Two different subtypes of early onset unspecified bipolar disorder (USBD)
The first subtype is classical BP NOS (Not Otherwise Specified) having all the characteristics of full-blown bipolar disorder except for only having brief durations of mania and responding to conventional treatment. The second is what is now called Temperature and Sleep Dysregulation Disorder (TSDD) and was formerly described by D. Papolos as the Fear of Harm (FOH) syndrome, and requires a different treatment approach.
Clinicians should be alert to unique symptoms in children who might have TSDD as such a diagnosis would lead to a unconventional treatment paradigm. We emphasize the importance of specifically asking parents about evidence of over heating (red face and red ears) and high tolerance for cold (going outside markedly under-dressed) and the presence of fear of sleep and horrific nightmares, as these may lead one to consider the diagnosis of TSDD.
If these two novel aspects (temperature and sleep dysregulation) occur in the presentation of a highly fearful and behaviorally dysregulated child with bipolar-like symptoms, these may lead to the consideration of an unconventional treatment paradigm. It utilizes 1) high dose lithium; 2) clonidine and other practical approaches to achieve cooling and relieve over heating; and 3) ascending doses of intranasal ketamine (as described by Papolos et al 2013; 2018). This may be of considerable clinical importance as a large group of children with this unique presentation respond very poorly to conventional treatments for bipolar disorder and remain highly impaired and dysfunction throughout their childhood and adolescence.
If these children instead are treated with: lithium (to achieve blood levels of 1.0 meq/L or higher); clonidine (0.1- 0.3mg IR and 0.1mg ER at noon and HS) and other practical ways to achieve cooling; followed by ascending intranasal doses of ketamine (starting at 20mg and increasing toward 80-260mg/day, repeated every 2-3 days), marked improvement can be achieved. This occurs in conjunction with ketamine’s positive effects on fear and aggressive behaviors in association with its ability to reduce core body temperature.
We highlight this potential alternative treatment approach as long term positive effects have been achieved with it in open case series (Papolos et al 2013; 2018 ). The efficacy of this treatment approach has not been validated in controlled clinical trials, but we believe wider recognition of the two subtypes of USBD– BPNOS and TSDD,– will lead to more systematic research on treatment. Actively looking for the unique features of TSDD and pursuing its unconventional treatment may lead to long term positive effects in a child previously viewed as having an intractable psychiatric illness.
Treating Symptoms of Bipolar Disorder in Children at Risk
At the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported. See previous articles for more on this symposium.
Sub-Threshold Bipolar Disorder or BP-NOS is Impairing and Requires Treatment
In research Danella M. Hafeman’s research, children with BP-NOS were almost as ill as those with bipolar I disorder (BP I) and experienced equal incidence of suicide attempts, substance abuse, other simultaneous psychiatric diagnoses, and functional impairment, clearly indicating that they were in need of treatment. About 50–65% of participants with a family history of bipolar disorder converted from diagnoses of BP-NOS to BP I, while those with BP-NOS and no family history of bipolar disorder converted to BP I at rates of about 30–48%.
Several presenters presented data showing that those with sub-threshold bipolar disorder had severe functional impairment, a high incidence of suicide attempts, and additional diagnoses including ADHD, conduct disorder, anxiety, and substance abuse.
Diagnostic Tool Can Help Identify Children with Bipolar Disorder
Researcher Amy Yule indicated that a tool called the Child Behavior Checklist (CBCL) is effective for making the diagnosis of conduct disorder in children with bipolar disorder, while researcher Joseph Biederman showed that the CBCL can also identify children with bipolar I disorder and is faster and simpler to use in clinical practice than are full structured diagnostic interviews.
Researcher Janet Wozniak found that there was a high incidence of bipolar disorder in first-degree relatives of children with sub-threshold bipolar disorder, suggesting the validity of identifying youth with sub-threshold bipolar symptoms.
As discussed above, there is also a high incidence of children with BP-NOS progressing to a full diagnosis of bipolar I or II disorder (as many as 50% of those with a family history of bipolar disorder). However, the point is not to wait for the negative effects of a full diagnosis before beginning treatment: BP-NOS itself requires treatment.
Discussion and Emerging Consensus on Treatment, Particularly of BP-NOS
Experts in the field agree that family focused therapy (FFT) or its equivalent is a crucial first step to treatment of depression, cyclothymia (cycling between depressive and hypomanic symptoms that do not meet the threshold for a diagnosis of bipolar disorder), and BP-NOS in children who are at high risk of bipolar disorder because they have a parent with the disorder.
