Neuropharmacology and depression

Question 1

Describe the monoamine hypothesis for major depression.

Answer 1

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).

Question 2

Define long-onset of action of treatment with anti-depressive agents (define the time it takes for the drug to work).

Answer 2

SSRIs: Min. 2 weeks, most commonly 4 weeks
- ketamine: 2 hours
- psychedelics: 2 days

Question 3

Provide examples of drugs used as first-line treatment of major depression.

Answer 3

Selective serotonine reuptake transporters (SSRIs): escitalopram (lexapro), fluoxetine (prozac), sertraline (zoloft)

Question 4

Describe the use of ketamine for treatment of depression.

Answer 4

• 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

Question 5

Briefly describe the serotonin system.

Answer 5

Main pathway: Raph nuclei –> almost all parts of the brain

Question 6

What is SERT?

Answer 6

Serotonin transporter (reuptake)

Question 7

What are the main functions of serotonin?

Answer 7

• mood and emotions
• sensory transmission
• sleep/wakefulness
• feeding and appetite
• sexual functions
• body temp
• nausea/vomiting

Question 8

Briefly describe the unifying theory.

Answer 8

• 5-HT1AR-rich –> decrease in depression (passive coping)
• 5-HT2AR-rich –> increase in well-bering (active coping)

Question 9

Briefly describe the NE system.

Answer 9

Main pathways: Locus coeruleus –> cortex, hippocampus, cerebellum

Question 10

What are the main functions of NE in the brain?

Answer 10

• increases arousal and alertness
• promotes vigilance and fear
• increases memory formation and retrival of memory
• regulates emotions
• regulates attention
• also possible autonomic effects

Question 11

What is NET?

Answer 11

NE reuptake transporter

Question 12

What is TCA, and what does it bind to?

Answer 12

• Tricyclic antidepressants
• promiscous: binds to both NE and 5-HT reuptakers –> inhibition
• varying affinity to alot of other receptors –> alot of side effects

Question 13

What is SNRI, and what does it bind to?

Answer 13

• 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

Question 14

What is NRI, and what does it bind to?

Answer 14

• NE reuptake inhibitors
• less efficacy (5-HT reuptake must be inhibited for decrease in symptoms)
• light side effetcs

Question 15

What is MAOI, and what does it bind to?

Answer 15

• 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

Question 16

What is NaSSA, and what does it bind to?

Answer 16

• 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

Question 17

What are the major side effects of SSRIs?

Answer 17

• 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

Question 18

Are SSRIs addictive?

Answer 18

• not in the classical sense, as they aren’t affecting the dopamine system
• can however induce withdrawal syndrome

Question 19

What is a possible expaination to why it takes 3-4 weeks before theres a significant antidepressive effect?

Answer 19

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

Question 20

Describe the use of lithium for treatment of bipolar disorder.

Answer 20

• 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