**6. Framework for securing the deployment of cloud-hosted services for guaranteeing multitenant isolation**

**85**

**Figure 3.**

*Securing the Deployment of Cloud-Hosted Services for Guaranteeing Multitenancy Isolation*

tenants (or components) experiences a high workload or security breach.

ability to change the underlying computing platform.

*6.1.1 Layer one: selection of a suitable architectural pattern*

The study presents a robust framework, CLAMP, for securing the deployment of cloud-hosted services for guaranteeing multitenancy isolation. The framework, CLAMP (Cloud-based architectural approach for securing services through Multitenancy deployment Patterns), is basically a framework for guiding software architects in securing the deployment of cloud-hosted services in a way that guarantees the required degree of isolation between other tenants when one of the

The CLAMP framework is illustrated as a layered architecture in **Figure 3**. It shows how the components of the framework work together to support the task of securing the deployment of components of a cloud-hosted service for guaranteeing multitenancy isolation. The development of CLAMP was inspired by the well understood architectural structure/pattern called layered pattern [1]. A layer is an abstract "virtual machine" that provides a cohesive set services through a managed interface. In a strictly layered system, a layer can only use the services of the layer immediately below it. This structure is used to imbue a system with portability, the

The different components of the CLAMP framework are described as follows.

This layer addresses the selection of a suitable architectural pattern. In order to secure the deployment of cloud-hosted services for guaranteeing multitenancy isolation, it may be very difficult if not impossible to use one cloud pattern to deploy the service to the cloud due to the different requirements of the service including accessibility of the service to a wider audience and a combined assurance for security and privacy. For instance, the architect would require a combination of

*A layered architecture for securing the deployment of cloud-services for guaranteeing multitenancy isolation.*

*DOI: http://dx.doi.org/10.5772/intechopen.92142*

**6.1 Developing the CLAMP framework**

The section discusses the framework for securing the deployment of cloudhosted services for guaranteeing multitenant isolation.

*Securing the Deployment of Cloud-Hosted Services for Guaranteeing Multitenancy Isolation DOI: http://dx.doi.org/10.5772/intechopen.92142*

## **6.1 Developing the CLAMP framework**

*Cloud Computing Security - Concepts and Practice*

ing component (e.g. load balancer).

**5. Related work on cloud security**

mechanism to prevent multitenancy attacks [1–3].

way that guarantees multitenancy isolation.

**guaranteeing multitenant isolation**

hosted services for guaranteeing multitenant isolation.

degrees of isolation between tenants.

suggested for use by SaaS providers such as Salesforce.com.

degree [17, 23].

tenants.

component (e.g. message queue), user interface component (e.g. AJAX) or process-

There are several solutions to multitenancy implementation which have been widely discussed in the literature. Multitenancy can be introduced at different cloud stack layers: application layer [16], middleware layer [19], and data layer [20, 21]. It has been suggested that customization is the solution to addressing the hidden constraints on multitenancy such as complexities, security, scalability and flexibility [22]. Furthermore, integrating a plugin into a cloud-based service can provide a workaround for true multitenancy. Again, most of the solutions available to incorporate multitenancy require a re-engineering of the cloud service to some

Apart from the general research on best practices in securing the cloud against

According to Bass et al., one of the significant security challenges introduced in the cloud is multitenancy [1]. Implementing multitenancy means that your cloudhosted services are utilising the virtual machine on a physical machine that host multiple virtual machines. Much of literature on multitenancy and cloud security has established that the obvious approach to addressing the problem is for cloud providers to allow users to reserve entire virtual machines for their use. Although this defeats some of the economic benefits of using the cloud, it is nevertheless a

Previous research has looked at this problem from the perspective of the cloud providers, for instance, autoscaling algorithms and supporting security-based strategies provided by IaaS providers such as Amazon and optimization frameworks

This study, however, looks at the issue from the tenant's viewpoint, who owns software components and is responsible for configuring them to build and deploy their own cloud-hosted application on a shared cloud platform where the cloud provider has no control over the software components. The focus of this chapter is to provide a framework for securing the deployment of cloud-hosted services in a

The work by [31] is one of the most detailed studies on cloud security. The author explores different aspects of security and the possible solutions that have been considered by different authors. The author did not consider approaches for securing the deployment of cloud-hosted services in a way that guarantees varying

**6. Framework for securing the deployment of cloud-hosted services for**

The section discusses the framework for securing the deployment of cloud-

various forms of attacks, there is little research on approaches to secure cloud services against attacks arising from implementing multitenancy architectures. There is also little research on approaches for securing the deployment of cloudhosted services in a way that guarantees varying degrees of isolation between

Other research work on multitenancy isolation include: [24–30].

**84**

The study presents a robust framework, CLAMP, for securing the deployment of cloud-hosted services for guaranteeing multitenancy isolation. The framework, CLAMP (Cloud-based architectural approach for securing services through Multitenancy deployment Patterns), is basically a framework for guiding software architects in securing the deployment of cloud-hosted services in a way that guarantees the required degree of isolation between other tenants when one of the tenants (or components) experiences a high workload or security breach.

The CLAMP framework is illustrated as a layered architecture in **Figure 3**. It shows how the components of the framework work together to support the task of securing the deployment of components of a cloud-hosted service for guaranteeing multitenancy isolation. The development of CLAMP was inspired by the well understood architectural structure/pattern called layered pattern [1]. A layer is an abstract "virtual machine" that provides a cohesive set services through a managed interface. In a strictly layered system, a layer can only use the services of the layer immediately below it. This structure is used to imbue a system with portability, the ability to change the underlying computing platform.

The different components of the CLAMP framework are described as follows.

#### *6.1.1 Layer one: selection of a suitable architectural pattern*

This layer addresses the selection of a suitable architectural pattern. In order to secure the deployment of cloud-hosted services for guaranteeing multitenancy isolation, it may be very difficult if not impossible to use one cloud pattern to deploy the service to the cloud due to the different requirements of the service including accessibility of the service to a wider audience and a combined assurance for security and privacy. For instance, the architect would require a combination of

#### **Figure 3.** *A layered architecture for securing the deployment of cloud-services for guaranteeing multitenancy isolation.*

several deployment patterns together with supporting technologies for archiving components of the cloud-hosted service (i.e., in a hybrid fashion) to integrate components located in a different cloud environment to form one cloud solution. Again, if communication is required internally to exchange messages between application components, then a message-oriented middleware technology would also be needed. Therefore, the challenge is that of selecting a suitable pattern (together with the supporting technologies) or a combination of patterns in order to secure the deployment of cloud-hosted services for guaranteeing multitenancy isolation. It is assumed that there is a repository of cloud deployment patterns from where a software architect can select a suitable pattern (s) to address the business requirements of the company/user.

### *6.1.2 Layer two: evaluation of the required degree of isolation between tenants*

The layer addresses the evaluation of the required degree of isolation between tenants. There are varying degrees of isolation between tenants that are accessing a cloud-hosted service. Some of the tenants would require a higher or different degree of isolation than others. Tenants would be able to share application components as much as possible at the very basic degree of multitenancy, which translates into increases use of underlying resources.

At the very basic degree of multitenancy, tenants would be able to share application components as much as possible which translates to increased utilisation of underlying resources. While some components of the application may benefit from a low degree of isolation between tenants, other components may require a higher degree of isolation because the component may be either too sensitive or cannot be shared as a result of certain corporate legislation and regulation.

