Background

Schizophrenia is most times a chronic and often debilitating illness that is associated with positive, negative and cognitive symptoms, impaired reward processing and illness insight, as well as poor functional and physical health outcomes.1–3 Although genetic and environmental factors have been implicated, including maternal infection due to seasonal birth findings,4 the pathophysiology of schizophrenia remains to be elucidated, and valid biomarkers are lacking.5 The median age at the onset of schizophrenia and schizophrenia-spectrum disorders (first-episode psychosis) is 20.5 years.6 All-cause mortality is increased in people with schizophrenia compared to the general population with the greatest risk in first-episode (RR = 7.4) and incident (ie, earlier-phase) schizophrenia (RR = 3.5), with suicide being the biggest relative risk factor compared to the general population.7

Early-onset schizophrenia (EOS) refers to the development of a first schizophrenia episode before the age of 18 years.8 EOS is associated with poor outcome: in fact, 3/5 individuals with EOS had poor functioning (GAF: ≤50) at follow-up.9 Furthermore, EOS is associated with more neurodevelopmental difficulties,10 poorer premorbid adjustment,11 as well as more negative symptoms12 and higher impulsivity,13 among other relevant outcomes, than adult-onset schizophrenia (AOS). A challenge in the care of these patients is the difficulty in obtaining adequate transitional care for adult services.14

The timing and manner in which the treatment of individuals with schizophrenia is managed in the acute phase has both short-term and long-term implications for individuals with EOS and AOS.15,16 Indeed, it is known that there is an association between delays in psychosis treatment – called duration of untreated psychosis or DUP – and poor outcomes.17 Furthermore, shared decision-making at this point is key to the patient’s further illness development.18,19 Previous narrative and systematic reviews have examined the pathways to mental health care for people with first-episode psychosis and factors that may predict relapse and acute exacerbation of psychotic symptoms in people with schizophrenia.17,20–23 A review found that the first contact for the largest proportion of patients was a physician and that the referral target for the largest proportion of patients was the emergency department.24 The most common first contacts to seek help appeared to be family members or relatives (26.7%), close friends (17.9%), psychiatrists in private practice (14.4%), and general practitioners (12.2%).22 Another review found that greater antipsychotic efficacy was associated with higher baseline total symptom severity, treatment-naive/first-episode status, shorter illness duration, and lower placebo effect.23 In addition, factors associated with better outcomes in people with schizophrenia included absence of substance abuse comorbidity, greater early treatment response, better antipsychotic adherence, and fewer relapses.17,20,21 While previous expert consensus groups have evaluated specific parts of the treatment pathway for people with schizophrenia, including the role of long-acting injectable antipsychotics in schizophrenia,25–28 no expert opinion has focused on the importance of finding the right setting and treatment for people with an acute psychotic episode. The aim of this study was to provide suggestions about the most appropriate management of acutely exacerbated patients with schizophrenia and to increase the awareness and skills regarding personalized medicine in the management of patients with acute schizophrenia, ultimately aiming to enhance the chance of positive outcomes from the early beginning of the treatment journey.

Methods Design: Narrative Review and Clinical Practice Guideline

A group of senior academics and clinicians with extensive experience in the field of psychosis (ie, the co-authors in the author line) met virtually on July 13, 2023. These experts represented both inpatient and outpatient as well as research settings, children, adolescents, adults and the elderly, as well as experience in the clinical care of patients with psychotic disorders in several countries, including Germany, Italy, Spain, UK and the USA. During this meeting, participants discussed and synthesized proposals for the acute treatment of people with schizophrenia, shared their research and clinical experiences, and offered suggestions for advancing knowledge in the field and improving clinical care. Published literature and scientific evidence relevant to the acute management of people with schizophrenia were critically reviewed.

This manuscript represents a narrative review of information from individual presentations, collective discussions, a comprehensive review of the evidence, and feedback from all panel members. During the development of this manuscript, all members provided critical and constructive feedback on at least two occasions.

The first part of the manuscript focuses on finding/creating the right treatment setting, looking at the role of emergency departments as well as hospital inpatient units and community settings. The second part focuses on strategies for finding the right treatment through stratified and personalized medicine approaches, addressing the challenges of identifying the right treatment-patient match.

Results Finding the Right Setting

First contact is very important for service users. In the first year after diagnosis, the incidence of treatment discontinuation is significant, reaching 30 events per 100 participant-years.29 To find the right setting, environmental and family factors should be taken into account.

It should be noted that sometimes the first contact may be in the context of pre-existing physical health problems and the patient may already be at the hospital. Other times, patients may be seeking help for other mental health conditions (eg, anxiety disorders). In these cases, it is particularly important to avoid misdiagnosis and mistreatment. In all cases, it is important to consider the patient’s preferences (Figure 1)

Figure 1 Pathways to care and treatment.

