pn schizophrenia case study

Module 11: Schizophrenia Spectrum and Other Psychotic Disorders

Case studies: schizophrenia spectrum disorders, learning objectives.

• Identify schizophrenia and psychotic disorders in case studies

Case Study: Bryant

Thirty-five-year-old Bryant was admitted to the hospital because of ritualistic behaviors, depression, and distrust. At the time of admission, prominent ritualistic behaviors and depression misled clinicians to diagnose Bryant with obsessive-compulsive disorder (OCD). Shortly after, psychotic symptoms such as disorganized thoughts and delusion of control were noticeable. He told the doctors he has not been receiving any treatment, was not on any substance or medication, and has been experiencing these symptoms for about two weeks. Throughout the course of his treatment, the doctors noticed that he developed a catatonic stupor and a respiratory infection, which was identified by respiratory symptoms, blood tests, and a chest X-ray. To treat the psychotic symptoms, catatonic stupor, and respiratory infection, risperidone, MECT, and ceftriaxone (antibiotic) were administered, and these therapies proved to be dramatically effective. [1]

Case Study: Shanta

Shanta, a 28-year-old female with no prior psychiatric hospitalizations, was sent to the local emergency room after her parents called 911; they were concerned that their daughter had become uncharacteristically irritable and paranoid. The family observed that she had stopped interacting with them and had been spending long periods of time alone in her bedroom. For over a month, she had not attended school at the local community college. Her parents finally made the decision to call the police when she started to threaten them with a knife, and the police took her to the local emergency room for a crisis evaluation.

Following the administration of the medication, she tried to escape from the emergency room, contending that the hospital staff was planning to kill her. She eventually slept and when she awoke, she told the crisis worker that she had been diagnosed with attention-deficit/hyperactive disorder (ADHD) a month ago. At the time of this ADHD diagnosis, she was started on 30 mg of a stimulant to be taken every morning in order to help her focus and become less stressed over the possibility of poor school performance.

After two weeks, the provider increased her dosage to 60 mg every morning and also started her on dextroamphetamine sulfate tablets (10 mg) that she took daily in the afternoon in order to improve her concentration and ability to study. Shanta claimed that she might have taken up to three dextroamphetamine sulfate tablets over the past three days because she was worried about falling asleep and being unable to adequately prepare for an examination.

Prior to the ADHD diagnosis, the patient had no known psychiatric or substance abuse history. The urine toxicology screen taken upon admission to the emergency department was positive only for amphetamines. There was no family history of psychotic or mood disorders, and she didn’t exhibit any depressive, manic, or hypomanic symptoms.

The stimulant medications were discontinued by the hospital upon admission to the emergency department and the patient was treated with an atypical antipsychotic. She tolerated the medications well, started psychotherapy sessions, and was released five days later. On the day of discharge, there were no delusions or hallucinations reported. She was referred to the local mental health center for aftercare follow-up with a psychiatrist. [2]

Another powerful case study example is that of Elyn R. Saks, the associate dean and Orrin B. Evans professor of law, psychology, and psychiatry and the behavioral sciences at the University of Southern California Gould Law School.

Saks began experiencing symptoms of mental illness at eight years old, but she had her first full-blown episode when studying as a Marshall scholar at Oxford University. Another breakdown happened while Saks was a student at Yale Law School, after which she “ended up forcibly restrained and forced to take anti-psychotic medication.” Her scholarly efforts thus include taking a careful look at the destructive impact force and coercion can have on the lives of people with psychiatric illnesses, whether during treatment or perhaps in interactions with police; the Saks Institute, for example, co-hosted a conference examining the urgent problem of how to address excessive use of force in encounters between law enforcement and individuals with mental health challenges.

Saks lives with schizophrenia and has written and spoken about her experiences. She says, “There’s a tremendous need to implode the myths of mental illness, to put a face on it, to show people that a diagnosis does not have to lead to a painful and oblique life.”

In recent years, researchers have begun talking about mental health care in the same way addiction specialists speak of recovery—the lifelong journey of self-treatment and discipline that guides substance abuse programs. The idea remains controversial: managing a severe mental illness is more complicated than simply avoiding certain behaviors. Approaches include “medication (usually), therapy (often), a measure of good luck (always)—and, most of all, the inner strength to manage one’s demons, if not banish them. That strength can come from any number of places…love, forgiveness, faith in God, a lifelong friendship.” Saks says, “We who struggle with these disorders can lead full, happy, productive lives, if we have the right resources.”

You can view the transcript for “A tale of mental illness | Elyn Saks” here (opens in new window) .

• Bai, Y., Yang, X., Zeng, Z., & Yang, H. (2018). A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy. BMC psychiatry , 18(1), 67. https://doi.org/10.1186/s12888-018-1655-5 ↵
• Henning A, Kurtom M, Espiridion E D (February 23, 2019) A Case Study of Acute Stimulant-induced Psychosis. Cureus 11(2): e4126. doi:10.7759/cureus.4126 ↵
• Modification, adaptation, and original content. Authored by : Wallis Back for Lumen Learning. Provided by : Lumen Learning. License : CC BY: Attribution
• A tale of mental illness . Authored by : Elyn Saks. Provided by : TED. Located at : https://www.youtube.com/watch?v=f6CILJA110Y . License : Other . License Terms : Standard YouTube License
• A Case Study of Acute Stimulant-induced Psychosis. Authored by : Ashley Henning, Muhannad Kurtom, Eduardo D. Espiridion. Provided by : Cureus. Located at : https://www.cureus.com/articles/17024-a-case-study-of-acute-stimulant-induced-psychosis#article-disclosures-acknowledgements . License : CC BY: Attribution
• Elyn Saks. Provided by : Wikipedia. Located at : https://en.wikipedia.org/wiki/Elyn_Saks . License : CC BY-SA: Attribution-ShareAlike
• A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy. Authored by : Yuanhan Bai, Xi Yang, Zhiqiang Zeng, and Haichen Yangcorresponding. Located at : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851085/ . License : CC BY: Attribution

Schizophrenia Case Study (45 min)

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A 21-year-old male is found outside of a gas station and according to bystanders, he was constantly talking for hours straight about the end of the world and the conspiracy of the government to control our minds. The patient appears to not have taken a shower in a long time; his hair is matted, his skin is dirty, he has a strong body odor and his nails are long with dirt under them. The patient is quoting the bible and asking everyone who enters the room if God has saved them yet. The nurse is assessing this patient and is asked if she could get Jesus a glass of water.

