6 - Antidepressants Flashcards
What are the 5 types of depression?
1) Major depression
2) Chronic depression
3) Atypical depression
4) Bipolar/manic depression
5) Seasonal depression
What is major depression?
- Generally recurring and disabling w/ sx that interrupt a persons ability to work, sleep, study, or eat
- Usually lasts greater than 2 weeks
What is chronic depression?
- Less severe or disabling
- Longer lasting sx
- Characterized by long term “melancholy” or depressive personality
What is atypical depression?
- Characterized as less pervasive sadness
- Can manifest as overeating, oversleeping, sensitivity, or rejection
What is bipolar/manic depression?
Oscillates btwn major depressive and mania episodes
What is seasonal depression?
- Result of a reduction in amount of sunlight
- Common during winter
- Scandinavian countries most affected
How is a person diagnosed w/ depression?
- Must have 1 of top 2 symptoms and at least 5 other sx which occur daily, and persist for at least 2 weeks
- Top 2 sx = persistently sad, anxious, or “empty” feelings and loss of pleasure in usual activities
- Other sx = crying, hopelessness, pessimism, helplessness, fatigue, loss of concentration, sleep problems, change in appetite, suicidal thoughts
What are the causes of depression?
- Genetic
- Death/abuse
- Medication
- Socio
- Environment
What are the various tx for depression?
- Psychotherapy (talk therapy) – useful when combined w/ drugs
- Natural alternatives – St. John’s Wort and exercise can help mild depression
- Electroconvulsive therapy (ECT) – fast and effective solution for major depression or suicidal thoughts
- Medications – SSRIs, SNRIs, NDRIs, MAOIs, TCAs, and TeCAs
What are sx of serotonin deficiency?
- Anxiety
- Panic
- Phobia
- Obsessive compulsive
What are sx of norepinephrine deficiency?
- Decreased concentration, working memory, and info processing
- Fatigue
What are sx of dopamine deficiency?
- Cognitive slowing
- Hypersomnia (excessive sleepiness)
- Anhedonia (inability to feel pleasure)
What are sx of serotonin and dopamine deficiencies?
- Food craving
- Bulimia
What are sx of dopamine and NE deficiencies?
- Decreased attention
- Psychomotor retardation
What are sx of serotonin, NE, and dopamine deficiencies?
Depressed mood
What does it mean when an antidepressant has a high NE/5-HT ratio?
The drug is more selective for 5-HT receptor
What is the function of serotonin?
Regulates mood, calmness, appetite, cognitions, memory, body temp, sexuality, and BP
Can circulating serotonin cross the BBB?
No, but serotonin is derived from tryptophan, and tryptophan can cross the BBB (but must compete w/ other AAs for the active AA transporters)
Is the indole ring of serotonin basic?
No
What percentage of tryptopharn consumed is converted to serotonin?
5%
Where does biosynthesis of serotonin occur?
Primarily in CNS presynaptic neurons and some GI tract cells
What happens to free 5-HT in blood plasma?
Rapidly taken up by platelets for storage
What does 5-HT stand for?
5-hydroxytryptamine
How is serotonin removed from the synaptic cleft?
- Removed by diffusion
- Binds to SERT receptor or 5-HT autoreceptor of serotonergic neuron
How is serotonin removed from a serotonergic neuron?
MAO inactive metabolites
How is serotonin released into a synapse?
- Action potential causes influx of Na+ and Ca+
- Increase in Ca+ in cytoplasm causes storage vesicles to fuse w/ presynaptic cell membrane, releasing 5-HT into synaptic cleft
5-HT reuptake is through the _____ on ______
Serotonin transporter (SERT); presynaptic membrane
What is the half life of free serotonin in blood? Why?
Short (few minutes) b/c of fast metabolism by MAO
What is produced from a minor route of 5-HT metabolism? How?
- Melatonin
- 5-HT is acetylated by 5-HT n-acetyltransferase to N-acetylserotonin, which is converted to melatonin y 5-hydroxyindole-O-methyltransferase (HIOMT)
Can melatonin cross the BBB?
Yes b/c not charged
What regulates the production of melatonin?
Light in the retina inhibits production
How is melatonin metabolized? Where does this take place?
- Melatonin is oxidized at position 6, followed by conjugation w/ sulfate
- Occurs in CNS
Do melatonin metabolites posses pharmacological properties?
Yes
What are the 2 main methods to modulate the effects of serotonin?
- Increase or decrease amount of serotonin (biosynthesis, release into synapse, metabolism, diffusion, reuptake)
- Agonism or antagonism of serotonin receptor
What are the 4 main classes of antidepressants?
1) Tricyclic antidepressants and tetracyclic
2) Selective serotonin reuptake inhibitors
3) Selective norepinephrine reuptake inhibitors
4) Monoamine oxidase inhibitors
What happens to the ring angles when chlorpromazine is converted to amitriptyline and then imipramine? What does this cause?
- Alpha angle is decreased in amitriptyline, and the beta and gamma angles are introduced in imipramine
- This causes decreased affinity for dopamine receptor, allowing TCAs to have no dopamine antagonism; and increased affinity for NE and serotonin reuptake transporters
How do TCAs work?
By competitively inhibiting serotonin or NE reuptake (generally more selective for NE transporter)
What almost always happens when a terminal methyl group is attached to an N or O?
N or O will be demethylated
Which type of amine on a TCA elicits the most selectivity for the serotonin transporter?
Tertiary
Which type of amine on a TCA elicits the most selectivity for the NE transporter?
Secondary
For SSRIs, the _____ group probably explains selectivity
Electron withdrawing
What type of antidepressants are venlafaxine and duloxetine?
SSNRIs
What are paroxetine and citalopram? What are their indications?
- Potent and most specific SSRIs
- Used in tx of major depression, OCD, PTSD, and panic disorders
What are atomoxetine and reboxetine? Why? What are their indications?
- Selective NE reuptake inhibitors
- Lack a strong electron withdrawer on the phenyl ring (such as fluorine), decreasing serotonin selectivity
- Atomoxetine used for ADHD and reboxitine for depression
What do TCAs inhibit?
Serotonin, norepinephrine, and dopamine
What part of the serotonin transporter do TCAs and SSRIs interact w/?
Asp-98
For SSRIs, the ____ residue appears to be determining factor in SSRI potency
Ser-438
What is the primary effect of MDMA?
- Openness
- Euphoria
- Empathy
- Love
What is MDMA believed to cause?
Serotonin vesicles to release serotonin into synapses
What can acute toxicity of MDMA lead to?
Hyperthermic syndrome, dehydration and hyperpyrexia
What are SSRIs the most commonly used drugs in depression therapy?
- Fewer adverse side effects and less toxicity than TCAs and MAOIs
- Don’t exhibit food-interaction toxicity, unlike MAOIs
- Diminished anticholinergic effect, unlike TCAs
What are some discontinuation sx of SSRIs?
- After taking SSRIs for more than 6 weeks, w/in 3 days of discontinuation experience flu-like sx, insomnia, nausea
- Can occur when switching SSRIs
When is serotonin syndrome a concern?
When combining SSRIs and MAOIs
What are some agents that can cause/induce serotonin toxicity?
- Tryptophan or 5-HTP (increase serotonin production)
- Amphetamines, MDMA (increase serotonin release)
- SSRIs, cocaine, TCAs (inhibit serotonin re-uptake)
- MAOIs (inhibit serotonin metabolism)
What are common structural features of all TCAs?
- Terminal secondary or tertiary nitrogen (protonatable)
- 2 aromatic rings, attached by middle ring
- Around 4 atom distance from protonatable nitrogen and aromatic ring
