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)
Psychosis
Dopamine hypothesis in Psychosis and Schizophrenia
4 important pathways:
1. Mesolimbic (excess DA —> positive symptoms)
2. Mesocortical (paucity of DA —> negative symptoms + cognitive symptoms)
3. Nigostriatal (DA blockade —> EPSE)
4. Tuberoinfundibular (DA blockade —> hyperprolactinaemia)
Dopamine receptors:
- 2 families: D1-like, D2-like
- D1-like family: D1, D5 —> ↑ intracellular cAMP
- D2-like family: ***D2, D3, D4 —> ↓ intracellular cAMP
1st Generation (Typical / Conventional) Antipsychotic
MOA:
- Potent D2 blockade
Chemical class:
1. Phenothiazine
- Chlorpromazine (aliphatic side chain)
- Thioridazine, Perphenazine (piperidine side chain)
- Trifluoperazine, Fluphenazine (piperazine side chain)
- Thioxanthene
- Thiothixene, Flupentixol (depot: still used), Zuclopenthixol (depot: still used) - Butyrophenone
- Haloperidol (still used) - Diphenylbutylpiperdine
- Pimozie - Substituted Benzamide
- Sulpiride (still used)
SE:
1. D2 blockade
- **EPSE (Nigostriatal), Negative symptoms (Mesocortical), Hyperprolactinaemia (Tuberoinfundibular), **Neuroleptic malignant syndrome
2. **H1 blockade
- sedation, weight gain
3. **α1/2 blockade
- α1: priapism, postural hypotension, dizziness
- α2: hypertension
4. ***M1 blockade
- blurred vision, dry mouth, constipation, sinus tachycardia, urinary retention, memory dysfunction
EPSE (記: DAPT):
- Result from Dopamine blockade at nigrostriatal pathway
1. **Dystonia
2. **Akathisia
3. **Parkinsonism (Dyskinesia, Tremor)
4. **Tardive dyskinesia
- delayed in onset, can be very subtle
- involuntary movement that can involve every muscle in body (mostly trunk, UL, lips)
- specific to antipsychotic
- >=3 month exposure to neuroleptic (DSM-IV)
5. Ataxia
2nd Generation (Atypical) Antipsychotic
- Comparable efficacy but less SE than Typical antipsychotic
- No particular SGA drug more efficacious (mainly patient-dependent)
MOA:
- **5HT2a + **D2 blockade
- Lower affinity to D2 than Typical antipsychotic (more limbic selective)
—> Less tight in binding to D2 receptor (“Fast-Off” theory)
—> Less EPSE + hyperprolactinaemia + Less risk of tardive dyskinesia
- D2 blockade: **Reduce positive symptoms
- 5HT2a blockade: **DA release in striatum + PFC —> **less EPSE + improve **negative symptoms + cognitive impairment
Drugs:
1. Clozapine (Prototype, Di-benzodiazepines)
2. Olanzapine (Thieno-benzodiazepine)
3. Quetiapine (Di-benzo-thiazepine)
4. Risperidone (Benzixasoles)
5. Sertindole (Imidazolidinone)
6. Asenapine (Dibenzo-oxepino)
7. Lurasidone (Benzo-iso-thiazol)
8. Ziprasidone (Benzo-thiazolyl-piperazine)
Additional receptor blockade:
1. Amisulpride: D2 + D3, negligible affinity on other receptors
2. Olanzapine: also M1 + M2
3. Sertindole: D2, 5HT2, α1 antagonist
4. Aripiprazole: D2 partial ***agonist —> called Dopamine system stabiliser (DSS) —> prevent too little dopamine activity in mesocortical pathway —> prevent negative symptoms as well + prevent other D2-mediated SE (e.g. N+V, agitation)
Latest class of Atypical antipsychotic are terms as
- **Serotonin-Dopamine activity modulator (SDAM) (e.g. Brexpiprazole)
—> 5HT1a partial agonist: improve **negative symptoms, ***depression, anxiety, cognitive impairment
SE:
1. **Metabolic syndrome
- Prevalence varies between different drugs
- Related to **broader receptor-binding profile (D2, 5HT1a, 5HT2a, 5HT2c etc.)
