Treatment Of Depression Research Paper
Scientific Investigation
Paul Devlin
The Treatment of Depression
Current Methods and Groundbreaking New Treatments
Introduction
Depression is a very real and serious mental health condition which statistics show will affect 1 in 5 people, either directly or through a friend or relative suffering from the condition. Several neuroscience and genetic investigations clearly demonstrate that depression is a disorder of the brain, one which modern imaging techniques can reveal. Where in the past, the general consensus was that depression was a condition directly related to environment, new neural imaging technologies can show that physical changes are present in the brain of a depressed person and that by studying certain areas of the brain …show more content…
believed to be involved in the control of emotion, we can better understand the mechanisms of depression and the areas of the brain where these mechanisms take place or have an effect.
As stated in Neuroimaging and depression: Current status and unresolved issues
Author(s): Gotlib Ian H. ; Hamilton J. Paul Volume 17 2008
“Over the past decade, neuroscientists examining the ‘‘emotion circuitry’’ of the brain have documented the involvement of the limbic system, a complex of structures including the amygdala, hippocampus, insula, and parts of the anterior cingulate cortex (ACC), in the experience and expression of emotional states. Among these structures, the amygdala and the ventral (i.e. bottom) aspect of the ACC, most often referred to as the subgenera ACC, have received the most attention from investigators interested in depression. Whereas the amygdala has been shown to play a prominent role in emotionally mediated attention, in assigning emotional significance to stimuli, and in remembering emotionally significant events, the subgenual ACC appears to mediate subjective experience of emotion and emotional reactions to stimuli, particularly stimuli associated with reward seeking. These two structures are involved directly in the experience and processing of emotion, but investigators have also examined cortical structures, most notably the dorsolateral prefrontal cortex (DLPFC), that appears to be involved in the regulation of emotion.” Symptoms of depression vary greatly from patient to patient but it is appropriate to list the most common and prevalent. As stated on the website mind.org.uk, depression is a state of low mood which can affect a person’s thoughts and feelings. This can then lead to changes in behaviour and aversion to normal activities. Depressed people often report very similar symptoms all usually report feelings of sadness and anxiety, intense feelings of worthlessness and hollowness. Symptoms often manifest themselves physically resulting in a loss of intrest in normal activities, the inability to experience pleasure in normally enjoyable activities, the inability to concentrate, weight loss, fatigue and panic attacks. Up until about 50 years ago depression was diagnosed as either a biological condition (endogenous) where there was an unknown biological reason for the person’s symptoms, or reactive, where an event in the person’s life, such as the death of a loved one initiated the depressive symptoms. The most universally accepted continuum is that both are major factors and that each can individually or both contribute to the depressive state.
This investigation will look at the science of depression, the new technologies being used to establish and cure depressive symptoms and some ground breaking research which is currently being conducted worldwide to find new effective, fast acting treatments. Major studies are being carried out to establish new drugs which can utilise specific circuitry in the brain to overcome the problems associated with the treatment of depression.
Psychotherapy CBT and Depression
As stated on the AAFP website (http://www.aafp.org/afp/2006/0101/p83.html January 1 2006) Psychotherapy can often be the initial course of treatment for someone diagnosed with depression. It involves the depressed person sitting down and talking with a qualified health professional about their thoughts, feelings and depressive behaviours. It takes on many forms and every psychotherapist will have their own approach, also the nature of the patient’s condition will heavily influence the course of action taken. Psychotherapy has been found to be very effective on its own for treatment of a wide range of mental illnesses, including depression and anxiety. However it is often found that psychotherapy or counselling along with pharmaceutical treatment produces the most effective results for curing depression. Where a person has suffered a hardship in his or her life such as the end of a relationship, the death of a loved one, or losing a job, psychotherapy can often be used alone to treat someone who has developed depressive symptoms because of this event. It is often the case however that a chemical imbalance in the brain has been established which can be corrected using pharmaceuticals. Before being prescribed any psychoactive medication, any patient should be assessed to determine the extent and nature of their depression and also to ensure they are not currently taking any other medications which could have negative interactions with a certain class of antidepressant. Cognitive behaviour therapy (CBT) is an area of psychotherapy which operates under the theory that the thought process proceeds and influences mood (happiness, depression, pro-activity), and that by enforcing positive thinking, a person’s mood can be influenced or controlled.
Use of Tricyclic Antidepressants
These were first discovered in the 1950’s and primarily used as treatment for depression. They are so named for the tri ring structure of the molecule as shown. In modern times more newly developed antidepressants, such as SSRI’s are much more widely prescribed than TCA and have virtually replaced them. This is largely due to the many adverse side effects associated with TCA’s.
As stated on the website http://www.rxlist.com/script/main/art.asp?articlekey=95236 TCA’s, along with most classes of anti-depressant can take weeks to take effect – a common issue with depression treatment. TCA’s work by affecting neurotransmitters in the brain, as do almost all antidepressants. For TCA’s it is primarily serotonin and norepinephrine which are affected. These chemicals are released naturally in the brain to help with normal bodily functions and control mood. However when depression is present, less of these chemicals are present in the brain, are not released in sufficient amounts, or are reabsorbed too quickly. TCA’s help control this reabsorption by the nerve cells of the brain. However TCA’s also block histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this lack of selectivity is what accounts for the unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. Of course all antidepressants tend to have negative associated side effects. We will now look at a common TCA which is prescribed for depression, Amitriptyline which is also prescribed in low doses for the treatment of insomnia.
