Anxiety and Depression in Children and Adolescents with Sickle Cell Disease Tami D. Benton, MD, Judith A. Ifeagwu, MD, and Kim Smith-Whitley, MD
Corresponding author Tami D. Benton, MD Department of Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia, 3440 Market Street, Suite 200, Philadelphia, PA 19104, USA. E-mail: bentont@ email.chop.edu Current Psychiatry Reports 2007, 9:114–121 Current Medicine Group LLC ISSN 1523-3812 Copyright © 2007 by Current Medicine Group LLC
A growing body of evidence suggests that depressive disorders and anxiety disorders are much more prevalent among medically ill children and adolescents when compared with the general population, and that the presence of comorbidity may adversely affect medical outcomes and quality of life. Whereas the prevalence and impact of anxiety and depressive disorders have been described in chronic conditions such as asthma, diabetes, and epilepsy, much less is known about sickle cell disease (SCD), a disorder that affects more than 70,000 Americans, primarily those of African and Mediterranean descent. A hallmark of this disorder is recurrent, acute, and chronic pain that often requires emergency management and hospitalization. Medical advances in the treatment of this illness have transformed SCD from a condition associated with very early morbidity and mortality into a chronic condition of adulthood. This article reviews the evidence describing our knowledge of anxiety and depression in children and adolescents with SCD, its clinical impact, and effectiveness of interventions.
Introduction A large body of evidence has demonstrated the negative impact of depressive disorders on the outcomes of many medical conditions, such as heart disease [1–3], cancer, neurologic disorders, and HIV/AIDS, in adult populations [4]. A growing body of evidence also points to a bidirectional relationship between depression and medical illness, suggesting that depression may be both a cause and a consequence of some medical illnesses, such as cardiovascular disease, HIV/AIDS, cancer, epilepsy, and stroke [4].
Relatively less is known about the prevalence and impact of anxiety and depressive disorders, two highly comorbid conditions, on children and adolescents with chronic illnesses. Whereas the evidence suggests that adolescents with chronic illness have rates of mental health disorders three to four times higher than those of their healthy peers, other studies suggest that the vast majority cope well with their illnesses [5]. Prevalence estimates of children and adolescents with chronic illness vary, ranging from 17% in community samples to 33% in clinical samples [6••,7,8]. The prevalence of anxiety and depressive disorders has been described in some specific diagnostic groups in children and adolescents (Table 1), whereas much less is known about other medical conditions that are prevalent among children and adolescents. Sickle cell disease (SCD), the most common genetic hemoglobin disorder, affects more than 70,000 Americans, primarily those of African and Mediterranean descent. Characterized by chronic hemolytic anemia, vasoocclusive complications, and an increased risk for infection, SCD is associated with a lifespan shortened by up to 30 years in affected individuals [9]. However, medical advances in the last 3 decades have supported the success of comprehensive care programs and have provided a realistic expectation for increased survivability and improved quality of life for patients with SCD. SCD, a group of hemoglobin syndromes in which sickle hemoglobin predominates, results when a gene for sickle hemoglobin is inherited in an autosomal recessive pattern or in a compound heterozygous state with another beta globin gene variant such as hemoglobin C or beta thalassemia. One in 375 African-American newborns has SCD, and one in 12 African-Americans has the sickle cell trait. The most common genotype, the SS type (SCDSS), occurs in approximately 65% of affected patients, followed by SCD-SC (25%), SCD-Sb+thalassemia (8%), SCD-Sb0thalassemia (2%), and a very small percentage of patients with other genotypes. Classically, patients with SCD-SS and SCD-Sb0thalassemia are at greater risk for severe complications when compared with those with the SCD-SC and SCD-Sb+thalassemia. However, the variability of complications within and between patients with various types of SCD is high [10].
