Predicting Onset of Bipolar Disorder in Children at High Risk: Part I

April 3, 2020 · Posted in Diagnosis, Risk Factors · Comment 

teenage boy sitting on floor with arms on kneesAt 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.

Symptom Progression

In offspring of parents with bipolar disorder, researcher Anne Cecilia Duffy found that symptoms in the children tended to progress in a typical sequence. Childhood sleep and anxiety disorders were first to appear, then depressive symptoms, then bipolar disorder.

Different Types of Illness May Respond Best to Different Medications

Duffy’s research also suggested links between illness features and a good response to specific medications. Those offspring who developed a psychotic spectrum disorder responded best to atypical antipsychotic medication. Those with classical episodic bipolar I disorder responded well to lithium, especially if there was a family history of lithium responsiveness. Those offspring with bipolar II (and anxiety and substance abuse) responded well to anticonvulsant medications.
If parents with bipolar disorder had experienced early onset of their illness, their children were more likely to receive a diagnosis of bipolar disorder.

The offspring of lithium-responsive parents tended to be gifted students, while those from lithium non-responders tended to be poorer students.

Comparing Risk Factors for Bipolar Disorder and Unipolar Depression

Researcher Martin Preisig and colleagues also showed that parental early onset of bipolar disorder (before age 21) was a risk factor for the offspring receiving a diagnosis of bipolar disorder. Parental oppositional defiant disorder (ODD) was also a risk factor for bipolar disorder in the offspring. The emergence of depression, conduct disorder, drug use, and sub-syndromal hypomanic symptoms also predicted the onset of mania during childhood.

Conversely, sexual abuse and witnessing violence were strong risk factors associated with a diagnosis of major (unipolar) depressive disorder. Being female and experiencing separation anxiety were also factors that predicted unipolar depression.

Predicting Conversion to Mania

Researcher Danella M. Hafeman reported that mood swings (referred to in the literature as “affective lability”), depression/anxiety, and having a parent who had an early onset of bipolar disorder were linked to later diagnoses of mania. Immediate risk factors that predicted an imminent onset of mania included affective lability, substance abuse, and the presence of sub-threshold manic symptoms.

Family Focused Therapy Effective in Youth at Risk for Bipolar Disorder Who Have Early Symptoms

March 27, 2020 · Posted in Current Treatments · Comment 

familyResearcher David Miklowitz developed Family Focused Therapy (FFT), in which families of young people at risk for bipolar disorder take part in therapy, learning about the illness and practicing strategies for communication and coping.

At a symposium at the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, Miklowitz reported findings from recent studies of youth who were at high risk for bipolar disorder because of a family history of the illness and the presence of early symptoms such as depression or cyclothymia or bipolar not otherwise specified (BP-NOS). Family focused therapy reduced symptoms. It also slowed onset of a first episode of mania and slowed the conversion to a diagnosis of bipolar I or bipolar II. These results converge with a total of 10 other positive studies of family focused therapy in different populations in children and adults. FFT or its equivalent should be made available to all symptomatic children who are at risk for bipolar disorder because of a family history of the disorder.

Quetiapine Reduced Childhood Mania, Especially in Those with Thicker Frontal Temporal Regions

March 20, 2020 · Posted in Brain Imaging, Current Treatments · Comment 

white matterIn a symposium at the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Melissa P. Delbello reported that six weeks of treatment with either lithium or quetiapine was effective in childhood mania, but quetiapine had a higher response rate of 71% versus 46% for lithium. Delbello found two types of structural changes on functional magnetic resonance imaging (fMRI). Some children had thicker frontal temporal regions, while others had thinning in these areas. The first group of patients had a 100% response to quetiapine, but only 53% of the second group responded to quetiapine.

In contrast, other researchers have found lithium superior to quetiapine. Vivian Kafantaris showed that patients who respond well to lithium show improvements in white matter abnormalities. Michael Berk and colleagues found that a year on lithium was superior to quetiapine on all measures including cognition and brain imaging in patients having their first episode of mania.

In Mice, Knockout of Circadian CLOCK Genes Resembles Mania

November 4, 2019 · Posted in Theory · Comment 

mouse

Colleen McClung reviewed and extended previous findings of hers that knocking out a gene known as CLOCK in mice could reproduce most aspects of bipolar mania, including symptoms such as hyperactivity; decreased sleep; less depression; more impulsivity, risk taking, and novelty seeking; and increased reward-seeking including substances such as cocaine, alcohol, and sucrose. This syndrome in mice can be reversed by giving the mice lithium and valproate.

Knocking out the CLOCK gene produced an increased firing rate and burst firing of dopamine neurons in the ventral tegmental area (VTA). Localized knockout of the CLOCK gene in the VTA alone also reproduced the increase in dopamine cell firing.

