HNS50 Anti-depressants Flashcards
Depression symptoms
- Sadness, emptiness, hopelessness
- Changes in sleep pattern (insomnia / oversleeping)
- Diminished pleasure / apathy towards life activities
- Increased anger / irritability
- Significant changes in appetite / body weight
- Fatigue / loss of energy
- Feeling of self-loathing / suicidal thoughts
For a period of weeks / months
Differences in men vs women symptoms
Difference in hormone (testosterone)
Men:
- Anger
- Compulsiveness
- Insomnia
Women (more likely to get depression):
- Sadness / Worthlessness
- Procrastination
- Oversleeping
Classifications of depression
- Minor depression disorder
- less severe
- >=2 symptoms
- duration ~2 weeks (short) - Major depression disorder
- severe
- >=5 symptoms that interfere with patient’s ability to function
- duration >2 weeks (relatively short) - Dysthymic disorder (dysthymia) —> persistent mild depression
- less severe
- >=2 symptoms
- duration >2 years (long)
Diagnosis: Based on clinical interview (Diagnostic and Statistical Manual of Mental Disorders)
Depression causes
Multifactorial, combination of factors
- Genes (Slc6a15 gene: neutral a.a. transporter)
- Environmental
- Personality
- Brain chemistry
- Brain hormones
- Stress (traumatic events)
2 hypothesis for cause of depression
- Monoamine hypothesis
- Neurotrophic (neurogenesis) hypothesis
Monoamine hypothesis
Depression is caused by Low levels / Deficit in function of neurotransmitters:
- Serotonin (from Tryptophan, mostly Inhibitory)
- Norepinephrine (Catecholamine, from Tyrosine, Excitatory)
- Dopamine (Catecholamine, from Tyrosine, Excitatory + Inhibitory)
ALL antidepressants enhance ***Synaptic availability of these neurotransmitter
Not a perfect hypothesis:
- Many do NOT have alterations in function / levels of monoamine
- Monoamines ↑ immediately with antidepressant use, but maximum benefits are not seen until many weeks later
- Common for patient to feel worse for the 1st week of treatment
- Removal of serotonin precursor (Tryptophan) in human did NOT lead to depressive response
Neurotrophic (neurogenesis) hypothesis
- Impaired growth of neurons —> associated with depression
—> Anti-depressants promote growth of neurons + synaptic connectivity - Depression associated with 5-10% volume loss in hippocampus
- Depressed, stressed / in pain —> ↓ BDNF (Brain-derived neurotrophic factor) levels
—> ↑ BDNF associated with ↑ neurogenesis
—> Infusion of BDNF into brain —> anti-depressant effects
—> Anti-depressants ↑ BDNF levels (in animals models with chronic administration but not with acute treatment)
BDNF regulate:
- **Neural plasticity (differentiation) + **Neurogenesis (growth)
- ***Emotions
Not a perfect hypothesis:
- BDNF knockout mice do NOT have depressive / anxious behaviour
- Social-stressed animals showed ↑ BDNF rather than ↓
Medications
- Takes several weeks to work
- NT only have short time to relay message to postsynpatic cells before reuptake / destroyed
—> Anti-depressant work by ↑ amount of NT in brain by
1. Prevent break down
2. Prevent reuptake into cell
NA:
- Alertness
- Energy
Dopamine:
- Attention
- Motivation
- Pleasure
- Reward
Serotonin:
- Obsession and compulsion
8 types of Anti-depressants
- Selective serotonin reuptake inhibitor (SSRI)
- Noradrenaline reuptake inhibitor (NARI)
- Serotonin-Norepinephrine reuptake inhibitor (SNRI)
- Tricyclic antidepressant (TCA)
- Serotonin antagonist-reuptake inhibitor (SARI)
- α2 adrenoceptor antagonist
- Monoamine oxidase inhibitor (MAOI)
- Melatonin receptor agonist
- Selective serotonin reuptake inhibitor (SSRI)
Drugs:
- Fluoxetine (Prozac)
- Paroxetine (relative severe weight gain / sexual dysfunction)
- Citalopram
- Escitalopram
- Sertraline
- Fluvoxamine
1st line pharmacological treatment
- Fewest SE
- Mild to moderate, transitory SE
- Safety in overdose
- Low cost
MOA:
- Selectively blocks reuptake of Serotonin by binding to ***serotonin transporter (normally take up excessive serotonin into presynpatic cell) on presynaptic neuron
—> ↑ 5-HT concentration in synaptic cleft
Therapeutic dose: 80% activity of transporter is inhibited
Pharmacokinetics:
- Fluoxetine, Paroxetine: CYP2D6 inhibitors
—> Tricyclic antidepressant (2D6 substrate) (elevation of TCA conc)
—> NOT used in combination
- Fluvoxamine: CYP3A4 inhibitors
—> Diltiazem (Ca channel blocker, 3A4 substrate)
—> Bradycardia / Hypotension - Citalopram, Escitalopram, Sertraline: more modest CYP interactions
SE (enhanced serotonergic tone):
- Nausea, GI disturbance, Diarrhoea
