Lithium May Reduce Cancer Risk

April 17, 2017 · Posted in Current Treatments · Comment 

smiling senior asian man

New research suggests that cumulative exposure to lithium may correlate with reduced cancer risk in patients with bipolar disorder. A 2016 article by Yi-Hsin Yang and colleagues in the British Journal of Psychiatry reports findings from a Taiwanese population database study of 4,729 adult patients with bipolar disorder, 115 of whom were diagnosed with cancer. Those who had been prescribed lithium (with or without anticonvulsants) had lower rates of cancer (1.96%) than those who received only anticonvulsants (2.65%).

Incidence of cancer was higher among the patients with bipolar disorder than the general population in the study. Other studies have indicated that cancer risk is higher among people with bipolar disorder than those without.

Those people who took a recommended maintenance lithium dose for 215 days or longer had a 44.8% lower risk of cancer than those who took only anticonvulsants.

Lithium May Work by Restoring Dendritic Spines

April 14, 2017 · Posted in Current Treatments, Neurobiology, Theory · Comment 
spines on a dendrite

spines on a dendrite

New research on mice clarifies lithium’s effects on neurons and suggests how it can lead to improved symptoms. Dendrites are the long projections on neurons that seem to reach out to form synapses with other neurons. The surface of these dendrites is covered in mushroom-shaped spines that help create these synaptic connections. A 2016 article by research Ben Cheyette and colleagues in the journal Molecular Psychiatry reports that in mice with a genetic mutation common to people with autism, schizophrenia, and bipolar disorder, lithium restored healthy numbers of the mushroom-shaped spines. The lithium treatment also reversed symptoms such as lack of interest in social interactions, lack of motivation, and anxiety in the mice.

Cheyette and colleagues first identified a genetic mutation that affects signaling in what is known as the brain’s Wnt pathway. The mutation, while rare, is 80% more common in people with bipolar disorder, autism, and schizophrenia than in people without these disorders.

When the mice were given a similar mutation, they exhibited symptoms such as anxiety, decreased sociability, and lack of motivation. They also had reduced numbers of dendritic spines and impaired Wnt signaling.

Lithium can improve Wnt signaling by blocking an enzyme called GSK-3 beta that impairs the signaling.

Treating the mice with lithium restored their dendritic spines and improved their behavior.

Wnt signaling and dendritic spines may offer the key to lithium’s success in treating a variety of psychiatric disorders in people.

Combo of Memantine and Sertraline Effective for Unipolar Depression

April 13, 2017 · Posted in Potential Treatments · Comment 

Content young woman lying on couch

A 2016 study in the Journal of Clinical Pharmacy and Therapeutics finds that the combination of memantine (Namenda), a drug used to treat Alzheimer’s disease, and the antidepressant sertraline (Zoloft) improved unipolar depression more than sertraline plus placebo.

The study by Meysam Amidfar and colleagues included 66 patients with moderate to severe unipolar depression. They were divided into two groups—one received sertraline plus memantine for six weeks, while the other received sertraline and a placebo.

The memantine group showed significantly greater improvement at 2 weeks, 4 weeks, and 6 weeks, and significantly greater response at 4 and 6 weeks. There were also more early improvers in the mematine group, and more rapid response to treatment. Both groups improved significantly over the six weeks of treatment.

Larger studies are needed to learn more about the safety and efficacy of memantine combined with sertraline for the treatment of unipolar depression, but this initial study is promising. In 2012, researcher Amit Anand and colleagues reported that in bipolar depression, memantine potentiates the effects of lamotrigine. Memantine also helped rapid cyclers when added to ongoing treatment in an open study of the drug treatment by Athanasios Koukopoulus and colleagues in 2012.

Immune Response to Repeated Stress Alters Behavior in Mice

April 12, 2017 · Posted in Course of Illness · Comment 

Laboratory black mouse in the hands of the experimenter

In research presented at the 2016 meeting of the Society of Biological Psychiatry, Jonathan P. Godbout described how an immune reaction to repeated stressors may lead to anxious behaviors in mice.

Mice were repeatedly defeated by a larger animal, a form of stress that produces a depression-like state. This provoked an immune response in the mice—the release of a type of white blood cells called monocytes from the bone marrow into the circulatory system. These inflammatory monocytes then traveled to the brain and spleen, attracted by signaling proteins called chemokines. The monocytes in turn produced inflammatory marker interleukin-1beta.

The defeat stress also provoked a reaction in the central nervous system, where microglia were activated.

These changes produced inflammation and anxiety-like behaviors in the mice. Blocking the microglial activation, monocyte recruitment to the brain, or interleukin-1beta signaling each reversed the anxiety-like behaviors.

Another researcher, Scott Russo, has shown that leukocytes, another type of white blood cells, secrete inflammatory interleukin-6 following defeat stress, and blocking this secretion prevents defeat stress–related behaviors.