There is increasing evidence, for example, that many cloud providers are reluctant to set up data centres in mainland Europe due to stricter legal requirements that prohibit data processing outside Europe [32, 33]. This requirement will traverse down to the IaaS level, and customers must take this into consideration if intending to host applications outsourced to such cloud providers [11] that host customers data outside Europe. Therefore, evaluating the required degree of isolation between the tenants will allow for the appropriate mapping of security requirements during the deployment of cloud-hosted services onto cloud provider's infrastructure.


**Comorbid Anxiety in Schizophrenia and Schizoaffective Disorder**

Delia M. Podea, Aurora I. Sabau and Karol J. Wild

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60643

#### **Abstract**

There is some evidence that antipsychotic medication (Quetiapine) is somewhat ef‐ ficient in reducing anxiety in schizophrenic patients.

This study compared the efficacy of Olanzapine and Quetiapine versus Risperi‐ done, Aripiprazole, and Haloperidolum in reducing the anxiety symptoms in pa‐ tients diagnosed with schizophrenia and schizoaffective disorder hospitalized in the Psychiatry Department of Arad between 2013–2014.

Considering the treatment, 63 subjects were divided in two groups: T1 (treated with Olanzapine and Quetiapine) and T2 (treated with Haloperidolum, Risperidone, and Aripiprazol).

Anxiety is frequent in the course of schizophrenia and schizoaffective disorder with significant differences among the two groups. After treatment, the level of anxiety reduced with significant improvement of total score of PANSS; the effect is higher in group T2 compared to T1. Before treatment, anxiety is positively correlated with scores of PANSSN (r=.285; p=0.010), PANSST (r=.260; p=0.040), and HAM-D (r=.455; p<0.0001).YMRS is negatively correlated with negative items of PANSSN scale (r=-. 321; p=0.010). IQ (intelligence quotient) was decreased posttreatment for both treat‐ ments, but T1 had had a higher effect on it.

Some antipsychotics have been reported to be successful in reducing the anxiety level in psychotic patients: in group T2 the treatment has a higher effect on anxiety and lower size effect on intelligence.

**Keywords:** Anxiety, Schizophrenia, Schizoaffective Disorder, Antipsychotics

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Anxiety disorders are serious, debilitating conditions, with wide discrepancies being found in the reports of the prevalence rates, in clinical and epidemiological studies.

Based on the literature, the rate of prevalence of anxiety disorder in patients with schizophrenia or schizoaffective disorder remains uncertain due to limiting factors: the definitions of the disorders themselves the sample size, the study procedures and the utilization of different measures and clinical assessments.

A meta-analysis by Achim et al., in 2011, found a prevalence rate for anxiety disorder of 38.3% in the schizophrenic population, compared with 28.8% reported for the general population [1].

Seedat et al., in 2007, in a study of hospitalized schizophrenic patients, found that 25% suffered from anxiety disorder [2]. In 2007, using a sample of inpatients, Ciapparelli et al. found anxiety disorders in 74% of the subjects [3].

In a study conducted by Braga et al., in 2004, 42% of schizophrenic outpatients presented anxiety disorders [4].

In schizoaffective disorder, the rates of anxiety disorders range from 32% in outpatients [3] to 45% in inpatients [5].

Schizophrenia is a common, chronic and severe mental illness defined by the presence of delusions, hallucinations, and disorganized behavior (positive symptoms); by the presence of apathy, social withdrawal, and involution (negative symptoms); and by cognitive disorgani‐ zation [6].

It has long been known that anxiety has an important role in the psychopathology of schizo‐ phrenia. However, the nature of the development of anxiety disorder in psychosis is not well understood.

The presence of the comorbidity of anxiety in major psychotic disorders (schizophrenia, schizoaffective disorder) results in reduced cognitive functioning, increases the severity of comorbid medical conditions, increases the risk of reoccurrence, adds to internalized stigma, reduces functioning, and has a negative impact on the overall outcome for the patient.

Comorbid anxiety in schizophrenia and schizoaffective disorder is associated with the more positive symptoms: extrapyramidal symptoms suggesting more severe medication side effects [6], an increase in drug/alcohol abuse, a worsening of social and professional functioning, and in the quality of life [7].

Anxiety is common among patients with schizophrenia or schizoafective disorder, and it may also manifest itself as a symptom during an acute psychotic episode [8], as a result of the side effects of medication or as a symptom of a comorbid anxiety disorder. Patients are generally discharged as soon as their psychotic episode is resolved, with little recognition of the presence of an anxiety disorder [9].

It is difficult to evaluate the relation of anxiety to psychotic symptoms since it is not clear which anxiety symptoms the disorder is associated with. Furthermore, the operational criteria developed for the assessment of the level of anxiety found in the nonpsychotic population (Hamilton Anxiety Rating Scale, Yale Brown Obsession Compulsion Rating) may themselves be problematic. Extrapyramidal symptoms which develop secondary to neuroleptic treatment may coincide with anxiety symptoms [7].

**1. Introduction**

132 A Fresh Look at Anxiety Disorders

measures and clinical assessments.

disorders in 74% of the subjects [3].

anxiety disorders [4].

45% in inpatients [5].

zation [6].

understood.

in the quality of life [7].

of an anxiety disorder [9].

Anxiety disorders are serious, debilitating conditions, with wide discrepancies being found in

Based on the literature, the rate of prevalence of anxiety disorder in patients with schizophrenia or schizoaffective disorder remains uncertain due to limiting factors: the definitions of the disorders themselves the sample size, the study procedures and the utilization of different

A meta-analysis by Achim et al., in 2011, found a prevalence rate for anxiety disorder of 38.3% in the schizophrenic population, compared with 28.8% reported for the general population [1]. Seedat et al., in 2007, in a study of hospitalized schizophrenic patients, found that 25% suffered from anxiety disorder [2]. In 2007, using a sample of inpatients, Ciapparelli et al. found anxiety

In a study conducted by Braga et al., in 2004, 42% of schizophrenic outpatients presented

In schizoaffective disorder, the rates of anxiety disorders range from 32% in outpatients [3] to

Schizophrenia is a common, chronic and severe mental illness defined by the presence of delusions, hallucinations, and disorganized behavior (positive symptoms); by the presence of apathy, social withdrawal, and involution (negative symptoms); and by cognitive disorgani‐

It has long been known that anxiety has an important role in the psychopathology of schizo‐ phrenia. However, the nature of the development of anxiety disorder in psychosis is not well

The presence of the comorbidity of anxiety in major psychotic disorders (schizophrenia, schizoaffective disorder) results in reduced cognitive functioning, increases the severity of comorbid medical conditions, increases the risk of reoccurrence, adds to internalized stigma, reduces

Comorbid anxiety in schizophrenia and schizoaffective disorder is associated with the more positive symptoms: extrapyramidal symptoms suggesting more severe medication side effects [6], an increase in drug/alcohol abuse, a worsening of social and professional functioning, and

Anxiety is common among patients with schizophrenia or schizoafective disorder, and it may also manifest itself as a symptom during an acute psychotic episode [8], as a result of the side effects of medication or as a symptom of a comorbid anxiety disorder. Patients are generally discharged as soon as their psychotic episode is resolved, with little recognition of the presence

It is difficult to evaluate the relation of anxiety to psychotic symptoms since it is not clear which anxiety symptoms the disorder is associated with. Furthermore, the operational criteria

functioning, and has a negative impact on the overall outcome for the patient.

the reports of the prevalence rates, in clinical and epidemiological studies.

