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

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Case Study: Schizophrenia and Work: Martin’s Story

Martin had been out of work for several years following a prolonged psychotic episode which began when he was studying at university. He desperately wanted to get into work but found that employers treated his prolonged absence “on the sick” with suspicion. He thought that if he could do a period of work experience that would show prospective employers that he was capable of working again but he was afraid that if he did it might affect his benefits.

So Martin made an appointment to see the Disability Employment Advisor at the Jobcentre to discuss his plans. She was understanding and helpful and explained that a work placement would not affect his benefits as long as it was done as part of the Jobcentre’s own scheme. She also told him that the scheme would pay his travel-to work expenses while he was on the placement.

Job-searching

Next Martin researched local employers using the internet and the local press, looking for companies that might have vacancies in the sort of clerical and administrative work he thought he could do. Then he called the companies by ‘phone and speaking to the person on the switchboard checked that he had the correct postal address for them and asked the name of the person in charge of recruiting. It is vital to be able to write to a named person rather than just the Human Resources Manager.

Martin had already spent a lot of time on his CV so now he compiled a covering letter to go with it. It took him about a month to work up his CV and covering letter using books that he got from the local library. He also managed to get advice from a local back-to-work scheme recommended by the Disability Employment Advisor at the Jobcentre. Martin knew that it was essential that his letter and CV had the maximum impact.

Martin sent his CV and letter off to six employers and then waited about a week before calling them up on the ‘phone. He asked to speak to the person he had written to but if the person on the switchboard asked the reason for his call he simply said that he was calling to follow up a letter he had written.

After approaching about 20 employers in this way he finally found one who said there could be an opening for work experience in a couple of months time. So over the next three months Martin kept in touch with the company by ‘phone once a month just to let them know that he was still keen on coming to work for them.

The interview

Finally the company asked him in for an interview. Before going to the interview Martin prepared really well in advance by researching the company well and trying to anticipate the sorts of questions he would be asked. He also went to the local library and took out some books on interview techniques and managed to get on a one day course on interview skills that the Jobcentre had told him about. This included a mock interview which he found particularly useful.

The day of the interview arrived and Martin was very nervous but he was up early and washed and dressed. To be sure of being on time he left an hour early and checked out the location of the office. Then he went to Starbucks for a coffee while he waited. This gave him an opportunity to flick through his notes and prepare on some of the answers he had been working on. He made sure that he was punctual and well groomed and did his best to present himself well at the interview.

Despite being really well prepared walking through the front door of the office was one of the hardest things that he had done for years. But the receptionist was polite and could not have been more helpful. She made him feel welcome and even offered him a coffee (which he declined).

The Human Resources Manager who interviewed Martin was very professional but quickly put him at his ease. He asked questions about his education at school, his hobbies and pastimes and his qualifications and then came the bit that Martin had been dreading when the HR Manager asked him why he had dropped out of college. Martin explained that he had had a breakdown caused by too much stress while he was at college. He went on to explain that although it was a bad breakdown it was behind him now and that with the help of his family and friends and his doctor he had been able to make a really strong recovery. He also explained that in some ways the experience had made him a stronger person and that he had matured as a result of it.

As the end of the interview approached Martin was sure that he had flunked it but the interviewer told him that he had been successful and asked him to start on Monday. Martin was delighted to be offered a period of three months unpaid work experience during which he would work for two days a week at their local office doing clerical and administrative work.

Martin was walking on air when he left the office. All his hard work had been worth it.

The next day Martin called the Disability Employment Advisor at the local Jobcentre to tell them about the offer and see how his benefits would be affected. She confirmed that his benefits wouldn’t be affected as long as he only worked for 16 hours a week.

The placement

For the next three months Martin worked hard at his placement. He made sure that he got all the basics right: being punctual and well groomed every day. At work he was helpful and got on well with the other workers. Although he was very shy at first he soon learned the importance of making small talk with his colleagues and building good working relationships.

As the end of his placement approached Martin wondered if he would be offered a permanent position. He asked the HR Manager about this but sadly he was told that there were no permanent vacancies at that time so when the end of his placement came Martin had mixed feelings. On the one hand he was disappointed that the work experience had not turned into a permanent job but on the other hand he had had three months experience in the workplace and had something to put on his CV to demonstrate to other employers that he could work. And most importantly he had that all important reference from a well respected local employer.

But that isn’t quite the end of the story. Martin continued searching for a job without success for another six months but continued to keep in touch with the HR Manager he had worked for during his work experience. One day he saw in the local press that they were advertising for a clerical assistant so he called them and explained that he was still jobsearching and would be available for this position. The HR Manager was very pleased to hear from him and said that he would call him back. The next day Martin got a call asking him to go in for an interview straight away and was offered the job.

Martin called the Jobcentre Plus helpline and found out what benefits he would be entitled to while he was working and was pleased to find out that he would be better off in work.

Martin has now been employed in his new job for two years and is delighted to be living an independent lifestyle free of the benefits culture he was in before. It has had its difficulties though. For instance Martin found that his illness had left him emotionally very sensitive and that he found it difficult to cope if his work was criticised. But he knew that this was something he had to learn to live with and gradually he managed to learn new social skills that helped him to cope better and at the same time helped him in other areas of his life.

Martin has enjoyed the structure that the new job has brought to his life. He enjoys the work and the social contact that the job entails. He has made new friends and above all his self-esteem has grown vastly. Now when people ask him what he does for a living he no longer has to say that he is unemployed.

Some Key Points from Martin’s Story:

• Research the local job market really well
• Before writing to a firm call to check the postal address.
• Find out the name of the person in charge of recruitment. Writing to a named person makes sure your letter gets read.
• You can’t spend enough time preparing your CV and cover letter. Get as much help as you can from books, the library etc.
• When making follow up calls avoid Mondays and Fridays as these are busy days for people in business. Similarly don’t call too early in the morning or after 3.30 pm and don’t call around lunchtime.
• When making follow up calls be prepared for few false starts but use these to develop your technique. Treat the first half a dozen calls as practice calls.
• Don’t pester firms with too frequent follow up calls. Once every three weeks is about right.
• Be prepared for disappointment and don’t feel let down by it.
• Before going for an interview research the firm really well. Google and Google News and the local press are useful sources.
• It is perfectly normal to be nervous at an interview. Try to minimise the nerves by making sure you have planned and prepared well and getting a good night’s sleep beforehand.
• At the interview you may be asked about your illness. Be honest but there is no need to disclose your diagnosis at this stage unless you are asked directly: a broad brush explanation such as “a breakdown” is sufficient.

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Case Study Illustrates How Schizophrenia Can Often Be Overdiagnosed

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Study shows how schizophrenia can often be over diagnosed. Learn how. Click to Tweet

Study author Russell Margolis, director of the Johns Hopkins Schizophrenia Center, answers questions on misdiagnosis of the condition and reiterates the importance of thorough examination.

It’s not uncommon for an adolescent or young adult who reports hearing voices or seeing things to be diagnosed with schizophrenia, but using these reports alone can contribute to the disease being overdiagnosed, says  Russell Margolis , clinical director of the Johns Hopkins Schizophrenia Center. 

Many clinicians consider hallucinations as the sine qua non, or essential condition, of schizophrenia, he says. But even a true hallucination might be part of any number of disorders — or even within the range of normal. To diagnose a patient properly, he says, “There’s no substitute for taking time with patients and others who know them well. Trying to [diagnose] this in a compressed, shortcut kind of way leads to error.”

A case study he shared recently in the  Journal of Psychiatric Practice  illustrates the problem. Margolis, along with colleagues Krista Baker, schizophrenia supervisor at Johns Hopkins Bayview Medical Center, visiting resident Bianca Camerini, and Brazilian psychiatrist Ary Gadelha, described a 16-year-old girl who was referred to the Early Psychosis Intervention Clinic at Johns Hopkins Bayview for a second opinion concerning the diagnosis and treatment of suspected schizophrenia.

The patient made friends easily but had some academic difficulties. Returning to school in eighth grade after a period of home schooling, she was bullied, sexually groped and received texted death threats. She then began to complain of visions of a boy who harassed her, as well as three tall demons. The visions waxed and waned in relation to stress at school. The Johns Hopkins consultants determined that this girl did not have schizophrenia (or any other psychotic disorder), but that she had anxiety. They recommended psychotherapy and viewing herself as a healthy, competent person, instead of a sick one. A year later, the girl reported doing well: She was off medications and no longer complained of these visions.

Margolis answers  Hopkins Brain Wise ’s questions.

Q: How are anxiety disorders mistaken for schizophrenia?

