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Depression and Anti-Depressants Flashcards

1
Q

Q: Which of the following neurotransmitters are most closely associated with depression?

A

A: Norepinephrine and serotonin.

Dopamine is a monoamine but has less of a role as NE and serotonin.

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2
Q

Q: The two major hypotheses for depression state that:

A

A: Levels of monoamines are too low in depression; depressed patients have decreased dendritic spines/sprouts

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3
Q

Depression Symptoms

A
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4
Q

SERT

A

serotonin reuptake transporter

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5
Q

NET

A

norepinephrine reuptake transporter

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6
Q

BDNF

A

brain derived neurotrophic factor

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7
Q

SSRI

A

selective serotonin reuptake inhibitor

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8
Q

SNRI

A

serotonin & NE reuptake inhibitors

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9
Q

TCA

A

tricyclic antidepressants

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10
Q

MAO

A

monoamine oxidase

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11
Q

Depression Definition

A

Definition—Persistent low mood with loss of enjoyment and pleasure

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12
Q

Types of Depression

A
  • Major depressive disorder – more serious – associated with an increased risk of suicide
  • Dysthymia – mild/moderate form of depression – not feeling 100%, persists for a very long time
  • Post-partum depression – seen in mothers after birth, seen after 6 weeks
  • Seasonal affective disorder – highly correlated with not getting enough sunlight, seen in winter months at higher parallels, often treated with light shining in the eyes in the morning or medication
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13
Q

Monoaminergic approach Goal

A

Goal: increase levels of serotonin and norepinephrine (NE is not raised alone – a stimulant may increase energy, but won’t fix the problem)

  • Block reuptake (primary way) – traps NT in the synapse à increased interaction with receptor on post-synaptic membrane.
  • Stop degradation in the pre-synaptic terminal and the synapse. (MAO/COMT)
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14
Q

Causes of Depression

A
  • Genetics
  • Environment
  • Biochemical
  • Psychological
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15
Q

Depression Neurophysiology

A

Decreased monoamines

  • Serotonin 5-HT
  • NE

Effective therapeutics increases monoamines

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16
Q

Monoamine Hypothesis

A
  • There is less NT available in the synapse, less acting on receptors postsynaptically (Don’t know what causes this)
  • Depressed + treatment – block reuptake transporters → synapse levels rise à bind at normal or greater levels → depression starts to lift on a behavioral level
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17
Q

Neurotrophic Hypothesis

A
  • Dendrites that create more synapses = healthier neuronal connection
  • Spines/sprouts – areas where other neurons make a synapse
  • BDNF(Brain Derived Neurotropic Factor) – growth factor secreted by neurons – responsible for health and wellness of neurons – creates more spines/sprouts
  • Depressed patients have less dendritic spines/sprouts, decreased level of BDNF
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18
Q

What increases BDNF?

A
  • Exercise
  • Smiling/laughing
  • Antidepressants
  • Electroconvulsive therapy
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19
Q

What decreases BDNF?

A
  • Stress
  • Pain (chronic moderate/severe)
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20
Q

Therapeutics and Pharmacology:

Monoaminergic Approach

A

MAO – only one in inside the cell – not COMT

COMT - is usually only found in synapse

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21
Q

Major classes of antidepressants

A
  • SSRI—Selective Serotonin Reuptake Inhibitors
  • SNRI—Serotonin and Norepinephrine Reuptake Inhibitors
  • Tricyclics
  • NDRI – Norepinephrine and Dopamine Reuptake Inhibitors
  • MAO Inhibitors
  • Atypicals – drugs that don’t fit into one of the other 4 categories
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22
Q

Selective Serotonin Reuptake Inhibitors (SSRI)

A
  • MOA: Block serotonin reuptake in the synapse – increases the opportunity for serotonin to bind to the receptor in the post-synaptic membrane
    • Drugs:
      • Fluoxetine (Prozac) – has a very long half-life
      • Citalopram (Celexa)
      • Escitalopram (Lexapro)
      • Sertraline (Zoloft)
      • Paroxetine (Paxil) – has a very short half-life
      • Fluvoxamine (Luvox)* (only FDA approved for OCD, but works for depression) – has a very short half-life
23
Q

Selective Serotonin Reuptake Inhibitors (SSRI)

General Side Effects

A
  • General Side Effects – caused by increases in serotonin levels everywhere, not just the brain
    • GI effects (5-HT3 mediated) – primarily related to 5-HT3 effects
      • Nausea (dose dependent)
    • Stimulation and anxiety – due to the non-specific activity of serotonin receptors in the brain
      • Insomnia, agitation
    • Sexual dysfunction – for both males and females – believed to be linked to non-specific agonist activity at 5-HT2 receptors
    • Headaches – due to increased vasoconstriction/vasodilation in the brain because of serotonin level fluctuating
    • KEY: keep the dose as low as possible
    • Rethink the drink→Alcohol use may worsen depressive symptoms, and combining with SSRIs may cause increased sedation
24
Q