Progress in understanding the etiology of comorbid anxiety in major psychotic disorders such as schizophrenia or schizoaffective disorder has been made. For example, in the field of genetics, two basic genetic strategies have been developed, enabling a better understanding of the etiology of anxiety: the linkage approach and the polymorphism or susceptibility allele, which associates different genes (e.g., dysbindin, the gene for the dystrobrevin-binding protein 1, located within the linkage peak on chromosome 6 p; or chromosomal regions, e.g., 6p22.3) with traits or illness [10].

Generally, anxiety disorders are relatively responsive to treatment so greater awareness should be paid to their comorbidity with psychosis in order to obtain clinical benefits.

Comorbid anxiety may have implications for treatment choice. Generally, anxiety is consid‐ ered to be secondary to the psychotic condition and it is expected to improve simultaneous with an improvement in the schizophrenic symptoms. There is some evidence that antipsy‐ chotic medication (such as Quetiapine) has some degree of efficacy in reducing anxiety in schizophrenic patients [11].

The treatment for acute schizophrenia involves one of the newer generation antipsychotic drugs which is well-tolerated and can be used for maintenance therapy. In particular, it is desirable to use drugs with little sedative effect in order to optimize functioning and to preserve the quality of life [12,13]. However, lack of compliance with antipsychotics must be taken in consideration as it is known that nonadherence plays a significant role in psychotic relapse. In these cases, long-acting injectable antipsychotics (administered at two to four week intervals) are preferable as they may result in a lower risk of dose-related adverse effects (because of lower peak antipsychotic plasma levels) and lower rates of hospitalization due to acute exacerbations. These factors contribute to improving the individual quality of life.

A personalized treatment approach is necessary in the management of comorbid anxiety with schizophrenia which should be based on the pathogeneses and the clinical assessments.

In clinical practice, in those patients with significant agitation and anxiety, drugs with low sedative potential are not sufficient for the reduction of these symptoms. In these patients, anxiety may interfere with compliance to medication. So, benzodiazepines or sedative neuroleptics (levomepromazine) are often incorporated into the antipsychotic treatment [13].

In practice, two strategies are available to satisfactorily manage the severe anxiety associated with acute psychotic episodes: the use of sedative antipsychotic drugs (thioridazine, pipam‐ perone, melperone, cyamemazine, a-flupenthixol, and levomepromazine) [14, 15, 16] or the use of adjuvant benzodiazepines therapy [17, 18, 19]. These sedative antipsychotics have been shown to have anxiolytic effects at low doses both in nonpsychotic patients and during acute psychotic episodes [18].

In order to prevent the risk of benzodiazepine dependence and rebound anxiety on the cessation of treatment, the use of benzodiazepines should be for as short a period as possible. Benzodiazepines should be prescribed in combination with nonsedative disinhibitory atypical antipsychotics.

Benzodiazepines used in psychotic episodes are drugs with potent anxiolytic action, a low propensity for pharmacokinetic drug interactions, and a long half-life to ensure uninterrupted cover [19, 20].

After the patient reaches a position where the symptoms are well-controlled, the treatment can be switched to a nonsedative antipsychotic for maintenance therapy.

Some atypical antipsychotics rely on the serotonin (5-HT) neurotransmitter system. The antagonism of 5-HT receptors permits the atypical antipsychotics to have a lower propensity to cause extrapyramidal symptoms and tardive dyskinesia.

The 5-HT actions may also result in improvements in the negative or cognitive symptoms of schizophrenia.

It has been proposed that the antagonism of 5-HT receptors and/or partial antagonism of 5- HT receptors and antihistaminic properties may play a role in the antianxiety effect of some atypical antipsychotics.

The literature indicates that Olanzapine and Quetiapine have a degree of efficacy in reducing anxiety in schizophrenic and schizoaffective patients [11, 19].

In order to explore the efficacy of atypical antipsychotics in reducing comorbid anxiety in schizophrenic and schizoaffective patients, we performed a study in our clinic.

We aimed to measure the efficacy of various antipsychotics in reducing anxiety levels in patients diagnosed with schizophrenia and schizoaffective disorder, who had been hospital‐ ized in Arad between 2013-2014.

### **2. Methodology**

#### **2.1. Objectives**

The aims of this study are: (a) to determine the relationship between anxiety and schizophre‐ nia/ schizoaffective disorder, (b) to determine if the anxiety level is reduced under pharma‐ cological treatment and to compare the efficacy in the two groups (T1- Olanzapine, Quetiapine; and T2- Haloperidolum, Risperidone, Aripiprazol), and (c) to estimate the effect of antipsy‐ chotic treatment on cognitive ability (intelligence level, IQ).

#### **2.2. Sample**

Sixty three patients diagnosed with schizophrenia, schizoaffective disorder, and anxiety were evaluated on admission and after 28 days of antipsychotic treatment. The patients were hospitalized in the Psychiatry Ward of The County Clinical Emergency Hospital in Arad, between 2013–2014. The patients were divided in two groups: T1, who receieved anthypsi‐ chotic treatment with Olanzapine or Quetiapine; and group T2, who received treatment with typical and atypical antipsychotics (Haloperidolum, Risperidone, and Aripiprazol).

The diagnoses of schizophrenia, schizoaffective disorder and anxiety disorders were estab‐ lished according to the ICD-1021[and DSM-V-TM22] criteria.

**Table 1.** Sample characteristics

The sample (Table 1) presented the following socio-demographic characteristics: (a) gender: 54% females, 46% males; (b) age: mean = 43.27, SD = 7.5; (c) education: 9% secondary school, 33.3% high school, 46% professional school and 7% university; (d) marital status: 7.9% never married, 20.6% married, 20.6% divorced, and 7.9% in a relationship; and (e) 6.3% alcohol use.

#### **2.3. Measures**

In order to prevent the risk of benzodiazepine dependence and rebound anxiety on the cessation of treatment, the use of benzodiazepines should be for as short a period as possible. Benzodiazepines should be prescribed in combination with nonsedative disinhibitory atypical

Benzodiazepines used in psychotic episodes are drugs with potent anxiolytic action, a low propensity for pharmacokinetic drug interactions, and a long half-life to ensure uninterrupted

After the patient reaches a position where the symptoms are well-controlled, the treatment

Some atypical antipsychotics rely on the serotonin (5-HT) neurotransmitter system. The antagonism of 5-HT receptors permits the atypical antipsychotics to have a lower propensity

The 5-HT actions may also result in improvements in the negative or cognitive symptoms of

It has been proposed that the antagonism of 5-HT receptors and/or partial antagonism of 5- HT receptors and antihistaminic properties may play a role in the antianxiety effect of some

The literature indicates that Olanzapine and Quetiapine have a degree of efficacy in reducing

In order to explore the efficacy of atypical antipsychotics in reducing comorbid anxiety in

We aimed to measure the efficacy of various antipsychotics in reducing anxiety levels in patients diagnosed with schizophrenia and schizoaffective disorder, who had been hospital‐

The aims of this study are: (a) to determine the relationship between anxiety and schizophre‐ nia/ schizoaffective disorder, (b) to determine if the anxiety level is reduced under pharma‐ cological treatment and to compare the efficacy in the two groups (T1- Olanzapine, Quetiapine; and T2- Haloperidolum, Risperidone, Aripiprazol), and (c) to estimate the effect of antipsy‐

Sixty three patients diagnosed with schizophrenia, schizoaffective disorder, and anxiety were evaluated on admission and after 28 days of antipsychotic treatment. The patients were

schizophrenic and schizoaffective patients, we performed a study in our clinic.

can be switched to a nonsedative antipsychotic for maintenance therapy.

to cause extrapyramidal symptoms and tardive dyskinesia.

anxiety in schizophrenic and schizoaffective patients [11, 19].

chotic treatment on cognitive ability (intelligence level, IQ).

antipsychotics.

