Molecular Biology of Depression

October 1, 2015 · Posted in Neurobiology, Risk Factors · Comment 

molecular biology of depressionDysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.

Early Life Experiences are Key

Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.

The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.

CLOCK Genes and Circadian Rhythms

Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.

Fibroblast Growth Factor

Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.

In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.

FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”

Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.

The Human Brain

Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.

In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).

Diabetes Complicates Bipolar Disorder

September 30, 2015 · Posted in Course of Illness, Risk Factors · Comment 

diabetes and bipolar disorder

People with bipolar disorder are three times more likely than the general population to develop type 2 diabetes. Type 2 diabetes typically occurs in adulthood and is associated with insulin resistance, as opposed to type 1, which is usually diagnosed in childhood and is associated with insulin deficiency.

In a talk at the 2015 meeting of the Society of Biological Psychiatry, researcher Tomas Hajek reported that in a large group of bipolar patients, 13% reported a history of type 2 diabetes, 21% were diagnosed with type 2 diabetes upon laboratory evaluation, and 32.2% had pre-diabetes without realizing it. Thus, about half of these patients with bipolar disorder were either affected by diabetes or at risk for it, many without knowing it.

The Bad News

Diabetes complicates the course of bipolar illness. Type 2 diabetes is associated with poorer response to treatment, atrophy of the hippocampus, cognitive impairment, and higher rates of conversion from mild cognitive impairment to full-blown dementia.

The main effect of type 2 diabetes is insulin resistance. The body produces enough insulin, but insulin’s effects at its receptors are impaired. Diabetes also causes deficits in growth factors, increases in the enzyme GSK3B, decreases in mitochondria and brain-derived neurotrophic factor (BDNF, which protects neurons), and glucose toxicity.

Recent research by Hajek and colleagues shows that diabetes has several other detrimental effects on the brain in bipolar disorder. On magnetic resonance spectroscopy (MRS) scans, people with type 2 diabetes had lower levels of NAA, a marker of neuronal integrity, in the prefrontal cortex. This can indicate impaired functioning. People with type 2 diabetes also had lower levels of creatine, indicating impaired energy metabolism. In addition, hippocampal volume decreases with aging, and type 2 diabetes accelerated this age-related decline.

Some of diabetes’ effects on the brain are mediated by other health factors, including obesity, cerebral blood vessel disease (which affects white matter integrity), and side effects from medications.

What You Can Do

Start early with a good diet and exercise, and have regular checkups with a doctor, who can tell you if you have diabetes or are at risk for it. If so, start long-term preventative treatment with the most effective and easy-to-tolerate medications, and periodically have your fasting blood sugar tested. If these tests are abnormal, have your hemoglobin A1c (HbA1c) checked. This is a measure of good glucose control, and should be under 6. If it creeps upward toward 6 (a sign of pre-diabetes), the drug metformin may be able to prevent the onset of type 2 diabetes. If you have type 2 diabetes, there are several types of effective medications that can minimize its effects.

Low Oxytocin Linked to Depression in Moms

September 21, 2015 · Posted in Risk Factors · Comment 

postpartum depression

At a panel at the 2015 meeting of the Society of Biological Psychiatry, researcher Andrea Gonzales described her team’s study of mechanisms related to postpartum depression and the bonding hormone oxytocin. In the study of 26 women at eight months postpartum, the team examined whether there were connections between a mother’s levels of oxytocin at baseline and after interacting with her child, her mood symptoms, and whether she was mistreated in childhood.

Those women who scored low on a history of maltreatment in childhood had bigger increases in oxytocin in their blood and saliva after interacting with their children. Those with high trauma scores but low levels of depression also saw big boosts in oxytocin after seeing their children. Those women who had both a history of trauma in childhood and current depressive symptoms did not get as big a boost of oxytocin after interacting with their children.

Gonzales and colleagues concluded that postpartum depression is linked to dysregulation of oxytocin levels, and that a history of trauma in the mother’s childhood can make this worse.

The researchers hope that these findings may make it easier to identify which women are at risk for postpartum depression, and that they may point to possible treatments in the future.

Postpartum depression is a problem for about 13% of mothers in the year after they give birth, and mother-child bonding may be disturbed if a mother is depressed. One way to foster better bonding between a depressed mother and her newborn is to use video feedback. A mother views video of herself interacting with her child while a trained professional helps her identify opportunities for greater physical contact.

Omega-3 Fatty Acids Prevent Conversion to Psychosis

September 18, 2015 · Posted in Course of Illness, Current Treatments, Risk Factors · Comment 

omega-3 fatty acids for psychosis preventionA new long-term study of omega-3 polyunsaturated fatty acids for psychosis prevention shows that almost seven years after a 3-month stint of receiving these dietary supplements daily, adolescents and young adults at high risk for psychosis showed fewer symptoms of conversion to full-blown psychosis than those who received placebo during the same period.

The research team, led by Paul Amminger, originally found that among 81 youth (mean age 16.5) at high risk of developing psychosis due to their family histories, the 41 who received 12 weeks of daily supplementation with 700mg of eicosapentaenoic acid (EPA) omega-3s and 480 mg of docosahexaenoic acid (DHA) omega-3s showed reduced likelihood of conversion to psychosis one year later than the 40 who received placebo.

