Journal of Affective Disorders 176 (2015) 1–7
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Special review article
Can unipolar and bipolar pediatric major depression be differentiated from each other? A systematic review of cross-sectional studies examining differences in unipolar and bipolar depression Mai Uchida a,d,n, Giulia Serra c,d, Lazaro Zayas b,d, Tara Kenworthy a, Stephen V. Faraone e, Joseph Biederman a,d a
Massachusetts General Hospital, Department of Pediatric Psychopharmacology, Boston, MA, United States Massachusetts General Hospital, Department of Psychiatry, Boston, MA, United States Sant'Andrea Hospital, Sapienza University, NESMOS Department, Rome, Italy d Harvard Medical School, Department of Psychiatry, Boston, MA, United States e SUNY Upstate Medical University, Departments of Psychiatry and of Neuroscience and Physiology, United States b c
art ic l e i nf o
a b s t r a c t
Article history: Received 7 January 2015 Accepted 15 January 2015 Available online 23 January 2015
Introduction: While pediatric mania and depression can be distinguished from each other, differentiating between unipolar major depressive disorder (unipolar MDD) and bipolar major depression (bipolar MDD) poses unique clinical and therapeutic challenges. Our aim was to examine the current body of knowledge on whether unipolar MDD and bipolar MDD in youth could be distinguished from one another in terms of clinical features and correlates. Methods: A systematic literature search was conducted on studies assessing the clinical characteristics and correlates of unipolar MDD and bipolar MDD in youth. Results: Four scientific papers that met our priori inclusion and exclusion criteria were identified. These papers reported that bipolar MDD is distinct from unipolar MDD in its higher levels of depression severity, associated impairment, psychiatric co-morbidity with oppositional defiant disorder, conduct disorder and anxiety disorders, and family history of mood and disruptive behavior disorders in firstdegree relatives. Limitations: Though we examined a sizeable and diverse sample, we were only able to identify four cross sectional informative studies in our review. Therefore, our conclusions should be viewed as preliminary. Conclusions: These findings can aid clinicians in differentiating the two forms of MDD in youth. & 2015 Published by Elsevier B.V.
Keywords: Bipolar disorder Major depressive disorder Pediatric
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Qualitative analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical differences between bipolar and unipolar MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Psychiatric co-morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Family history of psychiatric illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
n Corresponding author at: Massachusetts General Hospital, Department of Pediatric Psychopharmacology, 55 Fruit Street Warren 625, Boston, MA 02114, United States. Tel.: þ1 617 643 6865; fax: þ 1 617 724 3742. E-mail address: [email protected] (M. Uchida).
http://dx.doi.org/10.1016/j.jad.2015.01.037 0165-0327/& 2015 Published by Elsevier B.V.
2 2 2 2 2 2 2 3 3 3
2
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
3.4. 3.5. 3.6. 3.7.
Severity of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Level of impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Behavioral difficulties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Other characteristics associated with bipolar depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.7.1. Irritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.7.2. Early age of onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Introduction
2. Methods
Pediatric major depressive disorder (MDD) is a prevalent disorder in youth estimated to afflict up to 25% of youth in the U.S. (Lewinsohn et al., 1998). This disorder is associated with very high levels of morbidity, distress, and disability affecting all aspects of the afflicted child's life, including increased risk for psychiatric hospitalizations, substance use disorders, family dysfunction, distress, and deficits in both educational and work performance (Carlson and Kashani, 1988; Lewinsohn et al., 2000). MDD is also a major risk for suicide and suicide remains the second most common cause of death in youth, second only to accidents (Nock et al., 2013). The Center for Disease Control (CDC) considers pediatric MDD a major public health concern (Centers for Disease Control, 2012) and documents that even minor symptoms of MDD dramatically increase the risk for suicidal behavior, supporting efforts aimed at the identification and treatment of pediatric MDD. However, a major problem in the diagnosis and management of pediatric MDD is distinguishing children afflicted with bipolar forms of MDD from those with unipolar forms of the disorder. The literature suggests that up to 30% of youth presenting to clinical practice with prototypical symptoms of MDD have already experienced symptoms of mania or hypomania (bipolar MDD) (Geller et al., 1994). While antidepressants remain the mainstay of treatment for MDD, a major concern in treating children with an antidepressant is the risk of pharmacologically inducing manic symptoms, psychomotor agitation and mixed states, and increasing the risk for suicidal behaviors (Faedda et al., 2004; Akiskal and Benazzi, 2005; Baldessarini et al., 2005), a risk that is particularly concerning in children with bipolar MDD. Because the literature suggests that a substantial minority of pediatric patients who present with symptoms of MDD actually have bipolar MDD, identifying which children have histories of mania or hypomania is a difficult endeavor that further complicates treatment decisions. This state of affairs supports the need for efforts at identifying bipolar from unipolar forms of MDD in clinical and research settings. The authors of this paper recently conducted a literature review examining which clinical correlates are most predictive of ultimate manic switches in children initially presenting with depressive episodes (Uchida et al., 2014). In their systematic literature review, the authors elucidated that manic switches in pediatric depression can be predicted by several risk factors, including positive family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania, and psychosis. Because of the greater morbidity associated with bipolar MDD as described above, being able to cross-sectionally distinguish bipolar MDD from unipolar MDD is of paramount importance. As such, the main aim of this study was to investigate the current body of knowledge on whether unipolar and bipolar forms of pediatric MDD could be differentiated from one another. To this end, we conducted a systematic review of the extant literature addressing this important issue. To the best of our knowledge this is the first investigation of this topic.
2.1. Literature review We performed a literature search through PubMed utilizing the following search algorithm: (bipolar depression OR bipolar disorder) AND (unipolar depression OR major depressive disorder) AND (predictor OR prodrome OR risk factors OR comparison OR switch OR conversion) AND (childn OR adolescn OR youth). References were also reviewed and added if applicable to search criteria. 2.2. Selection criteria We included only original studies that specifically evaluated the differences in the clinical features and correlates between unipolar and bipolar MDD in youth. We implemented the following inclusion criteria: (1) original research, (2) has operationalized assessment of major depressive disorder and bipolar disorder, (3) documents comparison between unipolar and bipolar MDD, (4) subjects are limited to children of under the age of 18, and (5) a cross-sectional examination. Articles were excluded if (1) they did not differentiate symptomatic pictures of unipolar from bipolar MDD, (2) the study had a prospective design examining the risk factors of manic switching, or (3) not available in the English language. Two psychiatrists and a research assistant screened the articles for relevance by examining the abstracts, and two psychiatrists and a research assistant reviewed the identified relevant articles in full text to evaluate their eligibility. 2.3. Data extraction The following variables were extracted: study sample size, proband age range, and characteristics that differentiated subjects with unipolar and bipolar MDD. 2.4. Qualitative analysis We reviewed the included articles, extracting the relevant details. We also performed a qualitative analysis of the methods and results with particular note to characteristics that differentiated subjects with unipolar and bipolar MDD.
3. Results Fig. 1 provides the results of the identification of the articles. From the initial database search, 752 papers were identified and screened by 2 of the authors (MU and GS). After the initial screening, 45 articles were found to be relevant and the full text of each was carefully examined. Of these, 41 studies were excluded due to either 1) failure to report on the difference between the clinical correlates of
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
bipolar and unipolar MDD (N¼27), 2) including adult subjects (N¼7), or 3) examined the risk factors of manic switches (N¼ 7). Thus four studies met all of our inclusion and exclusion criteria and were included in this qualitative review. Together, these four studies included 1111 subjects with unipolar MDD and 365 with bipolar MDD, 3–18 years of age. Two studies used community samples (1 preschool sample, 1 national comorbidity study sample), and two studies used outpatient samples (1 general outpatient clinic sample, 1 attention deficit hyperactivity disorder (ADHD) sample). Table 1 gives the characteristics of each study; number of subjects, age of subjects, and the study's main findings that distinguished bipolar MDD from unipolar MDD. 3.1. Clinical differences between bipolar and unipolar MDD Four significant distinguishing clinical factors were found to be over represented in children with bipolar MDD compared to those with unipolar MDD: 1) high rates of psychiatric co-morbidities (3/4 studies), 2) high rates of family history of psychiatric illness (3/4 studies), 3) higher severity of depression (2/4 studies), and 4) higher level of impairment (2/4 studies). Although not statistically significant, high levels of irritability (2/4 studies) and early onset of mood symptoms (3/4 studies) in youth with bipolar MDD were also identified in some studies.
