Wednesday, 29 May 2013

Venlafaxine (EFFEXOR) and Desvenlafaxine (PRISTIQ) vs. SSRIs

Venlafaxine (EFFEXOR) is an antidepressant that appears to work by serving as a serotonin-norepinephrine reuptake inhibitor (SNRI; other drugs of this class include duloxetine [CYMBALTA] and milnacipran [SAVELLA]). What this means is that it increases the availability of the neurotransmitters serotonin and norepinephrine in the synapse [the parts of neurons (electrically signalling brain cells) where neurotransmitters are used as chemical messengers between cells]. This in turn leads to increase in signalling mediated by these two neurotransmitters and since they play key roles in mood regulation this tends to lead to improvements in the moods of the depressed. Interestingly clinical studies have demonstrated that on average venlafaxine is a superior antidepressant, when measured by how many patients achieve a remission (or disappearance) of their symptoms whilst on it, to the selective serotonin reuptake inhibitors (SSRIs) that work solely on serotonin such as sertraline [ZOLOFT], fluoxetine [PROZAC] and escitalopram [LEXAPRO]. On average clinical studies have demonstrated that around 45% of patients achieve a remission of their depression while on venlafaxine, whereas 35% of patients achieve a remission while on SSRIs and 25% of patients receiving a placebo achieve a remission. Albeit to be fair these clinical trials primarily involved fluoxetine as the SSRI used with only one using another SSRI, namely, sertraline.

How venlafaxine manages to achieve such high remission rates in clinical trials isn't 100% clear but we do have our theories, or rather theory since I've only seen one such theory. It is that by working both on serotonin and norepinephrine it manages to correct two anomalies found in depressed patients that we believe contribute to depression, that is low serotonin and norepinephrine levels in the synapse. The problem with this theory is that at the standard doses venlafaxine is relatively selective for serotonin, that is the increase in norepinephrine availability in the synapse it is able to induce is comparatively small compared to the increase in the availability of serotonin in the synapse it causes at the same doses and hence you would expect that norepinephrine would contribute negligibly to venlafaxine's antidepressant effects at therapeutic doses.

Interestingly venlafaxine is metabolised (or transformed) in the body to a drug known as desvenlafaxine, that similarly also serves as a SNRI, and it is believed that this is responsible for many of venlafaxine's antidepressant effects. What's particularly interesting is that desvenlafaxine is actually used in medicine as an antidepressant in its own rights and is currently sold under the brand name PRISTIQ. Despite desvenlafaxine hitting the market relatively recently (2008 in the US) so far the available evidence is suggesting that it is less effective an antidepressant than venlafaxine.

This isn't to say that there isn't any reasons why doctors would rather give their patients SSRIs instead of venlafaxine and desvenlafaxine. For one they both can cause dry mouth, which if chronic and uncontrolled can lead to poor dental health and cavities. Secondly they both pose a risk of causing insomnia and since a common complaint in patients with major depressive disorder (MDD) is difficulty falling and staying asleep this can very easily be seen as a potential issue. Thirdly they can both cause a loss of appetite which can be a problem in adolescents since drugs that suppress appetite have been linked to stunted growth in adolescents. On top of that they also have the following common (>5% of patients get these) side effects (according to Micromedex -- the online database JCU gives me access to):

  • Headaches
  • Blurred vision
  • Dizziness
  • Somnolence (a near-sleep state. People often have a very strong desire for sleep, or they sleep for unusually long periods)
  • Tremors
  • Nervousness
  • Sexual dysfunction, especially in males
  • Weight loss
  • High blood pressure
  • Sweating
  • Unusual dreams
  • Weakness/fatigue
  • Elevated blood triglycerides (desvenlafaxine only)
  • Elevated blood cholesterol (desvenlafaxine only)
  • Nausea (very common on venlafaxine 21-58%)
  • Vomiting (only with desvenlafaxine)

Venlafaxine and desvenlafaxine are also amongst the most "touchy" of antidepressants so to speak, namely if patients forget to take one of their doses odds are it won't be long before they know about it due to withdrawal symptoms. See antidepressants that work by increasing serotonin availability in the synapse cause some adaptive changes in the brain after chronic use and if these antidepressants are suddenly and abruptly stopped they can lead to the emergence of a collection of symptoms commonly referred to as SSRI withdrawal syndrome. Since venlafaxine and desvenlafaxine last a relatively short time in the body (and thus you are under their effects for a shorter time after you take them) compared to most other antidepressants they are particularly prone to causing SSRI withdrawal when doses are missed. Consequently when patients need to, for whatever reason, stop taking venlafaxine it is nearly always a good idea for them to gradually reduce their dosages over a period of weeks instead of abruptly stopping them. The only time a doctor is likely to recommend that a patient abruptly stops their treatment is when the side effects are just unacceptably and life-threateningly severe.

