L16: Drugs for Anxiety and Depression

Question 1

What is major depressive disorder? (MDD)

Answer 1

• 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

Question 2

stats about MDD

Answer 2

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

Question 3

describe the MDD prevalence over incomes

Answer 3

increases in all incomes (low, low-middle, upper-middle, high income countries)

Question 4

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)

Answer 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

Question 5

Give context about SSRIs (Serotonin reuptake inhibitors)

what is it?
does it have side effects if so what?

Answer 5

• 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

Question 6

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

Answer 6

• 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)

Question 7

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

Answer 7

• 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

Question 8

Describe the preclinical study: forced swim test and geprione

Answer 8

• 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

Question 9

describe how countries react to using the forced swim test

UK and Australia

Answer 9

• 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)

Question 10

what alternative behavioral tests might be used to test MDD

Answer 10

• 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?

Question 11

describe gepirones clinical trials and their eventual approval

Answer 11

• 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

Question 12

why was it so difficult for the eventual approval of gepirone

Answer 12

• 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

Question 13

what is the chemical structure of psychedelics? where is it found?

Answer 13

• 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

Question 14

describe the single dose psilocybin randomized clinical trial for MDD treatment

importance
objective
sample
doses
results
locations
key critical findings (2)

Answer 14

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

Question 15

what is LSD?

type of drug
category?
increase intensity of…?
psychological and physical effects?

Answer 15

• 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

Question 16

describe the usa drug schedules: 1-5

Answer 16

Schedule 1: no medical use, high potential for abuse and addiction (ex. LSD)

Schedule 2: regulated medical use, high potential for abuse, moderate potential for addiction (ex. adderall)

Schedule 3: medically used, moderate potential for abuse and addiction (ex. ketamine)

Schedule 4: medically used, moderate potential for abuse and addiction (ex. xanax)

Schedule 5: medically used, low potential for abuse and addiction (ex. cough syrup)

Question 17

what is the history of LSD research

Answer 17

after the 60-70s there has not been much clinical trial research for LSD. opened up again in 2022

Question 18

what is stress vs anxiety. what are the symptoms present when feeling both?

Answer 18

Stress
* Generally is a response to an external cause, such as taking a big test or arguing with a friend.
* Goes away once the situation is resolved.
* Can be positive or negative. For example, it may inspire you to meet a deadline, or it may cause you to lose sleep.

Anxiety
* Generally is internal, meaning it’s your reaction to stress.
* Usually involves a persistent feeling of apprehension or dread that doesn’t go away, and that interferes with how you live your life.
* Is constant, even if there is no immediate threat.

Both Stress and Anxiety
- Both stress and anxiety can affect your mind and body. – You may experience symptoms such as:
* Excessive worry
* Uneasiness
* Tension
* Headaches or body pain
* High blood pressure
* Loss of sleep

Question 19

what is Generalized Anxiety Disorder (GAD)? How does LSD work here?

Answer 19

• Generalized anxiety disorder – 2nd most common mental illness in adults
• Limited innovation in the GAD treatment space
  –> Cymbalta approved in 2007
• New LSD compound/ formulation (lysergide d-tartrate) given Breakthrough Designation by the FDA
• March 2024, phase 2b results reported, promising
• Phase 3 trials planned for later in 2024

Question 20

Describe the LSD molecular target sites.

what was the outcome of the LSD clinical trial? were there any bad trip side effects? why?

Answer 20

Agonist target sites:
* Serotonin 2A receptor agonist
* Also binds to dopamine D1 and D2 receptor
* “trip” persists long after the drug is gone

LSD clinical trial:
* Side effects in clinical trial did not observe “bad trips”
* Why? because they used LSD manufactured with pharmaceutical grade purity
–> LSD itself is difficult to make with high purity (illegal drug supply has limited purity)
–> tends to degrade quickly: light and water

Question 21

what was the clinical trial design for the LSD and GAD study

Answer 21

single dose ascending study and then a follow up

Question 22

what was the phase 2 clinical trial design and results for the LSD and GAD study

Answer 22

design
* 5 groups of patients with generalized anxiety disorder (GAD)
* Placebo or 25 – 200 micrograms of the compound
* Just one single dose of the compound
* Not added on to any other existing drug regimen

results
- LSD was fast acting
- Durable activity
- 48% of participants were in remission at week 12
- AEs and side effects were limited
- results achieved no additional therapy
- baseline participants were markedly ill and at week 12 they were borderline ill

Question 23

what is the use of medications like in pregnancy?

Answer 23

• Up to 90% of pregnant individuals use prescription or OTC drugs
• Many drugs have not been studied in pregnancy: pharmacokinetics, pharmacodynamics, efficacy, or safety
• Many drugs are prescribed/used off-label
• Goal is to maximize efficacy while minimizing risk to the mother, fetus, and placenta

Question 24

what is drug use like with birth defects?