The website http://www.drugbank.ca/drugs/DB00321 13/01/2005 states the following, Amitriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non depressed patients, it does not tend to affect mood, or sexual arousal but is often used for its sedative effects in small doses for the treatment of insomnia. In people who are depressed, amitriptyline exerts a positive effect on mood. TCAs are very potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. In this way TCA’s interact with the brains feel good circuitry and have a positive effect on a person’s general mental state. Their long list of negative side effects however has led to a vast reduction in their use, and major preference being given to SSRI’s and other drugs for the treatment of depression.
Chemical Structure of Amitriptyline (common TCA)
Chemical Formula: C20H23N
IUPAC Name: dimethyl({3-[(2Z)-tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene]propyl})amine
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Amytriptiline)
Use Of SSRI Antidepressants
As stated on http://www.brainphysics.com/howprozacworks.php SSRI’s or selective serotonin re-uptake inhibitors are a class of drug used to treat depression. SSRI’s are believed to increase the cellular level of the neurotransmitter serotonin. It does this by inhibiting the reuptake of serotonin into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available for binding to the postsynaptic receptor. They can also have an effect on the selectivity of other monoamine transporters, with pure SSRI’s having very weak affinity for noradrenaline and dopamine. SSRI’s work by inhibiting the reuptake of serotonin after being released by synapses. Serotonin (sometimes abbreviated 5-HT (5-hydroxytryptamine)) is a neurotransmitter that can affect several vital human functions, such as sleep, appetite, sex drive, general motivation. This can then have a knock on effect on human behaviours which affect the person suffering from depression in a wide range of ways from chronic fatigue to suicidal thoughts. SSRI’s are also subject to the common issue with antidepressant medications in that they can take weeks to have any positive effects.
In understanding how SSRI’s work, it is necessary to look at how the brain works in terms of synapses and neurotransmitters. A brain cell or neuron has 3 main parts, the axon, the cell body and dentrides. Dentrides protrude out from the neuron. The axon is a singular long protrusion from the cell body. The axon of one neuron connects to the dentrides of many others forming vast networks. The synapses are the points of connection between neurons – a gap between the axon of a neuron and the dentride and cell body of many others. This is where serotonin and other brain chemicals come into play. Electrochemical communication occurs at these junctions.
Neurotransmitters are chemicals, each with its own specific effects when activated in the brain. The axon releases these and they cross the synapse. Each brain chemical carries an individual message and fits like a key into a receptor on the other side to produce a desired effect on the brain. Each receptor has a very specific shape corresponding to the neurotransmitter it receives. So in these terms, serotonin provides the key to a network in the brain associated with positive, healthy thinking which in turn leads to what we consider a happy and stable emotional condition. This of course is a very small part of how the brain controls mood and emotions as a whole. Several other chemicals are involved and of course, human beings are subject to natural feelings of prolonged sadness or low mood due to the occurrence of things like the end of relationships, or death of a loved one. It is however serotonin which SSRI’s are specifically engineered to interact with and they come into play when someone experiences what we would consider an extreme emotional state, like clinical depression. Their use is based on the theory that someone with a healthy neurochemical balance has a stable mental condition and that when an imbalance occurs, mental states such as depression can occur. This imbalance is then in theory corrected by the use of an SSRI. Other antidepressant medications may have different effects on different neurotransmitters and in a variation of ways, but all operate under this theory: the correction of a chemical imbalance in the brain, using drugs which have been designed to target specific neurotransmitters to have a positive influence on a person’s mental state. We will now look at a specific SSRI called fluoxetine, a drug which is wildly prescribed around the world.
A stated in http://www.drugbank.ca/drugs/DB00472 Fluoxetine comes in capsule and tablet form and is prescribed for depression. It metabolizes to nor fluoxetine. It blocks the reuptake of serotonin on the serotonin reuptake pump of the neuronal membrane which enhances the actions of certain auto receptors. By binding with significantly less histamine, norepinephrine, and acetylcholine receptors than TCA antidepressant drugs, SSRI’s like fluoxetine produce far less undesirable side effects and are therefore are now far more widely used. This appear to be the case with antidepressant drugs on a whole – while we do have access and understanding of some of the medications we currently use, through drug development me can improve and optimise the way we treat these conditions.
Chemical structure of Fluoxetine
Chemical Formula: C17H18F3NO
IUPAC Name: methyl({3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl})amine
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Fluoxetine)
Use Of TeCA Anti-Depressants
The following information was partially taken from the website http://www.psyweb.com/Glossary/tca.jsp .Tetracyclic antidepressants, so called for their four ringed chemical structure are another class of antidepressants. They are closely related to TCA’s but some have been found to have far less adverse side effects. One very successful TeCA is mirtazapine. In a recent study it was found to be superior to several SSRI’s and other widely prescribed antidepressants. Mirtazapine was found to have very few serious side effects on most patients.
As stated in the website http://www.drugbank.ca/drugs/DB00370 13/06/2005 , By acting as an antagonist at central pre-synaptic alpha(2)-receptors, Mirtazapine inhibits negative feedback to the presynaptic nerve and causes an increase in NE release. By blocking heteroreceptors which are contained in serotonergic neurons, Mirtazapine interacts with the release of 5-HT. This in turn increases the interaction between 5-HT and 5-HT2 receptors, which increases the anxiolytic effects of the drug. Mirtazapine’s weak interactions with other receptors in the brain may explain why studies show the drug has lower reported adverse effects such as anxiety, insomnia and nausea. It also shows strong antagonistic effects on a particular receptor in the brain which contributes to its sedative effects. This is sometimes a positive side effect of the drug and it is often recommended as an antidepressant to be taken a night, helpful if the person taking the drug has trouble sleeping or relaxing at night as a result of their condition.