- ↑ serotonergic activity in gut - Diminished sexual function and interest
- ↑ serotonergic activity in spinal cord / above —> effect persist as long as on the drug - Reduced coagulation / ↑ Bleeding risk
- inhibit serotonin reuptake into platelets, reduce serotonin-mediated platelet activation - Vasoconstriction
- inhibits nitric oxide synthase —> CI in pregnant women with hypertension / pre-eclampsia
- Noradrenaline reuptake inhibitor (NARI)
Drugs:
- Atomoxetine
- Maprotiline
- Reboxetine
MOA:
- Selectively blocks reuptake of NA by binding to NA transporter on presynaptic neuron
—> ↑ NA concentration in synaptic cleft
SE (NA effects):
- ↑ BP
- Changes HR
- CNS activation (e.g. insomnia, anxiety, agitation)
- Serotonin-Noradrenaline reuptake inhibitors (SNRI)
Drugs:
- Venlafaxine
- Desvenlafaxine
- Duloxetine
(4. Bupropion: NDRI)
MOA:
- Blocks reuptake of Serotonin + NA by binding to BOTH Serotonin + NA transporter on presynaptic neuron
—> ↑ Serotonin + NA concentration in synaptic cleft
SNRI: do NOT have much affinity for other receptors (unlike TCA) —> less SE
SE:
- same as SSRI, NARI
- Tricyclic Antidepressants (TCA)
Drugs:
- Amitriptyline
- Nortriptyline
- Clomipramine
- Imipramine
- Dosulepin
MOA:
- Blocks reuptake of Serotonin + NA + Dopamine
—> more SE
Usage: - declined after SSRI introduction —> poor tolerability —> difficulty to use —> lethality in overdose —> serious drug interactions - ***ONLY used when patients NOT respond to SSRI
- Serotonin antagonist-reuptake inhibitor (SARI)
Drug:
Trazodone
MOA:
3 properties:
- 5-HT2a antagonism (most potent binding property)
—> 5-HT2a receptors increased in depressive patients
—> inhibit activation of 5-HT2a —> ↑ NT release - Block serotonin reuptake transporter (SERT) (100 fold less potent)
- 5-HT1a agonist
—> Trazadone converted to active metabolite mCPP (meta-chloro-phenylpiperazine)
—> agonist at 5-HT1a (very weak agonist at 5-HT2a)
—> specifically Antidepressant effect
SE:
- Agonist actions at other subtypes of serotonin receptors —> SE
- ***Desensitisation from activation of serotonin receptors over time
- α2 adrenoceptor antagonist
Drug:
- Mianserin
(2. Mirtazapine: NaSSA)
MOA:
Block α2 presynaptic autoreceptor (NOT transporter!!!) on presynpatic neuron
—> Suppress -ve feedback
—> ↑ NA release
SE:
- Sedation
- Dry mouth
- Dizziness
- Vertigo
- Monoamine oxidase inhibitors (MAOI)
Drugs:
- Non-selective MAOI: Phenelzine, Tranylcypromine
- Selective MAOI (MAOa): Moclobemide
MOA:
Inhibit monoamine oxidase in presynaptic cell
—> Inhibit degradation of NT
—> ↑ ALL 3 NT levels
2 isoforms of monoamine oxidase:
MAOa: 5HT, NA, Adrenaline, Dopamine, Tyramine
MAOb: Dopamine, Phenylethylamine, Tyramine
Usage:
- Rare (∵ toxicity, potential lethal food / drug interactions esp. Tyramine-rich food)
—> **Tyramine cause release of stored monoamines (dopamine, NA, adrenaline)
—> MAOI also block breakdown Tyramine (also ↑ NA, adrenaline, dopamine)
—> ↑ BP, HR
—> **Hypertensive crisis (stroke, heart attack, death)
—> ∴ must stick to low-tyramine diet
—> High-tyramine food: avocados, bananas, pineapple, eggplants
- Treatment of depression unresponsive to other antidepressant
SE:
**1. Hypertensive crisis with tyramine-rich food
2. Orthostatic hypotension
3. Weight gain
4. Insomnia
5. Restlessness
6. Confusion
**7. Serotonin syndrome: combination of MAOI with serotonergic agent (SSRI, SNRI, TCA)
—> over-stimulation 5HT receptor in brain
—> coma, confusion, chills, tremors, fever, hyperhidrosis
—> life-threatening
Guideline:
- Serotonergic antidepressant discontinued for >=2 weeks before starting MAOI (Fluoxetine 4-5 weeks ∵ long t1/2)
- MAOI discontinued for >=2 weeks before starting serotonergic antidepressant
- Melatonin receptor agonist
Drug:
Agomelatine (NOT approved by FDA as a drug yet: Supplement now)
Link between sleep problems and depressed mood
—> New target to combat depression: Body’s internal clock
—> Agomelatine as effect as widely prescribed antidepressant
MOA:
Synthetic version of melatonin
—> act on Melatonin receptor (+ 5-HT2c receptor —> NOT ↑ serotonin level BUT ↑ dopamine + NA level in brain)
Melatonin:
- Important for regulation of sleep
- Released in response to darkness by ***pineal gland
—> levels vary according to circadian rhythm
—> in tune: helps sleep and wake
—> out of tune: disrupt energy, alertness and mood
SE:
- Derangement in ***liver function —> Regular liver function monitoring
Common and Key SE of antidepressant
Common:
1. Dry mouth
2. Nausea
Etc.