A second area of agreement is that young people with BP-NOS should have a positive therapeutic coach (which could be a treating physician if no other person is available), who can emphasize important early steps that can improve short- and long-term health. These include maintaining a healthy diet, exercise (such as participation in school sports), the practice of mindfulness and/or meditation, and playing and practicing a musical instrument. Parental support is also critical to decreasing negative expressed emotion.
Early interventions and wellness programs that focus on these factors are part of the successful Vermont Family Based Approach, led by psychiatrist Jim Hudziak, Director of the Vermont Center for Children, Youth, and Families. Since programs like these are not widely available, treating physicians must create their own teams to provide such encouragement, and teach families how to find or establish such a support network.
School teachers should be engaged in support of the treatment of a child with bipolar disorder. Teachers should pay special attention to behavioral symptoms of an ill child. It also may be important for physicians to connect directly with teachers to ensure that children recovering from an episode of bipolar disorder receive extra time for assignments, a decreased academic burden, and other support. Researcher Manon H. Hillegers indicated that intervention by a physician will likely be listened to and believed, while parental requests alone to teachers or to the school may go ignored.
Hillegers, like researcher Lakshmi Yatham and colleagues, have found that it takes a year after a first manic episode for a child’s cognition to return to normal, so that special allowances should be made for such students even many months after they have recovered from their mania.
Predicting Onset of Bipolar Disorder in Children at High Risk: Part II
At the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported.
Early Recognition and Treatment Needed
Researcher Boris Birmaher, the discussant of the symposium, described a sample of 100 children between the ages of 2 and 5; half had a parent with bipolar disorder, and these were compared to community controls. Those children who had a parent with bipolar disorder had a high incidence of attention-deficit hyperactivity disorder (ADHD) and ODD, and their conversion to a diagnosis of bipolar disorder was predicted by early age of onset of bipolar disorder in the parent (again) and by the presence of family conflict.
Birmaher emphasized that a delay before children and adolescents with bipolar disorder received their first treatment for the illness had terrible effects—more suicide attempts, completed suicides, substance abuse, and school failure. Birmaher urged early recognition of bipolar disorder and adequate treatment in order to delay onset of the disorder and to render its course more benign.
Childhood-Onset Bipolar Disorder Incidence
Researcher Anna Van Meter and colleagues showed that the incidence of bipolar disorder in children is about 2% worldwide. Researcher Kathleen Merikangas and colleagues report that 80% of adolescents with a bipolar spectrum disorder are not receiving any kind of treatment. Researcher Ben Goldstein indicated that about 50% of those with a full diagnosis of bipolar disorder receive treatment in Canada (where such treatment is cost-free).
Delayed Treatment Leads to Compounding Challenges
Since longer intervals without treatment predict poorer outcomes in bipolar disorder and schizophrenia, and early onset bipolar disorder has been linked to longer delays before first treatment, a significant number of children, particularly in the US, are at risk for disastrous outcomes. Earlier recognition and treatment is imperative, especially since even bipolar disorder not otherwise specified (BP-NOS) can be severe, impairing, associated with multiple simultaneous comorbid diagnoses, and has a familial (genetic) basis.
Early Intervention Works in Schizophrenia: Also Needed in Bipolar Disorder
For twenty years, evidence has shown that early intervention can ameliorate many of the adverse consequences of schizophrenia. In a 2018 article in the journal Annual Review of Clinical Psychiatry titled “Transforming the treatment of schizophrenia in the United States: The RAISE Initiative,” Lisa B. Dixon and colleagues described the importance of early intervention in schizophrenia. RAISE stands for Recovery After an Initial Schizophrenia Episode. Dixon and colleagues emphasize that shortening the time that a patient’s psychosis goes untreated, which averages 74 months, is critical to achieving good outcomes. In parallel to these consistent findings, researchers of bipolar disorder (including this editor Robert M. Post and colleagues) have found that an increased length of the interval before treatment is initiated in childhood-onset bipolar disorder is associated with a poor outcome in adulthood.
The RAISE program consists of four interventions: personalized psychopharmacology using a computerized decision support system, individual resilience therapy, family psychoeducation and therapy, and supportive employment and education. Compared with patients receiving standard treatments, patients who participated in the RAISE program showed greater improvements on almost all measures, including the Heinrichs-Carpenter Quality of Life Scale (main outcome), the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, treatment duration, and engagement in work and school. Moreover, the improvements were more substantial among patients with a shorter duration of untreated psychosis.
