Depression

Question 1

Neurochemical implicated in depression

Answer 1

Monoamines (serotonin, 5-HT; dopamine; norepinephrine), BDNF (brain-derived neurotrophic factor, CRF (corticotropin releasing factor [or hormone]), Cortisol

Question 2

What does deficient monoamine signal?

Answer 2

Decreases in BDNF: decreases synaptogenesis, neuroplasticity, cell survival, neurogenesis, and increases apoptosis (planned cell death)

Question 3

Low “level” of the 5-HT system is associated with?

Answer 3

Increased “negative affect”: dysphoria, rumination, guilt/distrust, worthlessness, loneliness, fear/anxiety, irritability, hostility, suicidality, particularly affects the prefrontal cortex, amygdada, and hypothalamus

Question 4

Low “level” of the DA system is associated with:

Answer 4

Decreased “positive affect”: dysphoria, anhedonia, loss of motivation & enthusiasm, apathy, anergia or psychomotor retardation, impaired attention and cognition, decreased self-confidence, particularly affects prefrontal cortex, nucleus accumbens, basal ganglia, hypothalamus

Question 5

Low “level” of the NE system is associated with:

Answer 5

Increased “negative affect” and decreased “positive affect”

Question 6

NT interactions

Answer 6

neurotransmitter interactions: they affect each other and thus, the release of their own NTs and other monoamines

Question 7

Action of anti-depressants

Answer 7

Affect the metabolic/gene transcription: decrease various receptors & chemicals associated with stress, depression, anxiety, and increase chemicals associated with healthy neurons, resiliency, less depression & anxiety.

Question 8

Action of anti-depressants

Answer 8

Decrease excessive CRF (corticotropin releasing factor) and cortisol, caused by stress.

Question 9

What are the impact of too much CRF and cortisol?

Answer 9

Cause atrophy in the hippocampus, amygdala, prefrontal cortex, thereby impairing memory, cognitive/executive function, efficient emotional processing (anti-depressants decrease such atrophy associated with deficits)

Question 10

BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) in hippocampus

Answer 10

Increased by anti-depressants in the brain

Question 11

BDNF

Answer 11

cell repair, synaptogenesis, long-term memory, blocks toxic levels of cortisol

Question 12

Which of the 6 SSRIs is most “guilty” of causing withdrawal symptoms?

Answer 12

Paxil

Question 13

What is the difference between relapse and recurrence?

Answer 13

Relapse occurs after continuation of the anti-depressant during the 4-9 month period since beginning the drug (continuation phase). The recurrence period occurs during the maintenance phase after 1+ year of taking the drug.

Question 14

During what timeframe is the acute phase of beginning an anti-psychotic drug?

Answer 14

6-12 weeks.

Question 15

After 4 different anti-depressants, how many people still have not remitted (have residual symptoms)?

Answer 15

33%

Question 16

What are the least common residual symptoms in non-remitters?

Answer 16

Depressed mood, suicidal ideation, & psychomotor retardation

Question 17

What are the most common residual symptoms in non-remitters?

Answer 17

Insomnia, fatigue/pain, concentration, & loss of interest

Question 18

What populations don’t do as well with anti-depressants (don’t benefit as much, and risk is higher)?

Answer 18

adolescents and elderly

Question 19

What population has not been well studied in terms of the risks and benefits of giving them anti-depressants?

Answer 19

children (12 years and under)

Question 20

How long should anti-depressants be continued after the response or remission, to prevent relapse?

Answer 20

4-9 months: If 1st episode, you can probably d/c at the end of the continuation phase (appox. 1 year); If 2nd episode (assess if there are risk factors), and d/c gradually at end of continuation phase if no risk factors, or maintain for life to prevent recurrence in risk factors are present. After 3rd episode, maintain for life. Risk factors: bipolar, family history of mental illness, suicidal or para-suicidal behaviors, substance use

Question 21

How long should anti-depressants be continued after the response or remission, to prevent relapse?

Answer 21

4-9 months: If 1st episode, you can probably d/c at the end of the continuation phase (appox. 1 year); If 2nd episode (assess if there are risk factors), and d/c gradually at end of continuation phase if no risk factors, or maintain for life to prevent recurrence in risk factors are present. Risk factors: bipolar, family history of mental illness, suicidal or para-suicidal behaviors, substance use

Question 22

How long does it take for neurotransmitters to increase in the brain after an anti-depressant is started?

Answer 22

A few days.

Question 23

How long does it take for receptor sensitivity to decrease in the brain after an antidepressant is started?

Answer 23

Same amount of time it takes to experience a clinical effect

Question 24

How do SSRIs work?