How should the nurse respond to the patient?

• Ask the patient if they can see Jesus and if Jesus is telling the patient to do something.
• Safety first! Assessing the reality of a patient is more important than re-orienting them.
• Re-orienting them happens after the nurse knows the patient doesn’t think Jesus is saying to kill everyone

The patient states, “Don’t you know who Jesus is? He will kill you if he wanted to. Don’t upset Jesus and get him a glass of water.” What should the nurse do at this point?

• Inform the patient that the only people you can see are the patient and yourself.
• Do not say you see the patient’s hallucination or validate the patient’s idea by getting ‘Jesus’ a glass of water.
• Try to divert the conversation back to the assessment and avoid getting stuck talking about the delusion.

The patient cooperates and is answering the nurse’s questions. Vital signs are stable and the patient tells the nurse that he has never been treated for any mental health problems before. He also tells the nurse that he is running away from home because people keep breaking into his apartment to laugh at him and steal his peanut butter and all of his writings because they will lead people to the secrets the government has been keeping. The nurse asks about medications the patient takes at home and the patient replies, “I don’t take that poison.” 

All of a sudden the patient starts to question the nurse and accuse the nurse of trying to trick the patient into taking poison and make him conform to the societal norms that the government wants us to do. The patient becomes very anxious and is staring at the door.

What is the nurse’s priority at this time?

• Confirm an exit plan for and make sure that the nurse is not in any danger of being trapped in the room with the patient and no way out.
• Do not let the patient get between you and the door

How should the nurse handle the new found mistrust with this patient?

• The nurse should make positive statements and then move the focus of the conversation such as, “I will not poison you, I promise. You seem nervous, do you want to take a break for a few minutes?”
• Allowing the patient a break can help interrupt the concerning thoughts the patient was having

What is the most important thing for the nurse to do at this time?

• Get out of the room and call security.
• Do NOT attempt to take the pencil away or question the patient about the drawing before making sure you the nurse are safe and secure.
• Do not go into the room without a security officer present.
• And chart Chart CHART everything that is happening.
• This patient will need to be with a sitter one and one as well as alarms and safety protocols implemented.

What kind of antipsychotic medication (Typical or Atypical) do you think this patient should be on?

• Typical antipsychotics because this patient is experiencing positive symptoms of schizophrenia .

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Nursing Case Studies

This nursing case study course is designed to help nursing students build critical thinking.  Each case study was written by experienced nurses with first hand knowledge of the “real-world” disease process.  To help you increase your nursing clinical judgement (critical thinking), each unfolding nursing case study includes answers laid out by Blooms Taxonomy  to help you see that you are progressing to clinical analysis.We encourage you to read the case study and really through the “critical thinking checks” as this is where the real learning occurs.  If you get tripped up by a specific question, no worries, just dig into an associated lesson on the topic and reinforce your understanding.  In the end, that is what nursing case studies are all about – growing in your clinical judgement.

Nursing Case Studies Introduction

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Neuro Nursing Case Studies

Mental health nursing case studies.

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Metabolic/Endocrine Nursing Case Studies

Other nursing case studies.

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• J Can Acad Child Adolesc Psychiatry
• v.28(3); 2019 Nov

Language: English | French

Case Report of Childhood-Onset Psychosis in a Patient with a Known WNT10A Mutation

Alexandra o. kobza.

1 Department of Child and Adolescent Psychiatry, Children’s Hospital of Eastern Ontario, Ottawa, Ontario

Shuliweeh Alenezi

2 Department of Psychiatry, King Saud University, Riyadh, Saudi Arabia

To report on a patient with childhood-onset psychosis at age 12 with a known WNT10A mutation.

Case report.

The patient is a 12-year-old male who presented with an acute onset of psychosis in the context of a known WNT10A mutation.

WNT genes have only been previously linked to schizophrenia on a theoretical basis. To our knowledge, this is the first case report of an association between a childhood-onset psychosis and a WNT10A mutation. We conclude that there is a possibility that WNT10A may be one of the many genes contributing to the development of childhood-onset schizophrenia.

Résumé

Faire rapport sur un patient chez qui la psychose est apparue à 12 ans et qui a une mutation connue du WNT10A.

Méthodes

Rapport de cas.

Résultats

Le patient est un garçon de 12 ans qui a présenté un début de psychose aiguë dans le contexte d’une mutation connue du gène WNT10A.

Les gènes WNT n’ont précédemment été liés qu’à la schizophrénie sur une base théorique. À notre connaissance, ceci est le premier rapport de cas d’une association entre une psychose apparue dans l’enfance et une mutation du WNT10A. Nous en concluons qu’il existe une possibilité que le WNT10A soit l’un des nombreux gènes qui contribuent au développement de la schizophrénie apparue dans l’enfance.

Introduction

Schizophrenia is one of the most disabling and economically catastrophic medical disorders; it contributes 13.4 million years of life lived with disability to burden of disease globally ( Charlson et al., 2018 ).

Childhood-onset schizophrenia is defined as beginning before the age of 13. Such an early presentation is exceedingly rare. A study in the United States of America estimated a prevalence of 0.04% ( McKenna, Gordon, & Rapoport, 1994 ; Rapoport & Gogtay, 2011 ); while another in Germany estimated 0.01% ( Kallmann & Roth, 1956 )no significant inter-group differences have been found either with respect to twin concordance rates or with respect to the schizophrenia rates for the parents (12.5% and 9.2%. This is in contrast with the overall prevalence of the disease, estimated to be about 1% worldwide. The pathogenesis of childhood-onset schizophrenia is not thought be much different from the adult-onset form of the disease; however, the illness has proven to be more severe and debilitating than the adult-onset type ( Ordóñez, Luscher, & Gogtay, 2016 ).

