Efficacy of Quetiapine With Bipolar Depression in Children and Adolescents

Introduction

Bipolar Depressive Disorder is classified by the National Institute of Mental Health as a mental disease that significantly alters a person’s mood, energy, mental and social activity, as well as the capabilities for independence and performance of daily tasks (“Bipolar disorder,”2016). Typically, this disease appears in adults and is caused by numerous factors ranging from stress to hormonal dysfunctions and genetic predisposition. However, it is possible for children and teenagers to develop the disease as well. About two to four percent of the general population in the United States is affected by Bipolar Depressive Disorder. Approximately 5.7 million Americans are affected by the disease every year (“Bipolar disorder,”2016).

Modern medical science does not have a complete understanding of the processes behind the etiology and pathophysiology of the disease, which causes a great variance in treatment strategies, as different psychologists and psychiatrists have different views on what causes the disease and how to treat it. Medication treatment in conjunction with psychological therapy is very popular as it is aimed at improving the patient’s psychological condition during depressive episodes (“Bipolar disorder,”2016).

Choosing the right combination of medications in order to treat a patient’s condition is paramount for successful treatment. At the same time, it is very hard to find a correct combination in order to deal with the patient’s symptoms effectively. The process is lengthy and full of trial and error. For some patients, it takes years to find the right medications. The three types of medications used to treat Bipolar Depressive Disorder are as followed (“Bipolar disorder,”2016):

  • Antidepressants – these medications work by balancing out the neurotransmitters in a patient’s brain, which affect mood and emotions. Examples: Amoxapine, Doxepin, Amitriptyline.
  • Atypical antipsychotics – while their exact mechanisms are not fully understood, they block certain receptors in a patient’s mind in order to help restore their mental capacity and prevent psychotic disorders from progressing any further. Examples: Quetiapine, Abilify, Clozapine.
  • Mood stabilizers – similar to antidepressants in how they affect the brain, these medicines prevent mood fluctuations rather than relieve symptoms of depression. Examples: Carbamazepine, Divalproex Sodium, and Lamotrigine.

Quetiapine is an atypical psychotic that was initially introduced as one of the potential remedies to treat schizophrenia (Correll, Detraux, De Lepeleire, & De Hert, 2015). However, before the medication could be introduced into practice, extensive medical trials are required. A significant host of researchers stressed out the necessity of testing the effectiveness of Quetiapine in monotherapy and in combination with antidepressants and mood stabilizers on people of various age groups that have been afflicted with Bipolar Depressive Disorder (Correll et al., 2015). While the initial studies have proven the effectiveness of Quetiapine in treating the disease and significantly lowering some of the major depressive symptoms in patients, the results are still inconclusive. Not all age groups were covered in trials, meaning that there are gaps in knowledge on the effectiveness of the treatment. While existing research did not find any significant side effects, some authors, including Masi, Pisano, Pfanner, Milone, & Manfredi (2013), claimed that the current knowledge about the risks associated with the use of quetiapine among children and adolescents, such as weight gain, is rather poor.

PICOT Question

The purpose of this PICOT research is to eliminate some of the gaps in knowledge that exist in regards to the use of Quetiapine in Bipolar Depression treatment. The target population that will be covered in the research are children and adolescents aged 10-18. Quetiapine will be tested as the primary pharmacological monotherapy intervention against a standardized pharmacological treatment (lithium, combination therapy). The reduction of severity of depressive symptoms is expected within 12 months. The specific components of this PICOT are as followed:

  • P: Children and adolescents aged 10-18.
  • I: Pharmacological intervention of monotherapy extended release Quetiapine.
  • C: Standard pharmacological treatment, such as Lithium or combination therapies.
  • O: Reduce the number or severity of manic and depressive events.
  • T: Within 12 months.

