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We take you through the story of rational drug discovery that lead to the approval of guanfacine and clonidine for ADHD, and share some tips on how to use them. And the word of the day: Dyssymbole.

Published On: 10/26/2020

Duration: 19 minutes, 55 seconds

Article Referenced: “Guanfacine ER for Adults With ADHD?” The Carlat Psychiatry Report, October 2020

Transcript:

How did two blood pressure medications get FDA approved for ADHD? And how do you use them in practice?

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie Newsome:  In this month’s Carlat Report we brought you a new research update on guanfacine. It’s probably the last industry sponsored study of this recently-gone-generic medication, and the study is an important one because it possibly expands its use. Check it out in our October issue if you haven’t already. In this companion podcast we’re going to get more into the nuts and bolts of how to use guanfacine, otherwise known as Intuniv – and its alpha-agonist cousin clonidine, brand name Kapvay – in ADHD.

Clonidine and guanfacine were first released as antihypertensives  – clonidine in 1966 and guanfacine in 1986. Their approval in ADHD came much later, in 2010 and 2011, so Dr. Aiken how did these blood pressure medications come to be used in ADHD?

Dr. Aiken: This is a story of rational drug discovery, and it began in the 1930’s when scientists figured out the function of the prefrontal cortex. Later, they discovered that this part of the brain was impaired in ADHD, and that guanfacine and clonidine enhanced prefrontal cortex functioning. Much of this research took place at Yale – where neurosurgeons, neuroscientists, and psychiatrists were all working alongside each other and sharing ideas. For example, when Donald Cohen was treating intractable tic disorders in children, he brought George Aghajanian with him on rounds to see a child with particularly intractable tics. Dr. Aghajanian had been studying clonidine for opiate withdrawal, and he saw a similarity between the disinhibited movements of opiate withdrawal and the tics. He suggested they try clonidine, and it worked, and we continue to use clonidine and guanfacine for tics today. This made Dr. Cohen wonder if clonidine might treat another disorder of disinhibition – ADHD – and he and Robert Hunt conducted the first study of clonidine in ADHD in 1986. Now clonidine is sedating, and at the time they weren’t sure if the medication was inhibiting impulsive and hyperactive behavior through its sedating effects, but in a lab nearby Amy Arnsten and Patricia Goldman-Rakic were linking clonidine and guanfacine’s cognitive benefits to the prefrontal cortex.

Kellie Newsome: What exactly is the prefrontal cortex?

Dr. Aiken: The Prefrontal cortex is like a mental sketch pad where we can store recent memories and draw from old ones to regulate our regulates behavior, thought, and emotion. Suppose you’re going through TSA to get on an airplane, and they notice something suspicious in your bag and as you to step aside.  Hopefully you’re brain will recall past times when you had to interact with authorities and guide you to act in a way that doesn’t get you detained. That’s an example of drawing on old memories, and it’s also an example of set shifting, which the PFC is also involved in. So 1 minute you’re negotiating with a taxi driver to drop you off at the right gate, and the next minute you’re negotiating with an officer of the law about a pair of scissors that was found in your suitcase – the rules of engagement have changed, and your brain has to “shift sets.”

It’s also involved in making long-term plans so you can maneuver your way through school and careers. And as you move toward those goals, it keeps your brain from wandering into distractions, rushing in on impulse, or getting stuck in compulsions – two things that don’t work well in untreated ADHD. 

The role of the prefrontal cortex in memory was discovered by a neurosurgeon at Yale – John Fulton – and I have a lame claim to fame with Fulton from my days as a medical student. Fulton’s house was turned into a neuroscience research institute at Yale – it was a grand old mansion overlooking New Haven, and I actually lived there as medical student. My job was to make sure the pipes didn’t burst and the place didn’t catch on fire – which I succeeded in. And the hallway outside my bedroom was covered floor to ceiling with human brains from John Fulton and Harvey Cushing’s neurosurgery lab – all lined up in Jars from the 1930’s.  

Kellie Newsome: Sounds pretty dark.

Dr. Aiken:  Not if you’re a budding psychiatrist. But there was a darker side to Fulton’s work. He was the first to observe that when the frontal lobe was cut in monkeys they became calm and subdued, and this lead António Moniz to perform the first lobotomy in 1949. Lobotomies took off as a therapy for schizophrenia and various behavioral disorders in the 1950’s and 60’s – we scorn them today but they were heralded as a great cure at the time. The Kennedy family sought one out for JFK’s sister, and Dr. Moniz was awarded the Nobel Prize in medicine for his discovery. Psychiatrists today are not too different from 50 years ago – and PBS’s American Experience Documentary from 2008 The Lobotomist – which reveals how our enthusiasm for new therapies can blind us.