3
Wozniak et al. (2004) used a sample of ADHD children from 6 to 17 years of age, compared those with unipolar (N¼109) and bipolar MDD (N¼ 43), and found that youth exhibited significantly increased rates of oppositional defiant disorder (63% vs. 30% in bipolar and unipolar MDD respectively, po0.0001) and conduct disorder (60% vs. 12% in bipolar and unipolar MDD respectively, po0.0001) in bipolar vs. unipolar youth, respectively. This study also noted an increased level of other psychiatric comorbidities such as agoraphobia, obsessive–compulsive disorder and alcohol abuse in the youth with bipolar MDD. Luby and Belden (2008) compared rates of psychiatric comorbidity in a sample of preschool aged children 3–6 years of age with bipolar (N¼ 21) and unipolar (N¼ 54) MDD and found that that preschoolers with bipolar MDD were significantly more likely to have comorbid oppositional defiant disorder (OR¼4.65, 95% CI¼1.49–14.58, po0.01) and conduct disorder (OR¼54.40, 95% CI¼11.69–253.14, po.001), as well as comorbid ADHD (OR¼13.06, 95% CI¼3.38–50.40, po0.001) and anxiety disorders (OR¼7.60, 95% CI¼ 2.38–24.28, po0.001) than preschoolers with unipolar MDD. Merikangas et al. (2012)'s study included 805 adolescents with unipolar MDD and 246 adolescents with bipolar MDD, and reported that adolescents with bipolar MDD had significantly higher rates of conduct and oppositional defiant disorder (52% vs. 30%, OR¼2.45, 95% CI¼1.09–2.36). Adolescents in the bipolar MDD group were also twice as likely to have anxiety disorders (OR¼2.34, 95% CI¼ 1.47–3.72), and substance use (OR¼ 2.27, 95% CI¼ 1.09–4.75) disorders as the unipolar MDD group.
3.2. Psychiatric co-morbidity 3.3. Family history of psychiatric illness
Included
Eligibility
Screening
Identification
Three studies found significant associations between high levels of psychiatric comorbidities and bipolar MDD. All three studies reported that children with bipolar MDD had higher rates of oppositional defiant disorder, conduct disorder and anxiety disorders compared to children with unipolar MDD, and the two studies examining adolescents both reported higher rates of substance use disorders in the bipolar MDD group.
Records identified through database searching (n =752)
Three studies found significant associations between higher levels of family history of psychiatric disorders in children and adolescents with bipolar MDD as compared to children and adolescents with unipolar MDD. All three studies reported that those with bipolar MDD had higher rates of bipolar disorder in first-degree relatives as compared to those with unipolar MDD.
Records identified through other sources (n =25)
Records after duplicates removed (n =770)
Full-text articles assessed for eligibility (n = 45)
Excluded after screening (n = 725)
Full-text articles excluded, with reasons (n =41) 1) failure to report on differences between the clinical correlates of bipolar and unipolar MDD (N= 27), 2) included adult subjects (N=7), and3) examined the risk factors of manic switches (N=7)
Studies included in qualitative synthesis (n = 4)
Fig. 1. PRISMA Flow Diagram, this diagram shows that from 770 articles, 4 studies were included in the review.
4
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Table 1 Summary of cross-sectional studies. Author and year
N
Sample
Age (years)
Diagnosis
Wozniak et al. (2004)
109 MDD 43 BPD
ADHD sample, outpatient
6–17 (mean 12.4–13.5)
DSM-III, K-SADS
Luby and Belden (2008)
21 BPD 54 UPD
Community
3–6
DSM-IV
Depression severity Irritability Comorbid ADHD, conduct, ODD, anxiety
Merikangas et al. (2012)
246 BPD 805 MDD
Household sample and school sample
13–18
DSM-IV
Depression Severity Younger age of onset Recurrent episodes Disability Comorbid anxiety, substance use, conduct Family history of mood disorder
Outpatient
6–18
DSM-IV
Atypical features Mood change congruent with antidepressant Aggressive behaviors Family history of psychiatric illness
Shon et al. (2014) 20 BPI 10 BPII 25 BP-NOS 143 MDD
Two of the studies further revealed that those with bipolar MDD had higher levels of first-degree relatives with various psychiatric illnesses, including MDD, anxiety disorders, conduct disorder, and oppositional defiant disorder. Wozniak et al. (2004) reported that bipolar MDD was associated with higher levels of psychiatric disorders in first-degree relatives compared to unipolar MDD. Not only did the bipolar MDD group have higher rates of family history of bipolar disorder (20% vs. 8% in bipolar and unipolar MDD respectively, p ¼0.003), they also had stronger family history of various psychiatric illnesses, such as major depressive disorder (62% vs. 45% in bipolar and unipolar MDD respectively, p¼ 0.003), anxiety disorders (63% vs. 30% in bipolar and unipolar MDD respectively, p¼0.0002), conduct disorder (31% vs. 12% in bipolar and unipolar MDD respectively, p¼0.0001) and oppositional defiant disorder (43% vs. 20% in bipolar and unipolar MDD respectively, p¼0.0001). Merikangas et al. (2012) also reported that adolescents with bipolar MDD had significantly greater family history of MDD (87% vs. 73% in bipolar and unipolar MDD respectively, OR¼ 2.4, 95% CI¼1.19–4.84). Shon et al. (2014) performed a cross-sectional review of longitudinal observational data on 55 children with bipolar MDD and 143 with unipolar MDD, and they found family history of mania or hypomania (10% vs. 2% in bipolar and unipolar MDD respectively, p¼ 0.005), as well as other psychiatric disorders, was significantly higher in BP groups than those with unipolar MDD (30% vs. 10.5% in bipolar and unipolar MDD respectively, p¼0.018). 3.4. Severity of depression Three studies found significant associations between both a greater number of depressive episodes and higher severity of depressive symptoms in children with bipolar MDD as compared to those with unipolar MDD. According to these studies, children with bipolar MDD experienced greater levels of sadness, irritability, hopelessness, and suicidal or self-injurious behaviors. Furthermore, two of the studies found that children with bipolar MDD
Predictors of bipolar MDD Depression severity Hopelessness Suicidality Sad þmad mood School behavior Hospitalization Interpersonal difficulty Comorbid conduct or ODD Family history of mood disorder, anxiety disorder and conduct disorder
had markedly higher rates of inpatient hospitalizations as compared to children with unipolar MDD, thereby highlighting the greater depressive symptom severity experienced by children with bipolar MDD. In the study by Wozniak et al. (2004), children with bipolar MDD experienced a greater number of depressive episodes with symptoms of both sadness and irritability (74% vs. 54% in bipolar and unipolar MDD respectively, p¼ 0.02) and hopelessness (88% vs. 69% in bipolar and unipolar MDD respectively, p ¼ 0.02) than children with unipolar MDD. Children with bipolar MDD also reported a higher number of total major depressive episode symptoms (9.4 vs. 8.5 in bipolar and unipolar MDD respectively, p¼0.09). Higher rates of suicidality (69% vs. 50% in bipolar and unipolar MDD respectively, p¼0.03) and hospitalizations (36% vs. 6% in bipolar and unipolar MDD respectively, p¼ 0.001) were observed in children with bipolar MDD as well. Luby and Belden (2008) reported that preschoolers with bipolar MDD had significantly higher depression severity scores (mean¼11.14) than preschoolers with unipolar MDD (mean¼7.93, po0.0001), assessed through the Preschool Age Psychiatric Assessment (PAPA). Preschoolers with bipolar MDD also had greater levels of loss of interest, being easily annoyed, sleep problems, motor slowing, self-deprecation or self-hatred, death themes in their play, and suicidal or self-injurious behaviors. Merikangas et al. (2012) also found a higher number of major depressive disorder symptoms (7.4 vs. 6.8 in bipolar and unipolar MDD respectively, po0.001) and greater severity of depressive symptoms (11.4 vs. 10.4 in bipolar and unipolar MDD respectively, p¼0.04), measured through the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR). 3.5. Level of impairment Two studies found significant associations between children with bipolar MDD and high levels of impairment. Both studies described that these children exhibited severe disturbances in major life roles, including marked difficulties with peers and family members, and severe behavioral problems in school.
