1. Introduction
Schizophrenia is a chronic, severe mental disorder characterized by disturbances in thought, perception, emotion, and behavior. The disorder typically manifests during adolescence or young adulthood and often leads to substantial functional impairment and reduced quality of life 22. Current treatment relies primarily on antipsychotic medications, which modulate dopaminergic neurotransmission and other neurotransmitter systems.
Schizophrenia affects approximately 1% of the global population and represents a leading cause of disability worldwide. This comprehensive review synthesizes evidence from systematic reviews, meta-analyses, randomized controlled trials, and clinical practice guidelines published from 2015 to 2026 to provide clinicians with an evidence-based reference for antipsychotic medication management.
Recovery from schizophrenia encompasses three dimensions: clinical recovery (symptomatic remission and relapse prevention), functional recovery (social and occupational functioning), and personal recovery (subjective well-being and life satisfaction) 22. The median proportion of patients achieving both clinical and functional recovery is only 13.5%, highlighting the need for comprehensive treatment approaches integrating pharmacological, psychological, and social interventions 22.
2. Pharmacologic Classes and Mechanisms of Action
2.1 Dopamine D2 Receptor Antagonism: The Common Pathway
All currently approved antipsychotics share the fundamental property of modulating dopamine D2 receptor neurotransmission 22. The dopamine hypothesis of schizophrenia posits that positive symptoms result from excessive dopaminergic activity in mesolimbic pathways, while negative symptoms and cognitive impairment may relate to hypodopaminergic states in mesocortical pathways.
First-Generation Antipsychotics (FGAs): These agents, including haloperidol, chlorpromazine, and fluphenazine, function primarily as high-affinity dopamine D2 receptor antagonists. Their strong D2 blockade effectively reduces positive symptoms but frequently causes extrapyramidal side effects (parkinsonism, akathisia, dystonia) and tardive dyskinesia with chronic use 22.
Second-Generation Antipsychotics (SGAs): These agents demonstrate varied receptor binding profiles beyond D2 antagonism, including serotonin 5-HT2A antagonism, partial D2 agonism, and modulation of other receptors (α1-adrenergic, histamine H1, muscarinic) 22. The serotonin-dopamine antagonism hypothesis suggests that concurrent 5-HT2A blockade may mitigate D2-related extrapyramidal effects and potentially improve negative symptoms.
2.2 Mechanistic Classification of Approved Antipsychotics
Based on the comprehensive drug landscape analysis 23, antipsychotics can be classified by primary mechanism:
Traditional D2 Antagonists/Partial Agonists:
- Full D2 antagonists: remoxipride, iloperidone, asenapine, haloperidol, chlorpromazine, fluphenazine, risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, lurasidone
- Partial D2 agonists: aripiprazole, brexpiprazole, cariprazine
- Partial agonists theoretically provide "functional selectivity," stabilizing dopaminergic tone by acting as antagonists in hyperdopaminergic states and weak agonists in hypodopaminergic states 23
Multi-Receptor Modulators: Multiple antipsychotics antagonize dopamine D1, D2, D3, D4 receptors alongside serotonin 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7 receptors. Examples include brilaroxazine, milsaperidone, and ziprasidone. This broad receptor profile theoretically provides broader symptom coverage across positive, negative, and cognitive domains 23.
Novel Non-D2 Mechanisms (In Development):
- Muscarinic receptor agonists: KarXT (xanomeline-trospium, targeting M1/M2/M3/M4 receptors) and selective M4 agonists represent a fundamentally different approach, targeting cholinergic dysfunction without D2 blockade 23
- TAAR1 agonists: ulotaront (SEP-363856) modulates trace amine-associated receptor 1 and 5-HT1A receptors, offering a non-D2 mechanism with potential cognitive benefits 23
- Glycine transporter inhibitors: iclepertin (BI 425809) and bitopertin enhance NMDA receptor function through glycine modulation, targeting glutamatergic dysfunction underlying negative and cognitive symptoms 23
- Glutamate receptor modulators: pomaglumetad methionil acts as an mGluR2/3 agonist 23
- Sigma-1 receptor modulators: roluperidone combines 5-HT2A antagonism, alpha-1A antagonism, and sigma-1 receptor modulation for neuroprotection 23
2.3 Clozapine: The Gold Standard for Treatment Resistance
Clozapine occupies a unique position as the only antipsychotic with proven superior efficacy in treatment-resistant schizophrenia 11419. Its pharmacologic profile includes:
- Relatively weak D2 antagonism with preferential binding to D1 and D4 receptors
- Strong 5-HT2A, 5-HT2C antagonism
- Alpha-1 adrenergic, histamine H1, muscarinic antagonism
This complex receptor profile may contribute to its superior efficacy, though the precise mechanisms remain incompletely understood 47.
