BDNF Is Decreased in Depression and Mania

July 17, 2013 · Posted in Risk Factors · Comment 
lymphocyte

lymphocyte

Brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory, can be measured in blood. In a symposium on bipolar disorder at the 2012 meeting of the Society of Biological Psychiatry, researcher Flavio Kapsczinski reviewed evidence from several meta-analyses showing that low levels of BDNF in the blood correlate with severity of an episode of depression or mania. In addition to the findings that BDNF levels are low during a mood episode, there are other reliable biomarkers of illness, including increases in intracellular calcium, increases in cortisol and failure to suppress cortisol by dexamethasone, and a variety of indices of inflammation and oxidative stress.

There are several common variants of the gene responsible for the production of BDNF, depending on which types of amino acids appear in its coding—valine or methionine. The Val66Val allele of proBDNF is the most frequently occurring in the population, and is the best-functioning variant. Those with a methionine substitution (Val66Met or Met66Met) have less efficient forms of BDNF. Researcher Jair Soares reported that the Met allele was associated with deficits in declarative memory in patients with bipolar disorder, and was also associated with smaller volume of the anterior cingulate gyrus.

Researcher Ghanshyam N. Pandey reported that patients with pediatric or adult bipolar disorder had decreased BDNF protein and mRNA levels in platelets and lymphocytes compared to controls.  Treatment significantly increased these BDNF levels in the pediatric, but not in the adult bipolar subjects. These measurements in blood are consistent with findings that there are decreases in BDNF in the hippocampus and prefrontal cortex of patients who died while depressed or who committed suicide compared to controls.

CRP in Blood Predicts Onset of New Episode in Childhood Mood Disorders

July 16, 2013 · Posted in Diagnosis, Risk Factors · Comment 
C-reactive protein

C-reactive protein

At the 2013 meeting of the International Society for Bipolar Disorders, researcher Barbara Gracious presented evidence that increased levels of high sensitivity c-reactive protein (hsCRP), a marker of inflammation, were associated with an increased risk for developing a full-blown mood episode in 71 youth (average age 13.8) participating in a study called Longitudinal Assessment of Manic Symptoms (LAMS-2).  The children were selected for the study because they had manic symptoms that were not severe enough to meet criteria for a diagnosis of bipolar I or II disorder. This research has not yet been published in a peer-reviewed journal, but the abstract can be found in first 2013 supplement of the journal Bipolar Disorders (page 67).

CRP levels are also known to predict cardiovascular disease and Type II diabetes.

Levels of 25-OH vitamin D, TNF?, and IL-6 did not predict a later mood disorder.

Editor’s Note: These data suggest the importance of assessing CRP and other markers in youth who are either prodromal (having early symptoms of a mood disorder) or at high risk because of a family history of a mood disorder.

The next step for clinical research would be to determine what treatment might decrease CRP and whether it would also prevent the development of mood episodes.

Inflammatory Markers May Predict Antidepressant Response

July 15, 2013 · Posted in Current Treatments, Risk Factors · Comment 

depressed woman

There appears to be a link between inflammation and depression. In the journal Neuropsychopharmacology, Cattanes et al. reported in 2013 that compared to controls, depressed patients had significantly higher baseline levels of inflammatory cytokines, less glucocorticoid receptor function, less neuroplasticity, and fewer neuroprotective factors. Certain variables predicted response to treatment, others were seen only in responders, and still others changed in everyone with antidepressant treatment.

Higher baseline levels of inflammatory markers interleukin IB, macrophage inhibitory factor (MIF), and tumor necrosis factor TNF? were each associated with nonresponse to antidepressant treatment, and the three combined accounted for 50% of the variance in response­—that is, they were the major predictor of whether a patient responded to treatment.

Levels of other factors changed in only those patients who responded well to antidepressants. The biggest changes were the normalization in levels of the neurotrophic factors BDNF and VEGF.

Several other markers normalized with antidepressant treatment regardless of whether the patients responded to treatment, and these included decreases in cytokines interleukin-IB and MIF and improved glucocorticoid receptor function.

The three different kinds of findings about these biomarkers were observed regardless of what type of antidepressant was used—SSRI versus tricyclic nortriptyline (which blocks norepinephrine reuptake).

Editor’s Note: This study replicates other studies in depression where signs of inflammation have been observed, including increases in inflammatory cytokines, decreases in glucocorticoid receptor function (needed to suppress high levels of the stress hormone cortisol) and lower levels of neuroplasticity and neuroprotection markers. This, however, is one of the first studies to show that levels of these markers at baseline may predict response to antidepressant treatment.

