Classical Antidepressants - Ssri, Nri

Front 1

Time courses for effects of Antidepressants - Receptor sensitivity, NT levels, Clinical effect

Back 1

NT levels rise relatively rapidly. Clinical effect and receptor sensitivity/decrease in numbers take longer to occur
Stahl 201

Front 2

Two theories of how antidepressants work

Back 2

Neurotransmitter receptor hypothesis and monoamine action on gene expression hypothesis
Stahl 200

Front 3

Neurotransmitter receptor hypothesis of antidepressant action

Back 3

Depression itself is believed to be caused by abnormal functioning of the NT receptors (neurotransmitter receptor hypothesis of depression). The NT receptor hypothesis of antidepressant action states that no matter their MOA, all of the antidepressants lead to a down regulation/desensitization of key NT receptors on a time course consistent with the delayed onset of antidepressant actions.
Stahl 200-1

Front 4

Side effects as related to time course of antidepressant action

Back 4

Side effect decrease has delayed onset on the same time course as delayed onset of therapeutic effects of the antidepressant. Thus, decreasing side effects may be due to the desensitization of some NT receptors, and therapeutic actions related to desensitization of others.
Stahl 201

Front 5

Monoamine action on gene expression as related to depression and BDNF

Back 5

Depression believed according to monoamine receptor hypothesis to be linked to abnormal NT-induced gene expression, particularly neurotrophic factors, such as BDNF (Brain-derived neurotrophic factor), leading to atrophy and apoptosis of critical hippocampal neurons
Stahl 204

Front 6

Monoamine receptor hypothesis of antidpressant action on NT-induced gene expression

Back 6

According to this hypothesis, regardless of the validity of the monoamine hypothesis of depression, and regardless of the MOA/type of antidepressant, eventually cause critical genes to be activated/inactivated.
Stahl 204

Front 7

Implication of delayed onset of therapeutic effects of antidepressants on our understanding of their action as well as that of non-responders

Back 7

All antidepressants are believed to increase the concentrations of certain monoamines. But then there is a process between that and the therapeutic effect, one which is believed to involve receptor and gene expression modification, and which is poorly understood. This link might be broken in nonresponders, who might have increases in NT levels, but no therapeutic effect.
Stahl 204

Front 8

Pharmacokinetics

Back 8

How the body acts on drugs
Stahl 206

Front 9

Pharmacodynamics

Back 9

How drugs act on the body (for psychpharm, how drugs act on the brain specifically)
Stahl 206

Front 10

Five most important CYP classes for metabolism of antidepressant and mood stabilizer meds

Back 10

1A2, 2D6, 2C9, 2C19, 3A4
First number = family
Letter = subtype
Second number = gene product
Stahl 207

Front 11

Polymorphs for CYP450 - significance

Back 11

Not all individuals have all the same CYP450 enzymes. In such cases, the enzyme is said to be polymorphic. They must metabolize drugs by alternative routes, which may not be as efficient.
Stahl 208

Front 12

Polymorphs (CYP450) for antidepressants - examples

Back 12

about 5 to 10% of Caucasians are poor metabolizers via the enzyme CYP450 2D6.
Another CYP450 enzyme, 2C19, has reduced activity in approximately 20% of Japanese and Chinese individuals and in 3 to 5% of Caucasians
Stahl 208

Front 13

CYP450 1A2 - action

Back 13

demethylates
Stahl 208

Front 14

CYP450 1A2 - Antidepressant substrates, result

Back 14

TCAs, specifically clomipramine and imipramine, turning them into active metabolites desmethylclomipramine and desipramine respectively.
Stahl 208

Front 15

CYP450 1A2 inhibition by? Can cause dangerous interaction with (3)?

Back 15

SSRI Fluvoxamine. Can decrease metabolism of, and therefore increase levels of, theophylline (high enough levels can cause seizures), caffeine, and atypical antispychotics
Stahl 208

Front 16

CYP450 2D6 - action, substrate

Back 16

Hydroxylates (inactivating), works on TCAs. Metabolizes some atypical antipsychotics.
Stahl 209-10

Front 17

CYP450 2D6 inhibition (5)? Which are potent (2), and which less so (3)?

Back 17

CYP450 2D6 is inhibited by SSRIs. Potent = paroxetine, fluoxetine. Less potent = fluvoxamine, sertraline, citalopram. Must be careful if using concomitantly or overlapping
Stahl 209

Front 18

CYP450 3A4 - psychotropic substrates?