3. Comparative Efficacy and Safety
3.1 Treatment-Resistant Schizophrenia
The most comprehensive network meta-analysis of treatment-resistant schizophrenia (60 RCTs, 6,838 participants) demonstrated 1:
Overall Symptom Reduction:
- Clozapine and olanzapine showed superior efficacy compared to risperidone, haloperidol, fluphenazine, sertindole, chlorpromazine, and quetiapine (SMDs ranging from −0.11 to −0.48)
- The difference between clozapine and olanzapine was trivial and uncertain (SMD −0.05, 95% CI −0.21 to 0.11)
- In sensitivity analyses restricted to double-blind studies with high-dose clozapine in very refractory patients, clozapine was clearly superior to olanzapine
- When studies from olanzapine's manufacturer were excluded, olanzapine showed reduced efficacy compared to clozapine and several other drugs (though sample size was small, n=157)
Positive Symptoms: Risperidone showed no clear difference to clozapine and olanzapine but was more effective than haloperidol, chlorpromazine, and quetiapine 1.
Negative Symptoms: Results were largely uncertain, with chlorpromazine being clearly inferior to clozapine, olanzapine, quetiapine, risperidone, and haloperidol 1.
Discontinuation Outcomes:
- For all-cause discontinuation, clozapine showed no difference to olanzapine but was superior to chlorpromazine, quetiapine, haloperidol, and fluphenazine
- For discontinuation due to inefficacy, clozapine ranked first and outperformed olanzapine, risperidone, sertindole, quetiapine, haloperidol, placebo, and fluphenazine (RRs 0.14 to 0.53) 1
Adverse Events:
- Weight gain: Clozapine and olanzapine were associated with more weight gain than all other antipsychotics
- Sedation: Clozapine was associated with significantly more sedation than several other antipsychotics, including olanzapine
- Extrapyramidal symptoms: Both clozapine and olanzapine showed less use of antiparkinsonian medication compared with risperidone, fluphenazine, and haloperidol
- Prolactin elevation: Clozapine was associated with less prolactin increase than risperidone, haloperidol, chlorpromazine, and olanzapine 1
An earlier network meta-analysis (40 RCTs, 5,172 participants) found surprisingly few significant differences, with olanzapine more effective than quetiapine (SMD −0.29), haloperidol (−0.29), and sertindole (−0.46), and clozapine more effective than haloperidol (−0.22) and sertindole (−0.40) 7. This study concluded that "blinded randomized controlled trials—in contrast to unblinded, randomized effectiveness studies—provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics" 7.
A direct comparison meta-analysis of clozapine versus first- and second-generation antipsychotics in treatment-refractory schizophrenia (21 papers, 25 comparisons) found a number needed to treat of 9, with clozapine superior for positive symptoms in both short and long term, and superior for total and negative symptoms in the short term only 14. Both funding source and dosage moderated results, and higher baseline psychosis scores predicted better clozapine outcomes 14.
3.2 Non-Refractory Schizophrenia
In non-refractory patients, one network meta-analysis identified clear efficacy advantages for clozapine, amisulpride, olanzapine, and risperidone 19. Haloperidol, generally considered a reference neuroleptic and comparator drug, fared poorly in most comparisons 19.
A long-term effectiveness systematic review and meta-analysis (59 studies, 45,787 participants, mean duration 47.4±32.1 weeks) found 9:
All-Cause Discontinuation: No consistent superiority of any SGA emerged. Clozapine, olanzapine, and risperidone were significantly superior to several other SGAs. Quetiapine was inferior to several other SGAs.
Psychopathology: Clozapine and olanzapine were superior to several other SGAs. Quetiapine and ziprasidone were inferior to several other SGAs.
Intolerability-Related Discontinuation: Risperidone was superior and clozapine was inferior to several other SGAs.
