Children of addicted parents more likely to be depressed as adults

Children of parents who were addicted to drugs or alcohol are more likely to be depressed in adulthood, according to a new study by University of Toronto researchers.

“These findings underscore the intergenerational consequences of drug and alcohol addiction and reinforce the need to develop interventions that support healthy childhood development,” said the study’s lead author, Esme Fuller-Thomson, professor and Sandra Rotman Endowed Chair in the University of Toronto’s Factor-Inwentash Faculty of Social Work and the Department of Family and Community Medicine.

In a paper published online in the journal Psychiatry Research this month, investigators examined the association between parental addictions and adult depression in a representative sample of 6,268 adults, drawn from the 2005 Canadian Community Health Survey.

Of these respondents, 312 had a major depressive episode within the year preceding the survey and 877 reported that while they were under the age of 18 and still living at home that at least one parent who drank or used drugs “so often that it caused problems for the family.”

Results indicate that individuals whose parents were addicted to drugs or alcohol are more likely to develop depression than their peers. After adjusting for age, sex and race, parental addictions were associated with more than twice the odds of adult depression, says Fuller-Thomson.

“Even after adjusting for factors ranging from childhood maltreatment and parental unemployment to adult health behaviours including smoking and alcohol consumption, we found that parental addictions were associated with 69 per cent higher odds of depression in adulthood,” explains Fuller-Thomson. The study was co-authored with four graduate students at the University of Toronto: Robyn Katz, Vi Phan, Jessica Liddycoat and Sarah Brennenstuhl.

This study could not determine the cause of the relationship between parental addictions and adult depression. Co-author Robyn Katz, suggests that “It is possible that the prolonged and inescapable strain of parental addictions may permanently alter the way these children’s bodies react to stress throughout their life.

"One important avenue for future research is to investigate potential dysfunctions in cortisol production – the hormone that prepares us for ‘fight or flight’ – which may influence the later development of depression.”

“As an important first step, children who experience toxic stress at home can be greatly helped by the stable involvement of caring adults, including grandparents, teachers, coaches, neighbours and social workers,” said Fuller-Thomson. “Although more research is needed to determine if access to a responsive and loving adult decreases the likelihood of adult depression among children exposed to parental addictions, we do know that these caring relationships promote healthy development and buffer stress.”

Nerve stimulation for severe depression changes brain function

For nearly a decade, doctors have used implanted electronic stimulators to treat severe depression in people who don’t respond to standard antidepressant therapy.

Now, preliminary brain scan studies conducted by researchers at Washington University School of Medicine in St. Louis are beginning to reveal the processes occurring in the brain during stimulation and may provide some clues about how the device improves depression. They found that vagus nerve stimulation brings about changes in brain metabolism weeks or even months before patients begin to feel better.

The findings will appear in an upcoming issue of the journal Brain Stimulation and are now available online.

“Previous studies involving large numbers of people have demonstrated that many with treatment-resistant depression improve with vagus nerve stimulation,” said first author Charles R. Conway, MD, associate professor of psychiatry. “But little is known about how this stimulation works to relieve depression. We focused on specific brain regions known to be connected to depression.”

Conway’s team followed 13 people with treatment-resistant depression. Their symptoms had not improved after many months of treatment with as many as five different antidepressant medications. Most had been depressed for at least two years, but some patients had been clinically depressed for more than 20 years.

All of the participants had surgery to insert a device to electronically stimulate the left vagus nerve, which runs down the side of the body from the brainstem to the abdomen. Once activated, the device delivers a 30-second electronic stimulus to the vagus nerve every five minutes.

To establish the nature of the treatment’s effects on brain activity, the researchers performed positron emission tomography (PET) brain imaging before the initiation of stimulation, and again three and 12 months after stimulation had begun.

Eventually, nine of the 13 subjects experienced improvements in depression with the treatment. However, in most cases it took several months for improvement to occur.

Remarkably, in those who responded, the scans showed significant changes in brain metabolism following three months of stimulation, which typically preceded improvements in symptoms of depression by several months.

“We saw very large changes in brain metabolism occurring far in advance of any improvement in mood,” Conway said. “It’s almost as if there’s an adaptive process that occurs. First, the brain begins to function differently. Then, the patient’s mood begins to improve.”

Although the patients remained on antidepressants for several months after their stimulators were implanted, Conway says many of those who responded to the device eventually were able to stop taking medication.

“Sometimes the antidepressant drugs work in concert with the stimulator, but it appears to us that when people get better, it is the vagus nerve stimulator that is doing the heavy lifting,” Conway explained. “Stimulation seems to be responsible for most of the improvement we see.”