A:  Patients often say they have hallucinations, but that doesn’t always mean they’re experiencing a true hallucination. What they may mean is that they have very vivid, distressing thoughts — in part because hallucinations have become a common way of talking about distress, and partly because they may have no other vocabulary with which to describe their experience. 

Then, even if it  is  a true hallucination, there are features of the way psychiatry has come to be practiced that cause difficulties. Electronic medical records are often designed with questionnaires that have yes or no answers. Sometimes, whether the patient has hallucinations is murky, or  possible —  not yes or no. Also, one can’t make a diagnosis based just on a hallucination; the diagnosis of disorders like schizophrenia is based on a constellation of symptoms. 

Q: How often are patients in this age range misdiagnosed?

A:  There’s no true way to know the numbers. Among a very select group of people in our consultation clinic where questions have been raised, about half who were referred to us and said to have schizophrenia or a related disorder did not. That is not generalizable.

Q:   Why does that happen?

A:  There is a lack of attention to the context of symptoms and other details, and there’s also a tendency to take patients literally. If a patient complains about x, there’s sometimes a pressure to directly address x. In fact, that’s not appropriate medicine. It is very important to pay attention to a patient’s stated concerns, but to place these concerns in the bigger picture. Clinicians can go too far in accepting at face value something that needs more exploration. 

Q: What lessons do you hope to impart by publishing this case?

A:  I want it to be understood that the diagnosis of schizophrenia has to be made with care. Clinicians need to take the necessary time and obtain the necessary information so that they’re not led astray. Eventually, we would like to have more objective measures for defining our disorders so that we do not need to rely totally on a clinical evaluation. 

Learn more about Russell Margolis’ research regarding the challenges of diagnosing schizophrenia .

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• Open access
• Published: 27 April 2024

The burden of schizophrenia in the Middle East and North Africa region, 1990–2019

• Saeid Safiri 1 , 2 ,
• Maryam Noori 3 ,
• Seyed Aria Nejadghaderi 4 , 5 ,
• Ali Shamekh 6 ,
• Mark J. M. Sullman 7 , 8 ,
• Gary S. Collins 9 , 10 &
• Ali-Asghar Kolahi 11  

Scientific Reports volume  14 , Article number:  9720 ( 2024 ) Cite this article

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• Epidemiology
• Schizophrenia

Schizophrenia ranks as the third-most common cause of disability among mental disorders globally. This study presents findings on the prevalence, incidence and years lived with disability (YLDs) as a result of schizophrenia in the Middle East and North Africa (MENA), stratified by age, sex and sociodemographic index (SDI). We collected publicly accessible data from the Global Burden of Disease (GBD) study 2019. This study reports the burden of schizophrenia, from 1990 to 2019, for the 21 countries that comprise MENA. In 2019, MENA exhibited an age-standardised point prevalence of 248.2, an incidence rate of 14.7 and an YLD rate of 158.7 per 100,000, which have not changed substantially between 1990 and 2019. In 2019, the age-standardised YLD rate was highest in Qatar and lowest in Afghanistan. No MENA countries demonstrated noteworthy changes in the burden of schizophrenia from 1990 to 2019. Furthermore, in 2019, the highest number of prevalent cases and the point prevalence were observed among those aged 35–39, with a higher prevalence among males in almost all age categories. Additionally, in 2019, the age-standardised YLD rates in MENA were below the worldwide average. Finally, there was a positive correlation between the burden of schizophrenia and the SDI from 1990 to 2019. The disease burden of schizophrenia has remained relatively stable over the past thirty years. Nevertheless, as the regional life-expectancy continues to increase, the burden of schizophrenia is also expected to rise. Therefore, early planning for the increase in the burden of the disease is urgently needed in the region.

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Introduction.

Schizophrenia is defined as a cognitive and behavioral disorder that affects early brain development and manifests itself through several psychotic symptoms, including hallucinations, delusions, and disorganised behavior and speech 1 . The prognosis for patients with schizophrenia can vary from making a full recovery to a lifelong need for care, and patients typically have a life expectancy which is roughly twenty years less than that of the general population 1 , 2 . Psychiatric symptoms typically first appear during late adolescence or early adulthood, and suicidal behaviors are the most frequent cause of death early in the course of the disease 3 . Schizophrenia has also been linked to several comorbid conditions, which is partially as a result of the high prevalence of drug abuse and cigarette smoking, unhealthy lifestyles, and the potential impact of anti-psychotic medications on promoting obesity. These conditions predispose the patients to a higher rate of metabolic syndrome, diabetes, cardiovascular disorders, and respiratory diseases 4 , 5 .

In 2019, schizophrenia was the 42nd leading cause of disability among people of all ages and the 22nd among individuals aged 25–49 years old 6 , 7 . The lifetime prevalence of schizophrenia has been estimated to be just below 1% 8 . In 2019, the global age-standardised prevalence of schizophrenia was 287.4 per 100,000, and this rate was approximately the same as in 1990 6 . Also in 2019, schizophrenia accounted for 12.1% of all disability-adjusted-life-years (DALYs) attributable to mental disorders, and was surpassed only by depressive (37.4%) and anxiety (22.9%) disorders 6 . The highest incidence of schizophrenia was found in those aged 20–24, with no significant sex-based differences in the incidence rate 9 .

Several reports have been published in recent years discussing mental disorders, and more specifically the burden of schizophrenia at the regional level and across the world 6 , 9 , 10 , 11 , 12 , 13 . However, none of these articles have exclusively focused on the attributable burden of schizophrenia in the Middle East and North Africa (MENA) region. The countries located in MENA vary considerably in terms of socioeconomic profile, health system coverage and capacities, and healthcare infrastructures and provisions 14 , 15 . During the past three decades, the MENA region has witnessed several enhancements in health outcomes, resulting in rising life expectancies and decreased neonatal mortality 16 . Consequently, in parallel with increasing longevity, it is expected that the prevalence of chronic conditions, such as mental disorders, will continue to grow in MENA. Furthermore, as a stigmatized disease, schizophrenia is often overlooked among affected patients, especially in developing countries. Moreover, as the socioeconomic status of a country decreases the stigma of mental disorders increases, potentially leading to an underestimation of the burden of schizophrenia in lower socio-economic countries. Therefore, investigating the epidemiology of schizophrenia in the MENA region is of paramount interest 17 . Consequently, this study utilized data from the Global Burden of Disease (GBD) study 2019 to present the burden of schizophrenia in MENA from 1990 to 2019, stratified by sex, age and socio-demographic index (SDI).

The Global Burden of Disease (GBD) study, which was established by the Institute of Health Metrics and Evaluation (IHME), measures the burden of diseases and injuries in over 200 countries and territories. Although schizophrenia is a relatively common mental problem, its burden has not been quantified across all global regions. Therefore, this study presents an assessment of the burden of schizophrenia from 1990 to 2019 for all countries in MENA. There are 21 countries in MENA, which are: Afghanistan, Algeria, Bahrain, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Sudan, the Syrian Arab Republic, Tunisia, Turkey, the United Arab Emirates and Yemen. A full description of the methodology utilised by IHME to model the burden of disease has been previously described 7 , 16 , 18 . The GBD 2019 estimates, which cover the period 1990–2019, are available at the following links: http://ghdx.healthdata.org/gbd-results-tool and https://vizhub.healthdata.org/gbd-compare/ .

Case definition and data sources

Schizophrenia is a serious mental disorder which is characterised by a large number of symptoms, including: delusions, hallucinations, diminished interest, flat affect, thought disorders, and emotional withdrawal. The GBD disease modelling process only included data from studies that diagnosed schizophrenia using either the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria (DSM-IV-TR: 295.10-295.30, 295.60, 295.90) or the International Classification of Diseases (ICD) criteria (ICD 10: F20). The diagnostic criteria encompass the following key elements: (1) Presence of at least two of the following symptoms, each enduring for a substantial part of a one-month period (a shorter duration if effectively treated): (i) Delusions, (ii) Hallucinations, (iii) Disorganised speech (e.g., frequent incoherence or derailment), (iv) Markedly disorganised or catatonic behavior, (v) Negative symptoms (i.e., affective flattening, alogia, or avolition); (2) Dysfunction at work and socially; (3) Persistence of the disorder’s signs and symptoms for a duration of six months or more; (4) Exclusions included substance abuse, schizoaffective and mood disorders, and/or general medical conditions, as well as any connection to pervasive developmental disorders 7 .