It has long been known that schizophrenia has a substantial genetic component; with heritability being estimated from ~65–80% ( Sullivan, Kendler, & Neale, 2003 ). Through the recent advent of Genome-Wide Association Studies (GWAS) over 100 different forms of DNA variation—including both SNPs (single nucleotide polymorphisms) and CNVs (copy number variants)—have been associated with schizophrenia ( Aberg et al., 2013 ; Ripke et al., 2013 , 2014 ; Shi et al., 2009 ; Stefansson et al., 2009 )a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%; however, there are no confirmed causal mutations, nor families where schizophrenia segregates in a Mendelian fashion ( Harrison, 2015 ). Overall, GWAS has identified a large number of susceptibility loci each having a very small effect, meaning that schizophrenia has proven to be a highly complex, heterogeneous and polygenic disease ( Henriksen, Nordgaard, & Jansson, 2017 ). The WNT pathway has theoretically been thought to play a role in schizophrenia given its role in neuronal migration and programmed cell death during development, yet no WNT gene mutation has ever been associated with the development of schizophrenia ( Harrison, 2015 ; Panaccione et al., 2013 ). Epidemiologic and family studies looking at genetics in childhood-onset schizophrenia have been limited due to the low prevalence of this illness as described earlier. We report on a patient with a known WNT10A mutation who presented with psychosis at the age of 12. To our knowledge this is the first case of childhood-onset psychosis in a patient with a known WNT10A gene mutation.

Case Report

A 12-year-old male presented to our centre with a one-month history of odd beliefs and behaviour. He lived at home with his parents and ten-year-old sister. In the Emergency Room he began the interview by consistently repeating that he was “dead” and saying, “I don’t want to be here. I am not safe. I am drowning.” He tried to leave the room multiple times and required redirection. He was uncooperative, suspicious and guarded and his speech was often unintelligible. His thought content was consistent with paranoid delusions. No hallucinations were reported and the patient did not seem to be responding to any internal stimuli.

The patient was born post-term after an uncomplicated pregnancy except for antepartum fetal distress necessitating a C-section and concern for small birth weight. His mother was not on any medications during pregnancy and there was no exposure to alcohol, smoking, or drugs. Neonatal course was unremarkable except for jaundice requiring phototherapy. Motor milestones were normal, with walking at ten months, but the patient was drooling into his first year of life and had a language delay. He was found to have normal receptive language but considerable expressive language delay and articulation problems necessitating speech therapy from the age of two. At the time of presentation, he had a diagnosed reading disability and was in grade seven with an individualized education plan.

His past medical history was significant for asthma, eosinophilic esophagitis (well controlled for years with steroid medication), food protein enteropathy, and multiple IgE-mediated food allergies. He was evaluated by the Genetics Team for abnormal dentition in addition to developmental delay, failure to thrive, and feeding difficulties and was found to have two heterozygous mutations in WNT10A in trans, one of which is associated with tooth abnormalities and possibly hypohydrosis (variant p.F228I, Coding DNA c.682 T>A) and one of which is a variant of uncertain significance (variant p.G165R, Coding DNA c.493 G>A). His past psychiatric history was significant for being under the care of a community psychiatrist for generalized anxiety and social anxiety for the last two months.

His medications on presentation were: lansoprazole, inhaled budesonide (1mg/2mL inhalation suspension taken every three days), mometasone nasal spray, ciclesonide nasal spray, salbutamol and Co-enzyme Q10. Parents denied any substance use.

Parents had noticed a cognitive decline over the last three months. They described a more disrupted sleep cycle, and an increase in uncooperative behaviour that teachers were calling defiance but the parents felt was more consistent with confusion. For example, the patient would be walking in a familiar place and all of a sudden look around completely lost to his surroundings.

In the last month, he had started to voice a number of paranoid thoughts: the presence of hidden cameras, teachers putting ‘body parts’ in the closets, and snipers on the roof of the house. His parents also noticed new strange behaviours including waking up in the middle of the night screaming and hitting his mother and himself. At other times he seemed disconnected and parents found his emotional expression difficult to read. The night the family presented to the Emergency Room, the patient’s mother found him awake just after midnight packing a suitcase full of clothing and a kitchen knife. He was insisting on leaving the house (inappropriately dressed for the winter weather) because he felt unsafe.

Family history was significant for one episode of psychosis in the maternal uncle which had resolved with medication.

As this was a first presentation of childhood psychosis, our group adhered to the Canadian Schizophrenia Guidelines ( Pringsheim & Addington, 2017 ) and the NICE (National Institute for Health and Care Excellence) Psychosis and Schizophrenia in Children and Young People Guidelines ( National Institite for Health and Care Excellence, 2016 ) for a comprehensive diagnostic work-up. There were no significant abnormal findings found on blood work as seen in Table 1 or on brain MRI and EEG. The patient did have a slight hyperkalemia on presentation (K + 5.2) that normalized without treatment on subsequent bloodwork.

Laboratory values at presentation

All values are reported as the patient’s value (reference range)

Values outside of the normal range have been bolded .

With a negative neurological exam, cerebral spinal fluid testing (for toxicology and anti-NMDA receptor antibodies) was not pursued. The patient was started on Olanzapine and has achieved partial improvement one year later.

We described a patient, with a known WNT10A mutation, who presented with psychosis at age 12. Our assessment included a full psychiatric, medical, psychological, psychosocial, and developmental investigation. Given that our medical work-up was negative, our diagnosis of exclusion was that this was indeed a first presentation of psychosis of psychiatric origin. Possible etiological factors of this early onset psychosis include hypoxia at the time of birth and the WNT10A mutation. Although oral steroid medications are well known to cause neuropsychiatric side effects including psychosis ( Dubovsky, Arvikar, Stern, & Axelrod, 2012 ) these side effects have not been associated with inhaled corticosteroid use ( Toogood, 1998 ). Therefore, steroids were ruled out as the cause in our patient given that he had been maintained on a stable dose of inhaled budesonide over several years. The patient’s mild hyperkalemia on presentation that normalized without treatment was also ruled out as a potential cause as hyperkalemia is not known to have psychotic manifestations and there was no improvement in our patient’s behaviour upon normalization ( Shrimanker & Bhattarai, 2019 ).

Historically, mutations in the WNT10A gene have been associated with three syndromes: Tooth agenesis, Schopf-Schulz-Passarge syndrome, and Odonto-onycho-dermal dysplasia ( National Institute of Health, 2018 ). Classically, the WNT10A gene has not been associated with childhood-onset schizophrenia.

To our knowledge this is the first case of childhood-onset psychosis in a patient with a known WNT10A gene mutation. It is important to recognize that the specific mutations seen in our patient (variant p.F228I, Coding DNA c.682 T>A and variant p.G165R, Coding DNA c.493 G>A) have a frequency of 0.00599 and 0.00220 respectively in the population and there have been no cases thus far reporting psychosis (National Center for Biotechnology Information, n.d.-a, n.d.-b). Further, databases of human genetic variation demonstrate that there are individuals who are homozygous for these particular mutations, and they have not been reported to have psychosis (National Center for Biotechnology Information, n.d.-a, n.d.-b). In addition, the WNT10A gene has been shown to have a lack of intolerance to variation (pLI=0.000) meaning that a high amount of genetic disturbance is needed in order to produce a different phenotype (gnomAD browser, n.d.).