Answer 24

5HT1a receptor on dendrites or soma (somadendritic autoreceptor) inhibits (reduces) firing and, hence, 5-HT (serotonin) release. They block the reuptake pumps. Also, downregulation of the auto receptors (inhibitors of firing) causes the neuron to release more 5HT at the axon.

Question 25

How do SSRIs work?

Answer 25

5HT1a receptor on dendrites or soma (somadendritic autoreceptor) inhibits firing and, hence, 5-HT release.

Question 26

SSRI side effects

Answer 26

Acute actions at undesirable postsynaptic receptors

Question 27

SSRI side effects

Answer 27

Acute actions at undesirable postsynaptic receptors

Question 28

When do side effects of SSRIs appear?

Answer 28

In first 1-2 weeks when postsynaptic receptors (especially 5HTt2) are activated by the increase in 5HT caused by antagonism of transporter. Often they dissipate in several weeks when postsynaptic receptors have down regulated or desensitized.

Question 29

What is the relationship between 5HT1a and 5HT2a?

Answer 29

They have opposite effects. 5HT1a=increases DA & NE improving "positive affect" and decreases Glu release decreasing anxiety; 5HT2a=decreases DA & NE decreasing "positive affect", and increases Glu release increasing anxiety.

Question 30

What is the relationship between 5HT1a and 5HT2a?

Answer 30

They have opposite effects.

Question 31

What does acute/excessive activation of other 5-HT receptors cause?

Answer 31

Side effects: 5-HT2a/2c in amygdala, prefrontal cortex may cause mental agitation, anxiety, panic; 5HT2a in basal ganglia decreases DA release, thereby causing akathisia, psychomotor retardation, mild parkinsonism, dystonia; 5HT2c in mesolimbic pathway decreases DA release thereby causing apathy anhedonia and decreased libido; 5HT2c/2a in VTA and locus coeruleus decreases DA and NE release, respectively, in prefrontal cortex, thereby causing deficits in attention, cognition. ETC. ETC. ETC. see notes there are too many (slides 49-51). MAIN IDEA: side effects have to do with different receptors, which are located in different areas.

Question 32

What does acute/excessive activation of other 5-HT receptors cause?

Answer 32

Side effects: 5-HT2a/2c in amygdala, prefrontal cortex may cause mental agitation, anxiety, panic; 5HT2a in basal ganglia decreases DA release, thereby causing akathisia, psychomotor retardation, mild parkinsonism, dystonia; 5HT2c in mesolimbic pathway decreases DA release thereby causing apathy anhedonia and decreased libido; 5HT2c/2a in VTA and locus coeruleus decreases DA and NE release, respectively, in prefrontal cortex, thereby causing deficits in attention, cognition.

Question 33

SSRIs that increase synaptic concentration of monoamines

Answer 33

SSRI + 5-HT1a partial agonist (SPARI) = vilazodone (Viibryd) One method of action of SSRIs which blockade transporters (reuptake pumps); 5-HT1a partial agonism; a2 antagonism; 5-HT2a/2c antagonism/reuptake inhibition; inhibition of monoamine oxidase (MAO)

Question 34

SSRI + 5-HT1a partial agonist (achieved with vilazodone) reduces side effects, can also be achieved through:

Answer 34

SSRI plus aripiprazole (Abilify) or quetiapine (Seroquel) - both atypical antipsychotics (FDA approved to augment MDD tx with an SSRI); OR SSRI plus buspirone (BuSpar) - a 5-HT1a partial agonist --> good anti-anxiety effects in addition to anti-depressant.

Question 35

vortioxetine (Brintellix)

Answer 35

A complicated multimodal drug that just came out, (not an SSRI), but a partial agonist at multiple receptors, and an antagonist at other receptors, which all lead to precognitive, enhanced antidepressant effect? (not enough time for head on head comparisons yet) and less sexual, nausea SEs

Question 36

What does antagonizing NE reuptake do? (resulting in "low" NE)

Answer 36

increase positive affect, decrease negative affect, inhibit pain

Question 37

SNRIs = increase synaptic concentration of monoamines via blockade of transporters (reuptake pumps)

Answer 37

serotonin norepinephrine reuptake inhibitors: more active than SSRIs because of NE component. May be more likely to induce mania in bipolar patients. If NE is increased, activation is not usually excessive due to blunting by 5-HT (serotonin). Tend to off-set each other.

Question 38

SNRIs

Answer 38

serotonin norepinephrine reuptake inhibitors: more active than SSRIs because of NE component. May be more likely to induce mania in bipolar patients. If NE is increased, activation is not usually excessive due to blunting by 5-HT (serotonin).

Question 39

SNRIs and dopamine

Answer 39

NE reuptake inhibition (NRI) also increases DA in prefrontal cortex. They indirectly increase dopamine in the prefrontal cortex. Relevant to ADHD.

