Neuropharmacology and depression Flashcards
Describe the monoamine hypothesis for major depression.
The hypothesis states that depression is the result of monoamine deficiency in the brain, based on experminents where inhibition of NE and 5-HT reuptake alleviated symptoms, as well as inhibition of monoamine oxidase (MAO).
Define long-onset of action of treatment with anti-depressive agents (define the time it takes for the drug to work).
SSRIs: Min. 2 weeks, most commonly 4 weeks
- ketamine: 2 hours
- psychedelics: 2 days
Provide examples of drugs used as first-line treatment of major depression.
Selective serotonine reuptake transporters (SSRIs): escitalopram (lexapro), fluoxetine (prozac), sertraline (zoloft)
Describe the use of ketamine for treatment of depression.
- NMDA antogonist
- it’s not 100% understood how it works, but it’s hypothesized that it might work on the GABAergic system –> disinhibition –> more glutamatergic transmission –> increased plasticity and neuronal survival
Briefly describe the serotonin system.
Main pathway: Raph nuclei –> almost all parts of the brain
What is SERT?
Serotonin transporter (reuptake)
What are the main functions of serotonin?
- mood and emotions
- sensory transmission
- sleep/wakefulness
- feeding and appetite
- sexual functions
- body temp
- nausea/vomiting
Briefly describe the unifying theory.
- 5-HT1AR-rich –> decrease in depression (passive coping)
- 5-HT2AR-rich –> increase in well-bering (active coping)
Briefly describe the NE system.
Main pathways: Locus coeruleus –> cortex, hippocampus, cerebellum
What are the main functions of NE in the brain?
- increases arousal and alertness
- promotes vigilance and fear
- increases memory formation and retrival of memory
- regulates emotions
- regulates attention
- also possible autonomic effects
What is NET?
NE reuptake transporter
What is TCA, and what does it bind to?
- Tricyclic antidepressants
- promiscous: binds to both NE and 5-HT reuptakers –> inhibition
- varying affinity to alot of other receptors –> alot of side effects
What is SNRI, and what does it bind to?
- serotonine NE reuptake inhibitors
- binds with high affinity to both NE and 5-HT transporters
- a bit stronger than SSRIs
- same side effects as SSRIs + light side effects in relation to inhibition of NA uptake
What is NRI, and what does it bind to?
- NE reuptake inhibitors
- less efficacy (5-HT reuptake must be inhibited for decrease in symptoms)
- light side effetcs
What is MAOI, and what does it bind to?
- monoamine oxidase inhibitors
- prevents degradation of 5-HT, NE and dopamine
- little specificity for MOA
- long lasting effects
- many side effects!
- drug and food interactions
What is NaSSA, and what does it bind to?
- NE 5-HT selective antagonist
- antagonist at pre-synaptic alpha-2-R located on both NE and 5HT neurons –> increased release of 5ht and NE
What are the major side effects of SSRIs?
- headache and nausea
- tiredness
- diarrhea
- agitation
- sleep disturbances
- sexual dysfunction
- arrythmia
- suicidal behavior and personality changes
- 5HT syndrome when overdosed in combi with e.g., TCA –> tremor, hyperthemia, cardiovascular shock
Are SSRIs addictive?
- not in the classical sense, as they aren’t affecting the dopamine system
- can however induce withdrawal syndrome
What is a possible expaination to why it takes 3-4 weeks before theres a significant antidepressive effect?
The drug also work on the presynaptic autoreceptor –> inhibtion of 5-HT release in the beginning, but because of a gradual desensitization and downreg of presynaptic auto-receptors the drugs eventually leads to elevated levels of 5HT and NE
Describe the use of lithium for treatment of bipolar disorder.
- only efficient againt mania in an acute attack (no acute effect on depression)
- prevents mood swings
- monovalent cation mimicking Na+: permeates Na+ channels + not pumped by the Na/K pump –> accumulaiton inside cells –> depol
- inhibtion of signaling pathways:
inhibition of inositol monophophatase –> inhibition of PI pathway –> block effects mediated by GPCRs
inhibition of glycogen synthase kinase
inhibition of cAMP production