Therefore, we would like to emphasize that our finding does not imply causality. Rather, we are reporting on an association between a WNT10A gene mutation and childhood-onset psychosis. It is possible that our patient has an otherwise high genetic risk score for the development of childhood-onset schizophrenia. However, given the theoretical link between the WNT pathway and schizophrenia with its role in neuronal migration and programmed cell death during development, we cannot discount that these heterogeneous mutations in the WNT10A gene in our patient may be contributing to his presentation of childhood-onset psychosis. We conclude that there is a possibility that WNT10A may be one of the many genes contributing to the development of childhood-onset schizophrenia. Further research is needed to examine if there is truly a causal relationship and whether it can be attributed to one particular mutation. Given how rare childhood-onset schizophrenia is, future case reports and case series may provide insight into answering this question.

Acknowledgements / Conflicts of Interest

The authors have no known conflicts of interest in this case presentation.

Witnessed consent was obtained on March 15 th 2018 to present this case for academic purposes.

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Mindfulness and Compassion as a Path to Recovery and Personal Discovery: A First-Episode Schizophrenia Case Study

• First Online: 26 April 2023

Cite this chapter

• Gerardo Rivera 5 , 6 , 7 ,
• Reiner Fuentes-Ferrada   ORCID: orcid.org/0000-0001-5966-3907 6 , 8 , 9 ,
• Edwin Krogh   ORCID: orcid.org/0000-0002-2042-3137 5 &
• Álvaro I. Langer   ORCID: orcid.org/0000-0003-2983-5274 5 , 6 , 10 , 11  

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Research has gradually demonstrated that mindfulness-based interventions (MBIs) considerably improve the well-being of people with psychosis. However, the maintenance of these outcomes in the long term and the continuity of mindfulness practices in the transition from research to clinical contexts remain practically unexplored. Also, researchers have paid little attention to the movement of MBIs to compassion training and to how these approaches can complement one another. This clinical case study seeks to analyse the experience of a young woman with first-episode schizophrenia. The patient participated in an MBI for psychosis within the context of a research project, after which she received both individual and group clinical treatment, including compassion-focused therapy (CFT) training. The following aspects were measured at baseline, after the intervention, and at three-, nine-, twelve-, and forty-four-month follow-up: general symptomatology (DASS-21), worry (PSWQ-11), affect (PANAS), self-esteem (Rosenberg Scale), well-being (Ryff Scales), and mindfulness (FFMQ). Qualitative patient data were also recorded. Results show that the patient’s well-being improved after the MBI. Clinical observations show that, when the psychotic symptomatology had entered a second acute phase, the patient was better prepared to deal with the situation by using CFT skills instead of mindfulness. The applicability of MBIs and CFT is discussed considering the patient’s specific symptoms and the course of her disease within research settings and in clinical practice.

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Acknowledgements

The authors wish to thank P. for her generous decision to share her experience during the treatment process. This study was partly funded by FONDECYT No. 11150846, ANID–Programa Iniciativa Científica Milenio [Millennium Scientific Initiative]–NCS2021_081e ICS13_005.

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Rivera, G., Fuentes-Ferrada, R., Krogh, E., Langer, Á.I. (2023). Mindfulness and Compassion as a Path to Recovery and Personal Discovery: A First-Episode Schizophrenia Case Study. In: Díaz-Garrido, J.A., Zúñiga, R., Laffite, H., Morris, E. (eds) Psychological Interventions for Psychosis. Springer, Cham. https://doi.org/10.1007/978-3-031-27003-1_25

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Schizophrenia genomics: genetic complexity and functional insights

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Determining the causes of schizophrenia has been a notoriously intractable problem, resistant to a multitude of investigative approaches over centuries. In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia. In parallel, functional genomic and neurobiological studies have provided exceptionally detailed information about the cellular composition of the brain and its interconnections in neurotypical individuals and, increasingly, in those with schizophrenia. Taken together, these results suggest unexpected complexity in the mechanisms that drive schizophrenia, pointing to the involvement of ensembles of genes (polygenicity) rather than single-gene causation. In this Review, we describe what we now know about the genetics of schizophrenia and consider the neurobiological implications of this information.

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Acknowledgements

J.H.-L. was supported by the Swedish Research Council (Vetenskapsrådet, award 2018-00799), Swedish Brain Foundation (Hjärnfonden, award FO2018-0272) and European Research Council (SCHIZTYPE, grant agreement 819540). P.F.S. was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501) and the US National Institute of Mental Health (R01s MH124871, MH121545 and MH123724).

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Supplementary information

Supplementary information, supplementary methods.

Three-dimensional cell cultures that mimic the structure and function of the brain, derived from pluripotent stem cells.

(CNVs). Structural variations in the genome, in which large sections of DNA (containing from one gene to many genes) are duplicated or deleted, potentially influencing traits or diseases.

A theory proposing that dysregulation of dopamine neurotransmission in the brain contributes to the development of schizophrenia.

Referring to chemical modifications to DNA and histone proteins that regulate gene expression without altering the DNA sequence.

Variations in the DNA sequence that increase the likelihood of developing a particular trait or disease (such as schizophrenia).

Measurable differences in DNA sequence among individuals, including SNPs, coding and non-coding variants, copy number variants, insertion and deletions.

(GWAS). A method to identify genetic variations across the entire genome associated with traits or diseases.

The proportion of the total variation in a trait in a population that is owing to genetic differences among individuals.

An adult cell reprogrammed to exhibit embryonic stem-cell-like properties and capable of differentiating into various cell types.

The nonrandom association or correlation of alleles at different loci within a population. Linkage disequilibrium is detectible between pairs of genetic markers with tens of kilobases but may span many megabases in specific regions.

A method using genetic variants as instrumental variables to investigate causal relationships between modifiable exposures and health outcomes.

(PRS). A numerical score calculated from multiple genetic variants associated with a trait or disease, used as a summation of genetic predisposition of an individual.

A sequencing technique to analyse gene expression in single cells (or single nuclei), providing insights into cellular heterogeneity and functional diversity.

Variations in a single nucleotide at a specific position in the genome.

(WES). Sequencing of the protein-coding regions of the genome.

Sequencing of the entire genome, including coding and non-coding regions, providing a comprehensive view of the genetic makeup of an individual.