IHME conducted a systematic review for schizophrenia, which encompassed searching the scientific literature (i.e., PsycInfo, Embase, and PubMed), examining the grey literature, and consultation with an expert. As part of the GBD project, the electronic databases are searched biennially for mental disorders, including schizophrenia. The last systematic review for schizophrenia was carried out in GBD 2017, with the next review being due in GBD 2020. However, consulting the expert and searching the grey literature produced new data sources in GBD 2019 7 .

The inclusion criteria applied were as follows: (1) published after 1980; (2) cases were defined using DSM or ICD criteria; (3) inclusion of sufficient methodological details and sample characteristics for assessing study quality; and (4) samples that represented the general population. Specifically excluded were samples from inpatients or pharmacological treatments, case studies, veterans, or refugee cases. There were no constraints placed on the publication language. The data sources utilised to model the schizophrenia burden are accessible at this website: https://ghdx.healthdata.org/gbd-2019/data-input-sources 7 .

Data processing and disease model

When necessary, the data extraction process involved three different age and sex splitting procedures: (1) The available estimates were divided into specific five-year age groups by sex. For example, in studies which reported the prevalence in broad age ranges separately for males and females (e.g., 15–65 year old men and women individually), and in cases where studies had smaller age groups without sex separation (e.g., prevalence among 15 to 29 year olds, then in 30 to 70 year olds, for both sexes combined), the sex ratios reported and uncertainty ranges were used to divide the age specific estimates by sex. (2) Meta-Regression with Bayesian priors, Regularisation, and Trimming (MR-BRT) was used to split the remaining data. This method involved matching sex-specific estimates for each parameter, according to location, age, and year. MR-BRT regression was then employed to model the pooled sex ratios, along with their associated uncertainty bounds. These pooled sex ratios were then utilised to split the estimates in the dataset. The prevalence ratio between males and females was 1.17 (95% uncertainty interval (UI) 0.60–1.75). 3. For prevalence estimates covering age categories spanning 25 years or more, the age pattern estimated by DisMod-MR 2.1 was used to split the data into five-year age groups. It’s important to note that the DisMod-MR model used for estimating the age pattern did not contain any previously age split data 7 .

IHME utilised DisMod MR 2.1, using the standard GBD 2019 decomposition structure, to estimate the data related to schizophrenia. At each stage of the decomposition process, IHME compared the new model with the best model from GBD 2017 and the best model from the previous stage. If substantial differences were observed between models, these variances were thoroughly explored and elucidated. In cases where it was deemed necessary, adjustments were implemented to the dataset or the model priors. When outliers were identified, they were included or excluded based upon a re-examination of their quality and methodology.

Initially, all epidemiological parameters were integrated into the modelling process. It was believed, based on the literature on schizophrenia and discussion with the expert that no cases of schizophrenia occurred before the age of 10 or after the age of 80. Furthermore, the remission rate was restricted to a maximum of 0.04, in line with the data in the dataset. In areas lacking available data, prevalence estimates were informed by location-level covariates. Only one location-level covariate, lag distributed income (LDI), was utilised to model the prevalence of schizophrenia.

Compilation of results

The two sequelae (acute and residual) of schizophrenia, along with their corresponding disability weights (DWs), can be found in Table S1 . To calculate the years lived with disability (YLDs), the prevalence estimates for each sequela were multiplied by their respective DWs. The YLDs and DALYs were the same, since there was no mortality due to schizophrenia. All estimates were standardised using the GBD standard population. 95% uncertainty intervals (UIs) were included with all estimates and were generated by producing 1000 iterations at each stage of the estimation process. The final estimates represented the mean values over the 1000 iterations, and the 95% UIs were indicated as the 25th and 975th values among the numerically ordered iterations.

Smoothing Spline models 19 was employed to investigate the relationship the socio-demographic index (SDI) has with the burden of schizophrenia. The SDI is a composite model that contains per capita income, mean number of years attending school (aged 15 and above), and the fertility rate in women aged 25 or less. The SDI ranges from 0 to 1, representing the spectrum from the lowest to the highest development level 7 . The estimates for the point prevalence and annual incidence were obtained from the GBD website ( http://ghdx.healthdata.org/gbd-results-tool ) and all visual representations were created with R software (Version 3.5.2).

Ethics approval and consent to participate

The present study was approved by Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.RETECH.REC.1401.387).

The Middle East and North Africa region

In 2019, there were 1.6 million (95% UI: 1.3 to 1.9) prevalent cases of schizophrenia. In addition, the age-standardised point prevalence was 248.2 (203.9 to 294.9) per 100,000, which has hardly changed since 1990 [0.5% (-1.2 to 2.0)] (Tables 1 and S2 ). There were 97.7 thousand (79.8 to 119.7) incident cases of schizophrenia in 2019, with an age-standardised rate of 14.7 (12.1 to 17.9) per 100,000, which did not differ from 1990 [− 1% (− 2.7 to 0.7)] (Tables 1 and S3 ). A total of 1.0 million (0.7 to 1.3) YLDs were attributable to schizophrenia in 2019, having an age-standardised rate of 158.7 (113.2 to 207.8) YLDs per 100,000 population. This rate also has not changed since 1990 [0.4% (− 2.2 to 3.1)] (Tables 1 and S4 ).

Country level

The age-standardised point prevalence of schizophrenia varied from 217.8 to 285.0 cases per 100,000 in the region. Qatar [285.0 (225.4 to 351.1)], the United Arab Emirates [275.3 (218.5 to 337.2)] and Kuwait [273.8 (216.4 to 334.0)] were the three highest in 2019. Conversely, Afghanistan [217.8 (176.2 to 266.6)], Yemen [225.7 (180.7 to 273.9)] and Sudan [232.7 (186.1 to 284.0)] were the three lowest (Table S2 ). Figure  1 A presents the age-standardised point prevalence estimates of schizophrenia by country, separately for men and women, in 2019.

Age-standardised point prevalence ( A ), incidence rate ( B ), and YLD rate ( C ) of schizophrenia per 100,000 population in the Middle East and North Africa region in 2019, by sex and country. YLD years lived with disability. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool ).

The age-standardised incidence rate of schizophrenia in 2019 varied from 14.0 to 16.2 cases per 100,000 in the region. Qatar [16.2 (12.9 to 20.3)], the United Arab Emirates [15.7 (12.5 to 19.5)] and Kuwait [15.5 (12.4 to 19.3)] had the highest rates, with the lowest being in Afghanistan [14.0 (11.3 to 17.1)], Yemen [14.2 (11.4 to 17.4)] and Sudan [14.3 (11.7 to 17.7)] (Table S3 ). Figure  1 B presents the age-standardised incidence rates of schizophrenia by country, separately for males and females, in 2019.

The age-standardised YLD rate of schizophrenia in 2019 ranged from 135.6 to 182.5 cases (per 100,000) in the region. Qatar [182.5 (125.7 to 245.0)], the United Arab Emirates [176.5 (123.7 to 235.0)] and Kuwait [175.6 (121.0 to 234.3)] had the highest rates, while Afghanistan [135.6 (96.4 to 180.8)], Yemen [143.3 (100.6 to 191.3)] and Sudan [149.1 (104.2 to 199.5)] were lowest (Table S4 ). Figure  1 C presents the age-standardised YLD rates of schizophrenia by country, separately for males and females, in 2019.

The age-standardised prevalence, incidence and YLD rates of schizophrenia did not change significantly in any MENA countries from 1990 to 2019 (Tables S2 – S4 ). The changes in the age-standardised incidence, prevalence, and YLD rates for each country are depicted in Fig.  2 A–C, broken down by sex, for the period 1990–2019.

The percentage change in the age-standardised point prevalence ( A ), incidence rate ( B ), and YLD rate ( C ) of schizophrenia in the Middle East and North Africa region from 1990 to 2019, by sex and country. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool ).

Age and sex patterns

The total number of prevalent cases and the prevalence estimates in 2019 increased sharply for both sexes, starting from the 10–14 age range, reaching their highest level in those aged 35–39, before decreasing with age (Fig.  3 A). Similarly, the number of incidence cases and the incidence rates began to rise from the 10–14 age range, for both sexes, were highest in the 20–24 age range and then declined with age (Fig.  3 B). Furthermore, the YLD numbers rose with increasing age in both sex groups and peaked in those aged 30–34 years old, and then reduced with age. The pattern was similar for the YLD rate, but in both sexes the highest rate was seen in those aged 35–39 years old (Fig.  3 C). Males had a higher prevalence, incidence and YLD cases in all age categories. Likewise, males had higher prevalence, incidence and YLD rates of schizophrenia up to 80–84 years old, while the prevalence and YLD rates were higher for females in all remaining age groups.