Also novel are the findings that while some high interleukin levels at baseline predicted antidepressant non-response, other ones normalized only in responders, and still others changed with treatment independent of whether the patients’ depression improved. These exciting findings require replication, but suggest the future possibility of personalized medicine, that is, choosing medications based on an individual biochemical marker profile. Eventually direct use of anti-inflammatory agents may be necessary in those with the highest levels of cytokines (predicting non-response to conventional antidepressant treatment). The same types of studies are needed in bipolar depression to determine the relationship between these inflammatory markers and treatment response.

Proven Treatments for Fibromyalgia and Chronic Fatigue Syndrome

July 12, 2013 · Posted in Current Treatments · Comment 

women running together

At the 2012 meeting of the Collegium Internationale Neuro-Psychopharmacologicum (CINP), a symposium was held to discuss fibromyalgia and chronic fatigue syndrome, two illnesses that remain mysterious.

Fibromyalgia

Fibromyalgia is more common in women than in men and is characterized by aching all over, decreased sleep, stiffness upon waking, and most prominently, being tired all day, as well as a host of other symptoms including headache, dizziness, and gastrointestinal upset. Researcher Siegried Kasper suggested that treating fibromyalgia requires more than just medication. His approach is known as MESS, which stands for medication, exercise, sleep management, and stress management.

Medications to treat the illness include milnacipran (not available in the US), duloxetine (Cymbalta, a serotonin-norepinephrine reuptake inhibitor or SNRI), or pregabalin (Lyrica), and if tolerated, low doses of the tricyclic amitriptyline (Elavil).

According to Kasper, SSRIs and anti-inflammatory drugs don’t work, and benzodiazepines decrease the deepest phase of sleep (stage 4) and can exacerbate the syndrome.

Recommended exercise is moderate, graded (to a pulse of about 120, or at a level where the patient can still talk, but can’t sing), and should be done in the early morning rather than the late afternoon where it might interfere with sleep.

Good sleep hygiene is recommended, such as keeping the same sleep schedule every day and abstaining from caffeine (even in the morning).

Working on developing active coping strategies for stressors that are likely to occur is a good idea. Mindfulness and other meditative techniques may also be helpful. Joining a support group (that encourages exercise rather than discouraging it) was also recommended.

Chronic Fatigue Syndrome

At the CINP meeting researcher Simon Wessely discussed chronic fatigue syndrome (CFS), which has many overlaps with fibromyalgia. He reported that careful controlled study of more than 15,000 individuals has not indicated that the illness is associated with a viral infection. Just as many people with and without chronic fatigue syndrome were found to be infected with a virus.

However, like the myth that vaccines cause autism, the myth that chronic fatigue is associated with a virus remains popular despite the lack of evidence. A large randomized study validated Wessely’s treatment techniques, but he has continued to be vilified for the position that the illness is not virally based. The study showed that patients who participated in cognitive behavior therapy and graded exercise improved more than those who received conventional medical management.

Wessely thought the most important cognitive change to make was accepting that exercise is not harmful for patients with chronic fatigue syndrome, and is in fact helpful and therapeutic. Many older treatment approaches had advocated rest, rest, and more rest, or even “intensive rest.” However, Wessely indicated that this would be counter-productive, as the patient would lose muscle mass and cardiovascular conditioning, and would become even more tired and chronically fatigued.

Inflammation and Anti-Inflammatories in Depression

July 10, 2013 · Posted in Potential Treatments · Comment 

depressed woman

Depression is often associated with increases in markers of inflammation in blood, which include IL-1, IL-6, TNF-alpha, and CRP. Risk factors for increased inflammation include stress, obesity, a diet high in omega-6 fatty acids, sedentary lifestyle, social isolation, low socio-economic status, smoking, and being female. Treatments such as lithium, other mood stabilizers, and antidepressants can all have anti-inflammatory effects.

At the International Congress of Neuropsychopharmacology in 2012, researcher Michael Berk reviewed data on inflammation in depression. Berk shared prospective data that in the general population, people whose levels of CRP fall within the highest third have the highest risk for a new onset of depression over the next 9 years, while those with CRP values in the lowest third (indicating low inflammation) had the least likelihood of becoming depressed.

Drugs with more direct anti-inflammatory properties are beginning to be studied in unipolar depression with some success. In a trial by Abbasi et al. published in the Journal of Affective Disorders in 2012, the anti-inflammatory COX-2 inhibitor celecoxib (Celebrex) when added to the selective serotonin reuptake inhibit (SSRI) sertraline (Zoloft) had better antidepressant effects than the addition of placebo.

