Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting primarily individuals over the age of 65 [1]. This condition is characterized by the loss of neurons in the substantia nigra, which leads to a dopamine deficiency in the striatum. Additionally, it is marked by the presence of abnormal intracellular structures known as Lewy bodies, primarily composed of aggregated alpha-synuclein protein, in various brain regions. These Lewy bodies are a defining pathological feature of the disease and contribute to its neurodegenerative progression and clinical manifestations [1, 2, 3]. PD presents motor symptoms such as bradykinesia, resting tremor, rigidity, and postural instability [4, 5, 6]. Nevertheless, non-motor symptoms are common but often overlooked, including autonomic dysfunction, fluctuations, dyskinesias, cognitive/neurobehavioral disorders, sensory perception, and sleep abnormalities [1, 7]. The incidence of PD ranges from 5 to $>$35 new cases per 100,000 individuals annually, with higher rates observed in older age groups [8, 9, 10]. The global prevalence of the disease is estimated to be 0.3%, rising to 3% in individuals over 80 years old [11]. Genetic mutations account for only a small percentage of PD cases, with the most common genetic mutations associated with PD found in the PARK genes [12]. In addition, environmental factors, including exposure to pesticides or consumption of dairy products and a history of traumatic brain injury or melanoma, have been associated with an increased risk [12, 13]. Conversely, certain lifestyle factors, for example physical activity, may decrease the risk [13]. Molecular causes of PD involve various pathways and mechanisms, like $\alpha$-synuclein processing problems, mitochondrial dysfunction, oxidative stress, calcium imbalance, axonal transport issues, and neuroinflammation [1].

Among the non-motor symptoms of PD is Parkinson’s disease psychosis (PDP), characterized by hallucinations [14]. These encompass a range of sensory experiences, including visual, auditory, olfactory, tactile, and gustatory phenomena [15, 16]. To meet diagnostic criteria, hallucinations should occur after the onset of PD and persist for at least one month, while other potential causes must be ruled out [17]. Visual hallucinations (vHs) and illusions are commonly encountered forms. The prevalence rates of vHs in PD vary depending on the study design and population. In clinic-based samples, the prevalence ranges from 22% to 38%, while community-based samples have lower figures of 16% to 23% [15]. Considering “minor forms” of hallucinations, such as passage hallucination and sense of presence, the prevalence increases up to 75% [18, 19]. The prevalence of vHs in PD patients with associated dementia exceeds 50% [15]. Longitudinal studies indicate that the point prevalence of vHs increases over time, reaching 74% in a 20-year follow-up period [20, 21, 22]. Auditory hallucinations prevalence data is also diverse; some studies reported ranges from 22% to 48% [23]. However, a more recent analysis identified a prevalence of 8.9% for auditory hallucinations and 28.2% for vHs [24]. Olfactory hallucinations are less studied but can occur alongside vHs [25]. Tactile hallucinations involving sensations of insects or small animals are also reported, albeit less frequently [26]. Gustatory hallucinations in PD have been reported in a few case reports [27]. Overall, hallucinations in PD have significant psychosocial effects and have been a major factor contributing to the placement of patients in nursing homes [1, 23, 28].

The management of PDP is challenging due to the lack of prospective studies examining its long-term benefits and concerns about the increased risk of morbidity and mortality associated with antipsychotic use. Because of this, treatment for hallucinations is typically reserved until symptoms become bothersome or pose a safety concern [16]. The introduction of atypical antipsychotics (AAPs), with the discovery of Clozapine, has revolutionized the treatment of psychotic patients. AAPs not only reduce hospitalization rates and symptom severity but also enhance safety, socialization, and rehabilitation [29, 30]. Unlike typical antipsychotics, AAPs have a broader mechanism of action, targeting not only dopamine dopamine type 2 (D2) receptors but also other receptor systems involved in regulating neurotransmitters, such as serotonin type 2A (5-HT2A) serotonin receptors (Fig. 1) [30]. Antipsychotic options for hallucinations in PD that may be considered include Clozapine, Pimavanserin, and quetiapine, as they do not significantly worsen motor symptoms [16, 31]. However, each of them has different safety and efficacy concerns.

Fig. 1.

General mechanism of action of antipsychotics. Caption: The general mechanism of action of Antipsychotics involves the inhibition of dopaminergic neurotransmission by blockage of dopamine receptors in the brain. Abbreviations: D1, Dopamine 1; D2, Dopamine 2; D3, Dopamine 3.