Chemical Structure of Mirtazapine
Chemical Formula C17H19N3
IUPAC Name: 5-methyl-2,5,19-triazatetracyclo[13.4.0.0^{2,7}.0^{8,13}]nonadeca-1(19),8(13),9,11,15,17-hexaene
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Mirtazapine)
Use Of MAOI Antidepressants
As stated in http://maija-haavisto.suite101.com/maoi-antidepressants-a95231 MAOI’s or Monoamine oxidase inhibitors are another class of antidepressants traditionally used when the other classes such as SSRI’s and TCA’s have failed. This is due to the long list of negative and often potentially lethal drug interactions MAOI’s can be associated with if not correctly prescribed and monitored. MAOIs act by inhibiting the activity of monoamine oxidase in the human brain. By preventing the breakdown of monoamine neurotransmitters, their availability for use as a part of the brains feel- good circuitry - that which is associated with regulating a stable and happy emotional condition, is increased. Monoamine oxidase has two isoforms MAO-A and MAO-B. These act preferentially towards specific neurotransmitters and drugs can be developed to have stronger interactions with each isoform. Both MAO-A and MAO-B take part in deamination with certain neurotransmitters. This is a chemical function whereby an amine group is removed from a molecule. MAO-A is primarily involved with the deamination of serotonin, melatonin, epinephrine and norepinephrine. MAO-B is preferential, in deamination, to phenylethylamine and trace amines. Both MAO-A and MAO-B deaminate dopamine equally. Clearly the clinical implications of being able to manipulate drugs, at the molecular level , are vital in the proper use and development of MAOI’s.
Possible Development Of Ketamine For Treatment Of Depression
There are currently several scientific investigations under way involving surprising substances which may have properties which can be manipulated in the lab to produce molecules which could be extremely useful in the development of drugs for the treatment of depression. Ketamine is one such drug which is currently being investigated for this purpose. Traditionally used in veterinary (and rarely) human medicine for its anaesthetic properties, ketamine may hold the key to a new approach in the treatment of depression in humans. The key lies in the way ketamine molecules interact with the body and brain when compared to conventional medicines. Chemical Structure Of Ketamine
Chemical Formula: C13H16ClNO
IUPAC Name: 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one http://www.drugbank.ca/drugs/DB01221 Ketamine is a very fast acting general anaesthetic. It produces an anaesthetic state characterised by profound analgesia, cardiovascular and respiratory stimulation and other effects. It has been termed a dissociative anaesthesia, in that it selectively and temporarily disrupts association pathways in the brain before producing semesthetic sensory blockade
Ketamine is now a common recreational drug.
It is most often insufflated producing strong visual and out of body experiences. It acts very rapidly producing very strong and profound effects on the user (depending on dosage). Users often report what is referred to as ‘the k-hole’ where on taking large doses of the drug, one’s mind becomes ‘dissociated’ from the body resulting in very powerful and personal hallucinations, not just visual however like other hallucinogens such as LSD. When in a ‘k-hole’ the user can be unaware of their own existence, often forgetting where they are, what they are, and experiencing complete mental detachment from the …show more content…
body.
Ketamine’s unusual effects have evidently caught the attention of serious scientific researchers, and is now the subject of several ongoing studies of its possible medicinal uses. Firstly it has been shown that in very low doses the drug produces antidepressant effects which are extremely rapid in effect. Compared to traditional antidepressants, which can take days or weeks to take effect, studies involving ketamine show that the drug can have positive antidepressant effects within minutes, which can last up to ten days. These studies are in early stages and so data is limited. The really exciting possible outcome is that traditional and effective methods of reducing the symptoms of depression(SSRI’s, MAOI’s) could somehow be manipulated to have the same effects but use the mechanism which ketamine exploits to effect the brain so rapidly.
Over the past decade, much research has focused on the neurotransmitter glutamate, a substance responsible for the transportation of signals through the spinal cord and brain. Glutamate plays an important role in the brains signalling system, and evidence from recent studies suggests that controlling and moderating the system in which it is involved could hold the future key to the treatment of depression. As mentioned previously it is ketamine’s extremely rapid interaction which makes it so interesting, an article in The Guardian newspapers science blog revealed the following statistic:
“in trials on patients with treatment resistant MDD (Major Depressive Disorder) some showed improvements within only 40 minutes. Over 70% responded within 24 hours, reaching a level that took six to eight weeks to occur with traditional therapeutics.”
Ketamine is known to inhibit proteins which have interactions with glutamate. Other more familiar antidepressants are known to have interactions with members of the same chain. However ketamine appears to hold the key to a short cut in this process, explaining why the drug can take effect dramatically quicker. It should also be noted that as well as this so called ‘short cut’ mechanism ketamine utilises, it appears to trigger a chain of events leading to the formation of new synapses, furthermore enhancing its fast acting capabilities.
Dr. Ron Duman of Yale University is a well known neuroscientist who has focussed his research on the human brain and depression. He led a research team which has carried out an investigation into the possible clinical use of ketamine or similar substances as antidepressant medications. The reason for this study being carried out again highlights a worrying statistic about current antidepressants. About 40% of patients appear non responsive to current antidepressants, and almost all take weeks to take effect. Studies have been carried out by scientists at the National Institute of Mental Health into both major depressive disorder, and bipolar depression, both conditions tend to see treatment resistant patients. The studies showed that over 70% of patients like this showed dramatic improvements after just one day of treatment, and one dose of ketamine – such surprising and positive results cannot be ignored. Ketamine however is not the perfect agent for practical treatment – it must be administered intravenously and can have strong negative side effects. Therefor it is hoped another substance can be discovered or engineered to have the same positive neural effects but can be a practical medication at the same time. The study looks further into the mechanism which ketamine utilises in the brain.