Adverse Effects:
- Weight gain: Olanzapine was worse than all other compared non-clozapine SGAs; risperidone was significantly worse than several other SGAs
- Prolactin increase: Risperidone and amisulpride were significantly worse than several other SGAs
- Extrapyramidal symptoms: Olanzapine was superior to risperidone regarding parkinsonism; no significant differences for akathisia
- Sedation: Clozapine and quetiapine were significantly worse than some other SGAs 9
3.3 First-Episode Psychosis and Acute Treatment
In adolescents with schizophrenia, a Phase 3 trial (316 patients, mean age 15.3 years) demonstrated that brexpiprazole 2–4 mg/day achieved a mean PANSS total score reduction of −22.8 (SE 1.5) compared to −17.4 (1.6) with placebo (difference −5.33, 95% CI −9.55 to −1.10; p=0.014) 6. The safety profile was consistent with adult trials, with treatment-emergent adverse events in 40% of brexpiprazole patients versus 40% of placebo patients 6.
A network meta-analysis of antipsychotics in children and adolescents with early-onset schizophrenia (12 trials, N=2,158, ages 8–19) found comparable efficacy among antipsychotics (except ziprasidone, which appeared inferior, and asenapine, which was unclear) 18. All antipsychotics were superior to placebo except ziprasidone and asenapine. Adverse reaction profiles varied substantially: weight gain primarily with olanzapine, extrapyramidal symptoms and akathisia with molindone, and prolactin increase with risperidone, paliperidone, and olanzapine 18.
3.4 Long-Acting Injectable Formulations in Acute Illness
A network meta-analysis of second-generation LAIs in acutely ill patients (25 RCTs, 8,418 individuals) found that all SGA-LAIs outperformed placebo in reducing acute symptoms at study endpoint (median follow-up 13 weeks) and were more acceptable than placebo with the exception of olanzapine 4. Most LAI formulations outperformed placebo in the very short-term (≤2 weeks), regardless of the need for initial oral supplementation, supporting LAI use from the acute phases of illness 4.
4. Real-World Effectiveness and Adherence
4.1 Oral Versus Long-Acting Injectable Antipsychotics
The EULAST trial, a large-scale pragmatic randomized open-label trial across 50 sites in 15 European countries and Israel, compared oral versus LAI antipsychotics in early-phase schizophrenia (511 participants, mean age 30.5 years) 15. The primary outcome was all-cause discontinuation over up to 19 months.
Key Findings:
- In the combined oral group (n=247), 72 (29%) completed the study and 175 (71%) met all-cause discontinuation criteria
- In the combined LAI group (n=264), 95 (36%) completed the study and 169 (64%) met all-cause discontinuation criteria
- Treatment discontinuation for any cause did not differ between groups (hazard ratio 1.16, 95% CI 0.94–1.43, p=0.18)
- No significant difference in time to all-cause discontinuation was found (log rank test χ²=1.87, p=0.17) 15
Clinical Conclusion: "No substantial advantage for LAI antipsychotic treatment over oral treatment was found regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice" 15.
4.2 Real-World Observational Evidence
Despite the neutral findings in the EULAST trial, milestone schizophrenia studies reveal high discontinuation rates with oral antipsychotics 16:
- The CATIE study revealed a 74% rate of discontinuation of oral antipsychotics within 6 months of use
- The EUFEST study indicated that 42% of participants discontinued oral medications after 12 months
- The PRIDE study found that first hospitalization or arrest was 43% higher among patients in the oral antipsychotic group versus the depot group 16
Japanese guideline recommendations note that while randomized controlled trials show no difference between LAIs and oral drugs, observational studies in real-world conditions demonstrate that LAIs reduce rehospitalization, all-cause discontinuation, and mortality 22.
4.3 Adherence and Medication Continuation
Medication adherence is a primary factor in relapse prevention, with good adherence increasing the likelihood of remission and recovery 22. Optimal dosage is critical: too low diminishes effect, while too high causes adverse effects (akathisia, extrapyramidal symptoms, depression, discomfort), both of which reduce adherence 22.
Persistent adverse effects such as tardive dyskinesia, tardive dystonia, and dopamine hypersensitivity psychosis are linked to consistent or repeated excessive dopamine D2 receptor blockade, with dopamine hypersensitivity psychosis representing a significant risk factor for treatment resistance 22.
