Issue :2927
Date :27th of July 2013
'Depression that resists every treatment is on the rise, but luckily the key to a cure may already be in our hands, says Samantha Murphy.
Over the past decades it has been found that the effectiveness of anti-depressant drugs is overstated, so much so that some pharmaceutical companies have stopped researching the drugs altogether. The stubborn nature of these cases of depression has, however spurred research into new and sometime unorthodox treatments. Surprising and impressive results suggest that we have fundamentally understood the disorder.
In fact the new research has has opened the doors to thinking about depression not as a single condition nut a continuum of illnesses, all with different underlying neurological mechanisms which if understood could come to help us produce effective treatments. This new idea has sparked a recent interest in drug development which has not been since the 1950's.
Depression is a illness that it is estimated to effect 1/6 of the population at some point of our lives. The symptoms include insomnia, hopelessness, loss of interest in life, chronic exhaustion and is thought (although not proven ) to increase chances of ailments such as heart disease.
It is often thought that the social stigma surrounding depression prevents around half of suffers from reviving treatment and the world health organisation has stated depression as the leading cause if disability in the world.
So what causes people to become depressed ?
The dominant theory is that depression results from chemical imbalance in the brain, with the neurotransmitter serotonin thought to be the key chemical. Many think that depression is linked to low levels of serotonin something that was thought to disrupt the brains ability to pass messages across synapses (tiny gaps between neurons)
The theory was that a boost in serotonin should return neural signalling and mood to normal levels. (Interestingly the primary compound in ecstasy- MDMA is also a know serotonin booster.)
The first drug developed on the serotonin hypothesis was launched in the 1980's and nearly all anti depressants developed since have worked on the same principles i.e. keep levels of serotonin high and prevent the brain from reabsorbing and recycling it.
Though such drugs remain the go-to tools for fighting depression they however seem to be getting less and less effective. Clinical trial sin the 80's and 90's indicated that the drug should help up to 90 per cent of depressed people go into remissions. More recent studies however paint a different picture in the 2000's studies showed that standard antidepressants worked only 60 to 70 percent for suffers.
Is it possible that the drugs were not as effective as first thought ?
To approve a given antidepressant the US Food and Drug Administration only requries two large scale studies to verify that the drug is superior to a placebo.However the companies are under no legal obligation to supply the FDA with every study that they have conducted. When David Mischoulon, director of psychiatry research at the Massachusetts General Hospital in Boston and shifted through data of from pharmaceutical trials he found that there were in fact many more negative results. A high percentage of the studies showed that the drugs were only slightly better than the placebo.
''now we think its more in the neighborhood of 50% of people who may respond to a given antidepressant.'' says Mischoulon.
Indeed a 2007 study showed that the serotonin levels in the brains of depressed people not receiving treatment were double those in volunteers who were not depressed. It was in wake of this that several pharmaceutical companies have stopped their work on mood disorders altogether. GlaxoSmithKline- the company that makes the well known antidepressant Paxil and Wellbutrin announced in 2010 that it would be halting research into depression
With a reduction of new more effective treatment clinicians began to look for new therapies that could treat patients that did not respond to traditional serotonin deficit reducing drugs.
After drug treatment and behavioral therapy failed one treatment that patients responded to is know as repetitive transcranial magnetic stimulation (rTMS). Patients would put a big cap on there head and sit under a large machine for about 20 minutes while a brief electric current passed through a small coil positioned a few inches above the left temple, creating a fleeting high-intensity magnetic pulse. After treatments a previously drug resistant patients stopped self harming and found it easier to get out of bed in the mornings.
Since the start of 2013 10 people have been successfully treated using rTMS. The treatment is by no means producing paradigm shifting results in a study only 12 out of 28 people responded to rTMS however considering that these people had failed to respond to all other treatment it presents a step in the right definition.