134 A Fresh Look at Anxiety Disorders

cover [19, 20].

schizophrenia.

atypical antipsychotics.

ized in Arad between 2013-2014.

**2. Methodology**

**2.1. Objectives**

**2.2. Sample**

All subjects were evaluated using the following measures:

range (or in clinical remission), while a score of 20 or higher (indicating at least moderate severity) is usually required for entry into a clinical trial. HAMD have good internal consistency, between 0.77 to 0.91.

#### **2.4. Procedure and design**

The participants of this study filled in the tests package presented at the section work instru‐ ments. For the protection of the participants, they only noted a code on the answer papers. We shall use the variance analysis (ANOVA factorial) considering that we shall observe the simultaneous influence of two interdependent variables on the dependent variable.

We have structured our research into three studies as follows:

ANOVA 2 x 2 as a statistical indicator is helpful to observe as well the evolution in time, as well the effect on the dependent variables of the interaction between treatment condition and evolution in time as independent variables.

We have calculated **ANCOVA - General Lineal Model Univariate Analysis of Variance** for the cases in which we have observed an initial difference between the dependent variables means (e.g., PANSS-P, PANSS-G, PANSS-T, HAMD).

ANCOVA as a statistic indicator helps to eliminate the initial difference (preintervention) from the end-results (postintervention) in order to see if at the end the difference is significant as a result of intervention and to estimate which would be the end-results means if we wouldn't had initial differences.

**c.** a comparative study—on effect of the treatment on IQ as a dependent variable, for this propose we have used ANCOVA - Univariate Analysis of Variance, because we have observed a initial difference between the two groups regarding the IQ level.

### **3. Results**

range (or in clinical remission), while a score of 20 or higher (indicating at least moderate severity) is usually required for entry into a clinical trial. HAMD have good internal

**d. YoungMania Rating Scale (YMRS)**[26] is a rating scale used to evaluate manic symptoms in individuals with mania. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the previous 48 hours. The studies regarding the psychometric characteristics of YMRS report a high degree of internal consistency (α

**e. Raven's Progressive Matrices** [27] is a nonverbal multiple choice measure of general intelligence; in each test item, the subject is asked to identify the missing element that completes a pattern. On the Romanian sample of 2755 subjects, RPM reported a high

The participants of this study filled in the tests package presented at the section work instru‐ ments. For the protection of the participants, they only noted a code on the answer papers. We shall use the variance analysis (ANOVA factorial) considering that we shall observe the

**a.** a correlation study—for which we have used Pearson correlation "r," in order to establish

**b.** a comparative study—between pre- and postintervention, respectively, between the two treatments on the dependent variables (anxiety, mania, depression, and positive versus negative psychotic symptoms); we have calculated **ANOVA 2 x 2 - General Lineal Model for Repeated Measurements** for the cases in which there was no initial (pretreatment) difference between the dependent variables means (e.g., HAMA, YMRS, PANSS-N). ANOVA 2 x 2 as a statistical indicator is helpful to observe as well the evolution in time, as well the effect on the dependent variables of the interaction between treatment condition and

We have calculated **ANCOVA - General Lineal Model Univariate Analysis of Variance** for the cases in which we have observed an initial difference between the dependent variables

ANCOVA as a statistic indicator helps to eliminate the initial difference (preintervention) from the end-results (postintervention) in order to see if at the end the difference is significant as a result of intervention and to estimate which would be the end-results means if we wouldn't

**c.** a comparative study—on effect of the treatment on IQ as a dependent variable, for this propose we have used ANCOVA - Univariate Analysis of Variance, because we have

observed a initial difference between the two groups regarding the IQ level.

simultaneous influence of two interdependent variables on the dependent variable.

the relationship between all measurements in the pretreatment phase.

We have structured our research into three studies as follows:

consistency, between 0.77 to 0.91.

internal consistency (α =.91).

evolution in time as independent variables.

had initial differences.

means (e.g., PANSS-P, PANSS-G, PANSS-T, HAMD).

**2.4. Procedure and design**

= 0.91).

136 A Fresh Look at Anxiety Disorders

#### **3.1. Correlations**

Before treatment, anxiety is positively correlated with the total score of negative items on the PANSS scale (PANSSN: r =.285; p = 0.010); anxiety is also positively correlated with the total score on PANSS (PANSST: r =.260; p = 0.040) and the total score for depression assessed according to the Hamilton Depression Scale (HAM-D: r =.455; p<0.0001).

The score on the YMRS is negatively correlated with negative items on the PANSSN scale (r = -.321; p = 0.010). In general, it is to be expected that a subject with negative symptoms will have a lower level of mania.

The IQ was positive correlated with the total score on the PANSS scale (PANSST: r =.261; p = 0.036) suggesting, in our study, that a higher level of intelligence represents possible a risk in the development of psychotic symptoms. The observed positive correlation between PANSST and IQ accounts for approximately 9% of the variation.

PANSS-P = positive items of PANSS scale; PANSS-N = negative items of PANSS scale; PANNS-G = general items of PANSS scale; PANSS-T = total score of PANSS scale; HAMA = Hamilton anxiety scale; YMRS = Young Mania Rating scale; HAMD = Hamilton Depression scale; \*. Significant at the 0.05 level (2-tailed). \*\*. Significant at the 0.01 level (2-tailed).

**Table 2.** Preintervention correlations between all measurements

Based on these results, there is a possibility that IQ can be a risk factor in 9% of the cases to stimulate the productivity of psychotic symptoms. Given this fact, we need to exercise a degree of caution with regard to the afore mentioned conclusion.

#### **3.2. Comparing treatments**

To assess the level of the anxiety disorders in both groups before and after 28 days of antipsy‐ chotic treatment, we used an ANOVA 2 x 2 design.

Because we expected that there would be initial differences between the two groups (T1 and T2), we also performed a t-test for independent samples (table 2) for the pretreatment values, in order to eliminate, if necessary, any initial differences from the postintervention results by calculating ANCOVA in such cases.

We obtained statistically significant difference for the PANSS-P, PANSS-G, PANSS-T, and HAM-D. To compare the efficacy of the treatment for these dependent variables between the two groups we used ANCOVA.

PANSS-P = positive items of PANSS scale; PANSS-N = negative items of PANSS scale; PANNS-G = general items of PANSS scale; PANSS-T = total items of PANSS scale; HAMA = Hamilton anxiety rating scale; YMRS = Young Mania Rating SCALE; HAMD = hamilton depression rating scale;

**Table 3.** Preintervention differences between the two groups (in order to see if it is necessary to use ANCOVA

As the main goal of this study was to evaluate the efficacy of antipsychotic treatment for anxiety, we compared the level of anxiety pre and postintervention, by using ANOVA because there were no initial differences observed (see table 3).

Results showed that there were differences in the level of anxiety reduction between the two groups: in group T2, the efficacy of the treatment was significantly higher than that of group T1. The result obtained was confirmed by the t-test for independent samples applied postin‐ tervention at T1 and T2 (t = 3.018; p =.004).

**Table 4.** Comparing the level of anxiety pre and postintervention and between groups

The difference in anxiety reduction between the two groups (see table 4) was also measured, by comparing T2 with T1 with Cohen's D = 0, 7583; r = 0.3545.