5. Key Clinical Evidence and Emerging Therapeutic Directions in Schizophrenia
Efficacy Hierarchy
In treatment-resistant schizophrenia, clozapine and olanzapine demonstrate superior efficacy for overall symptom reduction compared to most other antipsychotics, with clozapine showing clear superiority in sensitivity analyses of high-quality studies 1. For non-refractory patients, clozapine, amisulpride, olanzapine, and risperidone show clear efficacy advantages 19. However, efficacy differences among second-generation antipsychotics are often modest and inconsistent across symptom domains 79.
Clozapine Remains Underutilized
Despite being the only FDA-indicated treatment for treatment-resistant schizophrenia (affecting ~30% of patients), clozapine is dramatically underutilized 47. In first-episode psychosis, clozapine initiation is delayed by a mean of 19.3 weeks and preceded by excessive antipsychotic dosing, with 29.4% of patients receiving doses above maximum limits and 75% receiving ≥3 different antipsychotics prior to clozapine 53. The FDA removed the Risk Evaluation and Mitigation Strategy (REMS) program effective June 13, 2025, eliminating mandatory enrollment and ANC reporting requirements to improve access 342.
Sequential Monotherapy Approach
Response rates to sequential antipsychotic trials decrease with each attempt: 53% respond to first-stage treatment, 26% to second-stage treatment, and 43% to clozapine in the third stage compared to 26% for non-clozapine alternatives 13. These findings strongly support guideline recommendations for clozapine after two adequate antipsychotic trials have failed.
Long-Acting Injectable (LAI) Formulations
LAI antipsychotics demonstrate superior effectiveness in real-world observational studies (reducing rehospitalization, all-cause discontinuation, and mortality) but show no significant advantage over oral formulations in randomized controlled trials for all-cause discontinuation 1522. The EULAST trial found no substantial advantage for LAI treatment over oral antipsychotics in early-phase schizophrenia (hazard ratio 1.16, 95% CI 0.94–1.43, p=0.18) 15. However, second-generation LAIs outperform placebo in acute symptom reduction and are effective from the acute phase of illness 4.
Antipsychotic Polypharmacy Associated with Poor Outcomes
Globally, 24.8% of populations receive antipsychotic polypharmacy, rising to 33.2% in schizophrenia spectrum disorders 17. Compared with monotherapy, polypharmacy is associated with increased relapse risk (RR 1.42), psychiatric hospitalization (RR 1.24), worse global functioning (SMD −0.31), more extrapyramidal symptoms (RR 1.63), and greater all-cause mortality (RR 1.19) 17.
Novel Mechanisms in Development
Approximately 30% of the development pipeline focuses on non-dopamine D2 mechanisms, including muscarinic receptor agonists (KarXT, M4 agonists), TAAR1 agonists (ulotaront), glycine transporter inhibitors (iclepertin, bitopertin), and glutamate receptor modulators (pomaglumetad methionil) 23.
Safety Monitoring is Essential
Clozapine myocarditis and bowel obstruction present greater mortality risk than agranulocytosis 47. Myocarditis risk is greatest in the first 8–12 weeks of treatment, with elevated CRP serving as an early indicator 3444. Patients with schizophrenia die on average 25 years earlier than the general population, with most excess mortality due to premature cardiovascular deaths 54. Coordinated specialty care with systematic metabolic and cardiac monitoring is essential 54.
Special Population Considerations
Brexpiprazole demonstrated efficacy in adolescents (ages 13+) with a safety profile consistent with adult trials 6. For children and adolescents with early-onset schizophrenia, efficacy is comparable among antipsychotics except ziprasidone (inferior) and asenapine (unclear), but adverse reaction profiles vary substantially 18. Clozapine use during pregnancy does not increase congenital malformation risk but doubles gestational diabetes rates; accumulation in breast milk necessitates infant monitoring 51.
6. Treatment-Resistant Schizophrenia
6.1 Definition and Prevalence
Treatment-resistant schizophrenia (TRS) affects approximately 30% of patients with schizophrenia 2247. Clozapine is the only drug indicated for TRS and remains dramatically underutilized due to prescriber inexperience with adverse event management 47.