The treatment is by no means cheap treatment is not available on the NHS due to insignificant evidence and so treatment will cost an individual up to £6000
A possible cheaper alternative came from the US which shows similar promises. Cranial electrical stimulation. It is also more simply it involves delivering a tiny current with two electrodes strapped to the head using a sweatband. Unlike rTMS equipment, which is very bulky this device is roughly the size of a deck of cards and is available with a prescription.
Stephen Xenakis is a doctor, former general and former adviser to the US department of defense. He asks patients to use the device for 20 minutes twice a day. He says ''sometimes this can help in ways that the medication does not'' '' The thing that I've seen it help the most with is insomnia and anxiety'' conditions which fuel and is both fueled by depression (and therefore treatment related depression )
In terms of the most convenient alternative treatments however the most promising appears to be in the drug ketermine. Ketamine was initially developed and still is used as a house tranquilizer and has found popularity over the last decade as a recreational club narcotic . A study in 2000 with 8 people showed that when given intravenously it had almost instant effects on lifting previously untreatable depression. Several larger scale studies have replicated results. A clinical study involving 72 people with previously untreated depression experienced relief from suicidal thoughts for up to 40 minutes. Some doctors are suggesting that it could work for up to 60% of people, while initially this may not seem like a large percentage these are people for which no standard form of treatment had been successful. Some patients go into remission within a day and some can remain free from depression for up to 10 days .
So why have this group of patients responded to Ketermine as a treatment when all conventional methods have failed ? Researchers have investigated the mechanisms by which they think ket works and have come up with the link of Glutamate. Glutamate is the most dominant stimulatory neurotransmitter in the brain, playing key roles in learning, motivation, memory and plasticity. Some researchers think that that levels of glutamate like serotonin are too low in the brains of depression suffers.
Glutamate differs from serotonin as instead of simply aiding in the transport between neurons, it is thought that glutamate may be a factor in helping the brains neurons repair themselves. This is line with a recent theory that depression causes some dendrites (message relaying fingers at the end of neurons ) to shrivel . The synapes effectively become like broken bridges with messages unable to cross the effective neurons.
Ketamine trials were the first indicators of glutamates possible significance. Ketamine sets off a complexed set off complex chain reactions. First it blocks the specific receptors that glutamate binds to, thus relesaing a tide of the chemicals into the synapes. This leads to an increase in the production of a protein called 'brain-derived neurotrophic factor' which has been shown in animal studies to help dendrites to sprout new spines which help them receive messages from nearby neurons.
A experiment where rats were injected with ketermine at Yale university showed that there was a boost of glutamate in the prefrontal cortex along with a fast increase in the formation of synapses. Similar studies with rTMS have shown similar results. Suggested ideas inculde that in some cases depression may be better explained as a disorder of neuron structure rather than being due to a chemical inbalance. This still doesn't mean that serotonin is out of the picture.
In the diagnostic and statistical manual of mental disorders, the bible of psychiatry in the US already subdivides depression into different categories such as post-natal or dipolar with the the same underlying neurophysiologial mechanisms however new research could change that with depression being potentially a wide continuum of illnesses lumped together under the general term with either serotonin and glutamate as a key factor.
New Beginnings
The next question to ask is how do we determine what kind of treatment a person will best respond to. Studies have shown that if you don't get a day one response to ketamine then you are unlikely to ever get one. Work to produce diagnostic tests are already under way with scientists trying to identify certian factors in the blood that could be ascribed to certain types of depression. Brain scans are another possibility of which are already used to find if somebody is responding to talk-theray or medication.
It is important to note that these ideas are in their infancy but luckly recently at least 5 companies have started work on ketamine, drugs such as GLYX-13 which has shown promise in preclinical trails. Large scale companies such as AstraZenca, Roche and Jassen among others are also developing pills and intervenous drugs the first of which are still a few years away from shelves. Some companies are focusing on use of glutamates drugs as a first line of treatment as opposed to last.
We are left with one tantalising possibility, if glutamate affects neuroplasicity could both treatment and depression lead to lasting changes in the structure of the brain ? George Aghajanian from Yale whose seminal work inspied the ketamine trials says that for people predisposed to to recurring depression depression, ketamine may help neurons permanently maintain new and thicker connections. In his recent work on rats he found that the drug combine with other compounds leads to long term structual repairs in the brain but whether the same is true in humans remains to be seen.