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Table 1. Prevalence of anxiety and depressive disorders in some specific diagnostic groups in children and adolescents Medical diagnosis Prevalence of depression, % Prevalence of anxiety, %
Asthma
Epilepsy
Diabetes
20–30 [48•]
20–30 [6••]
26 [49,50]
24.7
33
20
Historically, the pathophysiologic mechanisms underlying SCD have included solely intracellular polymerization of sickle hemoglobin, increased endothelial adhesion, and subsequent vascular occlusion. Chronic inflammation, erythrocyte hydration, and vasoactive cytokines are prominent pathophysiologic features, and pharmacologic therapies to address these mechanisms directly are being developed. Recently, chronic hemolysis and impaired nitric oxide metabolism have been shown to contribute to the pathophysiology of pulmonary hypertension, priapism, and leg ulcers. Nationwide newborn screening programs for SCD, established in many states starting in 1992, have facilitated the identification of newborns with SCD and the initiation of infection prophylaxis by age 2 months. Historically, many young children died from overwhelming bacterial infections, but presently, 93.6% of individuals with SCD survive to age 18 years when only SCD-related complications are considered [11], primarily due to infection prophylaxis and comprehensive care. Pain, the hallmark feature of SCD, occurs in acute and chronic forms. The more common acute pain syndromes are largely unpredictable but may be associated with triggers such as extreme temperatures, strenuous exercise, stress, infection, and dehydration. Although pain management is the most common reason for hospitalization, many patients manage painful episodes at home with oral analgesics and nonpharmacologic methods employing heat and rest. Hydroxyurea therapy, as demonstrated in a 1995 hallmark study, reduces the rate of acute painful episodes in patients with SCD-SS [12]. This is the fi rst effective pharmacologic intervention directed at improving SCD-related complications by altering known biologic properties specific to SCD. However, no disease-specific therapies have demonstrated significant effectiveness in reducing acute pain or chronic pain in large populations of patients with SCD. Neurologic complications, common in patients with SCD-SS, are associated with cognitive and motor dysfunction. Stroke, a potentially devastating complication, occurs in 10% to 15% of patients with SCD-SS. Once a stroke has occurred, chronic transfusion therapy can lower recurrent stroke risk. Recently, transcranial Doppler ultrasound screening has been shown to identify children with SCD-SS at high risk for stroke [13]. Chronic transfusion therapy using a goal hemoglobin S of less than 30% can reduce stroke risk by 92% in this patient population [14].
Cerebral infarction affecting nonmotor areas of the brain is classified as “silent” infarction. However, neurocognitive deficits are high in affected patients. Researchers are currently investigating whether chronic transfusions can prevent progression of “silent” infarction and decrease the progression of neurocognitive dysfunction. Pulmonary complications, frequently observed in patients with SCD, are the most common cause of death in adults with SCD. Acute chest syndrome, a pneumonia-like illness caused by infection; infarction; and bone marrow emboli can be rapidly progressive and result in pulmonary failure [15]. Acute management includes antibiotics and supportive care, but the use of blood transfusions early in the course may improve associated morbidity and mortality. Pulmonary hypertension, occurring in 33% of adult patients with SCD-SS, is associated with an increased risk of death [16]. Present management includes sildenafil and supportive care, although clinical research with other interventions is underway [17 ]. Medical therapies such as chronic transfusion programs and hydroxyurea therapy have decreased the rate of acute painful events and acute chest syndrome. More importantly, hydroxyurea reduces SCD-related mortality in patients with SCD-SS overall [18]. However, the need for frequent side effect monitoring and concern regarding long-term complications are potential barriers to the widespread use of these therapies. Although allogenic stem cell transplantation often results in a cure, availability of an HLA-identical sibling without SCD; acute toxicities; and long-term complications such as graft failure, endocrine abnormalities, and graft-versus-host disease limit its use. As survivability continues to improve, research efforts will be directed toward reducing the toxicity and complication profi le of present interventions, identifying new effective therapies, preventing chronic organ damage, and improving the quality of life of patients with SCD. Although these medical advances have optimized outcomes for individuals with SCD, children and adolescents with this illness continue to face many challenges related to their illness. Because adolescents with SCD may be smaller than their healthy peers in the early phases of puberty, they may experience heightened self-consciousness and dissatisfaction with their body images [19]. Fatigue may reduce participation in sports, further increasing social isolation and decreasing self-esteem. Cognitive deficits related to neurologic complications of the illness may impact academic performance and perceived competence, and
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Table 2. Estimated prevalence rates of depression among adults and adolescents Study Hasan et al. (adults) [25] Wilson Schaeffer et al. (adults) [24] Hilton et al. (adults) [51] Grant et al. [52] Belgrave and Molock (adolescents) [22] Yang et al. (adolescents) [34] Barbarin et al. (adolescents) [31]
Prevalence rate, % 44 (mild-severe); 26 (severe) 43.4 29 25.6 56.5 (mild-severe) 29 25 (adjustment problems)
recurrent painful crisis with missed school days or hospitalizations can cause academic and social disruptions. An adolescent’s experience of these limitations can contribute to pessimism, hopelessness, and social withdrawal [19, 20].
