Psychiatry SC086: I Heard Those Newer Drugs Are Better Than My Current Psychiatric Medications Flashcards
Benzodiazepine (aka Anxiolytics: 鎮靜劑)
vs Z-drugs (aka Hypnotics: 安眠藥)
MOA:
Bind to specific binding site in **GABAa-BDZ receptor complex on neuronal membrane but not directly on GABAa binding site
—> **Enhance GABA action
—> Modulate influx of Cl
—> **Hyperpolarisation for inhibitory effect
(*GABA is mandatory for BDZ action —> without GABA, BDZ has no effect on Cl ion channel)
Pharmacokinetics:
- Fast onset
- Difference in t1/2, presence / absence of active metabolite
- Common ones: Diazepam, Alprazolam (Xanax: shortest t1/2), Lorazepam
Indications:
1. ***Anxiety disorders (as Anxiolytic)
- longer t1/2 drugs indicated
- shorter t1/2 drugs are prone to withdrawal
- NOT as primary drug now
- ***Sleep disorders (as Hypnotic (sedation))
- shorter elimination t1/2 preferred
- short t1/2 compounds esp. helpful for sleep induction - ***Alcohol withdrawal (as Anxiolytic, Sedation, Anticonvulsant)
- longer t1/2 drugs indicated - ***Epilepsy (as Anticonvulsant / Muscle relaxant)
-
**Agitation / Restlessness (as Anxiolytic, Sedation, Psychomotor impairment)
- antipsychotics-related akathisia
- beware of **paradoxical agitation (esp. in learning disability ∵ disinhibition effect of BDZ but uncommon)
Issues:
- **Tolerance
- **Withdrawal (mild anxiety, if high dose + abruptly stop —> can have hyperstimulation, life-threatening withdrawal convulsion) —> Need taper off
SE:
- Common: drowsiness, dizziness, **psychomotor impairment, **withdrawal
- Occasional: blurred vision, GI upset, headache, **respiratory depression, increased fall risk in elderly (∵ sedation + hypotensive effect)
- Rare: amnesia, **paradoxical reaction (restlessness, disinhibition, agitation, aggression), respiratory arrest, convulsion on abrupt withdrawal
- Potential: abuse, **dependence syndrome (intoxication S/S, withdrawal (including **positive symptoms e.g. psychosis, paranoid ideas))
Z-drugs (aka Hypnotics: 安眠藥)
MOA:
~BDZ
Zolpidem (Stilnox): Shorter t1/2 (won’t cause oversedation in next morning), Fast onset (Good for sleep induction)
Zolpiclone (Imovane): Longer t1/2, Slower onset (Good for sleep maintenance)
SE:
- Addictive, Dependent (Manufacturer add bitter taste on purpose to avoid dependence)
From SC071:
SE (vary with individual):
1. Hangover (higher than recommended dose)
2. Daytime sleepiness (higher than recommended dose)
3. Falls
4. Motor Incoordination
5. Amnesia
6. Poor memory
7. Automatism
8. ***Sleepwalking (FDA warning on sleep related complex behaviour: sleepwalking, sleep driving)
(9. Tolerance, Abuse, Dependence)
Binding sites of GABA, BDZ, Z-drugs on GABA-BDZ receptor complex
GABA binding sites: Interface between α and β subunits
BDZ binding sites: Interface between α and γ subunits
Zolpidem, Zopiclone: Different sites in the complex
Not all GABAa receptors show affinity to BDZ
- 10% no affinity
- 10% low affinity
- 80% high affinity
High affinity groups can be subdivided by affinity to Zolpidem
- BDZ type 1 (ω1 receptor): high affinity to Zolpidem
- BDZ type 2 (ω2 receptor): low / no affinity to Zolpidem
Pharmacokinetics of BDZ
Rapid absorption:
1. Diazepam (t1/2: 20-100 hrs)
2. Flurazepam (t1/2: 2 hrs)
3. Zolpidem (t1/2: 2 hrs) (metabolised via phase 2 only i.e. no active metabolite)
4. Zopiclone (t1/2: 3-4 hrs)
Intermediate absorption:
1. Chlordiazepoxide (t1/2: 5-30 hrs)
2. Alprazolam (t1/2: 5-15 hrs)
3. Lorazepam (t1/2: 10-20 hrs) (metabolised via phase 2 only i.e. no active metabolite)
4. Nitrazepam (t1/2: 24 hrs)
Depression hypothesis
Hypothesis of Depression:
1. Monoamine deficiency
2. cAMP/CREB/BDNF hypothesis
3. Gut-brain hypothesis (newest)
Monoamine-related targets for antidepressants:
1. **Serotonin (5HT) system: Serotonin, 5HT1a, 5HT2a, 5HT2c
2. **NE system: α1, α2
3. ***Dopamine (DA) system
4. Monoamine oxidase (MAO)
—> Complex interaction of 5HT, NE, DA systems exist in patients with depression
Serotonin receptors:
- 7 subtypes (5HT1 to 5HT7)
- some subtypes further subdivided and mediate different functions
- **major targets: 5HT1a, 5HT2a, 5HT2c
- apart from increasing serotonin availability at synapse —> targeting specific subtypes of 5HT receptors also act via **NE + **DA system in PFC (by **GABA interneurons)
—> ***5HT2a, 2c overstimulation
—> activation of GABA interneurons
—> decrease NE + DA in PFC
—> depressive SE (e.g. anhedonia, insomnia, anxiety, sexual dysfunction) + delay in onset of action (takes a few weeks before effective)
Hypothalamic-Pituitary-Cortisol (cAMP/CREB/BDNF) hypothesis:
- Increased cortisol level shown to be associated with reduced hippocampal volume, reduced BDNF and neurogenesis —> cognitive + memory impairment
- Antidepressant help to stabilise cAMP/CREB/BDNF system
—> activation of cAMP cascade
—> enhanced induction of CREB
—> enhanced BDNF + neurogenesis
Gut-brain hypothesis:
- Inflammation in gut —> immune response —> cytokine release to brain causing depressive symptoms
- Some evidence that probiotic, omega 3 can help with depressive symptoms (can be used as an adjunctive therapy) (omega 3 need much higher dose than that in supplement to be effective)
***Antidepressant
Classification by mechanisms on monoamines:
1. Non-selective monoamine reuptake inhibitors (TCA)
2. SSRI
3. MAOI (non-selective)
4. MAOaI
5. Other antidepressants
- NAI: Reboxetine
- SNRI: Venlafaxine
- NaSSA: Mirtazapine
- SARI: Trazodone
- MT receptor antagonist / 5HT2c antagonist: Agomelatine
Indications:
1. Depressive disorders
2. Anxiety disorders
3. PTSD
4. OCD
5. Sexual disorder / Eating disorder (AN / BN)
Action:
- Increase 5HT, DA, NE
Unwanted actions:
- Antihistaminergic: sleep, weight gain
- 5HT: weight gain, delayed ejaculation
SE:
1. 5HT
- **Serotonin syndrome (delirium, autonomic instability, **pyrexia, diaphoresis, **GI symptoms, restlessness, agitation, **hyperreflexia, rigidity, convulsion, coma, (mydriasis))
- **SSRI discontinuation syndrome (sensory abnormality (shock-like sensation), dizziness, headache, lethargy, GI upset, insomnia, mood change (depressed / anxious feeling))
- **Weight gain
- **Sexual SE (erectile dysfunction, delayed ejaculation, retrograde ejaculation, anorgasmia, decreased libido)
2. **Antimuscarinic
- dry mouth, constipation, urinary retention, blurred vision, visual accommodation problems, glaucoma
3. **Antiadrenergic
- postural hypotension, sedation
4. **Antihistaminergic
- sedation, weight gain
Specific SE:
1. TCA (also in Citalopram): cardiotoxicity (prolong QTc, arrhythmia, sudden cardiac death (clomipramine))
2. Trazodone: priapism, idiosyncratic dystonia, tardive dyskinesia
3. NaSSA: weight gain, leukopenia
4. Venlafaxine (also in MAO-I with tyramine-containing food / sympathomimetic drugs): hypertension (hypertensive crisis)
5. Agomelatine: **elevated liver enzymes (ALT, AST) —> **LFT monitoring at 3, 6, 12, 24 week / when dose increased to 50mg (not compulsory in HK) —> discontinue if ALT / AST >3x UL
6. Esketamine: potential drug of abuse / dependence, ***dissociative SE, ?psychosis
FDA Black box warnings in prescribing for child + adolescents (<=24 yo):
- Potential increased risk of suicidality (decreased risk in >=25 yo)
Systematic review:
- ALL drugs are effective
- only 2 drugs are significantly favourable in acceptability: Agomelatine, Fluoxetine
- only 1 drug is significantly unfavourable in acceptability: Clomipramine
Why is there a delay in Antidepressant effect?