The fact that venlafaxine and desvenlafaxine increase norepinephrine availability in the synapse means that they also may be of benefit in Attention Deficit Hyperactivity Disorder (ADHD) because this is an action they share with the ADHD meds atomoxetine (strattera) and methylphenidate (ritalin, concerta). This may also be of benefit in depression seeing how a common symptom of major depressive disorder is a mental "clouding" and in particular concentration problems.

Aside from major depressive disorder venlafaxine has found use in the following conditions (according to Micromedex):

  • Generalised anxiety disorder (GAD. GAD is a disorder characterised by irrational and disproportionate worry over everyday things; it is FDA approved for this indication) 
  • Panic disorder (an anxiety disorder characterised by recurring and severe panic attacks. It is also FDA approved for this indication) 
  • Social phobia (intense and often disabling fear of social situations. It is FDA approved for this indication) 
  • Attention deficit hyperactivity disorder (ADHD; not FDA approved) 
  • Binging - Eating disorder (not FDA approved) 
  • Bipolar disorder, depressed phase (not FDA approved) 
  • Cerebrovascular accident - Depression (depression resulting from a stroke, not FDA approved) 
  • Depression - Perimenopausal disorder (not FDA approved) 
  • Dysthymia (mild chronic depression. Not FDA approved) 
  • Hot sweats, Breast cancer-related (not FDA approved) 
  • Menopausal flushing (not FDA approved) 
  • Obsessive-compulsive disorder (not FDA approved) 
  • Posttraumatic stress disorder (not FDA approved) 
  • Premenstrual dysphoric disorder (Basically a more severe form of the depressive symptoms associated with PMS; not FDA approved) 
  • Recurrent major depressive episodes; Prophylaxis (trying to prevent further major depressive episodes; not FDA approved) 
  • Tension-type headache; Prophylaxis (trying to prevent further further tension headaches; not FDA approved) 

Whereas aside from MDD desvenlafaxine is used (although not FDA approved) only for treating menopausal flushing according to Micromedex.

The standard adult doses of venlafaxine are 75-375 mg per day (usually 225 mg/day is the max adult dosage but sometimes 375mg is set as the upper limit) with higher doses usually preferred for patients with anxiety disorders. The standard adult dose of desvenlafaxine is around 50 mg a day.

Venlafaxine comes in two forms, immediate release and extended release tablets. They are basically what they sound like; immediate release tablets release the drug ASAP whereas extended release tablets release the drug gradually over a period of hours. Extended release tablets have the clear advantage of only having to be administered (or taken) once a day whereas immediate release tablets are usually required to be taken 2-3 times a day.

Tuesday, 28 May 2013

Alzheimer's Disease, what is it, what causes it, how is it treated and how can one prevent oneself from getting it?

Alzheimer's disease (AD), what is it, what causes it, how is it treated and how can we prevent ourselves from getting it? Alzheimer's disease is the most common form of dementia, which are a collection of diseases characterised by an abnormally rapid (beyond what can be explained by the normal process of aging) decline in cognitive functions (memory, learning, problem solving, etc.) particularly memory. While it usually effects the elderly (>65 years of age is usually when the disease begins) it can effect the middle-aged. Risk for AD doubles every five years. In the 60-64 year old cohort around 1% are afflicted by AD whereas in the 85-89 year old cohort around 40% have Alzheimer's disease. (Kumar, 2005)

It is caused by a selective (i.e. other brain regions are largely unaffected) destruction of the cerebral cortex and hippocampus due to, or so we believe, the build up of the proteins amyloid beta (AB) and tau proteins. The hippocampus is a structure of the brain that appears to play a key role in the formation of long-term memories (memories that last years or even indefinitely) from short-term memories and our ability to process the 3D spatial nature of the world we live in. Whereas the cerebral cortex is the grey matter of the brain, the outer layers of the brain where all the information processing occurs. Amyloid beta is a protein that is cleaved by enzymes in the brain from amyloid precursor protein (APP) which is a protein that plays a key role in the formation of synapses and neuronal (electrically signalling brain cells) survival. Tau proteins play key roles in brain development and maintenance. Patients with AD also have evidence of an inflammatory response playing a key role in their conditions. It has also been discovered that those with mutations in the genes that encode apolipoproteins, proteins involved in the breakdown of AB, that end up decreasing their efficiency have an increased risk for AD. Additionally the AB genes are found on chromosome 21, the very chromosome that is repeated in patients with Down's syndrome (DS) and it's been discovered that virtually every patient with DS develops AD before or during their 40s. Most cases of AD cannot be traced to genetics. On average around 5-10% of AD cases can be traced to genetics (Kumar, 2005).

