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We ask the big questions: Is topiramate a drug or a sugar? Do you need to use the FDA-approved combo pill for weight loss? And which of its 13 off-label psychiatric uses are ready for clinical practice?

Published On: 5/17/2021

Duration: 25 minutes, 58 seconds

Transcript:

Kellie Newsome: Today, we count off 13 reasons to use – or not use – topiramate in psychiatry.

Dr. Aiken: Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of The Psychiatry Carlat Report.

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

AIKEN: Bruce Maryanoff wasn’t looking for an anticonvulsant when he stumbled upon topiramate. Working out of McNeil laboratories in 1979, the 32 year old chemist was assigned to develop a medication for type II diabetes. His plan was to find a synthetic sugar that the liver would mistake for fructose. Like a monkey wrench thrown into the factory gears, this fructose look alike would get pulled into the the gluconeogenesis pathway and halt the product of the glucose at a critical, rate-limiting step. The result would be lower glucose levels and better glycemic control for diabetics.

So he set about creating synthetic sugars, and one of them was topiramate. Yes, topiramate is actually a carbohydrate sugar molecule. But Dr. Maryanoff saw something else in this molecule – it resembled acetazolamide, a medication used to treat seizures. So he sent it off for testing in an animal model of epilepsy and indeed topiramate calmed the seizures. 15 years later, McNeil delivered a tractor trailer half full of documents to FDA headquarters in Washington DC to seek approval for topiramate in Epilepsy. The approval came in 1996, and was followed in 2004 by a second approval for the prevention of migraines, followed by approval in 2012 for weight loss as a combo pill with the amphetamine-like phenteramine Qsymia.

KELLIE NEWSOME: Along the way, topiramate has inched its way into psychiatry, and in this podcast we’ll detail all of the off-label ways it’s been explored in our field – all 13 of them.

But first, to emphasize: Topiramate is not a first-line treatment in psychiatry, and is rarely useful on its own. In most of the research we’ll discuss it was used as an add-on med when other therapies didn’t work all the way. And most of the studies supporting its use in psychiatric patients are on the small side, so we usually don’t turn to it unless the patient has more than one disorder that might benefit from it. And here are those disorders:

Obesity and eating disorders

1. Weight loss
2. Bulimia
3. Binge eating disorder

Addictions

4. Alcohol use disorders
5. Cocaine use disorders
6. Methamphetamine abuse
7. Compulsive gambling

Other Psychiatric Disorders

8. Borderline personality disorder
9. Major Depression as antidepressant augmentation
10. Obsessive compulsive disorder
11. Post-traumatic stress disorder

Let’s look at each of those in more detail.

Obesity and eating disorders

AIKEN: Soon after topiramate’s launch, reports of an intriguing side effect came in. Patients were losing weight on the drug and had better glycemic control on it. No one has been able to pin down the mechanism behind this effect – about a dozen possibilities have been proposed – but it seems to be a combination of appetite loss and metabolic changes. Topiramate does lower appetite, but people lose weight on it even when their caloric intake is unchanged. Harkening back to its original development as an anti-diabetic agent, topiramate does lower glucose and lipid levels and improves insulin sensitivity.

Although the phenteramine-topiramate combo pill Qsymia is FDA approved for weight loss, we recommend sticking with pure topiramate in psychiatric populations. Phenteramine is a controlled substance, with cardiac risks and the potential to cause psychosis or mania. The FDA recognized the need to curtail its prescription and requires clinicians to register for a REMS program before prescribing Qsymia. In balance however, we do concede that the weight loss on Qsymia is meaningful – averaging 32 pounds after a year on the higher dose – which is about double what we see in studies of topiramate alone.

