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

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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.

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.

Methylphenidate Does Not Cause Mania When Taken with a Mood Stabilizer

September 8, 2017 · Posted in Comorbidities, Current Treatments · Comment 

ADHDMethylphenidate is an effective treatment for attention-deficit hyperactivity disorder (ADHD). Ritalin may be the most commonly recognized trade name for methylphenidate, but it is also sold under the names Concerta, Daytrana, Methylin, and Aptensio. A 2016 article in the American Journal of Psychiatry reports that methylphenidate can safely be taken by people with bipolar disorder and comorbid ADHD as long as it is paired with mood-stabilizing treatment.

The study was based on data from a Swedish national registry. Researchers led by Alexander Viktorin identified 2,307 adults with bipolar disorder who began taking methylphenidate between 2006 and 2014. Of these, 1,103 were taking mood stabilizers including antipsychotic medications, lithium, or valproate, while 718 were not taking any mood stabilizing medications.

Among those who began taking methylphenidate without mood stabilizers, manic episodes increased over the next six months. In contrast, patients taking mood stabilizers had their risk of mania decrease after beginning treatment with methylphenidate.

Viktorin and colleagues suggest that 20% of patients with bipolar disorder may also have ADHD, so it is not surprising that 8% of patients with bipolar disorder in Sweden receive a methylphenidate prescription.

Mood-stabilizing drugs can worsen attention and concentration, so methylphenidate treatment can be helpful if it can be done without increasing manic episodes. However, Viktorin and colleagues suggest that due to the risk of increasing mania, anyone given a prescription for methylphenidate monotherapy should be carefully screened to rule out bipolar disorder.

The researchers confirmed that taking methylphenidate for ADHD while taking a mood stabilizer for bipolar disorder is a safe combination.

TDCS May Improve ADHD Symptoms

August 9, 2017 · Posted in Potential Treatments · Comment 

tDCSTranscranial direct current stimulation (tDCS) is a therapy in which electrodes placed on the skull deliver a steady, low level current to the brain, changing its threshold for electrical activity. Anodal tDCS to the prefrontal cortex can improve working memory. In a small 2017 study in the Journal of Neural Transmission, Cornelia Soff and colleagues found for the first time that tDCS may improve symptoms of attention-deficit hyperactivity disorder (ADHD).

People with ADHD tend to have underactivation of the prefrontal cortex and deficits in working memory. The study randomized 15 young people aged 12–16 (three girls and twelve boys) to receive either real tDCS or a sham stimulation. The anodal tDCS was delivered at 1 mA targeting the left dorsolateral prefrontal cortex for 5 days. Those participants who received tDCS showed a reduction in inattention, impulsivity, and hyperactivity compared to those who received the sham stimulation. The effects were more pronounced 7 days after the stimulation, suggesting that tDCS’ effects may be long-term. Larger, more definitive trials are needed to clarify the effects of tDCS on ADHD, but these preliminary findings are promising.

Schizophrenia Drug May Treat ADHD with Impulsive Aggression

October 24, 2016 · Posted in Potential Treatments · Comment 

molindone for ADHD with impulsive aggression

The atypical antipsychotic drug molindone was used to treat schizophrenia for decades before it was pulled from the market in 2010 for business reasons. Now Supernus Pharmaceuticals is studying whether a reformulation of the drug may be used to treat attention deficit hyperactivity disorder (ADHD) that is accompanied by impulsive aggression.

Supernus tested an extended-release form of the drug in 118 children aged 6–12 with ADHD and impulsive aggression. They received either placebo or between 12mg and 54mg per day of molindone for 39 days. Those children who received between 12mg and 36mg per day of molindone showed fewer symptoms of impulsive aggression that those who received placebo. Side effects included headache, sedation, and increased appetite. Clinical trials of molindone will continue.

SNRI Viloxazine May Be Reintroduced as ADHD Treatment

October 20, 2016 · Posted in Potential Treatments · Comment 

new ADHD drug

The pharmaceutical company Supernus identifies older drugs that may be repurposed to treat other disorders. The company believes it may have found a new use for the discontinued antidepressant viloxazine, as a treatment for attention deficit hyperactivity disorder (ADHD).

Viloxazine is a selective norepinephrine reuptake inhibitor, or SNRI, that was approved in Europe but not in the US and was eventually removed from the market due to competition from other drugs. Its structure and mechanism of action resemble those of the ADHD treatment atomoxetine, so Supernus has begun trials of viloxazine for ADHD in adults.

