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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Children Who Are Bullied Have Poorer Mental Health

April 30, 2018 · Posted in Risk Factors · Comment 

girl being bullied

A 2017 study of twins between the ages of 11 and 16 found that being bullied around age 11 caused anxiety, depression, hyperactivity and impulsivity, inattention, and conduct problems, some of which lasted for years. Participants recorded their experiences with physical or verbal bullying, social manipulation, and property attacks (trying to break one’s belongings, for example).

The effects of bullying decreased over time. The bullied children were still significantly more anxious than their non-bullied twins two years later, but this difference faded by the five-year mark. However, paranoid thoughts and cognitive disorganization did persist for 5 years.
The twin study design helped researchers zone in on the causal effect bullying might have on the children’s mental health, rather than other factors the twins shared, such as genetics or family environment. The study included 11,108 twins born in England and Wales.

The research by Timothy Singham and colleagues was published in the journal JAMA Psychiatry. Interestingly, the researchers found that prior mental health difficulties increased children’s likelihood of being bullied, such that being bullied could be considered a symptom of preexisting vulnerabilities. Singham and colleagues suggest that in addition to interventions to reduce bullying and address familial factors that might make children susceptible to bullying, children should also be taught resilience skills.

Clinical Vignettes from Dr. Elizabeth Stuller

April 11, 2018 · Posted in Potential Treatments · Comment 

Dr. Elizabeth Stuller, a staff psychiatrist at the Amen clinics in Washington, DC and CEO of private practice Stuller Resettings in Baltimore, MD, provided this editor (Robert M. Post) with several interesting anecdotal observations based on her wide clinical experience with difficult-to-treat mood disordered patients.

  1. Stuller has used low-dose asenapine (Saphris), e.g. half a pill placed under the tongue, for depressed patients with alcohol use problems who have trouble getting to sleep. She has also used asenapine for rapid calming of agitated patients in her office.
  2. Stuller has also had success with the use of the atypical antipsychotic drug brexpiprazole (Rexulti) for patients with bipolar depression and low energy. She typically uses 0.5 mg/day for women and 1 mg/day for men. Stuller finds that there is little weight gain or akathisia with brexpiprazole.
  3. She has had success with the drug Nuedexta, which is a combination of dextromethorphan and quinidine and is approved for the treatment of sudden uncontrollable bouts of laughing or crying, known as pseudobulbar affect, which can occur as a result of neurological conditions or brain injuries. It is a combination of an NMDA antagonist and a sigma receptor agonist. Stuller starts with the 20mg dextromethorphan/10 mg quinidine dose once a day and increases to twice a day in week two. She finds it useful for behavioral effects of traumatic brain injury (TBI), anxiety resulting from the use of synthetic marijuana (sometimes called spice), and psychosis not otherwise specified. Stuller also finds that some patients appear to respond well to Nuedextra but not minocycline, or vice versa.

Editor’s Note: Note that these are preliminary clinical anecdotes conveyed in a personal communication, and have not been studied in clinical trials, thus should not be relied upon in the making of medical decisions. All decisions about treatment are the responsibility of a treating physician.

In Animals, Exposure to High Fat Diet During Pregnancy Can Affect Offspring’s Neurological Development

March 19, 2018 · Posted in Risk Factors · Comment 

baby macaque feeding

New research in non-human primates suggests that exposure to a high fat diet during pregnancy and in early development prior to weaning can increase the offspring’s propensity for anxiety later in life.

The new research echoes 2010 findings about rats. Researcher Staci D. Bilbo and colleagues reported in the journal of the Federation of American Societies for Experimental Biology that in rats, a high fat diet during pregnancy and lactation led to offspring with greater body weight, increased inflammation, and problems with anxiety and spatial learning. Switching to a standard diet after weaning did not eliminate these outcomes.

The recent research by Jacqueline R. Thompson and colleagues, published in the journal Frontiers in Endocrinology in July 2017, suggests that maternal nutrition in the primate during pregnancy and lactation can have long-lasting effects on offspring’s neurological development, altering the brain and endocrine system. These changes occurred even if the offspring began a normal diet after weaning.

65 female Japanese macaques were divided into two groups, one that received a high-fat diet and one that received a normal diet. In the offspring of mothers who ate a high-fat diet, the researchers found impaired development of neurons containing serotonin. The offspring of the high-fat diet group also showed behavioral alterations such as increased anxiety.

The high rates of obesity in the US and other developed nations make these findings particularly important. The researchers suggest that 64% of women in the US who are of reproductive age are overweight, and 35% are obese. Co-author Elinor Sullivan suggested that the findings from the study could motivate mothers to make healthy nutritional decisions, not only for themselves but for their children as well.

Link Clarified Between Gut Microbes and Emotions

February 12, 2018 · Posted in Neurobiology · Comment 

mice exercising

A 2017 article in the journal Microbiome suggests that gene-regulating molecules called microRNAs in the brain may be the link between microbes in the gut and emotions.
The research by Alan E. Hoban and colleagues looked at mice raised in a sterile, microbe-free environment. These mice had fewer anxiety-like behaviors than mice raised among the usual bacteria, viruses, and fungi. This finding implies that the microbiome—the trillions of microbes that live in and around our bodies—affects brain functions. In this case, the affected regions were the prefrontal cortex and the amygdala, which both play a role in the detection and response to fearful stimuli. These regions showed alterations in the level of microRNAs present.

When Hoban and colleagues introduced microbes into the animal’s systems, some microRNAs did not bounce back, suggesting that there may be a crucial window early in life when the presence of microbes is needed for the brain to develop normally.

In general, this research shows that microRNAs are key to understanding the link between the microbiome and the brain.