By itself, topiramate has pretty good data in obesity – 10 randomized controlled trials where patients lost on average 12 pounds or 5 and a half kilograms on topiramate. One thing unique about these studies is that – unlike most other weight loss medications – the weight loss with topiramate continues beyond six months. Patients can expect to keep losing weight on it for up to 1 year, which is how far out these studies go. Topiramate also has 4 controlled trials for weight loss on atypical antipsychotics, which is a bit less than the dozen or so supporting metformin. But it does work there, and the effect is meaningful, possibly causing more weight loss than metformin did and more than the FDA-approved orlistat. A good target dose for weight loss is 100 mg/day – higher doses have been studied up to 200mg/day but there the side effects usually outweigh the benefits.

KELLIE NEWSOME: Topiramate also causes weight loss in bulimia and binge eating disorders, but more importantly it seems to reduce the binge-eating behaviors. If you use topiramate in one of these disorders, you can expect the number of binge episodes to go down by about 5 per week, but a placebo will bring them down by 3 a week so the true medication effect is only 2 episodes per week. Altogether this data is fairly sound, involving a total of 5 trials of 656 patients, about a third of which involved bulimia nervosa.

Some of the most robust support for topiramate’s off-label use is in alcohol use disorders. Those controlled trials total 8, and 3 of them are large, leading one recent review paper to recommend it first-line in alcohol use disorders. It’s sometimes said that topiramate is particularly effective in binge drinking, but it has evidence in all kinds of populations – from heavy drinkers to moderate drinks – from reducing alcohol use to preventing relapse into alcoholism – and in patients with important comorbidities like schizophrenia, bipolar disorder, PTSD, and head injury. It reduces cravings, impulsivity, responses to alcohol triggers, improves mood during sobriety, and also lowers the common tendency to use nicotine along with alcohol. The dose ranged from 75-300 mg/day.

A lot of research is pouring in to identify genetic predictors of medication response in addictions, and there is some indication of that patients with a GRIK1*rs2832407 gene respond better to topiramate but this is mixed.

AIKEN: Topiramate takes a step down when it comes to evidence in cocaine use disorders, but then again there are less options to choose from here than there are for alcoholism so it still serves a useful role. The dose in these studies is similar to the dose for alcoholism – 100 to 200 mg a day, usually divided twice a day.

Topiramate has been tested in 5 small randomized controlled trials of cocaine use – but it only worked in two of them. One of the negative trials might be explained away by the fact that the patients had very poor adherence to topiramate, but even if we through that one out the glass is still half empty and half full. Also on the negative side are two studies of cocaine abuse combined with either an opioid or alcohol use disorders where topiramate failed to make a breakthrough, but on the positive side there are two trials where topiramate reduced cocaine use when it was given as a combo therapy with Adderall XR up to 60 mg per day.

So was it the Adderall or the topiramate that worked there? We don’t know. The story of stimulants in cocaine use disorders is quite intriguing but inconclusive. Adderall did work on its own but only in patients with comorbid ADHD and cocaine use – that was a single large study that used a large dose of Adderall 60-80 mg/day. Methylphenidate failed to reduce cocaine in 2 studies; and modafinil worked in one study.

You may not be comfortable giving amphetamines to patients with a history of cocaine abuse, so this intervention may be best reserved for addictionologists who are set up to monitor treatment with urine drug screens and make sure patients are enrolled in a psychotherapy program along with the medication. In nearly all of these addiction studies, including alcohol, topiramate was used as part of a counseling program, and it is only FDA approved in obesity as an adjunct to weight loss counseling.

There is, however, reason to think that topiramate may make Adderall a little less risky in patients with cocaine abuse. In one placebo controlled trial of 62 patients with methamphetamine abuse, topiramate reduced all measures of abuse with a significant effect.

KELLIE NEWSOME: Some people think that topiramate has anti-impulsive effects across the board. We certainly see some support for that in binge eating and addictions, and in 2013 Eric Hollander’s group from Mt Sinai added compulsive gambling to that list. The study was very small and the results meager – topiramate reduced impulsivity in compulsive gamblers and not much else – but was followed up in 2017 by another small controlled trial from Spain where topiramate reduced gambling behaviors when used along with a therapy program. Topiramate also has case studies in kleptomania, sexual compulsivity, and excessive hair pulling – trichotillomania.

