Abstract
Background. Norepinephrine transporter inhibitors that can alter the level of neurotransmitter in the brain are used to treat neurological disorders. However, a number of studies have reported their limited significance as a result of their slow onset of action and moderate efficacy.
Objectives. To determine the effects of norepinephrine reuptake inhibitors (NRIs), reboxetine and atomoxetine on schizophrenia and attention deficit hyperactivity disorder (ADHD).
Materials and methods. Relevant articles published between 2000 and 2022 were searched in the MEDLINE, CINAHL (via Ebsco), Web of Science and Scopus databases. Among the various NRIs, studies concerning the 2 potent drugs – reboxetine and atomoxetine – were selected for analysis. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated, along with the exploration of heterogeneity and publication bias, using RevMan software.
Results. A total of 14 eligible studies with a combined sample size of 970 patients were included. Using a random effects model, an OR of 0.55 (0.32–0.94), a Tau2 value of 0.23, a χ2 value of 12.31, 8 degrees of freedom (df), an I2 of 35%, a Z value of 2.19, and a p-value of 0.03 were recorded for reboxetine. Atomoxetine had an OR of 0.35 (0.13–0.97), a Tau2 value of 0.58, a χ2 value of 7.31, 4 df, an I2 of 45%, a Z value of 1.53, and a p-value of 0.04. All results were statistically significant with a low risk of publication bias, as was evident from the p-values >0.05 derived from the Egger’s test and the Begg’s test. These drugs provided comparable changes to control drugs in Hamilton Depression Rating Scale (HAM-D) scores, Positive and Negative Syndrome Scale (PANSS) scores and ADHD ratings. This confirms the efficacy of reboxetine for the treatment of schizophrenia and atomoxetine for the treatment of ADHD.
Conclusions. The present meta-analysis suggests that NRIs are efficacious and therefore they are potential candidate drugs for the treatment of schizophrenia and ADHD.
Key words: schizophrenia, neurological disorders, atomoxetine, attention deficit hyperactivity disorder, reboxetine
Introduction
Neurological disorders, including schizophrenia, attention deficit hyperactivity disorder (ADHD), depression, anxiety, and bipolar disorders, are very common medical ailments reported worldwide. These disorders are mainly associated with symptoms such as delusions, disorganized thinking, depression, abnormal social and motor behaviors, and hallucinations.1 Treatment of these neurological disorders is achieved through cognitive therapy, rehabilitation, psychoeducation, family therapy, behavioral therapy, and the use of a variety of antipsychotic and anti-tremor medicines.2 Among the various medications, drugs that can specifically alter the level of neurotransmitters in brain cells, such as dopamine reuptake inhibitors, gamma-aminobutyric acid reuptake inhibitors, and a variety of norepinephrine reuptake inhibitors (NRIs) are of much use.3 Norepinephrine reuptake inhibitors have the capacity to alter the activity of the norepinephrine transporter, which is a solute carrier protein that controls the movement of sodium and chloride ions. This mechanism of NRIs is dependent upon the reuptake of the neurotransmitters norepinephrine and dopamine, and therefore such drugs are potential candidates for the treatment of neurological disorders.4, 5, 6
A variety of NRI drugs, including atomoxetine, reboxetine, viloxazine, and edivoxetine, are currently available for the treatment of neurological disorders (Figure 1). Indeed, a number of randomized controlled trials have suggested the potential benefits of reboxetine for the treatment of schizophrenia patients.7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Similarly, the potential benefits of atomoxetine for the treatment of ADHD have been reported in randomized controlled trials.17, 18, 19, 20, 21 Salazar de Pablo et al. reported in their meta-analysis that these disorders are more prevalent in younger females.22 Meanwhile, Tanaka et al. reported in their review article that such neurological disorders arise due to neurodevelopmental defects or the alteration of normal brain development during early embryonic life.23 Such defects can be investigated using functional magnetic resonance imaging, as reported by Nyatega et al.24 Furthermore, these developmental defects led to higher levels of dissociative schizophrenia symptoms, as shown by Panov.25 Rog et al.26 reported in their study that altered fatty acid metabolism was responsible for schizophrenia, while Gaebler et al.27 demonstrated that vitamin D deficiency was responsible, and Correia et al.28 suggested that alterations in serum lipid levels as a major cause of schizophrenia. Therefore, NRIs that can alter the level of neurotransmitters are potential candidate drugs for these neurological disorders.29, 30 Additionally, De Crescenzo et al. contended that pharmacotherapy using noradrenergic agents was effective in the management of ADHD.31
Objectives
In this study, a meta-analysis was conducted to assess the efficacy of 2 NRI medications, reboxetine and atomoxetine, in the treatment of schizophrenia and ADHD, respectively.
Materials and methods
Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) normative recommendations were followed and the study protocol was registered at Shandong University, Jinan, China (registration No. SU#/
IRB/2021/554).
