Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review
Abstract
1. Introduction
2. Methods
3. Results
3.1. Mechanism Specifics
3.2. Side Effects Profiles of the Various Generations of Antipsychotics
3.3. Use with Other Antipsychotics and Psychotropic Medications
4. Discussion
4.1. Mechanistic Considerations
4.2. Patient Quality of Life and Logistical Considerations
4.3. Future Directions
5. Limitations
5.1. Methodological Limitations
5.2. Literature-Based Limitations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
First-generation antipsychotic | FGA |
Second-generation antipsychotic | SGA |
Dopamine D2 receptor | DRD2 |
Dopamine D2 receptor (long isoform) | D2LR |
Long-acting injectable | LAI |
Extrapyramidal symptoms | EPS |
Richmond Agitation-Sedation Scale | RASS |
Cytochrome P450 | CYP |
Antipsychotic polypharmacy | APP |
Antipsychotic monotherapy | APM |
Significant adverse events | SAE |
Muscarinic acetylcholine receptor | mAChR |
N-desmethylclozapine | NDMC |
Xanomeline-trospium | XT |
Positive and Negative Syndrome Scale | PANSS |
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Antipsychotic | Average Ki Value (nM) | Ki Value Range | Metabolism | Notes/Considerations |
---|---|---|---|---|
Fluphenazine | 0.54 | 0.540000 a,b | CYP2D6 | More susceptible to CYP2D6 inhibitors than other antipsychotics. d |
Pimozide | 0.65 | 0.650000 b | CYP2D6 | Moderate sensitivity to CYP2D6. d |
Thiothixene | 1.015 | 0.630000–1.400000 a,b | - | - |
Trifluoperazine | 1.3 | 1.300000 b | - | - |
Perphenazine | 1.4 | 1.400000 b | - | Multiple pathways of clearance, limited impact of CYP induction/inhibition on serum levels. d |
Aripiprazole | 2.455 | 0.660000–3.300000 a,b,c | CYP2D6, CYP3A4 | Manufacturer recommends twofold dose increase when administered with inducers like carbamazepine and a two-fold dose reduction with inhibitors such as fluoxetine, quinidine, or ketoconazole. d |
Chlorpromazine | 3 | 2.000000–4.000000 a,b | CYP1A2 | Recommended to avoid smoking tobacco as it induces CYP1A2. d |
Haloperidol | 3 | 2.000000–4.000000 a,b | Primarily CYP2D6, CYP3A4, and CYP3A5 | Has multiple pathways, limiting impact of CYP induction/inhibition on serum levels. d |
Risperidone | 5.7 | 4.900000–6.500000 a,b | CYP2D6 | Serum levels may rise with CYP2D6 inhibitors like fluoxetine or paroxetine, will increase to a lesser degree with bupropion. d |
Ziprasidone | 6.85 | 4.000000–9.700000 a,b | Primarily through glutathione and aldehyde oxidase with minor contribution from CYP3A4 | Inhibitors and inducers of CYP only cause modest effects in serum levels. d |
Sertindole | 9.1 | 9.100000 b | - | - |
Thioridazine | 10.5 | 10.000000–11.000000 a,b | - | Multiple pathways of clearance, limited impact of CYP induction/inhibition on serum levels. d |
Loxapine | 11 | 10.000000–12.000000 a,b | - | Multiple pathways of clearance, limited impact of CYP induction/inhibition on serum levels. d |
Olanzapine | 53 | 34.000000–72.000000 a,b | CYP1A2 | Avoid strong inhibitors or inducers of CYP1A2 as well as smoking tobacco. d |
Molindone | 63 | 63.000000 b | - | - |
Clozapine | 343.5 | 256.000000–431.000000 a,b | Primarily CYP1A2 and CYP3A4, some CYP2D6 | May require reduction of one-third dose with fluvoxamine or ciprofloxacin, smoking may require twofold increase in dose with 30–40% reduction of dose in settings where smoker is unable to smoke. d |
Quetiapine | 410.5 | 254.000000–567.000000 a,b | CYP3A4 | Manufacturer recommends up to a fivefold increase in dose with CYP3A4 inducers like carbamazepine and a reduction to one-sixth with inhibitors like voriconazole or ritonavir. d |
Receptor | G Protein Subtype | Function | Regions of the Brain Mainly Found in | Dopamine Pathway(s) Affected |
---|---|---|---|---|
M1 | Gq | Excitatory | Cerebral Cortex, basal ganglia | Nigrostriatal pathway more than Mesolimbic pathway |
M2 | Gi/o | Inhibition | Nucleus Basalis, hippocampus, basal ganglia | Mesolimbic pathway more than Nigrostriatal pathway |
M3 | Gq | Excitatory | Cerebral cortex, basal ganglia | Mesocortical pathway |
M4 | Gi/o | Inhibition | Basal ganglia and cortex | Nigrostriatal pathway more than Mesolimbic pathway |
M5 | Gq | Excitatory | Hippocampus, substantia nigra, and VTA | Mesolimbic pathway more than Mesocortical pathway |
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Shaw, J.; Kim, E.; Ton, E.; Lai, C.; Bota, P.; Allee, T. Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review. Diseases 2025, 13, 274. https://doi.org/10.3390/diseases13080274
Shaw J, Kim E, Ton E, Lai C, Bota P, Allee T. Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review. Diseases. 2025; 13(8):274. https://doi.org/10.3390/diseases13080274
Chicago/Turabian StyleShaw, Jonathan, Ethan Kim, Emily Ton, Charles Lai, Peter Bota, and Tina Allee. 2025. "Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review" Diseases 13, no. 8: 274. https://doi.org/10.3390/diseases13080274
APA StyleShaw, J., Kim, E., Ton, E., Lai, C., Bota, P., & Allee, T. (2025). Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review. Diseases, 13(8), 274. https://doi.org/10.3390/diseases13080274