This review aims to thoroughly analyze and compare the commonly used antipsychotic treatment options in PDP patients presenting hallucinations, focusing on evaluating their efficacy and safety based on available evidence.

Quetiapine, a dibenzothiazepine derivative, is a pharmacologic agent with demonstrated efficacy in treating various psychiatric disorders, including bipolar disorder, schizophrenia, and depression [81]. Its precise mode of action is still unspecified. However, it is thought to work as an antagonist for the dopamine D1 and D2 receptors and the serotonin 5-HT2 receptor [82]. It also demonstrates an affinity for muscarinic M1, M3, M5, histamine H1, and 1-adrenergic receptors [83]. The anticholinergic effects of quetiapine may be attributed to its metabolite, norquetiapine, which has an affinity for several muscarinic receptors [83]. Quetiapine’s antidepressant effect is postulated to result from antagonism of the 5-HT2 and $\alpha$2 receptors, as well as noradrenaline transporter inhibition by norquetiapine [84]. Norquetiapine, the active metabolite of quetiapine, has been shown to bind to several receptors, including the serotonergic 5-HT1E, 5-HT2A, 5-HT2B, and 5-HT7 receptors, as well as the muscarinic M1, M3, and M5 receptors and the 1-adrenergic receptors [85]. This broad range of receptor affinity may contribute to the multifaceted pharmacologic effects of quetiapine. Although quetiapine is typically prescribed to treat schizophrenia and bipolar disorder, it is occasionally used off-label to treat psychosis in Parkinson’s patients [86].

Treating psychosis in PD patients presents significant challenges. While quetiapine has been given a level C rating for probable efficacy in treating PD psychosis by the American Academy of Neurology’s evidence-based practice criteria, there is still insufficient data to conclude its effectiveness [87]. A recent study by the US Department of Veterans Affairs reported an increased risk of mortality associated with quetiapine and other antipsychotic use in Parkinsonism patients, with a hazard ratio of 2.16 for quetiapine compared to non-use [88]. These findings highlight the need for caution when prescribing quetiapine to PD patients with psychosis. Given these concerns, Pimavanserin, a newly authorized molecular entity, is clinically useful for treating PD psychosis. Unlike traditional antipsychotics, Pimavanserin does not block dopamine receptors and is less likely to worsen motor symptoms [89].

In PD, vHs can be a distressing and challenging symptom to manage. Two randomized, double-anonymized, placebo-controlled studies were conducted to probe the efficacy of quetiapine in treating vHs in PD patients. Fernandez et al. [48] found that quetiapine effectively reduced the severity of hallucinations compared to a placebo, although the study had a high dropout rate due to inefficacy and drowsiness. Meanwhile, Kurlan et al. [90] did not find substantial discrepancies in the effectiveness or adverse events between the quetiapine and placebo groups in treating psychosis and agitation.

It should be noted that although the American Academy of Neurology has given quetiapine a level C rating for probable efficacy in treating PD psychosis, other organizations have stated that more data is needed to draw a firm conclusion on its effectiveness. Additionally, a recent study has reported an increased risk of mortality associated with quetiapine and other antipsychotic use in Parkinsonism patients, highlighting the importance of cautious prescribing practices [53]. Thus, while quetiapine may be a potential treatment option for vHs in PD, its benefits and risks should be carefully weighed by healthcare professionals on a case-by-case basis.

Ondo et al. [49] and Rabey et al. [50] found no substantial distinctions in outcomes between the quetiapine and placebo groups for hallucinations and drug-induced psychosis (Table 2, Ref. [48, 49, 50, 51, 68, 87, 90, 91]), with somnolence being the most common adverse event reported and dropout rates being high. Shotbolt et al. [51] also conducted an RCT and reported no considerable disparities in outcomes between the quetiapine and placebo groups. In a comparative study, Merims et al. [68] found that both quetiapine and Clozapine reduced hallucination frequency, but only Clozapine significantly reduced delusion frequency. However, both groups had high dropout rates due to low efficacy and adverse effects. Chen et al.’s systematic review [91] found that quetiapine’s efficacy in treating psychosis in Parkinsonism is not superior to placebo or Clozapine, and RCT completion rates among quetiapine-treated patients are low.