Back 18

BZs - alprazolam, triazolam
Stahl 210

Front 19

CYP450 3A4 - inhibitors?

Back 19

Inhibitors
SSRIs - fluvoxamine, fluoxetine. Antidepressant - nefazodone. Others - erythromycin, itraconazole, ketoconazole
Stahl 210, J Psychiatry Neurosci. 2003 March; 28(2): 99–112.

Front 20

CYP450 3A4 nonpsychotropic substrates, consequences of interaction with inhibitors

Back 20

cisapride, terfenidine, and astemazole
Cardiac consequences, e.g. QT prolongation, sudden death
Stahl 210

Front 21

CYP450 Inducers (from step 1 studying)

Back 21

BCG PQRS + ethanol
Barbs
Carbamazepine
Griseofulvin
Phenytoin
Quinidine
Rifampin
St. John's Wort
Ethanol

Front 22

CYP450 inhibitors (from step 1 studying)

Back 22

PICCK EGS
Protease inhibitors
INH
Cymetidine (H2 blocker), Cipro
Ketoconazole (azole antifungals)
Erythromycin
Grapefruit Juice
Sulfonamides

Front 23

CYP450 and cigarettes - specific class? Effect?

Back 23

Induces CYP450 1A2 over time. May need to increase doses of substrates over time.
Stahl 211

Front 24

CYP450 and Carbamazepine - Specific class? Effect? Necessary adjustment to dosage?

Back 24

Substrate and inducer of 3A4. Chronic treatment makes levels fall. Must increase dose over time or risk failure of anticonvulsant or mood-stabilizer efficacy and breakthrough symptoms.
Stahl 211

Front 25

CYP450 metabolized drug - what happens if pt is smoker and stops smoking?

Back 25

CYP450 inducers, when stopped, will increase the levels of substrates of that class of CYP450, as its activity decreases
Stahl 212

Front 26

MAOI - history (discovery)? classical use? alternatively used for?

Back 26

anti-Tb drug found to reduce Depression via MAOI effect. Classically powerful antidepressants, but also effective for certain anxiety d/o, e.g. panic d/o and social phobia
Stahl 213

Front 27

MAOIs - MOA

Back 27

irreversible "suicide" inhibitors. Function isn't restored until MAO is synthesized again.
Stahl 213

Front 28

MAO subtypes? Which do original MAOIs work on?

Back 28

A and B. Original MAOIs work on both (nonselective)
Stahl 213

Front 29

MAO A functions? MAOI use significance?

Back 29

metabolizes monoamine NTs most closely linked to depression (NE and Serotonin). Via metabolism of NE (the NT most directly linked to control of BP), effects BP. Hence, blocking it leads to HTN side effect
Stahl 213-4

Front 30

MAO B functions? MAOI use significance?

Back 30

Thought to convert protoxins to neurodegenerative toxins. Hence, MAOIs that block these are linked to prevention of progression of diseases such as Parkinson's
Stahl 214

Front 31

MAOI - most worrisome side effect? development that may help prevent it?

Back 31

tyramine from food cannot be metabolized, and can lead to HTN crisis --> intracerebri hemorrhage and death. Also can result from meperidine (demerol). Reversible Inhibitors of MAO A (RIMAs) are displaced by tyramine from foods, which are then metabolized.
Stahl 214-8

Front 32

Classical MAOIs - e.g.s (3)

Back 32

Classical - Irreversible and nonselective
phenelzine (Nardil)
tranylcypromine (Parnate)
isocarboxazid (Marplan)
Stahl 217

Front 33

Reversible Inhibitor of MAO A (RIMA) - name

Back 33

moclobemide (Aurorix)
Stahl 217

Front 34

Selective inhibitor of MAO B - name

Back 34

deprenyl (Selegiline; Eldepryl)
Selective at low doses. Non-selective at higher doses
Stahl 217

Front 35

TCAs - MOA therapeutic effect

Back 35

block reuptake pumps for serotonin and NE. To lesser extent, block reuptake of dopamine. Some also block Serotonin 2A receptors, contributing to therapeutic effect.
Stahl 219-20

Front 36

TCA with selectivity for serotonin > NE

Back 36

clomipramine
Stahl 219

Front 37

TCAs with selectivity for NE > serotonin

Back 37

desipramine, maprotilene, nortriptyline, protriptyline
Stahl 219

Front 38

TCAs - MOA of side effects

Back 38

at least three other actions (other than S/NE/D reuptake blockage): blockade of muscarinic cholinergic receptors, blockade of H1I histamine receptors, and blockade of alpha 1 adrenergic receptors. Also block sodium channels in heart and brain, leading to possibility of cardiac arrhythmias/arrest and seizures in O/D.
Stahl 219-20