Sepaujnia et al. reported in Neuropsychopharmacology in 2012 that an anti-diabetes drug that also has anti-inflammatory properties, pioglitazone (Actos), also beat placebo in depression.

Laan et al. reported in the Journal of Clinical Psychiatry that the same was true of acetylsalicylic acid (ASA or aspirin).

Finally, Berk summarized data that the class of cholesterol-lowering drugs called statins are also able to decrease CRP and improve or prevent depression. Epidemiological data by Pasco et al. published in Psychotherapy and Psychosomatics showed that subjects without depression were less likely to develop a new onset of depression if they were treated with statins compared to those who were not. Stafford et al. reported in the Journal of Clinical Psychiatry in 2010 that patients taking statins had a 79% decreased likelihood of depression at 9 months of follow-up. A third study in Sweden showed that simvastatin, a lipophilic (fat-soluble) drug that can readily enter the brain, decreases the incidence of depression more than some of the non-lipophilic statins.

Moreover, a meta-analysis by O’Neil et al. reported that overall, statins had positive effects on mood.

Editor’s Note: All these data come from studies of unipolar depression, so one must consider how relevant they are to bipolar depression. They may be pertinent, since elevated inflammatory markers have consistently been reported in bipolar depression. However, this cannot be assumed until appropriate studies are performed. (As usual, research in bipolar depression lags far behind that in unipolar depression.)

Preliminary uncontrolled retrospective data from one study did suggest that those treated with lithium plus aspirin did better than those on lithium and no anti-inflammatory.

Thus it may make sense for unipolar and bipolar depressed patients with risk factors for heart disease such as a positive family history of heart disease and elevated cholesterol and triglycerides to discuss with their doctors the possibility of starting statin treatment earlier rather than later. This is because depression itself is a major risk factor for heart disease, so statins might lower risk both by their approved indication of lowering cholesterol and by their apparent ability to help fend off new episodes of depression.

A more complicated issue would be the question of when, if at all, to use primary anti-inflammatory drugs in the adjunctive treatment of unipolar or bipolar depression. Read more

One Doctor’s Protocol for the Treatment of Severe PTSD

July 8, 2013 · Posted in Comorbidities, Potential Treatments · Comment 

PTSDNote: The following article discusses “off-label” treatments for the treatment of PTSD or traumatic brain injury, i.e. those which are not FDA-approved for these purposes. In some of these instances, there is no controlled research to support the use of these drugs in patients with PTSD. Thus the ideas noted here cannot be taken as anything more than anecdotal information from personal experience. Patients and physicians must make their own decisions about any of the strategies reported in this or other issues of BNN.

At a recent scientific conference, Vaishali P. Bakshi, a renowned Canadian psychopharmacologist, shared a novel treatment strategy he has developed for patients with exceptionally profound degrees of post-traumatic stress disorder (PTSD), which, particularly among military veterans, can be compounded by traumatic brain injury.

Treatment options based on placebo-controlled clinical trials are sometimes insufficient for the treatment of seriously ill patients. FDA-approved treatment for PTSD consists of serotonin-selective antidepressants, while exposure therapies (in which the patient is gradually exposed to more of the stimuli that triggered symptoms) are the recommended psychotherapy, but these methods often leave patients highly disabled.

Bakshi’s typical treatment algorithm goes well beyond these treatment guidelines to find solutions for hard-to-treat patients. He first addresses sleep disturbance, which often occurs in PTSD. He suggests the anticonvulsant levetiracetam (Keppra), starting at doses of 150mg per night and increasing to 500–1000mg as tolerated. This highly sedating anticonvulsant not only improves sleep but may also help cognition, since it is structurally similar to other cognitive enhancers such as piracetam. Levetiracetam also decreases the hippocampal hyperactivity associated with some forms of cognitive dysfunction, as we’ve noted before. In order to further enhance sleep effects, Bakshi adds trazodone at 50­–150mg per night as needed.

Instead of selective serotonin reuptake inhibitors (SSRIs), Bakshi recommends the selective serotonin and norepinephrine reuptake inhibitors (SNRIs). Among these, he prefers desvenlafaxine (Pristiq) over venlafaxine, as desvenlafaxine has fewer interactions with other drugs. Theoretically, duloxetine (Cymbalta) is another SNRI that could be used.

Another component of Bakshi’s treatment plan is topiramate (Topamax), which can target many comorbidities of PTSD, including alcohol and substance abuse, particularly stimulant abuse. In addition, topiramate has efficacy in anger attacks, which often accompany PTSD.

