Treatment Approaches to Childhood-Onset Treatment-Resistant Bipolar Disorder

May 14, 2018 · Posted in Potential Treatments · Comment 

Dear readers interested in the treatment of young children with bipolar disorder and multiple other symptoms: In 2017, BNN Editor Robert M. Post and colleagues published an open access paper in the journal The Primary Care Companion for CNS Disorders titled “A Multi-Symptomatic Child: How to Track and Sequence Treatment.” The article describes a single case of childhood-onset bipolar disorder shared with us via our Child Network, a research program in which parents can create weekly ratings of their children’s mood and behavioral symptoms, and share the long-term results in graphic form with their children’s physicians.

Here we summarize potential treatment approaches for this child, which may be of use to other children with similar symptoms.

We present a 9-year-old girl whose symptoms of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), oppositional behavior, and mania were rated on a weekly basis in the Child Network under a protocol approved by the Johns Hopkins School of Medicine Institutional Review Board. The girl, whose symptoms were rated consistently for almost one year, remained inadequately responsive to lithium, risperidone, and several other medications. We describe a range of other treatment options that could be introduced. The references for the suggestions are available in the full manuscript cited above, and many quotes from the original article are reprinted here directly.

As illustrated in the figure below, after many weeks of severe mania, depression, and ADHD, the child initially appeared to improve with the introduction of 4,800 micrograms per day of lithium orotate (a more potent alternative to lithium carbonate that is marketed as a dietary supplement), in combination with 1 mg per day of guanfacine, and 1 mg per day of melatonin.

mood chart

Despite continued treatment with lithium orotate (up to 9,800 micrograms twice per day), the patient’s oppositional behavior worsened during the period from November 2015 to March 2016, and moderate depression re-emerged in April 2016. Anxiety was also generally less severe from December 2015 to July 2016, and weekly ratings of overall illness remained in the moderate severity range (not illustrated).

In June 2016, the patient began taking risperidone (maximum dose 1.7 mg/day) instead of lithium, and her mania improved from moderate to mild. There was little change in her moderate but fluctuating depression ratings, but her ADHD symptoms got worse.
The patient had been previously diagnosed with bipolar II disorder and anxiety disorders including school phobia, generalized anxiety disorder, and obsessive compulsive disorder.
Given the six weeks of moderate to severe mania that the patient experienced in October and November 2015, she would meet criteria for a diagnosis of bipolar I disorder.

Targeting Symptoms to Achieve Remission

General treatment goals would include: mood stabilization prior to use of ADHD medications, a drug regimen that maximizes tolerability and safety, targeting of residual symptoms with appropriate medications supplemented with nutraceuticals, recognition that complex combination treatment may be necessary, and combined use of medications, family education, and therapy.

Mood Stabilizers and Atypical Antipsychotics to Maximize Antimanic Effects

None of the treatment options in this section are approved by the US Food and Drug Administration for use in children under 10 years of age, so all of the suggestions are “off label.” Further, they may differ from what other investigators in this area of medicine would suggest, especially since evidence-based medicine’s traditional gold standard of randomized placebo-controlled clinical trials is impossible to apply here, given the lack of research in children with bipolar disorder.

As we share in the original article, reintroducing lithium alongside risperidone could be effective, as “combinations were more effective than monotherapy in a study [by] Geller et al. (2012), especially when they involved an atypical antipsychotic such as risperidone. This might include the switch from lithium orotate to lithium carbonate,” the typical treatment for bipolar disorder, on which more research has been done. “Combinations of lithium and valproate were also more effective than either [drug alone]…in the studies of Findling et al. (2006),” and many patients needed stimulants in addition.

“Most children also needed combinations of mood stabilizers (lithium, carbamazepine, valproate) in the study [by] Kowatch et al. (2000).” In a 2017 study by Berk et al. of patients hospitalized for a first mania, randomization to lithium for one year was more effective than quetiapine on almost all outcome measures.

Targeting ADHD

“[The increased] severity of [the child’s] ADHD despite improving mania speaks to the…utility of adding a stimulant to the regimen that already includes…guanfacine,” which is a common non-stimulant treatment for ADHD. “This would be supported by the data of Scheffer et al. (2005) that stimulant augmentation for residual ADHD symptoms does not [worsen] mania, and that the combination of a stimulant and guanfacine may have more favorable effects than stimulants alone.”