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Sullivan, P.F., Yao, S. & Hjerling-Leffler, J. Schizophrenia genomics: genetic complexity and functional insights. Nat. Rev. Neurosci. (2024). https://doi.org/10.1038/s41583-024-00837-7

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Relapse criteria for the double-blind (DB) study included psychiatric hospitalization, emergency department visit due to schizophrenia symptoms, participant behavior resulting in harm (self-injury, suicide, harm to another person, property damage, and/or suicidal or homicidal ideation and aggressive behavior), a 25% increase in Positive and Negative Syndrome Scale (PANSS) score from randomization (for patients with PANSS score >40 at randomization) or 10-point increase (for patients with PANSS score ≤40 at randomization) in PANSS total score from randomization for 2 consecutive assessments between 3 to 7 days, or PANSS scores of 5 or greater after randomization (if PANSS score was ≤3 at randomization) or 6 or greater (if PANSS score was 4 at randomization) after randomization for 2 consecutive assessments between 3 and 7 days on any of the following items: delusions, conceptual disorganization, hallucinatory behavior, suspiciousness or persecution, hostility, and uncooperativeness. ITT indicates intent-to-treat; OLE, open-label extension; PP, paliperidone palmitate.

Only patients who were relapse free during the 1-year, double-blind, randomized clinical trial (first 12 months) were included in this analysis.

Errors bars indicate SDs. CGI-S indicates Clinical Global Impression–Severity Scale (score range, 1-7 and baseline range, 1-5, with higher scores indicating more severe illness); PANSS, Positive and Negative Syndrome Scale (score range, 30-210, with higher scores indicating greater symptom severity); PSP, Personal and Social Performance Scale (score range, 45-100, with higher scores indicating better personal and social functioning).

Trial Protocol

eTable 1. CGI-S Change From Baseline to Month 36 by Age

eTable 2. CGI-S Change From Baseline at Each Visit by Body Mass Index

eTable 3. CGI-S Change From Baseline at Each Visit by Duration of Illness

eTable 4. CGI-S Change From Baseline at Each Visit by Sex

eTable 5. PANSS Total Score Change From Baseline to Month 36 by Age

eTable 6. PANSS Total Score Change From Baseline at Each Visit by Body Mass Index

eTable 7. PANSS Total Score Change From Baseline at Each Visit by Duration of Illness

eTable 8. PANSS Total Score Change From Baseline at Each Visit by Sex

eTable 9. PSP Total Score Change From Baseline at Each Visit by Age

eTable 10. PSP Total Score Change From Baseline at Each Visit by Body Mass Index

eTable 11. PSP Total Score Change From Baseline at Each Visit by Duration of Illness

eTable 12. PSP Total Score Change From Baseline at Each Visit by Sex

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Correll CU , Johnston K , Turkoz I, et al. Three-Year Outcomes of 6-Month Paliperidone Palmitate in Adults With Schizophrenia : An Open-Label Extension Study of a Randomized Clinical Trial . JAMA Netw Open. 2024;7(7):e2421495. doi:10.1001/jamanetworkopen.2024.21495

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Three-Year Outcomes of 6-Month Paliperidone Palmitate in Adults With Schizophrenia : An Open-Label Extension Study of a Randomized Clinical Trial

• 1 Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York
• 2 Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
• 3 Department of Child and Adolescent Psychiatry, Charité–Universitätsmedizin Berlin, Berlin, Germany
• 4 German Center for Mental Health, Berlin, Germany
• 5 Janssen Scientific Affairs, LLC, a Johnson & Johnson Company, Titusville, New Jersey
• 6 Janssen Research & Development, LLC, Titusville, New Jersey
• 7 Cytel, Cambridge, Massachusetts
• 8 University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Question   What are the long-term outcomes of paliperidone palmitate (PP) once every 6 months in adults with schizophrenia?

Findings   In an open-label extension study of a randomized clinical trial that included 121 patients receiving PP every 6 months, all were clinically and functionally stable, and outcomes were well maintained, with 95.9% of patients remaining relapse free for up to 3 years. No deaths were reported, and no new safety concerns outside the adverse event profile of the drug were identified.

Meaning   These results support favorable long-term outcomes of PP once every 6 months for up to 3 years in adults with schizophrenia.

Importance   Long-acting injectable (LAI) antipsychotics have the potential to improve adherence and symptom control in patients with schizophrenia, promoting long-term recovery. Paliperidone palmitate (PP) once every 6 months is the first and currently only LAI antipsychotic with an extended dosing interval of 6 months.

Objective   To assess long-term outcomes of PP received once every 6 months in adults with schizophrenia.

Design, Setting, and Participants   In a 2-year open-label extension (OLE) study of a 1-year randomized clinical trial (RCT), eligible adults with schizophrenia could choose to continue PP every 6 months if they had not experienced relapse after receiving PP once every 3 or 6 months in the 1-year, international, multicenter, double-blind, randomized noninferiority trial. The present analysis focused on patients receiving PP every 6 months in the double-blind trial through the OLE study (November 20, 2017, to May 3, 2022).

Intervention   Patients received a dorsogluteal injection of PP on day 1 and once every 6 months up to month 30.

Main Outcomes and Measures   End points included assessment of relapse and change from the double-blind trial baseline to the OLE end point in Positive and Negative Syndrome Scale (PANSS) total and subscale, Clinical Global Impression–Severity (CGI-S) Scale, and Personal Social Performance (PSP) Scale scores. Treatment-emergent adverse events (TEAEs), injection site evaluations, and laboratory tests were also assessed.

Results   Among 121 patients (83 [68.6%] male), mean (SD) age at baseline was 38.6 (11.24) years and mean (SD) duration of illness was 11.0 (9.45) years. At screening of the double-blind study, 101 patients (83.5%) were taking an oral antipsychotic and 20 (16.5%) were taking an LAI antipsychotic. Altogether, 5 of 121 patients (4.1%) experienced relapse during the 3-year follow-up; reasons for relapse were psychiatric hospitalization (2 [1.7%]), suicidal or homicidal ideation (2 [1.7%]), and deliberate self-injury (1 [0.8%]). Patients treated with PP every 6 months were clinically and functionally stable, and outcomes were well maintained, evidenced by stable scores on the PANSS (mean [SD] change, −2.6 [9.96] points), CGI-S (mean [SD] change, −0.2 [0.57] points), and PSP (mean [SD] change, 3.1 [9.14] points) scales over the 3-year period. In total, 101 patients (83.5%) completed the 2-year OLE. At least 1 TEAE was reported in 97 of 121 patients (80.2%) overall; no new safety or tolerability concerns were identified.