A systematic review and meta-analysis of sequential antipsychotic trials (14 articles from 9 unique studies, 2,522 participants) demonstrated the following response rates 13:
Overall Population:
- First-stage treatment: 53% response (95% CI: 0.38, 0.68)
- Second-stage treatment: 26% response (95% CI: 0.15, 0.39)
- Third-stage clozapine: 43% response (95% CI: 0.19, 0.69)
- Third-stage different antipsychotic: 26% response (95% CI: 0.05, 0.54)
First-Episode Psychosis Subgroup (4 studies, 907 participants):
- First-stage treatment: 63% response (95% CI: 0.45, 0.79)
- Second-stage treatment: 34% response (95% CI: 0.16, 0.55)
- Third-stage clozapine: 45% response (95% CI: 0.0, 0.97)
- Third-stage different antipsychotic: 15% response (95% CI: 0.01, 0.37)
Clinical Recommendation: These findings support the recommendation to have a trial of clozapine after two other antipsychotic medications have been found to be ineffective 13.
In the Singapore Early Psychosis Intervention Programme (1,603 first-episode psychosis patients), only 4.3% received clozapine, with initiation delayed by a mean of 19.3 weeks 53. Prior to clozapine initiation, 29.4% had received antipsychotic doses above maximum limits, and 75% had received ≥3 different antipsychotics (median=3; range, 2–7) 53.
6.2 Clozapine Efficacy and Dosing
A meta-analysis of clozapine versus first- and second-generation antipsychotics found the number needed to treat was 9, with clozapine superior for positive symptoms in both short and long term, and superior for total and negative symptoms in the short term only 14. Higher baseline psychosis scores predicted better outcomes for clozapine 14. The review recommended that if there is no response by 6 months, medications with lower adverse reactions should be considered 14.
6.3 Clozapine Augmentation Strategies
Aripiprazole Augmentation:
The most robust evidence comes from a meta-analysis combining Finnish (1995–2017, N=14,053) and Swedish (2006–2021, N=8,743) nationwide cohort data examining clozapine augmentation effectiveness 43:
- Medium-dose aripiprazole (9–<16.5 mg/day) plus high-dose clozapine (≥330 mg/day) was the only augmentation strategy associated with significantly decreased hospitalization risk for psychotic episodes in both countries (adjusted hazard ratio [aHR]=0.68, 95% CI: 0.62–0.75, p<0.0001)
- For patients on medium-dose clozapine (180–<330 mg/day), medium-dose aripiprazole augmentation was the only treatment superior to monotherapy after Bonferroni correction (aHR=0.79, 95% CI: 0.70–0.91, p=0.0006)
- All high-dose augmentations were associated with increased relapse risk
- When examining combined psychotic and somatic hospitalization, medium-dose aripiprazole plus high-dose clozapine showed the lowest risk (aHR=0.70, 95% CI: 0.58–0.84, p=0.0001)
- The study demonstrates a 20–30% relative risk reduction for severe relapse with medium-dose aripiprazole augmentation compared to clozapine monotherapy 43
Lamotrigine Augmentation:
A case report documented rapid-onset agranulocytosis in a 60-year-old clozapine-resistant patient who received lamotrigine augmentation 46. Discontinuation of both substances and granulocyte-colony stimulating factor (GCSF) treatment resulted in normalization of ANC. The case highlights the importance of blood count monitoring and early management when lamotrigine is used as augmentation in clozapine-treated patients, suggesting potential additive hematologic risk with this combination 46.
Electroconvulsive Therapy (ECT):
The Japanese guideline addresses ECT utility if clozapine is not used (CQ5-4), and ECT represents an established option for clozapine-resistant or clozapine-intolerant patients 22. However, specific efficacy data from the retrieved materials are limited.
6.4 FDA REMS Elimination
On February 24, 2025, the FDA eliminated the mandatory Risk Evaluation and Mitigation Strategy (REMS) program for clozapine, effective June 13, 2025, based on re-evaluation and recommendations from the November 19, 2024 Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Psychopharmacologic Drugs Advisory Committee 342.
The FDA determined that the REMS was no longer necessary to ensure that the benefits of clozapine outweigh the risk of severe neutropenia. Although severe neutropenia remains a serious, potentially fatal risk (greatest in the first several months of treatment but persisting at lower levels thereafter), clozapine labeling—including a new Medication Guide and Boxed Warning—is sufficient to mitigate this risk and maintain a positive benefit/risk profile 3.