Emergency Department

When patients arrive at the emergency department, there is an early triage process that affects patient flow. The emergency department (ED) as the point of entry into psychiatric care is often perceived by service users with schizophrenia as the most traumatic setting. However, the experience can be improved if the ED meets certain conditions (Figure 2 provides a hierarchy of ED elements and service provision).

Figure 2 Emergency Department provisions available.

Challenges to finding the right accommodations include (1) privacy, (2) safety, (3) ability to provide a timely assessment, (4) catchment area covered and location of on-call psychiatrist, (5) differences between public and private sectors, including difficulties with insurance coverage, (6) ambulances taking patients to the wrong hospital and inability to provide the appropriate treatment, (7) lack of specialized staff, including psychiatric nurses and social workers, and (8) need for isolation and associated procedures to ensure patient and staff safety.

Strategies and recommendations for patients to have a good experience in the ED include30 a) a dedicated environment with adequate space, b) specialized mental health nurses to support individuals while in the ED, c) consideration of direct admission to the inpatient unit if indicated by the community psychiatrist, if available, d) continuity of treatment provider across settings if available, e) training in de-escalation techniques (see ten domains of de-escalation and associated recommendations for the acute phase of schizophrenia in Table 1), and f) use less invasive rapid acting treatments than short-acting intramuscular antipsychotics and/or benzodiazepines for agitation and aggression, such as oral benzodiazepines and inhaled loxapine or sublingual dexmedetomidine, when indicated and available. Patients with schizophrenia require a comprehensive physical examination, including blood and drug tests, especially if physical illness and/or substance use is suspected. In cases with rapid onset psychosis and/or neurological signs, further tests, including brain imaging and lumbar puncture, may be indicated. The emergency department may be the most appropriate place to perform these tests.

Table 1 Ten Domains of De-Escalation and Recommendations

Hospitalisation vs Community Treatment

Hospitalization may be necessary in some contexts because of the need for medical or psychiatric evaluation and management, including safety concerns in the acute treatment of schizophrenia.

Reasons for hospitalization include assisting clinicians in conducting multiple tests for complex disorders and appropriately managing the risk of self-harm, aggression, or major disorganization. Of note, some studies suggest that patients discharged too soon are more likely to discontinue treatment29 and more likely need to be re-admitted,32 according to some studies. Admission may provide time to work with family members and caregivers and to provide psychoeducational strategies, as well as to liaise with social services and to refine the diagnosis. There are also reasons to support discharge. Indeed, according to other studies, hospitalization may contribute to a greater risk of poor adherence.33 In any case, hospitalization is often perceived as coercive. There may also be increased pressure to discharge due to a lack of beds.

Good outpatient care and community resources, including day hospital rehabilitation units that allow for safe discharge, ideally as part of a coordinated step-down approach to care in the least restrictive environment, are recommended. We suggest that an appointment should be arranged from the hospital with the community psychiatrist (or the same psychiatrist if the facility is affiliated), as well as with the general practitioner (who may continue to prescribe medication in some countries) and specialized mental health nurses where available.

The length of hospitalization varies between and within countries, depending on resources, the ratio of beds to catchment area, and the reimbursement system.

In Italy, there is considerable variation within the same country. In some hospitals (eg, University of Siena Medical Center), the average length of stay in an inpatient unit is as short as 5–6 days, after which patients are immediately transferred to a day hospital for further care and rehabilitation, and then to outpatient care. In most hospitals, however, the length of stay in an inpatient unit is about 12 days, after which patients are transferred to community care, outpatient and rehabilitation treatment centers. For children and adolescents, the length of hospital stay varies widely across the country, mostly depending on the number of available inpatient beds, which are usually very limited. In Spain, the average length of stay in inpatient units is 2–3 weeks. There are no differences in length of stay between children and adolescents and adults. In Germany, on the other hand, the length of hospitalization for adults is about 3–4 weeks, while for children and adolescents, the length of admission to psychiatric units may increase to 2–3 months (at least in university settings). In United Kingdom, the length of hospitalization for adults is typically longer than a month. In children and adolescents, it can be even longer and often discharge meetings with families and social services are arranged during hospitalization. The authors provide their expertise on the acute treatment of people with schizophrenia in their respective countries, but research and evidence coming from other countries (eg, equatorial regions or Asian countries)34 is important.

An important point is that certain conditions need to be met to facilitate safe discharge (Figure 3). Psychometric instruments can help assess whether individuals are ready for discharge. For example, the Readiness for Discharge Questionnaire (RDQ)35 assesses six items: suicidality/homicidality, control of aggression/impulsivity, activities of daily living, medication use, delusions/hallucinations interfering with functioning, and global status.

Figure 3 Factors to be addressed and hierarchy of needs in order to discharge patients with schizophrenia.

Finding the Right Treatment

General principles for finding the right treatment include establishing an appropriate and personalized treatment plan based on the patient’s diagnosis, comorbidities, previous treatment response and tolerability, adherence patterns, and preferences. A respectful and humane approach is recommended, as well as shared decision-making and motivational interviewing approaches. It is important to choose treatment adequately from the start and to consider switching in case of early non-response.36 Treatment approaches that can positively influence the patient’s “fate” of treatment engagement and response should be *feasible (in terms of access and adherence); *acceptable (taking into account patient preferences); *tolerable (associated with few or minimal side effects); and *efficacious (associated with good response and outcomes) (FATE).