Numbers of prevalent cases and point prevalence per 100,000 population ( A ), number of incidence cases and incidence rate per 100,000 population ( B ) and the number of YLDs and YLD rate per 100,000 population ( C ) for schizophrenia in the Middle East and North Africa region, by age and sex in 2019; Dotted and dashed lines indicate 95% upper and lower uncertainty intervals, respectively. YLD years lived with disability. (Generated from data available from  http://ghdx.healthdata.org/gbd-results-tool ).

The schizophrenia associated YLD rates in 2019 were below the global rates for both sexes over 20 years of age (ratio of MENA/global YLD rate < 1). For both sexes, people aged 10–19 years of age exhibited YLD rates that were close to the global rate (ratio of MENA/global YLD rate = 1). The YLD rate in females aged 80 and older was 0.7 times the global rate in 2019. Furthermore, in 2019 males had similar YLD ratios (ratio of MENA/global YKD rate = 1), to those in 1990, in most age groups except for 15–19, 40–44 and 95 + years old, which had higher ratios than in 1990. Similarly, in 2019 the YLD ratios (ratio of MENA/global YLD rate = 1) for females increased in the 15–19, 75–79 and older than 90 age-groups, compared to 1990, while all other age-groups had similar rates (Fig.  4 ).

Ratio of the Middle East and North Africa region to the global schizophrenia YLD rate by age and sex, 1990 and 2019. YLD years lived with disability. (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool ).

Relationship with socio-demographic index (SDI)

An almost linear positive association was evident between SDI and the YLD rate of schizophrenia between 1990 and 2019. In general, countries located within the region exhibited a steady rise in YLD rates, from 1990 to 2019, with increases in their SDIs. Qatar was the only country that had actual rates that were higher than those expected from 1990 to 2019, while all other countries had rates below the expected level (Fig.  5 ).

Age-standardised YLD rates of schizophrenia for 21 countries and territories, by SDI during 1990–2019; Expected values based on the Socio-demographic Index and disease rates in all locations are shown as the black line. Each point shows the observed age-standardised YLD rate for each country during 1990–2019. YLD years lived with disability, SDI Socio-demographic Index (Generated from data available from http://ghdx.healthdata.org/gbd-results-tool ).

This article presents an analysis of the burden of schizophrenia in MENA, encompassing the prevalence, incidence, and YLDs, using the most recent GBD 2019 data. This study is the first to present current information on the regional and national burden of schizophrenia in the MENA region. Previous studies were either been restricted to an individual country or investigated multiple causes with limited epidemiological data.

According to the latest research on the global burden of mental diseases, schizophrenia affects far fewer patients than several other mental conditions, but the YLDs attributable to this disorder are amongst the highest of these conditions 6 . Schizophrenia presents with a wide range of clinical symptoms and signs, and also varies greatly in the severity level. Schizophrenia requires lifelong treatment, which is demanding for both the patients and their families. Furthermore, some patients may develop resistance to conventional therapies, as their condition exacerbates with more frequent relapses 20 . These patients are also at a higher risk of suicide attempts and assault, further impacting the patient, their family, and their caregivers 21 , 22 . Due to economic crises, rapid population growth, a shortage of healthcare staff, weak coverage, political issues, and the stigmatizing attitudes of the general population against mental illnesses, many of the healthcare systems in the MENA region are yet to reach their full potential and provide acceptable standards of care. As a result, mismanagement, misdiagnosis, or missed cases might commonly occur 23 . Thus, the true burden of schizophrenia and the disability it imposes is expected to be far higher than the estimates reported here. Drug abuse, alcoholism, and smoking are common in schizophrenic patients, which can lead to comorbidities such as malnutrition, diabetes, vascular events, blood-borne infections, and chronic obstructive pulmonary disease (COPD), causing additional disability and mortality 24 . Although these comorbidities have a global importance, the impact is even larger in economically troubled healthcare systems, which is the situation in many MENA countries. Taken together, to alleviate the burden of schizophrenia, there is an urgent need for a plan to solve the widening socioeconomic disparities and implement measures to reduce the stigma associated with schizophrenia as soon as possible.

In line with the global trend for schizophrenia, the age-standardised prevalence, incidence, and YLDs in the region did not vary significantly between 1990 and 2019 6 . In general, countries which had higher age-standardised prevalence also had higher age-standardized incidence, and YLDs (i.e., Qatar, United Arab Emirates, and Kuwait). This same pattern was also the case for the countries which showed the lowest rates (i.e. Afghanistan, Yemen, and Sudan). Moreover, schizophrenia is linked to decreased fertility in both sexes, with males experiencing a more pronounced impact 25 . This can be attributed to the behavioral and social characteristics associated with schizophrenia. It is anticipated that decreased fertility will increase due to the ongoing delayed marriage patterns, even though the age of onset for schizophrenia will remain unchanged 26 . Natural selection is expected to reduce the population frequencies of genes associated with reduced fertility. Nonetheless, the prevalence of schizophrenia continues to be high, not only in the MENA region but also globally, with the frequency of the disease showing no significant change in recent decades 27 . This is commonly known as a "Darwinian paradox" 26 . Multiple hypotheses have been proposed to explain how schizophrenia evades the influence of natural selection, but the exact mechanism remains an enigma 28 , 29 , 30 . A plausible explanation for the unchanged prevalence of schizophrenia, despite its association with decreased fertility, is that the genetic factors contributing to schizophrenia may also confer advantages related to the development of essential human characteristics, including language, complex cognitive skills, and other favorable brain functions 31 . This hypothesis is substantiated by the presence of enhanced recent evolutionary markers near the loci linked to schizophrenia 31 , 32 . However, the evolutionary puzzle of schizophrenia remains complex and requires further research to be fully understood.

As illustrated in Fig.  2 A–C, the highest incidence of schizophrenia was observed in the 15 to 39 age group, and the disease’s prevalence peaked among those aged 20 to 54 years old, after which it gradually decreased with increasing age. The peak incidence starts earlier in life (20 to 24 age group) and the prevalence peaks in the 35 to 39 age group, and then reduces with age. This pattern was also seen for the YLD rates. The presented data emphasises the need for screening and intervention before the peak ages in the incidence, and also underlines the increased need for social, mental, and healthcare support during the peaks in the prevalence and YLDs. As the disease gets more chronic, and particularly when accompanied by more frequent relapses (either due to the nature of the disease or by mismanagement), more YLDs are observed and thus more access to medical care and social support is required to prevent treatment resistant conditions and worse outcomes, such as suicide, overdose, or domestic violence 33 . In almost all age groups, men showed higher prevalence, incidence and YLD values and rates, but these differences were not statistically significant. The changes in incidence, prevalence, and YLDs observed in both sexes generally show a decrease from 1990 to 2019 in most countries. Interestingly, the percentage changes in the incidence were negative in all MENA countries. Nevertheless, none of the changes were statistically significant, and thus should be carefully interpreted with regards to future planning and policy making.

The MENA YLD rates were below those found globally for all age groups, with the exception of those aged 10 to 19 year olds. This can be explained through the vast medical and non-medical problems faced by most countries in MENA. The burden of communicable diseases are substantially higher in MENA, than globally, and thus chronic conditions such as mental disorders might not receive the appropriate priority level for their management and treatment 34 . Furthermore, the burden of schizophrenia remained unchanged from 1990 to 2019 in most age groups, except for the elderly ages, which have increased.

As displayed in Fig.  4 , SDI has a positive linear relationship with the age-standardised YLD rate in MENA. These results should be carefully interpreted as there are major gaps between the countries showing the lowest values and those with the highest. Countries such as Afghanistan, Yemen, and Sudan were embroiled in prolonged conflicts during much of the measurement period, and their healthcare systems have been severely affected by their unbalanced economies and political problems 35 , 36 . Consequently, the low burden of schizophrenia in these countries is likely to be highly biased and artificially underestimated. In contrast, economically stable and high-income countries in this region have shown a higher burden of schizophrenia, which can be attributed to their more efficient healthcare systems and screening strategies. An alternative explanation for this finding might be that the high level of urbanisation and high density housing in the high income countries is related to the higher incidence of schizophrenia, due to elevated levels of stress and pollution in these areas 37 , 38 . While GBD continues to improve on the data and methodologies for estimating the burden of mental disorders, including schizophrenia, several challenges need acknowledging. Firstly, there were a large number of locations without high-quality raw data. Secondly, quantifying and eliminating all variation caused by measurement error in our prevalence estimates is a challenging task. Although IHME has refined the methodology to address known sources of bias (e.g., case definitions or survey methods), there are still very few data points available to inform such adjustments. Additionally, there is a paucity of research on the risk factors of mental disorders which can be used as predictive covariates in our epidemiological models 39 .

