Table 3.
Adverse effect profiles of selected FGA and SGA drugs#
| Adverse effect | Mechanism | Dose/titration dependent | AMI | ARI | ASE | BRE | CAR | CLO | ILO | LUR | OLA | PALI | QUE | RIS | SER | ZIP | CPZ | HAL | LOX | PER |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sedation | H1 blockade | +++ | 0/+ | 0/+ | + | 0/+ | 0/+ | +++ | 0/+ | +/++ | +/++ | 0/+ | ++ | + | 0/+ | + | +++ | + | + | + |
| Cognitive impairment | Anticholinergic, D2 blockade | ++ | + | 0 | + | 0 | 0 | + | 0 | 0 | + | + | + | + | + | 0 | ++ | ++ | ++ | ++ |
| Weight gain | H1, D2, 5HT2c blockade | 0/+ | 0/+ | 0 | + | 0 | 0/+ | +++ | +/++ | 0/+ | +++ | ++ | ++ | ++ | ++ | 0/+ | +++ | + | + | ++ |
| Metabolic syndrome | Weight gain, overeating, direct effects | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | +++ | + | 0/+ | +++ | + | ++ | + | + | 0/+ | +++ | 0/+ | + | + |
| Acute parkinsonism | D2 blockade | +++ | + | + | ++ | + | ++ | 0 | 0/+ | ++ | 0/+ | ++ | 0 | ++ | 0/+ | + | + | +++ | ++ | ++ |
| Akathisia | D2 blockade and α, 5HT interaction | +++ | + | ++ | + | ++ | ++ | + | 0/+ | +/++ | + | + | + | ++ | + | +/++ | + | +++ | ++ | ++ |
| TD | D2 receptor desensitization | ++ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0 | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | ++ | +++ | ++ | ++ |
| Withdrawal dyskinesia | D2 blockade rebound | +++ | + | +/++ | + | +/++ | +/++ | 0 | + | + | 0/+ | + | 0/+ | + | 0/+ | + | 0/+ | ++ | +/++ | +/++ |
| Seizures | D2 blockade | +++ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | + | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ |
| Increase in QTc interval | Cardiac ion channel effects | ++ | ++ | 0 | + | 0 | 0 | + | 0/+ | 0/+ | + | + | + | ++ | ++ | ++ | + | ++ | + | + |
| Hypotension | α1 blockade | +++ | 0/+ | 0/+ | + | 0/+ | 0/+ | +++ | +++ | 0/+ | ++ | + | ++ | ++ | + | ++ | +++ | ++ | + | ++ |
| Cardiovascular events (myocardial infarction and stroke) | Hypercoagulability, metabolic effects, direct channel toxic action | + | 0/+ | 0/+ | + | 0/+ | ? | ++ | ? | ? | ++ | + | ++ | ++ | 0/+ | + | ++ | ++ | + | ++ |
| Sialorrhea | M4 agonism | + | 0 | 0 | 0 | 0 | 0 | ++ | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neutropenia | Direct effect | + | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | + | 0/+ | 0/+ | 0/+ |
| Increase in prolactin/sexual dysfunction | D2 blockade | +++ | +++ | 0 | + | 0 | 0 | 0 | 0/+ | + | + | +++ | 0 | +++ | + | + | + | ++/+++ | ++ | ++ |
| Myocarditis and cardiomyopathy | Unknown | 0 | 0 | 0 | 0 | 0 | 0 | ++ | 0 | 0 | 0 | 0 | 0/+ | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pneumonia and acute respiratory failure | Sialorrhea, central sedation, muscle impairment | +++ | + | 0 | 0 | 0/+ | 0/+ | ++ | 0/+ | 0/+ | + | 0/+ | 0/+ | + | 0/+ | 0 | + | + | + | + |
| Gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea, and constipation) | Anticholinergic, D2 agonism | + | 0 | + | 0 | + | + | ++ | 0 | 0 | ++ | 0 | 0 | 0 | 0 | 0 | ++ | 0 | ++ | ++ |
| Pulmonary embolism and venous thromboembolism | Hypercoagulability | 0/+ | + | 0/+ | + | ? | ? | + | ? | ? | + | + | + | + | 0/+ | 0/+ | ++ | + | + | ++ |
| Dry mouth and dental caries | Anticholinergic | + | 0 | 0 | 0 | 0 | 0 | ++ | 0 | 0 | ++ | 0 | ++ | 0 | 0 | 0 | ++ | ++ | ++ | |
| Liver dysfunction | Metabolic syndrome, direct effect | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | + | 0 | + | + | 0/+ | 0 | ++ | 0/+ | 0/+ | 0/+ |
| Urinary and kidney functions | Anticholinergic (prolactin) | ++ | + | 0 | 0 | 0 | + | + | 0 | + | + | 0 | 0 | 0/+ | 0 | 0/+ | + | 0 | 0 | + |
| Osteopenia, osteoporosis, and fractures | D2 blockade (prolactin) | + | + | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | + | 0/+ | + | 0/+ | 0/+ | 0/+ | + | 0/+ | 0/+ |
| Binge eating, impulse control disorder, and gambling | H1 blockade, D2 agonism | + | 0 | + | + | ? | ? | ++ | 0 | 0 | ++ | + | 0 | + | 0 | 0/+ | + | 0 | 0 | 0 |
| Sexual and reproductive system dysfunction | D2 blockade (prolactin), α blockade, anticholinergic | ++ | + | 0/+ | + | ? | 0 | ++ | ? | + | ++ | ++ | + | ++ | + | 0/+ | ++ | ++ | ++ | ++ |
| Endocrine adverse effects (diabetes, ketoacidosis, hypothyroidism, and hyponatremia) | Unknown | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | ++ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ | 0/+ |
| Hyperprolactinemia | D2 blockade | +++ | +++ | 0 | + | 0 | 0 | + | + | ++ | + | +++ | +++ | ++ | ++ | + | +++ | + | + | |
| Breast and cervical cancers | Unknown | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Malignant neuroleptic syndrome | Unknown | ++ | 0/+ | 0/+ | 0/+ | ? | ? | +++ | ? | ? | + | 0/+ | + | + | + | + | +++ | +++ | + | + |
Notes: +, ++, and +++ indicate comparative, not absolute, and side effect relevance among drugs. ? indicates no evidence available. Italics represent FGAs.
Abbreviations: FGA, first-generation antipsychotic; SGA, second-generation antipsychotic; AMI, amisulpride; ARI, aripiprazole; ASE, asenapine; BRE, brexpiprazole; CAR, cariprazine; CLO, clozapine; ILO, iloperidone; LUR, lurasidone; OLA, olanzapine; PALI, paliperidone; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; CPZ, chlorpromazine; HAL, haloperidol; LOX, loxapine; PER, perphenazine; TD, tardive dyskinesia; FGA, first-generation antipsychotics.