Lecture 22: Pharmacological Interventions for Depression Flashcards
What is depression?
most common mood disorder in North America
recurring and debilitating mental disorder that impairs social and/or occupational functioning
lifetime prevalence of 14.4%
What are the symptoms of depression?
need 5/9 in a 2 week period
depressed mood
loss of interest in pleasurable activities
changes in weight or appetite
insomnia or hypersomnia
psychomotor agitation or retardation
fatigue
feelings of worthlessness
suicidal ideation
diminished concentration
What are emotions?
subjective feelings (anger, fear, sadness, jealousy, embarrassment, joy)
limbic system
What are motivations?
behavior that is purposeful and goal directed
mesocorticolimbic dopamine system
What is the limbic brain?
the limbic brain is a cortical border circling the brainstem
an evolutionarily “old” neocortex that includes the amygdala, hippocampus, basal ganglia, and cingulate gyrus with connections to the frontal cortex and hypothalamus
What is the relationship between depression and the limbic brain?
patients with major depression disorder (MDD) and health controls were shown images of emotionally evocative facial expression
major depression disorder was associated with increased engagement of limbic regions (amygdala) and decreased engagement of regions involved in motivation (striatum) compared to healthy controls
changes in brain activity reflect changes in neurotransmitter release and/or postsynaptic response
neurotransmitters concentrated within the limbic region may be involved in mediating depression
What is the amine hypothesis of depression?
dopamine, norepinephrine, and serotonin are collectively known as the monoaminergic neurotransmitters
they have overlapping synthesis and catabolic pathways
have a “modulatory” role in the brain, and are involved in mood, arousal, attention
alterations in these neurotransmitters are associated with mood disorders (among other things)
Why is depression associated with inadequate monoamine neurotransmission in the brain?
especially serotonin and noradrenaline
this may be due to: less neurotransmitter release, fewer receptors, impaired signal transduction
originated from serendipitous observations that manipulation of the monoaminergic system influences depression symptoms (i.e. reserpine and ipronazid)
What is reserpine?
15% of patients who receive long term treatment with antihypertensive drug reserpine developed a syndrome indistinguishable from naturally occurring depression
it was discovered that reserpine depletes neurons of dopamine and norepinephrine transmitters
What is ipronazid?
in the 1950s, it was noted that the anti-tubular drug, iproniazid, alleviated depression
it was later discovered this drug inhibited Monoamine oxidase (MAO) the enzyme responsible for the breakdown of monoamines
this led to increased synaptic concentrations of monoamine neurotransmitters
What are the problems with the amine hypothesis of depression?
drugs that restore monoaminergic levels are only moderately effective in 30-50% of patients
inconclusive evidence that serotonin and noradrenergic systems are disrupted in depression
antidepressant take several weeks before clinical effect is seen, despite immediate effects on synaptic neurotransmitter levels
What is the glutamatergic hypothesis of depression?
depression associated with reduction glutamatergic signaling in the cortex
loss of glutamatergic signaling impacts both excitatory and inhibitory function leading to reduced signal to noise
loss of glutamatergic signaling also impacts long-term potentiation, neurotropic production (BDNF), synapse formation, gene transcription (brain remodeling)
blocking amine neurotransmitter breakdown (particularly serotonin and noradrenaline) increase synaptic levels and can improve move
e.g. ipronazid
these drugs must be taken with a low tyramine diet to avoid “tyramine cheese reaction”
What is tyramine?
tyramine is a sympathomimetic monoamine (acts like noradrenaline) and is naturally found in certain foods, such as aged cheese
tyramine is also degraded by MAO
eating a meal rich in tyramine while taking an MAO inhibitor can lead to an acute hypertension reaction caused by tyramine binding to adrenergic receptors on blood vessels and in the heart
What are selective reuptake inhibitors?
inhibit the serotonin (SERT) or noradrenaline transporters (NET)
transporters move neurotransmitter from the synapse to the intracellular space
blocking transporters increase the extracellular concentration of neurotransmitters
drugs that are selective for SERT are called selective serotonin reuptake inhibitors (SSRIs)
drugs that inhibit both NET and SERT are called serotonin norepinephrine reuptake inhibitors (SNRI)
e.g. fluoxetine (e.g. Prozac)
What are the limitation of monoamine antidepressants?
drugs that restore monoaminergic levels are only moderately effective in 30-50% of patients
MAOIs, SSRIs and SNRIs take several weeks before clinical effect is seen, despite immediate effects on synaptic neurotransmitter levels
MAOIs, SSRIs, and SNRIs affect serotonin and noradrenaline levels throughout the body; this leads to side effects such as nausea, indigestion, dizziness, dry mouth, weight loss, etc.
How does the complex network of the brain affect treatment of depression?
conscious states (our thoughts, emotions, experiences) emerge not from an individual brain region or neurotransmitter, but emerges from coordinated activity across a network
mood disorders are a result of inappropriate coupling between brain regions
therefore, drugs that disrupt or reset neuronal activity on a global scale may eb effective at treating depression
What is ketamine?
ketamine is a noncompetitive NMDA receptor antagonist
dissociative anesthetic with hallucinogenic properties
recently been demonstrated to have potential as an anti-depressant medication
What is the mechanism through which ketamine treats depression?
depression associated with reduction in glutamatergic signaling in the cortex
ketamine causes a transient burst in glutamate resulting from blockage of NMDA receptors on GABA interneurons
glutamate burst causes synaptic remodeling and resetting of glutamate and GABA systems
other downstream signaling effects (BDNF release, gene transcription) = long term effects
What are the limitations of ketamine treatment?
initial clinical trials show promise in patients with treatment resistant depression
limitations because very narrow therapeutic index
must be administered intravenously within a hospital setting
How are psychedelics used to treat depression?
emerging evidence that classical psychedelics (psilocybin, LSD) can improve symptoms of depression
recent high quality study shows two doses of psilocybin improves mental health significantly better than SSRIs
What are the limitations to using psychedelics to treat depression?
binding is nearly impossible (participants know if they received psilocybin); may reflect an expectation effect (placebo)
other studies have reported serious side effects in some individuals (e.g. suicidal ideation, anxiety, negative trips)
What is the mechanism through with psychedelics treat depression?
emerging evidence shows psychedelics (and SSRIs) bind to the BDNF receptor (TRKB)
initiates neuroplasticity to “reset” cortical networks
