Psychotropic Polypharmacy and Related Factors in Children and Adolescents
Article information
Abstract
Objective
We aimed to investigate the clinical characteristics of patients presenting to child and adolescent psychiatry outpatient clinics across different age groups, and to assess the prevalence of polypharmacy along with its associated factors within a clinical sample.
Methods
A total of 569 patients with complete file data were included in the study. Psychiatric diagnoses were made by a clinician based on the diagnostic criteria stipulated in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. A detailed medical history was obtained for each patient, and their age, gender, education level, parents’ age and education level, psychiatric diagnoses, and administered treatments were recorded for further analyses.
Results
Based on a review of the relationship between complaints at presentation and polypharmacy, irritability was more prevalent among polypharmacy users, while domestic problems were more prevalent in those who did not use polypharmacy. Based on our regression analysis; conduct disorder (CD) diagnosis (B=2.405, Exp [B]=11.079, p<0.001), age (B=0.127, Exp [B]=1.136, p=0.008), and any psychiatric comorbidity (B=4.761, Exp [B]=116.874, p<0.001) were the variables most frequently and significantly associated with polypharmacy independent of other variables.
Conclusion
This study’s results indicate that the presence of CD, age, and comorbid psychiatric diagnosis significantly increase the risk of polypharmacy. A better understanding of the factors that pave the way toward polypharmacy is critical to reduce unnecessary medication use in children and adolescents.
INTRODUCTION
There is an increase in the prevalence of psychiatric disorders in children and adolescents worldwide [1]. Previous studies involving different age groups have reported prevalence rates ranging from 13.4% to 20.1% [2]. Increasing research has been conducted on the prevalence, selection, and side effect profiles of treatment methods with the increase in the number of child and adolescent psychiatry outpatient clinics and the number of cases presented to these clinics [3]. Based on a review of previous studies, there is an increase in the prescription rates of drugs among children and adolescents. Moreover, a transition to polypharmacy has been observed in many countries due to various factors, including increased detection of psychiatric disorders in children and adolescents, changes in diagnostic criteria over time, and expansion of the indications of certain medications used in adult psychiatry to the pediatric age group [4]. Although there are different definitions of polypharmacy, it is most commonly defined as the use of two or more medications per day [5]. A study conducted in the United States reported that 20% of children and adolescents on psychiatric treatment used psychotropic polypharmacy [6]. A meta-analysis reviewing previous studies on polypharmacy in children and adolescents reported that psychiatric drugs were a topic of great interest. After the analysis of all categories worldwide, antipsychotics (AP), antidepressants, attention deficit-hyperactivity/disorder (ADHD) drugs, and anxiolytic drugs were the most commonly reported drug groups after anticonvulsants in polypharmacy studies [6]. Nevertheless, psychotropic polypharmacy in children and adolescents has been a controversial topic due to drug–drug interactions, difficulties in treatment adherence, and the fact that there are only a few studies investigating the use of polypharmacy [6]. Although the concomitant use of psychotropic drugs may increase the benefit of treatment, it may also increase the risks if drug interactions are not considered [7]. During polypharmacy use, children and adolescents may be exposed to more severe side effects than expected because of their developing organ systems [8]. Despite these concerns, polypharmacy has been suggested to be more effective than monotherapy in some psychiatric conditions. Treatment guidelines for pediatric bipolar disorders also recommend the use of polypharmacy when monotherapy fails [9]. Considering the benefits and risks associated with drug use, clinicians have an important responsibility regarding the appropriate selection of key points in drug use and transition to polypharmacy [10].
The increase in polypharmacy rates over the years has attracted the attention of researchers in this field, leading to an increase in the number of studies in the literature. A literature review revealed that majority of research included large-sample studies examining national health record data of the general population or other studies investigating inpatient ward records [11,12]. This review indicated that there were only a limited number of studies with clinical samples in an outpatient setting. Furthermore, there is an ongoing need for future studies to guide clinicians, given the increased use of concomitant treatment in children and adolescents. This study aims to examine the clinical characteristics of patients presenting to child and adolescent psychiatry outpatient clinics across different age groups, and to assess the prevalence of polypharmacy along with its associated factors within a clinical sample. The current study may contribute to the literature and help clinicians as it aims to provide information about drug use from a different geography and culture perspective and investigate the factors affecting polypharmacy.