As we have already discussed, the most commonly prescribed antidepressants take effect primarily on the serotonin messenger circuit of the brain, whereas ketamine utilises the glutamate system. Evidence appears to suggest that the medications which act on serotonin trigger a series of events that promoted healthy brain development. It appears that they can stimulate the birth of new neurons. These neurons can then go on to establish new connections or synapses with other neurons which overall promotes healthy brain activity. It appears that this process of building and establishing new connections can take weeks to happen – explaining the apparent delay in response to treatment with traditional serotonin acting drugs. Ketamine’s use of the glutamate system appears to stimulate similar activity but much quicker, suggesting that its mechanism occurs closer and more directly to the source of the problem. Ketamine was known to block glutamate from binding to a specific receptor protein on cell membranes known as the NMDA receptor. To understand how this leads to an antidepressant effect in patients, the team carrying out the investigation traced the signal path in the brain which this blockade triggered.
The team found that in the pre frontal cortex of rats which had been treated with a low dose of ketamine, the rapid activation of an important enzyme was occurring. This is known as the mammalian target of rapamycin (mTOR) which makes proteins forming the connections between neurons or synapses. Neither common antidepressants, nor electroconvulsive therapy have been shown to similarly activate mTOR. Depression is known to have the exact opposite effect of ketamine on the synapses of the brain – they cause shrivelling and the reduction in the proteins needed to build new ones. A single dose of ketamine has been shown to make these proteins readily available, and promote healthy growth and development in the synapses and this is very significant.
In the image below we can see the budding synapses on the image displaying the pre frontal cortex of the rats treated with ketamine compared to those without.
(Image taken from http://www.nimh.nih.gov/science-news/2010/rapid-antidepressant-works-by-boosting-brains-connections.shtml)
Dr Duman had this to say about the image
“Neuronal spines, budding connections between brain cells, or synapses, sprouted in rats within hours of receiving ketamine (arrows). By contrast, fewer spines developed on neurons of control rats that didn't receive the drug. The boost in neuronal connectivity is thought to produce an antidepressant effect by enhancing brain circuit activity. The highly magnified two photon imaging pictures show extensions of neurons in rat prefrontal cortex.”
So what is the key idea the research has discovered? By identifying the cellular signalling system through which ketamine operates, it has been established that mTOR is essential for ketamine to boost and increase synapse formation. The serotonin based medications appear to trigger the birth of new neurons – known as neurogenesis, which in turn has an eventual anti-depressant effect on the brain. Ketamine however stimulated the glutamate circuitry which seems to be involved with the growth of existing neurons and synapses, a far more direct solution which takes place in the pre frontal cortex. It is this idea that may hold the key to the future development of medications to treat depression in human beings.
The ketamine studies used in this report come from Dr Duman, Yale University radio interview: NIMH Radio: Dr. Ron Duman of Yale University talks about ketamine research and treatment for major depression.
And also in the article in the guardian: http://www.guardian.co.uk/science/blog/2011/jan/27/ketamine-medicinal-use-treat-depression 27/01/2011
Conclusion
When examined it is quite surprising, given that depression is now so commonly experienced and that so many medications exist, treatment is currently relatively ineffective and slow acting.
It appears though that this problem has been recognised by the scientific community and that successful research is being carried out which has already shown extremely ground breaking results. The ketamine study carried out at Yale University by Dr Durman and his team is particularly exciting in terms of the discoveries which have already been made. The processes which have been identified, associated with ketamine, appear to address some of the big issues faced with common antidepressants. Firstly producing positive results in a high number of treatment resistant patients over a very short time period, highlights just how little the circuitry of the brain is currently understood in terms of depression. Also by specifically identifying that not only its interactions with glutamate and the mTOR process, but the fact that it takes place in the pre frontal cortex as opposed to the hippocampus are vital to the antidepressant effects observed in those treated with ketamine. As is commonly found with studies producing such dramatic and potentially profound results, those involving ketamine have exposed many unanswered questions but have also revealed a great stride forward in the field of drug development and treatment of
depression.