Search strategy
This meta-analysis was based on an extensive literature search of MEDLINE (via PubMed), CINAHL (via Ebsco), Scopus, and Web of Science databases. Studies published between the years 2000 and 2022 were searched using the following keywords: “neurological disorder”, “neurotransmitters”, “schizophrenia”, “systematic review”, ‘meta-analysis”, and “norepinephrine transporter inhibitors”. All of the included articles8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 were assessed using the PRISMA guidelines, and studies were selected randomly irrespective of the language, publication status or the type of study (prospective, retrospective, clinical trial). A demographic summary of the patients was designed, with consideration to the variables included in the searched studies.
To assess the efficacy and safety of NRIs, as well as their genetic variants, reboxetine and atomoxetine were selected for analysis. Event data from the selected studies were extracted. In the selected studies, patients of different age groups were treated with either reboxetine, atomoxetine or control drugs, and their Hamilton Depression Rating Scale (HAM-D) score, Positive and Negative Syndrome Scale (PANSS) score and metabolic parameters were observed. Statistical parameters, including diagnostic odds ratio (OR) with 95% confidence interval (95% CI) and heterogeneity of data of both drugs, were calculated with RevMan software v. 4.1 (https://training.cochrane.org/online-learning/core-software/revman). Data for both drugs were summarized using forest plots.
Two authors (XH and LP) scanned the relevant sources for related studies separately. Full-text articles of the studies were collected and abstracts were only used if they contained sufficient information for the review and meta-analysis. Obsolete references were excluded and useful studies were included as per the inclusion criteria. Event data with useful variables were collected by 2 researchers (XH and LP) independently.
Inclusion and exclusion criteria
Studies published between 2000 and 2022 that reported on the safety and efficacy of NRIs and their genetic variants for the treatment of schizophrenic patients were included. Mostly the full-text studies were included but some abstracts were also taken into account if had sufficient data, while studies with insufficient data, reporting the use of medicines other than NRIs, and those published before 2000, were excluded (Figure 2).
Evaluation of the analytical standard
Two reviewers (XH and LP) separately evaluated the methodological validity of the included studies and calculated the heterogeneity of the data. Author WL was responsible for resolving any disagreements between the authors XH and LP. The risk of bias of all the included studies was assessed and summarized using RevMan software.
Sources of heterogeneity
Investigated sources of heterogeneity included the use of full-text publication compared to abstracts, randomized controlled trials compared to retrospective studies, age group, number of patients, duration of treatment, scale of analysis, and comparison of St. John’s wort with different selective serotonin reuptake inhibitor controls.
Statistical analyses
Diagnostic ORs for both reboxetine and atomoxetine were calculated using the DerSimonian and Laird technique. For this, a 2 × 2 table was constructed and a meta-analysis was performed. Pooled diagnostic ORs were then calculated with their 95% CIs, and their respective forest plots were designed. To investigate heterogeneity, Tau2 value, χ2 test, Z value, and I2 index in random bivariate mode were calculated. To assess the risk of publication bias, the Deek’s funnel plot for both types of studies, using either reboxetine or atomoxetine, was designed using MedCalc software v. 20.118 (MedCalc Software Ltd., Ostend, Belgium). The risk of publication bias was assessed using Egger’s test and Begg’s test.
Results
Literature search results
A total of 1541 studies were found in different databases. Among these studies, 615 were excluded after reading their titles and abstracts, and 926 records were further examined. Moreover, 912 studies were excluded as 412 were animal studies, 204 were of a population of non-interest, 140 studies were of non-interest interventions, 21 were case reports, 33 were letters/responses to the editor, 50 were meta-analyses, 40 were systematic reviews, and 12 were excluded due to incomplete information. Key reasons for omission were inadequate evidence and inappropriate comparison criteria required to create 2 × 2 tables for review. Only 14 studies were selected for final screening and meta-analysis (Figure 2). Of the 14 studies included, 9 were related to the benefits of reboxetine and 5 were related to atomoxetine treatment.
Demographic details of the studies included in this meta-analysis are shown in Table 1. It describes authors of the study, year of publication, publishing journal, type of study, duration of study, total sample size, type and dosage of NRI used, control drug and its dosage, age and gender of patients, test scores analyzed, number of patients with positive outcomes, HAM-D scores, PANSS scores, metabolic parameters of patients, and p-values indicating statistical significance of the data. The risk of bias (Table 2) was assessed, summarized (Figure 3) and shown as a bar graph (Figure 4). Studies included in the analysis presented a low risk of bias, as is evident from the tables and graphs.
Fourteen clinical studies with a total of 970 schizophrenia patients were included, according to the inclusion criteria. The included studies encompassed adult patients of different age groups who were chosen randomly and treated with either placebo or NRIs. In both cases, reductions in HAM-D score and PANSS score, as well as changes in metabolic parameters were observed.