However, the consensus in the field is that mood stabilization should be achieved first, before low to moderate (but not high) doses of stimulants are added. “Thus, in the face of an inadequate response to the lithium-risperidone combination in this child, stimulants could be deferred until better mood stabilization was achieved.”

Other Approaches to Mood Stabilization and Anxiety Reduction

“The anticonvulsant mood stabilizers (carbamazepine, lamotrigine, and valproate) each have considerable mood stabilizing and anti-anxiety effects, at least in adults with bipolar disorder. With inadequate mood stabilization of this patient on lithium and risperidone, we would consider the further addition of lamotrigine.

Lamotrigine appears particularly effective in adults with bipolar disorder who have a personal history and a family history of anxiety (as opposed to mood disorders), and it has positive open data in adolescents with bipolar depression and in a controlled study of maintenance (in teenagers 13–17, but not in preteens 10–12) (Findling et al. 2015). With better mood stabilization, anxiety symptoms usually diminish…, and we would pursue these strategies [instead of using] antidepressants for depression and anxiety in young children with bipolar disorder.”

“Carbamazepine appears to be more effective in adults with bipolar who have [no] family history of mood disorders,” unlike lithium, which seems to work better in people who do have a family history of mood disorders.

“While the overall results of oxcarbazepine in childhood mania were negative, they did exceed placebo in the youngest patients (aged 7–12) as opposed to the older adolescents (13–18) (Wagner et al. 2006).

“There are long-acting preparations of both carbamazepine (Equetro) and oxcarbazepine (Oxtellar) that would allow for all nighttime dosing to help with sleep and reduce daytime side effects and sedation. Although data [on] anti-manic and antidepressant effects in adults are stronger for carbamazepine than oxcarbazepine,” there are good reasons to consider oxcarbazepine. First, there is the finding mentioned above that oxcarbazepine worked best in the youngest children. Second, there is a lower incidence of severe white count suppression on oxcarbazepine. Third, it has less of an effect on liver enzymes than carbamazepine. However, low blood sodium levels are more frequent on oxcarbazepine than carbamazepine.

Other Atypical Antipsychotics That May Improve Depression

Read more

Playing Tackle Football Before Age 12 May Be Bad for the Brain

May 3, 2018 · Posted in Risk Factors · Comment 

a football on grass

A 2017 study found that men who began playing American tackle football before age 12 were more likely to have depression, apathy, problems with executive functioning, and behavioral issues in adulthood than their peers who began playing football after age 12. Duration of football play did not seem to matter—those men who stopped playing football after high school were just as likely to be affected in adulthood as those who went on to play football in college or professionally.

The study by Michael L. Alosco and colleagues was published in the journal Translational Psychiatry. It included 214 men (average age 51) who had played football in their youth, but not other contact sports. The men reported their own experiences with depression, apathy, cognitive function, and behavioral regulation. Those who began football before age 12 were twice as likely to report impairment in behavioral regulation, apathy, and executive function than those who began playing later. Those who started younger were also three times more likely to have clinical depression in adulthood than those who started older.

According to Alosco and colleagues, between ages 9 and 12, the brain reaches peak maturation of gray and white matter volume, and synapse and neurotransmitter density also increases. The repeated head injuries that can occur during youth football play during this time may disrupt neurodevelopment, with lasting negative effects.

One drawback to the study was that recruitment was not random—men who volunteered for the study might have done so due to a recognition of their own cognitive problems. However, the results suggest more study is needed, and caution is encouraged when making decisions about youth football participation. Some youth football leagues have begun placing greater limits on the type of contact allowed during play.

FDA Approves Lurasidone for Bipolar Depression in Children and Adolescents

April 16, 2018 · Posted in Current Treatments · Comment 

In March 2018, the US Food and Drug Administration approved the antipsychotic drug lurasidone (Latuda) for the treatment of bipolar depression in children and adolescents aged 10–17 years. Lurasidone was already approved for adults with bipolar depression, as an add-on treatment to the mood stabilizers lithium and valproate, and for schizophrenia in people aged 13 years and up.

A 6-week clinical trial in 347 youth compared lurasidone (in doses ranging from 20 to 80 mg/day) to placebo and found that those who received lurasidone showed significant improvements in depression compared to those who received placebo. The average dose was below 40 mg/day. The research by Melissa P. DelBello and colleagues was published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2017.