METHODS
All children who presented to the Child Psychiatry Clinic of Kars Harakani State Hospital for psychiatric evaluation between October 2022 and May 2023 were included in the study. The data required for the study were obtained retrospectively from the case files after obtaining necessary permissions from the Kars Harakani State Hospital Chief Physician’s Office and approval of the Kafkas University School of Medicine Ethics Committee (09/11/2023; 08576354-050-99/355). The requirement for informed consent was waived by the Kafkas University School of Medicine Ethics Committee as the study involved retrospective analysis of anonymized health records. Patients with a minimum of two regular psychiatric presentations were included in the study. A total of 653 patients had at least 2 psychiatric presentations to the child psychiatry outpatient clinic during the study period. Patients who received two or more psychotropic drugs for a period longer than 30 days were considered to be on polypharmacy treatment, and the use of nonpsychiatric drugs was not considered polypharmacy [13]. Overall, 84 patients were excluded from the study because of the lack of data required for the study in the case files. A total of 569 patients with complete file data were included in the study. During psychiatric evaluation, a standard clinical interview of at least 40 min was conducted, and psychiatric diagnoses were made by a clinician based on the diagnostic criteria stipulated in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Then, the Kent E-G-Y [14] and Porteus Maze Test [15] were employed in patients with clinical signs of intellectual disability to determine the level of intelligence. A detailed medical history was obtained for each patient, and their age, gender, education level, parents’ age and education level, psychiatric diagnoses, and administered treatments were recorded for further analyses. Psychiatric diagnoses of the patients were evaluated and presented as the existence of the relevant diagnosis, regardless of whether there were comorbid psychiatric conditions specific to the case. Comorbid conditions were grouped separately as frequent dual and triple comorbidities, and there were no overlapping cases between the groups.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS) 22.0 (IBM Corp.) statistical software was used for analyzing the study data. The hypothesis of normal distribution of continuous variables was tested using visual (histogram and probability graphs) and analytical (Kolmogorov–Smirnov/Shapiro–Wilk tests) methods. Descriptive statistics were presented using number, percentage (%), and mean and standard deviation. The chi-squared test or Fisher’s exact test was used to determine differences between categorical variables, and the Student’s t-test was used to determine differences between numerical variables. Post hoc comparisons were conducted using the Bonferroni correction. Logistic regression analysis with the “enter” method was used to analyze the factors associated with polypharmacy among patients using any psychotropic medication and categorical or non-categorical variables with significant intergroup differences were included in the model. A p-value of <0.05 was considered to indicate statistical significance.
RESULTS
The mean age of the children and adolescents included in the study was 10.30 years, and the mean age of their mothers and fathers was 34.24 and 36.42 years, respectively. Overall, 62.4% of the participants were male and 37.6% were female. It was observed that 44.5% of the mothers were primary school graduates and 33.9% were high school graduates, whereas 44.5% of the fathers were primary school graduates and 43.2% were middle school graduates. Furthermore, 43.4% of the mothers and 87.9% of the fathers were employed. Meanwhile, 61.0% of the participants resided in the city center, 20.6% in counties, and 18.5% in villages (Table 1).
Sociodemographic characteristics (N=569)
Based on a review of the participants by their complaints at presentation, 9.0% of them presented with complaints of irritability, 6.9% with attention problems, 14.6% with restlessness, 6.0% with delayed speech, 7.0% with fear/anxiety, 12.7% with academic failure, 15.8% with sadness, and 6.3% with family problems. Moreover, 15.1% of them visited with the purpose of obtaining a disability report, and 6.7% visited upon referral from the Primary Health Care Center. Furthermore, 69.9% of the participants met the diagnostic criteria for psychiatric disorders, 35.3% for ADHD, 12.5% for major depressive disorder (MDD), 11.6% for oppositional defiant disorder (ODD), 7.4% for autism spectrum disorder (ASD), 7.2% for conduct disorder (CD), 6.0% for social anxiety disorder (SAD), 5.8% for speech disorder (SD), and 5.3% for specific learning disorder (SLD). Based on an analysis of common comorbid conditions, 8.6% of all participants met the criteria for ADHD+ODD, 4.9% for ADHD+CD, and 4.0% for ADHD+SLD (Table 2).
