antidepressants Flashcards
what are the different forms of depression?
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
symptoms of depression?
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
what is required for a diagnosis of depression?
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
what brain regions or involved in depression?
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)
what are some examples of genetics being involved in depression (x2)?
- postnatal depression - child more susceptible to depression as result of epigenetic changes in mother and baby
- 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
what animal experiments are used when investigating depression (with some info)?
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
what three drugs support the monoamine hypothesis?
first antidpressant, drug that induces depression, general group of anti
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
what is imipramine?
a classic tricyclic - It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons
what do monoamines do?
They’re not just NTs, can have longer term effects, including trophic effects (growth)
what is the most common MAOI?
moclobemide (reversible MAO- type A inhibitor)
aside from monoamines and BDNF, what has been implicated in depression?
Excess activation of glutamate (NMDA) receptors = neurodegeneration
what kind of drug being investigated for depression seems contradictory?
MA receptor antagonists - seems contradictory, but they work to inhibit the receptors on presynaptic membrane that promote re-uptake
monoamine oxidase - what versions are there and which do they target mostly?
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
what is the issue with MAOIs/why are they not the first port of call?
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…
phenelzine - what is it etc…
a MAOI (reversible)
how do tricyclics work and include an example?
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
why does TCAs have side effects?
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
how can TCAs be dangerous?
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
what is citalopram?
an SSRI, first port of call normally
what are the benefits of SSRIs?
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
serotonin pathways - where are the cell bodies found?
raphe nuclei, but project to basically all areas from the sounds of things, amygdala, hypothalamus etc…
how is serotonin made?
from tryptophan precursor
explain the different kinds of serotonin receptors?
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
antidepressants are slow to work, even tho they rapidly increase MA NTs. give two possible explanations as to why?
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
what does BDNF do?
Stabilises synaptic connections, essential in synaptic plasticity and strengthening connections, also growing neurons, and preventing apoptosis in neurons
what is theorised happens with neuronal growth in depression?
BDNF in stress? in treatment with antidepressants?
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
name some other approaches to treating depression
Anti-epileptic and some antipsychotics
Shock therapy - apparently no longer torture
Electromagnetic therapy
Deep brain stimulation or vagus stimulation
bipolar disorder - what is used to treat it?
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
name 2 recreational drugs being looked at for treating depression?
LSD = increased neuroplasticity and brain cell connections
Sub anaesthetic doses of Ketamine are good antidepressants especially in individuals resistant to other medications
reboxetine - what is it?
first NA selective reuptake inhibitor
Better for some individuals, and fewer side effects than non-selective drugs like TCAs and SSRIs