Conclusions and Relevance   In a 2-year OLE study of a 1-year RCT, results supported favorable long-term outcomes of PP once every 6 months for up to 3 years in adults with schizophrenia.

Schizophrenia is a chronic and debilitating mental illness that affects approximately 24 million people (0.3%) worldwide. 1 Patients with schizophrenia require lifelong treatment with antipsychotic medications; additionally, many experience reduced quality of life resulting from periods of exacerbated active symptoms leading to repeated hospitalizations, loss of productivity, incarceration, and mortality often due to nonadherence to medications. 2 - 4 Long-acting injectable (LAI) antipsychotics have the potential to improve treatment adherence and symptom control in patients with schizophrenia and have demonstrated superior efficacy compared with oral antipsychotics. 5 - 11 In a randomized pragmatic study including clinical sampling of a diverse population of patients with schizophrenia, once-monthly paliperidone palmitate (PP) demonstrated significant reductions in hospitalizations, incarcerations, and treatment failure compared with oral antipsychotics. 5 Certain first- and second-generation antipsychotics, including aripiprazole, olanzapine, paliperidone, and risperidone, are available in LAI formulations. 12 LAI antipsychotics differ in their pharmacokinetic properties and, as a result, in their initiation protocols and dosing intervals. 13

Paliperidone palmitate (PP) is an LAI that has been shown to be effective in maintaining symptom control, reducing risk of relapse, and delaying time to relapse in schizophrenia. 5 , 7 , 14 - 19 Paliperidone palmitate is available in 3 formulations: once monthly, 20 once every 3 months, 21 and a recently developed formulation of once every 6 months. 22 Paliperidone palmitate is the first (and currently only) LAI with a 6-month dosing interval, which is substantially longer than any other LAI antipsychotic. Treatment with PP every 6 months permits just 2 injections per year for patients who have been adequately treated with PP once monthly for 4 months or longer or PP every 3 months for at least 1 injection cycle. 7 , 16 , 22 Observational studies have suggested that there may be an advantage to longer injection intervals of LAI antipsychotics for greater medication treatment persistence, 23 which is a challenge with both oral medications and LAIs. 24 This analysis assessed the long-term outcomes of PP every 6 months in adults with schizophrenia. 7 , 16

This secondary analysis included patients from a 1-year, double-blind randomized clinical trial ( NCT03345342 ) through a 2-year, single-arm, open-label extension (OLE) study ( NCT04072575 ). Studies were approved by the independent ethics committees or institutional review boards of the respective sites and conducted in accordance with the Declaration of Helsinki, 25 Good Clinical Practice, and applicable regulatory requirements. All patients provided written informed consent for participation in this study. We followed the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline. The trial protocol is available in Supplement 1 .

Eligible patients were men and women aged 18 to 70 years with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) diagnosis of schizophrenia for 6 or more months before screening and a Positive and Negative Syndrome Scale (PANSS) total score of less than 70 points at screening (score range, 30-210, with higher scores indicating greater symptom severity). After screening and open-label transition and maintenance phases, clinically stable patients receiving moderate or high doses of PP once monthly (moderate, 156 mg [100-mg equivalent of paliperidone]; high, 234 mg [150-mg equivalent of paliperidone]) or every 3 months (moderate, 546 mg [350-mg equivalent of paliperidone]; high, 819 mg [525-mg equivalent of paliperidone]) were randomly assigned 2:1 to corresponding dorsogluteal injections of PP every 6 months (moderate, 1092 mg [700-mg equivalent of paliperidone]; high, 1560 mg [1000-mg equivalent of paliperidone]) or PP every 3 months (moderate, 546 mg [350-mg equivalent of paliperidone]; high, 819 mg [525-mg equivalent of paliperidone]) during the double-blind trial. 7 Eligible patients from 6 countries (Argentina, Hong Kong, Italy, Poland, the Russian Federation, and Ukraine) who completed the double-blind trial without experiencing relapse after receiving PP every 3 or 6 months and wished to continue treatment with PP every 6 months enrolled in the 2-year OLE study ( Figure 1 ). This analysis focused on patients receiving PP every 6 months in the double-blind trial through the OLE study (study period, November 20, 2017, to May 3, 2022).

During the OLE study, antiextrapyramidal symptom medications, benzodiazepines, sleep aids, and oral antipsychotics were permitted. Antipsychotic supplementation dose and duration were dependent on symptom exacerbation and the investigator’s judgment. Permitted oral antipsychotic medications included oral risperidone (moderate dose: 1-2 mg/d and high dose: 1-3 mg/d) and oral paliperidone extended release (moderate dose: 1.5-3 mg/d and high dose: 1.5-6 mg/d). 16 Coadministration with PP every 6 months had a maximum duration of 2 weeks. If the participant did not meet relapse criteria within a single 6-month injection cycle, an additional 2 weeks of oral antipsychotic was administered continuously for a maximum of 4 weeks. Per investigator’s discretion, if there was a clinical need for oral antipsychotic supplementation for greater than 4 continuous weeks, the study intervention was discontinued and the participant was withdrawn. Use of oral antipsychotic medications other than oral risperidone or oral paliperidone extended release was prohibited. 16

Relapse in the OLE study was defined as 1 or more of the following: psychiatric hospitalization, emergency department visit due to schizophrenia symptoms, participant behavior resulting in harm (self-injury, suicide, harm to another person, or property damage), and/or suicidal or homicidal ideation or aggressive behavior. In the double-blind trial, relapse criteria also included specific increases in PANSS total and subscale scores.

Changes from the double-blind trial baseline to the OLE study end point in PANSS total and subscale scores and in scores on the Clinical Global Impression–Severity (CGI-S) Scale (score range, 1-7 and baseline range, 1-5, with higher scores indicating more severe illness) and Personal and Social Performance (PSP) Scale (score range, 45-100, with higher scores indicating better personal and social functioning) were included as secondary end points. The PANSS and PSP assessments occurred at baseline (in the double-blind trial) and at months 3, 6, 9, 12, 24, and 36 (OLE study end point). The CGI-S assessments occurred at week 4 and then monthly up to 12 months after baseline (in the double-blind trial), after which point, data were collected every 3 months. Data are presented as collected; no missing data points were imputed. To ensure consistent use of the assessment tools, all raters were trained and certified.