Selective Serotonin Reuptake Inhibitors (SSRI)

Discontinuation Syndrome

A
  • Discontinuation Syndrome – biggest risk to patient – patient abruptly stops taking their medication – patient has down-regulation of receptors (decreased sensitivity in receptors) → they go through withdrawal
    • Dizziness
    • Nausea
    • Anxiety
    • Agitation
    • Lethargy
  • Shorter half-life = More problems (Paroxetine)
  • Levels go from high to low very quickly
  • Longer half-life drugs such as fluoxetine have the least risk of discontinuation syndrome
  • Patient should start back on their medication and slowly decrease their dose over time
25
Q

Selective Serotonin Reuptake Inhibitors (SSRI)

Suicide risk

A
  • Suicide risk
    • Patients under 25 y.o. are at greatest risk
      • SSRIs may not be appropriate for younger patients who have suicidal thoughts prior to starting an SSRI
    • Rare over 65 y.o.
26
Q

SSRI Selectivity of Action

A

The more activity outside of SERT, the more side effects

27
Q

(SNRI) Selective Serotonin and Norepinephrine Reuptake Inhibitors

A
  • MOA: Block SERT and NET. SNRI Selectivity of Action – very specific (no effects outside of SERT and NET)
    • Drugs:
      • Venlafaxine (Effexor)
      • Desvenlafaxine (Pristiq)
      • Duloxetine (Cymbalta)
      • Milnacipran (Savella)
      • Levomilnacipran
28
Q

(SNRI) Selective Serotonin and Norepinephrine Reuptake Inhibitors

General Side Effects

A
  • General Side Effects (globally increases serotonin levels and NE)
    • Sexual dysfunction – non-specifically increasing activity at 5-HT2 receptors (metabotropic)
    • Nausea - non-specifically increasing activity at 5-HT3 receptors (ionotropic)
    • Insomnia (CNS stimulation) – due to increase in serotonin and NE
    • Increased blood pressure possible – believed to be due to increased levels of NE
  • Discontinuation Syndrome with chronic use
    • Symptoms are like those with SSRIs
29
Q

(NDRI) Norepinephrine and Dopamine Reuptake Inhibitors

A
  • Bupropion—resembles amphetamine
    • MOA: Blocks NET & DAT (increases synaptic concentration of NE and DA)
      • NO direct 5-HT activity
  • Not for use in epileptics (lowers seizure threshold)
  • Not for use with MAO inhibitors (even though it doesn’t affect 5-HT…why?
    • Still blocking breakdown of NE and DA → risk of toxic levels of NE and DA - Can’t get rid of NE and DA causing high levels
  • Low risk of sexual dysfunction and weight gain…why? Do not increase serotonin levels. Increased NE will act as stimulate.
  • Adverse effects: dry mouth, insomnia (CNS stimulation), seizures (lowers seizure threshold), hypertension, hallucinations/psychosis (direct side effect of increased DA levels)
30
Q

Tricyclic Antidepressants (Block SERT and NET)

A
  • Tertiary amines (greater effect on SERT)
    • Amitriptyline (Elavil)
    • Imipramine (Tofranil)
    • Clomipramine (Anafranil)
    • Doxepin (Sinequan)
  • Secondary amines (greater effect on NET)
    • Nortriptyline (Pamelor)
    • Desipramine (Norpramin)
  • Work similarly to SNRIs, but they do a lot of other things as well – block a1, histamine, and muscarinic cholinergic receptors → can lead to increased risk of side effects
    • Very dangerous drugs, especially in children (low toxicity level)
  • They are very effective, so they are still being used – 30% of patients are not responsive to medication other than TCAs
31
Q

TCAs Major Concerns

A
  • Cardiac toxicity and seizures – especially in children…
    • Due to sodium channel blockade
    • Secondary amines tend to have less cardiac side effects than tertiary amines – may be due to structure and effects on serotonin
    • All have an increased risk of seizure activity
  • Side effects
    • Due to effects on other receptors – Differ by drug
  • Discontinuation Syndrome (possible) with chronic use
32
Q

Tricyclic Antidepressant Side Effects

A
  • Tricyclic Antidepressant Side Effects – dangerous in elderly patients
    • Anti-histaminergic
      • Sedation
      • Confusion
      • Increased appetite (weight gain)
    • Anti-muscarinic
      • Anti-SLUD effects
    • Adrenergic a1 antagonism (NE works at a2 receptors as well so it doesn’t lose its anti-depressive effect)
      • Orthostatic hypotension
  • Selectivity of Action
    • Very non-specific, “dirty” drugs
    • Secondary amines have less side effect concerns than tertiary amines
33
Q

Q: Which of the following would NOT be expected to increase levels of both 5-HT and NE?