AD is an incurable and relentlessly progressive disease. The usual life expectancy for AD patients is 5-15 years. The usual cause of death in AD patients is pneumonia or dehydration due to the fact that, given sufficient time, patients with AD become immobile, mute and basically empty shells waiting to die leaving pneumonia and dehydration to finish them off.

AD is usually treated by means of drugs and psychotherapy. Psychotherapy usually attempts to help patients and their families cope with the condition better and perhaps attempt to help them deal with some problems that AD can cause such as psychoses (hallucinations, delusions and thought disorders) and depression. Drugs on the other hand tend to include the following:

  • Acetylcholinesterase inhibitors
  • NMDA antagonists 

Acetylcholinesterase (AChE) inhibitors work by inhibiting the enzyme acetylcholinesterase that catalyses the breakdown of the neurotransmitter acetylcholine (ACh). Acetylcholine is a neurotransmitter that plays a wide range of roles in the body. In the brain it is involved in memory and learning, problem-solving, mood, nausea and vomiting regulation, wakefulness and a few other functions whereas in the rest of the body it is involved in our voluntary movements. Nicotine works by activating one set of receptors that respond to acetylcholine whereas the atypical hallucinogen, muscarine, that's found in the mushroom, amanita muscaria (fly amanita) activates the other set of acetylcholine receptors (NOTE: MOST PSYCHEDELIC MUSHROOMS CONTAIN PSILOCYBIN, NOT MUSCARINE, AS THEIR ACTIVE INGREDIENTS. ONLY THIS MUSHROOM CONTAINS SIGNIFICANT QUANTITIES OF MUSCARINE). These sets of acetylcholine receptors are the nicotinic and muscarinic acetylcholine receptors respectively. AChE inhibition in turns leads to an increase in nicotinic and muscarinic acetylcholine receptor activity. Many of the brain cells damaged by AD used acetylcholine for much of their signalling and hence it was theorised that drugs that elevate ACh would reduce the symptoms of AD and while this is true there is a limit as to how much symptomatic relief can be achieved before the inherit toxicity of AChE inhibitors enters the picture. See nerve gases also work via AChE inhibition and hence it should be clear to us that AChE inhibitors are certainly not without their dangers. Examples of AChE inhibitors in clinical practice include:

  • Donepezil (Aricept)
  • Galantamine (Razadyne; derived from a wide range of plants)
  • Physostigmine (antilirium; derived from the calabar bean of tropical Africa)
  • Rivastigmine (Exelon)

NMDA antagonists, unlike AChE inhibitors, are designed to be disease-modifying treatments, that is treatments designed to modify (and in this case slow) the clinical course of AD instead of just improving the symptoms temporarily. We have reason to believe that excitotoxicity, that is neuronal injury due to excess activity of said neuron, plays a key role in the damaging effects of AD on neurons. Since NMDA receptors play a key role in excitotoxicity it was proposed that a NMDA antagonist, such as say, memantine, may act to minimise this damage. It is normally prescribed in moderate-severe AD cases. (Memantine Hydrochloride, n.d.)

Epidemiological (spread/distribution of disease) studies have demonstrated that those that consume coffee and wine regularly, but in moderation, regularly undertake physical and mental exercise, take low doses of non-steroidal anti-inflammatory drugs like ibuprofen and aspirin regularly and have a higher degree of education are less likely to develop AD. High blood pressure, high blood cholesterol, diabetes mellitus and smoking are all risk factors for AD (Lindsay, 2002). There is some evidence to suggest that the regular consumption of antioxidants (e.g. vitamin C, E, green & black teas) (Frank, 2005) and vitamin D can prevent AD. (Lu'o'ng, 2013)

Reference List:

  1. Frank, B., Gupta, S. (2005). A review of antioxidants and Alzheimer's disease. Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 17(4), 269-286. doi: 10.1080/10401230500296428.
  2. Kumar, V., Abbas, A. K., Fausto, N. (2005). Robbins and Cotran Pathologic Basis of Disease 7th Edition. Philadelphia, Pennsylvania: Elsevier.
  3. Lindsay J, Laurin D, Verreault R, Hébert R, Helliwell B, Hill GB, McDowell I. (2002). Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. The American Journal of Epidemiology. 156(5), 445-453. doi: 10.1093/aje/kwf074.
  4. Lu'o'ng KV, Nguyen LT. (2013). The role of vitamin D in Alzheimer's disease: possible genetic and cell signaling mechanisms. The American Journal of Alzheimer's disease and other Dementias. 28(2), 126-136. doi: 10.1177/1533317512473196.
  5. Memantine Hydrochloride (n.d.). Retrieved May 28 2013 from DrugPoint Summary (Micromedex) for Memantine Hydrochloride.*
*I know I should put the website down but it's utterly useless for my purposes since it requires you to have access to JCU's databases. 