Treatment-emergent adverse events (TEAEs), mental status examination, injection site evaluations, and clinical laboratory tests were also assessed. Blood samples for serum chemistry and hematology and urine samples for urinalysis were collected.

All patients who received at least 1 dose of PP every 6 months during the OLE study were included in the intent-to-treat (ITT) analysis population. Outcomes were summarized descriptively. Subgroup analyses of outcomes were conducted using a mixed-model, repeated-measures analysis of covariance; these were exploratory analyses with no adjustment for multiplicity. Analyses were based on change from baseline in the double-blind trial in PANSS, CGI-S, and PSP scores at each visit for subgroups by age (18-25, >25 to 50, or >50 years), sex, body mass index (BMI) (<30 or ≥30; calculated as weight in kilograms divided by height in meters squared), and duration of illness (≤3 years or >3 years). Data were analyzed using SAS, version 15.1 (SAS Institute Inc). The statistical analysis plan is available in Supplement 1 .

A total of 121 patients were included in this 3-year ITT analysis ( Table 1 ). The mean (SD) age of patients was 38.6 (11.24) years; 38 (31.4%) were female and 83 (68.6%) were male. Mean (SD) baseline BMI was 27.9 (4.84). Mean (SD) duration of illness was 11.0 (9.45) years. At screening of the double-blind study, 101 patients (83.5%) were taking an oral antipsychotic and 20 (16.5%) were taking an LAI antipsychotic (injectable risperidone, PP once monthly, or PP every 3 months). Patients were observed for a median of 3.0 years (range, 1.0-3.1 years). Participants received either 1092-mg (700-mg equivalent of paliperidone; 3.5 mL) or 1560-mg (1000-mg equivalent of paliperidone; 5.0 mL) doses of PP every 6 months in prefilled syringes at each time point, and flexible dosing was allowed during the OLE study. Mean (SD) dose of PP every 6 months was 1367.7 mg (876.7-mg equivalent of paliperidone) (217.3 mg; 139.3-mg equivalent of paliperidone).

Five of 121 patients (4.1%) experienced relapse during the 3-year follow-up period ( Figure 2 ). The reasons for relapse were psychiatric hospitalization (2 patients [1.7%]), suicidal or homicidal ideation (2 [1.7%]), and deliberate self-injury (1 [0.8%]). Patients treated with PP every 6 months were clinically stable and outcomes were well maintained, as evidenced by stable PANSS, CGI-S, and PSP scores over the 3-year period ( Figure 3 ). Mean (SD) change from baseline to end point in PANSS total score was −2.6 (9.96) points, CGI-S score was −0.2 (0.57) points, and PSP total score was 3.1 (9.14) points. Altogether, 101 of 121 patients (83.5%) completed the 2-year follow-up period.

Overall evaluations of end points by age, sex, duration of illness, and BMI showed improvements over 3 years. Directional improvements within each subgroup did not deviate from the overall findings, and there were no statistically significant differences among the groups with the exception of CGI-S scores by sex, which showed that, in general, scores for female patients improved to a greater extent than those for male patients after 6 months. Subgroup estimate data for each scale (CGI-S, PANSS, and PSP) are included in eTables 1 to 12 in Supplement 2 .

Overall, 97 patients (80.2%) experienced 1 or more TEAEs ( Table 2 ); TEAEs deemed possibly related to treatment with PP every 6 months were reported in 65 patients (53.7%). The most common TEAEs as entered in the database (occurring in ≥5% of patients) were headache (22 [18.2%]), weight increased (15 [12.4%]), blood prolactin increased (14 [11.6%]), nasopharyngitis (13 [10.7%]), injection site pain (13 [10.7%]), diarrhea (10 [8.3%]), hyperprolactinemia (9 [7.4%]), blood thyroid stimulating hormone increased (6 [5.0%]), and back pain (6 [5.0%]). Most TEAEs were mild to moderate in severity and were consistent with those reported in other studies. 5 , 14 , 15 , 17 , 18

Seven patients (5.8%) experienced at least 1 serious TEAE, entered in the database as schizophrenia (3 [2.5%]), depression (1 [0.8%]), psychiatric symptom (1 [0.8%]), colon cancer (1 [0.8%]), cancer metastases to peritoneum (1 [0.8%]), and nephrotic syndrome (1 [0.8%]). Six patients (5.0%) experienced at least 1 TEAE leading to drug withdrawal: psychiatric disorders (5 [4.1%]), including schizophrenia (4 [3.3%]), intrusive thoughts (1 [0.8%]), psychiatric symptom (1 [0.8%]), and suicidal ideation (1 [0.8%]), and general disorders and administration site conditions (1 [0.8%]), including injection site edema, injection site pain, and injection site warmth. No deaths were reported in the cohort.

Results from this analysis revealed favorable long-term outcomes, with an adverse event profile consistent with previous studies of paliperidone, 5 , 7 , 14 - 19 of PP every 6 months for up to 3 years in adults with schizophrenia. Of the 121 patients receiving PP every 6 months who completed the 1-year double-blind trial without relapse and continued into the 2-year OLE study, 116 patients (95.9%) remained relapse free, with 83.5% completing the entire 2-year follow-up. This result was similar to the primary results observed for the OLE study, in which 96.1% of patients receiving PP every 6 months remained relapse free for up to 2 years. 16 Furthermore, patients receiving PP every 6 months were clinically and functionally stable and outcomes were well maintained, as evidenced by the stable PANSS, CGI-S, and PSP scores over the 3-year period. No new safety concerns outside the adverse event profile of the drug were identified, and no deaths were reported. Directional improvements within subgroup analyses by various baseline demographic and disease characteristics did not deviate from the overall findings. Overall, the 3-year adverse event profile of PP every 6 months was consistent with the known profile of PP. Notably, the frequency of TEAEs leading to drug withdrawal in this study of PP every 6 months (5.0%) was similar to those reported in a noninferiority study of PP every 3 months (48-week double-blind study: 3.0%) and PP monthly (17-week open-label study: 4.2%; 48-week double-blind study: 2.5%). 15