Meta-analysis results
Meta-analysis of the included studies using a random effects model indicated that they had a low risk of publication bias since both the Egger’s test and the Begg’s test p-values were > 0.05. Specifically, the Egger’s test gave a p-value of 0.25 and the Begg’s test gave a p-value of 0.11 (Figure 5). The analysis of reboxetine resulted in an OR value of 0.55 (0.32–0.94), a Tau2 value of 0.23, a χ2 value of 12.31, 8 degrees of freedom (df), I2 value of 35%, a Z value of 2.19, and a p-value of 0.03 (Figure 6). Similarly, atomoxetine produced an OR of 0.35 (0.13–0.97), with Tau2 value of 0.58, χ2 value of 7.31, 4 df, an I2 value of 45%, a Z value of 2.01, and a p-value of 0.04 (Figure 7). All results were statistically significant and heterogeneous.
Greater efficacy and safety of the NRIs reboxetine and atomoxetine were demonstrated for the treatment of schizophrenia and ADHD patients. Indeed, both drugs led to a larger change in the evaluated test scores, including HAM-D and PANSS, in comparison to the control drugs (Table 3 and Figure 8).
A statistical summary of the meta-analysis results is shown in Table 4. The pooled OR < 1 for both drugs suggests that they have comparable efficacy, and both have potential use in the treatment of schizophrenia and ADHD.
Combining all results of the meta-analysis, it is clear that reboxetine and atomoxetine are safe and as effective as comparable drugs. Indeed, these NRIs were effective in reducing HAM-D and PANSS scores, along with other clinical symptoms in schizophrenia patients. In fact, they have shown greater efficacy in comparison to control drugs and had fewer adverse side effects. Therefore, these drugs are a better alternative for the treatment of schizophrenia and ADHD.
Discussion
Neurological disorders such as schizophrenia and ADHD are serious health disorders that result in individuals becoming socially isolated, depressed, confused, unhappy, less organized, and sad. If left untreated, they can lead to more serious neurological issues such as borderline personality disorder, which can provoke suicide attempts.32, 33, 34, 35, 36 Studies suggest that fear conditioning, changes in the immune system and metabolic changes are also responsible for the development of these neurological disorders.37, 38, 39, 40 Therefore, these disorders need to be detected in a timely manner using various neuroimaging modalities41, 42, 43, 44 and should be treated using available strategies such as behavioral therapy, family therapy or with anti-psychotic medications.45, 46 Indeed, NRIs are widely applied in the treatment of mental disorders.
As Maletic et al. reported in their systematic review, alpha-adrenergic receptors play an important role in the aberrant regulation of arousal and cognition in schizophrenia.47 Similarly, Mäki-Marttunen et al. noted the importance of the locus coeruleus-norepinephrine system in cognition and the pathophysiology of schizophrenia.48 A study conducted by Navarra et al. reported on the potential benefits of atomoxetine for reducing clinical symptoms in an animal model of schizophrenia.49 Furthermore, Locher et al. presented potential benefits of NRIs for the treatment of these psychiatric disorders in children.50 Additionally, Outhred et al.,51 Ruhé et al.,52 Rubia et al.,53 and Papakostas et al.54 showed that NRIs are efficacious in the treatment of neurological disorders.
Similar to the available literature, current systematic review and meta-analysis also has low risk of bias of and demonstrated that reboxetine and atomoxetine have significant ORs and favorable statistical parameters for the treatment of schizophrenia and ADHD. Indeed, comparable pooled OR values were 0.55 (0.32–0.94) for reboxetine and 0.35 (0.13–0.97) for atomoxetine. Both of these values are significant as they are less than 1. The results were heterogeneous and significant (p < 0.05) and there was a low risk of publication bias. These results are predictive of the potential benefits of atomoxetine and reboxetine for the treatment of neurological disorders and favor their use as beneficial drug candidates.
Limitations
Limitations of the present study include the variability of NRIs and control drugs used for the treatment of schizophrenia and ADHD patients. Also, the calculation of different scores including HAM-D scores, PANSS scores and metabolic parameters, using varying analytical tests performed by different persons, increased the risk of false-negative results. Furthermore, the data could be impacted to some extent by the fact that several analyzed studies did not report on the comparable efficacy of NRIs with conventional drugs. Data from other relevant studies on the efficacy of NRIs for the treatment of schizophrenia and ADHD could have also included more results to guide the use of NRIs more precisely. Additionally, detailed data on patient’s case history, physical examination, social well-being, and pathological tests would make the results of the studies more useful in planning the treatment.
Conclusions
For the treatment of neurological disorders such as schizophrenia and ADHD, various medications that can block the activity of selective neurotransmitters are currently in use. The current study was designed to conduct a meta-analysis on the efficacy of the NRIs reboxetine and atomoxetine for the treatment of schizophrenia and ADHD, respectively. On the basis of the statistically significant findings and alleviation clinical symptoms in patients with the use of these drugs, we recommend the use of these NRIs for the treatment of these medical disorders.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