Additionally, the PET scans demonstrated that structures deeper in the brain also begin to change several months after nerve stimulation begins. Many of those structures have high concentrations of brain cells that release dopamine, a neurotransmitter that helps control the brain’s reward and pleasure centers and also helps regulate emotional responses.

There is a consensus forming among depression researchers that problems in dopamine pathways may be particularly important in treatment-resistant depression, according to Conway. And he said the finding that vagus nerve stimulators influence those pathways may explain why the therapy can help and why, when it works, its effects are not transient. Patients who respond to vagus nerve stimulation tend to get better and stay better.

“We hypothesized that something significant had to be occurring in the brain, and our research seems to back that up,” he said.

Negative Thoughts Can Be Contagious

The way the people around us respond to stressful events — whether those people react negatively or positively — may be contagious when we are in the midst of a major life transition, a new study says.

What’s more, the increased risk of depression that comes with negative thinking also seems to rub off during these times, the study found.

For the study, researchers looked at 103 pairs of college-freshmen roommates’ “cognitive vulnerability,” which is the tendency to think that negative events are a reflection of a person’s own deficiency or that they will lead to more negative events. Those with high cognitive vulnerability are at an increased risk of depression, studies have found.

"We found that participants’ level of cognitive vulnerability was significantly influenced by their roommates’ level of cognitive vulnerability, and vice versa," the researchers wrote. All roommates in the study were selected randomly; students did not choose their roommates. Only three months of living together was needed for this contagiousness to be seen.

The researchers also found that those who experienced an increase in cognitive vulnerability during the first three months of college had nearly twice the level of depressive symptoms at six months, compared with those who did not experience an increase in cognitive vulnerability, according to the study. The effect was particularly strong when participants were under high-stress conditions.

Prior to this study, it was thought that cognitive vulnerability didn’t change much once a person passed early adolescence. However, the new findings suggest that during big transitions in life — when a person is continually exposed to a new social situation — cognitive vulnerability can be altered, the researchers said.

They noted that genetic, biological and environmental factors all likely play a role in a person’s level of cognitive vulnerability.

Further research is needed to determine whether cognitive vulnerability may change over time, the researchers said, noting that college freshmen are in a unique social environment. 

"Our findings are consistent with a growing number of studies that have found that many psychological and biological factors previously thought to be set in stone by adulthood continue to be malleable,” the researchers said.

The study was published online April 16 in the journal Clinical Psychological Science.

Learned helplessness in flies and the roots of depression

When faced with impossible circumstances beyond their control, animals, including humans, often hunker down as they develop sleep or eating disorders, ulcers, and other physical manifestations of depression. Now, researchers reporting in the Cell Press journal Current Biology on April 18 show that the same kind of thing happens to flies.

The study is a step toward understanding the biological basis for depression and presents a new way for testing antidepressant drugs, the researchers say. The discovery of such symptoms in an insect shows that the roots of depression are very deep indeed.

"Depressions are so devastating because they go back to such a basic property of behavior," says Martin Heisenberg of the Rudolf Virchow Center in Würzburg, Germany.

Heisenberg says that the idea for the study came out of a lengthy discussion with a colleague about how to ask whether flies can feel fear. Franco Bertolucci, a coauthor on the study, had found that flies can rapidly learn to suppress innate behaviors, a phenomenon that is part of learned helplessness.

The researchers now show that flies experiencing uncomfortable levels of heat will walk to escape it. But if the flies realize that the heat is beyond their control and can’t be avoided, they will stop responding, walking more slowly and taking longer and more frequent rests, as if they were “depressed.”

Intriguingly, female flies slow down more under those stressful circumstances than males do. It’s not clear exactly what that means, but Heisenberg explains, “if we realize that the fly trapped in a strange, dark box, unable to get rid of the dangerous heat pulses, has to find a compromise between saving energy and not missing any chance of escape, we can understand that such a compromise may come out differently for males and females, as their resources and goals in life are different.”

Heisenberg’s team now intends to explore other questions, such as: How long does the flies’ depression-like state last? How does it affect other behaviors, like courtship and aggression? What is happening in their brain? And more.

Heisenberg says that the findings are a reminder of a lesson that children’s books are often best at showing: “Animals have lots in common with us humans. They breathe the same air, share many of the same resources, actively explore space, and have distinct social roles. Their brains serve the same purpose, too: they help them to do the right thing.”