Using the t-test for paired samples *t* (T1) = -4.901, p<0.0001 and *t* (T2) = -9.043, p<0.001, the results obtained in our preliminary study revealed that both types of treatments are effective in significantly reducing the intensity of anxiety both for schizophrenic and schizoaffective patients. in significantly reducing the intensity of anxiety both for schizophrenic and schizoaffective patients.

 TS1= schizophrenic patients in T1 group TA1 = schizoaffective patients in T1 group TS2= schizophrenic patients in T2 group TA2 = schizoaffective patients in T2 group

**Figure 1.** Pretreatment and posttreatment level of anxiety for both groups T1 (TS1 and TA1) and T2 (TS2 and TA2)

For both groups(Figure1), the results showed that with regard to the efficacy of the For both groups(Figure1), the results showed that with regard to the efficacy of the treatments for the patients diagnosed with schizoaffective disorder compared to schizophrenic patients, there was no difference, *t* (T1) = -3.94, p = 0.697 and *t* (T2) = 0.212, p = 0.933.

**Figure 1. Pretreatment and posttreatment level of anxiety for both groups T1 (TS1 and**

#### treatments for the patients diagnosed with schizoaffective disorder compared to **3.3. Comparing IQ**

**Comparing IQ**

in group T1.

**TA1) and T2 (TS2 and TA2)**

Because we expected that there would be initial differences between the two groups (T1 and T2), we also performed a t-test for independent samples (table 2) for the pretreatment values, in order to eliminate, if necessary, any initial differences from the postintervention results by

We obtained statistically significant difference for the PANSS-P, PANSS-G, PANSS-T, and HAM-D. To compare the efficacy of the treatment for these dependent variables between the

> **Mean Difference**

**.t. df Sig. (2-**

**tailed)**

*t-test for Equality of Means*

**-2.800 61 .007** -1.8589 .6638 -3.1862 -.5315

.578 61 .566 .6310 1.0926 -1.5538 2.8159

**4.302 61 .000** 6.1028 1.4187 3.2659 8.9397

**2.206 61 .031** 4.8468 2.1966 .4543 9.2392

1.025 61 .310 1.2319 1.2023 -1.1723 3.6360

.181 61 .857 .3992 2.2024 -4.0047 4.8031

**3.208 61 .002** 3.4980 1.0903 1.3179 5.6781

PANSS-P = positive items of PANSS scale; PANSS-N = negative items of PANSS scale; PANNS-G = general items of PANSS scale; PANSS-T = total items of PANSS scale; HAMA = Hamilton anxiety rating scale; YMRS = Young Mania

As the main goal of this study was to evaluate the efficacy of antipsychotic treatment for anxiety, we compared the level of anxiety pre and postintervention, by using ANOVA because

Results showed that there were differences in the level of anxiety reduction between the two groups: in group T2, the efficacy of the treatment was significantly higher than that of group T1. The result obtained was confirmed by the t-test for independent samples applied postin‐

**Table 3.** Preintervention differences between the two groups (in order to see if it is necessary to use ANCOVA

**Std. Error Difference** **95% Confidence Interval of the Difference**

**Lower Upper**

calculating ANCOVA in such cases.

two groups we used ANCOVA.

PANSS-P Equal variances assumed

PANSS-N Equal variances assumed

PANSS-G Equal variances assumed

PANSS-T Equal variances assumed

HAMA Equal variances assumed

HAMD Equal variances assumed

Equal variances assumed

Rating SCALE; HAMD = hamilton depression rating scale;

tervention at T1 and T2 (t = 3.018; p =.004).

there were no initial differences observed (see table 3).

YOUNG MANIA

**Pre-intervention measurments**

138 A Fresh Look at Anxiety Disorders

schizophrenic patients, there was no difference, *t* (T1) = ‐3.94, p = 0.697 and *t* (T2) = 0.212, p = 0.933. To eliminate the initial preintervention IQ differences between groups (*t*=5,162; p<.0001) we applied ANCOVA. In both groups of patients, antipsychotic treatment has a negative effect on cognitive functioning reducing IQ level, but the cognitive dysfunction was higher in group T1.

To eliminate the initial preintervention IQ differences between groups (*t*=5,162; p<.0001)

we applied ANCOVA. In both groups of patients, antipsychotic treatment has a negative effect on cognitive functioning reducing IQ level, but the cognitive dysfunction was higher

**Figure 2.** Evolution of the IQ levels in T1 and T2 group

The results obtained showed that in posttreatment (Figure 2) there were no statistically significant differences between the two groups, ANCOVA F = 1.085, p = 0.302. A possible explanation for these results is that the T1 treatment had a greater effect on cognitive func‐ tioning when compared with the T2 treatment, so that even if the T2 group initially had a lower intelligence level, after 28 days the difference was no longer significant (see Table 5).

**Table 5.** Estimated marginal means after eliminating the covariance of the Initial IQ

### **4. Discussions and conclusions**

**Figure 2.** Evolution of the IQ levels in T1 and T2 group

**Dependent Variable: IQ in evolution**

140 A Fresh Look at Anxiety Disorders

The results obtained showed that in posttreatment (Figure 2) there were no statistically significant differences between the two groups, ANCOVA F = 1.085, p = 0.302. A possible explanation for these results is that the T1 treatment had a greater effect on cognitive func‐ tioning when compared with the T2 treatment, so that even if the T2 group initially had a lower

T1 treatment **74.07a** .93 72.21 75.93

T2 treatment **75.551** .91 73.72 77.37

**95% Confidence Interval Lower Bound Upper Bound**

intelligence level, after 28 days the difference was no longer significant (see Table 5).

**Pre-Post Mean Std. Error**

Note: a.Covariates appearing in the model are evaluated at the following values: IQ initial = 82.048.

**Table 5.** Estimated marginal means after eliminating the covariance of the Initial IQ

The study's results proved that preintervention anxiety is positively correlated with the total score on PANSSN (r =.285; p = 0.010) and PANSST (r = 0.260; p = 0.040) and the total score on HAM-D (r = 0.455; p<0.0001). Also the score on the YMRS is negatively correlated with the negative items on the PANSSN scale (r = -0.321; p = 0.010). Our results are corroborated by international studies [28, 29].

Based on the results of our study, the efficacy of Olanzapine or Quetiapine is lower than that of the typical and other atypical antipsychotics (such as Haloperidolum, Risperidone, Aripi‐ prazol). Olanzapine or Quetiapine have a greater negative effect on cognitive functioning than other antipsychotics.

These results are contrary to the international findings [11, 19, 30, 31].

In a study by Riedl et al., 2007 [19], both Quetiapine and Olanzapine improved cognition; however, the improvement in cognitive index scores was more marked in patients receiving Quetiapine. Quetiapine produce a significantly better improvement in reaction quality/ attention than Olanzapine [11, 19].

Olanzapine, an atypical antipsychotic, has proved to be efficient in reducing the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well-controlled trials involving patients diagnosed with schizophrenia, Olanzapine (5 to 20 mg/day) was superior to Haloperidol (5 to 20 mg/day) in the treatment of depressive and negative symp‐ toms, comparable with effects on positive psychotic symptoms [28]. Contrary to these findings, in our study patients treated with haloperidol, Risperidone, and Aripiprazol (group T2) showed a greater reduction of symptomatology.

The 1-year risk of relapse of rehospitalisation was significantly lower with Olanzapine than with Haloperidol treatment [35].