Monday, 20 May 2013

Vortioxetine, a new antidepressant in the process of being approved in the US and the EU

Definitions of some terms used: 

Placebo - a drug, that despite having no therapeutic efficacy with respect to the action being tested, is designed to trick patients into improving due to the whole mind over matter situation.
Placebo-controlled, double blind clinical trial - a clinical trial in of which some study participants are given placebos and others are given the drug that is being tested in the clinical trial and neither the person giving the patient the drug, nor the patient, know which one the patient is receiving.


A new antidepressant is currently in the process of being approved in various countries, unfortunately, at the moment, from what I can tell, at least, Australia isn't one of them, but the US is. It's known as vortioxetine and is truly unique among antidepressants. Albeit it still works based on the monoamine hypothesis of depression, just as all, currently approved in Australia, antidepressants, except one, agomelatine, which works partly based on this hypothesis. The monoamine hypothesis of depression states that certain neurotransmitters, known as monoamine neurotransmitters that include serotonin, norepinephrine and dopamine are deficient (i.e. present in abnormally low quantities) in the brains of patients with depression.

It works, or so it appears, by a combination of actions: selective serotonin reuptake inhibition, agonism of the 5-HT1A receptor, partial agonism of the 5-HT1B receptor, antagonism of the 5-HT3 receptor and antagonism of the 5-HT7 receptor.

Selective serotonin reuptake inhibition is a mechanism of action vortioxetine shares with a class of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs) that include, sertraline (Zoloft), fluoxetine (Prozac), escitalopram (Lexapro), citalopram (Celexa, Cipramil), fluvoxamine (Luvox) and paroxetine (Aropax, Paxil).

5-HT, in the context of these receptors, is an acronym for 5-hydroxytryptamine, the chemical name for serotonin, that is, these receptors that vortioxetine interacts with are all serotonin receptors. 5-HT1A receptors regulate, among other things, the release and synthesis of serotonin in the brain (skip until the next paragraph if you understand the concept of a synapse from my last blog post or other sources). See expressed on neurons (the electrically and chemically signalling cells of the brain and spinal cord) there are two types of receptors: presynaptic and postsynaptic receptors, they are expressed pre- and post- synaptically respectively. See each neuron is joined to other neurons at something known as a synapse. Synapses are where one neuron (the presynaptic neuron this is known as) propagate signals, in the form of neurotransmitter release, to the next neuron (or the postsynaptic neuron). The receptors are called pre- and post- synaptic based on which of these neurons they are expressed in a particular synapse.

5-HT1A receptors are located both pre- and post- synaptically. Presynaptically they serve as autoreceptors, that is they are the receptors that send back negative feedback to the presynaptic neuron. That is, upon binding with serotonin they send back signals to the presynaptic neuron that tell it to reduce the amount of serotonin it is synthesising (serotonin synthesis only occurs in one region of the brain, the raphe nucleus, which is one place that the 5-HT1A receptor is highly expressed) and/or releasing. Over time, with repeat exposure to the neurotransmitter serotonin or other ligands (drugs that bind to it) these presynaptic 5-HT1A receptors becomes downregulated. This means there are fewer of this particular type of receptor, thus leading to reduced negative feedback to the presynaptic neuron. Additionally it has been found that postsynaptic 5-HT1A receptor agonism (activation) leads to lifting of depression and anxiety. It also appears to leads to pain relief and some cognitive (memory and learning) effects [there's some evidence saying it is a positive [enhancing] effect while other evidence suggests the reverse].

5-HT1B receptors also serve as autoreceptors but in other parts of the body. They also appear to play a key role in vasoconstriction (constriction of blood vessels) and as of such 5-HT1B receptor agonists are used in the treatment of migraines. Their effects on mood are unclear.

5-HT3 receptors appear to play roles in schizophrenia (5-HT3 receptor antagonists are known to improve the symptoms of schizophrenia) and emesis (nausea and vomiting). In fact 5-HT3 receptor antagonists are among the most well-tolerated (i.e. the best with respect to fewer side effects) antiemetics we have.

5-HT7 receptors on the other hand also appear to be primarily located presynaptically. 5-HT7 receptors serve as both auto- and hetero- receptors. Heteroreceptors, similarly to autoreceptors, are receptors located presynaptically that regulate the release of neurotransmitter from the neurons they're located on. Heteroreceptors, however, instead of regulating the release of the neurotransmitters that activate them, regulate the release of other neurotransmitters.