Citations
Neuroimaging and depression: Current status and unresolved issues
Author(s): Gotlib Ian H. ; Hamilton J. Paul Volume 17 2008 http://www.aafp.org/afp/2006/0101/p83.html http://www.brainphysics.com/howprozacworks.php http://www.drugbank.ca/drugs/DB00321 http://www.drugbank.ca/drugs/DB00370 http://www.drugbank.ca/drugs/DB00472 http://en.wikipedia.org/wiki/Fluoxetine http://en.wikipedia.org/wiki/Mirtazapine http://en.wikipedia.org/wiki/Amytriptiline http://maija-haavisto.suite101.com/maoi-antidepressants-a95231 10/02/2009 http://www.mind.org.uk/help/diagnoses_and_conditions/depression#symptoms http://www.psyweb.com/Glossary/tca.jsp http://www.rxlist.com/script/main/art.asp?articlekey=95236 Bibliography http://www.guardian.co.uk/science/blog/2011/jan/27/ketamine-medicinal-use-treat-depression http://www.anesthesiawiki.net/metrohealthanesthesia/MHAnes/edu/ivanes/ketamine2.htm http://mtnviewfarm.net/drugs-poisons-0750.html http://www.drugbank.ca/drugs/DB00472 http://www.brainphysics.com/howprozacworks.php http://biopsychiatry.com/mech.htm http://psychcentral.com/disorders/depressionresearch.htm http://www.medicinenet.com/psychotherapy/article.htm http://mtnviewfarm.net/drugs-poisons-0750.html http://www.brainphysics.com/howprozacworks.php http://www.telegraph.co.uk/health/healthnews/7953967/Ketamine-is-magic-drug-for-depression.html http://www.springerlink.com/content/7008l11645514130/ (ketamine case study – journal) http://www.pharmacy-and-drugs.com/reviews/Amitriptyline.html http://www.drugbank.ca/drugs/DB00321 http://mtnviewfarm.net/drugs-poisons-0750.html http://www.drugbank.ca/drugs/DB00472 http://www.brainphysics.com/howprozacworks.php http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=18897 http://www.drugbank.ca/drugs/DB00370 Organic Chemistry: 2008: Hart Crane Hart
FUNCTIONAL NEUROIMAGING STUDIES OF DEPRESSION: The Anatomy of Melancholia: Wayne C. Drevets, MD, Departments of Psychiatry and Radiology, University of Pittsburgh Medical Centre, Pittsburgh, Pennsylvania 15213
Paul Devlin
The Treatment of Depression
Current Methods and Groundbreaking New Treatments
Introduction
Depression is a very real and serious mental health condition which statistics show will affect 1 in 5 people, either directly or through a friend or relative suffering from the condition. Several neuroscience and genetic investigations clearly demonstrate that depression is a disorder of the brain, one which modern imaging techniques can reveal. Where in the past, the general consensus was that depression was a condition directly related to environment, new neural imaging technologies can show that physical changes are present in the brain of a depressed person and that by studying certain areas of the brain …show more content…
believed to be involved in the control of emotion, we can better understand the mechanisms of depression and the areas of the brain where these mechanisms take place or have an effect.
As stated in Neuroimaging and depression: Current status and unresolved issues
Author(s): Gotlib Ian H. ; Hamilton J. Paul Volume 17 2008
“Over the past decade, neuroscientists examining the ‘‘emotion circuitry’’ of the brain have documented the involvement of the limbic system, a complex of structures including the amygdala, hippocampus, insula, and parts of the anterior cingulate cortex (ACC), in the experience and expression of emotional states. Among these structures, the amygdala and the ventral (i.e. bottom) aspect of the ACC, most often referred to as the subgenera ACC, have received the most attention from investigators interested in depression. Whereas the amygdala has been shown to play a prominent role in emotionally mediated attention, in assigning emotional significance to stimuli, and in remembering emotionally significant events, the subgenual ACC appears to mediate subjective experience of emotion and emotional reactions to stimuli, particularly stimuli associated with reward seeking. These two structures are involved directly in the experience and processing of emotion, but investigators have also examined cortical structures, most notably the dorsolateral prefrontal cortex (DLPFC), that appears to be involved in the regulation of emotion.” Symptoms of depression vary greatly from patient to patient but it is appropriate to list the most common and prevalent. As stated on the website mind.org.uk, depression is a state of low mood which can affect a person’s thoughts and feelings. This can then lead to changes in behaviour and aversion to normal activities. Depressed people often report very similar symptoms all usually report feelings of sadness and anxiety, intense feelings of worthlessness and hollowness. Symptoms often manifest themselves physically resulting in a loss of intrest in normal activities, the inability to experience pleasure in normally enjoyable activities, the inability to concentrate, weight loss, fatigue and panic attacks. Up until about 50 years ago depression was diagnosed as either a biological condition (endogenous) where there was an unknown biological reason for the person’s symptoms, or reactive, where an event in the person’s life, such as the death of a loved one initiated the depressive symptoms. The most universally accepted continuum is that both are major factors and that each can individually or both contribute to the depressive state.
This investigation will look at the science of depression, the new technologies being used to establish and cure depressive symptoms and some ground breaking research which is currently being conducted worldwide to find new effective, fast acting treatments. Major studies are being carried out to establish new drugs which can utilise specific circuitry in the brain to overcome the problems associated with the treatment of depression.
Psychotherapy CBT and Depression
As stated on the AAFP website (http://www.aafp.org/afp/2006/0101/p83.html January 1 2006) Psychotherapy can often be the initial course of treatment for someone diagnosed with depression. It involves the depressed person sitting down and talking with a qualified health professional about their thoughts, feelings and depressive behaviours. It takes on many forms and every psychotherapist will have their own approach, also the nature of the patient’s condition will heavily influence the course of action taken. Psychotherapy has been found to be very effective on its own for treatment of a wide range of mental illnesses, including depression and anxiety. However it is often found that psychotherapy or counselling along with pharmaceutical treatment produces the most effective results for curing depression. Where a person has suffered a hardship in his or her life such as the end of a relationship, the death of a loved one, or losing a job, psychotherapy can often be used alone to treat someone who has developed depressive symptoms because of this event. It is often the case however that a chemical imbalance in the brain has been established which can be corrected using pharmaceuticals. Before being prescribed any psychoactive medication, any patient should be assessed to determine the extent and nature of their depression and also to ensure they are not currently taking any other medications which could have negative interactions with a certain class of antidepressant. Cognitive behaviour therapy (CBT) is an area of psychotherapy which operates under the theory that the thought process proceeds and influences mood (happiness, depression, pro-activity), and that by enforcing positive thinking, a person’s mood can be influenced or controlled.
Use of Tricyclic Antidepressants
These were first discovered in the 1950’s and primarily used as treatment for depression. They are so named for the tri ring structure of the molecule as shown. In modern times more newly developed antidepressants, such as SSRI’s are much more widely prescribed than TCA and have virtually replaced them. This is largely due to the many adverse side effects associated with TCA’s.