Depression and anxiety in SCD Current evidence suggests that psychiatric difficulties are significant among adults with SCD (Table 2). One of the fi rst studies examining depression and SCD, a case series describing three patients with SCD and depression, suggested that depression occurs more frequently than expected. These individuals were treated with elavil, 150 mg, and both pain and depression were responsive to antidepressant treatment [21]. Expanding upon this work, Belgrave and Molock [22] used a convenience sample to assess patients for coping with illness and depression using the Beck Depression Inventory (BDI). In this sample of 46 adult patients with SCD, the investigators identified 56.5% of the sample as being mildly to severely depressed using the BDI. In a larger study of 109 adults with SCD, Thompson et al. [23] examined the presence of depression and other psychological problems. A total of 56% of the sample met criteria for poor psychological adjustment, with 40% meeting criteria for depression. Wilson Schaeffer et al. [24] assessed 440 individuals with SCD using the Centers for Epidemiologic Studies Depression Scale during their yearly outpatient routine clinic visits. The authors found that 18% of the individuals interviewed exhibited significant levels of depression using stringent cutoff scores. This study reported rates much lower than prior studies but still significantly higher than those of the general population In a more recent study, Hasan et al. [25] assessed the prevalence of depressive symptoms in a population of 27 men and 23 women with SCD. Using the BDI to assess for depressive symptom severity in a convenience sample of patients presenting to an outpatient SCD clinic, these investigators found that 44% of their sample scored within
the mild to severe range of depression on the BDI, again suggesting that the prevalence of depressive symptoms in individuals with SCD is higher than the prevalence of those symptoms in the general African-American population.
Children and Adolescents Studies of children and adolescents with SCD have reported adjustment problems. These problems have included poor self concept; social adjustment problems; behavior problems; and symptoms of depression, anxiety, and pica. Those studies suggest that adjustment problems seem to increase with age, and boys demonstrate more problems than girls. The severity of illness appears to have less impact than gender and age [26]. Most of the data regarding prevalence of anxiety and depression in SCD have been derived from psychosocial studies examining these symptoms in the context of broader psychosocial issues such as mediators of coping and adjustment to illness. Depression and anxiety as predisposing, precipitating, or perpetuating factors in the course of SCD have been investigated in a limited number of studies and have not been well described in children and adolescents. Studies specifically examining the prevalence of anxiety and depressive disorders in children and adolescents have been contradictory. In one of the fi rst studies examining SCD in adolescent patients, Kumar et al. [27 ] compared 29 adolescents with SCD with a school-based sample of peers without SCD using standardized, validated instruments. These investigators found the adolescents with SCD to be less anxious than the comparison group, to exhibit more withdrawn behaviors, and to have a poorer self concept, but not to exhibit any more adjustment difficulties than peers. In a follow-up to this study, Morgan and Jackson [19] studied 24 adolescents with SCD and their mothers with a matched comparison group of adolescents without SCD and their mothers to determine whether adolescents with SCD exhibited less body satisfaction, more symptoms of depression, and greater social withdrawal than healthy peers. Using the Children’s Depression Inventory (CDI) and subscales of the Child Behavior Checklist (CBCL), these authors reported higher scores on the CDI and subscales of the CBCL, suggesting higher rates of depression and social withdrawal and less body satisfaction than healthy peers and supporting the earlier fi ndings. Lemanek et al. [28], studying psychological adjustment in children with SCD, compared 30 children with SCD and 30 healthy controls matched for age, sex, socioeconomic status, and IQ. They found that the children with SCD did not have significantly greater psychological maladjustment when compared with healthy peers. However, when the SCD group was compared with national norms, they were noted to have more behavior problems at home and in school. However, the behavior difficulties
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in both groups were higher than norms, suggesting that the psychological difficulties were perhaps related to environmental factors and not the SCD. In a more recent cross-sectional study of 50 children with SCD aged 7 to 12 years, 64% were found to have mother-reported behavior problems, and 50% met DSM III criteria for a psychiatric disorder. Internalizing behavior problems by mother report and anxiety diagnosis by child report were most common [29]. Lee et al. [30] compared 14 children with SCD with 14 nondiseased siblings using the Depression Self Rating Scale. In this study, children with SCD scored lower on measures of perceived physical competence, whereas their nondiseased siblings had higher depression scores. The authors hypothesized that the shift in dynamics of the family, requiring more attention to be paid to the sick child, might contribute to this finding of elevated depression scores in siblings. Although this small sample size might limit generalizability, it highlights the importance of providing support to