🧵Novel and Emerging Treatments for Agitation in Schizophrenia and Bipolar Disorder 🚀
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1/ Traditional approaches :
- Haloperidol (oral/IM/IV)
Limitations: High incidence of extrapyramidal symptoms (EPS), dystonia, and risk (albeit rare) of neuroleptic malignant syndrome. 🚨
- Lorazepam (oral/IM/IV)
Limitations: Tolerance, risk of respiratory depression, cognitive impairment - particularly problematic in elderly or medically fragile populations. 🚨
- Haloperidol (oral/IM/IV)
Limitations: High incidence of extrapyramidal symptoms (EPS), dystonia, and risk (albeit rare) of neuroleptic malignant syndrome. 🚨
- Lorazepam (oral/IM/IV)
Limitations: Tolerance, risk of respiratory depression, cognitive impairment - particularly problematic in elderly or medically fragile populations. 🚨
2/ Combined use of benzodiazepines and antipsychotics is common, but cumulative sedation and compounded side-effect profiles (EPS, falls, delirium) limit their utility.
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Additionally, these agents do not address treatment-resistant or affectively driven agitation
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Additionally, these agents do not address treatment-resistant or affectively driven agitation
3/ New Approaches:
Sublingual Dexmedetomidine
Mechanism: α2-adrenergic agonist.
• FDA-approved for acute agitation in schizophrenia and bipolar I/II (2022).
• Non-invasive, high bioavailability, minimal respiratory depression.
• Adverse effects: transient hypotension, bradycardia, somnolence, generally self-limited.
Sublingual Dexmedetomidine
Mechanism: α2-adrenergic agonist.
• FDA-approved for acute agitation in schizophrenia and bipolar I/II (2022).
• Non-invasive, high bioavailability, minimal respiratory depression.
• Adverse effects: transient hypotension, bradycardia, somnolence, generally self-limited.
5/ Subcutaneous Olanzapine
Mechanism: D2 and 5-HT2A receptor antagonism.
Provides an alternative to IM haloperidol with lower EPS risk.
Particularly useful in delirium and agitation, where rapid absorption is required.
Preliminary studies show favourable tolerability and injection site safety.
Mechanism: D2 and 5-HT2A receptor antagonism.
Provides an alternative to IM haloperidol with lower EPS risk.
Particularly useful in delirium and agitation, where rapid absorption is required.
Preliminary studies show favourable tolerability and injection site safety.
4/ Gabapentinoids (Gabapentin, Pregabalin)
Mechanism: α2δ subunit calcium channel modulation.
• Evidence supports utility in anxiety, insomnia, and certain mood states.
• Limited efficacy in acute agitation; better suited for chronic behavioural dysregulation.
• Sedative burden may worsen negative symptoms in schizophrenia.
Mechanism: α2δ subunit calcium channel modulation.
• Evidence supports utility in anxiety, insomnia, and certain mood states.
• Limited efficacy in acute agitation; better suited for chronic behavioural dysregulation.
• Sedative burden may worsen negative symptoms in schizophrenia.
5/ Ketamine / Esketamine
Mechanism: NMDA receptor antagonism, glutamatergic modulation.
• Rapid onset; useful in severe or prehospital agitation.
• Risk: dissociation, psychosis exacerbation, need for continuous monitoring.
• Esketamine’s enantiomeric profile may offer reduced side effects at lower doses.
Mechanism: NMDA receptor antagonism, glutamatergic modulation.
• Rapid onset; useful in severe or prehospital agitation.
• Risk: dissociation, psychosis exacerbation, need for continuous monitoring.
• Esketamine’s enantiomeric profile may offer reduced side effects at lower doses.
6/ Emerging Innovative Options: under investigation:
• Intranasal Olanzapine – 'exploits' nasal mucosa for direct CNS access; rapid onset without need for injection.
• Cannabidiol (CBD) – modulates endocannabinoid, serotonergic, and dopaminergic systems; has theoretical anxiolytic and antipsychotic effects.
• Intranasal Olanzapine – 'exploits' nasal mucosa for direct CNS access; rapid onset without need for injection.
• Cannabidiol (CBD) – modulates endocannabinoid, serotonergic, and dopaminergic systems; has theoretical anxiolytic and antipsychotic effects.
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