As stated on the website http://www.rxlist.com/script/main/art.asp?articlekey=95236 TCA’s, along with most classes of anti-depressant can take weeks to take effect – a common issue with depression treatment. TCA’s work by affecting neurotransmitters in the brain, as do almost all antidepressants. For TCA’s it is primarily serotonin and norepinephrine which are affected. These chemicals are released naturally in the brain to help with normal bodily functions and control mood. However when depression is present, less of these chemicals are present in the brain, are not released in sufficient amounts, or are reabsorbed too quickly. TCA’s help control this reabsorption by the nerve cells of the brain. However TCA’s also block histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this lack of selectivity is what accounts for the unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. Of course all antidepressants tend to have negative associated side effects. We will now look at a common TCA which is prescribed for depression, Amitriptyline which is also prescribed in low doses for the treatment of insomnia.
The website http://www.drugbank.ca/drugs/DB00321 13/01/2005 states the following, Amitriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non depressed patients, it does not tend to affect mood, or sexual arousal but is often used for its sedative effects in small doses for the treatment of insomnia. In people who are depressed, amitriptyline exerts a positive effect on mood. TCAs are very potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. In this way TCA’s interact with the brains feel good circuitry and have a positive effect on a person’s general mental state. Their long list of negative side effects however has led to a vast reduction in their use, and major preference being given to SSRI’s and other drugs for the treatment of depression.
Chemical Structure of Amitriptyline (common TCA)
Chemical Formula: C20H23N
IUPAC Name: dimethyl({3-[(2Z)-tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene]propyl})amine
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Amytriptiline)
Use Of SSRI Antidepressants
As stated on http://www.brainphysics.com/howprozacworks.php SSRI’s or selective serotonin re-uptake inhibitors are a class of drug used to treat depression. SSRI’s are believed to increase the cellular level of the neurotransmitter serotonin. It does this by inhibiting the reuptake of serotonin into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available for binding to the postsynaptic receptor. They can also have an effect on the selectivity of other monoamine transporters, with pure SSRI’s having very weak affinity for noradrenaline and dopamine. SSRI’s work by inhibiting the reuptake of serotonin after being released by synapses. Serotonin (sometimes abbreviated 5-HT (5-hydroxytryptamine)) is a neurotransmitter that can affect several vital human functions, such as sleep, appetite, sex drive, general motivation. This can then have a knock on effect on human behaviours which affect the person suffering from depression in a wide range of ways from chronic fatigue to suicidal thoughts. SSRI’s are also subject to the common issue with antidepressant medications in that they can take weeks to have any positive effects.
In understanding how SSRI’s work, it is necessary to look at how the brain works in terms of synapses and neurotransmitters. A brain cell or neuron has 3 main parts, the axon, the cell body and dentrides. Dentrides protrude out from the neuron. The axon is a singular long protrusion from the cell body. The axon of one neuron connects to the dentrides of many others forming vast networks. The synapses are the points of connection between neurons – a gap between the axon of a neuron and the dentride and cell body of many others. This is where serotonin and other brain chemicals come into play. Electrochemical communication occurs at these junctions.
Neurotransmitters are chemicals, each with its own specific effects when activated in the brain. The axon releases these and they cross the synapse. Each brain chemical carries an individual message and fits like a key into a receptor on the other side to produce a desired effect on the brain. Each receptor has a very specific shape corresponding to the neurotransmitter it receives. So in these terms, serotonin provides the key to a network in the brain associated with positive, healthy thinking which in turn leads to what we consider a happy and stable emotional condition. This of course is a very small part of how the brain controls mood and emotions as a whole. Several other chemicals are involved and of course, human beings are subject to natural feelings of prolonged sadness or low mood due to the occurrence of things like the end of relationships, or death of a loved one. It is however serotonin which SSRI’s are specifically engineered to interact with and they come into play when someone experiences what we would consider an extreme emotional state, like clinical depression. Their use is based on the theory that someone with a healthy neurochemical balance has a stable mental condition and that when an imbalance occurs, mental states such as depression can occur. This imbalance is then in theory corrected by the use of an SSRI. Other antidepressant medications may have different effects on different neurotransmitters and in a variation of ways, but all operate under this theory: the correction of a chemical imbalance in the brain, using drugs which have been designed to target specific neurotransmitters to have a positive influence on a person’s mental state. We will now look at a specific SSRI called fluoxetine, a drug which is wildly prescribed around the world.
A stated in http://www.drugbank.ca/drugs/DB00472 Fluoxetine comes in capsule and tablet form and is prescribed for depression. It metabolizes to nor fluoxetine. It blocks the reuptake of serotonin on the serotonin reuptake pump of the neuronal membrane which enhances the actions of certain auto receptors. By binding with significantly less histamine, norepinephrine, and acetylcholine receptors than TCA antidepressant drugs, SSRI’s like fluoxetine produce far less undesirable side effects and are therefore are now far more widely used. This appear to be the case with antidepressant drugs on a whole – while we do have access and understanding of some of the medications we currently use, through drug development me can improve and optimise the way we treat these conditions.
Chemical structure of Fluoxetine
Chemical Formula: C17H18F3NO
IUPAC Name: methyl({3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl})amine
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Fluoxetine)
Use Of TeCA Anti-Depressants
The following information was partially taken from the website http://www.psyweb.com/Glossary/tca.jsp .Tetracyclic antidepressants, so called for their four ringed chemical structure are another class of antidepressants. They are closely related to TCA’s but some have been found to have far less adverse side effects. One very successful TeCA is mirtazapine. In a recent study it was found to be superior to several SSRI’s and other widely prescribed antidepressants. Mirtazapine was found to have very few serious side effects on most patients.