Clinical practice guidelines recommend antipsychotic monotherapy for psychosis as a first and second step.37 Medications that are recommended and used long term are often not used acutely. This discontinuous approach affects acceptability and tolerability on the patient side and creates hesitancy to change a treatment regimen initiated on an inpatient service that helped stabilize and discharge the patient, on an outpatient care provider side. One option is to use non-sedating/less sedating, more tolerable antipsychotics acutely and if needed use those in combination with benzodiazepines, or choosing a sedating antipsychotic when rapid action and sedation are needed. Thereafter, the benzodiazepines or sedating antipsychotic can be tapered and the patient be discharged on the non-sedating/less sedating and more tolerable antipsychotic. Alternatively, one could start with a sedating antipsychotic but switch to a less sedating antipsychotic after initial response or if intolerance occurs. However, many troublesome side effects can accumulate over time, and once a medication has begun to work and is effective, clinicians are often reluctant to switch antipsychotics and possibly risk losing the initial response. When side effects or lack of efficacy become apparent, a switch to another medication should be considered. Nonpharmacologic strategies should be added as and when appropriate.

According to a recent network meta-analysis, most antipsychotics reduced total symptoms in acutely ill patients with schizophrenia more than placebo, with the highest effect size for clozapine (standardized mean difference–SMD=0.89). SMDs compared with placebo for reduction of positive symptoms were highest for amisulpride (SMD = 0.69), and for negative symptoms for clozapine (SMD = 0.62)38 However, in acutely exacerbated populations with prominent positive symptoms, it is not possible to clarify whether improvements in negative symptoms were related to primary or secondary negative symptoms.39 In a study of adults with predominant negative symptoms, cariprazine was superior to risperidone for negative symptoms, functionality and global illness severity.40 Treatment discontinuation varied between antipsychotics (risk ratio from RR = 0.52 for clopenthixol to RR = 1.15 for pimozide).38

In contrast to generally smaller and more “gradual” (ie, nonsignificant) differences in efficacy in meta-analyses, differences in adverse effect liabilities are generally larger, statistically significant and also more predictable. Mean differences from placebo for weight gain ranged from −0.16 kg for ziprasidone to 3.21 kg for zotepine, while prolactin elevation ranged from partial dopamine agonists being prolactin-neutral to 48.51 ng/mL for paliperidone.38 In general, some medications seem to be better tolerated in the long term (lurasidone; aripiprazole; brexpiprazole; cariprazine, lumateperone),41 in agreement with our expert opinion. Of note, antipsychotic use is protective against mortality compared with no antipsychotic use (RR = 0.71), with the largest effects for second-generation injectable long-acting antipsychotics (SGA-LAIs) (RR = 0.39), clozapine (RR = 0.43), any LAI (RR = 0.47), and any second-generation antipsychotic (RR = 0.53).42

Personalised Medicine

Several factors and individual circumstances need to be considered when deciding on the appropriate treatment for the acute phase of schizophrenia. Relevant factors include sociodemographic factors, such as age or gender, predominance or severity/functional impact of specific symptoms (positive symptoms, hostility/aggressive behaviours, self-harm/suicidal behaviours, negative symptoms, affective symptoms, cognitive symptoms), and comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia) (see Table 2).

Table 2 When a Patient Arrives with a First Psychotic Episode (FEP) the Treatment Depends on

Below are some recommendations for some relevant sociodemographic and clinical factors:

Children and adolescents: Brain development is relevant to symptom expression and treatment response in children and adolescents.43 Sometimes lower antipsychotic doses and/or slower titration are required in EOP. Note that many medications are prescribed off-label in paediatric populations; insurance companies may or may not pay for certain medications, which is important to know. Prescribers may need to seek approval from local insurance companies. In any case, more research studies are needed to make more medications available on-label for youth with schizophrenia (and other mental disorders). Aripiprazole, brexpiprazole, lurasidone, and risperidone are recommended by the panellists as on-label treatments for EOS with a more benign side effect profile. For children and adolescents with treatment-resistant schizophrenia, clozapine is recommended.44 Sex: Prolactin-raising antipsychotics should be avoided in females. Long-term exposure to prolactin-increasing, but not prolactin-sparing, antipsychotics (including clozapine, quetiapine, or aripiprazole) has been associated with an increased risk of breast cancer.45 Of note, some side effects (eg, gynecomastia, erectile dysfunction) may be associated with discomfort/decreased quality of life in males; amenorrhea can be associated with distress and osteoporosis in females; and galactorrhea, decreased libido and anorgasmia can decrease quality of life in both males and females.46,47 Presence of hostility/aggression or self-harm: Safety is a major concern in the acute treatment setting for many patients with schizophrenia. Staff should be trained in non-pharmacologic de-escalation techniques that should be used early and widely as much as possible.30 Adequate space should be available. Sedation may need to be added temporarily to ideally ultimately non-sedating, non-weight gain producing antipsychotics, utilizing targeted and time-limited benzodiazepine or sedating antipsychotic cotreatment. Short-acting injectable antipsychotics should be utilized as a last resort alternative, and second-generation antipsychotics are preferrable from a side effect perspective.30,48,49 Predominance of cognitive symptoms: In an acute episode, the degree of cognitive impairment may be difficult to assess (one would have to rely on informant reports), and in some cases, safety must be prioritized in the acute setting. When possible, it is recommended to avoid sedating and anticholinergic medications and medications that may cause extrapyramidal symptoms and worsen cognitive deficits.50 The differences between antipsychotics are not entirely clear.51 One study suggested that lurasidone may be better than quetiapine for cognitive symptoms.52 Benzodiazepines and anticholinergics for the treatment of parkinsonian side effects should be avoided in the long term. Cognitive remediation53–55 and aerobic exercise56,57 have shown benefits, but availability and adherence/persistence can be an issue. Social skills training is recommended, as is cognitive remediation, for patients who also have cognitive impairment associated with schizophrenia.53–55 For both cognitive remediation and exercise interventions, availability and adherence may be difficult. Predominance of negative symptoms: Medications that produce sedation and extrapyramidal symptoms may themselves produce secondary negative symptoms.58 These medications should therefore be avoided. According to EPA guidelines, based on meta-analytic evidence,59,60 the addition of antidepressants to antipsychotic treatment should be considered in people with negative symptoms secondary to depression or in people with negative symptoms that are resistant to antipsychotics. However, no pharmacological treatment has been shown to be effective for primary persistent negative symptoms with low-dose amisulpride and cariprazine coming closest to this aim.61 Presence of insomnia: Various therapeutic options should be considered, especially non-pharmacological strategies. Benzodiazepines may be considered in the short term. Quetiapine may also be considered, although not in the long term, due to the risk of cardiovascular side effects, even at low doses.62,63 Post-psychotic depression: The antidepressant effect typically decreases with higher doses of antipsychotics that lead to more postsynaptic dopamine receptor blockade. It should be noted that the antidepressant effect of lurasidone is also present at higher doses, which is an advantage. An antidepressant may need to be added, often after the acute episode. Psychosocial strategies and psychological interventions may also be considered (eg, cognitive behavioral therapy).Challenges for Finding the Right Treatment and Recommendations

A) Risk of discontinuation: 61% of individuals appear to have difficulty with consistent adherence over a 4-year period. Adherence problems appear to be associated with younger age, non-white race, and concomitant substance use.33 Medications with fewer side effects (eg, less sedation) are recommended64 (adverse effect profiles of selected antipsychotic drugs can be found in Table 3).

Table 3 Adverse Effect Profiles of Selected FGA and SGA Drugs

Benzodiazepines may be added temporarily to allow safe antipsychotic initiation. People with schizophrenia are 67% less likely to discontinue treatment with long-acting injectable antipsychotics than with oral antipsychotics.29 Benefits of LAIs over oral antipsychotics in preventing hospitalization or relapse have been found in settings ranging from limited research (eg, randomized clinical trials) to real-world settings.66 In fact, clinical practice guidelines recommend the use of long-acting injectable antipsychotics (LAIs) in schizophrenia, mainly in cases of nonadherence (77.8%), maintenance treatment (72.2%), or when patients prefer this treatment (66.7%).37 However, proactive and preventive LAI prescribing may yield even better results.67,68

B) Suboptimal response at current antipsychotic dose and side effects associated with dose escalation: All continuation strategies appear to be more effective in preventing relapse than discontinuing antipsychotic treatment, with a large risk reduction for continuation at standard doses (RR = 0.37) and antipsychotic switching (RR = 0.44) and a moderate risk reduction for dose reduction (RR = 0.68). Antipsychotic continuation and switching did not differ significantly in relapse prevention, whereas antipsychotic dose reduction was outperformed by both continuation and switching.69 A trial comparing standard versus reduced antipsychotic doses for relapse prevention in multi-episode schizophrenia found that reduced doses increased the risk of relapse and all-cause discontinuation.31

Several strategies have been proposed to address the challenge of suboptimal treatment response. Increasing the dose to the maximum dose in the summary of product characteristics may be indicated if the positive symptom response is partial and there are no side effects,36 but doses above the approved dose range have not been shown to increase treatment response.65 However, increasing the dose of antipsychotics because of persistent negative, affective, or cognitive symptoms should be avoided because the chances of improving these symptoms are low. Instead, other strategies should be considered.