At the moment there are only one indication (i.e. conditions for it to be used to treat) for which approval of vortioxetine is being sort by its developers: major depressive disorder (MDD; also known as unipolar or clinical depression). Four placebo-controlled, double blind clinical trials have been conducted to ascertain the efficacy of vortioxetine in treating MDD with conflicting results. Two found a statistically significant improvement in MDD patients receiving vortioxetine over placebo. One found no such improvement, whereas the other had an exceptionally high placebo response rate that clouded the results. Despite these conflicting results the drug's developers filed for approval in September 2012 in the US and October 2012 in the EU market. Another indication for which vortioxetine was being investigated was generalised anxiety disorder or GAD. There were two clinical trials conducted into its use in treating GAD, one managed to show a statistically significant improvement over placebo while the other failed to find such an improvement.

Thursday, 16 May 2013

Depression Treatment: Now What?

Clinical depression (also known as unipolar depression or major depressive disorder [MDD]) is a serious psychiatric illness that affects between 4 and 20% of the adult population. It is characterised by a generalised decline in mood, often accompanied by loss of appetite, decreased energy levels, impaired cognitive function (memory, learning, etc.), anxiety/stress and physical symptoms such as gastrointestinal symptoms (nausea, vomiting, diarrhoea, constipation) and chronic, otherwise ill-explained pain.

Better Health Victoria mentions the following common symptoms:

Some of the symptoms of depression can include:

  • Feeling sad or depressed
  • A loss of interest and pleasure in normal activities
  • Loss of appetite or weight
  • Inability to get to sleep or waking up early
  • Feeling tired all the time
  • Having trouble concentrating
  • Feeling restless, agitated, worthless or guilty
  • Feeling that life isn't worth living

As is the title of this blog this blog isn't just about what depression is, it is about the recent developments in the treatment of depression. Currently the standard treatments for depression focus on the monoamine hypothesis of depression. The monoamine hypothesis states that the monoamine (which is a chemical term; it's irrelevant for the purpose of this blog) neurotransmitters, namely serotonin, norepinephrine and dopamine, are out of balance in the brains of patients with depression. Consequently most antidepressants (>95%) in clinical use work via either directly interacting with the monoamine receptors or by increasing the concentrations of the monoamine neurotransmitters in the synapse (which is where, in brain cells, they're used). 

While this hypothesis still holds some ground in the medical community and is still often taught as almost gospel truths in psychiatry and pharmacology textbooks there is emerging evidence to the contrary. For instance the dissociative anaesthetic (anaesthetic with additional effects that induces states that closely resemble schizophrenia), ketamine, elicits substantially more rapid and robust antidepressant effects than drugs based on the monoamine hypothesis, with effects being seen within two hours in some patients and persisting for up to a fortnight after the last treatment session.[1]

In order for me to go any further I need to explain to you some elementary neuroanatomy and physiology. A major type of cells found in the brain, spinal cord and peripheral nerves (i.e. those that control muscles and sense pain, touch, pressure, etc.) is known as a neuron and has the following structures:

Figure 1: The Neuron

These dendrites and axon terminals link in with each other to form a structure known as a synapse. These synapses are where signals are transmitted.

Figure 2: The Synapse

The nerve impulse is basically an electrical signal that travels down the axon body of the neuron. The vesicles contain neurotransmitter to be released and the synaptic cleft is sometimes  used as a synonym for synapse.

Additionally to what is shown on this diagram on the axon terminal there are what's known as autoreceptors that, upon binding by the neurotransmitter, send back signals to the presynaptic neuron (the neuron who's axon is part of the synapse in question) that prevents further release of the neurotransmitter, thus suppressing neurotransmitter release and thus postsynaptic receptor activity.

The monoamine neurotransmitters serotonin and norepinephrine have two well-characterised autoreceptors that appear to play key roles in the therapeutic delay seen within monoamine antidepressants, the 5-HT1A (5-HT is the chemical name of serotonin) and the α2 adrenergic receptor. Dopamine has autoreceptors too but they are too complex for me to adequately explain them here and since there is little evidence regarding how they fit in with the therapeutic delay of antidepressants I felt it unwise to mention them here. Therapeutic effects are seen when these autoreceptors, after chronic exposure to relatively increased monoamine concentrations in the synapse due to antidepressant therapy become downregulated, i.e. fewer of them are found on presynaptic neurons. This theory is well supported by the finding that the 5-HT1A antagonist (blocker) pindolol is capable of speeding up response rates to serotonergic antidepressant therapy.[2] Additionally the α2 agonist (activator), clonidine, has been found to, likely due to its autoreceptor properties, induce depression in previously non-depressed individuals.