The team followed up an average of 6.7 years later with 71 of the original 81 participants. Among those who had received the omega-3 intervention, 9.8% had developed psychosis. Among the placebo group, 40% had developed psychosis, and they had done so earlier.

In addition, the omega-3 participants were better functioning, they had required less antipsychotic medication, and they had lower rates of any psychiatric disorder than the placebo group.
Amminger wrote in the journal Nature Communications, “Unlike antipsychotics, fish oil tablets have no side effects and arent’s stigmatizing to patients.”

Editor’s Note: Because of their lack of side effects, a good case can be made for omega-3 fatty acids for patients at high risk for psychosis. The novel thing about this study is that short-term treatment with omega-3 fatty acids had preventive effects almost 7 years later.

Blood and Now Brain Inflammation Linked to Depression

September 16, 2015 · Posted in Brain Imaging, Risk Factors · Comment 

microgliaThere is growing evidence of a link between inflammation of depression. At the 2015 meeting of the Society of Biological Psychiatry, researcher Jeff Meyer summarized past studies on inflammatory markers. These are measurements, for example of certain proteins in the blood, that indicate the presence of inflammation in the body.

Common inflammatory markers that have been linked to depression include IL-6, TNF-alpha, and c-reactive protein. At the meeting, Meyer reviewed the findings on each of these. Twelve studies showed that IL-6 levels are elevated in the blood of patients with depression. Four studies had non-significant results of link between IL-6 and depression, and Meyer found no studies indicating that IL-6 levels were lower in those with depression. Similarly, for TNF-alpha, Meyer found 11 studies linking elevated TNF-alpha with depression, four with non-significant results, and none showing a negative relationship between TNF-alpha and depression. For c-reactive protein, six studies showed that c-reactive protein was elevated in people with depression, six had non-significant results, and none indicated that c-reactive protein was lower in depressed patients.

Most studies that have linked inflammation to depression have done so by measuring inflammatory markers in the blood. It is more difficult to measure inflammation in the brain of living people, but Meyer has taken advantage of new developments in positron emission tomography (PET) scans to measure translocator protein binding, which illustrates when microglia are activated. Microglial activation is a sign of inflammation. Translocator protein binding was elevated by about 30% in the prefrontal cortex, anterior cingulate cortex, and insula in study participants who showed symptoms of a major depressive episode compared to healthy control participants. The implication is that the depressed people with elevated translocator protein binding have more brain inflammation, probably via microglial activation.

The antibiotic minocycline reduces microglial activation. It would be interesting to see if minocycline might have antidepressant effects in people with depression symptoms and elevated translocator protein binding.

Most SSRIs Free of Birth Defect Risk Early in Pregnancy, Fluoxetine and Paroxetine are Exceptions

August 26, 2015 · Posted in Current Treatments, Risk Factors · Comment 

antidepressants during pregnancy

A large study of women who took selective serotonin reuptake inhibitor (SSRI) antidepressants in the month before pregnancy and throughout the first trimester suggests that there is a smaller risk of birth defects associated with SSRI use than previously thought, though some risks were elevated in women who took paroxetine or fluoxetine.

The 2015 study, by Jennita Reefhuis and colleagues in the journal BMJ, investigated the drugs citalopram, escitalopram, fluoxetine, paroxetine, and sertraline, and examined birth defects that had previously been associated with SSRI use in smaller studies. The participants were 17,952 mothers of infants with birth defects and 9,857 mothers of infants without birth defects who had delivered between 1997 and 2009.

Sertraline was the most commonly used SSRI among the women in the study. None of the birth defects included in the study were associated with sertraline use early in pregnancy. The study found that some birth defects were 2 to 3.5 times more likely to occur in women who had taken fluoxetine or paroxetine early in their pregnancies.

Five different birth defects, while uncommon, were statistically linked to paroxetine use: anencephaly (undersized brain), heart problems including atrial septal defects and right ventricular outflow tract obstruction defects, and defects in the abdominal wall including gastroschisis and omphalocele. Two types of birth defects were associated with fluoxetine use: right ventricular outflow tract obstruction defects and craniosynostosis (premature fusion of the skull bones). Absolute incidence of these defects was also low.

A Note on Genetic Inheritance

August 19, 2015 · Posted in Course of Illness, Genetics, Risk Factors · Comment 

Genetic inheritance is not everything, according to J. Craig Venter, pioneering genetic scientist responsible for sequencing the human genome in 2001:

“Human biology is actually far more complicated than we imagine. Everybody talks about the genes that they received from their mother and father, for this trait or the other. But in reality, those genes have very little impact on life outcomes. Our biology is far too complicated for that and deals with hundreds of thousands of independent factors. Genes are absolutely not our fate. They can give us useful information about the increased risk of a disease, but in most cases they will not determine the actual cause of the disease, or the actual incidence of somebody getting it. Most biology will come from the complex interaction of all the proteins and cells working with the environmental factors, not driven directly by the genetic code.”