The present article highlights the importance of cautiously interpreting the currently available epidemiological information on the burden of schizophrenia in MENA, since the gathered data are prone to several biases. Thus, presumably the low burden of this condition might increase substantially in the future, as the healthcare systems start to screen and identify more patients. The most important aspect in preventing any future rise in the burden of schizophrenia lies in the efficient screening and prompt identification of patients, and then effectively treating these patients using a holistic approach. By reducing the prevalence of this mental condition, the burden of its related comorbidities and problems will also be addressed, significantly contributing to the overall health of the communities and the countries. Finally, it is important not to underestimate the significance of stigma directed towards people with psychiatric disorders. Initiatives aimed at increasing awareness about schizophrenia among patients, their families and their social networks can contribute significantly to reducing the disability associated with the disease.

Data availability

The data used for these analyses are all publicly available at http://ghdx.healthdata.org/gbd-results-tool .

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Acknowledgements

We would like to thank the Institute for Health Metrics and Evaluation staff and its collaborators who prepared these publicly available data. We would also like to thank the Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran for their assistance in this research.

The Bill and Melinda Gates Foundation, who were not involved in any way in the preparation of this manuscript, funded the GBD study. The Shahid Beheshti University of Medical Sciences, Tabriz, Iran (Grant No. 43002510) also supported the present report.

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Saeid Safiri

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Maryam Noori

HIV/STI Surveillance Research Center, WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran

Seyed Aria Nejadghaderi

Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

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Centre for Statistics in Medicine, NDORMS, Botnar Research Centre, University of Oxford, Oxford, UK

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SS and AAK designed the study. SS analysed the data and performed the statistical analyses. SS, MN, SAN, AS, MJMS, GSC, and AAK drafted the initial manuscript. All authors reviewed the drafted manuscript for critical content. All authors approved the final version of the manuscript.

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Safiri, S., Noori, M., Nejadghaderi, S. et al. The burden of schizophrenia in the Middle East and North Africa region, 1990–2019. Sci Rep 14 , 9720 (2024). https://doi.org/10.1038/s41598-024-59905-8

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Clinical pearl i – pharmacokinetics, clinical pearl ii – clozapine and agranulocytosis, clinical pearl iii – hyperprolactinemia and associated complications, case based clinical pearls: a schizophrenic case study.

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O. Greg Deardorff , Stephanie A. Burton; Case Based Clinical Pearls: A schizophrenic case study. Mental Health Clinician 1 February 2012; 1 (8): 191–195. doi: https://doi.org/10.9740/mhc.n95632

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Clinical pearls based on the treatment of a patient with schizophrenia who had stabbed a taxi cab driver are discussed in this case study. Areas explored include the pharmacokinetics of fluphenazine decanoate, strategies to manage clozapine-associated agranulocytosis, and approaches to addressing hyperprolactinemia.

Forensic psychiatry is a subspecialty in the field of psychiatry in which medicine and law collide. Practiced in many facilities such as hospitals, correctional institutions, private offices and courts, forensic psychiatry requires the cooperation of health care and legal professionals with the common goal of helping patients become competent of their legal charges and returning to a productive life in the community. In contrast to general psychiatric patients, the clients in this field have been referred through court systems instead of general practitioners and are evaluated not only for their symptoms but also their level of responsibility for their actions.

These patients can be some of the most challenging to treat because of factors such as non-compliance, an extensive history of failed medication trials, and the severity of their mental illness. Some of the most severe mentally ill patients reside in forensic psychiatric hospitals and have spent much of their lives institutionalized. Treatment refractory schizophrenia, defined as persistent psychotic symptoms after failing two adequate trials of antipsychotics, is a common occurrence in forensic psychiatric hospitals and often requires extensive manipulation of medication regimens to obtain a desired therapeutic response. Like other patients, these patients may present with barriers to using the most effective treatment such as agranulocytosis, inability to obtain and maintain therapeutic drug levels due to fast metabolism, or bothersome adverse effects such as hyperprolactinemia. In treatment resistant patients, it may still be necessary to use these medications even when barriers are present due to a lack of alternative therapeutic options not previously exhausted. In addition to complex regimens, treatment plans for these patients often require trials of multiple medication combinations or unique exploitation of interactions and biological phenomena.

We report a forensic case study that exemplifies multiple clinical pearls that may be useful in patients with treatment refractory schizophrenia. A 31-year-old African American female presented to the emergency room escorted by law enforcement after stabbing a cab driver with a pencil. The patient stated she was raped by the cab driver and while in the emergency room stated that “dirty cops brought me here.” She was admitted to the inpatient psychiatric unit to determine competency to stand trial for the assault of the cab driver. She had been in many previous correctional institutions with a known history of schizophrenia and additional diagnoses of amenorrhea, hyperprolactinemia, and obesity.

The patient's history was significant for auditory hallucinations and paranoid delusions beginning by age fourteen with a diagnosis of major depression with psychotic features. By age eighteen, she was diagnosed with schizophrenia, paranoid type. She had multiple previous hospitalizations and a history of poor compliance as an outpatient. There was no known history of tobacco, alcohol, or illicit drug use. Her family history was significant for schizophrenia, diabetes mellitus, and drug use. The patient reported abusive behavior by her grandmother, who was her primary caretaker as a child.

During hospitalization, the patient continued to report sexual assaults, accusing both patients and staff of rape, and declined to participate in groups. She denied any visual or auditory hallucinations but continued to exhibit paranoid delusions. The patient was later found to be permanently incompetent to stand trial and was committed to the state's department of mental health for long term treatment of her psychiatric illness.

The patient was previously treated with fluphenazine decanoate intermittently for two years with difficulty obtaining the desired therapeutic response. After approximately two months of therapy, the patient presumably at steady state (~14 day half-life) still failed to demonstrate any clinical response. There is no conclusive evidence that fluphenazine levels correlate with clinical outcomes, however the psychiatrist had worked with this patient in the past and felt the lack of response in this situation justified a fluphenazine level. 1 The fluphenazine level was shown to be 2.2ng/ml (therapeutic range 0.5–3 ng/ml) while taking fluphenazine decanoate 50mg intramuscularly (IM) every two weeks. Increasing the target drug level to the upper edge of the normal range was warranted in this patient due to the persistent positive symptoms and a desire to continue using a long-acting injectable agent, which can ensure the delivery of medication in uncooperative and noncompliant patients. Fluphenazine is a high potency first generation antipsychotic that can improve positive symptoms of schizophrenia; however it is not effective in treating the negative symptoms. It was decided that the addition of a CYP2D6 inhibitor such as fluoxetine would not only provide increased levels of fluphenazine, but would also improve the patient's negative symptoms such as flat affect, anhedonia, social isolation and amotivation. 2 Thus, fluoxetine was given as 20 mg orally (PO) daily resulting in an increase of the fluphenazine level by 0.9 ng/ml (40%) after twenty two days of therapy to 3.1 ng/ml. One month later the fluphenazine decanoate dose was increased to 125 mg IM every two weeks (max 100mg/dose), with continued fluoxetine treatment, resulting in a supratherapeutic level of 3.6 ng/ml. Positive and negative symptoms only showed minor improvement. A 6-week study by Goff, et al. demonstrated an increase of up to 65% in fluphenazine serum concentrations in patients administered concomitant fluoxetine 20 mg/day. 2 In this case, the addition of fluoxetine safely and effectively elevated fluphenazine blood levels. Addition of an inhibitor may be beneficial in patients who are CYP2D6 ultra-rapid metabolizers, as was suspected in this patient.

