6.2 Antidepressant drugs

Question 1

What is the criteria for major depressive disorder?

Answer 1

Major depressive disorder is defined as depressed mood or loss of interest/pleasure + ≥ 4 of the following over the span of 2 weeks:
• Weight loss/gain (5%)
• Increased/decreased appetite
• Insomnia/hypersomnia
• Psychomotor agitation/retardation
• Feelings of worthlessness
• Lack of concentration
• Recurrent thoughts of death
• Recurrent suicidal ideation

Question 2

The monoamine theory proposes that depression is characterised by a _________________ at certain sites in the brain:
• Antidepressant drugs work by elevating the levels of monoamine transmitters in the brain
• Drugs: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs)

Answer 2

deficit of monoamine transmitters (NA, 5-HT, DA)

Question 3

The serotonin theory of depression has evolved into the neurotrophic model then to the stress-cortisol neurotoxicity-suppressed neurogenesis-antidepressant rescue model:

SERETONIN METABOLISM: Serotonin is generated by ___________ and packaged into vesicles in the presynaptic knob before being exocytosed into the synapse:
• Act on postsynaptic 5-HT receptors → removed by serotonin transporter or metabolised by ____________________

SEROTONIN THEORY:
The serotonin theory is part of the monoamine theory of depression , which postulates that depression is a result of serotoninergic deficit in some parts of the brain:
1. Decreased 5-HT availability → compensatory ____________________
2. Primary defect in 5-HT receptor activity and/or signal transduction

Answer 3

tryptophan hydroxylase;

monoamine oxidase (MAO);

receptor upregulation/hypersensitivity ;

Question 4

The neurotrophic model is based on the density of the hippocampus and dentate gyrus:

Hippocampus: Memory (past experience) protects against development of depression:
• Greater hippocampal density → greater protective effect
*Neurotrophic factors regulate cell death, synaptic connectivity, fibre guidance, and dendritic morphology → helps to modulate _____________:
• ___________________ has a supportive role in increasing hippocampal density → protects against depression
• Serotonin has a positive effect on neurotrophic factors → improves hippocampal density

DENTATE GYRUS
- Determines density/neuronal growth of hippocampus
• _________________ migrate here → any pathology which affects the dentate gyrus may affect the progenitor cells and thus the growth of the hippocampus

• Receives information from other parts of the brain (e.g. entorhinal cortex, raphe nucleus, locus coeruleus, medial septum):
  • Information within hippocampus is relayed from perforant pathway via the dentate gyrus → other regions of hippocampus (_________________) → other parts of brain (entorhinal cortex)

Answer 4

adult brain plasticity (ability to adapt to environment);

Brain-derived neurotrophic factor (BDNF);

Neural progenitor cells of hippocampal neurones ;

CA3 → CA2 → CA1;

Question 5

Stressful events cause the production of high levels of cortisol, which has a neurotoxic effect on the _______________ → reduces hippocampal density:
• In response to stress, there is HPA axis activation (hypothalamus secretes _________________________ → anterior pituitary releases ACTH → adrenal cortex produces cortisol in response to ACTH)
• Cortisol is the most consistent biological marker of depression (~50% of depressed patients have elevated cortisol) → Cushing’s patients often present with depression
o Drugs that elevate cortisol (e.g. IFN-α) are linked to depressive symptoms
o Drugs which inhibit cortisol synthesis have antidepressant effects

Answer 5

development of the hippocampus;

CRH-41 (corticotrophin releasing hormone) and AVP (vasopressin)

Question 6

What is the effect of cortisol in the CA1 region?

Answer 6

Potentiates anoxia (severe hypoxia) → NMDA-induced exocytotic damage is enhanced by Ca2+ influx → damage in CA1 region

Question 7

What is the effect of cortisol in the CA3 region?

Answer 7

Induces cellular atrophy in CA3 region → impedes access to incoming information (from other parts of the brain)

Question 8

What is the effect of cortisol in the dentate gyrus?