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Wozniak et al. (2004) documented that compared to children with unipolar MDD, children with bipolar MDD had significantly higher impairment associated with major depressive episodes measured by the KSADS-E (77% vs. 43% in bipolar and unipolar MDD respectively, p¼0.002) and poorer functioning measured through Social Adjustments in Children and Adolescents (SAICA), particularly in school behavior problems and difficulties with peers and family members. The bipolar MDD group also had lower average Global Assessment of Function (GAF) scores (55.6 vs. 63.3 in bipolar and unipolar MDD respectively, po0.0001). In the study by Merikangas et al. (2012), adolescents with bipolar MDD were found to have spent a greater number of days out of role than adolescents with unipolar MDD (54% vs. 41% in bipolar and unipolar MDD respectively, OR¼ 1.91, 95% CI¼ 1.07–3.42). In addition, a greater proportion of adolescents with bipolar MDD experienced severe impairments associated with their symptoms (24% vs. 16% in bipolar and unipolar MDD respectively, OR¼2.52, 95% CI¼ 1.52–4.17). 3.6. Behavioral difficulties Two studies found significant associations between children with bipolar MDD and severe behavioral difficulties marked by aggression as compared to children with unipolar MDD. Merikangas et al. (2012) described that behavioral difficulties were reported more in children of bipolar MDD than the unipolar MDD group (OR¼2.45, 95% CI¼1.19–5.05). Shon et al. (2014) reported that aggressive behaviors were significantly more commonly observed in the bipolar MDD groups than in subjects with unipolar MDD (40% vs. 14.7% in bipolar and unipolar MDD respectively, p¼ 0.001). 3.7. Other characteristics associated with bipolar depression 3.7.1. Irritability Two studies found significant associations between children with bipolar MDD and symptoms of irritability. More specifically, children with bipolar MDD experienced depressive episodes characterized by more symptoms of irritability as compared to the depressive episodes experienced by children with unipolar MDD. Two studies (Wozniak et al. (2004); Luby and Belden (2008)) reported that more children with bipolar MDD experienced depressive episodes with symptoms of irritability. Wozniak reported that irritability was observed more in bipolar MDD children compared to unipolar MDD (88% vs. 75% in bipolar and unipolar MDD respectively, p¼ 0.1). Interestingly, although Wozniak's analysis suggests that the difference in the rate of irritability between bipolar and unipolar MDD is insignificant, this difference becomes significant when analyzing the children who endorsed “feeling both sad and irritable,” with the bipolar MDD groups exhibiting much higher rates of irritability as compared to the unipolar MDD group (74% vs. 54%, po0.02). Luby and Belden (2008) also documented that preschoolers with bipolar MDD reported more symptoms of irritability compared to unipolar MDD (100% vs. 76% in bipolar and unipolar MDD respectively, po0.01). Follow-up analyses indicated that compared to those with unipolar MDD, preschoolers with bipolar MDD consistently exhibited irritability at clinically significant levels. 3.7.2. Early age of onset Three studies found associations between early age of onset of depressive episodes and bipolar MDD. The three studies revealed that bipolar MDD emerges earlier in life that unipolar MDD, with two studies demonstrating the onset of bipolar MDD earlier than unipolar MDD. Three studies examined the differences in the age of onset in bipolar MDD and unipolar MDD, showing substantially earlier age
5
of onset of bipolar MDD than unipolar MDD, although only Merikangas et al. (2012)'s results reached statistical significance. Merikangas et al. (2012) documented that bipolar MDD emerges earlier in life compared to unipolar MDD (10.8 years old vs. 11.9 years old in bipolar and unipolar MDD respectively, p¼ 0.004). Wozniak et al. (2004) reported that the bipolar MDD group had a markedly earlier age of onset compared to those with unipolar MDD (6.5 years old vs. 7.8 years old in bipolar and unipolar MDD respectively). Shon et al. (2014) also reported earlier onset in bipolar MDD (13.6 years old vs. 15 years old in bipolar and unipolar MDD, respectively).
4. Discussion Our systematic review of the extant literature examined studies that evaluated differences in the clinical features and correlates between unipolar and bipolar MDD in youth. Four studies met our inclusion and exclusion criteria. These studies document that bipolar MDD can be distinguished from unipolar MDD by its higher levels of severity and impairments and its pattern of psychiatric comorbidity and famililaity. Three studies reported a strong association between bipolar MDD and a family history of both unipolar and bipolar disorders as well as anxiety disorder. These findings are consistent with those identified in adult patients with bipolar MDD (Akiskal et al., 1983; Coryell et al., 1995; Bechdolf et al., 2010) and with the literature on the risk factors for manic switching (Strober and Carlson, 1982; Geller et al., 1994; Biederman et al., 2009). Wozniak et al. (2010) previously reported on the significantly increased morbid risk of bipolar disorder in relatives of children with bipolar disorder as compared to relatives of children with only ADHD. This study also found that relatives of children with bipolar disorder have higher rates of psychosis, major, multiple anxiety disorders, substance use disorders, ADHD, and antisocial disorders as compared to relatives of non-bipolar probands. Taken together, these findings stress the critical importance of family history to help distinguish unipolar and bipolar form of MDD in juvenile patients. Three of the four studies reviewed reported a higher liability of comorbid psychiatric disorders in children with bipolar MDD as compared to children with unipolar MDD, including ADHD, conduct disorder, oppositional defiant disorder, anxiety disorders, and pervasive developmental disorders. These results are consistent with the higher rates of psychiatric comorbidities reported in children with bipolar disorder compared with those with unipolar MDD. Considering the high level of distress and disability associated with these comorbid disorders, these finding stress the higher level of clinical and therapeutic complexity associated with the clinical presentation of bipolar MDD than unipolar MDD. All four studies also described that children presenting with bipolar MDD exhibit variable manifestations of behavioral dysregulation, including aggressive behaviors as well as having comorbid disruptive behavior disorders including conduct disorder (CD) and oppositional defiant disorder (ODD). These findings are consistent with crosssectional studies that reported strong associations between bipolar MDD with both ODD and CD (Wozniak et al., 2004). One study reported a 69% rate of CD in a clinically referred sample of youths with bipolar disorder who were longitudinally followed over a period of 12years (Kovacs and Pollock, 1995). This very study suggested that comorbid CD may help identify a subtype of a very early onset bipolar disorder with a worse clinical course. More recent studies confirmed the association by documenting a bidirectional overlap between pediatric bipolar disorder and CD (Biederman et al., 1999, 2003). For example, Biederman reported that of 186 children and adolescents with mania and of 192 with CD, 76 satisfied criteria for both CD and
6
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
mania, representing 40% of youths with CD and 41% of youths with mania, respectively. The data suggest that when mania and CD cooccur in children, both are correctly diagnosed, thereby representing the bidirectional overlap between bipolar disorder and CD. This investigation further elucidated that the presence of CD in children with bipolar disorder may help identify a particularly severe form of pediatric bipolar disorder (Biederman et al., 2003). Children with bipolar MDD also experienced greater severity of quantity as well as quality of depressive symptoms. Quantitatively, authors found that bipolar MDD groups compared to unipolar MDD groups had higher numbers of depressed symptoms endorsed by individuals, as well as higher numbers of children who reported symptoms such as hopelessness and being both sad and angry. Qualitatively, there were higher incidences of suicidality and hospitalizations in the children of bipolar MDD. These findings are consistent with those of Beesdo's study examining depressed patients between the ages of 14–24-years (Beesdo et al., 2009). In this study, Beesdo also reported that subjects with bipolar disorder experienced depressive episodes that were longer in duration as compared to those who experienced unipolar depressive episodes. In addition, studies have revealed that children with bipolar disorder exhibit a greater deal of suicidal behavior as compared to those with unipolar MDD. More specifically, children with bipolar disorder had a younger age of first suicide attempt and a higher percentage of multiple suicide attempts that were higher in lethality than those children with unipolar MDD, thereby making bipolar disorder a highly morbid condition. As such, early identification of bipolar MDD is imperative, as early treatment may mitigate the lethal risk of suicide. A number of studies reported on the higher levels of the severity of impairment in children with bipolar MDD compared to those with unipolar MDD. Children with bipolar MDD were found to have poorer relationships with peers and family, as well as higher incidences of problems at school. In our review, bipolar MDD was also associated with higher numbers of days being absent from their roles. In fact, studies reveal that bipolar disorder is one of the most debilitating psychiatric disorders, estimated to cost Americans $45 billion per year, given work absenteeism, short-term disability, and decreased productivity (Centers for Disease Control, 2011). The high levels of psychiatric comorbidity, as well as the high levels of severity of depression itself likely contribute to the significantly impaired functions of children with bipolar MDD. While most studies found that early age of onset of mood disorders did not reach statistical significance, three studies documented an approximately 1.5 years earlier age of onset in children with bipolar MDD compared to unipolar MDD. Considering that 1.5 years consists of 10% of one's childhood, this result is clinically significant. The early age of onset of depression has been extensively reported as a strong risk factor of manic switches in the literature examining the course of illness in adults. However, “early onset” in these works is classified as the emergence of symptoms in adolescence to early adulthood (younger than 25 years old) (Akiskal et al., 1983; Coryell et al., 1995; Angst et al., 2005; Beesdo et al., 2009; Zimmermann et al., 2009; Gilman et al., 2012; Dudek et al., 2013). It is noteworthy that similar results were found for children under the age of 18. High levels of severe irritability also were found to be associated with bipolar MDD. Although irritability is a heterogeneous symptom with varying levels of severity that is associated with a number of psychiatric disorders (ADHD, ODD, unipolar MDD and bipolar disorder), the more severe forms of irritability are adequate predictors of unipolar MDD and bipolar MDD. More specifically, extreme/explosive irritability (super-angry/grouchy/cranky) is more highly associated with bipolar disorder, while persistent irritability of moderate severity without an explosive quality or severe impairment is highly associated with unipolar MDD. As such, while irritability in children is a heterogeneous symptom, attending to the severity and qualitative nature of the irritability might have
diagnostic implications for bipolar and unipolar forms of mood disorders (Mick et al., 2005). Our conclusions are strengthened by the fact that the reviewed papers included a study with a non-Caucasian sample, as well as both community and clinically referred samples, and together the studies included a sizeable number of children with unipolar and bipolar MDD. This review is not without limitations. While together we were able to examine a sizeable and diverse sample, we were only able to identify four cross sectional informative studies in our review. Therefore, our conclusions should be viewed as preliminary and should continue to be tested. Despite this limitation, our review of the literature indicates that bipolar MDD can be distinguished from unipolar MDD by their strong family history, high levels of disease severity and associated dysfunction, high levels of behavioral difficulties, and high rates of psychiatric co-morbidities.
