Mood Disorders II Flashcards
SSRI goal
to work on 5HT and NA
Without affecting Histamine, Muscarinic ach receptors or adrenergic receptors
i.e. have the same mechanism as TCAs w/o TCA side effects
How SSRIs work
prevent reuptake of 5HT by SERT –> increase 5HT in synapse
5HT precursor is
tryptophan
Best known SSRI
fluoxetine
Fluoxetine uses
Best known SSRI
Used for MDD, OCD, bullemia nervosa, panic disorder and premenstrual dysphoric disorder
SSRI uses
Most used ADs but also used for anxiety
and OCD, bullemia nervosa, panic disorder and premenstrual dysphoric disorder
SSRI side effects
- Anorexia, insomnia and drug interaction
- Can cause serotonin syndromes –> tremor, hyperthermia and cardiovascular collapse
- Lower affinity for mAchRs therefore fewer anti-cholinergic effects
NRIs (noradrenaline uptake inhibitor)
- NA specific
- Block activity of NET –> Accumulation of NE in synaptic space
Pathway for NE formation
Tyrosine –Via TH –> DOPA –> dopamine –> NE
NRI examples
Atomoxetine–ADHD in children
Reboxetine–most specific; Used for MDD and off label use for panic disorder and ADHD
Viloxazine–AD; Stimulant like amphetamine w/o dependence
Atomoxetine
NRI used for ADHD in children
Reboxetine
- most specific NRI
- Used for MDD
- Also used off label for panic disorder and ADHD
Viloxazine
NRI used as AD
Stimulant like amphetamine w/o dependence
NRI side effects
Hypertension, increased HR, tremor, decreased appetite
NRI eliminated by
CYP450 in liver
therefore there is potential for interaction with drugs that induce/decrease CYP450 levels
SNRI (Selective serotonin-noradrenaline uptake inhibitor) examples
two examples: Duloexetine and venlafaxine
SNRI side effects
- Headache, nausea, hypertension
- Also eliminated by CYP450 and can have drug interaction through CYP
SNRI eliminated by
CYP 450, can therefore have drug interactions
SNRI uses
as AD
but also effectie for anxiety and neuropathic pain
Duloxetine
SNRI used for MDD, generalized anxiety, fibromyalgia, neuropathic pain
Venlafaxine
SNRI used for MDD, generalized anxiety, panic disorder and social phobia
2 main ways to study mood disorders
In humans or animal models
Human research of mood disorders
Human research–usually observational using imaging (during tasks, or between controls and depressed patients)
Look at genes responsible–twins or GWAS
Imaging techniques used in human research of mood disorders
Imaging:
• Positron-emission tomography (PET)
• Magnetic resonance imaging (MRI)
• Functional magnetic resonance imaging or functional MRI (fMRI)
Genetic study of mood disorders in humans through
Twin studies OR Genome-wide association study (GWAS)
Human imaging in depression: how we study it
Brain scan while preforming 2 different tasks
1) Emotional discrimination task (EDT)
2) Object discrimination task (ODT)
Use FMRI to look at default mode network
Using EDT: ODT ratio–can measure whether Default mode network is activated or not
Depression test–how we measure depressive mood in humans
hamiliton depression rating scale
Default mode network
Most commonly active when brain is at active rest (ex. Daydreaming, mind wandering) or when indv is thinking of others, about the past or toward the future
Default mode network correlates to other networks like ______
Correlated with other networks
ex. Attn networks
EDT: OCT ratio
Using ration between EDT or ODT–can measure whether Default mode network is activated or not
Positive value = activated
Negative = deactivated
Studying default modenetwork: when goiven AD
Given Escitalopram (AD) and told to come back after 2 weeks - Measure Difference b/t first and second test (w/o AD and post-AD)
After given AD axis change in default mode network activation
X-axis changes in depression after 2 weeks
Y-axis activation of Default mode network
3 categories of people in depression test of default mode network
Non-responder = inactivation of default mode responded better
Early improver
responder
Non-responder =
inactivation of default mode; responded better
Why look at categories of people and default mode activation state
Might be able to predict whether a medication will be helpful or not based on a brain scan