the families of children with SCD. Barbarin et al. [31] attempted to estimate the prevalence of psychosocial problems in children with SCD. In a sample of 327 parents and children from a comprehensive sickle cell center, participants completed a structured interview during their annual medical visit. Parents were interviewed using a psychosocial interview covering illness, social, academic, psychological, and family adjustment domains. Frequencies of difficulties in each domain were assessed for the child and family. The authors also divided the study groups by age: 4 to 7 years, 8 to 13 years, and 14 to 17 years. The authors were able to look at gender differences as well. Overall, they found significant problems in social relationships, isolation, and shyness and significant academic problems, with school failure rate for boys being twice as high as that found for a national sample of African-American children matched for income. Adolescents were more likely to fail classes than the younger children. The younger children who reported more frequent painful episodes were more likely to be overprotected by parents and older siblings and more prone to anger, hopelessness, depression, and shame. The parents of children with more frequent pain also were more fearful and worried than the parents of children who were pain free. Girls who experienced more frequent pain were found to be more overprotected, with siblings who were found to be more fearful than the other group. Using an innovative approach, Trzepacz et al. [32] examined psychosocial adjustment of children with SCD and a group of demographically matched comparison peers. They did so from the perspectives of their parents/ caregivers using a measure with validated psychometric properties in African-American children. Home visits were used to complete evaluations to minimize the influence of the clinical setting and to optimize caregiver participation, with a total sample size of 70 caregivers and 67 comparison peers. Using the CBCL to interview the caregivers, the
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authors found slightly elevated concerns for children with SCD compared with comparison peers but no differences in internalizing symptoms between the groups. However, the scores for both groups were elevated compared with CBCL norms. Competence scores on the CBCL were significantly lower for children with SCD due to low social competence and school performance scores. Contrary to expectations, the authors found an increased frequency of externalizing problems with children with SCD; overall, the authors suggested that caregivers of children with SCD perceived their children as having slightly more problems than their well counterparts. One weakness of this study was that the children were not interviewed. Seigel et al. [33], in a study assessing the association between depression, self-esteem, and life events in adolescents with asthma, SCD, and diabetes, examined 80 adolescents aged 12 to 18 years and a comparison group of 100 demographically matched peers. Both groups completed the BDI, Rosenberg Scale of Self Esteem, and the McCutcheon Life Events Checklist. These authors found that the mean depression scores were significantly higher in the chronic disease groups when compared with healthy peers, and that the illness groups were more likely to have low selfesteem. However, they found no differences between the illness groups in depression, self-esteem, or life events. In one of the few studies examining depression specifically using psychiatric assessment, Yang et al. [34] studied a convenience sample of 38 adolescents aged 16 to 18 years using the Children’s Depression Rating ScaleRevised (CDRS-R) and a diagnostic assessment by a child and adolescent psychiatrist. The study subjects included 38 children with SCD and a demographically matched control group of adolescents without SCD. Detailed medical histories, including frequency of painful crisis and complications of SCD, were obtained to assess the severity of illness. Although 29% of the adolescents with SCD obtained high scores on the CDRS-R, compared with 12% of the controls, the authors concluded that the differences were related to elevated scores on somatic complaints, especially fatigue, worries about death, and self-esteem problems, suggesting that the differences were not significant between the two groups on other measures of depression. However, the study did identify a positive correlation between the clinical severity of SCD and the CDRS-R scores. The differing methodologies used in these studies make reaching consensus on these issues very difficult. Additionally, flaws in the study designs limit the interpretation of these data. Many of the studies suffer from small sample sizes that limit generalizability, nonrandom samples, absence of comparison groups, use of poorly validated instruments or instruments that have not been validated for this population, use of wide age ranges obscuring developmental issues, and the use of vague terms to defi ne anxiety and depression and psychological and social functioning [35]. Additionally, the potential
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influences of ethnicity, economic inequality, and racial discrimination on psychosocial outcomes have been largely overlooked [32]. Despite the methodological issues raised, the preponderance of the existing evidence supports an increased prevalence of anxiety and depression among adults and adolescents with SCD and increased anxiety and depressive symptoms among children, adolescents, and adults with SCD. Some of the relationships between the presence of these symptoms and medical outcomes have been described.