Narrative Evidence Review

Quetiapine Monotherapy versus Placebo in the Treatment of Children and Adolescents with Bipolar Depression: A Systematic Review and Meta-Analysis

This research was published in 2017 in Neuropsychiatric Disease and Treatment Journal. It is a systematic review that had a purpose of determining the effectiveness and acceptability of Quetiapine in patients aged 10-18, which coincides with the topic of this PICOT. The total number of analyzed participants was 251, which were spread into 2 groups – the test group and the controlled placebo group. In the end, the researchers concluded that Quetiapine showed poor results in the test group, while remission rates did not differ from one another, indicating that Quetiapine’s side-effects did not display themselves of were negligible. To summarize, Quetiapine was not found to be useful in treating depressive disorders (Maneeton et al., 2017). The strengths of this research lie in the fact that it is very recent and that it accumulates the knowledge gathered from numerous randomized control trials. Its weaknesses, however, come from its selection. The amount of chosen trials was not sufficient to cover every age group and every variation that could be statistically possible. In addition, the research did not include any specific control trials for overweight and obese child patients. The researchers recognize the limitations of their study and suggest that further exploration should include groups that weren’t cover in their systematic review (Maneeton et al., 2017).

Efficacy and Safety of Extended-Release Quetiapine Fumarate in Youth with Bipolar Depression: An 8 Week, Double-Blind, Placebo-Controlled Trial

This study was conducted in 2014 and published in the Journal of Child and Adolescent Psychopharmacology. This research had a primary goal of testing the safety of Quetiapine when used in young patients with Bipolar Depression. While the researchers did collect data on how effective the treatment was, this randomized control trial was not explicitly set up to test that parameter. The study found that, contrary to adults, children and adolescents do not respond to Quetiapine therapy (Findling, Pathak, Earley, Liu, & DelBello, 2013). At the same time, the side effects were deemed negligible. As it is a randomized control trial, the quality of evidence provided by it is very high – RCT is considered to be the golden standard of medical research. However, the weakness of the RCTs is in that it is a very small trial tied to a specific hospital and a specific location. Its results could have been affected by the quality of the staff that participated in the research as well as potential practice misalignments. However, it is unlikely that either of these factors had a significant effect on this particular RCT.

Quetiapine Monotherapy in Adolescents with Bipolar Disorder Comorbid with Conduct Disorder

This non-randomized control trial was performed in 2013 and later published in Journal of Child and Adolescent Psychopharmacology. This study used 40 adolescents with various degrees of depression and Bipolar Disorder Comorbid in order to test the effectiveness of Quetiapine monotherapy. The research found that in over 50% of all cases, monotherapy produced an increase of 30% in CGI-S and C-GAS scores when compared to tests done before the intervention was administered (Masi et al., 2013). The study found that extreme levels of Quetiapine brought about side effects such as moderate and extreme sedation. The strength of this research lies in the fact that it provides data regarding the effects of Quetiapine on a sample with varying degrees of severity of depression and BDC. However, due to being a non-randomized trial, it is subject to sampling bias, as the participants were elected on a convenience basis rather than using a randomized approach.

Comparison of the Effect of Lithium plus Quetiapine with Lithium plus Risperidone in Children and Adolescents with Bipolar I Disorder: A Randomized Clinical Trial

This is a recent research article published in Medical Journal of the Islamic Republic of Iran in 2017. The purpose of this study was to provide comparative data between two combinations of medications – Quetiapine + Lithium versus Risperidone + Lithium. The age range of the test group and control group was 10-18, which is compatible with our research. In order to measure the effectiveness of treatment, the researchers used Young Mania Rating Scale for similar purposes. The research found that Quetiapine + Lithium combination proved more effective than Risperidone + Lithium in countering symptoms of mania (Habibi, Dodangi, & Nazeri, 2017). As this is a randomized control trial, its strengths lie in lack of many potential biases present in different forms of research. The weakness of this research lies in the fact that they used YMRS to estimate the effects of the treatment of Bipolar I Disorder, which is not entirely fitting.