Editor’s Note: These findings are of great importance in their own right, but they also have great implications for treatment and research efforts in bipolar disorder. A 2013 randomized study by Lars Kessing and colleagues published in the British Journal of Psychiatry found that in bipolar patients hospitalized for a first or second episode of mania, two years of comprehensive treatment with psychotherapy, pharmacotherapy, and illness education that included mood monitoring and early symptom recognition was vastly superior to typical treatment, and this held true even six years later. In a 2014 article in the Journal of Clinical Psychiatry and a 2016 article in the journal Bipolar Disorders, researcher Jan Marie Kozicky and colleagues reported that in patients hospitalized with a first episode of mania, cognitive functioning and brain imaging abnormalities, respectively, returned to normal over the next year only if the patients experienced no further mood episodes. The message is clear: we must treat the first episode of mania comprehensively to avoid long-term deterioration, which occurs as a function of the number of episodes of mania or depression a patient experiences. However, this early multimodal approach is rarely taken in the US.
In schizophrenia, Dixon and colleagues noted that: “After the RAISE study reports were made available, Congress allocated additional funding to the community mental health …program, leading to growth in the number of…programs across the United States; they were expected to reach 48 states in 2018.”
The contrast between these efforts in schizophrenia and their virtual absence in bipolar disorder is incomprehensible and tragic. Studies in early schizophrenia have been funded for 25 years, while almost none have been funded in bipolar disorder, even in recent years. Community mental health programs for early schizophrenia will soon exist in 48 states; for patients with bipolar disorder there are no programs available in any state that I am aware of. The incidence of bipolar is about three times that of schizophrenia, and the long-term outcomes are often as devastating in bipolar disorder as in schizophrenia. There is a high incidence of drug abuse; social, educational and occupational deficits; and suicide in bipolar disorder. Early intervention with the many safe supplements, nutraceuticals, and well-tolerated drugs that are currently available to adult patients should be studied in young people with bipolar disorder, but such studies neither being funded nor conducted.
The reality is that childhood-onset bipolar disorder is poorly recognized and treated in the US, largely because of a paucity of treatment-related studies and knowledge about the best options for these young patients. If a reader of the BNN knows how to influence advocacy groups, leaders in the Substance Abuse Mental Health Services Administration (SAMHSA) and the National Institutes of Mental Health (NIMH), or influential politicians, it would be useful to take the initiative in bringing some of these deficits and disparities to their attention. Something must be done; ideas about how to do it are welcome. My own efforts to get funding for a childhood-onset bipolar research network in collaboration with such luminaries in the field as David Miklowitz (UCLA), Kiki D. Chang (Stanford University), Boris Birmaher (University of Pittsburg), Benjamin Goldstein (Stonybrook Research Institute), Eric Youngstrom (UNC, Chapel Hill), Soledad Romero (Hospital Clinic of Barcelona), and Josefina Castro Fornieles (University of Barcelona) have not been successful. We will keep trying, but the field needs to reach beyond the many investigators who are advocating for more treatment research to other people with more influence.
Early Intervention Improves Outcomes in Early-Stage Schizophrenia
A recent meta-analysis of 10 studies found that early intervention after a first episode of psychosis or in the early stages of a schizophrenia spectrum disorder led to better patient outcomes than treatment as usual.
The meta-analysis by researcher Christoph U. Correll and colleagues appeared in the journal JAMA Psychiatry in 2018. The 10 studies that were included had randomized a total of 2,176 patients to receive either treatment as usual or early intervention services, which typically include efforts at early detection of symptoms, early treatment with low doses of antipsychotic medication, interventions to prevent relapse, and strategies to help patients return to normal work and social activities.
Those patients who received early intervention services were less likely to discontinue treatment, were less likely to have a psychiatric hospitalization, were more involved in school or work, and had less severe symptoms, including both positive and negative symptoms of schizophrenia.
The authors called for better funding and implementation of early intervention services in early psychosis or the beginning stages of schizophrenia.
Editor’s Note: This finding with regard to schizophrenia spectrum disorders emphasizes the enormous disparity in allocation of research resources for the study of early psychosis versus early bipolar disorder, where almost no studies of this kind have been done.
The mean age of the patients in this psychosis meta-analysis was 27.5 years. Symptoms of bipolar disorder can often begin earlier, in childhood, and early onset of bipolar disorder predicts poor long-term outcomes into adulthood and is associated with a high risk of substance abuse and suicide. This editor (Robert M. Post) and many colleagues have witnessed two decades of scientific literature on early-onset bipolar disorder. We know that early intervention is necessary, but more treatment studies are needed at the early stages of the illness, and calls for funding treatment-focused research have gone unheeded.
More advocacy is needed among families affected by bipolar disorder and advocacy groups interested in better treatment of bipolar disorder. We must try to change the abysmal status quo and campaign publicly, privately, and politically for more funds and public health attention to be directed toward early intervention in bipolar disorder.