Hypothesis:
1. Depression has **upregulated 5HT receptor in post-synaptic neuron due to low serotonin level
—> antidepressant stimulate 5HT2a + 2c receptor
—> **5HT2a, 2c overstimulation
—> activation of GABA interneurons
—> **decrease NE + DA in PFC
—> **depressive SE (e.g. anhedonia, insomnia, anxiety, sexual dysfunction) + delay in onset of action (takes a few weeks before effective)
- —> 5HT1a stimulation also cause 5HT1a autoreceptor in **pre-synaptic neuron to **downregulate
—> **decrease Serotonin release at post-synaptic neuron
—> after downregulation it **takes time for post-synaptic neuron to release more 5HT in compensation (drug start to become effective)
—> later 5HT2a, 2c will downregulate (5HT1a greater proportion of effect now) —> less SE
Overall in the first few weeks: 5HT2a + 2c effect»_space; 5HT1a effect + Decrease in serotonin level due to auto-regulation
Tricyclic antidepressant (TCA)
MOA:
- **Non-selective monoamine reuptake inhibitors + antagonists
- Oldest antidepressant
- **Quite effective
- ***Broad range of receptor action —> Undesirable SE (High intolerability issue)
—> H1 receptor
—> M1 receptor
—> α receptor
—> 5HT receptor
Drugs:
1. Amitriptyline
2. Clomipramine
3. Imipramine
4. Nortriptyline
5. Prothiaden
Selective Serotonin Reuptake Inhibitor (SSRI)
Some SSRI possess additional (though weaker), monoamine antagonistic / RI properties
- Fluoxetine: NRI, 5HT2c
- Sertraline: Dopamine RI
- Paroxetine: M1, NRI
- Citalopram: H1
Drugs:
1. Fluoxetine
2. Sertraline
3. Paroxetine
4. Fluvoxamine
5. Citalopram (R + S isomer: competitive with each other but R-isomer has no effect)
6. Escitalopram (S-isomer of Citalopram: dose is halved)
Serotonin Noradrenaline Reuptake Inhibitor (SNRI)
- Now no longer regarded as 2nd line (∵ lower cost)
Drugs:
1. Venlafaxine
2. Desvenlafaxine (Active metabolite of Venlafaxine, ***better for liver impairment, only excreted by kidney)
3. Duloxetine (also for neuropathic pain)
4. Milnacipran (for excreted by kidney)
Serotonin Antagonist / Reuptake inhibitor (SARI)
Newer antidepressants
MOA:
- **Block 5HT2a + 2c —> prevent SE in first few weeks
- ↑ Serotonin only in 5HT1a receptor
- Also has **Antihistaminergic effect —> good sedating effect for insomnia patients
Drug:
1. Trazodone
Noradrenaline Selective Serotonin Antagonists (NaSSA)
Newer antidepressants
MOA:
- **Block 5HT2a, 2c receptor
- **Block α2 receptor —> enhance adrenergic + serotonergic neurotransmission
Drugs:
1. Mianserin (also act on α1 —> more hypotensive effect)
2. Mirtazapine
Noradrenaline (NRI) / Noradrenaline-Dopamine Reuptake Inhibitor (NDRI)
Newer antidepressants
Drugs:
1. Reboxetine (NRI) (N/A in HK)
2. Bupropion (NDRI) (also used in smoking cessation)
- Intermediate release: Smoking cessation
- Extended release: Depression
Noradrenaline Dopamine Disinhibitor / Melatonin Agonist
Newer antidepressants
MOA:
- **5HT2c antagonism —> disinhibit release of DA + NE at PFC
- **Melatonin agonist at MT1, MT2 receptor —> Melatonin increase intracellular signaling for ***BDNF + sleep-wake phase
- ↓ Glutamate
Drug:
1. Agomelatine
Other newer Antidepressants
Vortioxetine
MOA:
- Full agonist at 5HT1a
- Partial agonist at 5HT1b
- Antagonist at 5HT1d
- Antagonist at 5HT3 + 7 —> help with cognitive impairment
Esketamine (Spravato):
- Approved treatment as **Augmentation medication in treatment-resistant depression +/- high suicidality thoughts
- **S-enantiomer of racemic ketamine
- **Increase BDNF / Improve neuronal strength
- **High abuse potential —> cannot be prescribed on out-patient basis
- ***No limit on duration of treatment
MOA:
1. **Disinhibition hypothesis: NMDA receptor antagonist on GABA interneurons
—> ↓ GABA release
—> ↑ Glutamate release in synaptic cleft
—> Stimulation of **AMPA receptor (improve in neuroplasticity + neurogenesis through BDNF release)
—> Release of BDNF
—> Dendritic sprouting + synaptogenesis in corticolimbic brain regions
—> Restore activity + strength of synapses
- ***Direct inhibitor of NMDA receptors with GluN2B subunits
—> Disrupt basal activation of pyramidal neurons
—> GluN2B-dependent mechanism involving eukaryotic elongation factor (eEF2) dephosphorylation
—> ↑ BDNF translation
Pharmacokinetics:
- Extensive hepatic metabolism by CYP450 3A4 + 2B6
(SpC Psychiatry: Other drugs: Tianeptine)
