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REVIEW

Finding the Right Setting for the Right Treatment

During the Acute Treatment of Individuals with
Schizophrenia: A Narrative Review and Clinical
Practice Guideline
Christoph U Correll 1–4 , Celso Arango 5 , Andrea Fagiolini 6
, Giulia Maria Giordano 7 ,
Stefan Leucht 4,8 , Gonzalo Salazar de Pablo 5,9,10
1
Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 2Department of Psychiatry and Molecular Medicine,
Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA; 3Department of Child and Adolescent Psychiatry, Charité
Universitätsmedizin, Berlin, Germany; 4German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany; 5Department of Child and
Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad
Complutense, IiSGM, CIBERSAM, Madrid, Spain; 6Department of Molecular Medicine, School of Medicine, University of Siena, Siena, Italy;
7
Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 8Technical University of Munich, TUM School of Medicine and
Health, Department of Psychiatry and Psychotherapy, Munich, Germany; 9Child and Adolescent Mental Health Services (CAMHS) South London and
Maudsley NHS Foundation Trust London, London, UK; 10Department of Child and Adolescent Psychiatry Institute of Psychiatry, Psychology &
Neuroscience King’s College London, London, UK

Correspondence: Christoph U Correll, The Zucker Hillside Hospital, Department of Psychiatry, 75-59 263rd Street Glen Oaks, New York, NY,
11004, USA, Email [email protected]

Background: Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early
and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery.
The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizo­
phrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine.
Methods: A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13th 2023 to narratively
review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with
schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion.
Results: First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the
emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized
mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is
strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation
services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal
response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics.
Conclusion: Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment
and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be
considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as
acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the
possibility of improved short- and long-term outcomes.
Keywords: schizophrenia, first-episode psychosis, acute setting, clinical care

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

Neuropsychiatric Disease and Treatment 2024:20 1293–1307 1293

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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.

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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)

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).
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 environ­
ment 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

Figure 1 Pathways to care and treatment.

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Figure 2 Emergency Department provisions available.

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

Domains of De-Escalation

1. Respect personal space.

2. Do not be provocative.

3. Establish verbal contact.

4. Be concise.

5. Identify wants and feelings.

6. Listen closely to what the patient is saying.

7. Agree or agree to disagree.

8. Lay down the law and set clear limits.

9. Offer choices and optimism.

10. Debrief the patient and staff.

Recommendations from experts in schizophrenia.

1. Always ask for permission before making physical contact.

2. Be aware that depending on previous experiences and the content of delusional ideation, actions may be perceived differently to expected.

3. Avoid physical contact or getting closer to the individual without anticipation or permission.

4. Avoid non-literal or sarcastic language.

5. If unsure directly ask about feelings and desires.

6. If unsure, double check understanding with the patient.

7. Avoid unhelpful discussions about who is right or wrong.

8. Offer to help with what you can and if not possible offer to listen.

9. Ensure that although in a certain moment choices may be limited, the situation may change in the future.

10. Ensure appropriate training in de-escalation techniques.

Notes: Data from Højlund et al.31

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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 appro­
priately 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.

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

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

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 prefer­
ences); *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 benzo­
diazepines, or choosing a sedating antipsychotic when rapid action and sedation are needed. Thereafter, the benzodia­
zepines 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,

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

a) 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 risper­
idone 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
b) 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
c) 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

Table 2 When a Patient Arrives with a First Psychotic Episode (FEP) the Treatment Depends on
Predominance of Clinical Symptoms Other Factors

Positive symptoms Age

Negative symptoms Sex

Cognitive symptoms/ impairment Metabolic syndrome or risk of developing metabolic syndrome

Affective symptoms Social support

Residual symptoms Family or personal history of response to treatment

Catatonic symptoms Presence of comorbidities (mental health, physical health)

Suicidal behaviours Presence of substance abuse and type of substance

Aggressive behaviours Other predictors of conversion to bipolar disorder or schizophrenia

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be utilized as a last resort alternative, and second-generation antipsychotics are preferrable from a side effect
perspective.30,48,49
d) 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.
e) 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
f) Presence of insomnia: Various therapeutic options should be considered, especially non-pharmacological strate­
gies. 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
g) 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 anti­
psychotic drugs can be found in Table 3).
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

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Table 3 Adverse Effect Profiles of Selected FGA and SGA Drugs
Adverse Effect Mechanism Dose/ AMI ARI ASE BRE CAR CLO ILO LUR OLA PALI QUE RIS SER ZIP CPZ HAL LOX PER
Titration
Dependent