In patients with ongoing problems with depression and/or cognition, Bakshi adds bupropion (Wellbutrin). Read more

Prazosin Treats PTSD Nightmares

July 5, 2013 · Posted in Comorbidities, Current Treatments · Comment 

screaming man

Patients with PTSD often struggle with nightmares, but a treatment normally used for high blood pressure may also be able to prevent these sometimes horrific dreams. In a study that marks the third replication of this finding, Murray Raskind, a researcher from the University of Seattle, reported that prazosin was significantly better than placebo at selectively blocking nightmares in 77 Iraq war veterans with PTSD in a 15-week trial. (Interestingly, normal dreaming is uninterrupted.)

Editor’s Note: Prazosin is a noradrenergic alpha-1 receptor antagonist. Doses of this drug must be titrated upward slowly over a period of 6 weeks to avoid orthostatic hypotension (a sudden fall in blood pressure that occurs when a person stands up). Maximum doses achieved in this study were 5mg mid-morning and 20mg at night (although 10mg at night is often effective). This treatment, although not FDA-approved, is increasingly being used in veteran populations and other patients with PTSD.

Immune Mechanisms Are Important to the Emergence of Defeat Stress–Induced Depressive Behaviors

July 3, 2013 · Posted in Risk Factors · Comment 

Lab mouse

At a recent scientific meeting, researcher Georgia E. Hodes presented evidence that in mice, the immune system may play a role in behaviors that resemble human depression. Repeated social defeat stress (when an intruder mouse is threatened by a larger mouse defending its territory) is often used as a model to study human depression. Animals repeatedly exposed to social defeat stress start to exhibit social avoidance and lose interest in sucrose. Hodes et al. determined that interleukin 6 (IL-6), an inflammatory cytokine, or signaling molecule, secreted into the blood was crucial to these behaviors. When the researchers injected mice with antibodies that block the effects of IL-6, or when they irradiated the mice’s peripheral immune system to prevent the formation of IL-6, the depressive behaviors did not emerge following defeat stress.

Editor’s Note:  There are increasing data that immunological and inflammatory mechanisms play a role in human affective disorders, and these preliminary data raise the possibility that blocking some immune mechanisms more directly in humans could be a novel therapeutic approach to explore in the future.

In Veterans, PTSD Is Associated With Autoimmune Illnesses

July 2, 2013 · Posted in Comorbidities, Risk Factors · Comment 

US soldier

At a recent scientific meeting, Thomas Neylan and colleagues reported that post-traumatic stress disorder (PTSD) may be connected to autoimmune illnesses. In this study, 673,277 veterans of the US military who had served in Iraq and Afghanistan were screened for the development of PTSD. The illness was diagnosed in 31% of the veterans, and those individuals had a higher incidence of autoimmune-related disorders including thyroiditis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus. Neylan’s research group specifically examined those whose disorders developed after the onset of the PTSD, and found that the statistical relationship between their illnesses and PTSD was strong. However, the researchers also found that there was evidence of a similarly strong relationship in the other direction: veterans who were first diagnosed with some of these same autoimmune difficulties also went on to develop PTSD.

Many previous clinical and preclinical studies have linked altered immune and autoimmune mechanisms to severe stressors such as those that are involved in PTSD. This is the first study to unequivocally demonstrate the relationship in an extraordinarily large number of patients.

Editor’s Note:  These findings resemble those that suggest that among the general population, childhood adversity is associated with an increased incidence of a variety of medical disorders in adulthood. Similarly, in the Bipolar Collaborative Network in which this editor (Post) is an investigator, we found that a history of childhood adversity in patients with bipolar disorder was associated with an increased incidence of a variety of medical illnesses in adulthood, including some related to immune and autoimmune function.

More research that would measure inflammatory markers in PTSD and mood disorders is needed. It would also be important to ascertain whether treatment of mood disorders and PTSD reduces the risk of autoimmune disorders.

Cinnamon: A Dash is Good, a Spoonful is Dangerous

July 1, 2013 · Posted in Risk Factors · Comment 

cinnamon

Cinnamon seasoning is good for you; it sensitizes insulin receptors and helps prevent type 2 diabetes.

Attempting to swallow a whole spoonful—a stunt called the Cinnamon Challenge that was popularized by a viral YouTube video—can be dangerous. It induces violent coughing and a gag reflex that may lead to inhaling the spice into the lungs. Cinnamon is composed of cellulose fibers which do not dissolve or degrade in the lungs, and thus can cause scarring and other long-term lung complications. Details can be found in the May 2013 issue of the journal Pediatrics.

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