Role of funding source This work was supported in part by the Pediatric Psychopharmacology Council Fund. The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Conflict of interest In the past year, Dr. Faraone received income, travel expenses and/or research support from and/or has been on an Advisory Board for Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, NeuroLifeSciences and research support from the National Institutes of Health (NIH). His institution is seeking a patent for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health and Oxford University Press: Schizophrenia: The Facts. Dr. Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, Ironshore, Vaya Pharma/Enzymotec, and NIH. In 2014, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He has a US Patent Application pending (Provisional number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2013, Dr. Joseph Biederman received an honorarium from the MGH Psychiatry Academy for a tuition-funded CME course. He received research support from APSARD, ElMindA, McNeil, and Shire. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Shire and Sunovion; these royalties were paid to the Department of Psychiatry at MGH. In 2012, Dr. Joseph Biederman received an honorarium from the MGH Psychiatry Academy and The Children's Hospital of Southwest Florida/Lee Memorial Health System for tuitionfunded CME courses. Mai Uchida, Giulia Serra, Lazaro Zayas, and Tara Kenworthy report no conflicts of interest.
Acknowledgments This work was supported in part by the Pediatric Psychopharmacology Council Fund.
References Akiskal, H.S., Walker, P., Puzantian, V.R., King, D., Rosenthal, T.L., Dranon, M., 1983. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J. Affect. Disord. 5, 115–128. Akiskal, H.S., Benazzi, F., 2005. Psychopathologic correlates of suicidal ideation in major depressive outpatients: is it all due to unrecognized (bipolar) depressive mixed states? Psychopathology 38, 273–280. Angst, J., Sellaro, R., Stassen, H.H., Gamma, A., 2005. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J. Affect. Disord. 84, 149–157. Baldessarini, R.J., Faedda, G.L., Hennen, J., 2005. Risk of mania with antidepressants. Arch. Pediatr. Adolesc. Med. 159, 298–299. Bechdolf, A., Nelson, B., Cotton, S.M., Chanen, A., Thompson, A., Kettle, J., Conus, P., Amminger, G.P., Yung, A.R., Berk, M., Mcgorry, P.D., 2010. A preliminary evaluation of the validity of at-risk criteria for bipolar disorders in helpseeking adolescents and young adults. J. Affect. Disord. 127, 316–320.
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Beesdo, K., Hofler, M., Leibenluft, E., Lieb, R., Bauer, M., Pfennig, A., 2009. Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life. Bipolar Disord. 11, 637–649. Biederman, J., Faraone, S.V., Chu, M.P., Wozniak, J., 1999. Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. J. Am. Acad. Child Adolesc. Psychiatry 38, 468–476. Biederman, J., Mick, E., Wozniak, J., Monuteaux, M.C., Galdo, M., Faraone, S.V., 2003. Can a subtype of conduct disorder linked to bipolar disorder be identified? Integration of findings from the Massachusetts General Hospital Pediatric Psychopharmacology Research Program. Biol. Psychiatry 53, 952–960. Biederman, J., Petty, C.R., Byrne, D., Wong, P., Wozniak, J., Faraone, S.V., 2009. Risk for switch from unipolar to bipolar disorder in youth with ADHD: a long term prospective controlled study. J. Affect. Disord. 119, 16–21. Carlson, G.A., Kashani, J.H., 1988. Manic symptoms in a non-referred adolescent population. J. Affect. Disord. 15, 219–226. Centers for Disease Control. 2011. Burden of Mental Illness [Online]. Available: 〈http://www.cdc.gov/mentalhealth/basics/burden.htm〉 (accessed 24.12.14.). Centers for Disease Control. 2012. Suicide Data Sheet [Online]. Available: 〈http://www. cdc.gov/ViolencePrevention/pdf/Suicide_DataSheet-a.pdf〉 (accessed 25.11.13.). Coryell, W., Endicott, J., Maser, J.D., Keller, M.B., Leon, A.C., Akiskal, H.S., 1995. Longterm stability of polarity distinctions in the affective disorders. Am. J. Psychiatry 152, 385–390. Dudek, D., Siwek, M., Zielinska, D., Jaeschke, R., Rybakowski, J., 2013. Diagnostic conversions from major depressive disorder into bipolar disorder in an outpatient setting: results of a retrospective chart review. J. Affect. Disord. 144, 112–115. Faedda, G.L., Baldessarini, R.J., Glovinsky, I.P., Austin, N.B., 2004. Treatmentemergent mania in pediatric bipolar disorder: a retrospective case review. J. Affect. Disord. 82, 149–158. Geller, B., Fox, L., Clark, K., 1994. Rate and predictors of prepubertal bipolarity during follow-up of 6-to 12-year-old depressed children. J. Am. Acad. Child Adolesc. Psychiatry 33, 461–468. Gilman, S.E., Dupuy, J.M., Perlis, R.H., 2012. Risks for the transition from major depressive disorder to bipolar disorder in the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry 73, 829–836. Kovacs, M., Pollock, M., 1995. Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J. Am. Acad. Child Adolesc. Psychiatry 34, 715–723.
7
Lewinsohn, P.M., Rohde, P., Seeley, J.R., 1998. Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clin. Psychol. Rev. 18, 765–794. Lewinsohn, P.M., Rohde, P., Farrington, D.P., 2000. The OADP-CDS: a brief screener for adolescent conduct disorder. J. Am. Acad. Child Adolesc. Psychiatry 39, 888–895. Luby, J.L., Belden, A.C., 2008. Clinical characteristics of bipolar vs. unipolar depression in preschool children: an empirical investigation. J. Clin. Psychiatry 69, 1960–1969. Merikangas, K.R., Cui, L., Kattan, G., Carlson, G.A., Youngstrom, E.A., Angst, J., 2012. Mania with and without depression in a community sample of US adolescents. Arch. Gen. Psychiatry. Mick, E., Spencer, T., Wozniak, J., Biederman, J., 2005. Heterogeneity of irritability in ADHD subjects with and without mood disorders. Biol. Psychiatry 58, 576–582. Nock, M.K., Green, J.G., Hwang, I., Mclaughlin, K.A., Sampson, N.A., Zaslavsky, A.M., Kessler, R.C., 2013. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry 70, 300–310. Shon, S.H., Joo, Y., Park, J., Youngstrom, E.A., Kim, H.W., 2014. Comparison of clinical characteristics of bipolar and depressive disorders in Korean clinical sample of youth: a retrospective chart review. Eur. Child Adolesc. Psychiatry 23, 307–316. Strober, M., Carlson, G., 1982. Predictors of bipolar illness in adolescents with major depression: a follow-up investigation. Adolesc. Psychiatry 10, 299–319. Uchida, M., Serra, G., Zayas, L., Kenworthy, T., Hughes, B., Koster, A., Faraone, S.V., Biederman, J., 2014. Can manic switches be predicted in pediatric major depression? A systematic literature review. J. Affect. Disord. 172C, 300–306. Wozniak, J., Spencer, T., Biederman, J., Kwon, A., Monuteaux, M., Rettew, J., Lail, K., 2004. The clinical characteristics of unipolar versus bipolar major depression in ADHD youth. J. Affect. Disord. 82, S59–S69. Wozniak, J., Faraone, S.V., Mick, E., Monuteaux, M., Coville, A., Biederman, J., 2010. A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity. Psychol. Med. 40, 1079–1088. Zimmermann, P., Bruckl, T., Nocon, A., Pfister, H., Lieb, R., Wittchen, H.U., Holsboer, F., Angst, J., 2009. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch. Gen. Psychiatry 66, 1341–1352.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Special review article
Can unipolar and bipolar pediatric major depression be differentiated from each other? A systematic review of cross-sectional studies examining differences in unipolar and bipolar depression Mai Uchida a,d,n, Giulia Serra c,d, Lazaro Zayas b,d, Tara Kenworthy a, Stephen V. Faraone e, Joseph Biederman a,d a
Massachusetts General Hospital, Department of Pediatric Psychopharmacology, Boston, MA, United States Massachusetts General Hospital, Department of Psychiatry, Boston, MA, United States Sant'Andrea Hospital, Sapienza University, NESMOS Department, Rome, Italy d Harvard Medical School, Department of Psychiatry, Boston, MA, United States e SUNY Upstate Medical University, Departments of Psychiatry and of Neuroscience and Physiology, United States b c
art ic l e i nf o
a b s t r a c t
Article history: Received 7 January 2015 Accepted 15 January 2015 Available online 23 January 2015
Introduction: While pediatric mania and depression can be distinguished from each other, differentiating between unipolar major depressive disorder (unipolar MDD) and bipolar major depression (bipolar MDD) poses unique clinical and therapeutic challenges. Our aim was to examine the current body of knowledge on whether unipolar MDD and bipolar MDD in youth could be distinguished from one another in terms of clinical features and correlates. Methods: A systematic literature search was conducted on studies assessing the clinical characteristics and correlates of unipolar MDD and bipolar MDD in youth. Results: Four scientific papers that met our priori inclusion and exclusion criteria were identified. These papers reported that bipolar MDD is distinct from unipolar MDD in its higher levels of depression severity, associated impairment, psychiatric co-morbidity with oppositional defiant disorder, conduct disorder and anxiety disorders, and family history of mood and disruptive behavior disorders in firstdegree relatives. Limitations: Though we examined a sizeable and diverse sample, we were only able to identify four cross sectional informative studies in our review. Therefore, our conclusions should be viewed as preliminary. Conclusions: These findings can aid clinicians in differentiating the two forms of MDD in youth. & 2015 Published by Elsevier B.V.