b
Sedation H1 blockade +++ 0/+ 0/+ + 0/+ 0/+ +++ 0/+ +/++ +/++ 0/+ ++ + 0/+ + +++ + + +
Cognitive impairment Anti- cholinergic, D2 ++ + 0 + 0 0 + 0 0 + + + + + 0 ++ ++ ++ ++
blockade
a
Weight Gain H1, D2, 5HT2c 0/+ 0/+ 0 + 0 0/+ +++ +/+ 0/+ +++ ++ ++ ++ ++ 0/+ +++ + + ++
blockade +
Metabolic syndrome Weight gain, over- 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ +++ + 0/+ +++ + ++ + + 0/+ +++ 0/+ + +
eating, direct effects
Acute Parkinsonism D2 blockade +++ + + ++ + ++ 0 0/+ ++ 0/+ ++ 0 ++ 0/+ + + +++ ++ ++
Akathisia D2 blockade and, α, +++ + ++ + ++ ++ + 0/+ +/++ + + + ++ + +/+ + +++ ++ ++
5HT interaction +
Tardive Dyskinesia D2 receptor ++ 0/+ 0/+ 0/+ 0/+ 0/+ 0 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ ++ +++ ++ ++
desensitization
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/+
↑ QTc interval Cardiac ion channel ++ ++ 0 + 0 0 + 0/+ 0/+ + + + ++ ++ ++ + ++ + +
effects
b
Hypotension α1 blockade +++ 0/+ 0/+ + 0/+ 0/+ +++ +++ 0/+ ++ + ++ ++ + ++ +++ ++ + ++
Cardiovascular events Hyper-coagulability, + 0/+ 0/+ + 0/+ ? ++ ? ? ++ + ++ ++ 0/+ + ++ ++ + ++
(myocardial infarction, stroke) metabolic effects,
direct channel toxic
action
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/+
↑ Prolactin/ sexual dysfunction D2 blockade +++ +++ 0 + 0 0 0 0/+ + + +++ 0 ++ + + + + ++ ++
+ +/+
++
Myocarditis and Unknown 0 0 0 0 0 0 ++ 0 0 0 0 0/+ 0 0 0 0 0 0 0
cardiomyopathy
https://doi.org/10.2147/NDT.S459450

Pneumonia and acute Sialorrhea, central +++ + 0 0 0/+ 0/+ ++ 0/+ 0/+ + 0/+ 0/+ + 0/+ 0 + + + +
respiratory failure sedation, muscle
impairment
Gastrointestinal adverse effects Anti- Cholinergic, D2 + 0 + 0 + + ++ 0 0 ++ 0 0 0 0 0 ++ 0 ++ ++
(eg nausea, vomiting, diarrhea, agonism
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constipation)
Pulmonary embolism and Hyper-coagulability 0/+ + 0/+ + ? ? + ? ? + + + + 0/+ 0/+ ++ + + ++
venous thromboembolism

Correll et al
Dry mouth, dental caries Anti- cholinergic + 0 0 0 0 0 ++ 0 0 ++ 0 ++ 0 0 0 ++ ++ ++
1301

(Continued)

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Table 3 (Continued).

Adverse Effect Mechanism Dose/ AMI ARI ASE BRE CAR CLO ILO LUR OLA PALI QUE RIS SER ZIP CPZ HAL LOX PER
Titration
Dependent

Liver dysfunction Metabolic syndrome, 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ ++ 0/+ 0/+ + 0 + + 0/+ 0 ++ 0/+ 0/+ 0/+
direct effect
Urinary and kidney function Anti-cholinergic ++ + 0 0 0 + + 0 + + 0 0 0/+ 0 0/+ + 0 0 +
(Prolactin)
Osteopenia, osteoporosis and D2 blockade + + 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ + 0/+ + 0/+ 0/+ 0/+ + 0/+ 0/+
fractures (prolactin)
Binge eating, impulse control H1 blockade, D2 + 0 + + ? ? ++ 0 0 ++ + 0 + 0 0/+ + 0 0 0
disorder, gambling agonism
Sexual and reproductive D2 blockade ++ + 0/+ + ? 0 ++ ? + ++ ++ + ++ + 0/+ ++ ++ ++ ++
system dysfunction (Prolactin), α blockade,
anti-cholinergic
Endocrine adverse effects Unknown 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ ++ 0/+ 0/+ ++ 0/+ 0/+ ++ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+
(diabetes ketoacidosis,
hypothyroidism, and
hyponatremia).
Hyperprolactinemia D2 blockade +++ +++ 0 + 0 0 + + ++ + +++ ++ ++ ++ + +++ + +
+
Neuropsychiatric Disease and Treatment 2024:20

Breast and cervical cancer Unknown 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Malignant neuroleptic Unknown ++ 0/+ 0/+ 0/+ ? ? +++ ? ? + 0/+ + + + + +++ +++ + +
syndrome

Notes: Reproduced from 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;13:757-777.65
Abbreviations: AMI, amisulpride; ARI, aripiprazole; ASE, asenapine; BRE, brexpiprazole; CAR, cariprazine; CLO, clozapine; ILO, iloperidone; LOX, loxapine; LUR, lurasidone; OLA, olanzapine; PALI, paliperidone; QUE, quetiapine; RIS,
risperidone; SER, sertindole; ZIP, ziprasidone; CPZ, chlorpromazine; HAL, haloperidol; MOL, molindone; PER, perphenazine.

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 Dovepress Correll et al

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 con­
sidered 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 comor­
bidities (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.

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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.

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