Many complications, including prolonged jail time, can arise from forensic clients being non-compliant with their medications, which is the reason long acting injectables are often warranted. Our patient had a history of non-compliance and continued to experience positive symptoms despite treatment with fluphenazine. Therefore, the decision was made to try another long-acting antipsychotic injection. After reviewing the patient's chart, it was noted that a previous trial of oral haloperidol 30mg/day showed moderate improvement. Thus, after tolerability and efficacy was determined with oral haloperidol the patient was converted to haloperidol decanoate 300 mg (10–15 x oral daily dose of haloperidol) administered every three weeks beginning two weeks after discontinuation of fluphenazine decanoate 125 mg IM every two weeks. Fluphenazine levels approximately six weeks after its discontinuation (and two weeks after the discontinuation of fluoxetine 20 mg PO daily) were still supratherapeutic. Given that this patient had a fluphenazine level of 3.6 ng/ml near the time of haloperidol decanoate administration, it would be questionable whether another high potency antipsychotic would be of any additional benefit in comparison to the increased risk of extrapyramidal side effects (EPS). Data provided in one study showed fluphenazine decanoate as being detectable for up to 48 weeks after discontinuation. 3 Because fluphenazine decanoate can be detected for such an extended period of time, it leaves the patient at a continued risk for extrapyramidal side effects, especially if another antipsychotic is added shortly thereafter. In the forensic population, many patients have treatment refractory schizophrenia and the use of antipsychotics will need to be life-long. It is often common for these patients to be on multiple concurrent agents, increasing the risk for developing long-term extrapyramidal side effects. Therefore, it is important to minimize the risk of these symptoms whenever possible.

Despite supratherapeutic levels of fluphenazine, the psychiatrist felt it would be beneficial to continue haloperidol decanoate 300 mg every three weeks with increased monitoring for signs and symptoms of EPS.

During the current admission the patient continued to exhibit paranoid behavior and lack of insight, expressed anger, and disliked attending or participating in groups. Her medication history included haloperidol, fluphenazine, quetiapine, aripiprazole, asenapine, olanzapine, paliperidone, and sixteen days of clozapine therapy before leukopenia warranted discontinuation. Due to her extensive history of failed antipsychotics and the known superior effectiveness of clozapine, this patient was an ideal candidate for clozapine therapy. Additionally, because of the poor quality of life a declaration of incompetency would lead to, using the most effective possible agent is an important priority in forensic patients. Clozapine is the most effective antipsychotic based on the U.S. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the UK Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS). 4 , 5 In regards to the significant blood draws and monitoring that is continuously required, clozapine can be a challenging medication to use in treatment refractory patients.

One strategy we are currently working on in our hospital to help increase the number of patients on clozapine is using a point of care (POC) lab device which will allow a complete blood count (CBC) plus 5-part differential to be completed by finger stick, instead of weekly blood draws that our nurses, physicians and, especially, patients dislike. The cost of the POC lab device is approximately $20,000, although upon completion of a cost analysis it was found that five CBCs per day would pay for the cost of the machine after one year. Many times, these patients can become irritated and violent when having their blood drawn, especially, if on a consistent basis. Repetitive blood draws was noted by our physicians to be the largest obstacle in using clozapine in our treatment refractory patients.

Our primary challenge in using clozapine for this patient was finding a way to maintain the absolute neutrophil count (ANC) within acceptable limits (≥1500mm 3 ), which is not uncommon for many patients. The Clozaril Patient Monitoring Services revealed 0.4% of patients had pre-treatment white blood cell counts (WBC) too low to allow initiation of clozapine. Of these patients, 75% were of African or African-Caribbean descent, likely due to the increased leukocyte marginalization that has been shown to be more prominent in these populations. 6 Of all neutrophils in the body, 90% reside in the bone marrow and the remainder circulates freely in the blood or deposit next to vessel walls (margination). The addition of lithium has been shown to increase neutrophil counts by 2000/mm 3 through demarginalization of leukocytes. 7 This increase is not dose –related but may require a minimum lithium level of 0.4 mmol/L. 8 , 9 Lithium therapy used to increase neutrophil counts may be especially effective in patients of African or African-Caribbean descent due to demarginalization of leukocytes. In this patient case, lithium 300 mg by mouth three times daily was initiated for fifteen days to increase the absolute neutrophil count from 1200/mm 3 to ≥ 1500/mm 3 for continuation of clozapine while the white blood cells continued to stay within appropriate limits of ≥3000/mm 3 . It was soon realized that lithium was being cheeked, so liquid form was given, but discontinued after the patient continued to spit the medication out. Unfortunately, clozapine was discontinued thereafter as a result of noncompliance with the lithium causing failure to maintain appropriate white blood cell counts.

Another possible strategy for obtaining appropriate WBC and ANC levels that would enable clozapine continuation is to obtain blood samples later in the day. A study recently published compared the same set of patients having early morning blood draws to blood draws taken later in the day (mean sampling time - pre/post was 5 hours 24 minutes). 10 They showed a difference in the pre/post time change in WBC values being marginally significant (mean increase=667/mm 3 , p=.07), with a significant difference (mean increase=1,130/mm 3 , p=.003) between the pre/post time change in ANC values. ANC values were impacted to a greater extent by the time change than WBC values in this sample. Changing the time at which blood draws are taken during the day may allow for clozapine continuation by limiting the risk of pseudoneutropenia, however it remains the clinician's responsibility to discern between benign or malignant neutropenia. 10 It is recommended, for patients with WBC values trending down or below the predefined criteria, to have labs redrawn several hours after the morning lab before clozapine therapy is discontinued. 10 In this case study, obtaining the sample later in the day may have allowed our patient to continue clozapine therapy.

The patient in this case had additional diagnoses of amenorrhea and hyperprolactinemia. The diagnosis of amenorrhea prompted clinicians to obtain labs showing a prolactin level of 168.8 ng/ml (normal ranges: 3–20ng/ml for men; 4–25ng/ml for non-pregnant women; 30–400ng/ml for pregnant women). Lab monitoring of prolactin levels is not necessary if the patient is not exhibiting symptoms such as disturbances in the menstrual cycle, galactorrhea, gynecomastia, retrograde ejaculation, impotence, oligospermia, short luteal phase syndrome, diminished libido or hirsutism. Monitoring guidelines published in 2004 by APA recommend screening for symptoms of hyperprolactinemia at each visit for the first year and then yearly thereafter. Mt. Sinai Conference Physical Health Monitoring Guidelines for Antipsychotics published in 2004 recommended monitoring at every visit for the first twelve weeks and then yearly.

Occasionally, practitioners are confronted with the dilemma of whether treatment of hyperprolactinemia is warranted in asymptomatic patients. In answering that question, a few things should be considered, such as the patient's risk for osteoporosis and/or cardiovascular disorders. If there are no physical issues of concern, then psychological issues should be addressed. Estrogen deficiency, which may occur with increased prolactin, mediates mood, cognition and psychopathology. 11 Results of several studies conducted in women with hyperprolactinemia have demonstrated increased depression, anxiety, decreased libido and increased hostility. Men shared similar problems but did not exhibit an increase in hostility. 12 The authors hypothesized that women demonstrated increased hostility as a protective mechanism for their offspring.

Antipsychotic medications have differing potencies in regards to hyperprolactinemia, which may help guide product selection. The most potent inducer is risperidone, followed by haloperidol, olanzapine, and ziprasidone. 13 Clozapine and quetiapine are truly sparing, and aripiprazole has even been shown to reduce prolactin levels. 14 Aripiprazole may be a viable treatment option in some patients with hyperprolactinemia. In one study, females with risperidone induced hyperprolactinemia taking therapeutic doses of risperidone 2 to 15 mg/day showed significantly lower prolactin levels from weeks 8 to 16 compared to baseline when administered aripiprazole (3, 6, 9, or 12 mg daily). 15 The mean percent reductions in prolactin concentration at 3, 6, 9, and 12 mg daily were approximately 35%, 54%, 57%, and 63%; however, there was little variability in prolactin levels above 6 mg daily of aripiprazole. Therefore, unless giving liquid form, aripiprazole 5mg daily should be an optimal dose in lowering prolactin levels. In this case, the patient exhibited the clinical symptom of amenorrhea, which correlated with an elevated prolactin level. The addition of aripiprazole 10 mg by mouth once daily decreased this patient's prolactin level by 51 ng/mL (30.3%) after twelve days of treatment.

If an elevated prolactin level is incidentally found, the patient should be monitored for symptoms and labs may be repeated. In patients exhibiting symptoms of hyperprolactinemia with a serum level <200 ng/mL, the antipsychotic dose should be reduced or the agent changed to a more prolactin-sparing drug. 13 If switching the agent is not reasonable, the addition of a dopamine agonist such as bromocriptine or cabergoline may be beneficial, as well as the antiviral agent amantadine. 16 In patients with levels >200 ng/mL, or with persistently elevated levels despite changing to a more prolactin-sparing agent, an MRI of the sella turcica should be obtained to rule out a pituitary adenoma or parasellar tumor. 13 Practitioners should be aware that prolactin levels may remain elevated for significant periods of time following discontinuation of a long acting causative agent due to continued D 2 receptor antagonism. 1 One study found elevated prolactin levels in patients who discontinued fluphenazine decanoate as much as six months after the last injection. 1 , 3  

In summary, we have discussed a few clinical pearls to be considered when working with treatment refractory patients with schizophrenia and outlined some unique aspects of treatment in forensic clients. First, we reviewed potential complications and concerns with using fluphenazine decanoate. In addition, we discussed that ultra-rapid CYP2D6 metabolizers may need an increase in dose when appropriate and/or an addition of an inhibitor. Secondly, patients with agranulocytosis that may benefit from clozapine may find improvement in WBC and ANC values with the administration of lithium and/or changing the time of day in which labs are drawn.