Evidence for combination strategies is limited to pharmacological interventions. One study found that total PANSS scores improved significantly at eight weeks in the amisulpride plus olanzapine group compared with the olanzapine plus placebo group (d = 0.396).70 However, at eight and sixteen weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher in patients receiving amisulpride plus olanzapine than in those receiving amisulpride plus placebo, with no differences in serious adverse events.70 After failing to achieve remission on amisulpride, switching to olanzapine did not improve outcomes.71 Switching to clozapine, on the other hand, has been shown to be beneficial (even after a failure in a single antipsychotic trial).42,71,72

Other augmentation strategies that may be considered include the addition of an antidepressant59,60 or a partial dopamine agonist73 for negative symptoms. Benzodiazepines and second-generation antipsychotics may also be considered for agitation (see above). As mentioned above, there is limited evidence regarding pharmacological agents for cognitive symptoms. Cognitive remediation, exercise, and social skills training may be recommended.39

Combining pharmacological and psychological interventions is recommended. Early intervention services providing a combination of pharmacological and psychosocial interventions are associated with an improvement in clinical and functional outcomes.74 Cognitive remediation therapy and cognitive behavioural therapy can improve psychosocial functioning in some patients.75,76 Psychoeducation interventions and family interventions, on the other hand, can improve negative symptoms and decrease visits to emergency departments in early psychosis77 and reduce relapses in adults.76 Electroconvulsive therapy may be considered as well.78 Current indications include treatment resistance, pharmacotherapy augmentation, catatonia, suicidal behavior and severe agitation.79

Conclusions

Clinicians should work hard to find the right setting and the right treatment for their patients with schizophrenia from the acute phase onwards. A dedicated environment with adequate space is needed in emergency departments, as well as specialized mental health support. Good outpatient care and community resources, including rehabilitation units and day hospitals that allow for safe discharge, ideally as part of a coordinated step-down approach to care in the least restrictive environment, are recommended. Individual circumstances need to be considered when selecting the most appropriate pharmacologic and non-pharmacologic treatments for the acute phases of schizophrenia. Relevant factors include sociodemographic factors, such as age or gender, predominance of symptoms (positive symptoms, hostility/aggressive behaviours, self-harm/suicidal behaviours, negative symptoms, affective symptoms, cognitive symptoms), and comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia). Efficacy and feasibility, as well as acceptability (including patient preferences) and tolerability, must be considered at an early stage to increase the chance of enhanced outcomes.

Data Sharing Statement

All data generated or analysed during this study are included in this published article.

Ethics Approval and Consent to Participate

Our study did not involve experiments on humans or the use of human tissue samples. Patients were not involved; the evidence and previously published literature on the field that is reviewed by the group of senior academics.

Funding

This work was realized with an unconditional contribution from Angelini Pharma.

Disclosure

Prof Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. Prof Arango has been a consultant to or has received honoraria or grants from Abbott, Acadia, Angelini, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. Prof Arango has been supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union – NextGenerationEU (PMP21/00051), PI19/01024.  CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No.101034377), Project AIMS-2-TRIALS (Grant agreement No 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz. Professor Andrea Fagiolini reports grants, personal fees, non-financial support, from Angelini, Boehringer Ingelheim, Idorsia, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Sunovion, Viatris, outside the submitted work. Dr Giulia Giordano reports personal fees from Angelini, outside the submitted work. Prof. Dr. Stefan Leucht reports personal fees from Angelini, personal fees from Ethos, during the conduct of the study; personal fees from Angelini, personal fees from Boehringer Ingelheim, personal fees from Eisai, personal fees from GedeonRichter, personal fees from Janssen, personal fees from Karuna, personal fees from Kynexis, personal fees from Lundbeck, personal fees from Medichem, personal fees from Mitsubishi, personal fees from Otsuka, personal fees from NovoNordisk, personal fees from Recordati, personal fees from Rovi, personal fees from Teva, personal fees from Ethos, outside the submitted work. Dr Salazar de Pablo has received honoraria from Janssen Cilag, Lundbeck and Menarini. The authors report no other conflicts of interest in this work.

References

1. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067. doi:10.1038/nrdp.2015.67

2. Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163–180. doi:10.1002/wps.20420

3. Subotnik KL, Ventura J, Hellemann GS, Zito MF, Agee ER, Nuechterlein KH. Relationship of poor insight to neurocognition, social cognition, and psychiatric symptoms in schizophrenia: a meta-analysis. Schizophr Res. 2020;220:164–171. doi:10.1016/j.schres.2020.03.038

4. Coury SM, Lombroso A, Avila-Quintero VJ, et al. Systematic review and meta-analysis: season of birth and schizophrenia risk. Schizophr Res. 2023;252:244–252. doi:10.1016/j.schres.2022.12.016

5. Abi-Dargham A, Moeller SJ, Ali F, et al. Candidate biomarkers in psychiatric disorders: state of the field. World Psychiatry. 2023;22(2):236–262. doi:10.1002/wps.21078

6. Solmi M, Radua J, Olivola M, et al. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Mol Psychiatry. 2022;27(1):281–295. doi:10.1038/s41380-021-01161-7

7. Cassidy RM, Yang F, Kapczinski F, Passos IC. Risk factors for suicidality in patients with schizophrenia: a systematic review, meta-analysis, and meta-regression of 96 studies. Schizophr Bull. 2018;44(4):787–797. doi:10.1093/schbul/sbx131

8. Salazar de Pablo G, Moreno D, Gonzalez-Pinto A, et al. Affective symptom dimensions in early-onset psychosis over time: a principal component factor analysis of the young mania rating scale and the Hamilton depression rating scale. Eur Child Adolesc Psychiatry. 2021;2021:1.