A

A: citalopram – SSRI (bupropion would be a right answer too)

34
Q

Q: The adverse sexual dysfunction side effect of SSRIs, SNRIs, and TCAs is primarily due to:

A

A: increased 5-HT levels

35
Q

Q: What receptors may cause orthostatic hypotension and sedation

A

A: alpha-1 antagonist and H1 antagonist

36
Q

Monoamine Oxidase Inhibitors

A
  • Not frequently used due to increased side effect profile
    • MAO
      • MAO A → high affinity for NE and 5-HT; found in brain, gut and liver
      • MAO B→ more centrally located, metabolizes DA and other monoamines
      • Lifespan of MAO is about 2-3 weeks
      • Inhibitors available are irreversible and largely non-specific (takes a while to create a new molecule once medication has been stopped.
37
Q

MAOI Specificity

A
  • Highly non-specific – decrease degradation of dopamine, NE, and serotonin (the three monoamines)
    • No direct action at 5-HT or NE receptors
      • Isocarboxazid (Marplan)
      • Phenelzine (Nardil)
      • Selegiline (Emsam)—Patch
      • Tranylcypromine (Parnate)
38
Q

MAO Inhibitor Side Effects/Disadvantages

A
  • CNS stimulation
    • Tranylcypromine → directly to stimulant
  • Orthostatic hypotension—usually not seen until 3-4 weeks into treatment…why?
  • Weight gain—mechanism is unclear
  • Sexual dysfunction—mechanism via anticholinergic activity, changes in sympathetic tone, changes in serotonin levels (?)
  • Discontinuation or switching can be problematic
    • MAOIs are irreversible→ more MAO must be made – not a quick process
    • Can lead to very bad/fatal side effects
    • Must be very careful when switching MAOIs or adding additional drugs to MAOIs
      • Ensure SERT function is back to normal before adding MAOI or that MAO function is back to normal before adding a drug that affects SERT
  • Serotonin Syndrome – serotonin levels in the brain get to a toxic level – seen when a secondary drug is used that increases serotonin levels (cannot reuptake or degrade serotonin in the synapse)
  • Hypertensive Crisis – not due to SERT inhibition
39
Q

Serotonin Syndrome

A
  • Serotonin Syndrome – serotonin levels in the brain get to a toxic level – seen when a secondary drug is used that increases serotonin levels (cannot reuptake or degrade serotonin in the synapse)
    • Twitching muscles
    • Irregular or high heart rate
    • High fever (further along the toxicity scale)
    • Agitation, headache
    • Diarrhea
    • Seizures
    • Interactions with SERT inhibitors or TCA medications
    • Deadly in 2 – 12% of patients
    • As serotonin levels decrease, symptoms will resolve (self-limiting condition)
  • Major concerns
    • Interactions with SERT inhibitors or anything that increases serotonin
    • Deadly
    • Too much serotonin
40
Q

Hypertensive Crisis

A
  • Hypertensive Crisis – not due to SERT inhibition
    • Symptom is acute onset of severe throbbing headache, possibly accompanied by blurred vision, palpitations, chest pain, shortness of breath
    • Time from ingestion of food to symptoms: minutes
    • Tyramine containing foods aren’t metabolized by MAO since MAOI are being used
    • Tyramine containing foods (aged cheeses, red wine, beer)
    • And supplements (tyramine is often overlooked)
    • Also pseudoephedrine may exacerbate the response
      • Tyramine in food isn’t broken down
      • Gets absorbed in the stomach→ acts as sympathomimetic and increases blood pressure to dangerous levels!
      • Gut effect – caused by inhibition of MAO in the gut before it gets to the brain
        • Seen with oral MAOIs, not as much with the patch (absorbed in systemic circulation and may still have some effect on the gut)
        • Absorbed tyramines from the gut displace NE in vesicles, causing increased levels of NE in synapse and increased sympathetic activation (inc. blood pressure)
        • This is a local (gut) effect (inhibition of MAO in the stomach is the culprit)
      • Examples: beer (alcoholic and non-alcoholic), red wine, aged cheese, pickled/fermented foods, overripe fruit (raisins, bananas), aged meats (salami, pepperoni, etc)
  • Also pseudoephedrine or any sympathomimetic (cocaine, amphetamine, etc) with MAOI can add to the hypertensive risk
41
Q