Eye Movement Desensitization and Reprocessing Can Improve PTSD

January 18, 2018 · Posted in Current Treatments · Comment 

A 2014 meta-analysis of clinical trials showed that the therapeutic technique known as eye movement desensitization and reprocessing (EMDR) can reduce symptoms of post-traumatic stress disorder (PTSD). The meta-analysis also established that longer durations of EMDR treatment correlated with better outcomes.

The meta-analysis by Ying-Ren Chen and colleagues in the journal PLOS One evaluated 26 randomized controlled trials of EMDR in people with PTSD. Chen and colleagues found that EMDR reduced PTSD symptoms, depression, anxiety, and subjective distress.

EMDR is a psychotherapeutic technique intended to reduce the distress that a patient feels about a traumatic memory. The patient is encouraged to recall the traumatic event while focusing on an external stimulus. Typically this would mean using their eyes to track the therapist’s hand moving back and forth from left to right. This process can help patients reprocess the trauma and alleviate the stress that they feel upon recalling the traumatic memory.

Chen and colleagues found that EMDR sessions that lasted longer than one hour were more effective than those that lasted less than an hour. Another finding that was that groups led by therapists who were experienced in PTSD group therapy were more effective than groups led by therapists without that experience.

Other more recent research has established that traumatic memories can be reprocessed or even extinguished by making use of the memory reconsolidation window. Five minutes to one hour after a patient engages in active emotional recall of a traumatic memory, a window of time opens in which that memory is subject to reinterpretation and revision.

An experienced therapist can create a safe environment for a patient to recall traumatic events and find alternative ways of interpreting the experience—for example, by focusing on their strength in surviving the experience. This process resembles EMDR in many ways, but without the eye movements.

In a 2017 article in the journal Psychiatry Research, BNN Editor-in-Chief Robert M. Post and colleague Robert Kegan discuss the possibility of using the reconsolidation window to reprocess stressors that led to a depressive episode.

Immune Response to Repeated Stress Alters Behavior in Mice

April 12, 2017 · Posted in Course of Illness · Comment 

Laboratory black mouse in the hands of the experimenter

In research presented at the 2016 meeting of the Society of Biological Psychiatry, Jonathan P. Godbout described how an immune reaction to repeated stressors may lead to anxious behaviors in mice.

Mice were repeatedly defeated by a larger animal, a form of stress that produces a depression-like state. This provoked an immune response in the mice—the release of a type of white blood cells called monocytes from the bone marrow into the circulatory system. These inflammatory monocytes then traveled to the brain and spleen, attracted by signaling proteins called chemokines. The monocytes in turn produced inflammatory marker interleukin-1beta.

The defeat stress also provoked a reaction in the central nervous system, where microglia were activated.

These changes produced inflammation and anxiety-like behaviors in the mice. Blocking the microglial activation, monocyte recruitment to the brain, or interleukin-1beta signaling each reversed the anxiety-like behaviors.

Another researcher, Scott Russo, has shown that leukocytes, another type of white blood cells, secrete inflammatory interleukin-6 following defeat stress, and blocking this secretion prevents defeat stress–related behaviors.

Inflammation Predicts Depression and Anxiety Four Years Later in Older Americans

December 22, 2016 · Posted in Risk Factors · Comment 

inflammation predicts depression and anxiety

A large study of retired Americans found that those with high levels of the inflammatory marker C-reactive protein in the blood had more depression and anxiety. Higher CRP also predicted severity of depression and anxiety four years later.

The study, by researchers Joy E. Lin and Aoife O’Donovan, included 18,603 people over age 50 from the Health and Retirement Study. It was presented at the 2016 meeting of the Society of Biological Psychiatry.

Lin and O’Donovan hope that treating or preventing inflammation may be the key to preventing symptoms of depression and anxiety.

Vegan Diet Can Lead to Vitamin B12 Deficiency

October 26, 2016 · Posted in Risk Factors · Comment 
B12 may be deficient in vegans

Foods high in vitamin B12

Vitamin B12 deficiency is a risk associated with a vegan diet. B12 deficiency can lead to depression, anemia, and even irreversible neuron damage, according to researcher Drew Ramsey, who spoke on the topic at the 2016 meeting of the American Psychiatric Association.

A study of vegans showed that 52% were deficient in vitamin B12, while another 23% had insufficient levels of the vitamin. B12 is found in the highest concentrations in certain seafoods and liver. It is also found in dairy products, eggs, fortified breakfast cereals, and is available in supplement form.

Women who eat a vegan diet while pregnant may not be providing their offspring with enough nutrients, according to researcher Emily Deans, who also spoke at the meeting. A case report on 30 vegan mothers found that 60% of their offspring had developmental delays and 37% showed cerebral atrophy.

Deans said that eating no meat is associated with higher rates of depression, anxiety, and worse quality of life.

Ramsey believes that while the North American diet is probably weighted too heavily toward animal products, seafood remains an important source of B12.

Mindfulness Therapy Improves Anxiety in Youth with a Bipolar Parent

July 6, 2016 · Posted in Current Treatments · Comment 

mindfulness therapy

Children of parents with bipolar disorder are prone to anxiety and emotional dysregulation, but treating these symptoms with antidepressants can provoke symptoms of mania. Thus, non-pharmacological treatements for anxiety and depression are needed. A recent study by Melissa DelBello found that twelve weeks of mindfulness-based cognitive therapy improved symptoms of anxiety and mood dysregulation in 20 youth with a bipolar parent. DelBello used functional magnetic resonance imaging (fMRI) to observe that the therapy increased activation of brain structures related to emotion and sensing. Amygdala activation differed between those with anxiety and those with mood dysregulation, suggesting that the therapy’s effect was on regions that modulate the amygdala, including prefrontal and insular regions, rather than on the amygdala itself.

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