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.
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
3
Q
Depression Symptoms
A
4
Q
SERT
A
serotonin reuptake transporter
5
Q
NET
A
norepinephrine reuptake transporter
6
Q
BDNF
A
brain derived neurotrophic factor
7
Q
SSRI
A
selective serotonin reuptake inhibitor
8
Q
SNRI
A
serotonin & NE reuptake inhibitors
9
Q
TCA
A
tricyclic antidepressants
10
Q
MAO
A
monoamine oxidase
11
Q
Depression Definition
A
Definition—Persistent low mood with loss of enjoyment and pleasure
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
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)
14
Q
Causes of Depression
A
- Genetics
- Environment
- Biochemical
- Psychological
15
Q
Depression Neurophysiology
A
Decreased monoamines
- Serotonin 5-HT
- NE
Effective therapeutics increases monoamines
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
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
18
Q
What increases BDNF?
A
- Exercise
- Smiling/laughing
- Antidepressants
- Electroconvulsive therapy
19
Q
What decreases BDNF?
A
- Stress
- Pain (chronic moderate/severe)
20
Q
Therapeutics and Pharmacology:
Monoaminergic Approach
A
MAO – only one in inside the cell – not COMT
COMT - is usually only found in synapse
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
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
- Drugs:
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
- GI effects (5-HT3 mediated) – primarily related to 5-HT3 effects
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
Selective Serotonin Reuptake Inhibitors (SSRI)
Suicide risk
* 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
SSRI Selectivity of Action
The more activity outside of SERT, the more side effects
27
(SNRI) Selective Serotonin and Norepinephrine Reuptake Inhibitors
* 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
(SNRI) Selective Serotonin and Norepinephrine Reuptake Inhibitors
General Side Effects
* 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
(NDRI) Norepinephrine and Dopamine Reuptake Inhibitors
* 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
Tricyclic Antidepressants (Block SERT and NET)
* 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
TCAs Major Concerns
* 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
Tricyclic Antidepressant Side Effects
* 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: Which of the following would NOT be expected to increase levels of both 5-HT and NE?
A: citalopram – SSRI (bupropion would be a right answer too)
34
Q: The adverse sexual dysfunction side effect of SSRIs, SNRIs, and TCAs is primarily due to:
A: increased 5-HT levels
35
Q: What receptors may cause orthostatic hypotension and sedation
A: alpha-1 antagonist and H1 antagonist
36
Monoamine Oxidase Inhibitors
* 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
MAOI Specificity
* 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
MAO Inhibitor Side Effects/Disadvantages
* 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
Serotonin Syndrome
* 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
Hypertensive Crisis
* 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
MAOI Discontinuation or Switching
* 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
Irreversible MAO inhibitors
* 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
Atypical Antidepressants
Mirtazapine
Trazodone
Nefazodone
Vilazodone
Vortioxetine
44
Mirtazapine
* 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
Trazodone and Nefazodone
* 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
Vilazodone
* 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
Vortioxetine
* 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: A major concern for use of MAO inhibitors is hypertensive crisis which occurs when:
A: the patient consumes food with significant amounts of tyramine while on MAOI
49
Q: Phenelzine would increase levels of which of the following NT except?
A: None – it would increase the levels of DA, NE, and 5-HT
50
Q: Which of the following atypical antidepressants would NOT have decreased incidence of sexual dysfunction?
Vilazodone
51
Q: When should a patient switch from a SSRI to an MAOI?
A: The patient should have ample time after stopping fluoxetine to allow the fluoxetine to leave the body before starting on the MAOI
52
Delayed therapeutic effect
* 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: Which drug has the lowest incidence of sexual dysfunction?
A: Trazodone (atypical)
54
Ketamine
Ketamine is the newest drug that is given during the lag time for a patient with suicidality that has been started on an antidepressant