Do drugs for bipolar disorder “normalize” brain gene function?

Every day, millions of people with bipolar disorder take medicines that help keep them from swinging into manic or depressed moods. But just how these drugs produce their effects is still a mystery.

Now, a new University of Michigan Medical School study of brain tissue helps reveal what might actually be happening. And further research using stem cells programmed to act like brain cells is already underway.

Using genetic analysis, the new study suggests that certain medications may help “normalize” the activity of a number of genes involved in communication between brain cells. It is published in the current issue of Bipolar Disorders.

The study involved brain tissue from deceased people with and without bipolar disorder, which the U-M team analyzed to see how often certain genes were activated, or expressed. Funding support came from the National Institutes of Health and the Heinz C. Prechter Bipolar Research Fund.

“We found there are hundreds of genes whose activity is adjusted in individuals taking medication – consistent with the fact that there are a number of genes that are potentially amiss in people with bipolar,” says senior author Melvin McInnis, M.D., the U-M psychiatrist, U-M Depression Center member and principal investigator of the Prechter Fund Projects who helped lead the study. “Taking the medications, specifically ones in a class called antipsychotics, seemed to normalize the gene expression pattern in these individuals so that it approached that of a person without bipolar.”

Digging deeper into bipolar genetics

Scientists already know that bipolar disorder’s roots lie in genetic differences in the brain — though they are still searching for the specific gene combinations involved.  

McInnis and his colleagues have now embarked on research developing several a lines of induced pluripotent stem cells derived (iPSC) from volunteers with and without bipolar disorder, which will allow even more in-depth study of the development and genetics of bipolar disorder.

The newly published study looked at the expression, or activity levels, of 2,191 different genes in the brains of 14 people with bipolar disorder, and 12 with no mental health conditions. The brains were all part of a privately funded nonprofit brain bank that collected and stored donated brains, and recorded what medications the individuals were taking at the time of death.

Seven of the brains were from people with bipolar disorder who had been taking one or more antipsychotics when they died. These drugs include clozapine, risperidone, and haloperidol, and are often used to treat bipolar disorder. Most of the 14 brain donors with bipolar disorder were also taking other medications, such as antidepressants, at the time of death.

When the researchers compared the gene activity patterns among the brains of bipolar disorder patients who had been exposed to antipsychotics with patterns among those who weren’t, they saw striking differences.

Then, when they compared the activity patterns of patients who had been taking antipsychotics with those of people without bipolar disorder, they found similar patterns.

The similarities were strongest in the expression of genes involved in the transmission of signals across synapses – the gaps between brain cells that allow cells to ‘talk’ to one another. There were also similarities in the organization of nodes of Ranvier – locations along nerve cells where signals can travel faster.

McInnis, who is the Thomas B. and Nancy Upjohn Woodworth Professor of Bipolar Disorder and Depression in the U-M Department of Psychiatry, worked with U-M scientists Haiming Chen, M.D. and K. Sue O’Shea, Ph.D., of the U-M Department of Cell and Developmental Biology. They also teamed with Johns Hopkins University researcher Christopher Ross, M.D., Ph.D. on the new research; U-M and Johns Hopkins have a long history of collaboration on bipolar disorder research.

The research used brain tissue samples from the Stanley Brain Collection of the Stanley Medical Research Institute in Maryland.

Using “gene chip” analysis to measure the presence of messenger RNA molecules that indicate gene activity, and sophisticated data analysis, they were able to map the expression patterns from the brains and break the results down by bipolar status and medication use. The bipolar and control (non-bipolar) brains were matched by age, gender and other factors.

“In bipolar disorder, it’s not just one gene that’s involved – it’s a whole symphony of them,” says McInnis, who has helped lead U-M’s bipolar genetics research for nearly a decade. “Medications appear to nudge them in a direction that aligns more with the normal expression pattern.”

Among those that were “nudged” were genes that have already been shown to be linked to bipolar disorder, including glycogen synthase kinase 3 beta (GSK3β), FK506 binding protein 5 (FKBP5), and Ankyrin 3 (ANK3).

Going forward, says McInnis, cell culture studies will be critical to studying how medications for bipolar disorder work, and to screen new molecules as potential new medications.

Remarkable Success In Patients With Major Depression

For the first time, physicians from the Bonn University Hospital have stimulated patients’ medial forebrain bundles.

Researchers from the Bonn University Hospital implanted pacemaker electrodes into the medial forebrain bundle in the brains of patients suffering from major depression with amazing results: In six out of seven patients, symptoms improved both considerably and rapidly. The method of Deep Brain Stimulation had already been tested on various structures within the brain, but with clearly lesser effect. The results of this new study have now been published in the renowned international journal “Biological Psychiatry.”

