At 2019 NEI Congress, Dr. Andrew Cutler presented on novel antipsychotic mechanisms. Schizophrenia has been primarily associated wtih dopamine dysfunction, and all effective treatments directly target the dopamine D2 receptor. However, the core pathophysiology of schizophrenia may also involve dysfunction of multiple other neurotransmitter systems, including glutamater, serotonin, acetylcholine, and gamma-aminobutyric acid (GABA). To that end, novel treatment development is focusing on targets beyond dopamine (Tables 1 and 2).
Table 1. Beyond the D2 Hypothesis: Novel Treatment Targets for Schizophrenia |
Hypothesis |
Target |
Strategy |
Glutamate |
NMDA, AMPA, or metabotropic receptors |
Improve negative and cognitive symptoms |
Serotonin |
5HT1A agonists, 5HT2C antagonists and agonists, 5HT3 antagonists, 5HT6 and 5HT7 antagonists, 5HT reuptake inhibitors
|
Reduce EPS Improve negative, mood and cognitive symptoms Potential treatment for different phases of the illness |
Acetylcholine |
a-7 nicotinic and M1 muscarinic agonists and positive allosteric modulators |
Nicotinic agonists for cognitive symptoms Muscarinic agonists for positive symptoms |
GABA |
Selective GABA-A agonists, GABA-B antagonists, and allosteric modulators at GABA-A receptor subtypes |
Augmentation of psychosis treatment |
Inflammation |
Cytokines |
Possibly the early period of psychosis |
Phosphodiesterase (PDE) |
PDE-10A inhibitor |
Activates cAMP/PKA signaling, leading to potentiation of D1 receptor signaling, and inhibition of D2 receptor signaling |
NMDA: N-methyl-D-aspartate; AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid; 5HT: 5-hydroxytryptamine (serotonin); GABA: gamma-aminobutyric acid. |
Table 2. Agents in Phase III Clinical Trials |
Agent |
Mechanism of action |
Potential indication |
Lumateperone (ITI-007) |
5HT2A antagonist, 5HT
transport inhibitor, presynaptic, D2 partial agonist, postsynaptic D2 antagonist, D1-regulated NMDA and AMPA agonist |
Schizophrenia, bipolar depression, agitation in patients with dementia, neuropsychiatric/neurodegenerative diseases |
RO5263397 (monotherapy) |
Trace amine-associated redeptor (TAAR) 1 agonist |
Schizophrenia |
SEP-363856 (monotherapy) |
TAAR1 agonist |
Schizophrenia |
Roluperidone (MIN-101) (monotherapy) |
5HT2A antagonist, sigma 2
antagonist, alpha1-adrenergic antagonist |
Schizophrenia |
LuAF-35700 (monotherapy) |
D1 antagonist (>D2 antagonist), 5HT2A antagonist, 5HT6 occupancy |
|
Pimavanserin (add-on) |
5HT2A inverse agonist |
Schizophrenia, major depressive disorder, Parkinson’s psychosis, psychosis in Alzheimer’s disease |
Paliperidone Palmitate 6-monthly formulation (monotherapy) |
5HT2A antagonist, D2 antagonist |
Schizophrenia |
Risperidone extended release subcutaneous injection (TV46000) (monotherapy) |
5HT2A antagonist, D2 antagonist |
Schizophrenia |
Risperidone ISM
® (Doriafi) (monotherapy) |
5HT2A antagonist, D2 antagonist |
Schizophrenia |
Samidorphan/Olanzapine (ALKS3831) (monotherapy) |
mu-opioid antagonist/5HT2A antagonist, D2 antagonist |
Olanzapine-induced weight gain
+ schizophrenia |
NMDA: N-methyl-D-aspartate; AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid; 5HT: 5-hydroxytryptamine (serotonin). |
Of course, not all treatment for schizophrenia is pharmacological. In his presentation, Dr. Cutler also distilled the data for transcranial magnetic stimulation (TMS) for auditory hallucinations and cognitive impairment, as well as two approaches (training or strategy) for cognitive remediation therapy.
Reference:
Andrew J. Cutler, MD (November, 2019). I Blocked D2 and All I Got Was This Lousy Side Effect: What to Do When D2 Isn’t Enough. Presented at 2019 NEI Congress, Colorado Springs, CO.
Stay tuned for the Encore Presentation (releasing December 2019):
For more information on novel antipsychotic mechanisms: