East Asian Arch Psychiatry 2012;22:126-33

REVIEW ARTICLE

Schizophrenia and Suicide

精神分裂症和自杀关联性的文献回顾

YPS Balhara, R Verma

Dr Yatan Pal Singh Balhara, MD, DNB, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India.
Dr Rohit Verma, MD, Department of Psychiatry and De-addiction, PGIMER and Dr R. M. L. Hospital, New Delhi, India.

Address for correspondence: Dr Yatan Pal Singh Balhara, Department of Psychiatry, 4/F, Teaching Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029.
Tel: (91) 9868976365; email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Submitted: 26 January 2012; Accepted: 26 March 2012


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Abstract

Objective: Schizophrenia is characterised by distorted thinking and perception and tends to run a chronic course. The World Health Organization reported that suicide accounts for almost 2% of the world’s deaths. There is a close relationship between schizophrenia and suicide. Patients with schizophrenia experience personal distress and socio-occupational dysfunction and reduced life expectancy as a group. The current article presents a review of suicide in schizophrenia.

Data sources: The literature search included MEDLINE, CINHAL, EMBASE, and Cochrane Controlled Trials Register databases.

Study selection: Search terms used included ‘schizophrenia’, ‘suicide’, ‘positive symptoms’, ‘negative symptoms’, ‘self-harm’, ‘anti-psychotics’, ‘risk factors’ in different combinations.

Data extraction: We included epidemiological findings, socio-demographical variables, symptom profiles, biological underpinnings, risk factors, and management issues. No publication year limits were applied but the search was restricted to articles in English. The abstracts of articles retrieved in the search were manually scanned.

Data synthesis: Male gender and being unmarried are associated with an increased risk of suicide among individuals with schizophrenia. The presence of depression and depressive features is associated with an increased risk of suicidality. An association between insight into the illness, a consequent feeling of hopelessness, and increased risk of suicide has also been a consistent finding. In contrast the role of schizophrenia subtype in suicidal risk remains controversial.

Conclusions: To date, the impact of specific pharmacotherapeutic agents and non-pharmacological interventions on the suicidal behaviour of individuals with schizophrenia is also yet to be fully explored by robust research.

Key words: Schizophrenia; Suicide

摘要

目的:精神分裂症的特点是患者呈歪曲思想和感知且倾向慢性发病。世界卫生组织的数据显示自杀占全球死亡人口约2%。精神分裂症和自杀之间有著密切关係。精神分裂症患者一般出现个人困扰、社会职业障碍和较短预期寿命。本文回顾有关精神分裂症与自杀相关性的文献。

资料来源:从不同医学资料库进行文献搜索,包括MEDLINE、CINHAL、EMBASE和Cochrane临床对照试验资料库。

研究选取:透过以下不同组合的关键词进行搜索,包括「精神分裂症」、「自杀」、「阳性徵状」、「阴性徵状」、「自毁行为」、「抗精神病药」和「风险因素」。

资料选取:我们综合流行病学研究结果、社会人口统计学变数、症状、生物性基础、风险因素和治疗角度作出分析。搜索不限出版年份,但只限於英文文献;检索的文章撮要会再经人手筛选。

资料综合:男性和未婚的精神分裂症患者其自杀风险较高,患抑鬱症或呈抑鬱症状的也会增加自杀风险。此外,因对自己患病的认知导致的绝望感也与自杀风险上升呈相关性,但精神分裂症子型与自杀风险的相关性则仍未有定论。

结论:迄今也未有研究可充分发掘特定药物治疗剂和非药理干预对精神分裂症患者自杀行为的影响。

关键词:精神分裂症、自杀

Introduction

Schizophrenia is a major mental disorder characterised by distorted thinking and perception that tends to run a chronic course. Based on data reported by the World Health Organization (WHO) in 1998, suicide represented 1.8% of the global burden of disease.1 It is expected to increase to 2.4% by the year 2020. In 2000, this equated to approximately 1 million deaths from suicide worldwide.2

Added to this, there were 10 to 20 times as many attempted suicides. Such data from the year 2000 translates into approximately 1 death from suicide every 40 seconds and 1 suicide attempt every 3 seconds. It is expected to reach 1 death from suicide every 20 seconds and 1 suicide attempt every 1 to 2 seconds in 2020 according to WHO estimates.

There is a close relationship between schizophrenia and suicide. Bleuler3 referred to the suicidal drive as “the most serious of schizophrenic symptoms”. It has been reported that schizophrenia reduces the overall life span by around 10 years.4 Suicide is the biggest single contributor to this shortened life expectancy. A 5-year WHO study on 1056 individuals with psychosis found suicide to be the commonest cause of death among those with schizophrenia.5

This article presents a review of suicide in patients with schizophrenia. The review is based on a literature search carried out by the authors. The literature search included MEDLINE, CINHAL, EMBASE and Cochrane Controlled Trials Register databases. Search terms used included ‘schizophrenia’, ‘suicide’, ‘positive symptoms’, ‘negative symptoms’, ‘self-harm’, ‘anti-psychotics’, ‘risk factors’ in different combinations. No publication year limits were applied but the search was restricted to articles in English. The abstracts of articles retrieved in the search were manually scanned. Finally, full texts of the accessible articles were included in preparation of the manuscript. Additionally, standard textbooks on the topic were used during manuscript preparation.

Evidence of Association from Epidemiology

Until the last decade of the 20th century, the lifetime risk of suicide in schizophrenia was believed to be around 10%.6 In comparison, the lifetime risk of suicide in the general population of the United States is approximately 1%.7,8 Reports highlighting flaws with the methodological approach of epidemiological studies started to surface in the latter half of the last decade of the past century. Inskip et al9 reported that the accepted lifetime risk of suicide of 10% among those with schizophrenia might be an overestimation. Based on their re-analysis of the available literature, the suicide rate was estimated to be around 4%. The authors cited statistical issues as the potential reason for the difference observed.9

This observed difference between earlier and later reviews in terms of the prevalence of suicide in patients with schizophrenia appears due not only to the statistical technique employed, but also to the inclusion criteria used for the studies. As mentioned by Palmer et al,10 the difference is unlikely to be a reflection of changing criteria for diagnosing schizophrenia. Case fatality rates among those diagnosed with schizophrenia throughout the years have remained stable, even as the diagnostic criteria have changed.11 More recent reviews reported the case fatality rate at around the same level. Palmer et al10 reported that the lifetime suicide prevalence estimate in those observed from first admission or illness onset was 5.6%; they also estimated that 4.9% of patients with schizophrenia will commit suicide during their lifetimes, usually near illness onset. The authors ensured that the studies included in their review observed a cohort of schizophrenic patients for at least 2 years, with at least 90% follow-up, and reported suicides.10

Approximately 2 to 12% of all suicides are attributable to schizophrenia.12 The representation of schizophrenia is even higher in those committing suicide in inpatient settings, with studies reporting figures up to 76%.13 Harris and Barraclough14 reported the risk of suicide among those suffering schizophrenia to be 8.5 times higher than the general population. Between 15 and 26% of people with schizophrenia have made at least 1 suicide attempt by their first treatment contact, and between 2 and 11% have made at least 1 more during their first year of treatment.15-17

Annual death rates from suicide in this population have been reported to be 0.4 to 0.8%.6 Studies have reported that up to 50% of those suffering from schizophrenia experienced suicidal ideation, with or without suicidal attempt, at some time during the course of the illness.18-20

Studies have also shown that 38% had at least 1 episode of self-harm in a 2- to 12-year follow-up period.21 Between 50 and 80% of suicide attempts do not result in death, but a history of suicide attempts is common in patients with schizophrenia who die by suicide (40-61% of cases).22,23

Risk Factors in Schizophrenia Leading to Suicidal Behaviour

Various studies have explored the possible association of factors related to the patient, the illness, the associated conditions and treatment, with suicidal behaviour among individuals with schizophrenia. Findings from these studies have not been conclusive enough to identify causal roles but some associations have emerged. These risk factors can be classified according to whether they are modifiable or non-modifiable; those associated with increased suicidal risk in general or in schizophrenia in particular; and those related to socio-demographic profile, illness characteristics, associated conditions, and treatment and other factors (Tables 124 and 2).

The available literature indicated that males are over- represented among those with schizophrenia committing suicide. However, some studies have shown a higher standardised mortality ratio for women.25-27 In another study,28 of the 295 patients for whom data on completed suicides were available, slightly less than half (45%) were men.

Studies have shown that those who are married or cohabiting may be at somewhat lower risk of suicide (odds ratio [OR] = 0.68, 95% confidence interval [CI] = 0.45- 1.04).29 Having children also seems to have some protective effect.30

Interestingly, higher education has been found to be significantly associated with increased suicidal risk (OR = 5.66, 95% CI = 1.91-16.80).29 Systematic reviews failed to find any impact of being employed on the risk of suicide.29

Also, unemployment has not been shown to be associated with a heightened risk.30

The role of schizophrenia subtype in suicidal risk remains controversial. The available literature suggested that different schizophrenia subtypes are associated with different rates of suicidality. While the paranoid type has been associated with a higher risk, those with deficit or predominantly negative symptoms are less likely to demonstrate suicidal behaviour.29 In a study of different schizophrenia subtypes, paranoid type was associated with the greatest risk of committing suicide (12%), followed by the undifferentiated type (4%) and hebephrenic type (0%).28

Some evidence also suggested a higher risk of suicide in schizophrenia patients with predominantly positive symptoms, compared with those with predominantly deficit symptoms.31 However, it has been argued that the course of the illness, frequent relapses, a high severity of illness, a downward shift in social and vocational functioning, and a realistic awareness of the deteriorating effect of the illness are schizophrenia-specific suicide risk factors rather than the specific schizophrenia subtype itself.24

The role of positive symptoms (psychotic features) in suicidality among schizophrenia patients has been controversial. Delusions have not been associated with suicidal risk in systematic reviews of available individual studies; a systematic review of well-designed studies documented a lower risk of suicide in those with delusions (OR = 0.48, 95% CI = 0.24-0.94).29 However, individual studies have reported an association of suicide with paranoid ideation and suspiciousness.30 In a systematic review, hostility at admission has been shown to be associated with long-term suicidal risk.28

Hallucinations have been associated with an increased as well as a lower risk of suicide in different studies. Hawton31 noted that while 2 studies reported a statistically significant positive association between hallucinations and suicide, another 2 reported a significant negative association. Although individual studies have documented a role for command hallucinations in self-harm behaviour including suicidal behaviour,32 other studies failed to find any such association.33-35 Methodological limitations of some of these studies have been cited as the reason for the conflicting findings.

Studies assessing the impact of negative symptoms of schizophrenia on suicidal risk have also come up with inconsistent findings. Some studies have found a reduced risk of suicide with flat affect specifically and the negative symptoms in general.28 The study by Fenton et al28 revealed significantly lower global negative symptom severity at admission among patients who later committed suicide. Patients who committed suicide had lower severity ratings for each of the 7 negative symptoms.

It has been shown that mood disorders are major contributors to suicidal risk in those with psychiatric disorders, with the risk of suicide in monopolar depression being 20 times the risk in the general population.29 The association of depression with schizophrenia is now well established. Depressive symptoms are recognised as an important and distinct symptom domain in schizophrenia.36

The prevalence of depressive symptoms among people with schizophrenia has been reported to range from 25 to 81%.36

It has also been reported that the presence of depression (OR = 12.7, 95% CI = 6.7-24.1) or depressive features (especially pessimism, worthlessness [low self-esteem], and hopelessness) is associated with an increased risk of suicidality in individuals suffering from schizophrenia.37,38

Anxiety features may be co-morbid with schizophrenia or occur as a part of the syndrome of schizophrenia. Co- morbidity with panic attacks has been shown to be associated with higher suicide rates in patients with schizophrenia.39

Although no association with suicide has been found in a study using a continuous measure of anxiety,30 anxiety has been shown to contribute to suicidality in post-psychotic depression.40

The case fatality as well as the proportional mortality rate due to suicide in schizophrenia tend to vary as a function of the duration of illness. Case fatality rate refers to the proportion of the study sample who committed suicide.

Conversely, the proportional mortality rate refers to the deaths attributed to suicide out of the total reported deaths.10

The rate of suicide among first-admission and new-onset samples has been found to be higher than that in samples of ‘all comers’ (mixed new-onset and chronic samples). Palmer et al10 reported a case fatality rate of 4.9% and a proportional mortality rate of 30.6% for suicide among first-admission and new-onset samples of patients with schizophrenia. The corresponding figures for the mixed samples of chronic and new-onset subjects were 2.3% and 5.6%, respectively.10 Roy41 reported the mean age of suicide as 25.8 years, after a mean duration of illness of 4.8 years in a cohort of 30 patients with schizophrenia. The presence of relapsing illness also increased the likelihood of suicide among this patient cohort.

Fear of mental disintegration due to the presence of the disorder has been linked with increased risk of suicide. However, studies over the years failed to demarcate the contribution made by the hopelessness associated with the awareness of psychopathology and insight per se. Kim et al42 and Meltzer et al43 tried to tease out the contributions made by these 2 factors. In their respective studies, they found that on application of appropriate statistics only hopelessness was associated with increased suicidality. One however needs to take into account that these studies included both suicidal ideation as well as suicide attempts as evidence of increased suicidality. Given the contributions of multiple factors to suicidal ideation and / or attempts and completed suicide, one might expect different findings if these clusters were studied separately.

There has, however, been a consistent finding of an association between insight into the illness, a consequent feeling of hopelessness, and increased risk of suicide.44

Bourgeois et al45 reported that awareness of psychiatric condition at baseline was associated with an increased risk of suicide events over the follow-up period. This effect was mediated by depression and hopelessness levels. By contrast, changes in awareness associated with treatment were shown to decrease the risk of suicide. This association is of particular importance in newly diagnosed cases of schizophrenia where the person has recently recovered from an acute exacerbation and is trying to come to terms with their diagnosis. Besides, past suicidal behaviour, especially past suicide attempt, is one of the most important risk factors for prediction of a completed suicide.46

A psychiatric illness that necessitates hospitalisation is one of the strongest risk factors for suicide.47 Suicidal behaviour does tend to occur during contact with health services. Moreover, during the period following discharge from an inpatient care setting, the chances of suicidal behaviour may actually be increased.47 The time period after discharge from a psychiatric hospital, for up to 1 year, is known to be a high-risk time for both attempted and completed suicide.48

While some studies failed to find a specifically higher risk of suicide in the post-discharge period, these studies have been criticised for their small sample sizes.49 Studies of relatively larger samples through nationwide registry review have shown that schizophrenia spectrum and affective disorders carried an elevated risk for suicide soon after discharge.50 Case-control studies on this issue have also reported that affective- and schizophrenia-like disorders are the most frequent diagnoses among inpatient and discharged patient suicides.51 The registry review by Pirkola et al50 in Finland from 1980 to 2001 reported that those committing suicide within the first week after discharge were more often female, unmarried, had a higher grade of education, tended to use more drowning and jumping from heights as the methods of suicide, and had gained a smaller improvement in psychological functioning during hospitalisation.

There have been reports of an association between suicidal behaviour, including completed suicide, in the context of akathisia in patients with schizophrenia.52-54 Cem Atbaşoglu et al55 found an association between akathisia and suicidality using logistic regression analysis.

Cheng et al56 found that those who committed suicide were taking higher doses of medication which could have produced some dysphoric effects. However, the severity of the illness necessitating a higher dose of medication could be the underlying cause of increased suicidal behaviour in these individuals. The relationship between typical neuroleptics versus atypical neuroleptics and suicidal behaviour in schizophrenia continues to warrant further exploration.

Biological Basis

Schizophrenia is now conceptualised best as a consequence of the interaction of multiple biopsychosocial factors.57

The stress-diathesis paradigm has been used to elucidate the pathogenesis of this condition, with the psychosocial factors viewed as acting on innate biological vulnerability.57

The serotonin neurotransmitter system has gained a great deal of attention in the study of suicide. It has been found that individuals with schizophrenia who commit suicide have significantly lower concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in their cerebrospinal fluid.58 Prolactin has also been used as an assessment ‘tool’ to resolve the role of the serotonergic system in suicidal behaviour. It has been demonstrated that blunted prolactin secretion in response to D-fenfluramine is associated with suicidal behaviour in schizophrenic patients.59 Studies have also explored the role of genetic variants in serotonin receptors with regard to suicide among individuals diagnosed with schizophrenia. HTR3A and HTR3B polymorphisms have been postulated not to play a major role in this regard.60 Similarly, studies have failed to link 5-HT(2A) gene polymorphism (102T/C) to possible genetic susceptibility for suicidal behaviour.61

Polymorphisms in ADRA2B have been shown to be associated with suicidal behaviour among patients with schizophrenia. A significant association was observed between single nucleotide polymorphisms ADRA2B rs1018351 and SLC6A3 rs403636 and suicidal attempts.62

GABA A receptor subunits and glutamate-related genes have been shown to be differentially expressed in schizophrenia, as well as in suicide completers associated with these genetic disorders.63 Kim et al59 reported the differential expression of PLSCR4 (phospholipid scramblase) and EMX2 using real-time polymerase chain reaction. The biological role of PLSCR4 remains unknown. It is suggested that changes in phospholipid membrane composition might have pleiotropic effects, as evidence suggested that membrane composition can change G- protein–coupled receptor functioning and downstream effector signalling, as well as voltage-dependent K+ channels.59 The association of EMX2 seems to be even more interesting as it is in accordance with the proposed neurodevelopmental model of schizophrenia, with the forebrain playing a role. Being a homeodomain-containing transcription factor, EMX2 plays a crucial role in forebrain patterning and development in mouse models.64 Decreased expression levels of 2 glutamate-related genes, glutamate- ammonia ligase, and glial high-affinity glutamate transporter member 3 (SLC1A3) have been shown in schizophrenia suicide completers.59 However, this analysis failed to find any role of the genes related to the serotonergic and noradrenergic systems which have been proposed as the underlying neurochemical disturbances in schizophrenia, as well as in suicidal behaviour.

The limbic system is involved in the regulation of reward, motivation, emotional expression, memory, decision-making, and predicting outcomes of one’s behaviour. Neuroimaging studies of the limbic system have demonstrated volumetric abnormalities in these structures in individuals with schizophrenia as well as those who attempt suicide.65

Hypothalamic-pituitary-adrenal axis hyperactivity resulting in glucocorticoid neurotoxicity has been proposed as the underlying mechanism of the tissue damage in different regions of brain found in neuroimaging studies of those schizophrenia suicide attempters.66 Dexamethasone suppression test abnormalities have also been reported in people with schizophrenia who attempt suicide.67,68

Assessment and Management

Overall, suicidal behaviour in patients with schizophrenia and related disorders represent a major public health problem that has not been adequately addressed by the medical community. The assessing clinician should make a baseline assessment of risk factors for suicidal behaviour on the first contact with the individual. Special attention also needs to be given to early signs and relapse and to instructing the family in how to cope during the crisis.69

Findings from the National Comorbidity Survey showed that 13.5% of individuals with psychiatric disorders reported lifetime suicidal ideation, 3.9% a plan, and 4.6% an attempt.70 Cumulative probabilities were 34% for the transition from ideation to a plan, 72% from a plan to an attempt, and 26% from ideation to an unplanned attempt.70

About 90% of unplanned and 60% of planned first suicide attempts occurred within 1 year of the onset of ideation.

While the management of the underlying disorder is likely to benefit the individual, the clinician should keep in mind the findings of the available literature. Bringing the patient into treatment should not be considered the final aim with regard to the management and prevention of suicidal behaviour. According to the UK National Confidential Inquiry into Suicide and Homicide by People with Mental Illness, among those committing suicide, 50% had had contact with psychiatric services during the preceding 7 days, yet 85% were considered at low risk of suicide.48

While it might be argued that such a finding could be due to the ever-changing risk of suicidal behaviour, it is also important to consider inadequate assessment during the care a factor contributing to suicidal risk.

Role of Pharmacotherapy

The introduction of antipsychotics in the 1950s was a big advance in the management of schizophrenia. Not only it presented symptomatic improvement in these individuals but also led to deinstitutionalisation and better functioning in the community.