Question 40

SNRIs and dopamine

Answer 40

NE reuptake inhibition (NRI) also increases DA in prefrontal cortex.

Question 41

NDRI (norepinephrine dopamine reuptake inhibitor)

Answer 41

Increase dopamine in the mesolimbic pathway. Can be diagnosed alone, or as an augmenting agent (ex: buproprion being added to an SSRI) --> often increases positive affect, decreases negative affect, and reduces sexual SEs.

Question 42

NDRI (norepinephrine dopamine reuptake inhibitor)

Answer 42

Increase dopamine in the mesolimbic pathway

Question 43

What is the typical order of antidepressants that will be given/tried?

Answer 43

SSRI --> SNRI --> NDRI

Question 44

Alpha-2 Antagonism = Increase synaptic concentration of monoamines via a2 antagonism

Answer 44

What occurs when there is an increase in synaptic concentration of monoamines. Increased release and re-uptake of NE and 5-HT neurons. (mirtazapine=NaSS=norepinephrine and specific serotonergic antagonist). Decreases nausea, vomitting, diarrhea, but also blocks H1 receptors which causes daytime sleepiness. Also, might get weight gain from blocking H1 + 5-HT2c together.

Question 45

Blockage of H1 + 5-HT2c =

Answer 45

weight gain.

Question 46

Increased synaptic concentration of monoamines via 5-HT2a/2c antagonism/reuptake inhibition

Answer 46

Another mechanism of action for antidepressants (SARI - serotonin 2a/2c antagonist/reuptake inhibitor) - ex: trazodone (Desyrel, Oleptro). Used mainly for insomnia at low dose. Very sedating (blocks H1 and a1 receptors), with no "morning hangover" (short T1/2). Also used as an adjunct to other Ads by blocking some side effects associated with stimulation of 5HT2a receptors (anxiety, agitation, insomnia, sexual dysfunction).

Question 47

Increase synaptic concentration of monoamines via inhibition of monoamine oxidase (MAO)

Answer 47

Another mechanism of action of antidepressants - 2 forms MAOa and MAOb

Question 48

MAOa

Answer 48

metabolizes 5-HT, NE, DA, tyramine (found in gut and brain) - inhibition has antidepressant effect.

Question 49

MAOb

Answer 49

metabolizes DA, tyramine (in brain) - inhibition has no antidepressant affect.

Question 50

MAOa + MAOb =

Answer 50

Robust antidepressant effect. Irreversible MAOIs - permanently inhibit MAOs; new enzymes must be synthesized (takes 2 weeks). Considered "gold standard" because they're so powerful, but they're not given often because they're irreversible. (experts believe underutilized)

Question 51

Why are MAOIs used so infrequently?

Answer 51

many other others, dangerous side effects, and incomplete or incorrect beliefs concerning them

Question 52

Tyramine

Answer 52

An amine found in some foods that potently increases the release of NE, increasing blood pressure. Normally MAO is able to metabolize the extra tyramine and NE and result in no increase in blood pressure.

Question 53

Tyramine

Answer 53

An amine found in some foods that potently increases the release of NE, increasing blood pressure. Normally MAO is able to metabolize the extra tyramine and NE and result in no increase in blood pressure.

Question 54

Foods high in tyramine

Answer 54

dried, aged, smoked, fermented, spoiled, improperly stored meat, poultry, fish, broad bean pods (e.g., fava beans), aged cheese, NOT processed cheese slices, cottage cheese, ricotta cheese, yogurt, cream cheese, most cheese in most commercial chain pizzas. Tap and non-pasteurized beers, but NOT canned or bottled. Many wines have low amounts. Marmite, sauerkraut, soy products, tofu.

Question 55

Foods high in tyramine

Answer 55

dried, aged, smoked, fermented, spoiled, improperly stored meat, poultry, fish, broad bean pods (e.g., fava beans), aged cheese, NOT processed cheese slices, cottage cheese, ricotta cheese, yogurt, cream cheese, most cheese in most commercial chain pizzas. Tap and non-pasteurized beers, but NOT canned or bottled. Many wines have low amounts. Marmite, sauerkraut, soy products, tofu.

Question 56

Serotonin syndrome

Answer 56

More serious condition that can occur when MAOIs are combined with other drugs, but can occur with only one drug - myoclonus, agitation, diaphoresis (sweating), tremor, hyper-reflexia. Greater risk associated with greater selectivity for 5-HT transporter. D/C immediately, do not titrate off. Do not combine any MAOI with another drugs that increases serotonin.

Question 57

Serotonin syndrome

Answer 57

more serious condition that can occur when MAOIs are combined with other drugs - myoclonus, agitation, diaphoresis (sweating), tremor, hyper-reflexia. Greater risk associated with greater selectivity for 5-HT transporter. D/C immediately, do not titrate off.