Dr. Laura Ajram reviews the history of psychopharmacologic drug discovery. Despite the increase in technology the past years, we haven't seen this matched with much progress #BAPsych

We're seeing a shift from in-house research of big pharmaceutical companies to outsourcing and collaboration (e.g. CROs, academe) #BAPsych

Challenges:
-We've seen a lot of big genetic studies (GWAS), but better interpretations are needed (e.g. better biological context)

-More service user-led research, given heterogeneity of conditions (more focus on phenotypes)

-Better preclinical models #BAPsych

Syndicate model - a patient-centered collaborative model for drug discovery research #BAPsych

Collaboration can involve sharing of costs to mitigate risks associated with early-stage drug discovery #BAPsych

Funding available (see website) - up to 1M pounds. Focused on validating preclinical targets

#BAPsych

Website link: http://psychiatryconsortium.org  (for funding inquiries) #BAPsych

Next up is Dr. Richard Mead on Optimizing Preclinical Drug Discovery for Motor Neuron Disease: A Collaborative Approach

Motor neurone disease: adult onset neurodegenerative disease

Life expectancy of 2.5 years

Options available with some benefit: Riluzole, Edavarone

How do we get the right candidate?

A lot of failure of translating the research is in the model used (e.g. unreplicated false positives)

Mouse --xxxxx--> Man

#BAPsych

Ways issues were addressed:
1. Study design - defined genetics, quantitative measures for disease progression

2. Animal --> Man translation - kinetics & BBB penetration, translating animal quantitative measures to equivalent, suitable human tests #BAPsych

Issues:
3. Clinical relevance
-preclinical models - mice, patient-derived in vitro, non-mouse #BAPsych

SITraN pipeline
-negative allosteric modulator (NAM) for metabotropic glutamate receptor-5 (mGlur5) - receptor occupancy study in a relevant model

-KEAP1 inhibitors - selective activators of NRF2 - hits multiple patho. mechanisms in Parkinson's, motor neurone disease #BAPsych

Next up, Dr. John Atack on Psychiatric Drug Discovery: Low-Hanging Fruit in Industry and Academia

Pipeline shown

The one furthest ahead appears to be a positive allosteric modulator of the AMPA receptor for schizo cognitive symptoms #BAPsych

Low-hanging fruit
-Safe, well-tolerated

High hanging fruit: "sexy" targets - novel mechanism, unknown safety and tolerability in humans

Approaches to drug discovery/development:
-Classic: serendipidous (Lithium and the classic rat piss story, Haloperidol from Meperidine, etc.)
-Repositioning: Sildenafil
-Improvement of existing drugs' side effect profile
-Hypothesis-driven - disease pathway --> target #BAPsych

Pipeline examples:
Low-hanging fruit: alpha2,3 GABA-A PAM for anxiety disorders

High-hanging fruit: LIM Kinase for Fragile X #BAPsych

Neurodegenerative diseases: defined pathology

Psychiatric disorders: disease process poorly defined in comparison, multiple small risks from genome-wide association studies (GWAS) #BAPsych

Decrease in neuroscience drug discovery investments from pharmaceutical companies for the past decades.

Those remaining focusing on neurodegenerative disorders

Psychiatry also deprioritized #BAPsych

Last year was a good year for psych: Brexanolone, Esketamine, Lumateperone

1. Brexanolone (GABA-A PAM): postpartum dep
-inPx IV infusion, serious side effects, financial toxicity

Low-hanging: alpha2/3-selective GABA-A PAM- nonsedating anxiolytic w/out cognitive effects #BAPsych

Next up: Dr. Elizabeth Tunridge on Drug Discovery Targeting Genetic Hits in Psychiatry (focus on CACNA1C) #BAPsych

How to move from genes to treatment?

Study costs have decreased, so genetic research on larger numbers of people is becoming less difficult

Impt: research identifies parts of a genome conferring risk - common variants and rare variants #BAPsych

GENES DON'T ENCODE PSYCHIATRIC DISORDERS (see above: they confer *risk*)

Important to know what they do at multiple levels.

Ex. identify molecules involved, figure out what they do and how they affect processes and lead to the disorders #BAPsych

Focus: gene for a voltage-gated calcium channel

-Sequesteration (endoplasmic reticulum)(
-Buffering (binding to calcium-binding protein)
-Control movement in/out of cell

Robust and transdiagnostic (risk shown across multiple MH conditions) #BAPsych

Challenges:
-Single-nucleotide polymorphisms don't change how channel is encoded
-calcium channel gene mentioned above is large and complex
-diff flavors of channel from same gene via RNA splicing
-not very studied in human brains
-full length of sequence not certain #BAPsych

Most human brain CACNA1C isoforms are novel

Working on characterizing isoforms in human brain vs cardiovascular system. Human and CV isoforms separated. Different isoforms in rats and humans
#BAPsych

There's a lot we don't know

But I agree, the possibilities are also exciting

Just gota be careful about extrapolating from rats to humans #BAPsych

Did a bit of Q&A with Dr. Liz and asked about how clinical data on calcium channel blockers informed her preclinical work

She cited a study by Hayes et al. on how CCBs were correlated to decreased hospitalization in a cohort of people with schizophrenia and bipolar disorder 1/2

Not sure if this is the exact paper

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2719703

Interesting point tho was when some subanalyses were conducted, it was the CNS-penetrating CCBs with a stronger effect. Back to the importance of kinetics @sertraline_ 2/2 #BAPsych

Thread continues here: https://twitter.com/Jetlax/status/1285943967792590850