Clinical characteristics and diagnostic distribution (N=569)
A review of the age groups by psychiatric diagnoses indicated that the rate of psychiatric diagnosis was significantly lower in the 0–6 years age group than in the other two age groups. ADHD, ODD, and SAD diagnoses were less prevalent in the 0–6 years age group than in the other two groups. ASD diagnosis was more prevalent in the 0–6 years age group than in the other two groups. CD diagnosis was more prevalent in the 13–18 years age group than in the 0–6 years age group. Obsessive–compulsive disorder diagnosis was more prevalent in the 7–12 years age group than in the 13–18 years age group. There was a significant difference in MDD (13–18 years >7–12 years >0–6 years) and SD (0–6 years >7–12 years >13–18 years) diagnoses between the age groups. The prevalence of ADHD+ODD was lower in the 0–6 years age group than in the other two groups, based on a comparison of the age groups by frequently occurring comorbid conditions. ADHD+intellectual disability (ID) comorbidity was more prevalent in the 13–18 years age group than in the other two groups. ADHD+ASD comorbidity was significantly more prevalent in the 0–6 years age group than in the 7–12 years age group (Table 3). The number of psychiatric medication-naive participants was higher in the 0–6 years age group than in the other two age groups. The proportions of selective serotonin reuptake inhibitors (SSRI)-only users and methylphenidate (MPH)+AP users were lower in the 0–6 years age group than in the other two age groups. The proportion of SSRI+AP users was higher in the 13–18 years age group than in the 0–6 years age group. There was a significant difference in the use of MPH alone between the three age groups (7–12 years >13–18 years >0–6 years) (Table 3).
Association of age groups with clinical features (N=569)
Based on an analysis of the association of polypharmacy with sociodemographic and clinical factors in patients who used medications, the sociodemographic factors were not associated with polypharmacy. Based on a review of the relationship between complaints at presentation and polypharmacy, irritability was more prevalent among polypharmacy users, while domestic problems were more prevalent in those who did not use polypharmacy. Based on the analysis of the relationship between psychiatric diagnoses and polypharmacy, ADHD, ODD, CD, ID, and schizophrenia (SCZ) diagnoses were associated with polypharmacy (Table 4).
Association between clinical characteristics and polypharmacy among patients receiving psychotropic treatment (N=336)
Variables (presentation with complaints of irritability, domestic problems, ADHD, ODD, CD, ID, MDD, generalized anxiety disorder, and comorbidities) with significant differences between groups with and without polypharmacy were included in our logistic regression model. The results of the logistic regression analysis are presented in Table 5. The regression model of the study was statistically significant (χ2=209.232, p<0.001, Nagelkerke R2=0.657). CD diagnosis (B=2.405, Exp [B]=11.079, p<0.001), age (B=0.127, Exp [B]=1.136, p=0.008), and any psychiatric comorbidity (B=4.761, Exp [B]=116.874, p<0.001) were the variables most frequently and significantly associated with polypharmacy independent of other variables (Table 5).
The relationship between clinical factors and polypharmacy in patients who used medications
DISCUSSION
In our study, the mean age of the patients who presented to our outpatient clinic within a 6-month period was 10.30 years, and the proportions of male and female patients were 62.4% and 37.6%, respectively (Table 1). Overall, 24.8% of all patients were in the 0–6 years age group, 36.7% were in the 7–12 years age group, and 38.5% were in the 13–18 years age group (Table 3). Based on an analysis of the educational status of the patients’ parents and the place of residence of the families, fathers were more involved in working life than mothers and a significant proportion of the patients resided in city centers (Table 1). A study investigating the diagnoses of children and adolescents who were followed up in a child psychiatry outpatient clinic reported that 78% of the patients received at least one diagnosis, and a significant proportion of the patients who presented to the outpatient clinic were males [16]. In the present study, 69.9% of the patients met the diagnostic criteria for psychiatric disorders, consistent with previous studies. These proportions were compatible with the studies investigating outpatient clinic presentations in Türkiye, and it was concluded that the present study reflected the clinical sample of Türkiye [17,18].