Kellie Newsome: So on the one hand Fulton’s discovery lead to the lobotomy, and on the other hand it lead to Guanfacine and Clonidine.

Dr. Aiken:  Yes Fulton’s work spawned other research on the prefrontal cortex, which laid the groundwork for the basic science and then the clinical studies of clonidine and guanfacine in ADHD. Robert Hunt, who was at Yale and is now in private practice in Nashville, conducted the first clinical trials in ADHD – of clonidine in 1985 and then guanfacine in 1995. One thing worth knowing about these early studies is that they were done with the instant release formulations. Later, when it came time for FDA approval, the companies switched to the extended released versions because the instant released ones were generic. That’s why only the XR versions are FDA approved in ADHD.

Kellie Newsome:  For a while that held these drugs back, because they were very expensive to prescribe in the FDA approved forms. But that doesn’t matter so much now as the ER versions are both generic.  Clonidine ER comes as 0.1 and 0.2; guanfacine 0.1 0.2 0.3 0.4mg

Dr. Aiken:  And I would recommend starting with the ER forms as they are FDA approved. But there are times when you may need to switch to instant release, like if sedation is a problem and you have to manage that by giving one short-acting dose at night. And here’s a tip. Much of the ER form does not get absorbed, particularly with guanfacine, so you have to lower the dose a touch when converting to the instant release form – lower the dose by about by about 40% when switching from guanfacine XR to instant release, and lower by about 10-20% when switching to clonidine IR from XR.

Kellie Newsome:  But if you give it all at night how is that going to help ADHD during the day time?

Dr. Aiken: Unlike the stimulants, the alpha agonists have delayed effects in ADHD – they build up gradually over 2-4 weeks. This is probably because their pharmacodynamic effects are more downstream… they start by activating alpha-2A adrenergic receptors, and this inhibits the action of downstream neurons in the PFC. Now, I wouldn’t recommend this single-evening-dose strategy for everyone, as most of the studies dosed it twice a day as instant release or once a day as extended release, but evening instant release dosing worked in some studies and I’ve found it effective in practice.  Also, the half lives of these medications suggest that once a day dosing is feasible particularly with guanfacine – guanfacine’s half life is 18 hours, while clonidine’s is 12 hours. But these half lives are shorter in children – because children metabolize medications faster – which is another reason the XR was developed.

Kellie Newsome:  Clonidine is the more sedating of the two, but what are the other differences?

Dr. Aiken:  That’s right clonidine has stronger sedative and hypotensive effects. That can be a plus if insomnia is a problem, and clonidine does treat nightmares in PTSD.  The two alpha agonists have never been compared head to head, but judging from the clinical trials they appear to have similar benefits – and notably smaller benefits than the stimulants.  It’s hard to beat the stimulants – methylphenidate and amphetamine’s effect sizes are among the largest in psychiatry. Clonidine and guanfacine rank more in the area of atomoxetine – Strattera – their effect size is about 30-50% smaller than that of the stimulants.

Kellie Newsome: There are a few other technical differences between the two.  Guanfacine is more likely to become the victim of drug interactions – it is metabolized by CYP3A4 and CYP3A5 – so 3a4 inhibitors like Fluvoxamine, nefazodone Desvenlafaxine, and grapefruit juice will raise its levels, while 3a4 inducers like carbamazepine and st johns wort will lower its leves. Clonidine is less prone to drug interactions because it’s metabolized by by many enzymes in the liver. But clonidine suffers a separate fate when it comes to withdrawal – it is notorious for causing a rebound hypertension if it is stopped abruptly. Guanfacine also dose this, but less so. Both drugs should be stopped gradually, lowering the dose by 1mg for guanfacine or 0.1 mg for clonidine every 3-7 days. And hypertension is not the only withdrawal symptom – patients can experience  headaches, racing heart, nausea, flushing, hot flases, lightheadness, and anxiety.

Kellie Newsome: So which one would you use first – clonidine or guanfacine?

Dr. Aiken:  Child psychiatrists tend to prefer guanfacine, because it is less sedating. Physiologically, guanfacine has weaker presynaptic actions, but in animal studies guanfacine had stronger effects on working memory than clonidine, so I wouldn’t say these two meds are the same and some patients may respond better to one vs. the other. 