In the study, lurasidone was well-tolerated. Side effects included nausea, sleepiness, minimal weight gain, and insomnia. Lurasidone did not seem to affect glucose, triglycerides, cholesterol, or blood pressure.

Editor’s Note: This is the first drug to be approved for bipolar depression in this age range. This editor (Robert M. Post) has written extensively on the high incidence of childhood onset bipolar disorder in the US, and especially in the offspring of parents with bipolar disorder.
It is important to be alert to the possibilities of depression and bipolar disorder in children in the US (along with related illnesses such as anxiety, oppositional defiant disorder, and attention deficit hyperactivity disorder (ADHD)), as early-onset illness tends to have a more severe long-term course than adult-onset depression and bipolar disorder. A longer delay between the emergence of symptoms and the first treatment for bipolar disorder is also a risk factor for more severe depression, more time depressed, and a poorer outcome in adulthood.

Parents of children aged 2-12 who have mood or behavioral problems are encouraged to consider joining the Child Network at our website, bipolarnews.org (click on the tab for the Child Network). By participating in this research network, parents are able to make a weekly rating of the severity of their children’s symptoms of anxiety, depression, ADHD, oppositional behavior, and mania via the secure website. The ratings can then be shared with the child’s clinicians for easy visualization of the course of symptoms over time, which may help with treatment decisions.

Omega-3 Fatty Acids Improve ADHD

January 26, 2018 · Posted in Current Treatments · Comment 

sources of omega-3 fatty acidsA 2017 systematic review and meta-analysis found that omega-3 fatty acid supplementation improves symptoms of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. The article by Jane Pei-Chen Chang and colleagues in the journal Neuropsychopharmacology identified seven randomized controlled trials in which omega-3 fatty acids improved clinical symptoms of ADHD, and three trials in which omega-3s improved cognitive measures associated with attention.

The meta-analysis also found that children and adolescents with ADHD have lower than normal levels of the omega-3s DHA and EPA, in addition to lower total levels of omega-3s measured in blood and cheek tissues.

Chang and colleagues suggest that omega-3 fatty acid supplementation is a potentially helpful and largely risk-free treatment option for ADHD in children and adolescents.

Intranasal Ketamine for Bipolar Disorder

November 29, 2017 · Posted in Potential Treatments · Comment 

nasal sprayAn in-press article due out in January 2018 by Demitri F. Papolos and colleagues in the Journal of Affective Disorders reports that intranasal ketamine delivered every three to four days reduced symptoms of bipolar disorder in 45 teens (aged 16 years on average). The teens treated in one private practice had the ‘fear-of-harm’ subtype, which in addition to bipolar symptoms is characterized by treatment resistance, separation anxiety, aggressive obsessions, disordered sleep, and poor temperature regulation.

The repeated administration of ketamine produced long-lasting positive results, improving bipolar symptoms as well as social function and academic performance. Many participants reported via survey that they were much or very much improved after being treated for durations ranging from 3 months to 6.5 years. Side effects were minimal and included sensory problems, urination problems, torso acne, dizziness, and wobbly gait.

The ketamine was delivered to alternating nostrils via 0.1 ml sprays that included 50–200 mg/ml of ketamine in 0.01% benzalkonium chloride. Patients were instructed to increase the dosage just up until it became intolerable and then repeat the last tolerable dose every three to four days. Final doses ranged from 20–360 mg. The mean dose was 165 mg (plus or minus 75 mg) delivered every 3 days.

Papolos and colleagues called for placebo-controlled clinical trials based on the positive results from this open study.

Evidence-Based Psychotherapies for Young Children

September 25, 2017 · Posted in Current Treatments · Comment 

TherapyAs many as 7–10% of children under the age of 5 have mood or behavioral problems, and this risk is even higher when a parent has a mood disorder. However, many families are not able to access treatment for these children due to their location, a lack of providers, or insurance problems.

A 2016 article by Mary Margaret Gleason and colleagues in the journal Technical Report in Pediatrics summarizes psychotherapeutic treatments for children that are supported with rigorous evidence. Some of these include infant-parent psychotherapy, video feedback for positive parenting, attachment biobehavioral catch-up (or ABC, in which caregivers are taught to re-interpret the signals of children who previously experienced maltreatment, providing nurturing in response), parent-child interaction therapy, and programs that combine parenting support with illness prevention, such as the Incredible Years series (for behavioral difficulties), the New Forest Programme (for attention-deficit hyperactivity disorder or ADHD), and Helping the Noncompliant Child (for oppositional behavior).

