Long Acting Injectables and their Correlation with Subjectivity in Schizophrenia Spectrum Disorder

Abstract

Nowadays, mental illness can no longer be considered as a mere list of symptoms corresponding to localized brain dysfunctions but rather as a disturbance of the patient’s subjectivity. Thus, a solid, qualitative study of patients’ subjectivity could represent a useful tool in the complex evaluation of efficacy of pharmacotherapy in schizophrenic persons. In this perspective, authors performed a phenomenological oriented investigation on 49 patients, diagnosed with schizophrenia spectrum disorder, who were receiving long-acting injectable (LAI) antipsychotic therapy. From data analysis, authors found a positive correlation between general psychopathology and the use of LAI antipsychotic therapies. The present study highlighted the necessity of a careful investigation of patients’ subjectivity in a phenomenological way as an irreducible part of both psychopathological and psychopharmacological matters.

Introduction

Antipsychotic medications play a pivotal role in controlling symptoms of psychosis, minimizing the likelihood of relapse. Long-acting injectable (LAI) antipsychotic were developed in the 1960s and since then they have proved effective in schizophrenia and other psychotic disorder because they assure stable blood levels, representing an advantageous alternative to oral medication, particularly in the context of compliance management.¹ While a considerable amount of scientific effort has been addressed at describing antipsychotics effectiveness at symptoms’ control or drugs side-effects and their acceptability, in the scientific literature a complex phenomenological evaluation of treatment response is still missing.² Schizophrenia is a complex, lifelong condition that despite revolutionary progress held by molecular biology, genetics, neuroscience and many other fields of sciences and technology still leaves many fundamental questions about its functioning unanswered.³ The “brain myth” is not new to history of criticized.⁴ Even “brain research” itself, with its findings on neuronal plasticity, pointed out that the brain is constantly and epigenetically shaped by its relations to the world.^5–6 Thus, on a clinical perspective, mental illness can no longer be considered as “an aggregate of symptoms corresponding to localized brain dysfunctions but rather as a disturbance of the patient’s relations to the world and the others”, namely a disturbance of its subjectivity.⁷ Even though a dissertation on phenomenological psychopathology is beyond the scope of this article, it is necessary to briefly introduce to what makes Phenomenology a unique instrument within the psychiatric framework that allows the phenomenologically oriented psychopathologist to have a “careful, unprejudiced description of conscious, lived experiences, precisely according to the way they are experienced, without the imposition of external explanatory frameworks, whether they come from natural sciences, psychology, religion or common sense,⁸ making it clear that Phenomenology should be conceived as a science of subjectivity, that aims at describing the structural aspects of the pre-reflective experiential Self such as ipseity, spatiality, temporality, embodiment, intentionality as well as their possible deviations and derailments.⁹

Given these premises, authors hypothesized that a solid, qualitative study of patients’ subjectivity was a most needed tool in the complex evaluation of efficacy of pharmacotherapy in schizophrenic persons. In this perspective, authors performed a phenomenological oriented investigation on 49 schizophrenic patients who were receiving long-acting injectable (LAI) antipsychotic therapy, focusing specifically on two dimensions of phenomenological subjectivity: The Basal Self model¹⁰ and the Intentionality model,¹¹ that have been both empirically demonstrated to be specifically altered in schizophrenia, respectively in early and residual stages of the illness.

The primary aim of this study is to compare the clinical features of the sample, evaluated through the Positive and Negative Syndrome Scale (PANSS), with patients’ phenomenological characteristics, investigated with the Intentionality Scale (InSka) and the Examination of Anomalous Self Experience Scale (EASE), in order to investigate a possible correlation between general psychopathology and the use of long-acting injectable antipsychotic therapies. The secondary aim is the comparison between clinical and phenomenological characteristics in two subgroups of patients identified according to the type of LAI.