Impact on Practice:
- Elimination of the REMS is expected to improve access to clozapine and decrease the burden on the healthcare delivery system
- Prescribers, pharmacies, and patients are no longer required to participate in the REMS program and report ANC results to the REMS for clozapine to be dispensed
- Prescribers should continue to monitor patients' ANC according to monitoring frequencies described in the prescribing information 342
- The risk of severe neutropenia is greatest in the first 18 weeks of clozapine initiation 3
7. Research and Innovation Gaps
Approximately 30% of the current schizophrenia drug development pipeline is focused on mechanisms beyond dopamine D2 receptor blockade, reflecting growing interest in alternative neurobiological targets. Among these, muscarinic receptor agonists such as KarXT (xanomeline–trospium) and selective M4 agonists aim to address cholinergic dysfunction through a fundamentally different pharmacologic strategy that avoids direct D2 antagonism, though Phase III trials are still required to confirm their efficacy and safety. TAAR1 agonists, including ulotaront, represent another non-D2 approach with potential benefits for cognitive symptoms; however, their comparative effectiveness relative to established antipsychotics remains unclear. Additionally, glycine transporter 1 inhibitors such as iclepertin and bitopertin seek to modulate glutamatergic pathways to improve negative and cognitive symptoms, yet prior GlyT1 programs have yielded mixed outcomes, underscoring the need for rigorous clinical validation of these emerging therapies 23.
8. Comprehensive Drug Summary Tables
Table 1: Approved First-Generation (Typical) Antipsychotics
| Drug Name | Primary Mechanism | Typical Dosing Range | Key Efficacy Outcomes | Major Adverse Effects | Approval Status |
|---|---|---|---|---|---|
| Haloperidol | Dopamine D2 antagonist | Not specified in retrieved materials | Approved for schizophrenia, Tourette syndrome, certain behavioral disorders 57; fared poorly in most comparisons in TRS 19 | Extrapyramidal symptoms, tardive dyskinesia | FDA approved 5761 |
| Chlorpromazine | Dopamine D2, D1 antagonist | Not specified in retrieved materials | Clearly inferior to clozapine, olanzapine, quetiapine, risperidone, and haloperidol for negative symptoms in TRS 1 | Extrapyramidal symptoms, sedation, anticholinergic effects | FDA approved 61 |
| Fluphenazine | Dopamine D2 antagonist | Not specified in retrieved materials | Inferior to clozapine for all-cause discontinuation and discontinuation due to inefficacy in TRS 1 | Extrapyramidal symptoms, tardive dyskinesia | FDA approved 61 |
| Perphenazine | Dopamine D2 antagonist | Not specified in retrieved materials | FDA approved for schizophrenia in adults and children ≥12 years 56 | Extrapyramidal symptoms | FDA approved 56 |
| Remoxipride | Dopamine D2 antagonist | Oral, injectable, IV | Traditional D2 antagonist | Not specified in retrieved materials | BLA/NDA approved in Spain, USA 23 |
| Zuclopenthixol decanoate | Dopamine D2, D1 antagonist | Injectable, IM | Long-acting injectable | Extrapyramidal symptoms | BLA/NDA approved in Spain 23 |
| Zuclopenthixol acetate | Dopamine D2, D1 antagonist | Injectable, IM | Intermediate-acting injectable | Extrapyramidal symptoms | BLA/NDA approved in Spain 23 |
Table 2: Approved Second-Generation (Atypical) Antipsychotics
| Drug Name | Primary Mechanism | Typical Dosing Range | Key Efficacy Outcomes | Major Adverse Effects | Approval Status/Region |
|---|---|---|---|---|---|
| Clozapine | D2, D1, D4, 5-HT2A, 5-HT2C, α1, H1, muscarinic antagonism | Starting: 12.5 mg once or twice daily; Target: 150–225 mg twice daily; Max: 900 mg/day 39 | Superior efficacy in TRS; NNT=9 14; superior to haloperidol, chlorpromazine, quetiapine, fluphenazine, sertindole in TRS 1; only indicated treatment for TRS 47 | Boxed warnings: Severe neutropenia, orthostatic hypotension, seizures, myocarditis/cardiomyopathy 39; weight gain, sedation, constipation 139; gestational diabetes (2× higher in pregnancy) 51 | FDA approved 3941; BLA/NDA (OraSolv formulation) UK, Spain, Italy, France, Germany 23 |