9. Clemmensen L, Vernal DL, Steinhausen HC. A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry. 2012;12:150. doi:10.1186/1471-244X-12-150

10. Owen MJ, O’Donovan MC. Schizophrenia and the neurodevelopmental continuum: evidence from genomics. World Psychiatry. 2017;16(3):227–235. doi:10.1002/wps.20440

11. Díaz-Caneja CM, Pina-Camacho L, Rodríguez-Quiroga A, Fraguas D, Parellada M, Arango C. Predictors of outcome in early-onset psychosis: a systematic review. NPJ Schizophr. 2015;1:14005. doi:10.1038/npjschz.2014.5

12. Salazar de Pablo G, Catalan A, Vaquerizo Serrano J, et al. Negative symptoms in children and adolescents with early-onset psychosis and at clinical high-risk for psychosis: systematic review and meta-analysis. Br J Psychiatry. 2023;223:282–294. doi:10.1192/bjp.2022.203

13. Kao YC, Liu YP. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry. 2010;10:63. doi:10.1186/1471-244X-10-63

14. Arango C, Buitelaar JK, Correll CU, et al. The transition from adolescence to adulthood in patients with schizophrenia: challenges, opportunities and recommendations. Eur Neuropsychopharmacol. 2022;59:45–55. doi:10.1016/j.euroneuro.2022.04.005

15. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P T. 2014;39(9):638–645.

16. Wyatt RJ, Henter ID. The effects of early and sustained intervention on the long-term morbidity of schizophrenia. J Psychiatr Res. 1998;32(3–4):169–177. doi:10.1016/S0022-3956(97)00014-9

17. Howes O, Whitehurst T, Shatalina E, et al. The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis. World Psychiatry. 2021;20:75–95. doi:10.1002/wps.20822

18. Fiorillo A, Barlati S, Bellomo A, et al. The role of shared decision-making in improving adherence to pharmacological treatments in patients with schizophrenia: a clinical review. Ann Gen Psychiatry. 2020;19:43. doi:10.1186/s12991-020-00293-4

19. Benke T, Marksteiner J, Ruepp B, Weiss EM, Zamarian L. Decision making under risk in patients suffering from schizophrenia or depression. Brain Sci. 2021;11(9):1178. doi:10.3390/brainsci11091178

20. Samara MT, Leucht C, Leeflang MM, et al. Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry. 2015;172(7):617–629. doi:10.1176/appi.ajp.2015.14101329

21. Carbon M, Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci. 2014;16(4):505–524. doi:10.31887/DCNS.2014.16.4/mcarbon

22. Fridgen GJ, Aston J, Gschwandtner U, et al. Help-seeking and pathways to care in the early stages of psychosis. Soc Psychiatry Psychiatr Epidemiol. 2013;48(7):1033–1043. doi:10.1007/s00127-012-0628-0

23. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. 2018;8(11):303–318. doi:10.1177/2045125318781475

24. Anderson KK, Fuhrer R, Malla AK. The pathways to mental health care of first-episode psychosis patients: a systematic review. Psychol Med. 2010;40(10):1585–1597. doi:10.1017/S0033291710000371

25. Vita A, Fagiolini A, Maina G, Mencacci C, Spina E, Galderisi S. Achieving long-term goals through early personalized management of schizophrenia: expert opinion on the role of a new fast-onset long-acting injectable antipsychotic. Ann Gen Psychiatry. 2023;22(1):1. doi:10.1186/s12991-022-00430-1

26. Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1–24. doi:10.4088/JCP.15032su1

27. Sajatovic M, Ross R, Legacy SN, et al. Identifying patients and clinical scenarios for use of long-acting injectable antipsychotics - expert consensus survey part 1. Neuropsychiatr Dis Treat. 2018;14:1463–1474. doi:10.2147/NDT.S167394

28. Sajatovic M, Ross R, Legacy SN, et al. Initiating/maintaining long-acting injectable antipsychotics in schizophrenia/schizoaffective or bipolar disorder - expert consensus survey part 2. Neuropsychiatr Dis Treat. 2018;14:1475–1492. doi:10.2147/NDT.S167485

29. Rubio JM, Taipale H, Tanskanen A, Correll CU, Kane JM, Tiihonen J. Long-term continuity of antipsychotic treatment for schizophrenia: a nationwide study. Schizophr Bull. 2021;47(6):1611–1620. doi:10.1093/schbul/sbab063

30. Correll CU, Yu X, Xiang Y, Kane JM, Masand P. Biological treatment of acute agitation or aggression with schizophrenia or bipolar disorder in the inpatient setting. Ann Clin Psychiatry. 2017;29(2):92–107.