Materials and Methods

This observational, cross-sectional study evaluates data referring to 49 patients, diagnosed with Schizophrenia Spectrum Disorder, assessed at psychiatric facilities of the Psychiatric Unit of a teaching hospital in Norther Italy (Deliberate n. VIII/4221, February 28th, 2007). This study observed regulatory and legal requirements (DL n.211, 24 June 2003, and DM 17 December 2004), according to the Declaration of Helsinki’s ethical principles. Following the Institutional Review Board approval, all patients were specifically informed about the opportunity to participate in this study and signed a written specific consent before the enrolment. Data collected referred to the period between January and June 2019. To be enrolled in the present study, patients must fulfill the following inclusion criteria: age > 18 years old; have a diagnosis of Schizophrenia Spectrum Disorder according to ICD-10; receive a LAI antipsychotic therapy from at least 3 months; have subscribed a generic informed consent for processing data. Exclusion criteria were: current use of psychotropic substances and/or alcohol; suffer from psychological and neurological conditions that could compromise patients’ ability to actively understand and participate in the interview; to be enrolled in other ongoing studies. All patients provided a general informed consent as part of the routine quality check processes. The design, analysis, interpretation of data, drafting, and revisions followed the strengthening reporting of observational studies in epidemiology (STROBE) statement.

The following socio-demographic and clinical variables were taken into consideration: gender, age, education, marital status, employment, living conditions, type of LAI antipsychotic therapy, years on LAI antipsychotic therapy and precedent therapies. For the psychometric assessment three scales were used: The Positive and Negative Syndrome Scale (PANSS), the Intentionality Scale (InSka) and the Examination of Anomalous Self Experience Scale (EASE).

PANSS is one of the most popular rating scales for schizophrenia and, after is first publication in 1987, it has been validated in many languages, Italian included.^12–14 It has its theoretical foundation on the schizophrenic syndrome proposed by Crow and Andreasen who identified a “positive” and a “negative” syndrome with different symptoms and pathogenetic pathways.^15–16 It consists of 7 items evaluating the “positive” symptoms (P-PANSS), 7 items evaluating the “negative” symptoms (N-PANSS) and 16 items evaluating the “general psychopathology” (G-PANSS), with 30 items in total. Each item can be assigned a score from 1 to 7 according to its presence and severity (1 = absent; 7 = extreme).

InSka scale was developed by Christoph Mundt and first edited in German.¹⁷ The scale consists of 6 sections named “motor impulse”, “speech”, “affective reactions”, “delusion and autism”, “initiative and motivation”, “social behavior” for a total of 60 items that will be filled out by the rater with yes/no answers according to the presence or absence of the described psychopathological condition. “Yes” equals 1 point whereas “no” equals 0 points for 60 points in total.

EASE scale¹⁸ is a checklist for a phenomenological semi-structured investigation of experiential anomalies that can be considered as disturbances of the “basal” or “minimal” self. The scale is descriptive in a phenomenological way and the purpose of the description is essentially qualitative. It has been elaborated based on auto-description from patients affected by schizophrenia spectrum disorders. The scale is divided into 5 different domains: “cognition and stream of consciousness”, “self-awareness and presence”, “bodily experiences”, “mimetic experiences”, “existential reorientation”. Each domain contains a wide number of items that will be addressed during the interview and marked with a score from 0 to 5 depending on their severity and frequency. For this work authors decided to score each item according to the method mentioned above, to assign a generic score to each domain resulting from the summation of the scores of the items of the considered domain, so as to eventually proceed with a summation of the domains’ scores to represent the intensity of the disturbances of the “Basal Self”.

In order to compare the average scores from different scales we decided to standardize the score of each domain per number of items of the given domain so that: PANSS scores would range between 1 and 7, InSka scores would range between 0 and 1, and EASE scores would range between 1 and 5. It must be noted that the whole interview would take more than an hour and sometimes it needed to be split into different meetings in order not to exhaust patient’s emotional and attentive energies.

Given the small number of the sample, and the non-normality of the data confirmed through Kolmogorov-Smirnov and Shapiro-Wilk tests, we chose to use non-parametric tests to perform the statistical analysis. Specifically, a study of bivariate correlation with a two-tailed test of significance was carried out to quantify the ρ degree of correlation between the scales EASE, InSka and PANSS through the Spearman’s ρ test. The coefficient of correlation ρ can range between 0 and |1| where +1 stands for the maximum degree of positive correlation and −1 stands for the maximum degree of negative correlation. Moreover, authors evaluated the degree of internal coherency of each scale and of their relative sub-domains through the analysis of the Cronbach’s α, which represents a good internal coherency when α > 0.8. To highlight statistically significant differences between the two subgroups of patients undergoing first-generation vs second generation antipsychotic LAI therapy the Mann-Whitney U-test was used where the variable of interest was measured on a numeric scale, whereas the chi-square test or, alternatively, the Fisher’s test or the chi-square logarithm, were used in case of categorical type variable (precisely, where at least one contingency table’s subgroup was less than 5 in numbers we used the Fisher’s test for tables with 1 degree of freedom and the chi-square logarithm for tables with more than 1 degree of freedom). The threshold for statistical significance was set at p < 0.05. For all statistical analysis the IBM SPSS Statistics software version 26 was used.