After months of deep sadness, a first smile appears on a patient’s face. For many years, she had suffered from major depression and tried to end her life several times. She had spent the past years mostly in a passive state on her couch; even watching TV was too much effort for her. Now this young woman has found her joie de vivre again, enjoys laughing and traveling. She and an additional six patients with treatment resistant depression participated in a study involving a novel method for addressing major depression at the Bonn University Hospital.

Considerable amelioration of depression within days

Prof. Dr. Volker Arnd Coenen, neurosurgeon at the Department of Neurosurgery (Klinik und Poliklinik für Neurochirurgie), implanted electrodes into the medial forebrain bundles in the brains of subjects suffering from major depression with the electrodes being connected to a brain pacemaker. The nerve cells were then stimulated by means of a weak electrical current, a method called Deep Brain Stimulation. In a matter of days, in six out of seven patients, symptoms such as anxiety, despondence, listlessness and joylessness had improved considerably. “Such sensational success both in terms of the strength of the effects, as well as the speed of the response has so far not been achieved with any other method,” says Prof. Dr. Thomas E. Schläpfer from the Bonn University Hospital Department of Psychiatry und Psychotherapy (Bonner Uniklinik für Psychiatrie und Psychotherapie).

Central part of the reward circuit

The medial forebrain bundle is a bundle of nerve fibers running from the deep-seated limbic system to the prefrontal cortex. In a certain place, the bundle is particularly narrow because the individual nerve fibers lie close together. “This is exactly the location in which we can have maximum effect using a minimum of current,” explains Prof. Coenen, who is now the new head of the Freiburg University Hospital’s Department of Stereotactic and Functional Neurosurgery (Abteilung Stereotaktische und Funktionelle Neurochirurgie am Universitätsklinikum Freiburg). The medial forebrain bundle is a central part of a euphoria circuit belonging to the brain’s reward system. What kind of effect stimulation exactly has on nerve cells is not yet known. But it obviously changes metabolic activity in the different brain centers.

Success clearly increased over that of earlier studies

The researchers have already shown in several studies that deep brain stimulation shows an amazing and–given the severity of the symptoms– unexpected degree of amelioration of symptoms in major depression. In those studies, however, the physicians had not implanted the electrodes into the medial forebrain bundle but instead into the nucleus accumbens, another part of the brain’s reward system. This had resulted in clear and sustainable improvements in about 50 percent of subjects. “But in this new study, our results were even much better,” says Prof. Schläpfer. A clear improvement in complaints was found in 85 percent of patients, instead of the earlier 50 percent. In addition, stimulation was performed with lower current levels, and the effects showed within a few days, instead of after weeks.

Method’s long-term success proven

“Obviously, we have now come closer to a critical structure within the brain that is responsible for major depression,” says the psychiatrist from the Bonn University Hospital. Another cause for optimism among the group of physicians is that, since the study’s completion, an eighth patient has also been treated successfully. The patients have been observed for a period of up to 18 month after the intervention. Prof. Schläpfer reports, “The anti-depressive effect of deep brain stimulation within the medial forebrain bundle has not decreased during this period.” This clearly indicates that the effects are not temporary. This method gives those who suffer from major depression reason to hope. However, it will take quite a bit of time for the new procedure to become part of standard therapy.

First trial to investigate magic mushrooms as a treatment for depression delayed by UK and EU regulations

The world’s first clinical trial to explore the use of the hallucinogenic ingredient in magic mushrooms to treat depression is being delayed due to the UK and EU rules on the use of illegal drugs in research.

Professor David Nutt, president of the British Neuroscience Association and Professor of Neuropsychopharmacology at Imperial College London (UK), will tell the BNA’s Festival of Neuroscience today (Sunday) that although the UK’s Medical Research Council has awarded a grant for the trial, the Government’s regulations controlling the licensing of illegal drugs in research and the EU’s guidelines on Good Manufacturing Practice (GMP) have stalled the start of the trial, which was expected to start this year. He is calling for a change to the regulations.

He will tell the meeting at the Barbican in London, that his research has shown that psilocybin, the psychedelic ingredient in magic mushrooms, has the potential to alleviate severe forms of depression in people who have failed to respond fully to other anti-depressant treatments. However, psilocybin is illegal in the UK; the United Nations 1971 Convention on Psychotropic Substances classifies it as a Schedule 1 drug, one that has a high potential for abuse with no recognised medical use, and the UK has classified it as a Class A drug, the classification used for the most dangerous drugs. This means that a special licence has to be obtained to use magic mushrooms in research in the UK, and the manufacture of a synthetic form of psilocybin for use in patients is tightly controlled by EU regulations.