Answer 8

Inhibits proliferation and decreases survival rate of progenitor cells (regulation of neurogenesis) → decreases hippocampal density

Question 9

Antidepressants generally increase serotonin levels in the hippocampus to counteract the toxic effects of cortisol that cause depressive symptoms:
• Onset of action: usually 2 – 3 weeks before antidepressant effects are observed (even though MAO levels increase quickly after administration)
o Increased neuronal growth in the ___________ needs to be present before the antidepressant effect is observed
• Placebo effect: any effect is 30% placebo and 30% actual benefit (antidepressants work in 60% of cases; placebo drug (e.g. water pill) works in 20 – 30% of cases)
o Placebo effect is less pronounced in major depressive disorder

Answer 9

dentate gyrus

Question 10

The tricyclic antidepressants (TCAs) target the _________________ to prevent reuptake from the synapse, allowing for longer duration of monoamine receptor activation:
• Spectrum: _________ = ___________ > _______________

Answer 10

substrate binding site of monoamine transporters;

serotonin (5-HT) = noradrenaline (NA) > dopamine (DA)

Question 11

[TCAs]

what is the 1st ever TCA?

Answer 11

Imipramine: From chlorpromazine (antihistamine; sedative effect, improves thinking, emotional behaviour)

Question 12

[TCAs]

Amitriptyline (1st gen TCA): Greater effect on _______ + Inhibits ________________

Answer 12

NA;

CYP450 (potential for drug interactions)

Question 13

[TCAs]

Nortriptyline (2nd gen TCA): Greater effect on _______ (toxicity equal to SSRIs; safer than 1st gen TCAs and SNRIs)

Answer 13

5-HT

Question 14

[TCAs]
TCAs have a narrow therapeutic index (narrow range between the therapeutic dose and toxic dose → patients use it to commit suicide):
• Antimuscarinic effects (due to reduced parasympathetic output): mydriasis, bronchodilation, some degree of tachycardia, reduced GI motility, reduced secretions, relaxed detrusor muscle, constricted bladder sphincter, reduced sweating
• α1-adrenoceptor blockade: ______________
• H1 receptor blockade: ____________
• Quinidine-like effects (at higher doses): ______________

Answer 14

postural hypotension;

sedation;

cardiac dysrhythmias

Question 15

[MAOIs]

what is the activity of MAO-A on different monoamines?

Answer 15

noradrenaline (NA) = serotonin (5-HT) > dopamine (DA)

Question 16

[MAOIs]

what is the activity of MAO-B on different monoamines?

Answer 16

dopamine (DA) specific

Question 17

[MAOIs]

What are examples of MAOIs?

Answer 17

phenelzine, tranylcypromine, isocarboxazid, selegiline, moclobemide

Question 18

[MAOIs]

What are the side effects of MAOIs?

Answer 18

hypotension, antimuscarinic effects, weight gain (due to improved self-care), excessive central stimulation, tyramine cheese reaction (restrict diet)

Question 19

[MAOIs]
Tyramine cheese reaction: tyramine is an amino acid which is metabolised by _____________ –> found in foods like aged cheese, fava beans, cured/smoked meats , red wine –> Use of MAOIs causes reduced tyramine breakdown –> tyramine displaces NA in vesicles –> increased NA release into the synaptic cleft –> increased sympathetic output –> hypertensive crisis (precipitated by ingestion of foods with high tyramine)

•“Cheese reaction” is a misnomer; many different foods can cause this reaction

Answer 19

MAO (primarily MAO A )

Question 20

[SSRIs}

What is the mechanism of SSRI?

Answer 20

blocks serotonin reuptake → increased concentration in the synaptic cleft (hippocampus; esp. dentate gyrus) → serotonin binds to 5-HT1A receptor → antidepressive effect

Question 21

[SSRIs]

What is the activity of SSRIs?

Answer 21

5-HT transporter&raquo_space;> NA transporter&raquo_space;> muscarinic, α-adrenergic, H1 receptors

Question 22

[SSRIs}

What are the indications of SSRIs?

Answer 22

depression, anxiety disorders (e.g. GAD, PTSD, panic disorder, social anxiety disorder, premenstrual dysmorphic disorder), bulimia nervosa (only fluoxetine)

Question 23

[SSRIs}

What are the side effects of SSRIs?

Answer 23

potent CYP450 inhibitor* → exacerbation of cheese reaction (if used with MAOIs; cannot metabolise), increased suicidal thoughts (?), discontinuation syndrome (fluoxetine has lowest risk due to longer half-life), serotonin syndrome, sexual dysfunction (5-HT2 agonism)

Question 24

[SSRIs}

What are the side effects of fluvoxamine?

