Here are some facts about depression, then a comment on some fascinating new research about inflammation and the brain. It gets a bit technical but is worth the read!
Causes of depression
We don’t know what causes depression. The predominant theory for the past few decades pertains to reduction of two neurotransmitters in the brain (Serotonin and Noradrenaline) Neurotransmitters are molecules that pass between nerve cells and between nerve cells and their supporting glial cells, enabling them to communicate. The recent article by Setiawan et al in JAMA Psychiatry illustrates a growing interest in the role of inflammation as a potential cause.
Depression affects around 300 million people worldwide (WHO) and is projected to increase, with the greatest increase in the uk being in those over 75 (according to the Kings Fund think tank). Depression is a serious illness, robbing people of their enjoyment of life. It is accompanied by a high level of disability – in severe case people can become bed bound, unable to care for themselves or enter a type of stupor. At its most severe, depression can lead to suicide.
In many cases it is a recurring condition. Single episodes tend to last several months. It is also a costly condition from a national perspective as the cost services to treat depression for the whole of England in 2007 was approximately £1.7 billion. If you include the amount from lost employment the total comes to £7.5 billion. We are fortunate in this country, however fewer than half of those affected worldwide have access to adequate treatment and health care.
Symptoms of depression:
WHO: Depression is characterized by sadness, loss of interest or pleasure, tiredness, feelings of guilt or low self-worth, disturbed sleep or appetite, and poor concentration which can feel like a poor memory. There can be many physical complaints with no apparent cause such as back pain or tummy pain.
However depression is often used as a catch-all term for a range of mental health conditions. In a way this is good, as it shows there is very little social stigma these days in having this diagnosis. But it is important to get the diagnosis right, so that people can get the right treatment. Many other conditions such as anxiety, eating disorders, harmful alcohol use and some physical conditions such as heart attacks, commonly co exist with depression.
Andreas Lubitz, the Germanwings co pilot who intentionally and tragically crashed a passenger plane on 24th March was described as having depression. Yet he did not seem to have any of the symptoms – his problems seemed more to do with anger, possibly rejection, inadequacy and fear. No doubt he was sad at times and may have had co-existant depressive episodes, but that was not his only problem. Describing someone like him as having depression can lead to stigma of genuine sufferers. People with depression are mostly a risk to themselves and not to other people.
Inflammation and depression
Translocator Protein – TSPO - is located exclusively in glial cells therefore it can be used as a marker for reactive gliosis (Reactive gliosis comprises the activation of microglia and astrocytes and is a hallmark response of the CNS to injury – Chen and Guilarte 2008) Before this was discovered, the only way to tell was from a tissue sample obtained through biopsy or post mortem. The location of the TSPO gene is in the q13.3 region of the long arm of human chromosome 22 (Riond et al., 1991).
Under normal physiological conditions TSPO levels in the CNS are very low and limited to glial cells (astrocytes and microglia). Microglia constantly survey their environment and have the ability to respond to brain injury within minutes by directing their ramifications to the site(s) of damage (Nimmerjahn et al., 2005). They proliferate and migrate to the sites of brain injury (Kreutzberg, 1996; Streit et al., 1988,1999 and 2000), characteristics that are not possessed by astrocytes (Chen and Guilarte 2008) which are more to do with supporting new growth of damaged neurones.
A dramatic increase in TSPO levels occurs in response to brain injury or inflammation. Despite many studies showing this increase, the mechanisms and physiological implications of how and why TSPO responds are still not known (Chen and Guilarte 2008)
It is measured through a minimally invasive technique - a small amount of a weak radioactive chemical (called a radio ligand) is injected which temporarily binds to the TSPO in the brain. A type of brain scan called a PET scan can detect these small amounts of radioactivity and show it as a picture on a screen. So this can theoretically be used to monitor disease progression and to assess the effectiveness of treatments. Since the 1900s, research teams have been using this technique to work out which parts of the brain are inflamed in a number of conditions such as stroke, MS and alzheimers dementia.
Brain inflammation is associated with many neurological conditions (stroke, head injury and some dementias). Setiawan et al’s paper is important because it is the first study that definitively links markers of brain inflammation with a mental (rather than physical) illness, bringing the concepts of depressive illness closer to that of a physical illness.
Setiawan et al summary: They used PET scanning (isotope with affinity to TSPO) to identify the distribution volume (amount) of Trans locator Protein expression in brain areas of people with MDE compared with controls. TPSO is a protein that is expressed on the outer membrane of mitochondria in microglia. They chose to measure this because one reason for increased TSPO expression is neuro inflammatory process. They had 20 people with moderate to severe MDE and 20 age matched controls.
They found that TSPO expression is increased in people with MDE and this appears to be linked to severity of depressive symptoms as recorded by the HDRS.
