Tox and Hound – Don’t Pick the Scab

by Dan Rusyniak

Vilazodone an SSRI with partial agony properties.

When we think about the one-pill-can-kill drugs in kids, selective serotonin reuptake inhibitors (SSRIs) are notably absent. Although they can cause serotonin syndrome, toxicity from these drugs usually require ingestions of multiple agents or a single large ingestion. There are of course exceptions to every rule. For SSRIs, an exception is vilazodone (Viibryd®). To understand what makes this SRRI unique, and how it’s uniqueness makes it much more dangerous in overdose, we need to get all pharmacologic. Be warned – we are about to go deep DEEP DEEP into Nerdville™. First, we need to understand how SRRI’s work. As their name indicates, SSRI’s (e.g., fluoxetine and sertraline) are selective serotonin reuptake inhibitors. Which means exactly what? Take a look at this image of a serotonin neuron¹ . . .

As with all neurotransmitters, serotonin is made in a neuron and packaged inside vesicles. Vesicles serve as a convenient place for serotonin to hang out until it is asked to leave; kind of like the food court in a mall for teenagers (at least that is where we hung out when I was that age). When signaled, serotonin is released into the synaptic cleft. From there it has a few possible fates:

1. It can float across the cleft and bind to serotonin receptors (depicted here as serotonin 2A receptors)
2. It can stimulate a presynaptic receptor (serotonin 1A receptors)
3. It can be pumped back into the neuron that just released it and be repackaged in the vesicle (kind of like the teen sneaking back into the mall for another Orange Julius™).

SSRIs effect this third fate. By blocking the serotonin reuptake transporter, SSRIs allow for more serotonin to stay in the synaptic cleft. This is important since the serotonin reuptake transporter is the main way you get rid of released serotonin.² So, all the excess serotonin is going to bind to serotonin receptors and rapidly make us happy, right? Of course not. As most of you know, it takes 2-3 weeks for an SSRI to have any effect on the symptoms of depression. Why? Go back to the diagram. If you block reuptake there are still two possible fates for the serotonin. It can bind to postsynaptic receptors (depicted as type 2A receptors) or it can bind to presynaptic receptors (depicted as type 1A receptors). As it turns out, it is the presence of these serotonin 1A receptors that is thought to result in the delay of symptom relief in depression. This is because when serotonin binds to a presynaptic 1A receptor it causes a decrease in further release of serotonin. Think about that for a minute. You release serotonin and it binds to the 1A receptors which has the effect of decreasing the subsequent release of serotonin. What we are describing is a very convenient neuronal overflow valve. If you release too much serotonin you get into trouble (i.e., serotonin syndrome) so the presynaptic receptors are there to keep serotonin concentrations in check. But this is a problematic effect in the treatment of depression (at least from the pharmaceutical standpoint).

The goal of taking an SSRI is to get modest, but sustained, increases in the amount of serotonin present in the synaptic cleft. The problem is that these 1A receptors work so well that even this is hard to do. What’s the way around this? Eventually, the 1A receptors become desensitized. Another way of saying this is that they become less effective at preventing serotonin release. How long does it take for these 1A receptors to become desensitized? You guessed it — 2-3 weeks, the same amount of time it takes to see clinical benefit. At least this is what the current thinking is. So, what does this have to do with vilazodone and its increased toxicity? I am glad you asked. Among the SSRIs, vilazodone is unique in that along with blocking serotonin reuptake, it is a serotonin 1A receptor partial agonist. If the whole partial agonist thing has always confused you, rest assured you are not alone. The best way I can describe a partial agonist is that it is like football scabs. Not the ones you get on your knee playing flag football, but rather the people who played for the NFL during the 1987 strike (ESPN). For those of you too young to remember, that was the year NFL players went on strike. The owners responded by hiring replacement players. While these “scabs” put on the team uniform and played games, they were incomparable in skill/talent/etc to the drafted players. Partial agonists work in a similar way³. They bind to receptors and activate them, but pale in comparison to the normal neurotransmitter. Vilazodone’s partial type 1A receptor agonism means that synaptic concentrations of serotonin increase (via its SSRI effects) more rapidly by slowing down the normal overflow valve (kind of like a wad of hair that plugs up the overflow valve in your bathtub, another teenage problem). This is exactly what vilazodone was designed to do – speed up the 2-week time period it takes for the drug to work; although yet to be proven in clinical studies.⁴

The problem, of course, is that if you block the overflow value in your tub, you are likely to get flooding. And this is exactly what we see in kids who accidentally ingest this drug. Normally serotonin syndrome (e.g., seizures, clonus, tachycardia, hyperthermia, etc)⁵ develops only after a large overdose of a single SSRI or multiple drugs with serotonergic effects. This is because it takes a lot of serotonin in the synaptic cleft to overwhelm the 1A system. When you overwhelm the system, you get excess binding of serotonin to the 2A receptor, which are the receptors most involved in causing serotonin syndrome⁶. But with vilazodone, a less effective 1A system means a small overdose is clinically much more significant. As little as 1 pill of vilazodone can result in toxicity in kids. There are case reports of small ingestions with significant toxicity: seizures, status epilepticus, and coma^7–9. One of these cases reported symptoms in a kid who only had a pill in his mouth for a short period of time⁹. In a large poison center study, vilazodone had the highest rate of toxicity among all the SRRIs in accidental pediatric ingestions¹⁰. So, what dose do we consider safe to watch a kid at home? That would be exactly no dose¹¹ (and we are not talking about the caffeine pill). All asymptomatic pediatric exposures should be watched in a hospital for at least 8 hours.

So remember – don’t send home vilazodone

Is there anything good about this drug? Maybe. It doesn’t last that long. It has a relatively short half-life (25h) compared to other SRRIs (e.g., fluoxetine is 96 – 144 h). Fortunately, in the pediatric cases, most of the kids are improved within 24h. If you are in the business of prescribing antidepressants to kids, do what you Mom always taught you. Don’t pick the scab.

Super Nerd Tip – Some authors will say serotonin 1A agonists (full agonists, not partial) cause serotonin syndrome. They don’t – at least not the parts of the syndrome that matter. The claim that they do is based on an incorrect understanding of the word serotonin syndrome. In rats, drugs that are serotonin 1A receptor agonists (e.g., 8-hydroxy-DPAT) causes what researchers call serotonin syndrome. This syndrome is a behavioral syndrome. It involves the animal doing so weird stuff with its head, and back, and paws. What it does not do is cause tachycardia or hyperthermia. In fact, 8-hydroxy-DPAT causes bradycardia and hypothermia in rats¹². The syndrome we worry about in humans causes tachycardia and hyperthermia. Effects that are prevented by drugs that block 2A receptors⁶. This is why we use cyproheptadine as a treatment – it blocks 2A receptors.

Scab Hand by Brian Patrick Tagalog

All the references fit to print