Inflammation Associated With Duration of Untreated Unipolar Depression

February 14, 2019 · Posted in Brain Imaging, Course of Illness, Neurobiology · Comment 

depressed woman

Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.

Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.

Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.

Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.

This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.

Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.

In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017.  The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.

Family History of Lithium Response A Potent Predictor of Lithium Effectiveness

February 11, 2019 · Posted in Current Treatments · Comment 

family

Researcher Martin Alda and colleagues reported at a 2018 scientific meeting that a family history of good response to lithium is highly predictive of response to lithium in a current bipolar patient. A good prospective response to lithium was seen in 68.6% of patients with a family member who responded well to lithium. Only 22% of those without a family member with a positive lithium response responded well to lithium.

Editor’s Note: Other predictors of a good response to lithium include: a family history of mood disorder, classical euphoric mania with clear-cut well intervals between episodes, lack of a simultaneous anxiety or substance abuse disorder, starting lithium early rather than late in the course of illness after many episodes or rapid cycling has occurred, and a sequential pattern of episodes of mania followed by depression, and then an interval of wellness (i.e. M-D-I rather than D-M-I). Even in those without these characteristics, lithium has many benefits including neuroprotection, reduction of suicide risk, and improved medical health (perhaps through its ability to increase the length of telomeres which are bits of DNA at the end of each chromosome). Longer telomeres are protective, while people with shorter ones may be vulnerable to some medical and psychiatric illnesses.

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.

Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments

February 5, 2019 · Posted in Current Treatments · Comment 
CRP

C-reactive protein (CRP)

C-reactive protein, or CRP, is a marker or inflammation that has been linked to depression and other illnesses. People with high levels of CRP respond differently to medications than people with lower CRP, so assessing CRP levels may help determine which medications are best to treat a given patient.

High baseline levels of CRP (3–5pg/ml) predict a poor response to selective serotonin reuptake inhibitor antidepressants (SSRIs) and to psychotherapy, and are associated with increased risk of recurrent depression, heart attack, and stroke.

However, high baseline CRP predicts a better response to the antidepressants nortriptyline and bupropion. High CRP is also associated with better antidepressant response to infliximab (a monoclonal antibody that inhibits the inflammatory cytokine TNF alpha), while low levels of CRP predict worsening depression upon taking infliximab.

High baseline CRP also predicts good antidepressant response to intravenous ketamine (which works rapidly to improve treatment-resistant depression), minocycline (an anti-inflammatory antibiotic that decreases microglial activation), L-methylfolate (a supplement that can treat folate deficiency), N-acetylcysteine (an antioxidant that can improve depression, pathological habits, and addictions), and omega-3 fatty acids (except in people with low levels of DHA).

High baseline CRP also predicts a good response to the antipsychotic drug lurasidone (marketed under the trade name Latuda) in bipolar depression. In people with high baseline CRP, lurasidone’s positive results have a huge effect size of 0.85, while in people with low CRP (<3pg/ml) the improvement on lurasidone has a smaller effect size (0.35).

In personal communications with this editor (Robert M. Post) in 2018, experts in the field (Charles L. Raison and Vladimir Maletic) agreed that assessing baseline CRP levels in a given patient could help determine optimal strategies to treat their depression and predict the patient’s responsiveness to different treatment approaches.

At a 2018 scientific meeting, researchers Cynthia Shannon, Thomas Weickert, and colleagues reported that high baseline levels of CRP were associated with symptom improvement in patients with schizophrenia when they were treated with the drug canakinumab (marketed under the trade name Ilaris). Canakinumab is a human monoclonal antibody that targets the inflammatory cytokine interleukin-1 beta (Il-1b). Il-1b is elevated in a subgroup of patients with depression, bipolar disorder, or schizophrenia, and CRP levels are an indication of the associated inflammation.

Lithium Superior to Other Mood Stabilizers in a Longitudinal Study of Bipolar Youth

February 1, 2019 · Posted in Current Treatments · Comment 

teenagers

At a late-2018 scientific meeting, researcher Danella Hafeman and colleagues reported some results of the Course and Outcome of Bipolar Youth (COBY) study. The study includes long-term follow up of 413 youth with bipolar disorder, who ranged in age from 7 to 17 years old. Hafeman and colleagues reported that taking lithium more than 75% of the time was linked to fewer suicide attempts, fewer depressive symptoms, and fewer psychosocial difficulties than taking another mood stabilizer (such as an atypical antipsychotic, lamotrigine, or valproic acid) more than 75% of the time after adjusting for demographic variables.

Despite the limitations of observational studies such as this one, the authors concluded, “Our findings are consistent with studies in adult populations, showing that lithium (compared to other mood stabilizers) is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youth with [bipolar disorder].”

Editor’s Note: These observations are consistent with several other studies. Researcher Barbara Geller and colleagues observed in eight years of follow up of children diagnosed with bipolar disorder that those who were treated with lithium spent more time in remission than those who took other medicines. A randomized controlled study by researcher Robert Findling and colleagues documented that maintenance lithium treatment was more effective than placebo at preventing bipolar episodes. Together, these data suggest that lithium should be used more often in the long-term treatment of children with bipolar disorder.

Way ahead of his time in about 1993, the renowned child psychiatrist Dennis Cantwell said something like this: “If I had an adolescent child with a first manic episode, I would have him stay on lithium for the rest of his life.” He seems to have been prescient, as evidence of the many benefits of lithium over other alternatives in the treatment of both children and adults has been accumulating.

An open-access review article this editor (Robert M. Post) published in the journal Neuropsychopharmacology in 2017, “The New News about Lithium: An Underutilized Treatment in the United States,” argues that lithium’s many benefits have been underestimated, while its side effects have been overestimated. It is my view that it would be beneficial if lithium were more often included in the treatment regimen of adults as well as children and adolescents with bipolar disorder.