Quetiapine for Acute Bipolar Depression: A Systematic Review and Meta-Analysis

This study is, perhaps, the centerpiece of the presented PICOT research. It is a systematic review and meta-analysis of existing medical literature and RCTs available on the subject by the end of 2014. The study was published in Drug Design, Development, and Therapy Journal during the same year. The purpose of the study was to systematically review the efficacy and the tolerability of Quetiapine, either as monotherapy or combination therapy, for acute bipolar depression. The meta-analysis features the results of eleven RCTs with the total number of participants being 3,488. The results of the study state that in general, Quetiapine was efficient in treating Acute Bipolar Depression. When compared to the placebo groups, test groups showed higher degrees of variety for treatment efficiency as well as potential side effects. The research identified a number of side effects associated with Quetiapine treatment, such as extrapyramidal side effects, sedation, somnolence, dizziness, fatigue, constipation, dry mouth, increased appetite, and weight gain (Suttajit, Srisurapanont, Maneeton, & Maneeton, 2014). The strength of this research lies in the fact that it provided the widest amounts of coverage for all populations, regardless of sex, age, ethnicity, or weight. There are very few potential weaknesses in such research. However, its greatest limitation in regards to this research lies in the fact that it is not dedicated solely to patients between 10 and 18 years of age. The conclusions of this meta-analysis also come into conflict with findings mentioned in previous research articles.

Strengths and Weaknesses Table

Evidence Based Practice Question (PICO(T)): Efficacy of Quetiapine with bipolar depression in children and adolescents.
Source (Authors, year) Strengths Weaknesses Level of QualityRating
  1. Quetiapine monotherapy versus placebo in the treatment of children and adolescents with bipolar depression: a systematic review and meta-analysis (Maneeton, B., Putthisri, S., Maneeton, N., Woottiluk, P., Suttajit, S., Charnsil, C., & Srisurapanont, M., 2017)
The article is very recent so the information in it is not outdated. Accumulates knowledge gathered from several RTCs. The amount of RTCs analyzed in this systematic review is insufficient to make conclusion about the entire age group. 3
  1. Efficacy and Safety of Extended-Release Quetiapine Fumarate in Youth with Bipolar Depression: An 8 Week, Double-Blind, Placebo-Controlled Trial (Findling, R. L., Pathak, S., Earley, W. R., Liu, S., & DelBello, M., 2013)
Since it is an RTC, it is subjected to fewer potential biases when compared to other types of research. The number of participants is relatively small, quality of staff and practice misalignments could have had an effect on the results (though unlikely) 2
  1. Quetiapine Monotherapy in Adolescents with Bipolar Disorder Comorbid with Conduct Disorder (Masi, G., Pisano, S., Pfanner, C., Milone, A., & Manfredi, A., 2013)
The selection of participants with different levels of BDC offers a range of results to analyze the effectiveness of Quetiapine monotherapy with. Not an RTC, greater potential for bias. Research sample relatively small. 3
  1. Comparison of the Effect of Lithium plus Quetiapine with Lithium plus Risperidone in Children and Adolescents with Bipolar I Disorder: A Randomized Clinical Trial (Habibi, N., Dodangi, N., & Nazeri, A., 2017)
Since it is an RTC, it is subjected to fewer potential biases when compared to other types of research. The researchers used YMRS to estimate the effects of the treatment on Bipolar I Disorder, which is not entirely fitting. 2
  1. Quetiapine for Acute Bipolar Depression: A Systematic Review and Meta-Analysis (Suttajit, S., Srisurapanont, M., Maneeton, N., & Maneeton, B., 2014)
Strong evidential base, large number of participants, many age groups and ethnicities are covered. Different approaches to medication dosage and administration. Very few weaknesses, similar to RTCs. However, does not focus on the chosen group alone. 1

Evidence Synthesis

As it stands, current research findings conflict with one another. Some researchers have indicated that the use of Quetiapine did not bring any significant results in treating Bipolar Depression Disorder (Findling et al., 2013) (Maneeton et al., 2017), while others have noted a marked drop in several symptoms associated with depression, such as mania, anxiety, appetite loss, sleep deprivation, etcetera (Suttajit et al., 2014) (Habibi et al., 2017). However, it must be noted that the research articles supporting the effectiveness of Quetiapine were both too general and focused on both the adult and the adolescent populations, non-RTCs, or RTCs that analyzed patients diagnosed with symptoms of mania or mixed mania and depression. In addition, the articles that did not find any signs of Quetiapine effectiveness also stated a lack of significant adverse effects, whereas the rest managed to identify several of them, such as sedation and somnolence. Based on the evidence gathered so far, it could be speculated that Quetiapine, while not very effective on children suffering from Bipolar Depressive Disorder, is effective in adult populations and children suffering from manic episodes. The drug does have adverse effects compatible with other products from the atypical antipsychotics drug group, though they seem to manifest in adults rather than children when using larger doses.