Despite having a lower risk of extrapyramidal symptoms drawn a parallel between other AAPs, quetiapine has been linked to a higher death rate in older patients with dementia-related psychosis [81]. Its D2 receptor blockage can cause neuroleptic malignant syndrome, while its use in people with major depressive disorder may raise the risk of suicidal thoughts and actions. The most commonly reported side effects of quetiapine include somnolence, orthostatic hypotension, and dizziness, which are caused by antagonistic interactions with the H1 receptor and the alpha-1 receptor [81].

One of the most significant risks of quetiapine use is a high mortality risk in aged individuals with dementia-related psychosis [92]. This risk is shared with other AAPs, and caution should be exercised when prescribing these medications to this patient population. Another risk associated with quetiapine use is the potential for prolongation of the QT interval. This risk is heightened in patients with preexisting cardiac arrhythmia, hypokalemia, or hypomagnesemia, and clinicians should carefully monitor these patients for signs of cardiac dysfunction. Metabolic panels should be assessed before initiating quetiapine treatment to identify patients at increased risk of adverse events. Additionally, careful consideration should be given to medications that may prolong the QT interval or interact with quetiapine, such as fluoxetine or ciprofloxacin.

Pimavanserin, a selective serotonergic 5-HT2a receptor targeting drug, is a promising medication for treating PD psychosis. The drug’s ability to specifically target the 5-HT2a receptor has been demonstrated in studies, showing higher affinity than other receptors such as 5-HT2b, 5-HT2c, and D3 [93]. Furthermore, Pimavanserin possesses a unique D2-blocking activity, setting it apart from other antipsychotics like Clozapine and quetiapine.

In 2016, the US Food and Drug Administration (FDA) authorized Pimavanserin for treating hallucinations and delusions in PD based on a randomized placebo-controlled trial involving 185 patients [94]. However, the FDA’s approval for Pimavanserin raised concerns as two positive trials are typically necessary for drug approval. The boxed warning for Pimavanserin highlights the increased risk of mortality associated with the drug, which is also seen with other antipsychotics. In addition, the warning cautions against QT interval prolongation, a property shared by many psychotropic drugs and other agents, which can lead to fatal cardiac arrhythmias. Given these potential risks, caution should be exercised when prescribing Pimavanserin.

Mosholder et al. [95] investigated the use of Pimavanserin in Medicare beneficiaries with PDP. They found that the drug had a lower mortality rate than other atypical antipsychotics, particularly quetiapine, during the initial six-month follow-up period. However, the study found no significant benefit for short-term or long-term use of Pimavanserin in nursing home patients [95].

A clinical trial evaluated the efficacy and safety of Pimavanserin over six weeks in patients with PDP [47]. The study found a statistically significant reduction in Scale for the Assessment of Positive Symptoms-PD (SAPS-PD) scores of participants who received Pimavanserin compared to those who received the placebo. Patients well-tolerated Pimavanserin, but peripheral edema and confusion were reported as adverse events. Nonetheless, adverse effects leading to treatment discontinuation were rare.

The durability of Pimavanserin’s response was investigated in a study involving 424 patients who had completed one of three double-anonymized, placebo-controlled core studies [96]. The subsequent open-label extension study administered pimavanserin 34 mg once daily to all patients for an additional four weeks. The study’s results demonstrated that patients who had previously taken Pimavanserin 34 mg during the core studies showed sustained efficacy during the subsequent four-week open-label extension SAPS-PD assessment. After four weeks of taking open-label Pimavanserin, individuals who had previously taken a placebo also improved. The findings provide further evidence of Pimavanserin’s effectiveness in treating PDP.

A meta-analysis examined the efficacy of 5HT2A antagonists and inverse agonists, including Pimavanserin, in treating PDP [97]. The analysis included four randomized controlled studies that compared Pimavanserin versus a placebo. The findings showed that patients who received Pimavanserin had significantly lower Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D), SAPS-H, and SAPS-D scores than those in the placebo group. Discontinuation and adverse event rates were comparable between both groups. Pimavanserin has also been researched in combination with other antipsychotic drugs, and the results are encouraging, showing fewer side effects.