In the first double-blind comparative study [28, 29, 33]) of Olanzapine 10 to 20 mg/day and Risperidone 4 to 12 mg/day, Olanzapine proved to be significantly more effective than Risperidone in the treatment of negative and depressive symptoms but not for overall psychopathological symptoms.

In contrast, preliminary results from an 8-week controlled study [34] suggested that Risperi‐ done 2 to 6 mg/day was superior to Olanzapine 5 to 20 mg/day in the treatment of positive and anxiety/depressive symptoms, and that both agents demonstrated similar efficacy on overall psychopathology. These results are similar to our findings (Risperidone was superior to Olanzapine in reducing anxiety symptoms as confirmed by t-test for independent samples applied postintervention at T1 and T2: t = 3.018; p = 0.004).

However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects for Olanzapine and Risperidone in patients with schizophrenia or schizoaffective disorder [30]. In our study, in both groups of patients, (T1, T2), antipsychotic treatment has a

negative effect on cognition with a larger effect on group T1 treated with Olanzapine and Quetiapine.

Olanzapine demonstrated superior antipsychotic efficacy when compared to Haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with firstepisode or treatment-resistant schizophrenia [35].

The reduced risk of adverse events and the therapeutic superiority, compared with Haloper‐ idol and Risperidone, in the treatment of negative and depressive symptoms support the choice of Olanzapine as a first-line option in the management of schizophrenia in the acute and maintenance phase of treatment response [36].

Aripiprazole, a 5-H1A partial agonist was found to have a considerable antianxiety effect which may concur with procognitive and mood-ameliorating effects [32, 37, 38]. These are similar to our results: when comparing T2 with T1 using effect size based on differences between means (Cohen's D = 0.7583; r = 0.3545), Aripiprazol is superior to Olanzapine and Quetiapine in reducing anxiety in schizophrenic and schizoaffective disorder patients. Regarding the cognitive dysfunction, posttreatment, in both groups of patients, we noticed a negative effect on cognition, although there was no statistically significant differences between the groups as determined by analysis of covariance (ANOVA F = 1.085; p = 0.302).

One hypothesis could be that this agonism of Aripiprazole is a mechanism contributing to antianxiety effects. Case reports and studies on the antipsychotic augmentation by Aripipra‐ zole in partial responders to Clozapine found a considerable antianxiety effect [32].

However, this could be due to external factors or to the natural evolution of the illness. A randomized controlled study is required to evaluate the efficacy of the Clozapine-Aripiprazole combination in cases of treatment-resistant schizophrenia with a predominance of anxiety [39].

Risperidone's antianxiety action was demonstrated in the study by Blider et al. in 2002 [30], conducted on 62 patients hospitalized for acute exacerbations of schizophrenia, randomly assigned to receive Risperidone (a mean dose, 7.4 mg/day), Haloperidol (7.6 mg/day), or Methotrimeprazine (100 mg/day) for 4 weeks. The antianxiety effects were significantly greater in the Risperidone patients than the Methotrimeprazine patients. The difference between Haloperidol and Methotrimeprazine was not significant.

It is concluded that Risperidone is an effective antipsychotic and anxiolytic agent in schizo‐ phrenic patients. These result are confirmed by our findings in group T2 (t = 3.018; p = 0.004).

#### **New Drug Perspectives**

It is generally agreed upon that anxiety is a frequently occurring symptom of schizophrenia, strongly associated with an increased risk of relapse and more severe symptomatology. The effects of antipsychotics in reducing anxiety in psychotic patients remain controversial and the practice of prescribing adjuvants (benzodiazepines) is unsatisfactory [17, 18].

The next clinical trials for schizophrenia with comorbid anxiety perhaps will show the efficacy of some new compounds (the anticonvulsant/anxiolytic pregabalin and the atypical antipsy‐ chotic Quetiapine) [40].

Consequently, we think there is a need for more research in order to obtain a clear perspective of the efficacy of Olanzapine or Quetiapine. It should also be pointed out that our findings suffer from certain limitations: such as (a) the lack of a control group, (b) the small sample size, (c) the short treatment time, and (d) the lack of a follow-up evaluation after three and six months, and after one year. Our results can serve as a guide to future studies regarding the efficacy of psychopharmacological treatment on comorbid anxiety.

### **Limitations**

negative effect on cognition with a larger effect on group T1 treated with Olanzapine and

Olanzapine demonstrated superior antipsychotic efficacy when compared to Haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-

The reduced risk of adverse events and the therapeutic superiority, compared with Haloper‐ idol and Risperidone, in the treatment of negative and depressive symptoms support the choice of Olanzapine as a first-line option in the management of schizophrenia in the acute

Aripiprazole, a 5-H1A partial agonist was found to have a considerable antianxiety effect which may concur with procognitive and mood-ameliorating effects [32, 37, 38]. These are similar to our results: when comparing T2 with T1 using effect size based on differences between means (Cohen's D = 0.7583; r = 0.3545), Aripiprazol is superior to Olanzapine and Quetiapine in reducing anxiety in schizophrenic and schizoaffective disorder patients. Regarding the cognitive dysfunction, posttreatment, in both groups of patients, we noticed a negative effect on cognition, although there was no statistically significant differences between

One hypothesis could be that this agonism of Aripiprazole is a mechanism contributing to antianxiety effects. Case reports and studies on the antipsychotic augmentation by Aripipra‐

However, this could be due to external factors or to the natural evolution of the illness. A randomized controlled study is required to evaluate the efficacy of the Clozapine-Aripiprazole combination in cases of treatment-resistant schizophrenia with a predominance of anxiety [39]. Risperidone's antianxiety action was demonstrated in the study by Blider et al. in 2002 [30], conducted on 62 patients hospitalized for acute exacerbations of schizophrenia, randomly assigned to receive Risperidone (a mean dose, 7.4 mg/day), Haloperidol (7.6 mg/day), or Methotrimeprazine (100 mg/day) for 4 weeks. The antianxiety effects were significantly greater in the Risperidone patients than the Methotrimeprazine patients. The difference between

It is concluded that Risperidone is an effective antipsychotic and anxiolytic agent in schizo‐ phrenic patients. These result are confirmed by our findings in group T2 (t = 3.018; p = 0.004).

It is generally agreed upon that anxiety is a frequently occurring symptom of schizophrenia, strongly associated with an increased risk of relapse and more severe symptomatology. The effects of antipsychotics in reducing anxiety in psychotic patients remain controversial and the

The next clinical trials for schizophrenia with comorbid anxiety perhaps will show the efficacy of some new compounds (the anticonvulsant/anxiolytic pregabalin and the atypical antipsy‐

practice of prescribing adjuvants (benzodiazepines) is unsatisfactory [17, 18].

the groups as determined by analysis of covariance (ANOVA F = 1.085; p = 0.302).

zole in partial responders to Clozapine found a considerable antianxiety effect [32].

Quetiapine.

142 A Fresh Look at Anxiety Disorders

episode or treatment-resistant schizophrenia [35].

and maintenance phase of treatment response [36].

Haloperidol and Methotrimeprazine was not significant.

**New Drug Perspectives**

chotic Quetiapine) [40].

The methodological limitations of this study will be addressed in a follow-up study: this was a preliminary study with a small sample size, lacking follow up evaluations at 3 months, 6 months and 1 year. Given that some of these patients will be inevitably lost to the follow up, a large sample size will need to be used in order to ensure that sufficient numbers are available to obtain meaningful repeat measures.

### **Acknowledgements**

This paper is partly supported by the Sectorial Operational Programme Human Resources Development (SOPHRD), financed by the European Social Fund and the Romanian Govern‐ ment under contract number POSDRU 141531.

