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

Cytokine

Action

Relationship to MDD

TNF-α
Pro-inflammatory Direct; p<0.00001 [5]
IL-6
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).



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