Gleason and colleagues suggest that pediatricians should take the lead in assessing young children and recommending appropriate psychotherapeutic approaches.

One resource available to parents is our own Child Network. It consists of an online portal where parents can provide weekly ratings of their children’s symptoms. These can be provided to the child’s physician to facilitate diagnosis and to clinicians to more effectively evaluate the results of treatment. The data provided to the Child Network will in turn help us understand how children are being treated in the community. There a few initial forms to fill out, but the weekly rating process is quick and can provide a great picture of a child’s wellbeing over time, including evaluating the effectiveness of any treatments.

Offspring of Bipolar Parents Have More Psychiatric Illness

September 22, 2017 · Posted in Risk Factors · Comment 

family with boyA 2017 study from the Czech Republic found that children and adolescents with at least one parent with bipolar disorder had much higher lifetime rates of mood and anxiety disorders than their peers who did not have a parent with bipolar disorder. The offspring of bipolar parents also had lower quality of life, less social support, poorer self-perception, poorer relationships with their peers and parents, and more difficult home lives than those whose parents did not have bipolar disorder.

The study by Michal Goetz and colleagues in the Journal of Child and Adolescent Psychopharmacology reported that 86% of the children of bipolar parents would be diagnosed with a psychiatric disorder in their lifetime. Similarly, David Axelson and colleagues from the Pittsburgh Bipolar Offspring Study reported in the American Journal of Psychiatry in 2015 that 74.2% of children with a parent with bipolar disorder would receive a lifetime psychiatric diagnosis, and a 2006 study by Myrna M. Weissman in the American Journal of Psychiatry found that the offspring of a unipolar depressed parent were three times more likely to have a psychiatric illness than offspring of nondepressed parents over 20 years of follow-up. Another study by this editor (Robert M. Post) and colleagues in the Bipolar Collaborative Network published in the Journal of Affective Disorders in 2016 found that a third of children at high risk due to a parent’s bipolar diagnosis would go on to have a psychiatric illness.

The Goetz study included a total of 86 participants between the ages of 7 and 18. Half had a parent with bipolar disorder and half did not. One limitation of the study was its recruitment procedure. Parents with bipolar disorder who enrolled their children in the study may have done so out of concern for their offspring’s mental health, increasing illness rates in the group with bipolar parents. Researchers were also aware of parents’ diagnoses, which may have affected their ratings of the young people’s symptoms. Despite these limitations, the study and its predecessors still suggest that psychiatric illness in a parent puts children at very high risk for a psychiatric illness themselves and can affect their wellbeing in a variety of ways.

Goetz and colleagues suggest that there is a need for proactive and complex care of families with psychiatric illness. They suggest that good communication is needed between adult and youth psychiatric services, with physicians who treat adults with bipolar disorder inquiring about those patients’ children and referring them to specialized psychiatric services for youth.

Editor’s Note: I not only endorse the conclusions of Goetz and colleagues, but would further recommend that parents with a diagnosis of bipolar disorder or unipolar depression discuss their children’s mood and behavior with their own psychiatrists and the children’s primary care physicians.

Parents of children aged 2 to 12 may enroll in our own Child Network, a secure online portal where they can record weekly ratings of their children’s symptoms and share these with their physicians.

There are many effective psychotherapeutic interventions for children with anxiety and mood disorders that should be sought for a child with symptoms that impair his or her functioning. Two evidence-based treatments are Family Focused Therapy, which incorporates family members into treatment so that they better understand the illness and can be supportive of the affected child, and cognitive behavioral therapy, in which negative patterns of thoughts and behaviors are challenged and patients are taught more effective problem-solving skills. When childhood psychiatric illness is recognized and treated appropriately, the results are often excellent, and it is possible that heading off the illness early may even prevent the development of more severe illness later in the child’s life.

Systematic Review Finds Bupropion is Effective for ADHD in Young People

September 14, 2017 · Posted in Potential Treatments · Comment 

Teen takes bupropionA 2016 systematic review by Qin Xiang Ng in the Journal of Child and Adolescent Psychopharmacology found that the antidepressant bupropion (Wellbutrin) can improve attention deficit hyperactivity disorder (ADHD) in children and adolescents.