Whatever the future holds, glutamate and the new possibilities it has raised has at least enabled us to start thinking about depression in a different way which is a rare event in the troubled waters of psychiatry.
Depression is a illness that it is estimated to effect 1/6 of the population at some point of our lives. The symptoms include insomnia, hopelessness, loss of interest in life, chronic exhaustion and is thought (although not proven ) to increase chances of ailments such as heart disease.
It is often thought that the social stigma surrounding depression prevents around half of suffers from reviving treatment and the world health organisation has stated depression as the leading cause if disability in the world.
So what causes people to become depressed ?
The dominant theory is that depression results from chemical imbalance in the brain, with the neurotransmitter serotonin thought to be the key chemical. Many think that depression is linked to low levels of serotonin something that was thought to disrupt the brains ability to pass messages across synapses (tiny gaps between neurons)
The theory was that a boost in serotonin should return neural signalling and mood to normal levels. (Interestingly the primary compound in ecstasy- MDMA is also a know serotonin booster.)
The first drug developed on the serotonin hypothesis was launched in the 1980's and nearly all anti depressants developed since have worked on the same principles i.e. keep levels of serotonin high and prevent the brain from reabsorbing and recycling it.
Though such drugs remain the go-to tools for fighting depression they however seem to be getting less and less effective. Clinical trial sin the 80's and 90's indicated that the drug should help up to 90 per cent of depressed people go into remissions. More recent studies however paint a different picture in the 2000's studies showed that standard antidepressants worked only 60 to 70 percent for suffers.
Is it possible that the drugs were not as effective as first thought ?
To approve a given antidepressant the US Food and Drug Administration only requries two large scale studies to verify that the drug is superior to a placebo.However the companies are under no legal obligation to supply the FDA with every study that they have conducted. When David Mischoulon, director of psychiatry research at the Massachusetts General Hospital in Boston and shifted through data of from pharmaceutical trials he found that there were in fact many more negative results. A high percentage of the studies showed that the drugs were only slightly better than the placebo.
''now we think its more in the neighborhood of 50% of people who may respond to a given antidepressant.'' says Mischoulon.
Indeed a 2007 study showed that the serotonin levels in the brains of depressed people not receiving treatment were double those in volunteers who were not depressed. It was in wake of this that several pharmaceutical companies have stopped their work on mood disorders altogether. GlaxoSmithKline- the company that makes the well known antidepressant Paxil and Wellbutrin announced in 2010 that it would be halting research into depression
With a reduction of new more effective treatment clinicians began to look for new therapies that could treat patients that did not respond to traditional serotonin deficit reducing drugs.
After drug treatment and behavioral therapy failed one treatment that patients responded to is know as repetitive transcranial magnetic stimulation (rTMS). Patients would put a big cap on there head and sit under a large machine for about 20 minutes while a brief electric current passed through a small coil positioned a few inches above the left temple, creating a fleeting high-intensity magnetic pulse. After treatments a previously drug resistant patients stopped self harming and found it easier to get out of bed in the mornings.
Since the start of 2013 10 people have been successfully treated using rTMS. The treatment is by no means producing paradigm shifting results in a study only 12 out of 28 people responded to rTMS however considering that these people had failed to respond to all other treatment it presents a step in the right definition.
The treatment is by no means cheap treatment is not available on the NHS due to insignificant evidence and so treatment will cost an individual up to £6000
A possible cheaper alternative came from the US which shows similar promises. Cranial electrical stimulation. It is also more simply it involves delivering a tiny current with two electrodes strapped to the head using a sweatband. Unlike rTMS equipment, which is very bulky this device is roughly the size of a deck of cards and is available with a prescription.