Lastly, hyperprolactinemia may result in not only physical symptoms but psychological symptoms as well. Also, health care providers should not only be cognizant regarding how and when to monitor for hyperprolactinemia, but also the various treatment options available, such as changing to less offensive agents, dopamine agonists, or adding low dose aripiprazole. This patient case exemplified multiple strategies that can be considered when managing treatment refractory patients in which alternative options for therapy are not readily available.

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Case study: treatment-resistant schizophrenia

WELLCOME CENTRE HUMAN NEUROIMAGING/SCIENCE PHOTO LIBRARY

Learning objectives

After reading this article, individuals should be able to:

• Describe the management of schizophrenia;
• Understand pharmaceutical issues that occur during treatment with antipsychotics, especially clozapine ;
• Explain how the Mental Health Act 1983 impacts on care;
• Understand the importance of multidisciplinary and patient-centred care in managing psychosis.

Around 0.5–0.7% of the UK population is living with schizophrenia. Of these individuals, up to one-third are classified as treatment-resistant. This is defined as schizophrenia that has not responded to two different antipsychotics ​[1,2]​ .

Clozapine is the most effective treatment for such patients ​[3]​ . It is recommended by the National Institute for Health and Care Excellence (NICE)[4], and is the only licensed medicine for this patient group ​[4,5]​ . For treatment-responsive patients, there should be a collaborative approach when choosing a treatment ​[4]​ . More information on the recognition and management of schizophrenia can be found in a previous article here , and in accompanying case studies  here . 

This case study aims to explore a patient’s journey in mental health services during a relapse of schizophrenia. It also aims to highlight good practice for communicating with patients with severe mental illness in all settings, and in explaining the role of clozapine. 

Case presentation

Mr AT is a male, aged 26 years, who has been diagnosed with paranoid schizophrenia. He moved to the UK with his family from overseas five years ago. He lives with his parents in a small flat in London. His mother calls the police after he goes missing, finding his past two months’ medication untouched. 

He is found at an airport, attempting to go through security without a ticket. He is confused and paranoid about the police asking him to come with them. 

He is taken to A&E and is medically cleared (see Box 1) ​[6]​ . 

Box 1: Common differentials for psychotic symptoms

Medical conditions can present as psychosis. These include:

• Intoxication/effects of drugs (cannabis, stimulants, opioids, corticosteroids);
• Cerebrovascular disease;
• Temporal lobe epilepsy.

Mr AT’s history is taken by a psychiatrist, and his crisis plan sought (as per NICE recommendations) but he does not have one ​[7]​ .

He has been under the care of mental health services for two years and disputes his diagnosis of paranoid schizophrenia. He was admitted to a psychiatric hospital 18 months ago where he was prescribed the antipsychotic amisulpride at 600mg daily. 

He is teetotal, smokes ten cigarettes a day and smokes cannabis every day. His BMI is 26 and he has hypercholesterolaemia (total cholesterol = 6.1mmol/L, reference range <5mmol/L) but all other tests are normal. 

He has no allergies. His only medication is amisulpride 600mg each morning, which he does not take. 

Medicines reconciliation

Mr AT is transferred to a psychiatric ward and placed under Section 2 of the Mental Health Act , allowing detention for up to 28 days for assessment and treatment (see Box 2).

Box 2: The Mental Health Act 1983

This legislation allows for the detention and treatment of patients with serious mental illness, where urgent care is required. This is often referred to as “sectioning”.

It includes regulations about treatment against a patient’s consent to safeguard patients’ liberty, which become more stringent with longer detentions.

Patients may only be given medication to treat their mental illness without their consent and may refuse physical health treatment. 

He denies any mental illness and tells the team they are conspiring with MI6. He is visibly experiencing auditory hallucinations: seen by him talking to himself and looking to empty corners of the room. Amisulpride is re-prescribed at 300mg, which he declines to take. 

A pharmacy technician completes a medicines reconciliation and contacts the care coordinator. The technician provides information about Mr AT’s treatment and feels he is still unwell as he has continued to express paranoid beliefs about his neighbours and MI6.

The ward pharmacist speaks to the patient. As per NICE guidance on medicines adherence , they adopt a non-judgemental attitude ​[8]​ . Mr AT is provided with information on the benefits and side effects of the medication and is asked open questions regarding his reluctance to take it. For more information on non-adherence to medicines and mental illness, see Box 3 ​[9]​ .

Box 3: Medicines adherence and mental health

Adherence to medication is similar for both physical and mental health medicines: only about 50% of patients are adherent. 

Side effects and lack of involvement in decision making often lead to poor adherence. 

In mental illness, other factors are: 

• Denial of illness (poor ‘insight’); 
• Lack of contact by services;
• Cultural factors, such as family, religious or personal beliefs around mental illness or medication.

Mr AT reports gynaecomastia and impotence, and says that he will not take any antipsychotics as they are “poison designed by MI6”, although is unable to concentrate on the discussion owing to hearing voices. 

He is prescribed clonazepam 1mg twice daily owing to his distress, which is to be reduced as treatment controls his psychosis. He is offered nicotine replacement therapy but decides to use an e-cigarette on the ward. 

He is unable to weigh up information to make decisions owing to his chaotic thinking and is felt to not have capacity to make decisions on his treatment. The team debates what treatment to offer.

Patient preference

Mr AT refuses all options presented to him. A decision is made to administer against his will and aripiprazole is chosen as it is less likely to cause hyperprolactinaemia and sexual dysfunction. He then agrees to take tablets “if it will get me out of hospital”. 

After eight weeks of treatment with orodispersible aripiprazole 15mg, Mr AT is able have a more coherent conversation, but is hallucinating and distressed. He is clearly under treated. The pharmacist attempts to complete a side-effect rating scale ( Glasgow Antipsychotic Side-effect Scale [GASS] ) but he declines. He is pacing around the ward in circles: it is felt he may be experiencing akathisia (restlessness) — a common side effect of antipsychotics (see  Table 1 ). 

Treatment review

The team feels clozapine is the best option owing to the treatment failure of two antipsychotics.  

The team suggests this to Mr AT. He refuses, stating the ward is experimenting on him with new medication and he refuses to take another antipsychotics. 

The pharmacist meets the patient with an occupational therapist to discuss what his goals are. Mr AT states he wants to go to college to become a carpenter. They discuss routes to achieve this, which all involve the first step of leaving hospital and the conclusion that clozapine is the best way to achieve this. The pharmacist clarifies the patient’s aripiprazole will not continue once clozapine is established. They leave information about clozapine with the patient and offer to return to discuss it further. 

Mr AT agrees to take clozapine a week later (see Box 4) ​[10–14]​ . Aripiprazole is tapered and stopped.

Box 4: Clozapine characteristics

Clozapine significantly prolongs life and improves quality of life ​[10]​ . Delaying clozapine is associated with poorer outcomes for patients ​[11]​ . 

Clozapine is under-prescribed owing to healthcare professionals’ anxiety and unfamiliarity around its use ​[12–14]​ .

It causes neutropenia in up to 3% of patients so regular monitoring is required . Twice-weekly monitoring is needed if neutrophils are <2 x10 9 /L. Most patients should stop clozapine if neutrophils are <1.5×10 9 /L. These ranges can differ from some laboratory definitions of neutropenia. 

Other side effects include sedation, hypersalivation and weight gain. See  Table 2  for red flags for serious side effects. 

Clozapine is titrated up slowly to avoid cardiovascular complications. A treatment break of >48 hours warrants specialist advice for a retitration plan. 

The pharmacist meets with Mr AT to discuss clozapine. He is told that this is likely to be a long-term treatment. The pharmacist acknowledges that the patient disagrees with his diagnosis, but this treatment is likely to prevent him from returning to hospital. 

He is started on clozapine at 12.5mg at night, which is slowly increased. Pre- and post-dose monitoring of his vital signs is completed. 

On day nine of the titration, his pulse is 115bpm. He otherwise feels well and blood tests show no signs of myocarditis (see   Table 2), so the titration is continued but slowed.

