Surface Area of Cortex Is Reduced After Multiple Manic Episodes

cortex

In a 2020 article in the journal Psychiatric Research: Neuroimaging, researcher Rashmin Achalia and colleagues described a study of structural magnetic resonance imaging (MRI) that compared 30 people with bipolar I disorder who had had one or several episodes of mania to healthy volunteers. Compared to the healthy volunteers, people with bipolar disorder had “significantly lower surface area in bilateral cuneus, right postcentral gyrus, and rostral middle frontal gyri; and lower cortical volume in the left middle temporal gyrus, right postcentral gyrus, and right cuneus.”

The surface area of the cortex in patients with bipolar I disorder who had had a single episode of mania resembled that of the healthy volunteers, while those who had had multiple manic episodes had less cortical surface area.

The data suggest that compared to healthy volunteers, people with bipolar disorder have major losses in brain surface area after multiple episodes that are not seen in first episode patients. In addition, the researchers found that both the number of episodes and the duration of illness was correlated with the degree of deficit in the thickness in the left superior frontal gyrus. These decreases in brain measures occurred after an average of only 5.6 years of illness.

Editor’s Note:  These data once again emphasize the importance of preventing illness recurrence from the outset, meaning after the first episode. Preventing episodes may prevent the loss of brain surface and thickness.  

Clinical data has also shown that multiple episodes are associated with personal pain and distress, dysfunction, social and economic losses, cognitive deficits, treatment resistance, and multiple medical and psychiatric comorbidities. These and other data indicate that treatment after a first episode must be more intensive, multimodal, and continuous and include expert psychopharmacological and psychosocial support, as well as family education and support. Intensive treatment like this can be life-saving. The current study also supports the mantra we have espoused: prevent episodes, protect the brain and the person.

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.

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