31. Højlund M, Kemp AF, Haddad PM, Neill JC, Correll CU. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. Lancet Psychiatry. 2021;8(6):471–486. doi:10.1016/S2215-0366(21)00078-X

32. Manu P, Khan S, Radhakrishnan R, Russ MJ, Kane JM, Correll CU. Body mass index identified as an independent predictor of psychiatric readmission. J Clin Psychiatry. 2014;75(6):e573–577. doi:10.4088/JCP.13m08795

33. Valenstein M, Ganoczy D, McCarthy JF, Myra Kim H, Lee TA, Blow FC. Antipsychotic adherence over time among patients receiving treatment for schizophrenia: a retrospective review. J Clin Psychiatry. 2006;67(10):1542–1550. doi:10.4088/JCP.v67n1008

34. Albert-Ballestar S, García-Altés A. Measuring health inequalities: a systematic review of widely used indicators and topics. Int J Equity Health. 2021;20(1):73. doi:10.1186/s12939-021-01397-3

35. Potkin SG, Gharabawi GM, Greenspan AJ, et al. Psychometric evaluation of the readiness for discharge questionnaire. Schizophr Res. 2005;80(2–3):203–212. doi:10.1016/j.schres.2005.06.021

36. Rubio JM, Guinart D, Kane JM, Correll CU. Early non-response to antipsychotic treatment in schizophrenia: a systematic review and meta-analysis of evidence-based management options. CNS Drugs. 2023;37(6):499–512. doi:10.1007/s40263-023-01009-4

37. Correll CU, Martin A, Patel C, et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophrenia. 2022;8(1):5. doi:10.1038/s41537-021-00192-x

38. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951. doi:10.1016/S0140-6736(19)31135-3

39. Galderisi S, Kaiser S, Bitter I, et al. EPA guidance on treatment of negative symptoms in schizophrenia. Eur Psychiatry. 2021;64(1):1.

40. Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389(10074):1103–1113. doi:10.1016/S0140-6736(17)30060-0

41. Burschinski A, Schneider-Thoma J, Chiocchia V, et al. Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials. World Psychiatry. 2023;22(1):116–128. doi:10.1002/wps.21036

42. Correll CU, Solmi M, Croatto G, et al. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022;21(2):248–271. doi:10.1002/wps.20994

43. Pujol J, Blanco-Hinojo L, Macia D, et al. Differences between the child and adult brain in the local functional structure of the cerebral cortex. Neuroimage. 2021;237:118150. doi:10.1016/j.neuroimage.2021.118150

44. Pagsberg AK, Tarp S, Glintborg D, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: a systematic review and network meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56(3):191–202. doi:10.1016/j.jaac.2016.12.013

45. Taipale H, Solmi M, Lähteenvuo M, Tanskanen A, Correll CU, Tiihonen J. Antipsychotic use and risk of breast cancer in women with schizophrenia: a nationwide nested case-control study in Finland. Lancet Psychiatry. 2021;8(10):883–891. doi:10.1016/S2215-0366(21)00241-8

46. Korchia T, Achour V, Faugere M, et al. Sexual dysfunction in schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2023;80:1110. doi:10.1001/jamapsychiatry.2023.2696

47. Koch MT, Carlson HE, Kazimi MM, Correll CU. Antipsychotic-related prolactin levels and sexual dysfunction in mentally ill youth: a 3-month cohort study. J Am Acad Child Adolesc Psychiatry. 2023;62(9):1021–1050. doi:10.1016/j.jaac.2023.03.007

48. Paris G, Bighelli I, Deste G, et al. Short-acting intramuscular second-generation antipsychotic drugs for acutely agitated patients with schizophrenia spectrum disorders. A systematic review and network meta-analysis. Schizophr Res. 2021;229:3–11. doi:10.1016/j.schres.2021.01.021

49. Citrome L. Agitation in schizophrenia: origins and evidence-based treatment. Curr Opin Psychiatry. 2021;34(3):216–221. doi:10.1097/YCO.0000000000000685

50. Carbon M, Correll CU. Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr. 2014;19 Suppl 1:38–52; quiz 35–37, 53. doi:10.1017/S1092852914000601

51. Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SO, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia--A meta-analysis of randomized clinical trials. Acta Psychiatr Scand. 2015;131(3):185–196. doi:10.1111/acps.12374

52. Harvey PD, Siu CO, Loebel AD. Change in daytime sleepiness and cognitive function in a 6-month, double-blind study of lurasidone and quetiapine XR in patients with schizophrenia. Schizophr Res Cogn. 2016;5:7–12. doi:10.1016/j.scog.2016.05.002

53. Vita A, Barlati S, Ceraso A, et al. Effectiveness, core elements, and moderators of response of cognitive remediation for schizophrenia: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2021;78(8):848–858. doi:10.1001/jamapsychiatry.2021.0620

54. Prikken M, Konings MJ, Lei WU, Begemann MJH, Sommer IEC. The efficacy of computerized cognitive drill and practice training for patients with a schizophrenia-spectrum disorder: a meta-analysis. Schizophr Res. 2019;204:368–374. doi:10.1016/j.schres.2018.07.034

55. Vita A, Gaebel W, Mucci A, et al. European Psychiatric Association guidance on treatment of cognitive impairment in schizophrenia. Eur Psychiatry. 2022;65(1):1.

