In Mice, Knockout of Circadian CLOCK Genes Resembles Mania

November 4, 2019 · Posted in Theory · Comment 


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.

Cannabis May Produce More Brain Changes in Teens with Bipolar Disorder than in Healthy Teens

October 31, 2019 · Posted in Risk Factors · Comment 


At the 2019 meeting of the International Society for Bipolar Disorders, researcher Benjamin Goldstein of Sunnybrook Research Institute in Toronto reported that adolescents with bipolar disorder who smoked marijuana had greater deficits in certain brain areas than did adolescents who did not have bipolar disorder. The areas affected included the dorsal lateral and rostral middle frontal cortex, and middle cortex. Goldstein concluded, “Adolescents with [bipolar disorder] may be particularly sensitive to the neurostructural effects of cannabis.”

Marijuana in general causes adverse changes in brain structure and cognition and vulnerability to paranoia and psychosis. Heavy use in adolescence is associated with an increased incidence of the onset of bipolar disorder and schizophrenia. The Goldstein data suggest several possible causal mechanisms. Those with bipolar disorder may already have brain abnormalities that are exacerbated by marijuana use. Alternatively, marijuana and bipolar disorder together may impact brain structure more than either factor alone would.

Alcohol Use Disorders That Begin Before Age 21 May Cause Lasting Changes to Amygdala

October 29, 2019 · Posted in Risk Factors · Comment 

prefrontal cortex and amygdalaIn a 2019 article in the journal Translational Psychiatry, researcher John Peyton Bohnsack and colleagues report that people with alcohol use disorders that began before they were 21 years of age show amygdala changes that people with alcohol use disorders that began after the age of 21 do not appear to have.

The amygdalas of those who began abusing alcohol in adolescence showed greater expression of the long non-coding RNA known as BDNF-AS. The increased BDNF-AS was associated with decreased levels of brain-derived neurotrophic factor (BDNF) in the amygdala. BDNF protects neurons and is important for learning and memory.

According to Bohnsack and colleagues, “Adolescence is a critical period in brain development and adolescent drinking decreases orbitofrontal cortex activity and increases amygdala activity leading to less executive control, more emotional impulsivity, alterations in decision-making, and [a higher risk of engaging] in risky behaviors and develop[ing] mental health problems later in life.”

Psychiatric Risks in Offspring of Parents with Bipolar/Unipolar Disorders

October 25, 2019 · Posted in Risk Factors · Comment 

familyAt the 2019 meeting of the International Society for Bipolar Disorders, researcher Martin Preisig and colleagues from Lausanne, Switzerland reported on a longitudinal study of mood disorders in offspring of parents with bipolar disorder, unipolar depression, or no history of psychiatric illness. The study included 446 children (with an average age of 10.1 years at the beginning of the study), who participated for an average of 11.9 years.

Preisig and colleagues determined symptoms and other factors that preceded psychiatric illness. They found that bipolar disorder in the offspring was preceded by sub-threshold hypomania, major depression, and conduct disorder. Bipolar disorder in the offspring was also predicted by parental early-onset bipolar disorder.

Major depression was preceded by separation anxiety disorder, and witnessing violence or being a victim of sexual abuse.

Preisig and colleagues concluded that not only did bipolar disorder and major depressive disorder have different familial origins, they also had different antecedents and risk factors.

Inflammation Predicts Lower Frontal and Temporal White Matter Volumes in Early-Stage Bipolar Disorder

October 23, 2019 · Posted in Neurochemistry · Comment 

At the 2019 meeting of the International Society for Bipolar Disorders, researcher David Bond found that seven inflammatory cytokines predicted lower white matter volumes in the left frontal and bilateral temporal lobes, as well as in the cingulate and inferior frontal gyri. Cytokines are secreted by some immune cells and send signals that can produce an effect in other cells.

Bond noted that greater inflammation did not predict lower parietal or occipital white matter volumes, suggesting that inflammation had a greater effect on white matter volume in those parts of the brain most closely linked to mood disorders.

Comorbid Psychiatric Disorders Impair Response to Psychosocial Treatment in Adolescents with Bipolar Disorder

October 21, 2019 · Posted in Comorbidities · Comment 


At the 2019 meeting of the International Society for Bipolar Disorders, researcher Marc J. Weintraub and colleagues followed 145 adolescents with bipolar disorder over a period of two years. The adolescents with comorbid disorders (compared to those with bipolar disorder alone) fared more poorly in response to psychosocial treatment.

Weintraub and colleagues found that the adolescents who had anxiety disorders in addition to their bipolar disorder spent more weeks depressed, had more severe symptoms of (hypo)mania, and had more family conflict over the course of the study than those adolescents who had bipolar disorder alone.

Participants who had attention deficit hyperactivity disorder (ADHD) in addition to their bipolar disorder had more weeks with (hypo)manic symptoms, had more severe (hypo)manic symptoms, and greater family conflict than those with bipolar disorder alone.