Studies with conventional antipsychotic medications have shown increased,71,72 decreased,73 or unchanged19,74,75 rates of suicide in schizophrenia. Similar findings have been reported for the atypical antipsychotics, such as olanzapine, risperidone, and quetiapine.76

However, some retrospective studies documented a possible role for second-generation antipsychotics, including olanzapine, risperidone and quetiapine in reducing suicidal behaviour among schizophrenic patients.77,78

Barak et al79 carried out a retrospective review of the effects of exposure to second-generation antipsychotics on suicidality of patients with schizophrenia or schizoaffective disorder undertaken over a 5-year period. Of 378 patients who attempted suicide, 16.1% were exposed to second- generation antipsychotics while 37% were exposed to second-generation antipsychotics in the control group.79

The protective effect of treatment with a second-generation antipsychotic was seen in an OR of 3.54. Risperidone had a statistically insignificant larger effect size than olanzapine.79

Apart from the study by Sernyak et al,80 retrospective studies suggested that clozapine may be effective for treating suicidal behaviour in treatment-resistant patients with schizophrenia who have not been preselected for suicidal risk.78,81-83

The International Suicide Prevention Trial (InterSePT study)6 was a multi-centre, randomised, 2-year study conducted to investigate the effectiveness of clozapine for reducing suicidal behaviour, among individuals with schizophrenia and schizoaffective disorders who were preselected to be at high risk for suicide but were not otherwise treatment-resistant. The findings of this study suggested a significant role for clozapine in the reduction of different suicidal behaviours. There was significantly less suicidal behaviour seen in patients treated with clozapine compared to olanzapine. Fewer clozapine-treated patients attempted suicide, or required hospitalisations or rescue interventions to prevent suicide. Overall, few of these high-risk patients died of suicide during the study period.6

The potential decrease in suicide mortality with clozapine treatment is estimated to be as high as 85%.84 Clozapine has been approved for the treatment of suicidal behaviour in patients with schizophrenia or schizoaffective disorder by the US Food and Drug Administration.43

Psychotherapeutic Interventions

The role of psychotherapeutic interventions in prevention and management of suicidal behaviour is less well studied in schizophrenia. There are no studies to support the effectiveness of psychosocial interventions on suicide rates. For patients with severe and chronic schizophrenia, self- esteem becomes progressively eroded. Prolonged illness also reduces the quantity and quality of gratifying experiences. Delusional ideas and fantasies often enhance self-esteem. Patients with schizophrenia are prone to depression and despair when the delusional thinking disappears, especially when there are few other bases for self-esteem. Clinicians should consider assessing hopelessness and demoralisation to help evaluate potential suicidal risk activity.

Inappropriate goals for treatment might also reinforce the patient’s internal expectations and sense of inadequacy, especially if there are unrealistic expectations of the patient. The resulting cycle of negative feedback and decreased self-esteem may then push the patient’s internal struggle in the direction of suicide. Cotton et al85 considered that suicide potential is best evaluated by a dynamic assessment of the patient’s self-esteem. They also recommended that psychotherapeutic work with schizophrenic patients should concentrate on building mastery of life tasks, thereby increasing self-esteem.85 Patients need help specifically to accept their functional losses, give up inappropriate expectations, and to cope with despair. The therapist should share with the patient the burden of existential despair.85

Empathic support is essential for reducing suicidal risk. Clinicians should acknowledge the patient’s despair, discuss losses and daily difficulties, and help to establish new and accessible goals.86 Some recommended approaches include the use of outreach teams, psychiatric emergency clinics, and the use of small, short-stay units attached to casualty departments to provide crisis support. There is a lack of evidence that clinical measures, such as compliance therapy and assertive outreach, can lead to a consistent reduction in suicide rates.48 Moreover, the cost-effectiveness and feasibility of such approaches remain in question. A suicide prevention approach for patients with schizophrenia should centre on improving their overall functioning and decreasing their general discouragement and hopelessness.

Conclusion

Schizophrenia and suicide share an intricate, clinically relevant relationship. The available literature provides important insights into some aspects of this association. We do have some clear understanding of various risk factors associated with suicide in individuals diagnosed with schizophrenia. This includes information on various socio-demographic variables, various psychotic features, negative features, associated co-morbid anxiety and depression, medication side- effects and insight into the condition. Some understanding into the biological underpinnings of suicide among individuals with schizophrenia has also emerged. However, the association remains far from clearly and completely understood. Genetic studies have provided conflicting and non-replicated findings. Similarly, management of suicidal behaviour in schizophrenia remains inadequately studied. The impact of specific pharmacotherapeutic agents and non- pharmacological interventions on the suicidal behaviour of individuals with schizophrenia is also yet to be fully explored by robust research.

Declaration

The authors declared that there is no conflict of interest. No funding was received for the study.

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