Impact upon Illness Depression and anxiety have been identified as predictors of admission to the emergency room for treatment and/or hospitalization in older adolescents and adults [36, 37 ]. Depressive symptoms, depression, recent loss, and social and academic problems were common predictors. In a retrospective study of 22 hospitalized patients examining factors contributing to painful crisis, pain crisis was preceded by severe depression and responses to loss [37 ]. In another study examining hospital admissions for pain episodes, 56% (n = 47) of patients reported feelings of depression prior to hospitalization. The authors described depression and younger age (adolescence) to be the best predictors of both emergency room treatment and hospitalization [22]. Depression and anxiety also have been implicated as important factors in the adjustment of children and adolescents to SCD and their abilities to cope with its associated pain. Some of the research has documented that psychosocial factors explain substantially more variability in adaptability than biomedical factors [38, 39]. Most of the available studies to date have examined the effects of psychological adjustment, specifically interpersonal factors (coping styles, competence) and family factors (cohesion and parental adaptation), on the adaptation to living with SCD and management of pain. Studies of interpersonal factors have focused on stress processing in children with SCD, suggesting that active coping strategies and perceived control are associated with higher levels of adjustment, including fewer physical symptoms and psychological problems. Avoidance coping has been associated with more anxiety symptoms, reduced activity, and increased need for medical interventions; disengaged coping styles have predicted more internalizing behavioral problems [40]. Thompson et al. [23] have demonstrated that pain coping strategies characterized by passive adherence and negative thinking (catastrophizing and self-statements of fear and anger) were associated with more frequent emergency visits, less activity, and higher levels of self-reported distress. Active coping strategies such as cognitive and behavioral strategies, including diverting attention, calming self-statements, and reinterpreting pain sensations, were associated with fewer emergency visits and more activity during painful episodes [23].
The importance of family factors in child functioning has been well described as an important mediating factor in SCD [20,41]. Greater family cohesion has been associated with more adaptive coping, whereas greater family discord has been associated with less adaptive coping [41]. In a study examining the psychological adjustment of mothers to their children with SCD, Thompson et al. [29] found that maternal anxiety accounted for a significant proportion of the variance associated with the child behavior problems identified by mothers. These studies support the fi ndings of Telfair [36], underscoring the importance of the family in the process of illness adjustment of children with SCD. Telfair [36] suggested that the presence of anxiety and depression in parents/caregivers affected treatment outcomes, noting that early detection and reduction of psychosocial stressors should be part of a comprehensive continuity of care. These early fi ndings have been supported by a large body of literature describing the impact of all childhood chronic illnesses upon families and the need to assess families for pathology, stress, and/or difficulties coping, and to provide help and support when these are identified. Telfair [36] also recommended that all care providers understand the child/parent coping patterns when the child is not ill, as that will lead to better understanding and identification of an impending decompensation.