### **Author details**

Delia M. Podea1\*, Aurora I. Sabau1 and Karol J. Wild1

\*Address all correspondence to<EMAIL_ADDRESS>
1 "Vasile Goldis" Western University of Arad, County ClinicalEmergency Hospital of Arad, Psychiatry Department, Arad, Romania

"Vasile Goldis" Western University of Arad, Psychology Department, Arad, Romania

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*Review* **Healthcare Transition in Inherited Metabolic Disorders—Is a Collaborative Approach between US and European Centers Possible?**

**Jessica I. Gold 1,\* and Karolina M. Stepien 2,3,\***

**\*** Correspondence<EMAIL_ADDRESS>(J.I.G<EMAIL_ADDRESS>(K.M.S.)

**Abstract:** Inherited metabolic diseases (IMDs) are rare heterogenous genetic conditions. Advanced technology and novel therapeutic developments have led to the improved life expectancy of patients with IMDs. Long-term, they require close surveillance from specialist adult metabolic providers. Healthcare transition (HCT) is the planned, purposeful process of preparing adolescents for adultcentered medical care and has been recognized globally as a necessary component of care for IMDs. Two recent surveys outlined barriers to the HCT in the US and the UK. The limited knowledge of IMDs among adult physicians was one of the barriers. Some work on specialty curriculum has started and aims to improve the structured training and awareness of rare diseases. Other barriers included social and legal aspects of adulthood, social, vocational and educational support for young adults, care fragmentation and insurance coverage. Although various HCT tools are available, they cannot always be standardized for IMDs. Despite the remarkable differences in the healthcare systems and physicians' training, collaboration among metabolic centers is possible. International rare disease alliance may enhance the patients' management via guidelines development and standardized training for adult metabolic providers.

**Keywords:** transition service; adult metabolic medicine; collaboration; challenges; inherited metabolic diseases; healthcare systems

#### **1. Introduction**

Inherited Metabolic Diseases (IMDs) encompass an expanding group of rare diseases caused by inherited defects in various biochemical pathways [1]. Although the individual incidence is low (from 1 in 10,000 to 1 in 1 million), the overall incidence of all IMDs ranges from 1 in 800 to 1 in 2500 newborns [1,2].

Recent advances in screening, diagnosis, and management of IMDs have resulted in improved clinical and patient-reported outcomes, increased life expectancy, and new recognition of adult-onset phenotypes [3,4]. Latest estimates suggest that over 90% of patients with IMD now survive past 20 years old and that adults (16–80 years) comprise nearly 50% of those with IMD [3–5]. Despite this rapidly growing population, adult phenotypes remain underdefined and often diverge from pediatric ones. Specific challenges exist for metabolic providers—historically, this field was entirely within the purview of pediatricians and adult physicians have limited familiarity with these diagnoses or their management. Given the progressive and complex nature of many IMDs, adult age-related health problems, and multi-specialty support systems, these young adults require long-term surveillance of adult metabolic providers.

Healthcare transition (HCT)—the planned, purposeful process of preparing adolescents for adult-centered medical care—has been recognized globally as a necessary component of care for IMD [1,6,7]. HCT for youths with IMD must recognize these unique

**Citation:** Gold, J.I.; Stepien, K.M. Healthcare Transition in Inherited Metabolic Disorders—Is a Collaborative Approach between US and European Centers Possible?. *J. Clin. Med.* **2022**, *11*, 5805. https:// doi.org/10.3390/jcm11195805

Academic Editor: John Griffith Jones

Received: 4 August 2022 Accepted: 29 September 2022 Published: 30 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

barriers to optimize adult well-being. This report compares and contrasts barriers to HCT in two different healthcare systems.

#### **2. Report**

Two recent surveys answer the growing call to define HCT practice among metabolic providers in the United States (US) and European Union (EU) [1,8]. Both surveys assessed current facilitators and barriers to HCT, identifying several similarities among the US and EU responses. HCT is universally recognized as a critical component of IMD healthcare, yet few providers use validated tools to assess transition readiness. A significant barrier globally is the lack of knowledgeable adult providers in all areas of medicine, especially metabolic and psychology/psychiatry, leading to fragmented care. Limited training opportunities in adolescent and adult metabolic medicine are acknowledged by both groups. Despite the perceived importance of HCT, greater efforts need to be directed toward educating providers and standardizing transition practices.

How can metabolic providers in the US and EU collaborate on IMD-specific HCT tools? At first glance, bridging the wide gap between the nationalized health systems of the EU and the disjointed US amalgam of private and governmental health services seems challenging. However, similar initiatives for creation and dissemination of standardized HCT instruments are needed on both sides of the Atlantic. As an example, the 'Ready, Steady, Go' document has been translated into several languages and could be potentially adopted by many countries [9].

Lack of specific adult services or healthcare providers trained to care for rare metabolic diseases results in poor HCT transition program [10] Subspecialty providers are increasingly hailed as critical to HCT efforts due to their sphere of knowledge and strong longitudinal family relationships [11]. These initial steps are medical institution-independent and can be enhanced by integration of global methods. To identify the strengths in our differences, we visit several aspects of metabolic care and HCT in the US and the UK.

A common thread through both surveys was the predominance of pediatrically trained metabolic providers and general challenges with physician recruitment. In the US, metabolic physicians first complete a genetics residency coupled with a more general residency. In total, 67.2% of geneticists in the US are dual-certified in pediatrics and genetics while only 11.4% are dual certified in internal medical/family medicine and genetics [12]. An optional year of accredited training in medical biochemical genetics is gaining popularity and is increasingly required for employment. In total, most metabolic providers receive 4–5 years of post-graduate training in the field of genetics and metabolism.

The UK has a specific pathway for adult metabolic medicine through their Royal College of Pathologists. Physicians receive training in internal medicine or surgery followed by training in Chemical Pathology and Metabolic Medicine. Together, metabolic training in the UK occurs over 10 years. New diagnostic and therapeutic developments in the field of rare diseases has increased an interest among clinicians, but the current training pathway with difficult FRCPath examinations had a negative impact on recruitment. A new accredited curriculum on acute management of IMD is under development. It aims to attract clinicians from different specialties, e.g., neurology, renal medicine or cardiology to develop a special interest in this field [13,14]. Given the diversity of the specialty training backgrounds of clinicians in adult metabolic medicine, the training curriculum requires some flexibility to meet their training needs [15]. In addition, there is overlap of the knowledge-based competencies between the UK adult metabolic medicine training curriculum [13,15] and pediatric biochemical genetics [15].

Nearly 98.9% of US respondents take care of pediatric and adult patients compared to 84.1% of European centers [1,8]. European centers, mainly the UK, are more likely to have a separate adult metabolic clinic, which may vary in clinical scope from only lysosomal storage disorders to only intermediary disorders of metabolism. In contrast, US centers, where adults predominantly receive care in pediatric clinics, tend to offer wide-ranging IMD care, engaging a multidisciplinary team of dietitians, social workers

and genetic counselors. Continuity of care at pediatric metabolic clinics likely improves patient adherence to follow-up. The implementation of separate adult metabolic medicine clinics in the UK achieved similar goals. Prior to 2005, all patients were discharged from pediatric IMD clinics at 16 years old. The creation of adult-specific IMD clinics introduced a new medical home for these adolescents, ensuring continual care. It resulted in many childhood-onset cases being re-referred to adult services after many years of no follow up, no treatment or special diets.