Ways to model mood disorders in rodents (tests)
- Forced swim test
- Tail suspension test
- Learned helplessness
- Social defeat stress
Social defeat test
- Put small mouse together with a bigger, more aggressive mouse
- The bigger one will engage it and defeat it in every session, after ten sessions put them together but separated by a window
- Final test: big mouse in its own area and the small mouse is left to roam
- The amount of approaches to the large mouse indicates depression
How approach determines depression in social defeat test
The amount of approaches to the large mouse indicates depression
- Does not approach = more depression
- More it approaches = less depressed
Ketamine
A dissociative anesthetic (like PCP and DXM)
- first synthesized in 1962
- Used as anesthetic, but lacks deep
sedative effect
Ketamine tolerance
Tolerance can be developed after
repeated use
Ketamine as a AD
1 admin of ketamine can maybe be used for treatment-resistant depression
Goal of this study to find a drug that has the beneficial effects of ketamine w/o the side effects
First:
Compared ketamine to desipramine –> in forced swim test
Desipramine vs saline –> less time immobile with DA
Ketamine also decreased immobility in forced swim test
Ketamine is also an NMDA antagonist and they compared it to another NMDA-antag (MK 801)
Both MK-801 and ketamine reduced immobility time in forced swim test
But only ketamine was able to maintain its effect for 24 hours
Means that the AD effect of ketamine does not depend on NMDA-antagonism
Rodent study of ketamine in depression WHY
Goal of this study to find a drug that has the beneficial effects of ketamine w/o the side effects
Rodent study of ketamine in depression HOW
First: Compared ketamine to desipramine –> in forced swim test
- Desipramine vs saline –> less time immobile with DA
- Ketamine also decreased immobility
Ketamine is also an NMDA antagonist and they compared tit to another NMDA-antag (MK 801)
Both MK-801 and ketamine reduced immobility time in forced swim test
But only ketamine was able to maintain its effect for 24 hours
Means that the AD effect of ketamine does not depend on NMDA-antagonism
Forced swim test
The more the mouse stays afloat without moving the more depressed
Ketamine is an ____ _____ (antag/agonist)
Ketamine is also an NMDA antagonist and can be compared to another NMDA-antag (MK 801)
Ketamine in forced swim test
study compared ketamine and MK-801 because of NMDA antag properties
- Both MK-801 and ketamine reduced immobility time in forced swim test
- But only ketamine was able to maintain its effect for 24 hours
Does ketamine’s AD effect depend on NMDA actions
NO, as MK-801 another NMDA antag was not effective for 24 hours but ketamine was–citing different actions
Ketamine metabolism
Ketamine can be methylated to form nor-ketamine
OR hydroxylated to form hydroxy-ketamine or hydroxy-norketamine
Ketamine enantiomer in forced swim test
Hydroxynorketamine enantiomer had a simialr effect in reducing immobility in forced swim test to ketamine
2R,6R enantiomer worked BUT 25,26 enantiomer did not
Ketamine enantiomer in learned helplessness task
in learned helplessness test–2R, 6R enantiomer worked at reducing depressive phenotype like ketamine
Ketamine enatiomer in chronic social defeat test
Chronic social defeat stress test–2R, 6R ketamine showed more approaches to larger animal and therefore a decreased depressive phenotype
____ enatiomer of HNK (hydroxynorketamine) ____ side effects of ketamine like ______
2R, 6R-HNK lacks side effects of ketamine like locomotion
Ketamine side effects in mice: Increased locomotion
2s, 6s –> increased locomotion
2R, 6R –> no increase in locomotion
Rotarod in HNK enatiomers vs ketamine
Ketamine–fall immediately after 5 minutes, only acts normally after 15 mins
BUT enantiomers don’t show this initial lack of coordination
Rotarod
walking on rotating cylinder–measure amount of time on the rotarod without falling
More time on it = better the motor behaviour
Self-admin of ketamine vs. enatiomers
- Animals treated with ketamine–will increase their consumption of the drug
- While those taking 2R, 6R will not