When McClung and colleagues knocked out CLOCK in the medial prefrontal cortex, the normal development of a type of neurons called GABAergic parvalbumin interneurons did not occur in adolescent mice, and in adulthood, certain neural nets did not mature, leading to increases in oxidative stress, mitochondrial and cellular dysfunction, and the behavioral abnormalities that resembled mania. This animal model thus gives insight into how a genetic deficit in circadian rhythm genes in humans could influence the timing of behavioral abnormalities starting in adolescence and lasting through adulthood.

Links Between Mixed Depression, Insulin Resistance, Inflammation, and Cognitive Deficits

August 1, 2019 · Posted in Potential Treatments · Comment 

depressed man with woman

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre discussed links between obesity, diabetes, and cardiovascular problems; increased inflammation; and decreased functioning of the neural networks involved in cognition. 

He and his colleagues analyzed 121 studies that included empirical research and meta-analyses. McIntyre and colleagues found that patients with higher levels of inflammatory markers have more insulin resistance and cognitive dysfunction. A meta-analysis revealed that the inflammatory markers IL-6, TNF alpha, and CRP were significantly elevated in people with bipolar disorder compared to normal controls, while IL-1B was not.

People with depression who had a few manic traits (mixed depression) were particularly likely to have insulin resistance and elevated levels of pro-inflammatory markers.

People with mixed depression have increases in inflammation and increased incidence of cardiovascular disorder. People experiencing a first episode of mixed depression who are overweight show increased signs of brain aging.

In studies McIntyre and colleagues analyzed, diabetes or pre-diabetes occurred in 50% of depressed patients, and these patients had the greatest amount of cognitive dysfunction.

Treatment

McIntyre noted that taking the antipsychotic drug lurasidone for bipolar depression worked best in both adults and children who had elevated levels of CRP at baseline. The fast-acting antidepressant ketamine also works well in those who show baseline inflammation .

The anti-diabetes drug liraglutide (Victoza, Saxenda) improves mixed depression symptoms and cognition in obesity, diabetes, and mixed depression. Liraglutide belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists or incretin mimetics. They work by increasing insulin release from the pancreas and decreasing excessive glucagon release.

McIntyre now routinely uses liraglutide for cognitive deficits in patients with obesity or diabetes, including patients with mixed depression. It is injected under the skin at 0.6 mg daily, then the dosage is increased to 1.2 mg and then 1.8 mg. Victoza reduces major cardiovascular events in those with type 2 diabetes. The higher-dose Saxenda (3mg) can be used for weight control.

Another anti-diabetes drug, pioglitazine, has also been reported to be helpful in bipolar depression.

McIntyre found that the antibody infliximab, which can be used as an intravenous treatment for chronic inflammation and works by blocking the effects of TNF-alpha, did not improve depression, but did improve cognition.

McIntyre also supports the use of acetyl-L-carnitine, a potential adjunctive treatment that can reverse the insulin resistance that often occurs with obesity and thus could theoretically improve cognition.

McIntyre described preliminary literature suggesting the effectiveness of drugs such as statins, calcium channel blockers, and biguanides such as the diabetes treatment metformin in reducing inflammation.

Bariatric surgery to reduce the size of the stomach was another option discussed by McIntyre. He said the intervention is safe for patients with bipolar disorder and can help them recover cognitive function.

McIntyre noted that offspring of a mother with obesity have decreased response to sensory cues, reward preference, cognitive control, and motor control. Obesity and the inflammation that goes along with it apparently affect offspring via epigenetic mechanisms, meaning obesity may change the structure of inherited DNA (without changing its sequence).

Lithium FDA-Approved for Bipolar Disorder in Children 7–17

July 19, 2019 · Posted in Current Treatments · Comment 

lithiumIn April 2019, the US Food and Drug Administration approved lithium for both the acute treatment of mania and for ongoing maintenance treatment of bipolar disorder in children and adolescents aged 7 to 17. Combined analysis of several studies indicates that lithium is effective and well-tolerated in both children and adolescents with bipolar disorder, both for acute treatment and to prevent bipolar episodes.

Eating Beef Jerky and Other Nitrate-Cured Meats Linked to Increased Mania Risk

April 10, 2019 · Posted in Risk Factors · Comment 

In a 2018 article in the journal Molecular Psychiatry, researcher Seva G. Khambadkone and colleagues reported that a history of eating nitrated dry cured meat, such as beef jerky, was associated with a more than threefold increase in the risk of current mania. Eating other types of meat and fish products was not linked to mania.

The study included 217 people with mania, 91 with bipolar depression, 79 with unipolar depression, and 371 with schizophrenia, plus 343 control participants without a psychiatric disorder. Each participant responded to a questionnaire assessing whether they had ever eaten certain foods. The researchers had the idea that eating foods such as undercooked meat or fish, which might carry infectious agents, could be connected with mania, since inflammation seems to be linked to psychiatric illness. To the researchers’ surprise, their analysis found an independent link between eating nitrated dry cured meat (such as beef jerky, turkey jerky, or meat sticks) and being admitted to a hospital with acute mania.

