Thursday, December 3, 2009

The Cholinergic Hypothesis of Depression?

Come the year 2012 there could be a new antidepressant with a novel mechanism of action on the market in these United States (1). As the drug is still in development, it is known as "TC-5214."

According the the press release, TC-5214 is a "nicotinic channel blocker that is thought to treat depression by acting on neuronal nicotinic receptors, or NNRs, according to Targacept. Targacept says NNRs are found on nerve cells throughout the nervous system and regulate nervous system activity."

This is the first I've heard the term "neuronal nicotinic receptors." In all my texts they are referred to as nicotinic cholinergic receptors (nAChRs). In common parlance, they are simply referred to as "nicotinic receptors." My bias leads me to believe that this is the term that polled best in a focus group as being both "sciency" sounding and "catchy." But I digress...

In this abstract (2), this rationale is put forward, "based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214" (my emphasis).

I have never heard this "cholinergic" hypothese of depression before.

They add, "TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety... forced swim test, a classical depression model....behavioral despair test ... the social interaction paradigm, a model of generalized anxiety disorder...the light/dark chamber paradigm , a model of GAD and phobia."

Take this for what it is worth. I hold almost no faith in animal studies (3) since the animal models simply cannot mimic the complexities of human mental illness and that the majority of drugs that pass animal trials fail to generate positive result in humans.

And just like many other theories of depression, a complex mental illness can be boiled down to a single receptor, "the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the α4β2."

Since so much has been written about serotonin, norepinephrine, and dopamine, I've decided to dedicate the rest of post to acetylcholilne, the proposed "cause" of depression that this new drug will treat. (NERD ALERT: If you find this kind of stuff boring, stop reading now!)

Acetylcholine (ACh) is synthesized in one step (as opposed to the multiple steps required for the catecholamines). As you can see in the above image, there are two precursors: choline and acetyl coenyzme A (acetyl CoA). Choline is primarily derived from the fat in our daily diets. Acetyl CoA is produced within the cell by way of fat and sugar metabolism. The synthesis of ACh is catalyzed by the enzyme choline acetyltransferase (ChAT), which does as the name implies, it transfers the acetyl from CoA to choline to form ACh. ChAT is present in the cytoplasm of neurons that use ACh as their neurotransmitter.

Acetylcholinesterase (pictured above) breaks down ACh into choline and acetic acid (the acid that gives vinegar its smell and taste, 4). AChE is found within the presynaptic cell to metabolize excess ACh, on the membrane of the postsynaptic cell to break down ACh released into the synaptic cleft. It's also found in the neuromuscular junction (where PNS nerves stimulate muscles).

Cholinergic neurons play important roles in both the central and peripheral nervous systems (CNS & PNS). ACh neurons modulate both the sympathetic branch and the parasympathetic branches of the PNS. In the brain, the main neuclei that produce ACh are clustered in only a few areas. The first major pathway originates in the dorsal tegmental areas and projects to the thalamus. This pathway is part of the "reticular activating system," which govern the arousal level and alertness. Next is the septal nucleus that projects to the fornix and terminates in the hippocampus (ACh plays a prominent role in long-term memory formation). Next is the "ACh forebrain complex," which includes three "bands," the largest being the nucleus basalis of Meynert. These projections go all through the cortex and amygdala, the olfactory bulbs and the vestibular-cochlear nerve (important in balance).

There are two acetylcholine receptor subtypes, muscarinic and nicotinic.

Nicotinic receptors are highly concentrated on muscle cells, ganglionic neurons in the PNS, and on certain brain neurons. They are ionotropic (made up of an ion channel). When ACh binds to this receptor, sodium (Na+) and calcium (Ca2+) rush into the cell, causing depolorization, and increasing the cell's excitability. These receptors also enhance the release of other neurotransmitters.

The nicotinic receptor (above) is comprised of five proteins that form a channel. The subunits are label with Greek letters: beta, gamma, sigma, and two alpha subunits (ACh needs to bind to both of these to open the channel up). The structure, however, of the brain nicotinic neurons and muscles neurons are different, leading to different pharmacological difference between the two (see below).

The drug TC-5214 reportedly binds to neuron type three at the alpha4, beta2 subunit. (Contrary to what Wikipedia says, 5, this drug has NOT been tested in MDD patients).

Muscarinic receptors, conversely, are metabotropic (similar to monoamine NTs). So far, 5 muscarinic receptors have been discovered (M1 to M5), with some being excitatory and others inhibitory. Receptors are widely distributed throughout the brain including the neocortex, hippocampus, thalamus, striatum, and the basal forebrain. Outside of the brain muscarinic receptors are found mainly in cardiac muscle and smooth muscle (such as those found in the bladder). This is the receptor system associated with "anticholinergic syndrome" (6).

ACh's exact role in mood and cognition is still not known. It's associated with long-term memory formation (e.g., Alzheimer's disease) and attention and arousal (e.g., focused attention). Will TC-5214 actually treat depression? I doubt it. It seems to me, as a nicotinic receptor antagonist, it is better suited for smoking cessation (Chantix loses patent protection in 2012). Either way, it will be interesting to see how this one develops.


Nicholas Walsh said...

Wayne Drevets and Maura Furey have done quite a bit of work on this, on alterations in the cholinergic system and depression. Although not the whole story, it appears there is evidence for alterations in depressed patients.

See review below

Bernard Carroll said...

