Anxiety and Depression IV novel targets

Question 1

what is the effectiveness of anxiolytics and antidepressants

Answer 1

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)

Question 2

what do current treatments lack

Answer 2

progress
understanding of neurobiology of anxiety and depression
underlying cellular/molecular pathogenesis

Question 3

pharmacogenetics

Answer 3

study of genetic variations that lead to individual variations in the drug effect (efficacy) and adverse effect profile (toxicity)

Question 4

pharmacodynamics

Answer 4

what the drug does to the body
effect of the drug on the target organ

Question 5

pharmacokinetics

Answer 5

what the body does to the drug
drug absorption/distribution/metabolism/excretion

Question 6

drug metabolism

Answer 6

Phase I (cytochrome P450 enzymes) increase polarity (more likely to be rejected) oxidation/reduction/hydrolysis
phase II - conjugation with an endogenous substance (methyl)

Question 7

drug metabolising enzymes (DMEs) PK

Answer 7

P450 enzymes: CYP2D6/CYP2C19 metabolises antidepressants - highly polymorphic genes
affect response of TCAs

Question 8

DME classifications

Answer 8

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)

Question 9

p-glycoprotein

Answer 9

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

Question 10

5HT transporter
PD

Answer 10

target for SSRI (TCAs)
SLC6A4 encodes transporter - contains 2 polymorphisms (5HTTLPR)

Question 11

NA transporter PD

Answer 11

TCA target
transporter SLC6A4 affects response to TCAs
SNP: rs36029

Question 12

5HTTLPR

Answer 12

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

Question 13

Piquette-Miller & Grant (2007)

Answer 13

individuals with same diagnosis
non/toxic responders given alternative drug/dose
no toxicity responders given conventional dose

Question 14

pros and cons of personalised medicine

Answer 14

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

Question 15

metabotropic glutamate receptors

Answer 15

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

Question 16

NMDAR antagonism

Answer 16

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)

Question 17

HPA axis

Hyman (2009)

Answer 17

PVN releases CRH
ACTH release
AC releases glucocorticoid
stress response regulation (negative feedback)

Question 18

a/d patients and HPA axis

Answer 18

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

Question 19

HPA drugs

Answer 19

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)

Question 20

inflammatory system

Answer 20

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

Question 21

cytokines and NT metabolism

Answer 21

cytokines activate kynurenine pathway
converts 5HT precursor (tryptophan) to neurotoxic end products (deplete 5HT)

Question 22

how to alter the HPA axis

Answer 22

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

Question 23

epigenetics

Answer 23

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

Question 24

environmental effects of epigenetics

Answer 24

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

Question 25

new directions for epigenetics

Answer 25

use HDAC inhibitors (imipramine) as antidepressants
Boks et al., 2012

Question 26

multimodal vs monomodal approach

Answer 26

wilkinson et al., 2019
multimodel is synergistic (preferred)

Question 27

opposing neuromodulatory role of endocannabinoid system

Answer 27

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

Question 28

neuropeptides

located in brain areas implicated in anxiety

Answer 28

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)

Question 29

adult hippocampal neurogenesis

Answer 29

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

Question 30

enhancing neurogenesis

Answer 30

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