As stated in the website http://www.drugbank.ca/drugs/DB00370 13/06/2005 , By acting as an antagonist at central pre-synaptic alpha(2)-receptors, Mirtazapine inhibits negative feedback to the presynaptic nerve and causes an increase in NE release. By blocking heteroreceptors which are contained in serotonergic neurons, Mirtazapine interacts with the release of 5-HT. This in turn increases the interaction between 5-HT and 5-HT2 receptors, which increases the anxiolytic effects of the drug. Mirtazapine’s weak interactions with other receptors in the brain may explain why studies show the drug has lower reported adverse effects such as anxiety, insomnia and nausea. It also shows strong antagonistic effects on a particular receptor in the brain which contributes to its sedative effects. This is sometimes a positive side effect of the drug and it is often recommended as an antidepressant to be taken a night, helpful if the person taking the drug has trouble sleeping or relaxing at night as a result of their condition.
Chemical Structure of Mirtazapine
Chemical Formula C17H19N3
IUPAC Name: 5-methyl-2,5,19-triazatetracyclo[13.4.0.0^{2,7}.0^{8,13}]nonadeca-1(19),8(13),9,11,15,17-hexaene
(Image and chemical structure taken from http://en.wikipedia.org/wiki/Mirtazapine)
Use Of MAOI Antidepressants
As stated in http://maija-haavisto.suite101.com/maoi-antidepressants-a95231 MAOI’s or Monoamine oxidase inhibitors are another class of antidepressants traditionally used when the other classes such as SSRI’s and TCA’s have failed. This is due to the long list of negative and often potentially lethal drug interactions MAOI’s can be associated with if not correctly prescribed and monitored. MAOIs act by inhibiting the activity of monoamine oxidase in the human brain. By preventing the breakdown of monoamine neurotransmitters, their availability for use as a part of the brains feel- good circuitry - that which is associated with regulating a stable and happy emotional condition, is increased. Monoamine oxidase has two isoforms MAO-A and MAO-B. These act preferentially towards specific neurotransmitters and drugs can be developed to have stronger interactions with each isoform. Both MAO-A and MAO-B take part in deamination with certain neurotransmitters. This is a chemical function whereby an amine group is removed from a molecule. MAO-A is primarily involved with the deamination of serotonin, melatonin, epinephrine and norepinephrine. MAO-B is preferential, in deamination, to phenylethylamine and trace amines. Both MAO-A and MAO-B deaminate dopamine equally. Clearly the clinical implications of being able to manipulate drugs, at the molecular level , are vital in the proper use and development of MAOI’s.
Possible Development Of Ketamine For Treatment Of Depression
There are currently several scientific investigations under way involving surprising substances which may have properties which can be manipulated in the lab to produce molecules which could be extremely useful in the development of drugs for the treatment of depression. Ketamine is one such drug which is currently being investigated for this purpose. Traditionally used in veterinary (and rarely) human medicine for its anaesthetic properties, ketamine may hold the key to a new approach in the treatment of depression in humans. The key lies in the way ketamine molecules interact with the body and brain when compared to conventional medicines. Chemical Structure Of Ketamine
Chemical Formula: C13H16ClNO
IUPAC Name: 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one http://www.drugbank.ca/drugs/DB01221 Ketamine is a very fast acting general anaesthetic. It produces an anaesthetic state characterised by profound analgesia, cardiovascular and respiratory stimulation and other effects. It has been termed a dissociative anaesthesia, in that it selectively and temporarily disrupts association pathways in the brain before producing semesthetic sensory blockade
Ketamine is now a common recreational drug.
It is most often insufflated producing strong visual and out of body experiences. It acts very rapidly producing very strong and profound effects on the user (depending on dosage). Users often report what is referred to as ‘the k-hole’ where on taking large doses of the drug, one’s mind becomes ‘dissociated’ from the body resulting in very powerful and personal hallucinations, not just visual however like other hallucinogens such as LSD. When in a ‘k-hole’ the user can be unaware of their own existence, often forgetting where they are, what they are, and experiencing complete mental detachment from the …show more content…
body.
Ketamine’s unusual effects have evidently caught the attention of serious scientific researchers, and is now the subject of several ongoing studies of its possible medicinal uses. Firstly it has been shown that in very low doses the drug produces antidepressant effects which are extremely rapid in effect. Compared to traditional antidepressants, which can take days or weeks to take effect, studies involving ketamine show that the drug can have positive antidepressant effects within minutes, which can last up to ten days. These studies are in early stages and so data is limited. The really exciting possible outcome is that traditional and effective methods of reducing the symptoms of depression(SSRI’s, MAOI’s) could somehow be manipulated to have the same effects but use the mechanism which ketamine exploits to effect the brain so rapidly.
Over the past decade, much research has focused on the neurotransmitter glutamate, a substance responsible for the transportation of signals through the spinal cord and brain. Glutamate plays an important role in the brains signalling system, and evidence from recent studies suggests that controlling and moderating the system in which it is involved could hold the future key to the treatment of depression. As mentioned previously it is ketamine’s extremely rapid interaction which makes it so interesting, an article in The Guardian newspapers science blog revealed the following statistic:
“in trials on patients with treatment resistant MDD (Major Depressive Disorder) some showed improvements within only 40 minutes. Over 70% responded within 24 hours, reaching a level that took six to eight weeks to occur with traditional therapeutics.”