Emerging evidence suggests that while the monoamine hypothesis of depression has some validity to it there are other equally valid, and in some cases even more convincing, hypotheses of depression. These hypotheses include the following:

  • The glutamate hypothesis of depression
  • The cortisol hypothesis of depression
  • The inflammatory (cytokine) hypothesis of depression

While all three of these hypotheses have merit, my personal preference is the inflammatory hypothesis of depression because it is all-encompassing, in that it, without any stretching or reformulation is capable of explaining all observed phenomena in this field and more. 

The glutamate hypothesis of depression basically states that depression is due to abnormal (usually excessive) glutamatergic activity in the brain.[3] Glutamate receptors in the brain regulate a wide range of things, including memory, learning (to which they are pivotal), mood, anxiety/stress, pain and attachment to reality (glutamate blockers like ketamine are known to cause symptoms consistent with the psychiatric illness, schizophrenia). Glutamate receptors can be split up into four main categories:

  • The NMDA receptors
  • The AMPA receptors
  • The kainate receptors
  • The mGluR receptors

At the present time the NMDA receptors are the most well-investigated receptors as far as their interaction with mood. NMDA antagonists (blockers) include the aforementioned dissociative anaesthetic, ketamine. Other drugs with more complex interactions with the NMDA receptor that ultimately reduce NMDA activity but with fewer dangers and side effects (e.g. ketamine, with chronic and sustained use may cause irreversible brain damage) are currently being pursued as novel antidepressant agents.

Exactly how excessive/otherwise abnormal NMDA receptor activity leads to depression, while not entirely clear, does allow us to develop our theories. One is that a well-known phenomena associated with the NMDA receptor might be to blame. See the NMDA, AMPA and kainate glutamate receptors are all involved in what medical professionals refer to as excitotoxicity. This is when neurons, after being excessively activated, undergo, often extensive, cell damage and on some occasions die. One commonality of all currently known antidepressant agents is that they protect brain cells from further damage, particularly damage due to excitotoxicity. Since the NMDA receptor plays a pivotal role in excitotoxicity, it is thus theorised that excessive glutamate receptor activity and thus excitotoxicity might be to blame for the pathology (illness) we call depression. The AMPA receptor appears to also play a key role in the antidepressant properties of NMDA receptor antagonists like ketamine, or at least according to one study that found that AMPA antagonists reversed the antidepressant effects, in lab animals, that were seen during NMDA receptor antagonist therapy.[4]

The cortisol hypothesis of depression proposes that chronic hypersecretion (increased secretion) of cortisol is the cause of depression. This theory is supported by the fact that a common method of inducing depression in lab animals is to chronically expose the animals to mild stress. Stress triggers, among other things, the secretion of cortisol. Chronic corticosteroid (the same class of chemicals as cortisol) use has been linked to depression too which supports this theory. People with depression tend to respond more poorly to corticosteroid treatment, which is proposed to be due to downregulation of the corticosteroid receptors due to chronic elevated cortisol exposure the receptors are subjected to in depressed patients.

The inflammatory theory of depression is, while currently still an "underground" theory is steadily gaining support. It was proposed some twenty years ago, and while still not making an appearance in the textbooks it is definitely gathering support. It proposes that depression is due to the biochemical changes that take place in the brain during an inflammatory response. This theory condenses and explains so many findings in a single framework, it quite simply to me, is beautiful. It even manages to explain the current support for the other two theories. For some time medical researchers/professionals knew of the fact that sick patients, particularly those suffering an infection and the associated inflammation, often suffer a collection of behavioural and psychological symptoms collectively called sickness behaviour syndrome (SBS). Symptoms of SBS include:

  • Lethargy
  • Depression
  • Anxiety
  • Difficulty concentrating
  • Inattentiveness to personal appearance
  • Sleepiness
  • Loss of appetite

The interesting thing is that if you look through this list, many of these are common symptoms of major depressive disorder. This caused researchers to propose that maybe they are one in the same conditions. That maybe, in at least some patients, their symptoms are due to a chronic infection that leads to SBS. The chemical mediators of SBS have been found to be cytokines, which are signalling molecules that help coordinate the body's immune response to infections and cancers. A finding that supports the theory that major depressive disorder is, in fact, a case of SBS due to a chronic, uncontrolled infection/inflammatory process is that MDD patients have been found to have increased blood concentrations of pro-inflammatory cytokines when compared to healthy, non-depressed controls.

A relatively common complication of chronic therapy with cytokines, like those used in the treatment of hepatitis B, C, cancers and multiple sclerosis is depression further supports this theory. Antidepressant medications have also been found, without exception, to possess to anti-inflammatory effects thus explaining their clinical efficacy in treating depression under this theory.