56. Firth J, Stubbs B, Rosenbaum S, et al. Aerobic exercise improves cognitive functioning in people with schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2017;43(3):546–556. doi:10.1093/schbul/sbw115

57. Stubbs B, Vancampfort D, Hallgren M, et al. EPA guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and position statement from the European psychiatric association (EPA), supported by the international organization of physical therapists in mental health (IOPTMH). Eur Psychiatry. 2018;54:124–144. doi:10.1016/j.eurpsy.2018.07.004

58. Correll CU, Schooler NR. negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16:519–534. doi:10.2147/NDT.S225643

59. Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry. 2016;173(9):876–886. doi:10.1176/appi.ajp.2016.15081035

60. Galling B, Vernon JA, Pagsberg AK, et al. Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia. Acta Psychiatr Scand. 2018;137(3):187–205. doi:10.1111/acps.12854

61. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5(8):664–677. doi:10.1016/S2215-0366(18)30050-6

62. Højlund M, Andersen K, Ernst MT, Correll CU, Hallas J. Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study. World Psychiatry. 2022;21(3):444–451. doi:10.1002/wps.21010

63. Højlund M, Støvring H, Andersen K, Correll CU, Hallas J. Impact of low-dose quetiapine-use on glycosylated hemoglobin, triglyceride and cholesterol levels. Acta Psychiatr Scand. 2023;147(1):105–116. doi:10.1111/acps.13515

64. Dibonaventura M, Gabriel S, Dupclay L, Gupta S, Kim E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20. doi:10.1186/1471-244X-12-20

65. Solmi M, Murru A, Pacchiarotti I et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13():757–777.

66. Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry. 2021;8(5):387–404. doi:10.1016/S2215-0366(21)00039-0

67. Correll CU, Benson C, Emond B, et al. Comparison of clinical outcomes in patients with schizophrenia following different long-acting injectable event-driven initiation strategies. Schizophrenia. 2023;9(1):9. doi:10.1038/s41537-023-00334-3

68. Wei Y, Yan VKC, Kang W, et al. Association of long-acting injectable antipsychotics and oral antipsychotics with disease relapse, health care use, and adverse events among people with schizophrenia. JAMA Network Open. 2022;5(7):e2224163. doi:10.1001/jamanetworkopen.2022.24163

69. Ostuzzi G, Vita G, Bertolini F, et al. Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis. Lancet Psychiatry. 2022;9(8):614–624. doi:10.1016/S2215-0366(22)00158-4

70. Schmidt-Kraepelin C, Feyerabend S, Engelke C, et al. Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial. Lancet Psychiatry. 2022;9(4):291–306. doi:10.1016/S2215-0366(22)00032-3

71. Kahn RS, Winter van Rossum I, Leucht S, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry. 2018;5(10):797–807. doi:10.1016/S2215-0366(18)30252-9

72. Sarkar S, Grover S. Antipsychotics in children and adolescents with schizophrenia: a systematic review and meta-analysis. Indian J Pharmacol. 2013;45(5):439–446. doi:10.4103/0253-7613.117720

73. Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35(2):443–457. doi:10.1093/schbul/sbn018

74. Correll CU, Galling B, Pawar A, et al. Comparison of early intervention services vs treatment as usual for early-phase psychosis a systematic review, meta-analysis, and meta-regression. JAMA Psychiatry. 2018;75(6):555–565. doi:10.1001/jamapsychiatry.2018.0623

75. Anagnostopoulou N, Kyriakopoulos M, Alba A. Psychological interventions in psychosis in children and adolescents: a systematic review. Eur Child Adolesc Psychiatry. 2019;28(6):735–746. doi:10.1007/s00787-018-1159-3

76. Solmi M, Croatto G, Piva G, et al. Efficacy and acceptability of psychosocial interventions in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. Mol Psychiatry. 2023;28(1):354–368. doi:10.1038/s41380-022-01727-z

77. Calvo A, Moreno M, Ruiz-Sancho A, et al. Intervention for adolescents with early-onset psychosis and their families: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2014;53(6):688–696. doi:10.1016/j.jaac.2014.04.004

78. Rosson S, de Filippis R, Croatto G, et al. Brain stimulation and other biological non-pharmacological interventions in mental disorders: an umbrella review. Neurosci Biobehav Rev. 2022;139:104743. doi:10.1016/j.neubiorev.2022.104743

79. Grover S, Sahoo S, Rabha A, Koirala