The review identified 25,455 studies of bupropion for ADHD, but only six included children. All six studies showed that bupropion improved ADHD symptoms in children and adolescents. Head-to-head trials of bupropion and methylphenidate (one of the most common medications to treat ADHD, which most people know by the name Ritalin) found the drugs had similar efficacy rates, although a large double-blind, placebo-controlled multicenter study found that bupropion had a smaller effect size than methylphenidate.

In terms of side effects, methylphenidate was more likely to cause headaches than bupropion, but otherwise the drugs were similar.

Ng suggests that bupropion should be considered for the treatment of ADHD in children and adolescents, but more large trials of the drug are needed. Bupropion may also help children whose ADHD appears alongside conduct, substance abuse, or depressive disorders.

Teens with Bipolar Disorder at Increased Risk for Cardiovascular Disease

July 14, 2017 · Posted in Comorbidities, Risk Factors · Comment 

teen blood pressure checkA scientific statement from the American Heart Association reported in 2015 that youth with major depressive disorder and bipolar disorder are at moderate (Tier II level) increased risk for cardiovascular disorders. The combined prevalence of these illnesses in adolescents in the US is approximately 10%.

There are many factors that contribute to this risk, including inflammation, oxidative stress (when the body falls behind neutralizing harmful substances produced during metabolism), dysfunction in the autonomic nerve system, and problems with the endothelium (the inner lining of blood vessels). Lifestyle factors include adversity in early life, sleep disturbance, sedentary lifestyle, poor nutrition, and abuse of tobacco, alcohol, or other substances.

Taking some atypical antipsychotics as treatment for bipolar disorder also contributes to the risk of cardiovascular problems by increasing weight and/or lipid levels. Among the atypicals, ziprasidone (Geodon) and lurasidone (Latuda) come with the lowest likelihood of weight gain.

The statement by Benjamin I. Goldstein and colleagues that appeared in the Heart Association-affiliated journal Circulation suggested that therapeutic interventions should address some of these risk factors to help prevent cardiovascular problems and improve life expectancy for young people with depression or bipolar disorder. These could include a good diet, regular exercise, and treatments with good long-term tolerability that are aimed at preventing episodes.

The Role of Inflammatory Markers and BDNF

Inflammation worsens the risk of cardiovascular problems, while brain-derived neurotrophic factor (BDNF), which protects neurons and plays a role in learning and memory, may improve prospects for someone with depression or bipolar disorder.
A 2017 article by Jessica K. Hatch and colleagues including Goldstein in the Journal of Clinical Psychiatry suggests that inflammation and BDNF are mediators of cardiovascular risk in youth with bipolar disorder. The study looked at 40 adolescents with bipolar disorder and 20 healthy controls.

Those with bipolar disorder had greater waist circumference, body mass index, and pulse pressure than the controls. The youth with bipolar disorder also had higher levels of the inflammatory cytokine Il-6. Participants who had lower BDNF had greater thickness of the carotid vessel internal lining (intima media).

Hatch and colleagues point to the importance of prevention strategies in adolescents with these indicators of increased cardiovascular risk. These data complement the American Heart Association’s recognition of adolescent mood disorders as a large problem that deserves wider attention both in psychiatry and in the media.

Early Marijuana Use Linked To Abnormal Brain Function, Low IQ

May 10, 2017 · Posted in Risk Factors · Comment 

young marijuana usersA study of depression and marijuana use found that using marijuana before the age of 17 was linked to abnormal brain function and lower IQ. In a 2016 article in the journal Acta Psychiatrica Scandinavica, researcher Elizabeth Osuch and colleagues described a study that compared four categories of youth: frequent pot users with depression, frequent pot users without depression, those with depression who did not use pot, and healthy individuals who did not use pot. The researchers also compared those who began using pot after the age of 17 to those who began earlier.

The main findings were that brain function in the areas of reward processing and motor control differed across the four groups. Depression was linked to deficits in brain function. Marijuana use did not correct these deficits, and in some parts of the brain, worsened them.

Those who had used marijuana before the age of 17 had abnormalities in memory, visuo-spatial processing, self-referential activity, and reward processing. Those who had started using marijuana at younger ages also had lower IQ scores.

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