People who suffer from PD often experience psychotic symptoms, leading to adverse health consequences, including higher mortality rates, increased likelihood of being placed in a nursing home, and more stress for caregivers [98]. In 2016, US FDA approved Pimavanserin as the first antipsychotic drug specifically designed to treat PDP [47]. The use of second-generation or atypical Antipsychotics (APs), such as Clozapine, quetiapine, risperidone, olanzapine, and aripiprazole, for PDP has nevertheless long been done off-label [99]. Additionally, these drugs have been used to treat adult patients with neurodegenerative illnesses’ behavioral or mood problems. Clinical safety recommendations, however, do not support their use for such reasons or in populations of older adults [99].

It is commonly believed that the use of AP in patients with PD could worsen their symptoms of Parkinsonism because of its ability to block dopamine receptors, potentially harming their safety and tolerance towards the treatment [100]. Currently, there is not a clear understanding of the exact process that leads to the decreased occurrence of Parkinsonism observed with atypical APs [100]. Several theories have been proposed to explain why atypical APs may lead to a lower incidence of Parkinsonism compared to typical APs, including the blocking of 5-HT2A receptors, the balance between 5-HT2A and D2 receptor blocking, as well as the speed at which atypical APs bind and unbind to D2 receptors in comparison to typical APs [100]. Aripiprazole, for instance, is believed to have a lower incidence of extrapyramidal side effects (EPS) because it partially antagonists the D2 receptor and the 5-HT2A receptor [101]. On the other hand, Pimavanserin is a specific 5-HT2A inverse agonist that does not have a strong affinity for most of the other receptors that atypical APs typically target [30]. As a result, it is used to treat the psychotic symptoms present in PD without aggravating the motor symptoms.

Typically, second-generation antipsychotics (SGAs) are considered a safer treatment option for individuals with PD, as they tend to exhibit less D2 antagonism than other antipsychotics [7]. However, compared to first-generation antipsychotics (FGAs), they still have a decreased propensity to cause extrapyramidal symptoms [102]. According to retrospective cohort research, 61.4% of PD patients maintained receiving overall treatment within six months after starting antipsychotic medicine, while 38.6% stopped after receiving the first prescription [103]. In contrast to the serotonin receptor-targeting medication pimavanserin, drugs that have established dopamine receptor-blocking effects, such as quetiapine, aripiprazole, risperidone, and olanzapine, were found to have a higher likelihood of leading to the discontinuation of therapy. Increased dopamine-receptor-blocking activity drug use was also linked to the termination of the first antipsychotic therapy. To ensure proper antipsychotic use in this population, the study stresses the need to understand antipsychotic cessation in PD better.

In early reports and subsequent randomized, placebo-controlled trials, Clozapine was the foremost AAP reported to reduce psychotic symptoms in patients with PDP without worsening motor symptoms [104]. According to a meta-analysis, the effectiveness of Clozapine was demonstrated by a significant effect size difference for treating psychotic symptoms against a placebo [44]. Although the empiric use of antidepressants and acetylcholinesterase inhibitors has been suggested for PDP, there is only anecdotal proof of their effectiveness and tolerability. Additionally, decreasing dopaminergic medications for motor symptoms can make psychosis worse and is ineffective in treating it in some cases. A significant decrease in the frequency and severity of hallucinations and delusions in PDP patients was observed without a decline in motor function in a critical six-week clinical trial. This study employed a placebo-controlled, randomized approach and utilized Pimavanserin, an antipsychotic with a unique pharmacological profile as a serotonin 5HT-2a receptor inverse agonist and antagonist, which does not exhibit dopaminergic antagonism [48]. Additionally, many patients receiving Pimavanserin showed complete remission, and the long-term investigations revealed no unanticipated adverse events or fresh safety concerns. However, when motor symptoms appeared unchanged, data from the four double-blind, randomized clinical studies of quetiapine for PDP have not typically supported using this medication [49, 50, 51, 68].

The efficacy of quetiapine and Clozapine in treating psychosis and PD was evaluated in two randomized studies by researchers. In one of these studies, conducted by Merims et al. [68], the efficacy of quetiapine and Clozapine was compared by analyzing the delusion and hallucination items of the Neuropsychiatric Inventory (NPI) and the Clinician Global Improvement-Change Scale (CGI-C) [105]. Despite decreased hallucination frequency in both treatment groups, only the clozapine group showed a statistically significant difference between the baseline and final assessment. Delusions were statistically significantly less frequent among participants in the clozapine group, while they were more frequent, albeit inconsistently, among those taking quetiapine. Between the two groups, there was a relative change in CGI-C scores. The motor score was absent, but the Unified Parkinson’s Disease Rating Scale (UPDRS) total score was given. No treatment group saw an increase in Parkinsonian symptoms as judged by the UPDRS. However, the completion rate of the study was only 59.26%, with lower leukocyte count being the most commonly reported reason for discontinuation in the quetiapine group and a lack of treatment effectiveness being the most frequent reason for discontinuation in the placebo group.