Answer 24

• Only 2-3% of birth defects are thought to be associated with drug treatment during pregnancy
• Very few drugs are proven or suspected teratogens:

Proven: alcohol, cocaine, plus 11 prescription drugs

Suspected: three additional prescription drugs

Question 25

how did thalidomide effect pregnant mothers?

Answer 25

* First marketed in 1957 in Germany * Treatment for nausea in pregnancy * Thalidomide stops blood vessel development in the limb bud * Caused phocomelia in thousands of children worldwide * One 1 mg/kg dose can cause phocomelia * Took four years to realize thalidomide was involved

Question 26

what are some challenges of drug research in pregnancy (5)

Answer 26

* Ethics: health of mother vs. health of fetus * Understanding physiological & pharmacological changes (e.g., increased blood volume, altered levels of drug-metabolizing enzymes) * Reproductive toxicology studies are expensive * >90% of FDA approved drugs from 1980 to 2010 lack sufficient safety data for use in pregnancy * Safety in pregnancy usually ascertained from post-marketing surveillance

Question 27

what was the timeline of clinical trials with pregnant women when were they banned and not for being tested on

Answer 27

1977: FDA banned women with reproductive potential 1993: Exclusion was lifted 1994: Clinical trials can include pregnant women - Only if there is both a benefit to the woman and no risk to the fetus; tough to predict! Currently: pregnant women can participate in research under FDA Common Rule Subpart B; 10 criteria must be met Note: Inclusion criteria are similar for Health Canada

Question 28

when does it make sense to conduct clinical trials on pregnant women? usually there is minimal trials due to ethics

Answer 28

1. Pravastatin for prevention of preeclampsia (making drugs for pregnant women's cholesterol and blood pressure levels) 2. Randomized trial to prevent pregnant women's congenital cytomegalovirus viral infection 3. Antimalarials in pregnant women and children in Uganda

Question 29

what are the FDA: Pregnancy Exposure Registries

Answer 29

* A type of post-marketing surveillance, but is prospective * Actively collects information on exposure during pregnancy and pregnancy outcomes; compare outcomes with women who did not take medication * Can be used to update safety information & drug labels * Subject to selection bias: captures only patients who are aware of registry & willing to participate; health care providers can educate patients

Question 30

describe what postpartum depression is and the drug that was approved for it in 2023

Answer 30

* Effective in 3 days * A synthetic neurosteroid - Zurzuvae - (related to pregnancy hormones) that acts on GABA-A receptors (calming) * Drug not effective in Major Depressive Disorder --> implies the biology/mechanisms of Postpartum Depression is different than MDD

Question 31

what is the drug development in pediatric populations like historically and now?

Answer 31

* Historically children were protected from research * More recently the idea is to protect children through research

Question 32

what are some challenges of drug research in children (4)

Answer 32

* Most trials are for re-positioning already approved drugs for use in children * randomized controlled trials (RCTs) of new chemical entities exceedingly rare Issues: 1. Patient recruitment 2. Consent --> Capacity, risk/benefit, foreseeable consequences, free from coercion 3. “Children are not little adults” -->Pharmacokinetic differences (e.g. rate of renal clearance) -->Phase 1 and 2 trials in children are rarely done 4. Ethical issues --> Autonomy (does the child understand the decision to participate?) --> Beneficence (is the drug beneficial?) --> Non-maleficence (is the drug doing harm?) --> Justice (is it fair for the child to participate?)

Question 33

What is an example of a phase III clinical trial in children -- cystic fibrosis

Answer 33

Ramsey et al, New England Journal of Medicine, 2011 * 161 children with cystic fibrosis with a specific mutation in chloride channel gene * Tested ivacaftor + standard of care vs. just standard of care * Improvement in lung function * Exciting prospect for the future of cystic fibrosis care * Ivacaftor therapy costs >$300,000/year- very expensive --> In summer of 2014, governments of Ontario, Alberta, Saskatchewan began to cover the cost of the drug --> Requires pharmacogenetic testing

Question 34

what were the results of the cystic fibrosis study in children

Answer 34

- dramatic decrease of mucous 6 months after the Ivacaftor treatment -- helps with breathing. * Lung function is significantly improved with Ivacaftor * Quality of life is significantly improved with Ivacaftor

Question 35

what is the “Pediatric Exclusivity Provision” initiative

Answer 35

- FDA initiative to incentivize companies to conduct pharmacokinetic studies or small clinical trials in children - Important when a drug may be useful for children or could pose a serious risk if these studies are not completed (e.g., a new antibiotic) - If a company conducts the required studies, they may receive six months of additional patent life --> Can lead to millions of dollars (up to $500M) in profits (Li et al, JAMA, 2007) -->Huge potential benefit/cost ratio