Results

Socio-demographic and clinical characteristics of the considered sample are listed in Table 1. For the study purposes the sample was divided in two groups: those who were receiving a first-generation antipsychotic LAI (FGA-LAI) and those receiving a second-generation antipsychotic LAI (SGA-LAI). Statistically significant results are reported in bold. From the evaluation of socio-demographic characteristics, no statistically significance differences emerged, except for a different level of education that resulted to be higher among the SGA-LAI group (p = 0.025 at Chi-square test). Among clinical characteristics it is interesting to note that the FGA group was in therapy from many years compared to SGA-LAI group, with a statistically significance difference (13.2 vs 4.57, p = 0.004 at Mann-Whitney U-test). Also dealing with a previous LAI therapy a statistically significance difference emerged among the two groups: a previous LAI therapy was significantly more present among the SGA-LAI group (71.4% vs 38.1%, p = 0.02 at chi-square test).

Table 1. Socio-Demographic and Clinical Features of the Sample.

		Total		FGA-LAI		SGA-LAI		Test of significance
Gender  Male  Female		30 (61,2%) 19 (38,8%)		19 (67,9%) 9 (32,1%)		11 (52,4%) 10 (47,6%)		p = 0,271
Age  Mean		51,98		53,14		50,43		p = 0,571
Education  None  Primary School  Junior High School  High School  Bachelor’s degree		1 (2%) 6 (12.2%) 27 (55,1%) 14 (28,6%) 1 (2%)		1 (3.6%) 3 (50%) 20 (71.4%) 4 (14,3%) 0 (0%)		0 (0%) 3 (50%) 7 (33,3%) 10 (47,6%) 1 (4,8%)		p = 0,025
Marital Status  Unmarried  Married  Divorced  Widowed		33 (67,3%) 7 (14,3%) 7 (14,3%) 2 (4,1%)		18 (64,3%) 4 (14,3%) 5 (17,9%) 1 (3,6%)		15 (71,4%) 3 (14,3%) 2 (9,5%) 1 (4,8%)		p = 0,584
Employment  Unemployed  Employed  Retired		14 (28,6%) 10 (20,4%) 25 (51%)		7 (25%) 4 (14,3%) 17 (60,7%)		7 (33,3%) 6 (28,6%) 8 (38,1%)		p = 0,104
Living Condition  Alone  Family of origin  Own family  Other		16 (32,7%) 24 (49%) 7 (14,4%) 2 (4,1%)		9 (32,1%) 14 (50%) 5 (17,9%) 0 (0%)		7 (33,3%) 10 (47,6%) 2 (9,5%) 2 (9,5%)		p = 0,921
Diagnosis  Schizophrenia  Schizo-affective disorder		41 (83,7%) 8 (16,3%)		22 (78,6%) 6 (21,4%)		19 (90,5%) 2 (9,5%)		p = 0,438
Years on LAI therapy  Mean  Median		9,67 6		13,5 12		4,57 4		p = 0,004
Switch from other LAIs  Yes  No		21 (42,9%) 28 (57,1%)		8 (28,6%) 20 (71,4%)		13 (61,9%) 8 (38,1%)		p = 0,02

All the used scales proved to have a good to excellent internal consistency to the Cronbach’s α test with α = 0.948 for the PANSS, α = 0.857 for the InSka and α = 0.932 for the EASE. The internal consistency of each EASE domains, namely “cognition and stream of consciousness”, “self-awareness and presence”, “bodily experiences”, “mimetic experiences”, “existential reorientation”, was also assessed. All the domains, except the “mimetic experiences” (Cronbach’s α = 0.722), show a good internal consistency with a Cronbach’s α of 0.832, 0.815, 0.808 and 0.821, respectively.