Lithium has an astounding range of effectiveness. It prevents recurrent depressions and suicide (even in those with unipolar depression), increases hippocampal and cortical volume, protects memory, and increases the length of telomeres (the end portions of chromosomes that protect them as they replicate). In multiple animal models of neurological diseases, it has also been found to be neuroprotective and to reduce the size of brain lesions.

Nimodipine Decreases Frontal and Parietal Cortical Activity During Working Memory in Healthy Subjects

January 30, 2019 · Posted in Genetics, Potential Treatments · Comment 

brain

At a recent scientific meeting, researcher Kristin Bigos and colleagues described the effects of nimodipine, a treatment for brain hemorrhage, on the brain during working memory tasks. Nimodipine is a dihydropyridine L-type calcium channel blocker. Calcium channel blockers prevent calcium from entering cells in the heart and blood vessel walls, and they are often used to treat high blood pressure.

Nimodipine acts on the CACNA1C calcium influx gene. Certain genetic variations in this gene (particularly the rs1006737 A allele) have been linked to vulnerability to bipolar disorder, schizophrenia, depression, and autism. Carriers of the risk allele also have higher CACNA1C mRNA expression in the dorsolateral prefrontal cortex and exhibit more activity in the frontal and parietal regions of the brain during working memory tasks, suggesting inefficient brain processing in these regions. Bigos and colleagues found that 60mg/day of nimodipine decreased frontal and parietal cortical activity by 39.1% and 42.8%, respectively, during a working memory task, suggesting that nimodipine improved the efficiency of memory processing. Nimodipine’s positive effects were greater in those participants who had the CACNA1C risk allele.

Editor’s Note:  Using a placebo-controlled off-on-off-on study design (meaning patients took placebo for a period, then nimodipine, then placebo again and nimodipine again), this editor (Robert M. Post), Peggy J. Pazzaglia and colleagues found that nimodipine had positive effects in both mania and depression in patients with bipolar disorder (described in the 2008 book Treatment of Bipolar Disorder: A Casebook for Clinicians and Patients by Robert M. Post and Gabriele S. Leverich). In a large randomized study of patients with bipolar disorder presented by Haroon R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry, lithium was associated with about a 50% response rate while the combination of lithium and nimodipine was associated with a 73% response rate.

It remains to be seen whether people with bipolar disorder who have the CACNA1C risk gene would respond better to nimodipine than those without the risk gene, and whether it would improve working memory more in the subgroup with the risk gene.

Ketamine May Enhance the Effects of Cognitive Training Therapy

January 28, 2019 · Posted in Potential Treatments · Comment 
group therapy

Woman receiving cognitive training

Rebecca B. Price, a professor of Psychiatry and Psychology at the University of Pittsburgh, and colleagues reported at a recent scientific meeting that the combination of intravenous ketamine treatment and four days of cognitive training to enhance positive self-representations improved depression better than either intervention alone (IV ketamine plus a sham training or a non-medicated saline drip plus 4 days of cognitive work).

Price and colleagues suggested that priming brain plasticity with ketamine could enhance cognitive training focused on increasing positive self-representations. Psychologists have theorized that self-representations (or assessments of one’s strengths and other qualities) can be a resource that helps people cope with life stress.

Il-6 Inhibitor Sirukumab May Improve Anhedonia, But Not General Depression

January 25, 2019 · Posted in Potential Treatments · Comment 

cyclingAt a 2018 scientific meeting, researcher Giacomo Salvadore and colleagues reported that the drug sirukumab, a monoclonal antibody that targets the inflammatory marker Il-6 and that was originally developed to treat rheumatoid arthritis, did not have a statistically significant effect on overall depression compared to placebo. However, by the twelfth week of treatment, sirukumab did have a significant effect on anhedonia (loss of interest or pleasure in activities that one previously enjoyed).

The degree of improvement in anhedonia was significantly correlated with patients’ baseline levels of the inflammatory marker CRP. Since the inflammatory marker that sirukumab targets, Il-6, is one of those most often elevated in depression, it appears that more study of sirukumab would be warranted.

Low Levels of Acetyl-L-Carnitine Associated with Insulin Resistance in Traumatized Children

January 22, 2019 · Posted in Risk Factors · Comment 

childhood traumaResearcher Carla Nasca and colleagues from the Rockefeller University reported at a late-2018 scientific meeting that depressed patients with a history of childhood adversity had low levels of the amino acid acetyl-L-carnitine and also exhibited insulin resistance. This is noteworthy because in a series of small studies, acetyl-L-carnitine supplements have had antidepressant effects. In laboratory animals, acetyl-L-carnitine also sensitizes insulin receptors. This suggests the possibility that the supplements could provide a two-for-one benefit in depressed patients with a history of adversity in childhood.

Inflammation Linked to Poor Sleep Quality and Worse Executive Functioning

January 18, 2019 · Posted in Risk Factors · Comment 

man drooling while sleeping

At a recent scientific meeting, researcher Ellen E. Lee and colleagues reported that compared to healthy volunteers, people with bipolar disorder or schizophrenia had elevated levels of inflammatory markers, which were associated with poor sleep. 

According to self-reports, people in the schizophrenia and bipolar disorder group had worse sleep quality than the control group. Those with schizophrenia or bipolar disorder also had significantly higher levels of the inflammatory markers CRP, IL-6, and TNF alpha compared to the healthy volunteers. Among people with bipolar disorder, executive functioning and sleep quality had a strong inverse association to levels of IL-6, such that lower sleep quality and worse executive functioning were associated with higher levels of IL-6. These findings suggest that sleep disturbance and inflammation may have negative consequences for cognitive functioning.

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