antidepressants

Question 1

what are the different forms of depression?

Answer 1

Unipolar - always in negative direction, 2 kinds:

Reactive (75%) - in response to an event

Endogenous (25%) = unidentifiable reason (genetic components - many)

Bipolar disorder = depression alternates with mania (excessive self confidence + enthusiasm)
Treatment for unipolar not same as bipolar

Question 2

symptoms of depression?

Answer 2

Anhedonia (low mood + irritable + negative thoughts)
Apathy - loss of interest in daily activities
Weight loss or gain
Low self esteem. Worthlessness + guilt
Insomnia OR excessive sleep (more so later on)
Low libido
Can’t concentrate

Question 3

what is required for a diagnosis of depression?

Answer 3

2 weeks of depressive behaviour and impacts on daily typical function

(note) - Can be result of another condition e.g. cushing’s syndrome, or stress or genetics

Question 4

what brain regions or involved in depression?

Answer 4

adrenal glands = cortisol in response to stress = can enter the CNS

ghrelin and leptin - involved in appetite may be affected, but they can enter CNS and effect that as well as the periphery

Amygdala - fear + emotion

Changes in hippocampus - high levels of cortisol change neuron structure. Less growth factor BDNF (more later)

Ventral tegmental area - reward/important for dopamine - changes with growth factors (an inc in BDNF for some reason)

Cingulate nucleus - deep stimulation of this area can be effective treatment (when drugs aren’t proving to be very effective)

Question 5

what are some examples of genetics being involved in depression (x2)?

Answer 5

1. postnatal depression - child more susceptible to depression as result of epigenetic changes in mother and baby
2. Some SSRIs bind to P-glycoprotein in BBB, which transports drugs back into the bloodstream, but human polymorphisms in gene for it alter efficacy of antidepressants

Question 6

what animal experiments are used when investigating depression (with some info)?

Answer 6

Forced swim test -
Acute stress to animals - depressed state when they give up. Test response to different drugs (try to survive for longer).
Effective drugs often cause inc. in monoamine NTs

Other models used too like shocking the animal - learn helplessness
Analgesics don’t combat ‘stressed behaviour’ but antidepressants do

Question 7

what three drugs support the monoamine hypothesis?

first antidpressant, drug that induces depression, general group of anti

Answer 7

Iproniazid - first specific antidepressant, found to be a MAO inhibitor

Reserpine (not clinically used) produces depression, causes depletion of MA NTs

Tricyclic antidepressants - inhibit re-uptake of 5-HT (serotonin) + NA

Question 8

what is imipramine?

Answer 8

a classic tricyclic - It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons

Question 9

what do monoamines do?

Answer 9

They’re not just NTs, can have longer term effects, including trophic effects (growth)

Question 10

what is the most common MAOI?

Answer 10

moclobemide (reversible MAO- type A inhibitor)

Question 11

aside from monoamines and BDNF, what has been implicated in depression?

Answer 11

Excess activation of glutamate (NMDA) receptors = neurodegeneration

Question 12

what kind of drug being investigated for depression seems contradictory?

Answer 12

MA receptor antagonists - seems contradictory, but they work to inhibit the receptors on presynaptic membrane that promote re-uptake

Question 13

monoamine oxidase - what versions are there and which do they target mostly?

Answer 13

2 genes code for MOAs, type A and type B. Type A MAO are more linked to depression, has preference for 5-HT, so better target

Question 14

what is the issue with MAOIs/why are they not the first port of call?

Answer 14

Type A also found in peripheral SNS, so aren’t breaking down NA, inc. in NA causes reuptake transporters to work in reverse, resulting in NA depletion when an AP comes along, causing postural hypotension

also, Cheese effect - tyramine, an Aa v. similar to tyrosine used in MA synthesis - usually broken down by MAO but on these drugs this doesn’t happen, results in efflux of NA = rise in BP etc…

Question 15

phenelzine - what is it etc…

Answer 15

a MAOI (reversible)

Question 16

how do tricyclics work and include an example?

Answer 16

Non-selective inhibitors of transporters, affecting reuptake of 5-HT and NA and DA and ACh and histamine. Differs from person to person.

E.g. amitriptyline

Question 17

why does TCAs have side effects?

Answer 17

as result of lack of selectivity - these drugs sometimes effect receptors, not just transporters, causing side effects like dry mouth, constipation and blurred vision
Blocking of H1 = sedation effects

Question 18

how can TCAs be dangerous?

Answer 18

in overdose cause excitement, delirium, convulsions…then coma and respiratory depression (exacerbated by alcohol), cardiotoxicity due to block of HERG channels
Also can cause postural hypotension from NA receptor a2 blocking

Question 19

what is citalopram?

Answer 19

an SSRI, first port of call normally

Question 20

what are the benefits of SSRIs?

Answer 20

selectivity to serotonin = less side effects
Side effects of SSRIs nausea, insomnia, sexual dysfunction but LESS sedating and less antimuscarinic side effects than TCAs cause don’t have receptor blocking

Question 21

serotonin pathways - where are the cell bodies found?

Answer 21

raphe nuclei, but project to basically all areas from the sounds of things, amygdala, hypothalamus etc…

Question 22

how is serotonin made?

Answer 22

from tryptophan precursor

Question 23

explain the different kinds of serotonin receptors?

Answer 23

LGICs - these are 5-HT3 (A and B and C)

GPCRs -
if 5-HT1, coupled to Gi

if 5-HT2, coupled to Gq

if 5-HT4 or 5 or 6, coupled to Gs

Question 24

antidepressants are slow to work, even tho they rapidly increase MA NTs. give two possible explanations as to why?

Answer 24

Possibly because the drugs first given, you get 5-HT building up in the synapse, causing desensitisation of autoinhibitory serotonin receptors, resulting in their downregulation, but these changes in expression of (commonly 5-HT1A receptors) takes time

OR

changes in neurotrophins (particularly BDNF) in the hippocampus
antidepressants may target the receptors that inc cAMP = more of the TF, CREB = more BDNF
This process takes time

Question 25

what does BDNF do?

Answer 25

Stabilises synaptic connections, essential in synaptic plasticity and strengthening connections, also growing neurons, and preventing apoptosis in neurons

Question 26

what is theorised happens with neuronal growth in depression?

BDNF in stress? in treatment with antidepressants?

Answer 26

reduced excitability of neurons reduces this presynaptic activity, so synapse no longer reinforced and is therefore loss

Chronic stress = decrease in BDNF in hippocampus
Chronic treatment with antidepressants = increases BDNF signalling

Question 27

name some other approaches to treating depression

Answer 27

Anti-epileptic and some antipsychotics

Shock therapy - apparently no longer torture

Electromagnetic therapy

Deep brain stimulation or vagus stimulation

Question 28

bipolar disorder - what is used to treat it?

Answer 28

Different treatment entirely, lithium most common
Neuroprotective - promoting the growth of neurons and enhancing the survival of existing neurons, thought to modulate NTs like serotonin and noradrenaline

Question 29

name 2 recreational drugs being looked at for treating depression?

Answer 29

LSD = increased neuroplasticity and brain cell connections

Sub anaesthetic doses of Ketamine are good antidepressants especially in individuals resistant to other medications

Question 30

reboxetine - what is it?

Answer 30

first NA selective reuptake inhibitor

Better for some individuals, and fewer side effects than non-selective drugs like TCAs and SSRIs