Although textbooks and pharmaceutical company literature often claim that the biological component of depression has been clearly defined, the fact is that we still have no certain knowledge about the molecular and biochemical disturbances in depressive disorders. Furthermore, our theories of how antidepressants are constantly being revised, and it is now thought likely that these drugs have several mechanisms of action.

There is an interesting study from the University of Illinois at Chicago College of Medicine and Maryland Psychiatric Research Center in Baltimore in today’s issue of the Journal of Neuroscience.

They have discovered that a change in the location of a protein in the brain could serve as a biomarker for depression. This is exceptionally important, since it may give us a simple and rapid laboratory test to identify patients with depression and, more importantly, to predict clinical response to specific antidepressants.

Over the last few years this same team of researchers, and others around the globe, have been examining a protein named Gs alpha that activates adenylyl cyclase. Adenylyl cyclase is a link in signal transduction that is in part responsible for the action of neurotransmitters including serotonin. Instead of just looking at the biochemical properties of the protein, they have also been looking at the way that it moves in the cell membrane, which in turn impacts the way in which neurotransmitters act on cells.

In both rats and cultured brain cells, Gs alpha changes its location in response to antidepressants, moving out of lipid “rafts” in the cell membrane, to areas of the membrane that allow more efficient communication among membrane components responsible for the action of neurotransmitters. Both antidepressant and antipsychotic drugs have been shown to concentrate in these lipid rafts.

In this new study, brain samples from depressed people who had committed suicide were compared with controls who had no history of psychiatric disorders. Although the total amount of Gs alpha was the same in the depressed and non-depressed, in people with depression, Gs alpha was stuck in these lipid “rafts.” Therefore the protein is unable to do its job of mediating the action of neurotransmitters. Antidepressants have the opposite effect, moving it to regions of the membrane where it can do its work. The localization of other G proteins was not different.

This is such a robust finding, that identifying the location of Gs alpha in the cell membrane may provide an objective diagnosis of depression and second, whether someone is responding to the chosen antidepressant therapy.

The senior author in this research is Mark Rasenick, who is distinguished university professor of physiology and biophysics and psychiatry at the University of Illinois. He described the lipid “rafts” and the importance of the findings like this:

“These “rafts” are thick, viscous, almost gluey areas, that either facilitate or impede communication between membrane molecules… When Gs alpha is caught in these lipid raft domains, its ability to couple with and activate adenylyl cyclase is markedly reduced. Antidepressants help to move the Gs alpha out of these rafts and facilitate the action of certain neurotransmitters.”

He goes on to say,

“This test could serve to predict the efficacy of antidepressant therapy quickly, within four to five days, sparing patients the agony of waiting a month or more to find out if they are on the correct therapeutic regimen.”

The findings may also help explain two old puzzles:

• Why do antidepressants take so long to work?
• Why do such chemically different compounds produce similar clinical effects?

Further studies to confirm and expand these findings, and to examine the clinical utility of the test.

An important story has been flashed around the world, but unfortunately some of the interpretations of the story have been intemperate. In a study published in PLOS Medicine a team of researchers from the University of Hull team concluded the drugs actively help only a small group of the most severely depressed. They based this on a meta-analysis of all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available.

The researchers reviewed data on 47 clinical trials, both published clinical trial data, and unpublished data secured under Freedom of Information legislation.

They focused on four antidepressants: fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone) and paroxetine (Paxil).

Many of the reports in the media have taken this research to mean that antidepressants are no better than placebo. That is not the case. The medications can be very effective and even life saving in people with severe depression. However, the effect in people with mild depression is no greater than placebo.

What this tells us is that the over-prescription of antidepressants for normal variations in mood is probably not justified. We are all allowed to be miserable from time to time, but that does not mean that we need to take medications.

Not surprisingly, some of the manufacturers have strongly disputed the findings.

The biggest worry after reading some of the news reports is that some people might stop their medications abruptly, and that can cause many problems. And some folk really do need to be on the medications and stopping them without clear guidance can be very risky.

It matters where you live.