Only Fluoxetine is More Effective Than Placebo for Children and Adolescents with Depression

April 11, 2017 · Posted in Current Treatments · Comment 

Young Latina woman showing white medication tabletIn a meta-analysis published in 2016, researchers Andrea Cipriani, Xinyu Zhou, and colleagues reported that many antidepressants are not effective in children and adolescents. Fluoxetine alone was more effective than placebo. Other antidepressants also caused high study drop-out rates compared to placebo.

In an article published in the journal The Lancet, Cipriani, Zhou, and colleagues analyzed 34 randomized, controlled clinical trials of antidepressants in children and adolescents. These trials included a total of 5,260 participants and 14 different antidepressants.

The researchers determined that much of the evidence was of a low quality. Only fluoxetine was statistically significantly more effective than placebo. Fluoxetine was also more tolerable to patients than duloxetine or imipramine. Patients who received imipramine, venlafaxine, or duloxetine were more likely to drop out of studies due to adverse events compared to patients who received placebo.

The authors suggest that prescribing antidepressants to children or adolescents may not necessarily be beneficial, and that fluoxetine is probably the best option to consider.

Editor’s Note: It may be best to use caution when prescribing antidepressants to children or adolescents. First, these data that suggest that many antidepressants are ineffective in young people. In addition, depression in children and adolescents may be a sign of bipolar disorder, and antidepressant use may cause activation or switching into mania in vulnerable patients.

While there is a warning about using antidepressants in young people because of the risk of increased suicidal ideation, the actual suicide rate in young populations decreases when these patients take antidepressants and cognitive behavioral therapy. Psychotherapy should be a high priority. Other safe adjunctive approaches might include omega-3 fatty acids, N-acetylcysteine, vitamin D3, and folic acid. Evidence for the efficacy of rTMS in young people is also positive and growing.

Inflammation Predicts Poor Response to Fluoxetine in Kids

April 10, 2017 · Posted in Current Treatments · Comment 

Nurse taking blood sample from patient at the doctors office

Inflammation upsets the balance of neurotransmitters in the brain and can make antidepressants less effective. In new research by Maya Amitai and colleagues, children and adolescents were less likely to respond to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine if they had high levels of inflammation measured in the blood.

Amitai’s study included 41 patients between the ages of 9 and 18. They met criteria for a diagnosis of either major depression or an anxiety disorder. The participants were treated with the SSRI fluoxetine for eight weeks. Those with high levels of the inflammatory markers tumor necrosis factor (TNF) alpha, interleukin-6, and interleukin 1 beta were less likely to respond to the antidepressant treatment. The research was published in the Journal of Child and Adolescent Psychopharmacology in 2016.

Editor’s Note: These findings parallel those from studies of adults, suggesting that inflammation can predict poor response to antidepressants in all age groups.

Supplement Acetyl-L-Carnitine May Treat Stress and Depression

April 7, 2017 · Posted in Potential Treatments · Comment 

stressed woman

N-acetylcysteine (NAC), an antioxidant sold in health food stores, has several beneficial effects on brain and behavior. It improves depression and can reduce cravings for cocaine, alcohol, marijuana, and nicotine, and can also help control habit-driven behaviors such as gambling, compulsive hair-pulling, and symptoms of obsessive-compulsive disorder (OCD).

New research, particularly by researcher Nascaa and colleagues in 2014 and 2016, has identified a related compound, acetyl-l-carnitine (ALC), as an anti-stressor and antidepressant in animals, and researchers have begun to explore its use in people. ALC has been found to improve mitochondrial function and improve recovery from peripheral nerve damage. ALC also inhibits the release of glutamate, which can prevent depressive behaviors following stress.

A 2004 study by P. Ruggenenti and colleagues in the journal Hypertension found that in people, 1 gm of ALC taken twice daily safely improved arterial hypertension, insulin resistance, impaired glucose tolerance, and low levels of adiponectin in the blood (a risk factor for diabetes) in subjects at increased cardiovascular risk.

In a 2014 article in the Journal of Psychiatric Research, researcher S.M. Wang and colleagues reviewed evidence that ALC improves mild depression. Two randomized clinical trials indicated that ALC was more effective than placebo for mild depression. Two other randomized clinical trials showed that ALC was as effective as the antidepressants fluoxetine and amisulpride for mild depression. The supplement was as tolerable as placebo and better tolerated than fluoxetine and amisulpride. Wang and colleagues suggested that more clinical trials are needed to confirm that ALC is effective in depression.

Editor’s Note: If further clinical trials confirm the antidepressant effects of ALC, it could represent a new way to treat chronic stress and depression and regulate insulin. Together these effects could reduce the cardiovascular risks that accompany depression.

Astrocytes Can Turn Toxic

April 6, 2017 · Posted in Neurobiology · Comment 

neurons and neuroglial cells

Astrocytes usually play a helpful role in the brain. These glial cells facilitate neural connections and prune unnecessary ones. However, new research details how infection or trauma can render astrocytes toxic, leading to brain disorders. In a 2017 article in the journal Nature, researcher Shane A. Liddelow and colleagues describe how resting astrocytes can become harmful reactive astrocytes.