Those participants with comorbid oppositional defiant disorder (ODD) or conflict disorder in addition to their bipolar disorder had more depressive symptoms and family conflict throughout the study.

Editor’s Note: How to better approach treatment in these diagnostically complex young people is an urgent unmet need, as most research excludes participants with more than one psychiatric disorder. Clinicians treating young people with bipolar disorder and comorbidities such as anxiety disorder, ADHD, and ODD must generally rely on inferences from children with these illnesses, using their own intuition about best treatment approaches rather than having evidence from systematic studies about how best to treat these children. It appears that both psychosocial and pharmacological treatments must be tailored to these more complicated presentations.

More Than 70% of People with Bipolar Disorder Have Additional Psychiatric Illness

October 17, 2019 · Posted in Comorbidities · Comment 

depressed man

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Kathleen R. Merikangas reviewed large scale community studies of people with bipolar disorder in multiple countries. She reported that more than 70% of people with bipolar disorder have three or more lifetime disorders, not just bipolar disorder.

Preliminary findings suggested that adolescents with bipolar disorder did not tend to have other disorders in addition to their bipolar disorder, but as they approached young adulthood these became more common. Merikangas concluded, “These findings suggest that early intervention may prevent the secondary comorbidity that is related to greater impairment, worse course and poorer treatment response in bipolar disorder.”

Editor’s Note: It is a major deficit that not only is there limited data on early intervention in general, but virtually none about early intervention in the face of multiple comorbidities. This lack of treatment knowledge means that the majority of people with bipolar disorder are facing challenges that could be mitigated if only the needed clinical treatment research were done.

Inflammation Associated with Cognitive Deficits

October 15, 2019 · Posted in Risk Factors · Comment 

woman thinking

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Katherine E. Burdick and colleagues at Brigham and Women’s Hospital and Harvard Medical School reported that in 240 patients with bipolar disorder who were not currently having a manic or depressive episode, markers of inflammation were associated with cognitive deficits.

Inflammation was associated with cognitive deficits in general, and there were also some relationships between specific inflammatory markers and types of cognitive processing. They found that the inflammatory markers TNF-alpha, TNFR1, and TNFR2 influenced cognitive flexibility. The inflammatory marker VEGF influenced reward processing, while IL-6/IL-6r influenced spatial processing. IL-1beta and IL-1RA influenced social cognition.

Burdick and colleagues found it was important to include both primary and secondary mediators of inflammation in their research “as the effects of the primary pro-inflammatory cytokines can be blocked by a number of decoy receptors and soluble antagonists.” Elevations in these can provide additional information about the function of the immune system.

Editor’s Note: Targeting inflammation with the anti-inflammatory treatments minocycline and celecoxib has been shown to improve depression. Now the role of anti-inflammatory drugs in improving cognition deserves further attention.

Infliximab Helps the Subgroup of Bipolar Depressed Patients Who Faced Adversity in Childhood

October 11, 2019 · Posted in Potential Treatments · Comment 

child with bruised face

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Mike Cosgrove and colleagues described a study of the immune-suppressing drug infliximab in adults with bipolar disorder. The researchers found persistent significant improvements on infliximab only in those with bipolar disorder who also had a history of childhood adversity. Childhood adversity is consistently associated with elevated levels of inflammatory cytokines, and baseline inflammation may be a prerequisite for a positive effect from infliximab, which works by blocking the inflammatory cytokine TNF alpha.

Lithium Reverses Thinning of the Cortex That Occurs in Bipolar Disorder

October 9, 2019 · Posted in Brain Imaging · Comment 

gray matter

In a 2018 article in the journal Molecular Psychiatry, researcher Derrek P. Hibar reported findings from the largest study to date of cortical gray matter thickness. Researchers in the ENIGMA Bipolar Disorder Working Group, which comprises 28 international research groups, contributed brain magnetic resonance imaging (MRI) from 1837 adults with bipolar disorder and 2582 healthy control participants.

Hibar and colleagues in the working group found that in adults with bipolar disorder, cortical gray matter was thinner in the frontal, temporal, and parietal regions of both brain hemispheres. They also found that bipolar disorder had the strongest effect on three regions in the left hemisphere: the pars opercularis, the fusiform gyrus, and the rostral middle frontal cortex.

Those who had had bipolar disorder longer (after accounting for age at the time of the MRI) had less cortical thickness in the frontal, medial parietal, and occipital regions.

A history of psychosis was associated with reduced surface area.

The researchers reported the effects of various drug treatment types on cortical thickness and surface area. In adults and adolescents, lithium was associated with improvements in cortical thickness, and the researchers hypothesized that lithium’s protective effect on gray matter was responsible for this finding. Antipsychotics were associated with decreased cortical thickness.

In people taking anticonvulsant treatments, the thinnest parts of the cortex were the areas responsibly for visual processing. Visual deficits are sometimes reported in people taking anticonvulsive treatments.

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