Keywords: Bipolar disorder Major depressive disorder Pediatric
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Qualitative analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical differences between bipolar and unipolar MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Psychiatric co-morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Family history of psychiatric illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
n Corresponding author at: Massachusetts General Hospital, Department of Pediatric Psychopharmacology, 55 Fruit Street Warren 625, Boston, MA 02114, United States. Tel.: þ1 617 643 6865; fax: þ 1 617 724 3742. E-mail address: [email protected] (M. Uchida).
http://dx.doi.org/10.1016/j.jad.2015.01.037 0165-0327/& 2015 Published by Elsevier B.V.
2 2 2 2 2 2 2 3 3 3
2
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
3.4. 3.5. 3.6. 3.7.
Severity of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Level of impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Behavioral difficulties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Other characteristics associated with bipolar depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.7.1. Irritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.7.2. Early age of onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Introduction
2. Methods
Pediatric major depressive disorder (MDD) is a prevalent disorder in youth estimated to afflict up to 25% of youth in the U.S. (Lewinsohn et al., 1998). This disorder is associated with very high levels of morbidity, distress, and disability affecting all aspects of the afflicted child's life, including increased risk for psychiatric hospitalizations, substance use disorders, family dysfunction, distress, and deficits in both educational and work performance (Carlson and Kashani, 1988; Lewinsohn et al., 2000). MDD is also a major risk for suicide and suicide remains the second most common cause of death in youth, second only to accidents (Nock et al., 2013). The Center for Disease Control (CDC) considers pediatric MDD a major public health concern (Centers for Disease Control, 2012) and documents that even minor symptoms of MDD dramatically increase the risk for suicidal behavior, supporting efforts aimed at the identification and treatment of pediatric MDD. However, a major problem in the diagnosis and management of pediatric MDD is distinguishing children afflicted with bipolar forms of MDD from those with unipolar forms of the disorder. The literature suggests that up to 30% of youth presenting to clinical practice with prototypical symptoms of MDD have already experienced symptoms of mania or hypomania (bipolar MDD) (Geller et al., 1994). While antidepressants remain the mainstay of treatment for MDD, a major concern in treating children with an antidepressant is the risk of pharmacologically inducing manic symptoms, psychomotor agitation and mixed states, and increasing the risk for suicidal behaviors (Faedda et al., 2004; Akiskal and Benazzi, 2005; Baldessarini et al., 2005), a risk that is particularly concerning in children with bipolar MDD. Because the literature suggests that a substantial minority of pediatric patients who present with symptoms of MDD actually have bipolar MDD, identifying which children have histories of mania or hypomania is a difficult endeavor that further complicates treatment decisions. This state of affairs supports the need for efforts at identifying bipolar from unipolar forms of MDD in clinical and research settings. The authors of this paper recently conducted a literature review examining which clinical correlates are most predictive of ultimate manic switches in children initially presenting with depressive episodes (Uchida et al., 2014). In their systematic literature review, the authors elucidated that manic switches in pediatric depression can be predicted by several risk factors, including positive family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania, and psychosis. Because of the greater morbidity associated with bipolar MDD as described above, being able to cross-sectionally distinguish bipolar MDD from unipolar MDD is of paramount importance. As such, the main aim of this study was to investigate the current body of knowledge on whether unipolar and bipolar forms of pediatric MDD could be differentiated from one another. To this end, we conducted a systematic review of the extant literature addressing this important issue. To the best of our knowledge this is the first investigation of this topic.
2.1. Literature review We performed a literature search through PubMed utilizing the following search algorithm: (bipolar depression OR bipolar disorder) AND (unipolar depression OR major depressive disorder) AND (predictor OR prodrome OR risk factors OR comparison OR switch OR conversion) AND (childn OR adolescn OR youth). References were also reviewed and added if applicable to search criteria. 2.2. Selection criteria We included only original studies that specifically evaluated the differences in the clinical features and correlates between unipolar and bipolar MDD in youth. We implemented the following inclusion criteria: (1) original research, (2) has operationalized assessment of major depressive disorder and bipolar disorder, (3) documents comparison between unipolar and bipolar MDD, (4) subjects are limited to children of under the age of 18, and (5) a cross-sectional examination. Articles were excluded if (1) they did not differentiate symptomatic pictures of unipolar from bipolar MDD, (2) the study had a prospective design examining the risk factors of manic switching, or (3) not available in the English language. Two psychiatrists and a research assistant screened the articles for relevance by examining the abstracts, and two psychiatrists and a research assistant reviewed the identified relevant articles in full text to evaluate their eligibility. 2.3. Data extraction The following variables were extracted: study sample size, proband age range, and characteristics that differentiated subjects with unipolar and bipolar MDD. 2.4. Qualitative analysis We reviewed the included articles, extracting the relevant details. We also performed a qualitative analysis of the methods and results with particular note to characteristics that differentiated subjects with unipolar and bipolar MDD.
3. Results Fig. 1 provides the results of the identification of the articles. From the initial database search, 752 papers were identified and screened by 2 of the authors (MU and GS). After the initial screening, 45 articles were found to be relevant and the full text of each was carefully examined. Of these, 41 studies were excluded due to either 1) failure to report on the difference between the clinical correlates of
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
bipolar and unipolar MDD (N¼27), 2) including adult subjects (N¼7), or 3) examined the risk factors of manic switches (N¼ 7). Thus four studies met all of our inclusion and exclusion criteria and were included in this qualitative review. Together, these four studies included 1111 subjects with unipolar MDD and 365 with bipolar MDD, 3–18 years of age. Two studies used community samples (1 preschool sample, 1 national comorbidity study sample), and two studies used outpatient samples (1 general outpatient clinic sample, 1 attention deficit hyperactivity disorder (ADHD) sample). Table 1 gives the characteristics of each study; number of subjects, age of subjects, and the study's main findings that distinguished bipolar MDD from unipolar MDD. 3.1. Clinical differences between bipolar and unipolar MDD Four significant distinguishing clinical factors were found to be over represented in children with bipolar MDD compared to those with unipolar MDD: 1) high rates of psychiatric co-morbidities (3/4 studies), 2) high rates of family history of psychiatric illness (3/4 studies), 3) higher severity of depression (2/4 studies), and 4) higher level of impairment (2/4 studies). Although not statistically significant, high levels of irritability (2/4 studies) and early onset of mood symptoms (3/4 studies) in youth with bipolar MDD were also identified in some studies.