| Olanzapine | D2, D3, D1, D4, 5-HT2A, 5-HT2C, H1 antagonism | Not specified in retrieved materials | Superior efficacy in TRS (comparable to clozapine in many outcomes) 1; more effective than quetiapine, haloperidol, sertindole in TRS 7; superior to several SGAs in long-term studies 9 | Worst weight gain among non-clozapine SGAs 9; metabolic syndrome; sedation | FDA approved 4161; Most cost-effective in Morocco (ODT formulation) 26 |
| Risperidone | D2, 5-HT2A, H1 antagonism | Not specified in retrieved materials | No clear difference to clozapine/olanzapine for positive symptoms in TRS 1; superior to several SGAs for all-cause discontinuation in long-term studies 9 | Highest prolactin elevation among SGAs 9; extrapyramidal symptoms; weight gain | FDA approved 4161; LAI formulation Phase III in USA 23 |
| Quetiapine | D2, D1, 5-HT1A, H1 antagonism | Not specified in retrieved materials | FDA approved for schizophrenia and bipolar disorder 57; inferior to several other SGAs in TRS and long-term studies 19 | Sedation (significantly worse than some other SGAs) 9; metabolic effects | FDA approved France 2341; Reformulations in Phase III (USA, China) 23 |
| Aripiprazole | D2, 5-HT1A partial agonist; 5-HT2A antagonist | Not specified in retrieved materials | FDA approved; adjunct for major depressive disorder 59 | Generally well-tolerated; akathisia | FDA approved 4161; Digital medicine system (Abilify Mycite) approved France, Italy, Spain, Germany, UK 23; Once-monthly ICER: $6,285.30/QALY 27 |
| Paliperidone | D2, 5-HT2A antagonist (active metabolite of risperidone) | Not specified in retrieved materials | FDA approved 41 | Prolactin elevation; extrapyramidal symptoms | FDA approved 4041; PP1M ICER: $8,247.46/QALY; PP3M ICER: $873.13/QALY 25 |
| Lurasidone | D2, 5-HT2A, 5-HT7 antagonist; 5-HT1A partial agonist | Not specified in retrieved materials | FDA approved 41; probably results in little to no difference in irritability in ASD 8 | Akathisia; nausea | FDA approved 4161 |
| Brexpiprazole | D2, D3 partial agonist; 5-HT1A partial agonist; 5-HT2A antagonist | 2–4 mg/day in adolescents 6 | PANSS reduction −22.8 vs −17.4 placebo in adolescents (p=0.014) 6; FDA approved; adjunct for major depressive disorder 59 | TEAEs in 40% (comparable to placebo 40%; lower than aripiprazole 52%) 6; headache, nausea | FDA approved; BLA/NDA approved China 23; EMA approved for adolescents ≥13 years 65676869 |
| Cariprazine | D3-preferring partial agonist; D2 partial agonist | Not specified in retrieved materials | FDA approved; adjunct for major depressive disorder 59 | Akathisia; extrapyramidal symptoms | FDA approved 61; Phase III in Japan 23 |
| Asenapine maleate | D2, D1, 5-HT2A antagonist | Sublingual | NME; unclear efficacy in adolescent schizophrenia 18 | Weight gain; sedation | BLA/NDA approved France, UK 2341 |
| Iloperidone | D2, 5-HT2A antagonist | Oral, injectable | NME; dual D2/5-HT2A antagonism | Orthostatic hypotension; weight gain; sedation | BLA/NDA approved Spain, UK, Germany, Italy, France 2341 |
| Ziprasidone | D2, 5-HT2A, NET, SERT antagonist | Oral, injectable, IM | FDA approved 41; inferior to several SGAs in long-term studies 9; inferior efficacy in adolescent schizophrenia 18 | QTc prolongation; akathisia | FDA approved 41; Phase III in Japan 23 |
| Zotepine | Norepinephrine transporter (NET) modulation | Oral | NME; NET modulation | Sedation; weight gain | BLA/NDA approved France 23; Phase III in USA 23 |
Table 3: Antipsychotics in Late-Stage Development (Phase III)
| Drug Name | Primary Mechanism | Route | Development Regions | Mechanistic Innovation | Development Status |
|---|---|---|---|---|---|
| KarXT (xanomeline-trospium) | Muscarinic M1, M2, M3, M4 agonist | Oral | China 23 | Novel non-D2 mechanism; fixed-dose combination; muscarinic agonism | Phase III 23 |