The researchers determined that reactive astrocytes are found in brain tissues following brain injuries, or in neurological disorders including Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Liddelow and colleagues also determined that microglia play a role in transforming resting astrocytes into a subtype of harmful reactive astrocytes, dubbed A1 astrocytes, and that the latter secrete a neuron-killing toxin.

A1 astrocytes lose their ability to promote neuronal survival and to create new synapses. The researchers showed that blocking the formation of A1 astrocytes prevented certain neuron deaths, and they hope this finding will lead to new treatments for brain injuries and neurological disorders.

Editor’s Note: It is possible that A1 astrocytes are also induced in patients with bipolar disorder, post-traumatic stress disorder (PTSD), and schizophrenia, as well as head traumas and neurological disorders.

Mysteries Remain in the Relationship Between Inflammation and Depression

April 5, 2017 · Posted in Course of Illness, Theory · Comment 

Test tube with blood for CRP test

At the 2017 meeting of the American College of Psychiatrists, researchers Charles L. Raison and Vladimir Maletic gave a plenary lecture on the role of inflammation in depression. Meta-analyses have confirmed that inflammatory markers including Il-1, Il-6, TNF alpha, and CRP are elevated in about 1/3 of depressed patients. However, Raison and Maletic made the point that anti-inflammatory medications are not for everyone. While patients with elevated levels of CRP at baseline responded to an anti–TNF alpha antibody, patients with low CRP values at baseline actually got worse.

Raison and Maletic cited three studies that have also linked CRP to differential response to traditional antidepressants. In unipolar depression, those with low CRP respond well to selective serotonin reuptake inhibitor (SSRI) antidepressants, while those with elevated blood levels of CRP seem to respond better to a dopamine-active antidepressant such as bupropion or a noradrenergic-active antidepressant such as nortriptyline or the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant duloxetine. Patients with high inflammation at baseline also seem to respond better to intravenous ketamine and oral doses of omega-3 fatty acids.

Studies of animals have suggested that inflammation throughout the body is implicated in depression. Studies in which rodents are repeatedly defeated by larger animals show that these animals have increased inflammation from lymphocites (a type of white blood cells) in the blood, and monocytes (another type of white blood cells) from the bone marrow and spleen. This inflammation can induce depression-like behaviors in the rodents, which is prevented if the inflammatory mechanisms are blocked. These data suggest that depression is not just in the brain—inflammation from all over the body plays an important role.
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How Stress Triggers Inflammation and Depression

April 4, 2017 · Posted in Course of Illness, Neurobiology · Comment 

woman squeezing stress ballDepression and bipolar disorder are associated with increases in markers of inflammation that can be found in the brain and blood. It is increasingly clear that the mechanisms that cause depression are not just in the brain, but actually throughout the body. These include two signaling systems that begin in the bone marrow and the spleen.

When a small mouse is repeated defeated by a larger animal, they show depression-like symptoms known as defeat stress. Animal studies have shown that stress and danger signals are perceived and relayed to the amygdala and the hypothalamus. The sympathetic nervous system releases the neurotransmitter norepinephrine into bone marrow, where stem cells are turned into activated monocytes (a type of white blood cells) that are then released into the blood. The monocytes travel to the brain, leading to the activation of more inflammatory cells.

Blocking part of this process can prevent the depression-like behaviors from occurring. If the bone marrow monocytes are blocked from entering the brain, inflammation and defeat stress behaviors like social avoidance do not occur. However, if there is a second bout of defeat stress, primed monocytes that have been stored in the spleen are released and travel to the brain, producing further increases in inflammatory cells and even more defeat stress behaviors.

If these monocytes from the spleen are blocked, the inflammation and the reaction to the new stressor do not occur.

Stress also activates lymphocytes (another type of white blood cells) to secrete the inflammatory cells Il-6. If this Il-6 secretion is inhibited, defeat stress behaviors can be prevented.

Defeat stress also leads to the release of the neurotransmitter glutamate. Some of this cascade begins in the brain, which evaluates stressors and releases IL-1 beta, another type of inflammatory cell. It slows down the production of glutamate, while IL-6 can endanger neurons and is associated with anhedonia—loss of interest in pleasurable activities. This cascade also leads to the production of another type of inflammatory cell, TNF-alpha, which has adverse effects on biochemistry, brain, and behavior.
This understanding of the role of the brain and body provides new targets for drug development. If inflammatory processes are blocked, defeat stress behaviors do not occur. Researcher Michael D. Weber and colleagues described this process in detail in the journal Neuropsychopharmacology Reviews in 2017.

Together these observations suggest that inflammatory processes in the body are crucial to the development of some stress- and inflammation-related depressive behaviors.

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