While not all patients may respond to LAI antipsychotics, 26 they are some of the most effective treatments for schizophrenia in adults and are underused in clinical practice. 6 , 11 Reasons for underuse include clinician preference for oral medications in early treatment, a lack of discussion about LAI antipsychotics between patients and health care practitioners, assumption of patients’ negative perceptions or refusal of LAIs, clinician overestimation of medication adherence, and limited support for staff with expertise to administer injections. 6 , 11 , 27 , 28 However, compared with oral antipsychotics, LAI antipsychotics are associated with a lower risk of relapse and rehospitalization, treatment discontinuation, work disability, and mortality. 2 , 29 - 31 Such evidence suggests that schizophrenia-related outcomes could improve with increased use of LAI antipsychotics. 31 Consensus reached by a recent Delphi panel regarding LAI antipsychotics use in early-phase schizophrenia aligns with this suggestion, recommending that all patients should be evaluated for potential suitability for LAI treatment. 32 The panel also agreed that the use of LAIs increases medication adherence and reduces treatment burden and functional decline, thereby promoting functional recovery. 32 Although the definition of functional recovery is complex, recent studies have stressed the importance of factors influencing life engagement and quality of life, such as cognition, personal autonomy, professional activity, social relationships or support, and environmental factors. 32 - 35 The longer dosing intervals associated with LAI antipsychotics contribute to clinical stability, providing potential for long-term improvements in functionality, social integration, and patient empowerment. 36 , 37 Furthermore, LAI antipsychotic treatment in combination with nonpsychopharmacologic treatment strategies may encourage personal recovery beyond the framework of traditional outcome measures and mental health services.

Recovery, the combination of symptomatic remission and adequate psychosocial and educational or vocational functioning, 38 - 41 is an established goal of treatment in adults with schizophrenia and usually involves integration of pharmacologic and psychologic approaches. 42 , 43 Although improvements are often measured through traditional methods, such as changes in PSP, PANSS, and CGI-S scale scores, recovery may also be assessed through other psychosocial outcome measures. For example, the San Francisco Adult Strengths and Needs Assessment score has tracked reductions in criminal behavior and improvements in spirituality among patients who switched from an oral antipsychotic medication to an LAI antipsychotic. 44 Regardless of approach, psychosocial interventions paired with LAI antipsychotic treatment are associated with improved functioning. 45 In this context, symptomatic stability and relapse prevention are important first steps on the path toward achieving and maintaining functional recovery. The low rate of relapse reported in this study highlights the important role that LAI antipsychotics have as a treatment that can facilitate and support the recovery process. In this regard, treatments such as PP every 6 months can play a potentially important role in long-term recovery in patients with schizophrenia.

Several limitations must be considered when analyzing this study’s results. First, the study lacked a comparator group. However, the results presented align with those of network meta-analyses of LAI and oral antipsychotics in that LAI PP was associated with a low risk for relapse and hospitalization and with a large improvement in mean rating scale scores. 31 , 46 Second, there was a potential for effects of confounding demographic factors on data stemming from the small number of countries participating in the OLE study. Third, patients who started PP every 6 months and experienced relapse, died, or withdrew from the double-blind trial (year 1) and those who did not opt into the OLE study (years 2 and 3) were not included in this analysis. Fourth, patients agreed to be part of a double-blind randomized trial in the beginning, potentially restricting the generalizability of the findings. Fifth, patients included in this study were clinically stable; thus, our results may not be generalizable to the broader study population. Sixth, this study focused on relapse prevention. While these findings are important, we recognize that functional recovery in areas such as work functioning and social determinants of health are also key aspects of remission. Future research should include a focus on person-centered care and overall wellness and test the efficacy of psychosocial interventions for the achievement of functional recovery in patients treated with an LAI vs oral antipsychotic over the long term. However, despite these limitations, few studies have followed patients initiating LAI antipsychotic treatment prospectively for such a long period.

In a 2-year OLE study of a 1-year randomized clinical trial, a high proportion (95.9%) of patients receiving PP once every 6 months remained relapse free for up to 3 years with no new safety concerns emerging and with high treatment persistence. The findings suggest that PP every 6 months, the first antipsychotic to date that can be administered effectively only twice per year, adds to the range of long-term treatment options for patients with schizophrenia.

Accepted for Publication: May 11, 2024.

Published: July 17, 2024. doi:10.1001/jamanetworkopen.2024.21495

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License . © 2024 Correll CU et al. JAMA Network Open .

Corresponding Author: Christoph U. Correll, MD, Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549 ( [email protected] ).

Author Contributions: Drs Correll and Sajatovic had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Correll, Johnston, Turkoz, Sun, Sajatovic.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Johnston, Turkoz, Gray, Doring.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Turkoz, Sun.

Administrative, technical, or material support: Johnston, Gray, Doring.

Supervision: Correll, Johnston, Doring.

Conflict of Interest Disclosures: Dr Correll reported receiving royalties from UpToDate outside the submitted work; being a consultant and/or advisor to or receiving honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/Johnson & Johnson, Karuna, LB Pharmaceuticals, Lundbeck, MedAvante-ProPhase, Medincell, Merck, MindPax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, ROVI, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris; providing expert testimony for Janssen and Otsuka; serving on data safety monitoring boards for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, ROVI, Supernus, and Teva; receiving grant support from Janssen and Takeda; and holding stock options in Cardio Diagnostics, Küleon Biosciences, LB Pharmaceuticals, Mindpax, and Quantic. Dr Johnston reported holding stock in Johnson & Johnson. Ms Doring reported holding stock in Johnson & Johnson. Dr Sajatovic reported receiving personal fees from and being a consultant to Janssen outside of the submitted work; receiving grants from Neurelis, Intra-Cellular, Merck, Otsuka, Alkermes, the International Society for Bipolar Disorders, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Patient-Centered Outcomes Research Institute; receiving personal fees for consulting from Alkermes, Otsuka, Lundbeck, Teva, and Neurelis; receiving royalties from Springer, Johns Hopkins University Press, Oxford University Press, and UpToDate; and receiving compensation for preparation of or participation in continuing medical education activities from the American Physician Institute (CMEtoGO), Psychopharmacology Institute, American Epilepsy Society, Clinical Care Options, American Academy of Child and Adolescent Psychiatry, and Neurocrine outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by Janssen Scientific Affairs, LLC, a Johnson & Johnson company.

Role of the Funder/Sponsor: Janssen Scientific Affairs, LLC, participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: This study was presented in part at Psych Congress; September 8 and 9, 2023; Nashville, Tennessee.

Data Sharing Statement: See Supplement 3 .

Additional Contributions: Cindi A. Hoover, PhD, ApotheCom, provided editorial and writing assistance, which was funded by Janssen Scientific Affairs, LLC, a Johnson & Johnson company.

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