Upon an analysis of the diagnoses by age groups, the rates of SD (p<0.001) and ASD (p<0.001) diagnoses were significantly higher in the 0–6 years age group than in the other groups (Table 3). A review of previous studies on SD and ASD worldwide suggested that, with the increase in the prevalence of ASD over the years, awareness about ASD has increased. Similar to our study, the cases were concentrated in the age group of 5 years and younger [19,20]. The referral of children who did not develop expressive and receptive language skills in the 0–6 years age group to higher level health institutions for further diagnosis and treatment in routine controls along with the increasing prevalence of primary healthcare services in Türkiye might be another factor that was associated with increases in the rates of SD and ASD diagnoses in this group. The rates of psychiatric diagnoses after the age of 7 years were significantly higher than those in the 0–6 years age group (p<0.001) (Table 3). A detailed analysis by age groups indicated that the rates of ADHD (p<0.001) and ODD (p<0.001) diagnoses were significantly higher after the age of 7 years, and those of MDD (p<0.001) and CD (p=0.006) were significantly higher after the age of 12 years (Table 3). The fact that the diagnostic rates of psychiatric disorders, including ADHD and ODD, increased after the age of 7 years indicates that the rates of general psychiatric diagnoses were higher in this age group than in the 0–6 years age group, consistent with previous studies [19]. Although a previous study reported that the age of CD onset was late childhood and early adolescence, further research was recommended for phenomenological purposes [21]. A meta-analysis of MDD reported that 34% of adolescents aged 10–19 years worldwide are at risk of developing clinical depression; this rate was higher after the age of 12 years in the present study. It was reported that prefrontal dysfunction, which inhibited suppression of excessive responses to emotional cues during adolescence, increased the rates of certain disorders, including CD and MDD [22]. In the present study, it was considered that the physical, emotional, and social changes that occur during adolescence, when peer relations and interaction tend to increase, contribute to the increased rate of CD and MDD diagnoses. Nevertheless, studies with larger samples are required to better understand the factors affecting psychiatric diagnoses specific to different age groups.
Currently, many medications are actively used in child and adolescent psychiatry clinics, and multiple factors affecting the patients can determine the drug preferences [23]. In the present study, psychiatric diagnoses by age groups also had an effect on the psychotropic preferences of clinicians. Upon a review of medication use in the pre–6-year-old group, 83.0% of the patients did not use any medication, and MPH and AP treatment were more preferred than other psychotropics among patients who used medications (Table 3). A previous study focusing on early ages suggested that combined treatment was not significantly superior to monotherapy [24]. In the present study, an analysis of the psychotropic preferences used in the 0–6 years age group indicated that psychotropic polypharmacy was rarely preferred, consistent with the finding of previous studies. Concerns about the long-term side effects of psychotropics might have influenced the preference for monotherapy in this age group. The use of psychotropics, especially AP, among preschool children has increased over the years, and psychotropics are mostly preferred for managing ADHD, CD, ID, and ASD [25]. Previous studies have reported that psychotropic drug use was considerably more prevalent in children with ASD than in those without ASD, regardless of the presence of other psychiatric diagnoses [26]. In the present study, the fact that patients diagnosed with ASD were in the earlier age group might have affected the preference of drugs in this group. A study investigating ADHD treatment during early childhood reported that similar results were obtained from stimulant and AP treatments before the age of 6 years and that AP could also be used in this age group [25]. Another striking result was that the preference for MPH and SSRIs increased after the age of 7 years (Table 3). Although the main symptoms of ADHD appear before the age of 5 years in several cases, starting school can be an important transition point in the lives of children with ADHD, which may accentuate functional impairments [27]. Accordingly, it was considered that the need for stimulant treatment increased with the beginning of school. Furthermore, SSRI use increased after the age of 7 years and was the most preferred psychotropic in the 13–18 years age group (Table 3). Considering the effect of environmental factors that increase with age, we considered that MDD and anxiety disorders (AXD) are more prevalent in our study group, consistent with the previous studies. Accordingly, the rate of secondary SSRI use was higher than that during early childhood [28]. Upon a review of the relationship between the complaints at presentation and polypharmacy use, the rate of irritability was significantly higher among polypharmacy users (Table 4). Irritability is one of the determinant characteristics of ODD, a behavioral disorder usually observed in children [29]. A review of children diagnosed with ODD indicated that 92% of cases were accompanied with another mental health disorder [29]. Furthermore, previous studies have suggested that the irritability component was also strongly associated with internalizing problems, including AXD and MDD [30]. The fact that psychiatric disorders, including ODD, MDD, and AXD, were frequently accompanied with comorbid disorders might be a factor in the preference for polypharmacy among patients who presented with complaints of irritability. In addition, it would be instrumental to consider the complaint of irritability in the context of the accompanying aggression and in terms of rapid expectations from the medical management of aggression. The aggression profile frequently accompanied with irritability might have influenced the preference for psychotropic polypharmacy over other complaints.