I have lived or stayed in many countries, and there is no doubt that some places are a lot more congenial than others. I don’t just mean a beach in Thailand compared with the North of Scotland in winter. Some places just make you feel better. There are many physical, psychological, social and subtle reasons, but here is a relatively new one.

There is an important paper in this month’s issue of the American Journal of Public Health looking at the possibility of a link between dampness and mold in the home and clinical depression.

Molds are fungi that are found in many environments but most of them grow best in warm, damp, and humid conditions. Therefore, dwellings that have problems with damp also commonly have problems with mold. Although the physical health consequences of living in a damp and moldy dwelling are quite well known, the effect of living in such an environment on mental health has not.

Some of the known health problems associated with high levels of airborne mold spores include^:

• Allergic reactions
• Asthma
• Irritations of the eyes, nose and throat
• Sinus congestion and other respiratory problems
• In people with with weakened immune systems, inhaled mold spores may germinate, attaching to cells along the respiratory tract
• Immunocompromised individuals exposed to high levels of
  mold may get a systemic fungal
  infection
• Infections of the digestive tract, lung and skin

The researchers used survey data from 8 European cities. They created a dampness and mold score from resident- and inspector-reported data. Depression was assessed using a validated index of depressive symptoms.

The results showed that dampness and mold were associated with depression, independent of individual and housing characteristics. This association was independently mediated by perception of control over one’s home and by physical health.

This link is most likely because of the psychological and physiological consequences of living in poor housing conditions. But there could also be a direct pathological effect of mold itself.

Humans have a wonderful ability to expect positive events in the future, even when there is no shred of evidence to support them. One of the key components of resilience is optimism. Though there is data to show that there is a genetic contribution to optimism, it is also a psychological attribute that can flow from life experiences as well as attitude that can be developed. Though the motivational coaches who tell us that putting on a happy face will make you happy and optimistic are probably overstating the truth! A lack of optimism is often a sign of clinical depression so learning more about it, is not just an academic exercise.

New research just published in the journal Nature indicates that there are two regions of the brain linked to optimism.

The team from New York University and University College, London, says that the act of imagining a positive future event, for example winning an award or receiving a large sum of money, activates two brain areas: the amygdala and the rostral anterior cingulated cortex (rACC). The finding ties in with earlier studies that suggested that these brain regions malfunction in depression. (1,2)

The investigators first measured how optimistic 15 volunteers were using a standard questionnaire. They were then scanned using functional magnetic resonance imaging (fMRI) while reflecting on one of a number of potential scenarios.

In one part of the trial, subjects followed specific instructions to recall a negative event in the past, such a funeral that they had attended in the past five years. In another experiment they had to imagine what it would be like to be involved in a car crash in the near future. At other points in the study subjects had to reflect on positive events such as winning an award in the past or receiving a large sum of money in the future.

Reflecting on both past and future events activated the amygdala and the rACC regions of the brain. However, positive events, and particularly those imagined in the future, generated a significantly larger response in these regions than reflecting on negative events.

When imagining happy events, the more pessimistic subjects in the trial had less activation of these brain areas than their optimistic counterparts when imagining happy events.

For some time now, many researchers have assumed that the amygdala and rACC are only involved in negative thoughts and negative reactions, but this research indicates that they have an important role in signaling cheerful thoughts. And, what is more, these are also regions of the brain that have been implicated in depression. Previous research has suggested that patients with depression have decreased nerve signaling and fewer cells in the rACC and amygdala.

Is this why people with depression find it so hard to generate positive thoughts?

This is important work that will likely have a great many practical applications.

“Children are born optimists and we slowly educate them out of their heresy.”
–Louise Imogen Guiney (American-born English Poet, 1861-1920)

“Although the world is full of suffering, it is full also of the overcoming of it.”
–Helen Keller (American Blind and Deaf Swedenborgian Philosopher, 1880-1968)

“No man is so old as not to think he can live one year more.”
–Marcus Tullius Cicero (Roman Political Figure and Orator, c.106-43 B.C.E.)