Front 39

Side effects of TCAs
Blockade of alpha-adrenergic receptors

Back 39

Causes orthostatic hypotension and dizziness
Stahl 220

Front 40

Side effects of TCAs
Anticholinergic effects

Back 40

Dry mouth, blurred vision, urinary retention, constipation, memory difficulties
Stahl 220

Front 41

Side effects of TCAs
Blockade of H1 Histamine receptors

Back 41

sedation and weight gain
Stahl 222

Front 42

Name 10 TCAs

Back 42

clomipramine (Anafranil)
imipramine (Tofranil)
amitriptyline (Elavil; Endep; Tryptizol; Loroxyl)
nortriptyline (Pamelor; Noratren)
protriptyline (Vivactil)
maprotiline (Ludiomil)
amoxapine (Asendin)
doxepin (Sinequan; Adapin)
desipramine (Norpramin; Pertofran)
trimipramine (Surmontil)
Stahl 221

Front 43

Other forms of TCAs
Other functions of TCAs

Back 43

Biogenic amine uptake inhibitors have 1-4 rings in structure, not just three. They are also used in OCD and panic d/o
Stahl 222

Front 44

SSRI MOA (vs. TCA)

Back 44

Selectively, powerfully blocks serotonin reuptake, with little effect on H1, alpha-adrenergic, muscarinic cholinergic receptors, or norepinephrine reuptake. Virtually no ability to block sodium channels, even in O/D.
Stahl 222

Front 45

Name the five classic SSRIs

Back 45

fluoxetine (Prozac)
sertraline (Zoloft)
paroxetine (Paxil)
fluvoxamine (Luvox, Feverin, Dumirox, Floxyfral)
citalopram (Celexa, Cipramil, Serostat, Cipram)
Stahl 226

Front 46

Where are the two sites where SSRIs work in the presynaptic neuron?

Back 46

They block serotonin receptors in the axon terminal and somatodendritic regions
Stahl 227

Front 47

How does the monoamine hypothesis of delayed gene action explain the regulation of serotonin receptors in the neuron of a depressed patient?

Back 47

It says that there is an up-regulation of autoreceptors in the somatodendritic and post-synaptic regions. These receptors may not be able to transduce receptor occupancy into the necessary regulation for post-synaptic genes, including BDNF. (It is also possible that the neuron is normal, but the SSRI compensates for neurochemical deficiencies elsewhere in the brain).
Stahl 227

Front 48

Where do serotonin levels increase the most immediately after SSRI Tx initiation?

Back 48

They increase slightly in the synapse, but much more in the somatodendritic area
Stahl 228

Front 49

What does SSRI-initiated increases in 5-HT in the somatodendritic area result in? What does that lead to? It takes time for this process to occur. To what does this time correlate?

Back 49

Down-regulation and desensitization of autoreceptors in the somatodendritic area. Since these autoreceptors have a negative feedback function, their decrease/desensitization leads to an inability for 5-HT to block its own release - hence, 5-HT release from the end bulbs is turned on via increased neuronal impulses. The time it takes for this process to occur correlates to the delayed onset of therapeutic action.
Stahl 228-9

Front 50

What is the effect of an increase in synaptic levels of 5-HT? To what does the time of this process correlate?

Back 50

It is recognized by postsynaptic serotonin receptors 2A, 2C, 3, and others. These send a signal to the post-synaptic genome to desensitize/down-regulate these receptors. The time it takes for this process to occur correlates to the onset of tolerance to side effects.
Stahl 229

Front 51

What is 5-HT?

Back 51

5-hydroxytryptamine, aka serotonin

Front 52

Serotonergic pathways - which is involved in antidepressant therapeutic actions?

Back 52

Midbrain raphe nucleus --> frontal cortex
Stahl 231

Front 53

Serotonergic pathways - which is involved in bulimia/binge eating/eating d/o therapeutic actions?