Key SE:
***↑ Suicidal risk under 25, >65 no associated suicidal risk
—> FDA Black box warning MUST be added to ALL antidepressant
Antidepressant discontinuation symptoms
ABCDEF: A: agitation, anxiety B: balance problems, bad dreams C: concentration problems D: dizziness, diarrhoea E: electric shock-like sensations F: flu-like symptoms
—> Severe: Psychosis, Confusion, Excitement
***Doses should be gradually reduced over >=4 week period
Other applications of antidepressant
- Panic disorder
- GAD
- PTSD
- OCD
- Pain disorder
- Premenstrual dysphoric disorder
- Smoking cessation (Bupropion)
- Bulimia
Non-responders
25% of patients
—> were worse on antidepressant
—> could be due to cause of depression (NOT altered level of NT)
Even though antidepressant changed level of NT
—> do not help
Antidepressant effect and placebo
People’s belief in the power of antidepressant may explain why they do well on placebo
- Mild / Moderate depression: difference is nonexistent to negligible
- Severe cases (13%): significantly more effective
Alternative therapy
Antidepressant use only when risk of untreated depression»_space;> risk of antidepressant
Psychotherapy / Talk therapies
1. Cognitive-behavioural therapy
2. Interpersonal therapy
—> teaching new ways of thinking / behaving
—> changing habits that contribute to depression
Indication:
- Mild / Moderate depression —> Psychotherapy relieves symptoms at the same rate as drugs / placebos
Barriers:
1. Many doctors prescribing antidepressant are primary care doctor (NOT psychiatrist)
—> cannot offer talk therapy
2. Insurance companies resist paying session of talk therapy (high cost)
3. Time consuming
Summary
8 drugs
- SSRI:
- Fluoxetine (2D6 inhibitor)
- Citalopram
- Sertraline
MOA: Selectively blocks reuptake of Serotonin by binding to ***serotonin transporter (normally take up excessive serotonin into presynpatic cell) on presynaptic neuron - NARI:
- Atomoxetine
- Maprotiline
- Reboxetine
MOA: Selectively blocks reuptake of NA by binding to NA transporter on presynaptic neuron - SNRI:
- Venlafaxine
- Duloxetine
(- Bupropion: NDRI)
MOA: Blocks reuptake of Serotonin + NA by binding to BOTH Serotonin + NA transporter on presynaptic neuron - TCA:
- Amitriptyline
- Clomipramine
- Dosulepin
MOA: Blocks reuptake of Serotonin + NA + Dopamine - SARI:
- Trazodone - 5-HT2a antagonism (most potent binding property) —> inhibit activation —> ↑ NT
- Block serotonin reuptake transporter (SERT)
- 5-HT1a agonist
- α2 adrenoceptor antagonist:
- Mianserin
(- Mirtazapine: NaSSA)
MOA: Block α2 presynaptic autoreceptor on presynpatic neuron —> Suppress -ve feedback - MAOI
- Phenelzine, Tranylcypromine (Non-selective MAOI)
- Moclobemide (Selective MAOI (MAOa))
MOA: Inhibit monoamine oxidase in presynaptic cell —> Inhibit degradation of NT - Melatonin receptor agonist
- Agomelatine
MOA: Synthetic version of melatonin —> act on Melatonin receptor —> Regulation of sleep