Morgante et al. [105] conducted a randomized controlled study to compare the effectiveness of quetiapine and Clozapine in treating psychosis and PD [106]. Seventy-five participants were randomly assigned to either quetiapine or Clozapine. Their hallucinations, suspicion, and anger were assessed using various tools, such as the brief psychiatric rating scale (BPRS), Clinician Global Improvement-Severity Scale, Abnormal Involuntary Movement Scale, and UPDRS. The participants were aware of the medication they received, while the assessors were blinded to the treatment assignments. After treatment, the BPRS, Clinician Global Improvement-Severity Scale, and Abnormal Involuntary Movement Scale scores were higher for both groups than the baseline. Three individuals receiving more than 100 mg of quetiapine daily experienced a moderate deterioration of Parkinsonism, but the overall UPDRS scores remained stable. There was no significant difference in efficacy between quetiapine and Clozapine. Both medications had few adverse effects, and there was no significant statistical difference between them. In the quetiapine group, sedation was the primary reason for dropout, while sedation, dizziness, and severe hypotension caused dropout in the clozapine group. Most participants completed the 12-week study.

In a retrospective cohort study, researchers assessed the effectiveness of quetiapine and Pimavanserin in treating psychosis in patients with PD or dementia with Lewy bodies (DLB) [107]. The study included 92 patients diagnosed with psychosis with no severe mental illness or missing follow-up data. Of those patients, 47 were treated with quetiapine and 45 with Pimavanserin. The researchers used Kaplan-Meier survival analysis to determine the duration until the antipsychotic therapy was discontinued, assuming that the discontinuation rate would be lower in the pimavanserin group. The results indicated that patients in the pimavanserin group were likelier to have DLB and a history of antipsychotic use. The time-to-discontinuation analysis showed that the pimavanserin group had a lower rate of early discontinuation and a higher rate of late discontinuation. There was no significant difference in mortality between the two groups. Quetiapine was more often prescribed for non-primary purposes than Pimavanserin. Considering the efficacy, safety, and tolerability factors, Pimavanserin might be a more suitable option for rapidly treating psychosis in PD and DLB patients. At the same time, quetiapine could provide additional secondary benefits in the long run.

In a recent study, the relative safety of Pimavanserin and quetiapine for treating PD psychosis in medicare patients was evaluated concerning the risk of hospitalization and mortality [108]. Eight hundred forty-four new pimavanserin users and 2505 new quetiapine users were enrolled in the trial. The results showed that pimavanserin users had a decreased chance of hospitalization than quetiapine users, but no discernible difference was found between the two groups’ mortality rates (Table 3, Ref. [68, 105, 106, 107]). These findings shed significant light on the safety profile of Pimavanserin and quetiapine in treating PD psychosis in elderly patients.

Additionally, the doses that resulted in dopamine blocking and sedation, as well as the effectiveness of Pimavanserin, Clozapine, and quetiapine for the treatment of PDP in an animal model, were identified. Rats with bilateral substantia nigra lesions underwent increased amphetamine-induced locomotion tests to evaluate the effectiveness of antipsychotic drugs. In rats with unilateral 6-hydroxydopamine lesions, inhibition of apomorphine-induced rotations was used to assess the antidopaminergic activity. Sedation was evaluated by looking at the amount of spontaneous movement. A selective 5-HT2A inverse agonist/antagonist, pimavanserin, may be preferable to quetiapine or Clozapine as a PDP treatment because it has a therapeutic ratio of at least 170. Therefore, Pimavanserin might be a suitable PDP medication because it can reduce psychotic symptoms at levels that do not cause drowsiness or impair motor skills.

The selection of antipsychotics for individuals with PD demands meticulous consideration of various factors, given the intricate interplay between the neurodegenerative process and psychiatric symptoms. Psychosis, hallucinations, and delusions often manifest alongside PD, necessitating a cautious approach to minimize potential adverse effects of modulating dopamine levels. Prioritizing medications with diminished affinity for dopamine D2 receptors is advised to mitigate the risk of exacerbating motor symptoms already compromised in this patient population [108].