Answer 24

nausea, sedation

Question 25

[SSRIs}

What are the side effects of fluxetine?

Answer 25

nausea, sedation

Question 26

[SSRIs}

What are the side effects of citalopram?

Answer 26

QTc prolongation (in overdose)

Question 27

[SSRIs}
SSRIs (especially fluoxetine and paroxetine) are potent ____________, thus may affect the elimination of TCAs, antipsychotic drugs, some antiarrhythmic and β-adrenergic antagonist drugs → do not give together

Answer 27

CYP2D6 inhibitors

Question 28

[SNRIs}

What are the side effects of SNRIs?

Answer 28

Mechanism: blocks serotonin uptake (and norepinephrine at medium to higher doses) → increased concentration in the synaptic cleft → antidepressive effect
(dual inhibition makes it sometimes effective in relieving pain)

Question 29

[SNRIs]

What is the activity of SNRIs?

Answer 29

Activity: 5-HT transporter = NA transporter&raquo_space;> muscarinic, α-adrenergic, H1 receptors (less adverse effects than TCAs; at high doses is marginally superior to SSRI, otherwise similar efficacy)

Question 30

[SNRIs}

What are the side effects of SNRIs?

Answer 30

nausea, headache, sexual dysfunction, dizziness, insomnia, sedation, constipation, hypertension & tachycardia (at high doses due to sympathetic overdrive from increased NA activity), serotonin syndrome, discontinuation syndrome

Question 31

[SNRIs}

What are the indications of SNRIs?

Answer 31

depression (where SSRIs are ineffective), backaches & muscle aches (associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, lower back pain)

Question 32

[SNRIs]

What is considered a safer SNRI?

Answer 32

Venlafaxine is safer (no exacerbation of cheese reaction → tyramine requires NA transporters to enter nerve terminals)

Question 33

What is the mechanism of buproprion?

Answer 33

Weak NA-DA reuptake inhibitor (NDRI) and nicotinic receptor antagonist

Question 34

What is the indication for buproprion?

Answer 34

depressive symptoms (adjunct to SSRIs), smoking cessation (attenuate withdrawal)

Question 35

What is the side effect for buproprion?

Answer 35

dry mouth, sweating, nervousness, tremor, dose-dependent increased risk of seizures (avoid if seizure risk or bulimia nervosa)

Question 36

What is the mechanism of mirtazapine?

Answer 36

Noradrenergic and specific serotonergic antidepressant (NaSSA) → potent antihistaminic, anti-α2-adrenergic, antiserotonergic activity

Question 37

What is the indication for mirtazapine?

Answer 37

Indications: depression with sleep disturbances (most potent antihistamine of the TCAs and TeCAs)

Question 38

What is the side effect for mirtazapine?

Answer 38

Side effects: increased appetite, weight gain

no antimuscarinic effects of the TCAs or sexual dysfunction like SSRIs

Question 39

What is the mechanism of Nefazodone & Trazodone?

Answer 39

5-HT antagonist and reuptake inhibitor (SARI) and weak 5-HT-NA-DA reuptake inhibitor (SNDRI) → potent 5-HT2A and 5-HT2C receptor antagonist

Question 40

What is the indication for Nefazodone & Trazodone?

Answer 40

Indications: major depression, aggression, panic disorder + insomnia (off-label use; potent antihistaminic H1 activity)

Question 41

What is the side effect for Nefazodone & Trazodone?

Answer 41

Side effects: priapism (trazodone), hepatotoxicity (nefazodone), orthostasis & dizziness (mild α1 receptor antagonism)

Question 42

The SSRIs are the most commonly prescribed (60 – 70%), followed by the SNRIs (10 – 15%), then the TCAs (3 – 5%) and MAOIs (< 1%; due to need for diet adjustment):

The SSRIs are generally the safest drugs to be used in patients with depression (albeit with their own side effects as well):
• 2nd generation TCAs (_________) are equal in toxicity to SSRIs, but still remain safer than 1st generation TCAs (______) and SNRIs (_____________)
• _________ are dangerous in combination with MAOIs (serotonin syndrome + exacerbation of cheese reaction)
• SNRIs are safer as they also block the _____________, preventing the cheese reaction

Answer 42

nortriptyline;

amitriptyline;

venlafaxine;

SSRIs;

NA transporter