Diagnostic and treatment strategies Our review did not reveal studies specific to the treatments for depression and anxiety disorders in individuals with SCD. Most treatment studies have focused on cognitive and behavioral strategies as adjuncts to analgesics for SCD pain. These strategies consist of behavioral interventions such as relaxation, deep breathing, biofeedback, behavioral modification, or exercise, or psychological interventions such as cognitive therapies, hypnotherapy, imagery, distraction, or social support. Physical interventions might include hydration, heat, massage, hydrotherapy, ultrasound, acupuncture, transcutaneous electrical nerve stimulator, or physical therapy [42]. This focus on pain management is extremely important, as many studies support a positive correlation between pain, anxiety, and depression, fi nding the prevalences of these disorders to be much higher among those experiencing recurrent and chronic pain in the adult population. Studies also suggest higher rates of suicidal thinking and actions among adults with chronic pain [43]. Diagnosing anxiety and depression in patients with SCD can be difficult because the disease itself can confound symptoms of the disorders. Many of the symptoms of anxiety or depression (fatigue, low energy, poor appetite and concentration, irritable mood, insomnia or hypersomnia, and psychomotor agitation or retardation) may result from mood or anxiety symptoms or SCD or medications related to its treatment. However, symptoms of worthlessness, inappropriate guilt, suicidal thoughts,
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and inability to think or concentrate are much less common and should help to clarify the diagnosis [44]. There is also a defi nite relationship between depressive symptoms and pain. Depressive symptoms complicate pain, may lower the threshold for tolerance of pain, and may interfere with a child or adolescent’s ability to cope with pain [26]. Pain may precipitate depressive or anxiety symptoms in individuals who are vulnerable. Patients who are taking analgesics such as opiates, or who are discontinuing those same medications, may experience medication-induced depression and anxiety. The psychiatric assessment of the child or adolescent with SCD should include a thorough assessment for psychosocial disruption or psychiatric symptoms, especially those related to anxiety or depression, or school or social problems that could reflect subtle neurocognitive problems, pica, and problems with chronic pain [42]. When depression or anxiety has been identified in a child or adolescent with SCD, those disorders should be treated aggressively using interventions that are currently validated for children and adolescents without SCD. Successful treatment of anxiety symptoms can reduce pain and pain-related distress. All patients with SCD should be carefully evaluated using a biopsychosocial approach to determine the presence and severity of psychiatric illness that may decrease adherence to medical regimens and complicate the course of their illness. If an anxiety or depressive disorder is identified, the patient and family should be educated about the illness and the impact of comorbidity and provided with a treatment plan that incorporates pharmacotherapy, psychotherapy, and school- and home-based supports as appropriate, and family interventions, including education, support, and family therapy if indicated [45]. Although there are no studies examining the use of antidepressants for the treatment of anxiety or depression in children or adolescents with SCD, the current antidepressant agents used for the treatment of depression and anxiety, specifically the selective serotonin reuptake inhibitors, have favorable side effect profi les and are not likely to interact with the medications commonly prescribed to individuals with SCD. Although other psychotropics are not contraindicated in SCD, it is important to be mindful of P450 interactions and additive drug effects. Phenothiazines may antagonize the analgesic effects of opiate agonists, and tricyclic antidepressants, monoamine oxidase inhibitors, and other central nervous system depressants may potentiate adverse effects of opioids [42]. There has been one case report of an adolescent male aged 16 years who developed priapism after initiating venlafaxine, 37.5 mg, for depression and attention-deficit disorder, although it was unclear whether the priapism was related to the venlafaxine or concurrent alcohol and marijuana use. Given the occurrence of priapism in adolescents with SCD, it is important to monitor for this side effect [46 ].
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Conclusions Whereas studies suggest that anxiety and depressive symptoms are more prevalent among patients with SCD, the evidence of clinical anxiety and depression in children remains unclear. Although the evidence has demonstrated that multiple influences, such as illness severity, child coping, parent coping, social support, adaptive functioning, and treatment compliance, impact outcomes and quality of life for these individuals, the presence of psychopathology will impact all of the above considerably. The presence of symptoms of depression and anxiety, or the presence of anxiety or depressive disorders, could serve as a predisposing, precipitating, or perpetuating factor for poor coping adaptation to illness and adherence. In fact, some studies suggest that the presence of a psychiatric disorder predicts a worse outcome for children and adolescents than the presence of the chronic illness itself [47••]. Chen et al. [47••] assessed quality of life for a community sample of 705 adults 17 years after an initial assessment for chronic physical conditions and Axis I and II psychiatric disorders as teens. These authors found that mental disorders during adolescence were more strongly associated with reduced quality of life in adulthood than adolescent physical illnesses, that individuals living with physical illnesses were at increased risk of living in a more adverse environmental context as adults, and that adolescents with comorbid physical illness and mental disorder tended to experience a particularly large reduction in quality of life by adulthood. This further emphasized the need for prevention, recognition, and treatment of comorbid mental health conditions.
Acknowledgments None of the authors has a possible confl ict of interest, fi nancial or otherwise.
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