3
Wozniak et al. (2004) used a sample of ADHD children from 6 to 17 years of age, compared those with unipolar (N¼109) and bipolar MDD (N¼ 43), and found that youth exhibited significantly increased rates of oppositional defiant disorder (63% vs. 30% in bipolar and unipolar MDD respectively, po0.0001) and conduct disorder (60% vs. 12% in bipolar and unipolar MDD respectively, po0.0001) in bipolar vs. unipolar youth, respectively. This study also noted an increased level of other psychiatric comorbidities such as agoraphobia, obsessive–compulsive disorder and alcohol abuse in the youth with bipolar MDD. Luby and Belden (2008) compared rates of psychiatric comorbidity in a sample of preschool aged children 3–6 years of age with bipolar (N¼ 21) and unipolar (N¼ 54) MDD and found that that preschoolers with bipolar MDD were significantly more likely to have comorbid oppositional defiant disorder (OR¼4.65, 95% CI¼1.49–14.58, po0.01) and conduct disorder (OR¼54.40, 95% CI¼11.69–253.14, po.001), as well as comorbid ADHD (OR¼13.06, 95% CI¼3.38–50.40, po0.001) and anxiety disorders (OR¼7.60, 95% CI¼ 2.38–24.28, po0.001) than preschoolers with unipolar MDD. Merikangas et al. (2012)'s study included 805 adolescents with unipolar MDD and 246 adolescents with bipolar MDD, and reported that adolescents with bipolar MDD had significantly higher rates of conduct and oppositional defiant disorder (52% vs. 30%, OR¼2.45, 95% CI¼1.09–2.36). Adolescents in the bipolar MDD group were also twice as likely to have anxiety disorders (OR¼2.34, 95% CI¼ 1.47–3.72), and substance use (OR¼ 2.27, 95% CI¼ 1.09–4.75) disorders as the unipolar MDD group.
3.2. Psychiatric co-morbidity 3.3. Family history of psychiatric illness
Included
Eligibility
Screening
Identification
Three studies found significant associations between high levels of psychiatric comorbidities and bipolar MDD. All three studies reported that children with bipolar MDD had higher rates of oppositional defiant disorder, conduct disorder and anxiety disorders compared to children with unipolar MDD, and the two studies examining adolescents both reported higher rates of substance use disorders in the bipolar MDD group.
Records identified through database searching (n =752)
Three studies found significant associations between higher levels of family history of psychiatric disorders in children and adolescents with bipolar MDD as compared to children and adolescents with unipolar MDD. All three studies reported that those with bipolar MDD had higher rates of bipolar disorder in first-degree relatives as compared to those with unipolar MDD.
Records identified through other sources (n =25)
Records after duplicates removed (n =770)
Full-text articles assessed for eligibility (n = 45)
Excluded after screening (n = 725)
Full-text articles excluded, with reasons (n =41) 1) failure to report on differences between the clinical correlates of bipolar and unipolar MDD (N= 27), 2) included adult subjects (N=7), and3) examined the risk factors of manic switches (N=7)
Studies included in qualitative synthesis (n = 4)
Fig. 1. PRISMA Flow Diagram, this diagram shows that from 770 articles, 4 studies were included in the review.
4
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Table 1 Summary of cross-sectional studies. Author and year
N
Sample
Age (years)
Diagnosis
Wozniak et al. (2004)
109 MDD 43 BPD
ADHD sample, outpatient
6–17 (mean 12.4–13.5)
DSM-III, K-SADS
Luby and Belden (2008)
21 BPD 54 UPD
Community
3–6
DSM-IV
Depression severity Irritability Comorbid ADHD, conduct, ODD, anxiety
Merikangas et al. (2012)
246 BPD 805 MDD
Household sample and school sample
13–18
DSM-IV
Depression Severity Younger age of onset Recurrent episodes Disability Comorbid anxiety, substance use, conduct Family history of mood disorder
Outpatient
6–18
DSM-IV
Atypical features Mood change congruent with antidepressant Aggressive behaviors Family history of psychiatric illness
Shon et al. (2014) 20 BPI 10 BPII 25 BP-NOS 143 MDD
Two of the studies further revealed that those with bipolar MDD had higher levels of first-degree relatives with various psychiatric illnesses, including MDD, anxiety disorders, conduct disorder, and oppositional defiant disorder. Wozniak et al. (2004) reported that bipolar MDD was associated with higher levels of psychiatric disorders in first-degree relatives compared to unipolar MDD. Not only did the bipolar MDD group have higher rates of family history of bipolar disorder (20% vs. 8% in bipolar and unipolar MDD respectively, p ¼0.003), they also had stronger family history of various psychiatric illnesses, such as major depressive disorder (62% vs. 45% in bipolar and unipolar MDD respectively, p¼ 0.003), anxiety disorders (63% vs. 30% in bipolar and unipolar MDD respectively, p¼0.0002), conduct disorder (31% vs. 12% in bipolar and unipolar MDD respectively, p¼0.0001) and oppositional defiant disorder (43% vs. 20% in bipolar and unipolar MDD respectively, p¼0.0001). Merikangas et al. (2012) also reported that adolescents with bipolar MDD had significantly greater family history of MDD (87% vs. 73% in bipolar and unipolar MDD respectively, OR¼ 2.4, 95% CI¼1.19–4.84). Shon et al. (2014) performed a cross-sectional review of longitudinal observational data on 55 children with bipolar MDD and 143 with unipolar MDD, and they found family history of mania or hypomania (10% vs. 2% in bipolar and unipolar MDD respectively, p¼ 0.005), as well as other psychiatric disorders, was significantly higher in BP groups than those with unipolar MDD (30% vs. 10.5% in bipolar and unipolar MDD respectively, p¼0.018). 3.4. Severity of depression Three studies found significant associations between both a greater number of depressive episodes and higher severity of depressive symptoms in children with bipolar MDD as compared to those with unipolar MDD. According to these studies, children with bipolar MDD experienced greater levels of sadness, irritability, hopelessness, and suicidal or self-injurious behaviors. Furthermore, two of the studies found that children with bipolar MDD
Predictors of bipolar MDD Depression severity Hopelessness Suicidality Sad þmad mood School behavior Hospitalization Interpersonal difficulty Comorbid conduct or ODD Family history of mood disorder, anxiety disorder and conduct disorder
had markedly higher rates of inpatient hospitalizations as compared to children with unipolar MDD, thereby highlighting the greater depressive symptom severity experienced by children with bipolar MDD. In the study by Wozniak et al. (2004), children with bipolar MDD experienced a greater number of depressive episodes with symptoms of both sadness and irritability (74% vs. 54% in bipolar and unipolar MDD respectively, p¼ 0.02) and hopelessness (88% vs. 69% in bipolar and unipolar MDD respectively, p ¼ 0.02) than children with unipolar MDD. Children with bipolar MDD also reported a higher number of total major depressive episode symptoms (9.4 vs. 8.5 in bipolar and unipolar MDD respectively, p¼0.09). Higher rates of suicidality (69% vs. 50% in bipolar and unipolar MDD respectively, p¼0.03) and hospitalizations (36% vs. 6% in bipolar and unipolar MDD respectively, p¼ 0.001) were observed in children with bipolar MDD as well. Luby and Belden (2008) reported that preschoolers with bipolar MDD had significantly higher depression severity scores (mean¼11.14) than preschoolers with unipolar MDD (mean¼7.93, po0.0001), assessed through the Preschool Age Psychiatric Assessment (PAPA). Preschoolers with bipolar MDD also had greater levels of loss of interest, being easily annoyed, sleep problems, motor slowing, self-deprecation or self-hatred, death themes in their play, and suicidal or self-injurious behaviors. Merikangas et al. (2012) also found a higher number of major depressive disorder symptoms (7.4 vs. 6.8 in bipolar and unipolar MDD respectively, po0.001) and greater severity of depressive symptoms (11.4 vs. 10.4 in bipolar and unipolar MDD respectively, p¼0.04), measured through the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR). 3.5. Level of impairment Two studies found significant associations between children with bipolar MDD and high levels of impairment. Both studies described that these children exhibited severe disturbances in major life roles, including marked difficulties with peers and family members, and severe behavioral problems in school.
