6.2 Antidepressant drugs Flashcards
What is the criteria for major depressive disorder?
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
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)
deficit of monoamine transmitters (NA, 5-HT, DA)
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
tryptophan hydroxylase;
monoamine oxidase (MAO);
receptor upregulation/hypersensitivity ;
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)
adult brain plasticity (ability to adapt to environment);
Brain-derived neurotrophic factor (BDNF);
Neural progenitor cells of hippocampal neurones ;
CA3 → CA2 → CA1;
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
development of the hippocampus;
CRH-41 (corticotrophin releasing hormone) and AVP (vasopressin)
What is the effect of cortisol in the CA1 region?
Potentiates anoxia (severe hypoxia) → NMDA-induced exocytotic damage is enhanced by Ca2+ influx → damage in CA1 region
What is the effect of cortisol in the CA3 region?
Induces cellular atrophy in CA3 region → impedes access to incoming information (from other parts of the brain)
What is the effect of cortisol in the dentate gyrus?
Inhibits proliferation and decreases survival rate of progenitor cells (regulation of neurogenesis) → decreases hippocampal density
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
dentate gyrus
The tricyclic antidepressants (TCAs) target the _________________ to prevent reuptake from the synapse, allowing for longer duration of monoamine receptor activation:
• Spectrum: _________ = ___________ > _______________
substrate binding site of monoamine transporters;
serotonin (5-HT) = noradrenaline (NA) > dopamine (DA)
[TCAs]
what is the 1st ever TCA?
Imipramine: From chlorpromazine (antihistamine; sedative effect, improves thinking, emotional behaviour)
[TCAs]
Amitriptyline (1st gen TCA): Greater effect on _______ + Inhibits ________________
NA;
CYP450 (potential for drug interactions)
[TCAs]
Nortriptyline (2nd gen TCA): Greater effect on _______ (toxicity equal to SSRIs; safer than 1st gen TCAs and SNRIs)
5-HT
[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): ______________
postural hypotension;
sedation;
cardiac dysrhythmias
[MAOIs]
what is the activity of MAO-A on different monoamines?
noradrenaline (NA) = serotonin (5-HT) > dopamine (DA)
[MAOIs]
what is the activity of MAO-B on different monoamines?
dopamine (DA) specific
[MAOIs]
What are examples of MAOIs?
phenelzine, tranylcypromine, isocarboxazid, selegiline, moclobemide
[MAOIs]
What are the side effects of MAOIs?
hypotension, antimuscarinic effects, weight gain (due to improved self-care), excessive central stimulation, tyramine cheese reaction (restrict diet)
[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
MAO (primarily MAO A )
[SSRIs}
What is the mechanism of SSRI?
blocks serotonin reuptake → increased concentration in the synaptic cleft (hippocampus; esp. dentate gyrus) → serotonin binds to 5-HT1A receptor → antidepressive effect
[SSRIs]
What is the activity of SSRIs?
5-HT transporter»_space;> NA transporter»_space;> muscarinic, α-adrenergic, H1 receptors
[SSRIs}
What are the indications of SSRIs?
depression, anxiety disorders (e.g. GAD, PTSD, panic disorder, social anxiety disorder, premenstrual dysmorphic disorder), bulimia nervosa (only fluoxetine)
[SSRIs}
What are the side effects of SSRIs?
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)
[SSRIs}
What are the side effects of fluvoxamine?
nausea, sedation