MAOI Discontinuation or Switching

A
  • Washout required for MAO inhibitors
    • Use with extreme caution with ANY drug that a serotonin agonist or increases serotonin
    • switching away from MAOI wait at least 2 weeks
    • moving to MAOI depends on half-life of other drug that increases 5-HT levels (be careful because you don’t want both effects at the same time.
42
Q

Irreversible MAO inhibitors

A
  • MAO A is responsible for breaking down tyramine in the gut and preferentially mediates the breakdown of serotonin and NE in the brain (will still breakdown dopamine)
  • MAO B is primarily in the brain and preferentially breaks down dopamine
  • Selegiline at low doses is considered specific
43
Q

Atypical Antidepressants

A

Mirtazapine

Trazodone

Nefazodone

Vilazodone

Vortioxetine

44
Q

Mirtazapine

A
  • Atypical
    • A2 antagonist (increase release of NE and 5-HT)
      • A2 receptors are presynaptic auto-receptors (generally function to inhibit NT release) →inhibit inhibition (no slow down of NE release) – blocks negative feed back
      • NE can diffuse to 5-HT pre-synaptic auto-receptors and block inhibition of 5-HT release
      • NE can act on 5-HT cell body → stimulate 5-HT neuron to fire action potential→ increase serotonin release
    • Antagonist 5-HT2 and 5-HT3 (direct)
      • No/low risk of sexual dysfunction or nausea – selectively increase NE, increase serotonin, but block the 2 receptor subtypes that have the most side effects with them
      • Still have a risk of dry mouth, sedation, and weight gain
      • 5-HT2 receptors are also found preferentially on GABA interneurons (inhibitory)
        • GABA interneurons inhibit dopamine and NE neurons from firing
        • Antagonist: Serotonergic disinhibition of NE and DA release (increases release à antidepressant)
    • Agonist at 5-HT1A receptor (indirect)
      • Believed to be antidepressant
  • Adverse effects: weight gain, dry mouth, sedation
    • Less sexual dysfunction and nausea than others
45
Q

Trazodone and Nefazodone

A
  • Antagonists at 5-HT2R, inhibition of SERT at higher dose
    • Controversial, and unkown how much blockade of NET adds to antidepressant activity
    • Disinhibit NE and DA firing → increase release of NE and DA
  • Nefazodone - Liver toxicity (black box warning)
    • MOA is not well understood
  • Adverse effects: sedation (anti-histamine activity), orthostatic hypotension (antagonist at alpha-1 receptors), priapism (prolonged erection - not considered sexual dysfunction, especially in trazodone)
  • Low risk of sexual dysfunction (due to 5-HT2 antagonism)
46
Q

Vilazodone

A
  • Selective SERT inhibitor
    • Very little activity on NET or DAT
  • 5-HT 1A partial agonist
  • Adverse effects: Nausea and diarrhea, some risk of sexual dysfunction
    • Maybe some affinity for 5-HT3 receptors
47
Q

Vortioxetine

A
  • Selective SERT inhibitor
  • 5-HT 1A receptor agonist, 5-HT3 receptor antagonist (low incidence of nausea)
  • Adverse effects: Sexual dysfunction (agonist activity at 5-HT2)
48
Q

Q: A major concern for use of MAO inhibitors is hypertensive crisis which occurs when:

A

A: the patient consumes food with significant amounts of tyramine while on MAOI

49
Q

Q: Phenelzine would increase levels of which of the following NT except?

A

A: None – it would increase the levels of DA, NE, and 5-HT

50
Q

Q: Which of the following atypical antidepressants would NOT have decreased incidence of sexual dysfunction?

A

Vilazodone

51
Q

Q: When should a patient switch from a SSRI to an MAOI?

A

A: The patient should have ample time after stopping fluoxetine to allow the fluoxetine to leave the body before starting on the MAOI

52
Q

Delayed therapeutic effect

A
  • Problem: Pharmacologically relevant concentrations reached very fast
    • Therapeutic effect lags behind (2-8 weeks) – usually around 4 weeks
  • Possible causes:
    • Receptor down regulation
      • Remodeling is crucial for the full effects to be seen
    • Uptake of 5-HT by other transporters – due to excess serotonin being packaged by other neuron types
    • Downstream effects (gene transcription or neurogenesis) – changing second messenger system or cascade for full efficacy
    • The brain needs to rebuild the dendritic spines/sprouts – it takes time
      • Healthier BDNF environment may lead to full efficacy
    • NOT because the patient did not reach steady state levels
53
Q

Q: Which drug has the lowest incidence of sexual dysfunction?

A

A: Trazodone (atypical)

54
Q

Ketamine

A

Ketamine is the newest drug that is given during the lag time for a patient with suicidality that has been started on an antidepressant

Neuro (4 decks)

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