K2 - drug discovery Flashcards
(20 cards)
give a brief history of pharmacological treatments for psychiatry
pre 1900s: opiates, alcohol, barbiturates
1949: lithium (Cade)
1952: chlorpromazine (schizo)
1954: benzos
1957: imipramine (Kuhn)
1988: clozapine (schizo) (Kane)
2000: ket for depression (Berman)
2024: muscarinic agonists for psychosis
how has drug discovery been done in psychiatry historically?
- astute observations by clinicians/patients
- elucidation of pharmacology
- drug repurposing from pharm knowledge
how was chorpromazine used as an antipsychotic?
1950: anti-histaminic component of ‘lytic cocktail’ used in anaesthesia
1951: Laborit suggests psychiatric use due to sedative properties
1952: noted as antipsychotic by Denicker + Delay
what is the link between D2R affinity and clinical potency of antipsychotics?
strong correlation
seen from correlation between D2R binding and average clinical dose
[Seeman et al 1976]
i.e. antipsychotic must be D2R blockers
How has DA been imaged in the brain?
striatal 6-fluoro-L-dopa F 18-dopa summation images from PET scans
highest signal intensity occurs in the striatum indicating DA synthesis and accumulation here, and shows pre-syn terminals are working in SNc
[Howes 2009]
what is the problem with neurotransmission in schizophrenia?
problem occurs with pre-syn DA release, its not that there are too many post-syn D2Rs
cholinergic drugs can reduce pre-syn DA release
what are ICD-11 criteria for depression?
affective: depressed mood/anhedonia
cognitive behavioural: difficulty concentrating, worthlessness, hopelessness, suicidal
neurovegetative: altered sleep, appetite, energy
what are some other effects of TCAs?
- histamine -> sedative
- a1R-blockers -> postural hypotension
- anti-muscarinic cholinergic -> autonomic side effects
- dangerous for overdose
- 5-HT reuptake blockade (took this function and make it SSRIs)
benefits of SSRIs
- simple dosing (use PET scan to find out how much antidepressant is needed for 80% receptor occupancy (20mg) [Meyer 2004])
- fairly well tolerated
- relatively safe in overdose
- generic + cost effective
- effective in co-morbid anxiety
disadvantages of SSRIs
- slow onset
- limited efficacy in severe depression [Cipriani 2018 meta-analysis]
- induction of anxiety early on
- sexual dysfunction
- withdrawal symptoms
- concern about incr suicidality in young people
timeline of ketamine development
- introduced as dissociative anaesthetic in 1964: use restricted due to delusions, hallucinations (‘emergence’ effects)
- analgesic + amnestic
- recreational use
- sub-anaesthetic doses used as a model of schizophrenia [Krystal 1995]
- Berman 2000: 0.5mg/kg, 7 patients, crossover model, HRDS-17 decreased. neuroplasticity theorised.
how can big data be used in psychiatric drug discovery?
- population studies explore associations between use of general medical drugs and psychiatric outcomes
- risk of confounding despite stats
- subsequent randomised follow-up studies needed
why might we investigate 5-HT4 receptors as targets for antidepressants?
*5-HT4 receptors widely expressed in the brain in networks related to emotional processing and cognition
* 5-HT4 receptor agonists have rapid antidepressant actions in animal models of depression – single dose improves performance in FST
* Cortical 5-HT4 receptors decreased in patients with depression (PET studies).
* 5-HT4 receptors also present in GI tract and the 5-HT4 receptor agonist, prucalopride, is licensed for the treatment of constipation – drug is available
describe the emulated target trial of prucalopride
- big data comparison of prucalopride against therapeutic comparators on target outcome (depression) after one year i.e. emulated clinical trial
- 8,700 patients on electronic health record
- risk of depression is less in prucalopride than in other comparator drugs [De Cates et al 2024]
- need control clinical trial due to confounding
key criteria for mania
- abnormally elevated or irritable mood + increased activity for at least one week
- plus increased talktativeness, self-esteem + grandiosity, decreased need for sleep
- distractibility
- incr in goal directed behaviours + reckless behaviour
what are the uses of lithium?
- improved mania strikingly in 1948 John Cade study
- effective in acute treatment of mania + prevention of mood episodes in bipolar patients [Geddes 2004]
problems of lithium?
- not well tolerated
- thirst
- risk of long-term renal impairment + toxic effects on kidney
- hypothyroidism
- rebound mania
- 2x therapeutic dose = toxic
what is the hypothesis of lithium action?
inositol depletion hypothesis:
lithium inhibits inositol monophosphatase, inhibits inositol 1-phosphate conversion to inositol, decreasing free inositol & PIP2 –> alters IP3 + DAG systems –> dampens overactive signalling pathways
[Berridge 1989]
what is a lithium mimetic candidate?
ebselen: same actions on IMPase as lithium
[Singh et al 2013]
lowers brain inositol in ACC in humans (magnetic resonance spectroscopy)
[Singh 2016, Masaki 2016]
also: ‘add on’ trial in 60 patients w DSM-V mania/hypomania, reduced CGI-S significantly compared to placebo by week 3 [Sharpley 2020]