There is indeed a cholinergic hypothesis of depression. More accurately, it is termed a cholinergic-adrenergic balance hypothesis. It began in the early 1970s when John Davis and David Janowsky gave the acetylcholinesterase inhibitor called physostigmine to manic patients.… the patients quickly entered a period of marked depressive behavior that persisted until the drug had cleared (an hour or two). I did some work with this paradigm myself – it is one of the most dramatic findings in experimental clinical psychopharmacology. See Carroll, B.J., Frazer, A., Schless, A. and Mendels, J. Cholinergic reversal of manic symptoms. Lancet, 1:427-428, 1973.

This effect of physostigmine is prevented by pretreatment with atropine but not methylatropine (which does not enter the brain). So your point about a muscarinic rather than a nicotinic mechanism is on target.

In unipolar depression, the effects of physostigmine are not as dramatic. Just the same, there have been suggestions that the early tricyclic antidepressant drugs were so good partly because of their associated muscarinic anticholinergic property. And there some inconclusive experimental evidence that the muscarinic anticholinergic drug biperiden has positive effects in some depressed patients (see Kasper, S. Moises, H W. Beckmann, H. The anticholinergic biperiden in depressive disorders. Pharmacopsychiatria. 14(6):195-8, 1981).

As for the new Targacept compound, time will tell, but I agree with your skepticism.

Barney Carroll.

Neuroskeptic said...

Excellent write-up as usual.

According to Wikipedia, bupropion is a nACh alpha3beta4 antagonist, and it's an antidepressant (although it's also a DNRI so that probably explains the antidepressant effect.)

And Champix (varenicline) is a partial agonist at a number of nACHRs. It has been accused of causing depression & suicidality.

Anonymous said...

I am surprised that you did not catch the following:

Targacept Presents Data from Highly Successful Phase 2b Trial of TC-5214 as Augmentation Treatment for Major Depressive Disorder
Business Wire News ReleasesPublished: 10/15/09 06:35 PM EDTReleased By: Targacept, Inc.Rating:
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Six Point Advantage over Placebo (p<0.0001) on Primary Outcome Measure (HAM-D)
Targacept, Inc. (NASDAQ: TRGT), a clinical-stage biopharmaceutical company developing a new class of drugs known as NNR Therapeutics™, today announced the presentation of data from its recently completed Phase 2b clinical trial of TC-5214 as an augmentation (add-on) treatment in subjects with major depressive disorder, or MDD, who did not respond adequately to first-line treatment with the representative SSRI citalopram hydrobromide. In the trial, the add-on TC-5214 arm (TC-5214 + citalopram) outperformed the add-on placebo arm (placebo + citalopram) on the primary outcome measure, the Hamilton Rating Scale for Depression-17, or HAM-D, and all of the secondary outcome measures, with high statistical significance.

Selective serotonin reuptake inhibitors, or SSRIs, are the most commonly prescribed class of drugs for depression, but many patients do not respond well to SSRIs. The National Institute of Mental Health, or NIMH, has estimated that 14.8 million American adults suffer from MDD. In the NIMH’s large-scale Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, study, approximately 63% of participants did not achieve remission following initial treatment with citalopram alone.

In the TC-5214 trial, the magnitude of clinical response (change from double blind baseline after eight weeks) on HAM-D was 6.0 points greater for the add-on TC-5214 arm (13.75 point improvement) than for the add-on placebo arm (7.75 point improvement). This result was highly statistically significant (p < 0.0001) on an intent to treat basis. Highly statistically significant results (p < 0.0001) were also achieved on an intent to treat basis on all of the trial’s secondary outcome measures, including the Montgomery-Asberg Depression Rating Scale, or MADRS, the Quick Inventory of Depressive Symptomatology – Self Reporting scale and assessments of irritability, disability, cognition, severity of illness and global improvement. As previously reported, TC-5214 exhibited a favorable tolerability profile in the trial.

Anonymous said...

This is all way over my head, but my spouse recently discovered an intolerance (or delayed hypersensitivity) to eggs. The egg whites cause stomach distress; the egg yolk causes a sudden negative mood shift which lifts by the end of the day (having eaten the eggs at breakfast.)

Anonymous said...

NeuroPsych presents a nice basic science overview of the cholinergic system and is probably correct on the 'NNR' term probably 'polled best in a focus group'. For example, it sounds a lot like 'SSRI'.

Those interested in this area should read the paper below, which explains mechanistically why nicotinic blockers like TC-5214 should have anti-depressant properties. Moreover, it resurrects the cholinergic theory of depression highlighting the role of nicotinic receptors as opposed to muscarinic receptors.

Molecular Psychiatry (2002) 7, 525–535 [Nature Publishing Group]

Nicotinic acetylcholine receptors as targets for Antidepressants

RD Shytle, AA Silver, RJ Lukas, MB Newman, DV Sheehan and PR Sanberg
University of South Florida College of Medicine, Tampa, FL, USA

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications - the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In accordance with this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

BTW, physiostigmine is not only a acetylcholinesterase inhibitor (AChEi) increasing brain levels of ACh, but unlike most other AChEi's, is also an allosteric agonist of nicotinic receptors.

Consistent with this paper’s hypothesis, Chantix, a partial agonist of nicotinic receptors, may increase depressive symptoms in those undergoing treatment for smoking cessation. In fact, the signal seems clear in the NDA safety data Pfizer filed with the FDA, which is available online if you know where to find it :-).

I believe it was honestly 'missed' initially by Pfizer and the FDA, but the black box warning was justified.