They assume that this TSPO expression is the result of microglial activation (microglia are monitoring and support cells in the brain which can become activated to respond to infection) and thus an indication at the cellular level of an inflammatory or immune mediated process. They make this assumption because of past studies that showed that i) induction of inflammation in humans is associated with depressed mood (27 ,39) and ii) that direct induction of central inflammation in rodents is associated with anhedonia. However they acknowledge that TSPO expression can arise for other reasons such as i) translocating cholesterol from the outer to the inner mitochondrial membranes for steroid hormone synthesis and ii) participating in the mitochondrial permeability transition pore hetero-oligomer, which influences predisposition toward apoptosis (programmed cell death). So there is no guarantee that the TSPO that they measured in their scans had anything to do with depression.
Also, this increased TSPO expression is not linked to increased expression of inflammatory markers in the peripheral system (similar results have occurred in other studies). A Danish study also published in JAMA Psychiatry (2013) showed a link between psychological distress (beyond that of typical stress) and CRP serum levels.
This study is not saying that when you are depressed your brain becomes inflamed (like a hot and swollen sprained ankle). It is only saying that there is evidence that some of the cells involved in the inflammatory response are more active or more numerous in some areas of the brain in people with severe depression. They are also not saying whether this is cause or effect. Another study (Otte et al) has shown correlation between one allele (version) of the serotonin transporter and increased adrenaline and it has been suggested that there is a link between depression, stress, and heart disease possibly related to inflammation. Again, more studies are required.
It is early days with this fascinating and important research, so we don't know for sure how clinically useful this will turn out to be. One reasons is because these changes in TSPO occur long before there is any visible structural change to the brain tissue itself.
One paper has proposed that exercise is a common mechanism that might be related to inflammation. (Exercise builds brain health: key roles of growth factor cascades and inflammation. Cotman et al, Trends in Neurosciences, Volume 30, Issue 9, p464–472,2007) ,.
After all this, it is tempting to think then that we should take anti inflammatory medications (like ibuprofen) for depression however a meta analysis (Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects A Systematic Review and Meta-analysis of Randomized Clinical Trials Ole Köhler et al JAMA Psychiatry. 2014;71(12):1381-1391) did not find any conclusive results. So we should be careful about over interpreting Setiawan et al's results for now. And obviously all drugs come with side effects, including anti inflammatories.
Despite these fascinating advances, it is important to remember that depression is a serious illness and people do sadly take their lives as a result. People suffering with depression should be encouraged to seek help and support. Talking therapies such as CBT and psychotherapy have also been shown to cause brain changes and it is important that people seek help if they are concerned.
Causes of depression
We don’t know what causes depression. The predominant theory for the past few decades pertains to reduction of two neurotransmitters in the brain (Serotonin and Noradrenaline) Neurotransmitters are molecules that pass between nerve cells and between nerve cells and their supporting glial cells, enabling them to communicate. The recent article by Setiawan et al in JAMA Psychiatry illustrates a growing interest in the role of inflammation as a potential cause.
Depression affects around 300 million people worldwide (WHO) and is projected to increase, with the greatest increase in the uk being in those over 75 (according to the Kings Fund think tank). Depression is a serious illness, robbing people of their enjoyment of life. It is accompanied by a high level of disability – in severe case people can become bed bound, unable to care for themselves or enter a type of stupor. At its most severe, depression can lead to suicide.
In many cases it is a recurring condition. Single episodes tend to last several months. It is also a costly condition from a national perspective as the cost services to treat depression for the whole of England in 2007 was approximately £1.7 billion. If you include the amount from lost employment the total comes to £7.5 billion. We are fortunate in this country, however fewer than half of those affected worldwide have access to adequate treatment and health care.
Symptoms of depression:
WHO: Depression is characterized by sadness, loss of interest or pleasure, tiredness, feelings of guilt or low self-worth, disturbed sleep or appetite, and poor concentration which can feel like a poor memory. There can be many physical complaints with no apparent cause such as back pain or tummy pain.
However depression is often used as a catch-all term for a range of mental health conditions. In a way this is good, as it shows there is very little social stigma these days in having this diagnosis. But it is important to get the diagnosis right, so that people can get the right treatment. Many other conditions such as anxiety, eating disorders, harmful alcohol use and some physical conditions such as heart attacks, commonly co exist with depression.
Andreas Lubitz, the Germanwings co pilot who intentionally and tragically crashed a passenger plane on 24th March was described as having depression. Yet he did not seem to have any of the symptoms – his problems seemed more to do with anger, possibly rejection, inadequacy and fear. No doubt he was sad at times and may have had co-existant depressive episodes, but that was not his only problem. Describing someone like him as having depression can lead to stigma of genuine sufferers. People with depression are mostly a risk to themselves and not to other people.