The symptomatology considered by PANSS, meaning positive symptoms, negative symptoms and general psychopathology is equally distributed in our sample, with negative symptoms being slightly more represented. It seems interesting to highlight that on a range from 1 to 7 even the most represented psychopathological domain (negative symptoms) has an average score of 2.7, with positive symptoms and general psychopathology scoring 2.1 and 2.0 respectively. Therefore, it is possible to affirm that the general picture described by PANSS psychometrics is one of a non-severe level of psychopathology in our sample of 49 patients undergoing LAI antipsychotic therapy. As regards the InSka, the total average mark is 18/60 reflecting a good general picture of patients Intentionality, even though it must be noted that the “social behavior” domain got an average score of 0.43/1, significantly higher than the others. The average EASE total score is 97/285 which shows the presence of disturbed Basal Self experiences in the sample while they are not characterized by extreme severity. The most altered domains resulted to be “cognition and stream of consciousness” and “self-awareness and presence” with a score near to 2/5 for both. As described above, the average scores of the scales followed the same trend. It should not be surprising then that the degree of correlation between the PANSS, the InSka and the EASE proved to be a statistically significant positive degree of correlation at the Spearman’s test (PANSS-EASE ρ = 0.540; PANSS-InSka ρ = 0.697; EASE-InSka ρ = 0.729) with a level of statistical significance of 0.01. The degree of correlation between the scales is represented in the scatterplot graphics below (shown in Fig. 1–3).

Despite a positive correlation between the qualitative investigation of Basal Self and Intentionality by the EASE and the InSka and the operational symptomatology evaluation by the PANSS in patients undergoing LAI antipsychotic therapy was detected, no statistically significant differences regarding psychopathology were found between the two selected sub-populations undergoing first-generation and second-generation antipsychotics LAI therapy.

Discussion

As mentioned above, from analysis of available data a positive correlation between general psychopathology and the use of LAI antipsychotic therapies emerged, confirming the upcoming evidence that recommend LAI therapy as a first line treatment in schizophrenic patients.^19–20 Despite this result, no statistically significant differences were detected comparing first-generation and second-generation antipsychotics, as highlighted by recent scientific literature,²¹ indicating that LAI therapy in general offers good control of psychopathological symptoms. Furthermore, despite the advantage related to the SGA-LAIs, such as a better side-effects profile and a better control of negative, cognitive and affective symptoms, the use of these medication is complicated by higher financial costs and metabolic side effects.^22–23

All the used psychometric tools, with a special focus on the phenomenological oriented EASE and InSka, proved to have a good to excellent internal consistency. While this was expected for the PANSS, given its widespread use in operational-oriented clinical practice and literature support, these can be considered quite interesting results for Inska and EASE, backing other promising results in demonstrating that phenomenological oriented research can both look at the complexity of human experience and produce reliable psychometric instruments.²⁴ The need to evaluate the patient in his complexity^25–26 fits in the era of precision medicine, in which the opportunity to tailor pharmacologic therapies on each individual, through the use of clinical and genetic and information,^27–30 could lead to shorter waiting time between the diagnosis and the beginning of an effective treatment and, consequently, to a reduction of costs.^31–32 Always in this view, a deep evaluation of the patient could surely help clinicians avoiding unnecessary investigations and treatments.³³ All the scales used in the present study have some degree of correlation between each other, as highlighted by the authors. The strongest degree of correlation was found among the EASE and the InSka, suggesting that Basal Self disturbances go together with a coarctation of Intentionality. Although the PANSS offers a good clinical evaluation of patients affected by schizophrenia the two instruments, provided by Phenomenology, touch upon different psychopathological aspects that are left aside by the PANSS. A-theoretical, symptoms-based tools like PANSS stand as good proxies of patients’ psychopathology as long as single unities of symptoms are concerned. They tend to lack accuracy where florid psychotic symptomatology is absent but a “praecox feeling” remains.³⁴

The limitations of this work are the small sample size and the lack of a longitudinal evaluation.

Conclusion

This work highlights the role of LAI antipsychotic therapies in improving deeper aspects of schizophrenia spectrum disorder, such as Self, and not only for symptoms control.

In fact the efficacy and tolerability profile of psychopharmacological treatment are not the sole goal to pursue in clinical practice but a careful investigation of individuals’ subjectivity in a phenomenological way has been demonstrated to be an irreducible part of a deeper assessment of patients affected by schizophrenia.

Such qualitative research on subjectivity allows moving from a merely descriptive to a functional psychopathology that gives back coherence to an apparently disjointed set of symptoms and allows reaching an intermediate level of analysis between the highly specific neurobiological dysfunction and the heterogeneity of clinical syndromes. Further researches would be desirable to confirm these study’s results.

Figure 1.

Ease-Panss Correlation

Figure 2.

Inska-Ease Correlation

Figure 3.

Inska-Panss Correlation