At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, the researchers reported that compared to placebo, viloxazine was about twice as likely to reduce ADHD symptoms. Side effects included nausea, decreased appetite, headache, and insomnia. Supernus hopes to create an extended release form of the drug for both adults and children.

Guanfacine Improves ADHD Symptoms and Academic and Social Functioning in Children

April 20, 2016 · Posted in Potential Treatments · Comment 

guanfacine improves academic functioning in ADHD

A study by researcher J.H. Newcorn and colleagues published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2013 found that eight weeks of treatment with the drug guanfacine (extended release) improved symptoms of attention deficit hyperactivity disorder (ADHD) in North American children compared to placebo. A 2015 study by M.A. Stein and colleagues in the journal CNS Drugs extended this research, determining that guanfacine also improved academic and social functioning, including family dynamics, in the same group of children.

Children aged 6–12 who had been diagnosed with ADHD received either placebo or 1 to 4 mg of guanfacine extended release either in the morning or evening. The children in both guanfacine groups showed improvements in family interactions, learning and school, social behavior, and risky behavior compared to those taking placebo. No improvements were seen in life skills or self-concept. The improvements in functioning were linked to the drug’s effectiveness in improving ADHD symptoms. Those children whose ADHD symptoms improved on guanfacine were also more likely to see improvements in academic and social functioning.

Stimulants Linked to Psychotic Symptoms in Offspring of Parents with Psychiatric Illness

April 18, 2016 · Posted in Current Treatments, Risk Factors · Comment 

stimulants linked to psychotic symptoms

Stimulants are one of the most common medications prescribed to children and adolescents, typically for attention deficit hyperactivity disorder (ADHD). In children of parents with major depression, bipolar disorder, or schizophrenia, stimulant use may come with a risk of psychotic symptoms. A 2016 study by L.E. MacKenzie and colleagues in the journal Pediatrics reported that among children and youth whose parents had one of these psychiatric illnesses, 62.5% of those who had taken stimulants had current psychotic symptoms, compared to only 27.4% of those who had not taken stimulants. The participants with psychotic symptoms tended to have hallucinations that occurred while they were taking stimulants. Doctors may want to consider whether parents have a history of psychiatric illness when deciding whether to prescribe stimulants to children and adolescents with ADHD. Activation is a common side effect of antidepressants in children who have a parent with bipolar disorder. Young people taking stimulants for ADHD should be monitored for psychotic symptoms, particularly if they have a parent with a history of depression, bipolar disorder, or schizophrenia.

Surprisingly, Adult ADHD Is Distinct From Childhood ADHD

July 29, 2015 · Posted in Course of Illness, Diagnosis · Comment 

ADHD

In a longitudinal study of 1,037 people born in Dunedin, New Zealand in 1972 and 1973, most participants with attention deficit hyperactivity disorder (ADHD) in adulthood did not have the disorder as children. The study by Terrie E. Moffitt and colleagues in the American Journal of Psychiatry is the first prospective longitudinal study to describe the childhood of adults with ADHD.

When the study participants were children, about 6% were diagnosed with ADHD (mostly males). These children also had comorbid disorders, neurocognitive deficits, multiple genes associated with risk for ADHD, and some life impairment when they reached adulthood.

In adulthood, about 3% of the participants had ADHD (roughly equal between men and women), and 90% of these participants had no history of ADHD in childhood. The participants with ADHD in adulthood also had substance dependence and life impairment, and had sought treatment for the disorder. The researchers were surprised to find that these participants with adult ADHD did not show neuropsychological deficits in childhood, nor did they have the genetic risk factors associated with childhood ADHD.

If the findings of this study are replicated, researchers will have to rethink the current classification of ADHD as a neurodevelopment disorder that begins in childhood, and begin to determine how adult ADHD develops.

Editor’s Note: Before the publication of this article, most investigators (including this editor Robert M. Post) thought that virtually all ADHD in adulthood evolved from the childhood disorder, and if it did not begin in childhood, the diagnosis was suspect. I still believe the ADHD that appears in adulthood in patients with bipolar disorder is likely attributable to residual depression and anxiety or hypomania and that more concerted treatment of the patient to full remission will often result in much better attention, concentration, and ability to follow through and stay on task.

 

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