51 people got the placebo, Niacin (not a true placebo, makes the patient flush red and feel warm so it makes them think they weren’t in the placebo category)
results:
- 19.1 drop in MDD for psilocybin
- 6.8 drop in MDD scores for Niacin
locations
- 11 research cites in the US for geographic diversity
Key clinical findings:
- Psilocybin showed great improvement in lowering MDD when compared to Niacin
- Approximately 75% of the patients were responders (>/= 50% improvement in MADRS scores) following two doses of 16mg
what is LSD?
type of drug
category?
increase intensity of…?
psychological and physical effects?
- its a schedule I drug – no medical use at all
- it is definitely a psychedelic
Increase intensity of:
* Thoughts
* Emotions
* Sensory perception
Dose-dependent
* Hallucinations
psychological effects:
- euphoria, paranoia, sensory distortion, hallucinations
physical effects:
- profuse sweating, increased heart rate, dehydration, dry mouth