Having eaten other cured meats such as salami or prosciutto was not linked to mania, nor was having eaten any other food.

Following these findings, Khambadkone and colleagues designed a study in which rats were given meat with added nitrate. The rats showed hyperactivity that resembled human mania, alterations in brain pathways that have been linked to bipolar disorder, and changes to gut microbes.

Risk Gene for Bipolar Disorder Implicated in Depressed Behaviors and Abnormal Firing of GABA Neurons

February 8, 2019 · Posted in Genetics, Neurobiology · Comment 

DNA

At a 2018 scientific meeting and in a 2017 article in the journal PNAS, researcher Shanshan Zhu and colleagues reported that mice genetically engineered to lack the protein Ankyrin-G in certain neurons showed increases in depression- and mania-like behavior after being exposed to defeat stress (by repeatedly being placed in physical proximity to a larger, more aggressive mouse), which is often used to model human depression.

The researchers targeted the gene ANK3, which is responsible for the production of Ankyrin-G, and has been linked to bipolar disorder in genome-wide association studies. By manipulating the gene, they could eliminate Ankyrin-G in pyramidal neurons in the forebrain, a region relevant to many psychiatric disorders. Pyramidal neurons perform key brain functions, sending nerve pulses that lead to movement and cognition.

The missing Ankyrin-G affected sodium channels (which allow for the flow of sodium ions in and out of cells) and potassium channels. The neurochemical GABA (which typically inhibits nerve impulses) was also dysregulated, resulting in the kind of disinhibition seen in psychosis. Mice showed dramatic behavioral changes ranging from hyperactivity to depression-like behavior (e.g. giving up in a forced swimming test). The hyperactivity decreased when the mice were given treatments for human mania, lithium or valproic acid.

While mutations in the ANK3 gene may disturb sodium channels, another gene linked to depression and bipolar disorder, CACNA1C, affects calcium channels.

In a related study by researcher Rene Caballero-Florán and colleagues that was also presented at the meeting, mice were genetically engineered in such a way that interactions between Ankyrin-G and GABA Type A Receptor-Associated Protein (GABARAP) were disrupted, leading to deficits in inhibitory signaling. These deficits were partially corrected when the mice were treated with lithium.

The study by Caballero-Florán and colleagues used mice with a mutation known as W1989R in the ANK3 gene. Through a program that examines the genes of people with bipolar disorder, the researchers also identified a family with this genetic mutation, including a patient with type I bipolar disorder with recurrent mania and depression who has responded well to lithium treatment.

Specific Probiotics Reduce Re-Hospitalizations for Bipolar Disorder

June 7, 2018 · Posted in Potential Treatments · Comment 

taking pill

In a 2018 article published in the journal Bipolar Disorders, researcher Faith Dickerson and colleagues reported that in a small study of 66 people who had been hospitalized for mania, taking specific probiotic supplements upon their release reduced re-hospitalizations compared to taking placebo.

The study followed patients for 24 weeks after their hospitalization. They were randomized to receive either the combination of Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12 or placebo in addition to their regular medications. While 17 of the 33 participants in the placebo group (51.5%) had at least one re-hospitalization during the study period, only eight (24.2%) of the participants taking probiotics had a re-hospitalization. The duration of the re-hospitalizations was also shorter for those taking probiotics (2.8 days on average versus 8.3 days for those taking placebo).

In a personal communication to this editor (Robert M. Post), Chris Aiken, Instructor in Clinical Psychiatry at Wake Forest University School of Medicine, who was not involved in the study, provided some clarifying details to this editor about the use of probiotics to reduce manic relapse. Aiken explained, “Apparently, it’s important to get both the right species (e.g. Bifidobacterium lactis) and the right strain (e.g. Bb-12) in choosing a probiotic. The study mentions that one of the strains (Bb-12) is patented and only available in Europe, but it has been licensed to a few U.S. companies.

“I found two products that contain the exact strains in the study and wrote this up for patients: In [the] study [noted above], a probiotic capsule containing Bifidobacterium lactis Bb-12 and Lactobacillus rhamnosus GG lowered the risk of psychiatric hospitalization threefold. [Both] strains are available in the supplement Emergen-C and in a liquid probiotic designed for infants, Culturelle Baby Grow and Thrive. The infant serving would suffice for adults as well. You could also get the two strains by combining two separate probiotic capsules: Align Daily Immune Support and Culturelle Digestive Health Daily Priobiotic.”

Editor’s Note: We are grateful to Dr. Aiken for this added information. We also found that USANA probiotic also contains both strains used in the study. Recent research has found more and more connections between inflammatory processes and mental health. This study contributes to our understanding of the connection between gut health and the brain.

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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