The next table I'm able to show you requires you to understand a piece of statistics you're unlikely to have learnt at school so I will explain. In statistics, the p value, is the statistical likelihood that a link between the data does NOT exist. p values are given as a decimal point, multiply by 100 to get the percentage likelihood of an absence of a link.

Table 1: Cytokines and Depression



Relationship to MDD

Pro-inflammatory Direct; p<0.00001 [5]
Pro-inflammatory (chronic)/
Anti-inflammatory (acute)
Direct; p<0.00001 [5]

Some studies indicate some link between the concentrations of other cytokines and depression but overall, statistical analyses of all clinical trials provide support for roles of these two cytokines, only, in depression. 

Figure 3: The Inflammatory and Neurodegenerative (I&ND) pathways in depression [source: 6]

A very good explanation of the inflammatory hypothesis of depression is available here.[6] This hypothesis also conjectures that the symptoms of depression are in fact due to the pro-inflammatory cytokines and their damaging direct and indirect effects on the brain. 

This hypothesis also proposes that free oxidative radicals (commonly called quite simply free radicals) that are created as a side effect of cytokine penetration of the central nervous system (CNS; brain and spinal cord) cause part of this damage that in turn leads to depression. 

This would suggest that, at the very least, antioxidant supplementation during antidepressant therapy would lead to improved response rates. This theory has been confirmed in one relatively well-designed clinical trial (only real limitation was the small sample size of just twelve children with MDD; p<0.0001 which indicates a very strong correlation, especially for such a small sample size; p values tend to go down with higher p values provided there's a link). 

It also proposes that anti-inflammatory drugs, such as celecoxib, a drug originally created to replace aspirin and ibuprofen, might improve depressive symptoms. Which it did in these studies.[7][8]

This theory also proposes, based on the fact that omega-3 fatty acids suppress the synthesis of pro-inflammatory prostaglandins (which is secondary to [the result of] pro-inflammatory cytokine release) that omega-3 fatty acid supplementation would improve mood in depressed patients, which thing it has been found to do in clinical trials.[9][10]

Treatment wise the following are in some degree of development:
# Indicates that these drugs are hoped, with strong supporting evidence, to speed up therapeutic responses
* Indicates that these drugs are hoped, with strong supporting evidence, to improve response rates

Based on the monoamine hypothesis:

  • Drugs that block the presynaptic 5-HT1A receptor while simultaneously increasing synaptic concentrations of serotonin.#
  • Drugs that increase the synaptic concentrations of all three major monoamines, serotonin, norepinephrine and dopamine.#*

Based on the glutamate hypothesis:

  • Drugs that block, via complex and safer means the NMDA receptors#*
  • AMPA receptor positive allosteric modulators (PAMs; drugs that despite failing to activate the receptor assists other compounds in doing so)

Based on the cortisol hypothesis:

  • Drugs that block the corticosteroid receptors

Other hypotheses/unclear:

  • Drugs that activate the nicotinic receptors responsible for the effects of nicotine*
  • Drugs that activate the cannabinoid receptors
An ABC radio podcast in 2011 discussed the link between Depression and Inflammation (goes for 30 mins).

Wednesday, 15 May 2013

Autism, what is it and what do we know about its causes?

Autism, that's the name of a relatively common developmental and behavioural disorder, that is it is a condition in of which a child's mental and behavioural development is impaired, or stunted. According to Better Health Victoria, a Victorian Government website, the following are the symptoms:

Language – absent, delayed or abnormal patterns
Play – isolated, repetitive, a preference for predictable play, difficulty with flexible thinking, such as pretending that a box is a boat or a stick is a horse
Body movements – stereotypical behaviour, such as flapping and toe walking, and other behaviours that may cause self-injury, such as hand biting
Restricted or obsessive behaviour – with favourite topics, objects, places, people or activities
Rituals and routines – bring some order to chaos and confusion. A change to routine can result in the individual displaying high levels of stress, anxiety or acting out
Tantrums – can be a way to express extreme confusion, stress, anxiety, anger and frustration when unable to express their emotions in another way
Sensory sensitivities – to certain sounds, colours, tastes, smells and textures.

These symptoms usually become apparent in the child before the age of four. There are some children in of which the symptoms can begin later in life. These children are said to have regressive, or late-onset autism. 

Additionally autism, isn't a single condition, it's a "spectrum" of conditions known collectively as autism spectrum disorders (ASD). Asperger syndrome, is an ASD that's usually described as comparatively mild, in that people with it are usually high functioning and capable of living independently.

The cause of autism isn't exactly clear, but the environment a child grows up in and their genetics appear to play pivotal roles. While, from what I could find, there have been no specific genetic risk factors (i.e. specific faulty genes that contribute to the disorder) identified so far there appears to be a strong and definite genetic component of autism.