Ketamine is known to inhibit proteins which have interactions with glutamate. Other more familiar antidepressants are known to have interactions with members of the same chain. However ketamine appears to hold the key to a short cut in this process, explaining why the drug can take effect dramatically quicker. It should also be noted that as well as this so called ‘short cut’ mechanism ketamine utilises, it appears to trigger a chain of events leading to the formation of new synapses, furthermore enhancing its fast acting capabilities.
Dr. Ron Duman of Yale University is a well known neuroscientist who has focussed his research on the human brain and depression. He led a research team which has carried out an investigation into the possible clinical use of ketamine or similar substances as antidepressant medications. The reason for this study being carried out again highlights a worrying statistic about current antidepressants. About 40% of patients appear non responsive to current antidepressants, and almost all take weeks to take effect. Studies have been carried out by scientists at the National Institute of Mental Health into both major depressive disorder, and bipolar depression, both conditions tend to see treatment resistant patients. The studies showed that over 70% of patients like this showed dramatic improvements after just one day of treatment, and one dose of ketamine – such surprising and positive results cannot be ignored. Ketamine however is not the perfect agent for practical treatment – it must be administered intravenously and can have strong negative side effects. Therefor it is hoped another substance can be discovered or engineered to have the same positive neural effects but can be a practical medication at the same time. The study looks further into the mechanism which ketamine utilises in the brain.
As we have already discussed, the most commonly prescribed antidepressants take effect primarily on the serotonin messenger circuit of the brain, whereas ketamine utilises the glutamate system. Evidence appears to suggest that the medications which act on serotonin trigger a series of events that promoted healthy brain development. It appears that they can stimulate the birth of new neurons. These neurons can then go on to establish new connections or synapses with other neurons which overall promotes healthy brain activity. It appears that this process of building and establishing new connections can take weeks to happen – explaining the apparent delay in response to treatment with traditional serotonin acting drugs. Ketamine’s use of the glutamate system appears to stimulate similar activity but much quicker, suggesting that its mechanism occurs closer and more directly to the source of the problem. Ketamine was known to block glutamate from binding to a specific receptor protein on cell membranes known as the NMDA receptor. To understand how this leads to an antidepressant effect in patients, the team carrying out the investigation traced the signal path in the brain which this blockade triggered.
The team found that in the pre frontal cortex of rats which had been treated with a low dose of ketamine, the rapid activation of an important enzyme was occurring. This is known as the mammalian target of rapamycin (mTOR) which makes proteins forming the connections between neurons or synapses. Neither common antidepressants, nor electroconvulsive therapy have been shown to similarly activate mTOR. Depression is known to have the exact opposite effect of ketamine on the synapses of the brain – they cause shrivelling and the reduction in the proteins needed to build new ones. A single dose of ketamine has been shown to make these proteins readily available, and promote healthy growth and development in the synapses and this is very significant.
In the image below we can see the budding synapses on the image displaying the pre frontal cortex of the rats treated with ketamine compared to those without.
(Image taken from http://www.nimh.nih.gov/science-news/2010/rapid-antidepressant-works-by-boosting-brains-connections.shtml)
Dr Duman had this to say about the image
“Neuronal spines, budding connections between brain cells, or synapses, sprouted in rats within hours of receiving ketamine (arrows). By contrast, fewer spines developed on neurons of control rats that didn't receive the drug. The boost in neuronal connectivity is thought to produce an antidepressant effect by enhancing brain circuit activity. The highly magnified two photon imaging pictures show extensions of neurons in rat prefrontal cortex.”
So what is the key idea the research has discovered? By identifying the cellular signalling system through which ketamine operates, it has been established that mTOR is essential for ketamine to boost and increase synapse formation. The serotonin based medications appear to trigger the birth of new neurons – known as neurogenesis, which in turn has an eventual anti-depressant effect on the brain. Ketamine however stimulated the glutamate circuitry which seems to be involved with the growth of existing neurons and synapses, a far more direct solution which takes place in the pre frontal cortex. It is this idea that may hold the key to the future development of medications to treat depression in human beings.
The ketamine studies used in this report come from Dr Duman, Yale University radio interview: NIMH Radio: Dr. Ron Duman of Yale University talks about ketamine research and treatment for major depression.
And also in the article in the guardian: http://www.guardian.co.uk/science/blog/2011/jan/27/ketamine-medicinal-use-treat-depression 27/01/2011
Conclusion
When examined it is quite surprising, given that depression is now so commonly experienced and that so many medications exist, treatment is currently relatively ineffective and slow acting.
It appears though that this problem has been recognised by the scientific community and that successful research is being carried out which has already shown extremely ground breaking results. The ketamine study carried out at Yale University by Dr Durman and his team is particularly exciting in terms of the discoveries which have already been made. The processes which have been identified, associated with ketamine, appear to address some of the big issues faced with common antidepressants. Firstly producing positive results in a high number of treatment resistant patients over a very short time period, highlights just how little the circuitry of the brain is currently understood in terms of depression. Also by specifically identifying that not only its interactions with glutamate and the mTOR process, but the fact that it takes place in the pre frontal cortex as opposed to the hippocampus are vital to the antidepressant effects observed in those treated with ketamine. As is commonly found with studies producing such dramatic and potentially profound results, those involving ketamine have exposed many unanswered questions but have also revealed a great stride forward in the field of drug development and treatment of
depression.
Citations
Neuroimaging and depression: Current status and unresolved issues
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FUNCTIONAL NEUROIMAGING STUDIES OF DEPRESSION: The Anatomy of Melancholia: Wayne C. Drevets, MD, Departments of Psychiatry and Radiology, University of Pittsburgh Medical Centre, Pittsburgh, Pennsylvania 15213