- Suggest 2R,6R hydroxynorketamine may be a ketamine alternative for depression treatment that lacks the side effects of ketamine (including tolerance and addiction)
Fear
a complex physiological, behavioral, cognitive, and subjective response
to a threatening stimulus
• adaptive response to real threats, usually transient
Anxiety
Anxiety is a longer-lasting response to danger signals that can arise from:
A. immediate circumstances (well defined danger)
B. vague indications of ill-defined events that are thought to have adverse
consequences
Aspects of anxiety that are beneficial
arousal, vigilance, and physical preparedness increase the likelihood of
survival in dangerous situations
___ in fear systems leads to anxiety
issues/dysregualtion
Anxiety differs from fear due to
the vagueness of threat AND duration of response
If it was to a real threat and shorter term it would be helpful and adaptive (i.e. FEAR)
Threat detection network
Brain regions for fear: threat detection network
Amygdala, ACC, ventromedial PFC, hippocampus, insular cortex
Amygdala
- Amygdala is the key region in threat detection network
- Regulates fear and anxiety through bidirectional connections to the ACC and vmPFC, hippocampus
In anxiety (esp. ______) get ______ (hypo/hyperactivity) of ______ and _____ (increased/decreased) activity of ______
In anxiety ( esp. PTSD) get hyperactivity of amygdala and diminished vmPFC activity
PTSD effects in threat detection network
Functional connectivity b/t amygdala, hipp, vmPFC, dACC and the anterior insula is deficient in PTSD
Social anxiety and threat detection network
treatment with CBT has been shown to rectify the disturbances in the threat network
4 step model of threat detection network
1) External events detected
a. Regions: thalamus, sensory cortex
2) External stimuli interpreted as threatening or non-threatening
a. In amygdala or hipp
3) Evaluation of stimuli
a. By VTA, NAc and PFC
4) Initiation of response
Whether an event is interpreted as threatening or non-threatening is due to the _____________________
the balance b/t opposing circuits
The balance between threat/non-threat is ____ in anxiety
shifted towards threat in anxiety
Many of the ____ in anxiety are also involved in ________
Nuclei; depresseion
Many of the nuclei involved in anxiety are the same as those involved in depression
Differences b/t anxiety and depression circuits
Main differences: NTs
Anxiety: gaba and glut
Depression: catecholamines
Anxiety disorders characterized by
Excessive and enduring fear, anxiety and/or the avoidance of perceived threats
external (social situations)
internal (bodily sensations)
Panic attack
abrupt fear response
Anxiety disorders onset
May occur throughout life but some have a specific age of onset
Ex. Separation anxiety –mainly during childhood
Social anxiety–in adolescence or early adulthood
Panic disorders/panic disorder and GAD–age of onset varies but typically around early adulthood
Separation anxiety onset
Mainly in childhood
Social anxiety onset
in adolescence and early adulthood
Panic disorders onset
Typically around early adulthood BUT varies
GAD onset
Typically around early adulthood BUT varies
Anxiety tretaments
CBT or pharmacological tretament
Anti-anxiety drugs
most commonly SSRIs or SNRIs
Can also use benzos
Benzodiazepines–alternatives for anxiety
Anti-epileptic drugs
(GABA - gabapentin, pregabalin)
Atypical antipsychotics (risperidone,
quetiapine)
Benzos how they work
Allosteric modulators of GABA-aRs
Results in anxiolytic, muscle-relaxant, anti-convulsant props
Issues with Benzos
BUT possible issues of abuse or dependence
Esp. In those with past alcohol abuse or other substance abuse disorders
Benzo uses
Treat insomnia, anxiety, seizures
Also can use anti-epileptics–target GABA
Drugs used instead of Benzos
Ex. Gabapentin or pregabalin–used in place of Benzo when worried about abuse
Can also use atypical antipsychotics
Ex. Risperidone, quetiapine
Might also be useful; esp. As an adjacent therapy to SSRIs
SSRIs
Paroxetine. sertraline, fluoxetine, venlafaxine, citalopram
NRIs
Atomoxetine, viloxazine, reboxetine, maprotiline, nisoxetine, talopram
SNRIs
duloxetine, velafaxine