2. QTc prolongation (usually safe)
Other SE profile
1. D2 blockade
—> **EPSE (Nigostriatal)
—> Negative symptoms (Mesocortical)
—> Hyperprolactinaemia (Tuberoinfundibular)
—> **Neuroleptic malignant syndrome
2. **H1 blockade —> sedation, weight gain
3. **α1/2 blockade —> α1: priapism, postural hypotension, dizziness, α2: hypertension
4. **M1 blockade —> blurred vision, dry mouth, constipation, sinus tachycardia, urinary retention, memory dysfunction
5. **D2 agonism —> psychomotor activation, akathisia
Neuroleptic malignant syndrome
- Medical emergency
- Incidence: 0.01-3%
- Potentially fatal
Pathophysiology:
1. Hypothalamic dopamine blockade —> Hyperthermia + SNS activation
2. Frontal lobe dysfunction / Mesocortical blockade —> Altered mental status
3. Autonomic dysfunction (loss of hierarchical integration + control) —> SNS + Vasomotor + Adreno-medullary dysfunction
Clinical features:
1. Hyperthermia
2. Altered mental status
3. EPSE: Muscle rigidity —> Rhabdomyolysis, Tremor
4. Tachycardia
5. Hypertension
Treatment:
1. Discontinuation of antipsychotic
2. Supportive treatment
Vs Serotonin syndrome:
- delirium, autonomic instability, **pyrexia, diaphoresis, **GI symptoms, restlessness, agitation, hyperreflexia, **rigidity, convulsion, coma, (*mydriasis))
- NMS:
—> **Bradyreflexia
—> **No GI symptoms
—> ***Normal pupil
Clozapine
Indication:
1. Treatment-resistant schizophrenia
2. Tardive syndrome
Risks:
1. **Agranulocytosis / **Neutropenia
- Regular **CBC + **ANC (worldwide consensus)
2. Seizure (dose-dependent)
- **EEG evaluation
- **Anticonvulsant prophylaxis
SE:
1. Over-sedativeness
2. Weight gain
3. Hypotension
4. **Hypersalivation
5. Nocturnal enuresis
6. Constipation
7. **IO
8. ***Cardiotoxicity (Myocarditis)
Mood stabilisers
Acute Mania:
1. Lithium
2. Valproate
3. Atypical antipsychotics (Olanzapine, Risperidone, Quetiapine, Aripiprazole)
4. Typical antipsychotics
5. Carbamazepine
Acute Depression:
1. Quetiapine
2. Lithium
3. Olanzapine
4. Lamotrigine
5. Fluoxetine
Maintenance for both Mania + Depression:
1. Lithium
2. Lamotrigine
3. Atypical antipsychotics (Olanzapine, Aripiprazole, Quetiapine, Risperidone)
(4. Valproate
5. Carbamazepine)
MOA of Mood stabilisers
- Lithium
- Inositol monophosphatase inhibition
- GSK-3β inhibition (Glycogen synthase kinase)
- Upregulation of mitochondrial Bcl-2 - Valproate
- HDAC (Histone deacetylases) inhibition - Carbamazepine
- Inhibition of voltage dependent Na channel
- Adenosine receptor antagonism - Lamotrigine
- Inhibition of voltage dependent Na channel
- Inhibition of glutamate release - Atypical antipsychotics (Quetiapine, Olanzapine) —> Suitable for both phases of Bipolar (Mania + Depression)
- Downregulate 5HT2a (Olanzapine)
- Downregulate GABAa receptors (Olanzapine)
- GSK-3β inhibition (Quetiapine, Olanzapine)
- Upregulation of mitochondrial Bcl-2 (Olanzapine)