| Ulotaront (SEP-363856) | TAAR1 agonist; 5-HT1A modulator | Oral | USA, China, Japan 23 | Novel non-D2 mechanism; TAAR1 agonism | Phase III 23 |
| Iclepertin (BI 425809) | Glycine transporter 1 (GlyT1) inhibitor | Oral | China, Spain, Japan, Germany, UK, USA, France, Italy 23 | NMDA enhancement; GlyT1 inhibition for negative/cognitive symptoms | Phase III 23 |
| Pomaglumetad methionil | Glutamate mGluR2/3 agonist | Oral | Spain, France, Germany, USA 23 | Glutamatergic modulation | Phase III 23 |
| Roluperidone (MIN101) | 5-HT2A, α1, sigma-1 receptor modulation | Oral | France, UK, USA, Spain, Italy, Germany 23 | Sigma-1 receptor neuroprotection | Phase III 23 |
| Brilaroxazine (RP-5063) | D2, D3, D4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, 5-HT7 modulation | Oral | USA 23 | Broad multi-receptor profile | Phase III 23 |
| Pimavanserin tartrate | Selective 5-HT2A inverse agonist | Oral | Spain, USA 23 | Selective serotonergic without D2 blockade | Phase III 23 |
| Olanzapine + samidorphan (ALKS-3831, Lybalvi) | D2, D3, D1, D4, 5-HT2A, 5-HT2C, opioid receptor modulation | Oral | UK, Italy, Spain, Germany 23 | Fixed-dose combination to mitigate olanzapine weight gain | Phase III 23 |
| Bitopertin | Glycine transporter 1 (GlyT1) inhibitor | Oral | Italy 23 | GlyT1 inhibition for negative/cognitive symptoms | Phase III 23 |
| Sodium benzoate | D-amino acid oxidase (DAAO) inhibitor | Oral | USA 23 | NMDA enhancement via glycine modulation | Phase III 23 |
Table 4: Long-Acting Injectable Formulations
| Drug | Formulation | Route | Approval Status | Key Outcomes |
|---|---|---|---|---|
| Paliperidone palmitate 1-month (PP1M) | Monthly LAI | IM | Approved 40 | ICER: $8,247.46/QALY 25; superior to placebo in acute illness 4 |
| Paliperidone palmitate 3-month (PP3M) | Quarterly LAI | IM | Approved 40 | ICER: $873.13/QALY (most cost-effective LAI) 25 |
| Aripiprazole once-monthly (AOM) | Monthly LAI | IM | Approved 61 | ICER: $6,285.30/QALY 27; superior to placebo in acute illness 4 |
| Brexpiprazole | LAI | IM, SC | BLA/NDA (China) 23 | SC route offers alternative to IM 23 |
| Risperidone LAI (RISPERDAL CONSTA) | LAI | IM | Approved 40 | Superior to placebo for relapse prevention in bipolar disorder (RR=0.63, p<.0001) 12 |
| Zuclopenthixol decanoate | Long-acting | IM | BLA/NDA (Spain) 23 | FGA LAI formulation 23 |
| Zuclopenthixol acetate | Intermediate-acting | IM | BLA/NDA (Spain) 23 | FGA intermediate-acting formulation 23 |
Note on LAI Efficacy: LAIs show no significant advantage over oral formulations in RCTs for all-cause discontinuation (EULAST: HR 1.16, 95% CI 0.94–1.43, p=0.18) 15, but real-world observational studies demonstrate reduced rehospitalization, discontinuation, and mortality 22. Japanese guidelines weakly recommend LAIs when adherence is a concern 22.
8. Research and Innovation Gaps
Approximately 30% of the current schizophrenia drug development pipeline is focused on mechanisms beyond dopamine D2 receptor blockade, reflecting growing interest in alternative neurobiological targets. Among these, muscarinic receptor agonists such as KarXT (xanomeline–trospium) and selective M4 agonists aim to address cholinergic dysfunction through a fundamentally different pharmacologic strategy that avoids direct D2 antagonism, though Phase III trials are still required to confirm their efficacy and safety. TAAR1 agonists, including ulotaront, represent another non-D2 approach with potential benefits for cognitive symptoms; however, their comparative effectiveness relative to established antipsychotics remains unclear. Additionally, glycine transporter 1 inhibitors such as iclepertin and bitopertin seek to modulate glutamatergic pathways to improve negative and cognitive symptoms, yet prior GlyT1 programs have yielded mixed outcomes, underscoring the need for rigorous clinical validation of these emerging therapies 23.