Based on an analysis of the factors affecting polypharmacy in the treatment of psychiatric disorders, ADHD, ODD, CD, and ID diagnoses were associated with polypharmacy (Table 4). A study investigating psychotropic polypharmacy revealed that ADHD, ODD, CD, and ID diagnoses were predictive of polypharmacy use, similar to the results of the present study [31]. We considered that the expectation of a rapid symptomatic response increases the rates of polypharmacy, especially in disorders affecting academic performance, including ADHD, ODD, and CD. This is mainly because parents’ academic expectations have increased over the years. Upon a review of the relationship between comorbid conditions and polypharmacy, comorbidities of neurodevelopmental disorders (ADHD+ODD, ADHD+CD, ADHD+ODD+CD, and ADHD+ID) were associated with polypharmacy. Previous studies have suggested that children and adolescents diagnosed with neurodevelopmental disorders might often have additional psychiatric and neurological comorbidities; therefore, psychotropic polypharmacy could be used in the treatment of complex and relatively severe conditions [32].
In our regression model, age, CD, and any psychiatric comorbidity were associated with polypharmacy. In addition to being one of the most prevalent reasons for presentation in adolescents, CD is a highly heterogeneous disorder, with possible determinants defined by comorbidity patterns with specific developmental trajectories [33]. Although it has been suggested that psychosocial interventions are used as the first choice in early treatment, some conditions, including clinical heterogeneity and severity of symptoms, might lead to a choice of psychotropic use. The relative severity of CD symptoms also increases the families’ expectations of a rapid symptomatic response from treatment and might be effective in their preference for psychotropics. Upon a review of previous studies, psychiatric diagnoses and comorbidities in children and adolescents increased with aging [34]. A 2017 study reported that the most effective factors influencing polypharmacy were the presence of comorbid psychiatric disorders and psychotropic side effects [5]. It was reported that the presence of comorbid psychiatric diagnosis was associated with polypharmacy as it complicated the clinical picture [11]. In the current study, the presence of any psychiatric comorbidity increased the rate of polypharmacy use in the clinical sample, regardless of the type of psychiatric disorder. Comorbid diagnoses combined with psychiatric disorders complicate the existing clinical picture and are presented to clinicians with a wide range of target symptoms. Therefore, we suggest that the rates of psychiatric disorders and comorbidities increase with aging and lead to a preference for psychotropic polypharmacy by complicating the existing psychiatric picture. Similarly, considering the increasing rates of presentation to different child and adolescent mental health clinics, increased patient burden on clinicians, shortened examination times, and expectations of rapid response, psychotropic polypharmacy has become a treatment option especially in difficult cases.
The present study had certain limitations. Study data were collected retrospectively from a single center. Therefore, more detailed information on duration of drug use, treatment responses, and dynamic processes could not be obtained. The study’s generalizability may be limited as it is specific to certain geographical or cultural groups due to its single-center design. Although data from patients who attended a minimum of two psychiatric consultations were included in the study, longer-term polypharmacy did not provide sufficient data on safety and side effects, and the risks associated with polypharmacy could not be fully assessed.
In conclusion, the increasing use of psychotropic drugs in children and adolescents is associated with increasing interest of researchers in the topic. The study results indicate that the presence of CD, age, and comorbid psychiatric diagnosis significantly increase the risk of polypharmacy. In particular, the presence of comorbid psychiatric diagnosis is an important determinant leading to medication use. A better understanding of the factors that pave the way toward polypharmacy is critical to reduce unnecessary medication use in children and adolescents, minimize the risks of side effects, and develop more effective treatment strategies. In this context, it is important to adopt multidisciplinary approaches and apply pharmacological and nonpharmacological treatment methods through a balanced methodology. We suggest that interventions focusing on risk factors will lead to safer and more effective treatment outcomes. We believe that there is a requirement for large-scale longitudinal studies on the long-term effects and side effects of psychotropic polypharmacy.
Notes
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
Author Contributions
Conceptualization: Mutlu Muhammed Özbek. Data curation: Mutlu Muhammed Özbek, Ekin Atay. Formal analysis: Doğa Sevinçok, Mehmet Akif Cansız. Investigation: Tuğçe Canol Özbek. Methodology: Mutlu Muhammed Özbek, Hasan Can Özbay. Project administration: Doğa Sevinçok, Hasan Can Özbay. Resources: Mehmet Akif Cansız. Software: Doğa Sevinçok. Supervision: Tuğçe Canol Özbek. Validation: Ekin Atay. Visualization: Hasan Can Özbay. Writing—original draft: Mutlu Muhammed Özbek, Tuğçe Canol Özbek. Writing—review & editing: Mutlu Muhammed Özbek, Ekin Atay, Hasan Can Özbay.
Funding Statement
None
Acknowledgments
We would like to thank all patients and their parents who agreed to participate in the study.