The administration of antipsychotics may give rise to EPS, including Parkinsonism, dystonia, and akathisia. Considering the inherent susceptibility of PD patients to motor complications, careful deliberation is necessary while choosing antipsychotics with a favorable side effect profile, thereby minimizing the probability of inducing or worsening motor symptoms. Moreover, specific antipsychotics can potentially prolong the QT interval, thereby elevating the risk of life-threatening cardiac arrhythmias [109]. Given the presence of cardiac autonomic dysfunction in PD, a comprehensive assessment of the cardiac safety profile of antipsychotics assumes paramount significance [110]. It is recommended to prioritize agents with a lower inclination toward QT interval prolongation to ensure the well-being of patients [111].

PD’s management, which often entails intricate medication regimens, a comprehensive evaluation of potential drug interactions between antipsychotics and other medications is pivotal. Particular attention should be devoted to the concurrent use of dopaminergic agents to circumvent compromised efficacy or adversities stemming from drug interactions [108]. When selecting antipsychotics, individual patient characteristics exert considerable influence. Factors such as age, overall health, comorbidities, and previous medication responses should be thoughtfully considered [112]. Elderly patients may exhibit heightened vulnerability to side effects, necessitating personalized approaches, while patients with specific comorbidities may require alternative antipsychotic choices or closer monitoring.

Due to the potential risks associated with available treatments, it is essential to manage hallucinations related to PD carefully. This review analyzed the effectiveness of AAPs such as Pimavanserin and Clozapine in controlling hallucinations. However, there is limited evidence supporting the effectiveness of quetiapine in this regard. AAPs function through broad mechanisms of action involving dopamine and serotonin receptors, leading to improved outcomes and fewer side effects. Conversely, other antipsychotics like risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone can exacerbate motor symptoms and are generally not recommended.

Although AAPs have revolutionized the treatment of hallucinations related to PD, they may give rise to extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment. Clozapine poses a risk of agranulocytosis, while Pimavanserin may prolong the QTc interval. It is crucial to acknowledge that the use of antipsychotics in PD is associated with increased mortality, necessitating caution. While AAPs have demonstrated significant improvements compared to typical antipsychotics, further prospective studies are recommended to evaluate their long-term benefits and risks. These studies provide evidence that could help clinicians select and prescribe antipsychotics for hallucinations associated with PD, thereby enhancing the patients’ care.

PD, Parkinson’s disease; PDP, Parkinson’s disease psychosis; vHs, Visual hallucinations; NMDA, N-methyl-D-aspartate; AMPA, $\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; RCTs, Randomized controlled trials; 5-HT2A, serotonin type 2A; D2, Dopamine type 2; EPS, Extrapyramidal side effects; SGAs, second-generation antipsychotics; FGAs, first-generation antipsychotics; NPI, Neuropsychiatric Inventory; CGI-C, Clinician Global Improvement-Change Scale; DLB, Dementia with Lewy bodies; UPDRS, Unified Parkinson’s disease rating scale.

Conceptualization of Ideas: GMA, AA, TA-R, AAW. Sort out references: TA-R, AAW, FTA, NIM, AA, MNA, AP, GMA, LL. Create tables and figure: REH-C, NA, MK, OE, LL. Supervision: AA, GMA. Visualization: TA-R, AAW, FTA, LL. Writing Original Draft: TA-R, REH-C, NA, MK, AAW, FTA, OE, LL, NIM, AA, MNA, AP, GMA. Writing – review & editing: TA-R, REH-C, NA, MK, AAW, FTA, OE, LL, NIM, AA, MNA, AP, GMA. Funding acquisition: MNA. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Authors would like to acknowledge Toufik’s World Medical Association and ICORMed Collaborative for organizing this project.

This research work was funded by the Institutional Fund Projects under grant no. (IFPDP-80-22). Therefore, authors gratefully acknowledge technical and financial support from Ministry of Education and Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia.

The authors declare no conflict of interest. Athanasios Alexiou and Ghulam Md Ashraf are serving as the Guest editors of this journal. We declare that Athanasios Alexiou and Ghulam Md Ashraf had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel. Additionally Athanasios Alexiou is employed by AFNP Med Austria but he declares no conflict of interest with this work.