Stephen Xenakis is a doctor, former general and former adviser to the US department of defense. He asks patients to use the device for 20 minutes twice a day. He says ''sometimes this can help in ways that the medication does not'' '' The thing that I've seen it help the most with is insomnia and anxiety'' conditions which fuel and is both fueled by depression (and therefore treatment related depression )
In terms of the most convenient alternative treatments however the most promising appears to be in the drug ketermine. Ketamine was initially developed and still is used as a house tranquilizer and has found popularity over the last decade as a recreational club narcotic . A study in 2000 with 8 people showed that when given intravenously it had almost instant effects on lifting previously untreatable depression. Several larger scale studies have replicated results. A clinical study involving 72 people with previously untreated depression experienced relief from suicidal thoughts for up to 40 minutes. Some doctors are suggesting that it could work for up to 60% of people, while initially this may not seem like a large percentage these are people for which no standard form of treatment had been successful. Some patients go into remission within a day and some can remain free from depression for up to 10 days .
So why have this group of patients responded to Ketermine as a treatment when all conventional methods have failed ? Researchers have investigated the mechanisms by which they think ket works and have come up with the link of Glutamate. Glutamate is the most dominant stimulatory neurotransmitter in the brain, playing key roles in learning, motivation, memory and plasticity. Some researchers think that that levels of glutamate like serotonin are too low in the brains of depression suffers.
Glutamate differs from serotonin as instead of simply aiding in the transport between neurons, it is thought that glutamate may be a factor in helping the brains neurons repair themselves. This is line with a recent theory that depression causes some dendrites (message relaying fingers at the end of neurons ) to shrivel . The synapes effectively become like broken bridges with messages unable to cross the effective neurons.
Ketamine trials were the first indicators of glutamates possible significance. Ketamine sets off a complexed set off complex chain reactions. First it blocks the specific receptors that glutamate binds to, thus relesaing a tide of the chemicals into the synapes. This leads to an increase in the production of a protein called 'brain-derived neurotrophic factor' which has been shown in animal studies to help dendrites to sprout new spines which help them receive messages from nearby neurons.
A experiment where rats were injected with ketermine at Yale university showed that there was a boost of glutamate in the prefrontal cortex along with a fast increase in the formation of synapses. Similar studies with rTMS have shown similar results. Suggested ideas inculde that in some cases depression may be better explained as a disorder of neuron structure rather than being due to a chemical inbalance. This still doesn't mean that serotonin is out of the picture.
In the diagnostic and statistical manual of mental disorders, the bible of psychiatry in the US already subdivides depression into different categories such as post-natal or dipolar with the the same underlying neurophysiologial mechanisms however new research could change that with depression being potentially a wide continuum of illnesses lumped together under the general term with either serotonin and glutamate as a key factor.
New Beginnings
The next question to ask is how do we determine what kind of treatment a person will best respond to. Studies have shown that if you don't get a day one response to ketamine then you are unlikely to ever get one. Work to produce diagnostic tests are already under way with scientists trying to identify certian factors in the blood that could be ascribed to certain types of depression. Brain scans are another possibility of which are already used to find if somebody is responding to talk-theray or medication.
It is important to note that these ideas are in their infancy but luckly recently at least 5 companies have started work on ketamine, drugs such as GLYX-13 which has shown promise in preclinical trails. Large scale companies such as AstraZenca, Roche and Jassen among others are also developing pills and intervenous drugs the first of which are still a few years away from shelves. Some companies are focusing on use of glutamates drugs as a first line of treatment as opposed to last.
We are left with one tantalising possibility, if glutamate affects neuroplasicity could both treatment and depression lead to lasting changes in the structure of the brain ? George Aghajanian from Yale whose seminal work inspied the ketamine trials says that for people predisposed to to recurring depression depression, ketamine may help neurons permanently maintain new and thicker connections. In his recent work on rats he found that the drug combine with other compounds leads to long term structual repairs in the brain but whether the same is true in humans remains to be seen.
Whatever the future holds, glutamate and the new possibilities it has raised has at least enabled us to start thinking about depression in a different way which is a rare event in the troubled waters of psychiatry.
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