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Wozniak et al. (2004) documented that compared to children with unipolar MDD, children with bipolar MDD had significantly higher impairment associated with major depressive episodes measured by the KSADS-E (77% vs. 43% in bipolar and unipolar MDD respectively, p¼0.002) and poorer functioning measured through Social Adjustments in Children and Adolescents (SAICA), particularly in school behavior problems and difficulties with peers and family members. The bipolar MDD group also had lower average Global Assessment of Function (GAF) scores (55.6 vs. 63.3 in bipolar and unipolar MDD respectively, po0.0001). In the study by Merikangas et al. (2012), adolescents with bipolar MDD were found to have spent a greater number of days out of role than adolescents with unipolar MDD (54% vs. 41% in bipolar and unipolar MDD respectively, OR¼ 1.91, 95% CI¼ 1.07–3.42). In addition, a greater proportion of adolescents with bipolar MDD experienced severe impairments associated with their symptoms (24% vs. 16% in bipolar and unipolar MDD respectively, OR¼2.52, 95% CI¼ 1.52–4.17). 3.6. Behavioral difficulties Two studies found significant associations between children with bipolar MDD and severe behavioral difficulties marked by aggression as compared to children with unipolar MDD. Merikangas et al. (2012) described that behavioral difficulties were reported more in children of bipolar MDD than the unipolar MDD group (OR¼2.45, 95% CI¼1.19–5.05). Shon et al. (2014) reported that aggressive behaviors were significantly more commonly observed in the bipolar MDD groups than in subjects with unipolar MDD (40% vs. 14.7% in bipolar and unipolar MDD respectively, p¼ 0.001). 3.7. Other characteristics associated with bipolar depression 3.7.1. Irritability Two studies found significant associations between children with bipolar MDD and symptoms of irritability. More specifically, children with bipolar MDD experienced depressive episodes characterized by more symptoms of irritability as compared to the depressive episodes experienced by children with unipolar MDD. Two studies (Wozniak et al. (2004); Luby and Belden (2008)) reported that more children with bipolar MDD experienced depressive episodes with symptoms of irritability. Wozniak reported that irritability was observed more in bipolar MDD children compared to unipolar MDD (88% vs. 75% in bipolar and unipolar MDD respectively, p¼ 0.1). Interestingly, although Wozniak's analysis suggests that the difference in the rate of irritability between bipolar and unipolar MDD is insignificant, this difference becomes significant when analyzing the children who endorsed “feeling both sad and irritable,” with the bipolar MDD groups exhibiting much higher rates of irritability as compared to the unipolar MDD group (74% vs. 54%, po0.02). Luby and Belden (2008) also documented that preschoolers with bipolar MDD reported more symptoms of irritability compared to unipolar MDD (100% vs. 76% in bipolar and unipolar MDD respectively, po0.01). Follow-up analyses indicated that compared to those with unipolar MDD, preschoolers with bipolar MDD consistently exhibited irritability at clinically significant levels. 3.7.2. Early age of onset Three studies found associations between early age of onset of depressive episodes and bipolar MDD. The three studies revealed that bipolar MDD emerges earlier in life that unipolar MDD, with two studies demonstrating the onset of bipolar MDD earlier than unipolar MDD. Three studies examined the differences in the age of onset in bipolar MDD and unipolar MDD, showing substantially earlier age
5
of onset of bipolar MDD than unipolar MDD, although only Merikangas et al. (2012)'s results reached statistical significance. Merikangas et al. (2012) documented that bipolar MDD emerges earlier in life compared to unipolar MDD (10.8 years old vs. 11.9 years old in bipolar and unipolar MDD respectively, p¼ 0.004). Wozniak et al. (2004) reported that the bipolar MDD group had a markedly earlier age of onset compared to those with unipolar MDD (6.5 years old vs. 7.8 years old in bipolar and unipolar MDD respectively). Shon et al. (2014) also reported earlier onset in bipolar MDD (13.6 years old vs. 15 years old in bipolar and unipolar MDD, respectively).
4. Discussion Our systematic review of the extant literature examined studies that evaluated differences in the clinical features and correlates between unipolar and bipolar MDD in youth. Four studies met our inclusion and exclusion criteria. These studies document that bipolar MDD can be distinguished from unipolar MDD by its higher levels of severity and impairments and its pattern of psychiatric comorbidity and famililaity. Three studies reported a strong association between bipolar MDD and a family history of both unipolar and bipolar disorders as well as anxiety disorder. These findings are consistent with those identified in adult patients with bipolar MDD (Akiskal et al., 1983; Coryell et al., 1995; Bechdolf et al., 2010) and with the literature on the risk factors for manic switching (Strober and Carlson, 1982; Geller et al., 1994; Biederman et al., 2009). Wozniak et al. (2010) previously reported on the significantly increased morbid risk of bipolar disorder in relatives of children with bipolar disorder as compared to relatives of children with only ADHD. This study also found that relatives of children with bipolar disorder have higher rates of psychosis, major, multiple anxiety disorders, substance use disorders, ADHD, and antisocial disorders as compared to relatives of non-bipolar probands. Taken together, these findings stress the critical importance of family history to help distinguish unipolar and bipolar form of MDD in juvenile patients. Three of the four studies reviewed reported a higher liability of comorbid psychiatric disorders in children with bipolar MDD as compared to children with unipolar MDD, including ADHD, conduct disorder, oppositional defiant disorder, anxiety disorders, and pervasive developmental disorders. These results are consistent with the higher rates of psychiatric comorbidities reported in children with bipolar disorder compared with those with unipolar MDD. Considering the high level of distress and disability associated with these comorbid disorders, these finding stress the higher level of clinical and therapeutic complexity associated with the clinical presentation of bipolar MDD than unipolar MDD. All four studies also described that children presenting with bipolar MDD exhibit variable manifestations of behavioral dysregulation, including aggressive behaviors as well as having comorbid disruptive behavior disorders including conduct disorder (CD) and oppositional defiant disorder (ODD). These findings are consistent with crosssectional studies that reported strong associations between bipolar MDD with both ODD and CD (Wozniak et al., 2004). One study reported a 69% rate of CD in a clinically referred sample of youths with bipolar disorder who were longitudinally followed over a period of 12years (Kovacs and Pollock, 1995). This very study suggested that comorbid CD may help identify a subtype of a very early onset bipolar disorder with a worse clinical course. More recent studies confirmed the association by documenting a bidirectional overlap between pediatric bipolar disorder and CD (Biederman et al., 1999, 2003). For example, Biederman reported that of 186 children and adolescents with mania and of 192 with CD, 76 satisfied criteria for both CD and
6
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
mania, representing 40% of youths with CD and 41% of youths with mania, respectively. The data suggest that when mania and CD cooccur in children, both are correctly diagnosed, thereby representing the bidirectional overlap between bipolar disorder and CD. This investigation further elucidated that the presence of CD in children with bipolar disorder may help identify a particularly severe form of pediatric bipolar disorder (Biederman et al., 2003). Children with bipolar MDD also experienced greater severity of quantity as well as quality of depressive symptoms. Quantitatively, authors found that bipolar MDD groups compared to unipolar MDD groups had higher numbers of depressed symptoms endorsed by individuals, as well as higher numbers of children who reported symptoms such as hopelessness and being both sad and angry. Qualitatively, there were higher incidences of suicidality and hospitalizations in the children of bipolar MDD. These findings are consistent with those of Beesdo's study examining depressed patients between the ages of 14–24-years (Beesdo et al., 2009). In this study, Beesdo also reported that subjects with bipolar disorder experienced depressive episodes that were longer in duration as compared to those who experienced unipolar depressive episodes. In addition, studies have revealed that children with bipolar disorder exhibit a greater deal of suicidal behavior as compared to those with unipolar MDD. More specifically, children with bipolar disorder had a younger age of first suicide attempt and a higher percentage of multiple suicide attempts that were higher in lethality than those children with unipolar MDD, thereby making bipolar disorder a highly morbid condition. As such, early identification of bipolar MDD is imperative, as early treatment may mitigate the lethal risk of suicide. A number of studies reported on the higher levels of the severity of impairment in children with bipolar MDD compared to those with unipolar MDD. Children with bipolar MDD were found to have poorer relationships with peers and family, as well as higher incidences of problems at school. In our review, bipolar MDD was also associated with higher numbers of days being absent from their roles. In fact, studies reveal that bipolar disorder is one of the most debilitating psychiatric disorders, estimated to cost Americans $45 billion per year, given work absenteeism, short-term disability, and decreased productivity (Centers for Disease Control, 2011). The high levels of psychiatric comorbidity, as well as the high levels of severity of depression itself likely contribute to the significantly impaired functions of children with bipolar MDD. While most studies found that early age of onset of mood disorders did not reach statistical significance, three studies documented an approximately 1.5 years earlier age of onset in children with bipolar MDD compared to unipolar MDD. Considering that 1.5 years consists of 10% of one's childhood, this result is clinically significant. The early age of onset of depression has been extensively reported as a strong risk factor of manic switches in the literature examining the course of illness in adults. However, “early onset” in these works is classified as the emergence of symptoms in adolescence to early adulthood (younger than 25 years old) (Akiskal et al., 1983; Coryell et al., 1995; Angst et al., 2005; Beesdo et al., 2009; Zimmermann et al., 2009; Gilman et al., 2012; Dudek et al., 2013). It is noteworthy that similar results were found for children under the age of 18. High levels of severe irritability also were found to be associated with bipolar MDD. Although irritability is a heterogeneous symptom with varying levels of severity that is associated with a number of psychiatric disorders (ADHD, ODD, unipolar MDD and bipolar disorder), the more severe forms of irritability are adequate predictors of unipolar MDD and bipolar MDD. More specifically, extreme/explosive irritability (super-angry/grouchy/cranky) is more highly associated with bipolar disorder, while persistent irritability of moderate severity without an explosive quality or severe impairment is highly associated with unipolar MDD. As such, while irritability in children is a heterogeneous symptom, attending to the severity and qualitative nature of the irritability might have
diagnostic implications for bipolar and unipolar forms of mood disorders (Mick et al., 2005). Our conclusions are strengthened by the fact that the reviewed papers included a study with a non-Caucasian sample, as well as both community and clinically referred samples, and together the studies included a sizeable number of children with unipolar and bipolar MDD. This review is not without limitations. While together we were able to examine a sizeable and diverse sample, we were only able to identify four cross sectional informative studies in our review. Therefore, our conclusions should be viewed as preliminary and should continue to be tested. Despite this limitation, our review of the literature indicates that bipolar MDD can be distinguished from unipolar MDD by their strong family history, high levels of disease severity and associated dysfunction, high levels of behavioral difficulties, and high rates of psychiatric co-morbidities.
