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.

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).

Small Percentage of Patients Do Not Re-Respond After Stopping Lithium

July 29, 2019 · Posted in Current Treatments · Comment 

man taking a pillResearcher Ralph Kupka reviewed the literature on the small subgroup of patients who do well on long-term lithium treatment, stop taking the drug, suffer a relapse, and then fail to re-respond as well as they had (or, in some cases, at all) once they begin taking lithium again. These observations are supported by small case series, and appear to occur in approximately 10 to 15% of patients who stop taking lithium. Slowly tapering off lithium treatment did not seem to influence whether or not patients would re-respond to lithium later, while there was some indication that more time off lithium could lower the likelihood of a good re-response.

Earlier data from researcher Trisha Suppes suggested that slowly tapering off lithium treatment (over about two weeks) is superior to tapering rapidly (over a few days), and a slow taper reduced the rate of relapse. Kupka added that he would taper lithium even more slowly (over a period of one to two months) so that early signs of relapse could more readily be observed.

Optimum Lithium Levels

July 26, 2019 · Posted in Current Treatments · Comment 

doctor with teen boy

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Willem Nolen discussed optimal lithium levels to prevent episodes of bipolar disorder. Based on the limited number of controlled trials that have examined this issue and a survey of experts in the field, Nolen concluded that the standard dosing target to prevent bipolar episodes would be a blood concentration of 0.6 to 0.8 mEq/liter. This concentration could be dropped to 0.4 to 0.6 mEq/liter for patients who responded well to a higher dosage but needed to reduce side effects, and the concentration could be increased to 0.8 to 1.0 mEq/liter for patients who tolerated lithium treatment but showed an inadequate response.

There was no consensus as to optimal blood concentrations of lithium to prevent bipolar episodes in children and adolescents, but some researchers endorsed the same standard recommended for adults. For elderly patients, the majority of researchers recommended a slightly lower concentration of 0.4 to 0.6 mEq/liter, with the option to increase to a maximum of 0.8 mEq/liter in those under age 80 and 0.7 mEq/liter in those over age 80.

Lithium Reverses Some White Matter Abnormalities in Youth with Bipolar Disorder

July 23, 2019 · Posted in Brain Imaging, Current Treatments · Comment 

white matterMultiple groups of researchers have reported the presence of white matter tract abnormalities in patients with bipolar disorder. Some of these abnormalities correlate with the degree of cognitive dysfunction in these patients. These white matter tract abnormalities, which are measured with diffusion tensor imaging (DTI), are widespread and can appear as early as childhood in people with bipolar disorder. Researcher Vivian Kafantaris mentioned at the 2019 meeting of the International Society for Bipolar Disorders that lithium treatment in children and adolescents normalizes these alterations, as described in an article she and her colleagues published in the journal Bipolar Disorders in 2017.

Editor’s Note: This is another reason to consider the use of lithium in children with bipolar disorder. Lithium treatment may help normalize some of the earliest signs of neuropathology in the illness.

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.

Mounting Evidence of Mitochondrial Dysfunction in Bipolar Disorder

July 16, 2019 · Posted in Risk Factors · Comment 
mitochondrion

mitochondrion

At the 2019 meeting of the International Society for Bipolar Disorders, researchers Ana Andreazza, Olivia Dean and colleagues reviewed substantial data that implicate mitochondrial dysfunction in the mood and energy fluctuations that make up bipolar disorder. Most of the neurobiological alterations known to occur in bipolar disorder have a relationship to mitochondria, which produce energy within cells. These alterations include abnormalities in glutamate, gene expression, apoptosis (cell death), oxidative stress, low ATP (a molecule that stores energy), altered ion pumps, increased intracellular calcium, and insufficient glutathionine (an antioxidant made up of three amino acids).

Coenzyme Q10 is a mitochrondrial enhancer of Complex I, an enzyme that is key to the first step in mitochondrial energy production. A 2018 controlled study by Maryam Mehrpooya and colleagues published in the Journal of Clinical Psychopharmacology found that 200mg/day of CoQ10 was more effective than placebo at reducing symptoms of bipolar depression when added to patients’ stable treatment regimens that included mood stabilizers and antidepressants. The effect size was large (0.87), and it took eight weeks for the benefit over placebo to appear. Response rate to CoQ10 was 72% compared to 12% to placebo.

Editor’s Note: Some formulations of CoQ10 do not cross the blood-brain barrier easily, so only a very small percentage of the CoQ10 gets into the brain. Thus, consumers should be careful about the type of product they purchase. The one made by Takeda Pharmaceutical Company is likely to be effective.

Early Predictors of Suicide and Lithium as an Anti-Suicide Drug

July 11, 2019 · Posted in Current Treatments, Risk Factors · Comment 

vitamin B6At the 2019 meeting of the International Society for Bipolar Disorders, researcher Gin S. Malhi discussed early predictors of suicide in people with bipolar disorder, such as younger age of illness onset, early life stressors, and family history of suicide. Impulsivity, hopelessness, cognitive deficits and substance use are risk factors, both for suicide in general and for an imminent suicide attempt. Proximal risk factors that indicate someone may make a suicide attempt soon include: mood swings, rapid cycling, increased depression, hospitalization, and severe anxiety.

Editor’s Note: Among all psychotropic drugs, lithium has the best data supporting its anti-suicide effects, both at therapeutic doses in patients with bipolar disorder and at trace levels in the water supply in the general population. People who live in locations where more lithium is naturally present in the water supply have lower rates of suicide than those who live in places with less lithium in the water. Malhi also noted that the antioxidant N-acetylcysteine (NAC), which has positive effects on mood and habitual behaviors, can reduce the incidence of lithium-induced dysfunction of the kidneys.

Treating Bipolar Depression in an Adolescent

July 9, 2019 · Posted in Potential Treatments · Comment 

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Ben Goldstein discussed a case of a 15-year-old with bipolar depression and his recommended treatments for the adolescent. Goldstein endorsed the use of an atypical antipsychotic such as lurasidone, and perhaps also quetiapine. Goldstein noted 2015 findings from researcher Robert Findling that lamotrigine was significantly more effective than placebo in adolescents 13–18 years old, but was not effective in those aged 10–12.

(In adults, researcher John Geddes and colleagues found that in patients with an inadequate antidepressant response to quetiapine, the addition of lamotrigine was more effective than adding a placebo, both acutely and in long-term follow-up. The only caveat was that lamotrigine was less effective in those who were also being treated with folate.)

Editor’s Note: Some other treatments could augment the effects of the regimen proposed by Goldstein, including lithium and the antioxidant N-acetylcysteine, which, it should be noted, takes more than eight weeks to become effective. Vitamin D3 could also be considered, as it is often low in children with psychiatric disorders. One treatment that went unmentioned at the meeting was repeated transcranial magnetic stimulation, or rTMS, which is effective and well-tolerated in adolescents with depression.

For patients with more rapidly cycling bipolar disorder and only partial response to medications, the combination of the ‘three Ls’ (lurasidone, lamotrigine, and lithium) could have considerable appeal, given that each drug is from a different class of medications, has a different mechanism of action, targets a different mood phase, and is relatively well-tolerated both alone and in combination with other drugs.

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