Care fragmentation occurs in both health systems. The UK's National Health Service (NHS) provides government-funding (through taxation) for consultation, investigations, and follow-up appointments. There is little involvement from the private sector. However, while pediatric and adult patients are seen within the same health system, visits occur at different hospitals with separate non-integrated electronic health records. The US system of private and government-funded health insurance leads to greater splintering of healthcare delivery. Many tertiary pediatric hospitals are stand-alone institutions, unaffiliated with any local adult institution. IMD patients who received centralized pediatric medical care may be forced to seek care at several different adult institutions due to limitations of their medical insurance. Adult hospitals that are not affiliated with pediatric institutions rarely have genetic or metabolic specialists. They are unlikely to carry metabolic formula, medications for acute IMD care, or run IMD-specific laboratories [8]. For many American institutions, this prevents adults from receiving acute metabolic care in adult hospitals.

US health insurance coverage changes as patients age. Adolescents must apply for adult Medicaid, the public aid-based insurance, even if previously receiving pediatric Medicaid. Private health insurance is usually employment-based, though 2010's Affordable Care Act allows youth to remain on their parent's health insurance through age 26 and created marketplaces to purchase independent plans. Regardless of insurance, many states do not mandate coverage of metabolic formula, medical food, or supplements for adults [16]. In contrast, every employed patient in the UK pays monthly into the National Insurance Scheme, which covers universal healthcare for everyone. Unemployed patients are not required to make these monthly payments, but still receive free medical care. Refugees and certain other citizen groups are also treated for free with access to a General Practitioner, acute medical care and social services support.

Optimal HCT should prepare youth for social and legal aspects of adulthood. The age of majority is 16 in the UK and 18 in the US. At this age, adolescents automatically become their own legal decision-maker, regardless of comorbidities. Youth should receive counseling on decision-making supports, such as guardianship or healthcare power of attorney, prior to this birthday. Guardianship, the legal process to become the primary decision-maker for a young adult, is very complex in the UK. While youths reach adulthood at 16, they do not receive all legal rights until 18 years of age. Thus, a guardian cannot be assigned before 18 years old. Between the ages of 16–18, there is a void for a designated decision-maker, which is especially apparent for patients lacking capacity [17]. For complex options, court involvement may be required [17]. Discussing capacity prior to age 16–18 is crucial for avoiding confusion during medical emergencies or to protect patients from predatory behavior.

Education, vocation, and income supports factor largely into HCT planning. Many youths receive healthcare support, such as physical therapy, through their school system. At the completion of schooling (in the US at 21 and the UK at 18), these supports are discontinued, forcing patients to pay out of pocket or through insurance. Day programs or vocational programs exist for those over 21 but can be expensive and usually have limited availability. Income support in the UK is administered at the national level. For many youths with IMD, their caregivers are also able to register for benefits, allowing them to be compensated for full-time care. In the US, income support is administered at the state level with each state setting their own application criteria. Some states will use a medical diagnosis for approval, while others require documented intellectual disability [18]. This

inequity can be harmful for young adults with IMD who may have complex medical needs but normal IQs.

#### **3. Discussion**

Despite systemic differences, the basic tenets of HCT permit international collaboration. Emphasizing HCT research and training is timely—expanded newborn screening via tandem mass spectroscopy began nearly twenty years ago in many countries [19], leading to a growing population of adolescents with IMD requiring transition to adult-centered medical care. International collaboration has been critical in other HCT-related fields, such as long-term follow-up for survivors of childhood cancer to determine rare late sequalae and compile surveillance recommendations [20]. Rare disease alliances, including the Europe Union's International Rare Disease Research Consortium (IRDiRC) and the US's National Organization for Rare Disorders (NORD), illustrate the greater impact of collective research efforts and data sharing [21]. The main HCT principles are consistent throughout these medical systems. Adolescents need preparation for adult-centered medical care, education and vocational opportunities, income support, and assistance with decisionmaking. Defining measurable outcomes for young adults with IMD is also necessary, permitting evaluation and refinement of HCT programs [5,7]. Some parameters will vary by country—such as insurance lapses or care fragmentation. However, creating unified measures to track and assess HCT internationally is beneficial for all. Here, collaboration between international IMD societies on HCT is a necessary first step. Since these disorders are rare and there is a limited pool of metabolic specialists, international collaboration is necessary to implement full-scale HCT planning including best practice recommendations.

One imperative for designing international IMD-related instruments is that current standardized HCT tools, such as "Ready, Steady, Go" are not comprehensive enough for IMD and IMD-specific assessments have not been validated [22]. Managing a rare disease is challenging in adult-centered healthcare. HCT requires a partnership between pediatric and adult providers. Yet, commitment to HCT is skewed toward greater participation and knowledge from pediatric providers and greater disinterest from adult providers. Many adult clinicians have no knowledge of the clinical care of IMD [23]. Adults are likely to see several care teams due to the multisystemic complications. For patients with intermediary disorder of metabolism, self-management is complex and there is an underlying risk of presenting for acute care in a state of transient encephalopathy [24]. Adults with IMD commonly need to educate their own physicians and act as strong advocates for their care. Providing young adults with the educational tools to accomplish this level of selfcare is important [5,7]. Disease-specific guidelines will be necessary to properly inform adult-trained clinicians of current management, long-term complications, and surveillance recommendations. A collaborative approach to develop and disseminate these tools would be beneficial for the international IMD community.

Globally, recruitment of adult metabolic physicians and engagement of local clinicians about IMD are critical barriers to successful HCT and transfer. A stronger international alliance of professional societies and patient support groups could lead to greater promotion of adult metabolic medicine and resource curation. Together, IMD societies could partner with general internal medicine or adolescent medicine organizations to increase IMD representation, for example—by expanding the SSIEM Adult IMD course [15]. As both societies have active adult IMD sections, joint meetings are possible. Additionally, institution-based transition coordinators are instrumental in preparing young adults for this process [7]. Employing a transition coordinator may alleviate HCT barriers due to workforce limitations and clinician knowledge and has been shown to improve health outcomes [25,26]. International IMD societies should lead in developing guidelines that include a job description for transition coordinators. Representatives from many countries should be solicited to collaborate on HCT. The current report is limited by the comparison of two developed countries with individualistic attitudes to health care. Our HCT experience may not be generalizable to nations with more community-based health care.

Last, we must reiterate the difference between healthcare transition and healthcare transfer. HCT is the process of preparing adolescents for medical, social, and fiscal autonomy. Transfer, when a young adult leaves a pediatric practice and initiates care with an adult practice occurs more commonly in the EU (90%) than the US (25%) [1,8]. HCT is required for all adolescents with IMD, even those who will receive from the same IMD provider through adulthood. Metabolic physicians are well poised to promote HCT. International collaboration on HCT will strengthen its delivery.

#### **4. Conclusions**

Despite the differences in the health systems and physicians' training, collaboration between metabolic centers is possible. International rare disease alliance may enhance the patients' management via guidelines development and standardized training for adult metabolic providers. Further research and careful planning of coordination of transition care is required to ensure a smooth patients' transfer to adult metabolic services and empower them in decision making and improve their adherence to follow-up. The successful transfer of care will result in better patients' engagement with healthcare system.

**Author Contributions:** J.I.G. and K.M.S.—Concept, design, data acquisition, revision. All authors have read and agreed to the published version of the manuscript.

**Funding:** J.I.G. is supported by NIH T32 GM008638.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors would like to thank all patients with inherited metabolic disorders who inspired us to write this article.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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