Prof Nutt will say: “The law for the control of drugs like psilocybin as a Schedule 1 Class A drug makes it almost impossible to use them for research and the reason we haven’t started the study is because finding companies who could manufacture the drug and who are prepared to go through the regulatory hoops to get the licence, which can take up to a year and triple the price, is proving very difficult. The whole situation is bedevilled by this primitive, old-fashioned attitude that Schedule 1 drugs could never have therapeutic potential, and so they have to be made impossible to access.”

“The knock-on effect is this profound impairment of research. We are the first people ever to have done a psilocybin study in the UK, but we are still hunting for a company that can manufacture the drug to GMP standards for the clinical trial, even though we’ve been trying for a year to find one. We live in a world of insanity in terms of regulating drugs at present. The whole field is so bogged down by these intransient regulations, so that even if you have a good idea, you may never get it into the clinic.”

He will say that the regulations need to be changed. “Even if I do this study and I show it’s a really useful treatment for some people with depression, there’s only four hospitals in this country that have a licence to hold this drug, so you couldn’t roll out the treatment if it worked because the regulations would make it difficult to use,” he said.

Prof Nutt and his team at Imperial College London (UK) have shown that when healthy volunteers are injected with psilocybin, the drug switched off a front part of the brain called the anterior cingulate cortex, which is known from previous imaging studies to be over-active in depression. “We found that, even in normal people, the more that part of the brain was switched off under the influence of the drug, the better they felt two weeks later. So there was a relationship between that transient switching off of the brain circuit and their subsequent mood,” he will explain. “This is the basis on which we want to run the trial, because this is what you want to do in depression: you want to switch off that over-active part of the brain.

“The other thing we discovered is that the major site of action of the magic mushrooms is to turn down a circuit in the brain called the ‘default mode network’, which the anterior cingulate cortex is part of. The default mode network is a part of the brain between the front and back. It is active when you are thinking about you; it coordinates the thinking and emotional aspects of you.”

The researchers discovered that the ‘default mode network’ had the highest density of 5HT2A receptors in the brain. These are known to be involved in depression and are the targets for a number of existing anti-depressive drugs that aim to improve levels of serotonin – the neurotransmitter [1] that gives people a sense of well-being and happiness. Psilocybin also acts on these receptors.

“We have found that people with depression have over-active default mode networks, and they are continually locked into a mode of thinking about themselves. So they ruminate on themselves, on their incompetencies, on their badness, that they’re worthless, that they’ve failed; these things are not true, and sometimes they reach delusional levels. This negative rumination may be due to a lack of serotonin and what psilocybin is doing is going in and rapidly replacing the missing serotonin, switching them back into a mind state where they are less ruminating and less depressed,” Prof Nutt will say.

The proposed trial will be for patients with depression who have failed two previous treatments for the condition. Thirty patients will be given a synthetic form of psilocybin and 30 patients will be given a placebo. The drug (or placebo) will be given during two, possibly three, carefully controlled and prepared 30-60 minute sessions. The first session will be a low dose to check there are no adverse responses, the second session will give a higher, therapeutic dose, and then patients can have a third, booster dose in a later session if it’s considered necessary. While they are under the influence of the drug, the patients will have guided talking therapy to enable them to explore their negative thinking and issues that are troubling them. The doctors will follow up the patients for at least a year.

“What we are trying to do is to tap into the reservoir of under-researched ‘illegal’ drugs to see if we can find new and beneficial uses for them in people whose lives are often severely affected by illnesses such as depression. The current legislation is stopping the benefits of these drugs being explored and for the last 40 years we have missed really interesting opportunities to help patients.”

Ethical approval for the trial was granted in March and Prof Nutt says he hopes to be able to start the trial within the next six months – so long as he can find a manufacturer for the drug.

(Image: coolchaser.com)

Depression stems from miscommunication between brain cells

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression. The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

"Dr. Thompson’s groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine. "This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells. “Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard,” says Dr. Thompson. “Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?”

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable. For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding. This depression-like behavior strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals’ brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the ‘depressed’ brains. Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behavior was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn’t get through," says Dr. Thompson. Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning. The team’s observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions. Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

(Image: McGovern Institute, MIT)