Inflammation and depression
Translocator Protein – TSPO - is located exclusively in glial cells therefore it can be used as a marker for reactive gliosis (Reactive gliosis comprises the activation of microglia and astrocytes and is a hallmark response of the CNS to injury – Chen and Guilarte 2008) Before this was discovered, the only way to tell was from a tissue sample obtained through biopsy or post mortem. The location of the TSPO gene is in the q13.3 region of the long arm of human chromosome 22 (Riond et al., 1991).
Under normal physiological conditions TSPO levels in the CNS are very low and limited to glial cells (astrocytes and microglia). Microglia constantly survey their environment and have the ability to respond to brain injury within minutes by directing their ramifications to the site(s) of damage (Nimmerjahn et al., 2005). They proliferate and migrate to the sites of brain injury (Kreutzberg, 1996; Streit et al., 1988,1999 and 2000), characteristics that are not possessed by astrocytes (Chen and Guilarte 2008) which are more to do with supporting new growth of damaged neurones.
A dramatic increase in TSPO levels occurs in response to brain injury or inflammation. Despite many studies showing this increase, the mechanisms and physiological implications of how and why TSPO responds are still not known (Chen and Guilarte 2008)
It is measured through a minimally invasive technique - a small amount of a weak radioactive chemical (called a radio ligand) is injected which temporarily binds to the TSPO in the brain. A type of brain scan called a PET scan can detect these small amounts of radioactivity and show it as a picture on a screen. So this can theoretically be used to monitor disease progression and to assess the effectiveness of treatments. Since the 1900s, research teams have been using this technique to work out which parts of the brain are inflamed in a number of conditions such as stroke, MS and alzheimers dementia.
Brain inflammation is associated with many neurological conditions (stroke, head injury and some dementias). Setiawan et al’s paper is important because it is the first study that definitively links markers of brain inflammation with a mental (rather than physical) illness, bringing the concepts of depressive illness closer to that of a physical illness.
Setiawan et al summary: They used PET scanning (isotope with affinity to TSPO) to identify the distribution volume (amount) of Trans locator Protein expression in brain areas of people with MDE compared with controls. TPSO is a protein that is expressed on the outer membrane of mitochondria in microglia. They chose to measure this because one reason for increased TSPO expression is neuro inflammatory process. They had 20 people with moderate to severe MDE and 20 age matched controls.
They found that TSPO expression is increased in people with MDE and this appears to be linked to severity of depressive symptoms as recorded by the HDRS.
They assume that this TSPO expression is the result of microglial activation (microglia are monitoring and support cells in the brain which can become activated to respond to infection) and thus an indication at the cellular level of an inflammatory or immune mediated process. They make this assumption because of past studies that showed that i) induction of inflammation in humans is associated with depressed mood (27 ,39) and ii) that direct induction of central inflammation in rodents is associated with anhedonia. However they acknowledge that TSPO expression can arise for other reasons such as i) translocating cholesterol from the outer to the inner mitochondrial membranes for steroid hormone synthesis and ii) participating in the mitochondrial permeability transition pore hetero-oligomer, which influences predisposition toward apoptosis (programmed cell death). So there is no guarantee that the TSPO that they measured in their scans had anything to do with depression.
Also, this increased TSPO expression is not linked to increased expression of inflammatory markers in the peripheral system (similar results have occurred in other studies). A Danish study also published in JAMA Psychiatry (2013) showed a link between psychological distress (beyond that of typical stress) and CRP serum levels.
This study is not saying that when you are depressed your brain becomes inflamed (like a hot and swollen sprained ankle). It is only saying that there is evidence that some of the cells involved in the inflammatory response are more active or more numerous in some areas of the brain in people with severe depression. They are also not saying whether this is cause or effect. Another study (Otte et al) has shown correlation between one allele (version) of the serotonin transporter and increased adrenaline and it has been suggested that there is a link between depression, stress, and heart disease possibly related to inflammation. Again, more studies are required.
It is early days with this fascinating and important research, so we don't know for sure how clinically useful this will turn out to be. One reasons is because these changes in TSPO occur long before there is any visible structural change to the brain tissue itself.
One paper has proposed that exercise is a common mechanism that might be related to inflammation. (Exercise builds brain health: key roles of growth factor cascades and inflammation. Cotman et al, Trends in Neurosciences, Volume 30, Issue 9, p464–472,2007) ,.
After all this, it is tempting to think then that we should take anti inflammatory medications (like ibuprofen) for depression however a meta analysis (Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects A Systematic Review and Meta-analysis of Randomized Clinical Trials Ole Köhler et al JAMA Psychiatry. 2014;71(12):1381-1391) did not find any conclusive results. So we should be careful about over interpreting Setiawan et al's results for now. And obviously all drugs come with side effects, including anti inflammatories.
Despite these fascinating advances, it is important to remember that depression is a serious illness and people do sadly take their lives as a result. People suffering with depression should be encouraged to seek help and support. Talking therapies such as CBT and psychotherapy have also been shown to cause brain changes and it is important that people seek help if they are concerned.
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