As an adult psychiatrist, I often find more reasons to use clonidine. Adults with ADHD often have complex comorbidities and clonidine has potential benefits in a lot of these. Here’s a short list of some of the conditions where clonidine has shown benefits in:

1. opioid withdrawal – it’s often used to treat the symptoms of opioid withdrawal, but a recent study found that continuing clonidine helps prevent opioid relapse
2. borderline personality disorder – it’s the only medication I know of that can be taken as needed to prevent self-cutting in borderline patients – it worked better than placebo there.
3. Autism – the transdermal version of clonidine was used in a 1992 study where it helped social relationships, emotional reactivity, and sensory responses. The dose was around 0.005 mg/kg/day, which equates to around 0.2-0.4mg/day depending on weight.
4. Irritability – it’s been used for aggression and irritability in various populations
5. Tic disorders – stimulants can worsen tics, but clonidine improves them
6. Smoking cessation. Guanfacine actually has some evidence here as well – in a study from the 1990’s people were less likely to smoke under stress while taking guanfacine. And here’s a tip: One of the main side effects of Varenicline/Chantix is vivid dreams, and clonidine treats that side effect, so the two can be used synergistically for smoking cessation.
7. Insomnia and anxiety
8. PTSD nightmares
9. Perimenopausal hot flashes
10.  Sweating – which is a common side effect of SSRIs
11. Mania – there are 6 small trials from the 1980’s of clonidine in mania – 

Kellie Newsome:  That’s just about every psychiatric disorder except schizophrenia

Yes – neither of these have very clear results in schizophrenia, where the studies are small and the results are unclear. But guanfacine is gaining ground in schizotypal personality disorder. There was a randomized controlled trial last year in the American Journal of Psychiatry where guanfacine improved reasoning, problem solving, and social cognition in schizotypal personality, it’s a follow up from a similar study from 2007 by the same research team lead by from Margaret McClure.  This is important because people with schizotypal personality often present with ADHD like cognitive symptoms – and the last thing you want to do is give them a stimulant. You know, schizotypical was discovered by Seymour Kety’s group at NIMH – they were interviewing the relatives of people with schizophrenia to figure out if the illness had a genetic basis, and they discovered that many of the relatives had odd and eccentric personality traits that eventually became classified as Cluster A – schizoid, schizotypal, and paranoid personality.

Kellie Newsome:  OK so let’s recap. Guanfacine and clonidine sharpen the prefrontal cortex – which is involved in a lot of disorders like ADHD, autism, schizotypal… but what about age related cognitive decline? The prefrontal cortex declines with age, starting around age 45 and the decline becomes sharper after age 75. Are these meds useful there?

Dr. Aiken: That’s less clear. Amy Arden’s group at Yale published a controlled study of guanfacine in the elderly in 2018, and it did not work. So it may be that the prefrontal cortex declines with age in ways that guanfacine’s mechanism does not address. These alpha receptor agonists don’t work for everyone. We covered age related cognitive decline in April 2019, and this month – in our October 2020 issue – we have an update on a medication that did work in age-related cognitive decline. 

Kellie Newsome:  And back to ADHD – I’ve heard it said that guanfacine and clonidine worked better in younger children – like under age 12 – than they did in teens. And these are only FDA approved in childhood ADHD – so do you use them in adults?

Dr. Aiken: That’s another thing that has held back these alpha agonists, and in our October issue we cover the first randomized controlled trial of guanfacine in adult ADHD. Check it out online, and use our special code PODCAST in all caps to get $30 off your first year’s subscription: 

Kellie Newsome: But wait we have to do the word of the day…. Dyssymbole  [Dis-sim-bola]

Dr. Aiken:  Di-ssombola is a a type of concrete thinking characteristic of schizophrenia and other disorders. It is an inability to describe personal emotions or to express thoughts about personal topics or the self.  The word was first used in 1939 by IAN SKOTTOAVE, and it comes from the greek word for “bad or poor” – dys – and the French word for symbol – so the patient has a poor symbolic representation of their inner life. Here’s how doctor Skottoave described it:

Kellie Newsome: “the patient cannot use the right word symbols to convey what is in his mind or what he feels; and he is aware subjectively of a change. He is aware that something has gone wrong with his thinking process, but he cannot formulate what he feels about it because the very function which he would use to put his feelings into language is the very one which has gone wrong.”

So when you see a young person with new onset schizophrenia struggle to convey the terrifying changes that are taking place inside them, now you understand. 

A related word is alexithymia, which describes a similar phenomenon on a less psychotic level – we’ll save that for next week.

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