After 3 weeks he is taking 150mg twice daily of clozapine and his symptoms have significantly improved: he is regularly bathing, not visibly hallucinating and engaging with staff.

The pharmacy technician completes a GASS form. Mr AT reports constipation, hypersalivation and sedation. 

A pharmacist meets the patient to reiterate important counselling points, and discuss questions he may have about his treatment and how to manage side effects. Medication changes are made with the patients’ input: 

• His constipation is monitored with a stool chart and he is started on senna 15mg at night;
• He is started on hyoscine hydrobromide 300 micrograms at night for salivation;
• He is switched to clozapine 300mg once daily at night to simplify his regime and reduce daytime sedation. His clonazepam is reduced and stopped.

Smoking is discussed owing to tobacco’s role as an enzyme inducer (more information on tobacco smoking and its potential drug interactions can be found in a previous article here ). Mr AT states he will continue to use an e-cigarette for now. He is informed that if he starts smoking again, his clozapine may become less effective and he should immediately inform his team. 

He is discharged a few weeks later via a home treatment team and attends a clinic once weekly. On each attendance, he has a full blood count taken and analysed on site. He is assessed by a pharmacy technician and nurse for side effects and adherence to treatment, and his smoking status is clarified. 

The technician asks what he thinks the clozapine has done for him. Mr AT states he is still unsure about having a mental illness, but recognises that clozapine has helped him out of hospital and intends to continue taking it. 

Good practice in the pharmaceutical care of psychosis involves:

• Active patient involvement in discussions on treatment decisions;
• Regular review of treatment: discussing efficacy, side effects and the patient’s view and understanding of treatment; 
• Multidisciplinary approaches to helping patients choose treatment;
• For patients who dispute their diagnosis and the need for treatment, open dialogue is important. Such discussions should involve the patient’s goals, which are likely to be shared by the team (rapid discharge, preventing admissions, reducing distress); 
• Information about treatment should be provided regularly in both written and verbal form;
• Where appropriate, involve carers/next of kin in decision making and information sharing. 

Important points

• Schizophrenia affects 1 in 200 people, meaning such patients will present regularly in all settings;
• Patients with acute psychosis, who are in recovery, may be managed by specialist teams, who are the best source of information for a patient’s care;
• Collaborating with the patient on a viable long-term treatment plan improves adherence;
• Clozapine is recommended where two antipsychotics have failed;
• Clozapine is a high-risk medicine, but the risks are manageable;
• Hydrocarbons produced by smoking (but not nicotine replacement therapy, e-cigarettes or chewing tobacco) induce the enzyme CYP1A2, which reduces clozapine levels markedly (up to 20–60%). Starting or stopping smoking could precipitate relapse or induce toxicity, respectively.
• 1 Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biological Psychiatry. 2001; 50 :898–911. doi: 10.1016/s0006-3223(01)01271-9
• 2 Gillespie AL, Samanaite R, Mill J, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review. BMC Psychiatry. 2017; 17 . doi: 10.1186/s12888-016-1177-y
• 3 Taylor DM. Clozapine for Treatment-Resistant Schizophrenia: Still the Gold Standard? CNS Drugs. 2017; 31 :177–80. doi: 10.1007/s40263-017-0411-6
• 4 Psychosis and schizophrenia in adults: prevention and management. NICE. 2014. https://www.nice.org.uk/guidance/cg178/ (accessed Jan 2022).
• 5 Clozaril 25 mg tablets. Electronic medicines compendium. 2020. https://www.medicines.org.uk/emc/product/4411/smpc (accessed Jan 2022).
• 6 Psychosis and schizophrenia: what else might it be? NICE. 2020. https://cks.nice.org.uk/topics/psychosis-schizophrenia/diagnosis/differential-diagnosis/ (accessed Jan 2022).
• 7 Service user experience in adult mental health: improving the experience of care for people using adult NHS mental health services. NICE. 2011. https://www.nice.org.uk/guidance/cg136/ (accessed Jan 2022).
• 8 Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence . NICE. 2009. https://www.nice.org.uk/guidance/cg76/ (accessed Jan 2022).
• 9 Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry . 13th ed. Hoboken, New Jersey: : Wiley 2018.
• 10 Meltzer HY, Burnett S, Bastani B, et al. Effects of Six Months of Clozapine Treatment on the Quality of Life of Chronic Schizophrenic Patients. PS. 1990; 41 :892–7. doi: 10.1176/ps.41.8.892
• 11 Üçok A, Çikrikçili U, Karabulut S, et al. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. International Clinical Psychopharmacology. 2015; 30 :290–5. doi: 10.1097/yic.0000000000000086
• 12 Whiskey E, Barnard A, Oloyede E, et al. An Evaluation of the Variation and Underuse of Clozapine in the United Kingdom. SSRN Journal. 2020. doi: 10.2139/ssrn.3716864
• 13 Nielsen J, Dahm M, Lublin H, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol. 2009; 24 :965–71. doi: 10.1177/0269881108100320
• 14 Verdoux H, Quiles C, Bachmann CJ, et al. Prescriber and institutional barriers and facilitators of clozapine use: A systematic review. Schizophrenia Research. 2018; 201 :10–9. doi: 10.1016/j.schres.2018.05.046
• This article was corrected on 31 January 2022 to clarify that tobacco is an enzyme inducer, not an enzyme inhibitor

Useful structured introduction to the subject for clinical purposes

Thank you Amrit for your feedback, we are pleased that you found this article useful.

Michael Dowdall, Executive Editor, Research & Learning

Please note that smoking causes enzyme INDUCTION not INHIBITION as stated. (Via aromatic polyhydrocarbons, not nicotine)

Hi James. Thank you for bringing this to our attention. This has now been corrected. Hannah Krol, Deputy Chief Subeditor

Only with Herbal formula I was able to cure my schizophrenia Illness with the product I purchase from Dr Sims Gomez Herbs A Clinic in South Africa

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• 1 Department of Pulmonary and Critical Care Medicine, Zhejiang Taizhou Hospital, Taizhou, China
• 2 Department of Pulmonary and Critical Care Medicine,Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou，Zhejiang, China
• 3 Department of Mental Health, Sir Run Run Shaw Hospital, School of Medicine, Graduate School, Zhejiang University, Hangzhou, Jiangsu Province, China

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Objective: The risk of venous thromboembolism in patients with mental illness has been insufficiently addressed. This study aimed to assess the correlation between hyperhomocysteinemia and venous thromboembolism prevalence among this population.Methods: Patients with a diagnosis of mental illness and concurrent venous thromboembolism, admitted to Sir Run Run Shaw Hospital at Zhejiang University School of Medicine between January 2014 and December 2021, were included in the venous thromboembolism group. The control group, approximately twice the size, comprised individuals with mental illness but without venous thromboembolism.Basic clinical data were gathered for both cohorts.Results: In psychiatric patients, elevated D-dimer levels(OR=5.60,95% CI 3.28-10.00), hyperhomocysteinemia (OR=2.37 ,95% CI 1.10-5.14), and hyperprolactinemia(OR= 2.68 ,95% CI 1.12-6.42)were significant risk factors for venous thromboembolism. According to further subgroup analyses, hyperhomocysteinemia is a significant risk factor associated with pulmonary embolism, with an OR of 5.08 (95% CI 1. 20-21.48). An interaction effect between gender and homocysteine level was found, with a p-interaction of 0.022. A subsequent analysis confirmed the association between hyperhomocysteinemia and venous thromboembolism in female psychiatric patients, with an OR of 3.34 (95% CI 1.68-6.65), indicating that hyperhomocysteinemia is a significant risk factor for venous thromboembolism in women.Conclusion: Patients with psychiatric disorders were found to have an elevated risk of venous thromboembolism, which was associated with increased levels of D-dimer, hyperprolactinemia, and hyperhomocysteinemia. A strong correlation between hyperhomocysteinemia and pulmonary embolism was identified in patients with mental illnesses. Furthermore, the study revealed that female psychiatric patients with hyperhomocysteinemia constituted a high-risk group for venous thromboembolism. This finding holds significant clinical implications, suggesting that early preventative measures could be implemented for this high-risk population to reduce the incidence of thromboembolic events during hospitalization for psychiatric patients.

Keywords: mental illness, Venous Thromboembolism, Hyperhomocysteinemia, Hyperprolactinemia, pulmonary thromboembolism

Received: 17 Nov 2023; Accepted: 29 Apr 2024.

Copyright: © 2024 Wang, Zhang, Ren, Li and Ying. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Kejing Ying, Department of Pulmonary and Critical Care Medicine,Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou，Zhejiang, China

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