“The way to become happy
Is to think
And to feel
That the very best is yet to come.”
–Sri Chinmoy (a.k.a. Chinmoy Kumar Ghose, Indian Philosopher and Spiritual Teacher, 1931-2007)

Most of the time we are in control of our moods, rather than our moods being in control of us. One of the main things that we learn as we get older is not simply to damp down our emotional reactions, but to make them “contextually relevant:” we produce the right emotional response for the right situation. Yet we also know that there are exceptions: times when our emotions over-run any attempts at our control.

Second, we all know that sleep deprivation can be a Bad Thing. It is known to impair a range of mental and physical activities, including immune function, metabolic control and many cognitive processes, including learning and memory.

It has long been suspected that sleep deprivation can have significant effect on mood. Many of us feel irritable and distractible if we haven’t slept enough, and you may have had the experience of being up all night and feeling a little bit “high” in the morning. It has also been known for centuries that mood disorders are very commonly associated with sleep disturbances, and sleep disturbance is often the first sign that someone with mood problems is running into trouble. So mood and sleep must be linked in some way.

Despite these common observations, there has never been that much empirical evidence for the impact of sleep deprivation on mood, and in particular the effects of sleep deprivation on the brain.

An important new study by researchers from Harvard Medical School and the University of California at Berkeley has just been published in the journal Current Biology, and it is beginning to fill in some of the gaps in our knowledge.

The amygdala is known to be involved in processing of emotionally salient information, particularly unpleasant or aversive stimuli. In mature individuals, the emotional centers of the brain are usually controlled and modulated by an array of connected systems, mainly in the frontal regions of the brain. One particularly important part of the frontal lobes that is involved in controlling the amygdala is the medial-prefrontal cortex (MPFC). Under normal conditions the MPFC is supposed to exert an inhibitory, top-down control of the amygdala, so that we only generate appropriate emotional responses.

The scientists worked with 35 volunteers who were deprived of sleep for 35 hours. Blood flow can be used to deduce which specific regions of the brain are active. The researchers used functional magnetic resonance imaging (fMRI) to examine the blood flow – and therefore activity - in the brains of the volunteers in real time, both during and after sleep deprivation.

After going without sleep, the participants were asked to look at images that were designed to trigger angry or sad emotional responses. The investigators discovered that the amygdala showed 60% higher reactions to the images compared with people who are not sleep-deprived.

This is an extraordinarily large effect and implies that sleep deprivation knocks out the normal control mechanisms in the frontal lobes so that the sleep-deprived brain reverts to a more primitive pattern of activity. As a result we become unable to put emotional experiences into context and produce controlled, appropriate responses.

If we needed any more reasons to get a good night’s sleep, this one is very powerful. It also re-iterates something very important: if you or a loved one have had problems with mood, anger or anxiety, it is essential to watch your sleep pattern. Any change may be a harbinger or trouble, and is an excellent early warning that you or they need a hand to make sure that things stay on an even keel.

“Your brain shall be your servant instead of your master, you will rule it instead of allowing it to rule you.”
–Charles E. Popplestone (American Author of Every Man a Winner, 1936)

“Control your emotions or they will control you”
–Chinese Proverb

“For the uncontrolled there is no wisdom, nor for the uncontrolled is there the power of concentration; and for him without concentration there is no peace. And for the unpeaceful, how can there be happiness?”
–Bhagavad Gita (Ancient and Sacred Sanskrit Poem Incorporated into the Mahabharata)

“He who controls others may be powerful, but he who has mastered himself is mightier still.”
–Lao Tzu (Obscure Chinese Philosopher, Founder of Taoism and Alleged Author of the Tao-Te Ching, c. 604-c. 531 B.C.E.)

“ . . . let every man be swift to hear, slow to speak, slow to wrath.”
–The Bible, James 1:19

“When angry, count ten before you speak; if very angry, a hundred.”
–Thomas Jefferson (American Writer, Philosopher, Politician and, from 1801-1809, 3rd President of the United States, 1743-1826)