Summative Evidence Rating Table

Evidence Based Practice Question (PICO):
Level of Evidence Number of
Studies
Summary of Findings Overall Quality
1 1 The article finds Quetiapine to be effective in treatment of Acute Bipolar Depression in the majority of patients of all age groups and ethnical backgrounds. 1
2 2 While the researches find Quetiapine to be inefficient against classic symptoms of Bipolar Depression, they indicate that the medicine is good at reducing manic episodes. 2
3 2 Contradictory evidence – one article found no evidence of Quetiapine being efficient in treating Bipolar Depression, whereas the other article found it effective in treating over 50% of cases of Bipolar Disorder Comorbid. 3

Potential Gaps

The biggest gap in the current research is that there is not enough compelling and overwhelming evidence of Quetiapine being an effective medication for Bipolar Depressive Disorder. Some of the evidence suggests such a conclusion while the others deny it. In addition, no evidence was provided on how weight and complexity of the patient affect the chances of Quetiapine being effective or ineffective. The information about side effects in regards to patients of 10-18 years of age remains inconclusive. There were no dedicated studies on how the gender of the patient affects the effectiveness of the drug. The articles were difficult to compare due to the fact that their objects and research goals did not perfectly co-align. Significant differences in criteria for the research samples caused a lack of result cohesion. In order to close the gaps, dedicated researches must be conducted in order to address each of the identified gaps. To remove the contradictions in the existing evidence, the research designs should be replicated in order to see if the results remain the same.

Recommendations

Based on the existing evidence, it is not recommended to use Quetiapine to treat Bipolar Depressive Disorder in patients between 10 and 18 years of age due to insufficient and contradicting evidence about the effectiveness of the drug. While the research studies did not find any indication of serious drawbacks for patients of this age group, Quetiapine is unreliable to produce results and would otherwise be a waste of resources. At best, it prevents the condition of the patients from worsening. At the same time, the available evidence suggests that Quetiapine can be effective in child and adolescent patients, should BDD be accompanied by manic episodes. In that case, the combination of Quetiapine and Lithium provides a more efficient and less expensive alternative to Risperidone and Lithium combination. Potential barriers to implementing Quetiapine in adolescent patients include a lack of conclusive evidence and ethical issues that derive from implementing it on a large scale, without the effects of the medicine being fully studied in relation to the target population.Based on the studies evidence, similarities and differences between studies, major validity threats, the feasibility of the decision, resources needed, ethical issues, potential risks and benefits at the patient, nursing, and organizational levels, this research gives Quetiapine a rating C of the USPSTF grading rubric.

References

Bipolar disorder. (2016). Web.

Correll, C. U., Detraux, J., De Lepeleire, J., & De Hert, M. (2015). Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry, 14(2), 119-136.

Findling, R. L., Pathak, S., Earley, W. R., Liu, S., & DelBello, M. (2014). Efficacy and safety of extended-release Quetiapine fumarate in youth with bipolar depression: An 8 week, double-blind, placebo-controlled trial. Journal of Child and Adolescent Psychopharmacology, 24(6), 325-335.

Habibi, N., Dodangi, N., & Nazeri, A. (2017). Comparison of the effect of lithium plus quetiapine with lithium plus risperidone in children and adolescents with bipolar I disorder: a randomized clinical trial. Medical Journal of the Islamic Republic of Iran, 31(1), 1-6.

Masi, G., Pisano, S., Pfanner, C., Milone, A., & Manfredi, A. (2013). Quetiapine monotherapy in adolescents with bipolar disorder comorbid with conduct disorder. Journal of Child and Adolescent Psychopharmacology, 23(8), 568-571.

Maneeton, B., Putthisri, S., Maneeton, N., Woottiluk, P., Suttajit, S., Charnsil, C., & Srisurapanont, M. (2017). Quetiapine monotherapy versus placebo in the treatment of children and adolescents with bipolar depression: a systematic review and meta-analysis. Neuropsychiatric Disease and Treatment, 13, 1023–1032.

Suttajit, S., Srisurapanont, M., Maneeton, N., & Maneeton, B. (2014). Quetiapine for acute bipolar depression: A systematic review and meta-analysis. Drug Design, Development and Therapy, 8(1), 827-838.