A study was conducted a few years ago in of which patients with autism that had since died due to a wide range of unrelated causes and a few living patients were found to either have swelling in their brains (or neuroinflammation; these patients were the dead ones, such tests would be dangerous to perform on living subjects) or had markers of inflammation in their cerebrospinal fluid (CSF; a fluid, that is not blood that flows throughout your brain and spinal cord. This was taken from living subjects, these markers of inflammation were determined, directly, from the deceased's brain tissue in the case of the deceased subjects). None of these patients' causes of death or their pre-existing conditions, both in the living and deceased subjects, could have explained this, thus leaving their one major and apparent thing in common to be the cause: their autism. One study demonstrated that persons with late-onset autism have abnormal gastrointestinal (GI) flora (bacteria living in their stomachs, small and large intestines) compared to unaffected individuals. This would further support the aforementioned neuroinflammatory hypothesis of autism. 

Another finding that supports the neuroinflammatory hypothesis of autism is that patients with autism often find some respite from their symptoms from antidepressant therapy. It so happens there's a theory that that depression is due to certain pro-inflammatory compounds that are released during an inflammatory reaction. This theory is well-substantiated by the fact that every antidepressant I'm aware of, at least, has been demonstrated to posses additional anti-inflammatory effects.[1]

You may, of course, be asking me how could we maintain that there is a strong genetic component to autism while also proposing that it is due to an inflammation of the brain when inflammation is usually, as the abnormal GI flora finding supports, environmental in cause and not genetic. While there are some exceptions to this very broad view of inflammation genes do a play a key role in determining our susceptibility to different microbes and the inflammation they can cause. Faulty genes can also cause inflammatory responses to things that are meant to be in our body, a good example of multiple sclerosis which is when an inflammation arises in response to the myelin we all have insulating our brain, spinal cord and nerve cells. 

I would like to clear up a few things some of you may have heard about the cause of autism, there is a large body of evidence to discredit the following theories:

  •  The immunisation-based theory, that vaccines cause autism [2][3][4]
  •  That a casein (milk protein)-free and gluten-free diet can prevent or reverse the symptoms of autism [5][6]

Although both these theories would be supported by an inflammatory framework of autism the vast body of evidence has severely discredited them. The casein and gluten theory could also work without the inflammatory theory of autism.

Casein and gluten are interesting proteins in that the body converts them to opioid peptides. The term opioid refers to the fact that these peptides bind to and activate the very receptors that the opioids, morphine, codeine, fentanyl and pethidine (meperidine; demerol) bind to and activate. The term peptide refers to the chemistry of these compounds. Chemically they are basically relatively (relative to the giant chains that make up proteins) short chains of amino acids (the building blocks of proteins) chemically bonded head-to-tail. Opioids, even when they are administered in low doses, if they are given to young lab animals has, in one study, been found to lead to behaviours and other symptoms consistent with autism in humans.[7] This finding, however, makes no sense. See, if this were true for humans, guess what? Breast milk, or for that matter any milk would cause similar permanent deficits in children as they are good sources for casein. The amount and potency of opioid peptides produced after the consumption of casein and gluten is minuscule. The strongest of the casomorphins (casein-derived opioid peptides) is 1/10th the strength of codeine or less than 1/100th the strength of morphine. The other thing about this theory is that it proposes that removal casein and gluten will cause the disappearance of symptoms. The study in lab animals showed permanent damage, not reversible damage. Additionally, as animals and humans develop our blood-brain barrier, the cellular barrier that keeps large and water soluble compounds, both of which peptides like casomorphins and gluten opioid peptides are, away from the brain and spinal cord.

While I still stand by the evidence, recently there was a journal article published that proposed that maybe these anti-vaccine cranks were onto something. Thiomersal, a common mercury-based preservative used in vaccines, has been found, when administered to baby rats, to cause permanent changes in the rats' mu opioid receptors. The mu opioid receptor (MOR) is a receptor that opioids like morphine, fentanyl and pethidine bind to in order to elicit the bulk of their effects like pain relief, sedation and, in sufficient doses, memory and learning impairment. The changes found in these rats' brains included a decreased mu opioid receptor expression (or density) in the dentate gyrus, a part of the brain that appears to play a key role in memory formation. While this finding is unclear in the context of autism it is interesting and is causing, in many countries, the removal of thiomersal from vaccine formulations. This study also found that thiomersal causes increased MOR expression (or densities) in the periaqueductal grey, a part of the brain that appears to play a key role in pain perception. Some anecdotal (anecdotes are stories that are recalled, in this case, likely to the patients' health care professional. This means that as far as the strength of evidence goes this is very weak, hearsay evidence) evidence suggests that autistic patients have an increased sensitivity to pain, which is in accordance with this finding.