Verbal Abuse in Childhood, Like Physical and Sexual Abuse, Linked to Earlier Onset and More Difficult Course of Bipolar Disorder

July 22, 2015 · Posted in Course of Illness, Risk Factors · Comment 

verbal abuse

Earlier research has shown that childhood adversity is linked to earlier age of onset of bipolar disorder and more difficult course of illness. Physical and sexual abuse are associated with both earlier age of onset and more difficulties such as anxiety disorders and substance abuse. Now, new research by this editor (Robert M. Post) and colleagues links verbal abuse (even in the absence of physical and sexual abuse) to earlier onset of bipolar disorder and to more severe and complicated course of illness.

The study, published in the journal Bipolar Disorders, was based on the self-reports of 634 adult outpatients with bipolar disorder at four sites in the US. These participants were interviewed about their history of illness and the frequency of adverse events they experienced in childhood, adolescence, and adulthood, including physical, sexual, and verbal abuse. Twenty-four percent of these participants reported having experienced verbal abuse occasionally or frequently in childhood, but not other forms of abuse, while another 35% had a history of verbal abuse as well as physical or sexual abuse, for a total of 59% with a history of verbal abuse.

The greater the frequency of verbal abuse in childhood, the earlier the average age of onset of bipolar disorder. Participants with no history of abuse had a mean age of onset of 20.6 years, but verbal abuse by itself reduced the mean age of onset to 16.5 years, and verbal abuse plus sexual abuse reduced the mean age of onset to 15.3 years. (The mean age of onset for participants who experienced sexual abuse alone was 17.5 years.) It was impossible to determine the combined effect of verbal and physical abuse because verbal abuse was almost always present when physical abuse occurred. For the 14% of the participants who had experienced verbal, physical, and sexual abuse in childhood, the mean age of onset of bipolar disorder was 13.1 years.

Those who were verbally (but not physically or sexually) abused in childhood had more anxiety disorders, drug abuse, and rapid cycling than those who were not abused, but not more alcohol abuse. Those who were verbally abused also showed increasing severity of illness, including increased frequency of cycling.

Genetics can also play a role. Having a parent with a mood disorder also contributed to an earlier age of onset of bipolar disorder.

Editor’s Note: Researcher David J. Miklowitz and colleagues have shown that family focused therapy (FFT), which emphasizes illness education and communication enhancement within the family, is more effective than treatment as usual for children with a family history of bipolar disorder and a diagnosis of depression, cyclothymia, or bipolar not otherwise specified (BP NOS).

FFT was particularly effective in reducing symptoms in children from families with high expressed emotion, suggesting that this kind of family-based intervention could reduce levels of verbal abuse.

“De Novo” Mutations in Dozens of Genes Cause Autism

July 3, 2015 · Posted in Genetics, Risk Factors · Comment 


Two studies that incorporated data from more than 50 labs worldwide have linked mutations in more than 100 different genes to autism. Scientists have a high level of statistical confidence that mutations in about 60 of those genes are responsible for autism. So-called de novo mutations (Latin for “afresh”) do not appear in the genes of parents without autism, but arise newly in the affected child. The mutations can alter whether the genes get “turned on” or transcribed (or not), leading to disturbances in the brain’s communication networks.

The studies led by Stephan Sanders and Matthew W. State appeared in the journal Nature in late 2014. The identified genes fall into three categories. Some affect the formation and function of synapses, where messages between neurons are relayed. Others affect transcription, the process by which genes instruct cells to produce proteins. Genes in the third category affect chromatin, a sort of packaging for DNA in cells.

Before the new studies, only 11 genes had been linked to autism, and the researchers involved expect to find that hundreds more are related to the illness.

Editor’s Note: This new research explains how autism could be increasing in the general population even as most adults with autism do not have children. It should also put to rest the idea, now totally discredited, that ingredients in childhood immunizations cause autism. It is clearer than ever that kids who will be diagnosed with autism are born with these mutations.

With these genetic findings, the search for new medications to treat this devastating illness should accelerate even faster.

Bottom line: Childhood immunizations don’t cause autism, newly arising mutations in the DNA of parents’ eggs or sperm do. However, parental behavior could put their children and others at risk for the measles and other serious diseases if they do not allow immunizations. The original data linking autism to immunization were fraudulent, and these new data on the genetic origins of autism provides the best hope for future treatments or prevention.

Inability to Balance on One Leg May Indicate Stroke Risk

June 22, 2015 · Posted in Risk Factors · Comment 

stroke risk

A balance test may indicate declining cognitive health and risk for stroke. Researchers led by Yasuharu Tabara had previously found that balancing on one leg became more difficult for people with age. Now the same team has found that this type of postural instability is associated with decreases in cognitive functioning and with risk of stroke. Fourteen hundred participants with an average age of 67 were challenged to balance on one leg for up to 60 seconds. They also completed computer surveys, magnetic resonance imaging (MRI) scans, and a procedure to measure the thickness of their carotid artery. Those who could not balance on one leg for 20 seconds or longer were more likely to have cerebral small vessel disease.

Editor’s Note: Whether exercise would reverse this vulnerability remains to be seen, but lots of other data suggest the benefit of regular (even light) exercise on general health.

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