503.Mood Disorders: Preclinical Studies and Animal Models.
503.09. Vortioxetine improves a reversal learning deficit in rats induced by serotonin depletion or chronic stress. DA MORILAK, A WALLACE, A PEHRSON, C SANCHEZ-MORILLO; Pharmacol. and Ctr. for Biomed. Neurosci., Univ. of Texas Hlth. Sci. Ctr., SAN ANTONIO, TX; Lundbeck Res. USA, Paramus, NJ
People generally consider depression as something purely emotional – an inescapable distaste towards oneself, an unshakable apathy towards the world, a persistent slow, sticky feeling of exhaustion, as if walking the path of life with glue on both feet.
Yet depression has a strong cognitive component, one so powerful that some scientists believe it to be the root of emotional imbalance. Many sufferers describe their thought patterns as “stuck in a rut”, where they’re only capable of framing things in a negative light, thus seeing the world as pale and hopeless. This observation has prompted two groups of researchers to ask: can we treat depression by targeting cognitive inflexibility?
AMP-A(p) the synapse
Luckily for researchers from Florida State University, we already have a class of cognitive enhancers on the market. AMPAkines are known to enhance attention span and improve learning and memory in the elderly and those suffering from neurodegenerative diseases. These drugs get their name from strongly enhancing the function of the AMPA receptor as a positive modulator. Interestingly, ketamine, the club-drug-turned-fast-acting-anti-depressant requires AMPAR activation to work, suggesting that AMPAkines may not only alleviate depressive symptoms but also act more rapidly than traditional anti-depressants.
Researchers gave a group of young adult rats a single injection of either ketamine or CX614, one of the best-characterized AMPAkines. 24hrs later, they exposed the rats to water and measured how long they swam before giving up in despair. Compared to saline-injected control animals, both ketamine and CX614 reduced the amount of time they spent immobile, though ketamine was slightly more effective at the doses used.
In another cohort of rats, researchers used a stressor (they didn’t say what, but it could be anything from bullies to cats to robots) to acutely trigger depression-like symptoms. Rats have quite the sweet tooth; normally given the choice between sugar and plain water, they lap up the sweet stuff in earnest. However, once depressed, they seem to loose the ability to enjoy life’s pleasures and no longer prefer the treat. Once again, a single injection of either ketamine or CX614 restored their love for sugar within a day. Remarkably, the antidepressant-like effects of CX614 lasted up to 8 days, even longer than that of ketamine.
On the molecular level, many previous studies show that depression reduces the number of synapses, thus negatively affecting the way neurons communicate. In fact, ketamine is known to rapidly reverse this defect, which may be one of the reasons behind its anti-depressant effect. Does CX614 work in the same way?
Using brain tissue isolated from CX614-injected animals, researchers found that within 30min neurons in the hippocampus were actively making more proteins, as evidenced by increased activity of the protein translation machinery. At the same time, CX614 also triggered a cascade of molecular signalling to reconstruct and stabilize actin, a “skeletal” protein that helps a cell maintain or alter its structure.
These two processes – protein translation and actin remodelling – allow neurons to form new spines, the little protrusions along dendrites that host synapses formed with (typically) another neuron. In other words, spines provide an anatomical structure for synaptic transmission. Although researchers did not directly prove their case with imaging techniques, these molecular changes certainly suggest that CX614 increases synapse formation.
Thus, like ketamine, AMPAKines may rapidly reduce depressive symptoms; unlike ketamine, they have very low potential for abuse. Whether their cognitive enhancing effects directly contribute to anti-depression though will have to be answered another day.
Flexible thoughts, sunny mind?
Researchers from the University of Texas and Lundbeck Research took the opposite approach – they picked an anti-depressant and investigated its cognitive enhancing effects. Vortioxetine is a selective serotonin reuptake inhibitor (SSRI) like Zoloft and Celexa. However, it also directly binds to and activates numerous types of serotonin receptors, giving it a unique pharmacological profile.
As mentioned above, patients with depression are often unable to flexibly reframe their thoughts. Neuroscientists can identify and measure a similar deficit in rats with a rather sneaky task. They first trained rats to dig for cheerios (yum!) from several pots, some of which smelled like cloves, others nutmeg; some filled with dry grainy sand, others with moist soft dirt. Unbeknownst to the rat, the digging material was just a distraction. Scent was the only clue they had to follow to find the treat.
After rats finally figured out the rules of the game, researchers suddenly switched the cheerios from the clove-sand pot to the nutmeg-sand pot, sat back, and watched how fast the rats updated their strategy as a measure of cognitive flexibility. In the first set of rats, researchers depleted ~90% of their serotonin levels with a chemical, thus coarsely mimicking the dearth of serotonin transmission seen in depressive patients. Unsurprisingly, they performed horribly, steadily going back to the original pot. However, when researchers gave them an injection of Vortioxetine 30min before testing, they rapidly ditched the old pot for the new.
Researchers then stressed a new group of rats with bouts of intense and unpredictable cold for 14 days straight. This treatment is often used to trigger deficits in reversal learning as well as depression-like behaviours (imagine being randomly thrown into a fridge for two weeks – you’d be constantly on edge and most likely depressed by the end too!). In the meantime, some rats received Vortioxetine in their food while others got placebo. In the end, those on placebo failed miserably on the cheerio-finding task, while those treated with Vortioxetine performed just as well as non-stressed controls.
These results suggest that Vortioxetine, an SSRI-type antidepressant, improves cognitive flexibility in stressed-out (and perhaps depressed) rats. However, the researchers did not show whether it also relived depressive-like symptoms at the doses used, how long the effect lasted, or whether the drug would perform in other (arguably more common) models of depression such as social defeat.
Taken together, these two studies complement each other beautifully, even though the results are still preliminary. Depression is a tough nut to crack, but the search for novel and fast-acting anti-depressants is in full swing. Among those presented at #SfN13 are the anesthetic gas isofluorane and the anti-cough medication dextromethorphan. Unfortunately as of now neither are ready for clinical use for depression.
The discovery of ketamine revolutionized the field of anti-depressant research in the last decade or so. Perhaps tackling depression on both cognitive and emotional ends – with cognitive enhancers or others – will prove to be even more effective at taming the beast.
Sappy little end-note: Back when I was studying pharmacy the best we could offer depressive patients were the atypical SSRIs, which takes weeks to months to start working. Many don’t respond to them at all and those who do built tolerance quickly. I’m so happy to have watched the story of ketamine unfold. If you’d like to know more, Gary Stix has a great 3-part series on Scientific American that’s well worth a read.
Check out my previous post on another potentially fast-acting anti-depressant L- acetyl-carnitine, a common fitness supplement.