Role of funding source This work was supported in part by the Pediatric Psychopharmacology Council Fund. The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Conflict of interest In the past year, Dr. Faraone received income, travel expenses and/or research support from and/or has been on an Advisory Board for Pfizer, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA Pharma, Neurovance, Impax, NeuroLifeSciences and research support from the National Institutes of Health (NIH). His institution is seeking a patent for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health and Oxford University Press: Schizophrenia: The Facts. Dr. Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, Ironshore, Vaya Pharma/Enzymotec, and NIH. In 2014, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He has a US Patent Application pending (Provisional number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2013, Dr. Joseph Biederman received an honorarium from the MGH Psychiatry Academy for a tuition-funded CME course. He received research support from APSARD, ElMindA, McNeil, and Shire. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Shire and Sunovion; these royalties were paid to the Department of Psychiatry at MGH. In 2012, Dr. Joseph Biederman received an honorarium from the MGH Psychiatry Academy and The Children's Hospital of Southwest Florida/Lee Memorial Health System for tuitionfunded CME courses. Mai Uchida, Giulia Serra, Lazaro Zayas, and Tara Kenworthy report no conflicts of interest.
Acknowledgments This work was supported in part by the Pediatric Psychopharmacology Council Fund.
References Akiskal, H.S., Walker, P., Puzantian, V.R., King, D., Rosenthal, T.L., Dranon, M., 1983. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J. Affect. Disord. 5, 115–128. Akiskal, H.S., Benazzi, F., 2005. Psychopathologic correlates of suicidal ideation in major depressive outpatients: is it all due to unrecognized (bipolar) depressive mixed states? Psychopathology 38, 273–280. Angst, J., Sellaro, R., Stassen, H.H., Gamma, A., 2005. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J. Affect. Disord. 84, 149–157. Baldessarini, R.J., Faedda, G.L., Hennen, J., 2005. Risk of mania with antidepressants. Arch. Pediatr. Adolesc. Med. 159, 298–299. Bechdolf, A., Nelson, B., Cotton, S.M., Chanen, A., Thompson, A., Kettle, J., Conus, P., Amminger, G.P., Yung, A.R., Berk, M., Mcgorry, P.D., 2010. A preliminary evaluation of the validity of at-risk criteria for bipolar disorders in helpseeking adolescents and young adults. J. Affect. Disord. 127, 316–320.
M. Uchida et al. / Journal of Affective Disorders 176 (2015) 1–7
Beesdo, K., Hofler, M., Leibenluft, E., Lieb, R., Bauer, M., Pfennig, A., 2009. Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life. Bipolar Disord. 11, 637–649. Biederman, J., Faraone, S.V., Chu, M.P., Wozniak, J., 1999. Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. J. Am. Acad. Child Adolesc. Psychiatry 38, 468–476. Biederman, J., Mick, E., Wozniak, J., Monuteaux, M.C., Galdo, M., Faraone, S.V., 2003. Can a subtype of conduct disorder linked to bipolar disorder be identified? Integration of findings from the Massachusetts General Hospital Pediatric Psychopharmacology Research Program. Biol. Psychiatry 53, 952–960. Biederman, J., Petty, C.R., Byrne, D., Wong, P., Wozniak, J., Faraone, S.V., 2009. Risk for switch from unipolar to bipolar disorder in youth with ADHD: a long term prospective controlled study. J. Affect. Disord. 119, 16–21. Carlson, G.A., Kashani, J.H., 1988. Manic symptoms in a non-referred adolescent population. J. Affect. Disord. 15, 219–226. Centers for Disease Control. 2011. Burden of Mental Illness [Online]. Available: 〈http://www.cdc.gov/mentalhealth/basics/burden.htm〉 (accessed 24.12.14.). Centers for Disease Control. 2012. Suicide Data Sheet [Online]. Available: 〈http://www. cdc.gov/ViolencePrevention/pdf/Suicide_DataSheet-a.pdf〉 (accessed 25.11.13.). Coryell, W., Endicott, J., Maser, J.D., Keller, M.B., Leon, A.C., Akiskal, H.S., 1995. Longterm stability of polarity distinctions in the affective disorders. Am. J. Psychiatry 152, 385–390. Dudek, D., Siwek, M., Zielinska, D., Jaeschke, R., Rybakowski, J., 2013. Diagnostic conversions from major depressive disorder into bipolar disorder in an outpatient setting: results of a retrospective chart review. J. Affect. Disord. 144, 112–115. Faedda, G.L., Baldessarini, R.J., Glovinsky, I.P., Austin, N.B., 2004. Treatmentemergent mania in pediatric bipolar disorder: a retrospective case review. J. Affect. Disord. 82, 149–158. Geller, B., Fox, L., Clark, K., 1994. Rate and predictors of prepubertal bipolarity during follow-up of 6-to 12-year-old depressed children. J. Am. Acad. Child Adolesc. Psychiatry 33, 461–468. Gilman, S.E., Dupuy, J.M., Perlis, R.H., 2012. Risks for the transition from major depressive disorder to bipolar disorder in the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry 73, 829–836. Kovacs, M., Pollock, M., 1995. Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J. Am. Acad. Child Adolesc. Psychiatry 34, 715–723.
7
Lewinsohn, P.M., Rohde, P., Seeley, J.R., 1998. Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clin. Psychol. Rev. 18, 765–794. Lewinsohn, P.M., Rohde, P., Farrington, D.P., 2000. The OADP-CDS: a brief screener for adolescent conduct disorder. J. Am. Acad. Child Adolesc. Psychiatry 39, 888–895. Luby, J.L., Belden, A.C., 2008. Clinical characteristics of bipolar vs. unipolar depression in preschool children: an empirical investigation. J. Clin. Psychiatry 69, 1960–1969. Merikangas, K.R., Cui, L., Kattan, G., Carlson, G.A., Youngstrom, E.A., Angst, J., 2012. Mania with and without depression in a community sample of US adolescents. Arch. Gen. Psychiatry. Mick, E., Spencer, T., Wozniak, J., Biederman, J., 2005. Heterogeneity of irritability in ADHD subjects with and without mood disorders. Biol. Psychiatry 58, 576–582. Nock, M.K., Green, J.G., Hwang, I., Mclaughlin, K.A., Sampson, N.A., Zaslavsky, A.M., Kessler, R.C., 2013. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry 70, 300–310. Shon, S.H., Joo, Y., Park, J., Youngstrom, E.A., Kim, H.W., 2014. Comparison of clinical characteristics of bipolar and depressive disorders in Korean clinical sample of youth: a retrospective chart review. Eur. Child Adolesc. Psychiatry 23, 307–316. Strober, M., Carlson, G., 1982. Predictors of bipolar illness in adolescents with major depression: a follow-up investigation. Adolesc. Psychiatry 10, 299–319. Uchida, M., Serra, G., Zayas, L., Kenworthy, T., Hughes, B., Koster, A., Faraone, S.V., Biederman, J., 2014. Can manic switches be predicted in pediatric major depression? A systematic literature review. J. Affect. Disord. 172C, 300–306. Wozniak, J., Spencer, T., Biederman, J., Kwon, A., Monuteaux, M., Rettew, J., Lail, K., 2004. The clinical characteristics of unipolar versus bipolar major depression in ADHD youth. J. Affect. Disord. 82, S59–S69. Wozniak, J., Faraone, S.V., Mick, E., Monuteaux, M., Coville, A., Biederman, J., 2010. A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity. Psychol. Med. 40, 1079–1088. Zimmermann, P., Bruckl, T., Nocon, A., Pfister, H., Lieb, R., Wittchen, H.U., Holsboer, F., Angst, J., 2009. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch. Gen. Psychiatry 66, 1341–1352.
