Anxiety and Depression IV novel targets Flashcards
what is the effectiveness of anxiolytics and antidepressants
30% patients have minimal benefits from BZDs/SSRIs
30% experience no benefits from antidepressants
high placebo response rates (30%)
risk of suicide
trials use less severely depressed patients (ethical reasons)
what do current treatments lack
progress
understanding of neurobiology of anxiety and depression
underlying cellular/molecular pathogenesis
pharmacogenetics
study of genetic variations that lead to individual variations in the drug effect (efficacy) and adverse effect profile (toxicity)
pharmacodynamics
what the drug does to the body
effect of the drug on the target organ
pharmacokinetics
what the body does to the drug
drug absorption/distribution/metabolism/excretion
drug metabolism
Phase I (cytochrome P450 enzymes) increase polarity (more likely to be rejected) oxidation/reduction/hydrolysis
phase II - conjugation with an endogenous substance (methyl)
drug metabolising enzymes (DMEs) PK
P450 enzymes: CYP2D6/CYP2C19 metabolises antidepressants - highly polymorphic genes
affect response of TCAs
DME classifications
PM - poor metabolising linked to adverse effects (increased plasma levels = increased toxicity) dose correction via CYP gene
IM - intermediate metabolism
EM - extreme metabolism
UM - ultrarapid metabolism (treatment resistance)
p-glycoprotein
transports drugs across the BBB
reduces uptake of some antidepressants (citalopram/amitriptyline/paroxetine/venlafaxine)
3 functional variants: c3435T/c1236/g262T), SNPs with drug response, faulty p-gp associated with better drug response
5HT transporter
PD
target for SSRI (TCAs)
SLC6A4 encodes transporter - contains 2 polymorphisms (5HTTLPR)
NA transporter PD
TCA target
transporter SLC6A4 affects response to TCAs
SNP: rs36029
5HTTLPR
S allele involved in depression aetiology (depressive symptoms/clinical depression/suicidality only with stress/childhood maltreatment)
S allele involved in poor response to psychological treatment
Piquette-Miller & Grant (2007)
individuals with same diagnosis
non/toxic responders given alternative drug/dose
no toxicity responders given conventional dose
pros and cons of personalised medicine
pro: simple/helps clinicians to pick patients which respond to treatment/understand genetics of responders
cons: what do doctors do with non-responders?/responders do better with other treatment/co-founded by spontaneous remission/placebo
metabotropic glutamate receptors
type 1: mGlu1/5 - postsynaptic excitatory terminals in limbic areas
type 2: mGlu2/3 - presynaptic excitatory terminals in limbic areas
mGluR5 antagonist - fenobam - effective in animal models/GAD/panic attacks - psychostimulant side effect
mGluR2/3 agonist (LY354740/LY544344) - good efficacy/convulsants
NMDAR antagonism
delay in therapeutic effect of current antidepressants (increased risk of suicide) loss of synaptic connections
ketamine (fast acting antidepressant) anaesthetic/analgesic/quickest response (40min up to 10 day post infusion) subanaesthetic conc gives rapid antidepressant in rodent/patients (Berman et al., 2000) - enhances neuroplasticity (blocks GABA release/blocks mTOR activation)
HPA axis
Hyman (2009)
PVN releases CRH
ACTH release
AC releases glucocorticoid
stress response regulation (negative feedback)
a/d patients and HPA axis
HPA axis hyperactivity/increased cortisol
abnormal function of glucocorticoid receptor (imparied GR mediated feedback inhibition)
dexamethasone suppression test impaired ~50% depressed patients
detrimental effect on limbic brain structures
HPA drugs
FKBP5 antagonist - SAFit1/2 - FKBP5 regulates response of GRs and HPA axis
GR antagonist (mifepristone) GRs in hippocampus/PVN/AP inhibit further CRH release
CRH1 R antagonist (R121919) - reduces cortisol release in response to stress w/o inhibiting CRH-induced release of ACTH (retains responsiveness to CRH)
inflammatory system
increased cytokines in depression (IL-6/TNF-a/C-reactive protein)
cytokines produce symptoms which overlap with depression (fatigue/loss of appetite/anxiety/sickness behaviour)
increased inflammation in childhood maltreatment/adult life stress
cytokines normalised with antidepressants
cytokines and NT metabolism
cytokines activate kynurenine pathway
converts 5HT precursor (tryptophan) to neurotoxic end products (deplete 5HT)
how to alter the HPA axis
cytokines decrease GR expression - prevent translocation of GR into nucleus (disturb feedback inhibition) adjunction with NSAIDS to increase remission/response
antibiotics to improve depressive symptoms
gut-microbiome (carlessi et al., 2022) - leaky gut releases pro-inflammatory molecules
epigenetics
causal interaction between genes and their products, bring the phenotype into being
regulate chromatin structure and gene expression/histone &chromatin remodeling/DNA methylation of cytosine/non-coding RNA mediated gene silencing
environmental effects of epigenetics
severe childhood trauma - DNA methylation in GR regulating protein (FKBP5)/linked to HPA abnormalities/psychiatric disorders
rodent model of decreased maternal care - increases DNA methylation of GR exon 17 promoter/decreased histone K9 acetylation/reverse HDAC inhibitor,trichostatin A
rodent model of chronic defeat stress - decreased histone acetylation in hippocampus - reversed by antidepressants
new directions for epigenetics
use HDAC inhibitors (imipramine) as antidepressants
Boks et al., 2012
multimodal vs monomodal approach
wilkinson et al., 2019
multimodel is synergistic (preferred)
opposing neuromodulatory role of endocannabinoid system
DSI - depolarisation induced suppression of inhibition DSE - depolarisation induced suppression of excitation
CB1 (most common receptor-GPCR)
CB1 antagonism has mixed effects in animal studies studies (target endocannabinoid ost-release uptake and degrade)
promising preclinical finsigs for anandamine transporter blocker and inhibitor of fatty acid amide hydrolase
neuropeptides
located in brain areas implicated in anxiety
CCK - CCK2 R ant clinical trials unsuccesful
NPY - anxiolytic effect - no drug targetting NPY in clinical trials
Tachykinins - NK1/NK2 R ant anxiolytic - inconclusive clinical trials
OT - emotions (fear/anxiety/stress) intranasal spray (clincial trials)
adult hippocampal neurogenesis
formation of new neurons from hippocampal SCs (SVZ/SGZ)
levels of DG neurogenesis correlate to hippocampal dependent learning tasks
decreased hippocampal neurogenesis in depressed patients and animal models
enhancing neurogenesis
antidepressants promote neurogenesis
functional integration of new neurons (6-8 weeks) delay in changing neuronal function/circuitry
develop drugs which promote hippocampal neurogenesis e.g. BDNF