Back 53

Midbrain raphe nucleus --> hypothalamic appetite and eating centers
Stahl 231

Front 54

Differences between SSRI use for depression vs. bulimia

Back 54

Antidepressant: Starting/maintenance doses usually same. Onset of response ~ 3-8 wks. Response is frequently complete remission of symptoms Target Sx do not worsen when Tx initiated
Antibulimic: Starting dose usually >. Onset may be faster. May not be as effective at maintaining chronic effects. Fluoxetine has best data to date, also Serotonin 2C properties. Target Sx don't worsen on initiation of Tx.
Stahl 231-3

Front 55

Name early side effects of SSRIs with their pathways and receptors

Back 55

2A/2C; raphe --> limbic cortex; mental agitation, anxiety, panic attacks
2A; raphe --> BG; 5HT inhibition of DA neurotransmission --> akathisia, psychomotor retardation, mild parkinsonism, dystonic movements
2A; brainstem sleep centers; nocturnal myoclonus/awakenings
2A; spinal cord; inhibition of reflexes of orgasm and ejaculation
2A; mesocortical pleasure centers; decreased DA activity --> apathy, decreased libido
3; hypothalamus/brainstem; nausea/vomiting respectively
3,4; GIT; increased bowel motility, diarrhea, cramps
Stahl 233

Front 56

Differences between five classical SSRIs

Back 56

Large studies show no differences, but they have different effects on other NTs and on CYP450, and an individual may respond strongly to one and not another of these, so they are not all the same for any given individual
Stahl 234

Front 57

How selective are TCAs such as desipramine and maprotiline?

Back 57

Not so selective, as they still block alpha 1, histamine 1, and muscarinic cholinergic receptors, as do all tricyclics
Stahl 234-5

Front 58

What drug is the logical complement to SSRIs?

Back 58

Reboxetine, as it lacks the TCA tendencies to block alpha 1, histamine 1, and muscarinic cholinergic receptors
Stahl 235

Front 59

Other than acting as SRIs, what secondary actions do SSRIs have at other receptors/enzymes?

Back 59

They have lesser degrees of actions at other neurotransmitter receptors and enzymes, including
NRI, DRI, serotonin 2C agonist actions, muscarinic/cholinergic antagonist actions, sigma actions, and inhibition of nitric oxide synthetase, CYP450 2D6, 3A4, or 1A2
Stahl 235

Front 60

Are SRIs and NRIs equivalent in therapeutic action?

Back 60

No. Noradrenergic and serotonergic deficiency syndromes aren't exactly the same. Not all patients respond to one or the other. Many who respond to SRIs do not remit completely and seem to have improved mood but an enduring noradrenergic deficiency syndrome, AKA apathetic response to SSRI
Stahl 236

Front 61

What Sx in a patient make an SRI more appropriate for Tx than an NRI?

Back 61

Sx of 5-HT deficiency syndrome (depression associated
with anxiety, panic, phobias, posttraumatic stress disorder, obsessions, compulsions, or eating disorders), as SSRIs have been effective in MDD, OCD, eating d/o panic, social phobia, and even PTSD, while NRIs are not shown to be effective with GAD, panic, phobias, OCD, eating d/o
Stahl 237-8

Front 62

Which Sx show pt may be more responsive to NRIs than SRIs?

Back 62

Those of NE deficiency syndrome (depression + fatigue, apathy, psychomotor retardation; disorders (not just depression) characterized by cognitive disturbances (inc. those of schiz.), esp. impaired concentration, problems w/ sustaining/focusing attention, slow info. processing, deficiencies in working memory)
Stahl 238-9

Front 63

What is the prototypical NDRI?

Back 63

Bupropion
Stahl 241

Front 64

Bupropion MOA/pharmacokinetics

Back 64

Bupropion is a weak DRI and weaker still NRI, but its active metabolite is a potent NRI and is concentrated in the brain.
Stahl 241

Front 65

Bupropion - side effect profile vs. SSRIs

Back 65

less sexual dysfunction. Can lower seizure threshold
Stahl 241

Front 66

Modafanil - MOA/class, use?

Back 66

Acts as DRI, but does not release it (ala amphetamine). Used in narcolepsy. Potential use as antidepressant.
Stahl 242

Front 67

DRIs - concern for use as antidepressants

Back 67

May be reinforcing, leading to abuse potential similar to stimulants
Stahl 242

Front 68

Pseudo-anticholinergic syndrome - related to which class of anti-depressants? Mechanism?

Back 68

Caused by NRIs via stimulation of NE receptors in sympathetic ANS, as sympathetic and parasympathetic have reciprocal roles in peripheral organs/tissues. Thus, can induce syndrome (dry mouth, constipation, and urinary retention) not through direct blockade of muscarinic cholinergic receptors, but via indirect reduction of net parasympathetic tone. This is usually milder and of shorter duration than direct blockade.
Stahl 240