One place where we see a lot of impulsivity is borderline personality disorder. Here we counted 3 controlled trials of topiramate, all using the usual dosage of 100-200 mg a day. All were small and all came from the same group lead by Marius Nickel in Germany. These studies looked at reductions of aggression and anger – which topiramate achieved. The benefits held up when they followed up on the patients a year and a half later. Nickels showed a similar anti-aggressive effect in women with depression – where topiramate reduced anger and depression. So topiramate might be useful in borderline patients with high aggression, but what about broader symptoms in borderline personality disorder? There we have one small controlled trial – again from Nickels – where it proved useful in a long list of symptoms. I’ll read them here, as they also give us a good sense of the multitude of problems that people with borderline personality suffer from: Somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and being overly autocratic, competitive, introverted, and expressive in their relationships.

AIKEN: Anticonvulsants are often used in borderline personality disorder, but in major depression? Not so much. So it’s remarkable that Nickel’s found that topiramate worked by itself, as monotherapy not just for anger but for depression in women with major depression. That study was replicated by an independent group who tested topiramate in a small randomized placebo controlled trial of major depression. This time they used men and women, and they used it to augment an SSRI in patients who failed to respond to that SSRI trial. The Hamilton depression rating scale improved with the topiramate 100-200 mg/day. The effect size was moderate to large – we calculated it in the 0.4-1.0 range (0.73 +/- 0.32) – and it wasn’t just because associated symptoms like anxiety, agitation, and insomnia improved – indeed they did – but actual depressed mood improved as well.

I’m on the fence about this depression data though. I’ve used a lot of topiramate in practice, and I’ve not noticed any antidepressant effects, but this could just be my own observer bias as I tend to think of topiramate as anti-impulsive rather than anti-depressant. Also I had a few patients call me back with marked depression and dysphoria on it. I’ve seen that reaction with most anticonvulsants, even gabapentin, though it’s rare. Anticonvulsants have complex neuropsychological effects – most of them have a warning about suicidality – so warn your patients when you use them that there’s a small chance they may feel mentally worse on them.

With so many options for depression that are better studied, it’s unlikely you’ll turn to topiramate on the basis of these small trials. But this research at least opens our eyes to the possibility, so if your patient starts topiramate for a more established use like migraines, weight loss, or alcoholism, watch to see if their mood improves. As Louis Pasteur said in 1854, Where observation is concerned, chance favors the prepared mind.

One place where I have seen benefits with topiramate is OCD, and there are 4 randomized placebo controlled trials that tested it in OCD based on the theory that its glutamateric actions would be useful there. As usual, most of these are small studies, each enrolling 30-50 patients, with a dose range from 50-400 mg/day. Three were positive, and one was negative. All of them used it to augment SSRIs except one study, which is notably one of very few controlled trials of any therapy in OCD with bipolar disorder. If you’ve noticed a lot of OCD in your bipolar patients you’re not just seeing things – the rate of this comorbidity is high, with 1 in 6 bipolar patients having OCD and evidence of common familial transmission for the two. If you haven’t noticed it, start screening for it. OCD is one of those silent disorders that can take years to detect. Patients often don’t complain of it unless you ask. I remember one patient where I had worked with her for 3 years before figuring out she had OCD, and when I shared this revelation to her she looked at me like I was dense and said, “Didn’t you know that – why do you think I always ask you if you want your door open or closed when I leave your office – shouldn’t I know which way you want it by now – but my OCD makes me keep asking.” Yea, sometimes we all miss obvious signs.

KELLIE NEWSOME: The final place where topiramate may have some psychiatric utility is in PTSD. That is the subject of our cover story in this month’s Carlat Report, where we go over some strong reasons to use it, and equally strong reasons not to use it, and settle on a place where it’s worth considering in PTSD. But we won’t spoil the surprise. Check it out online. Now, let’s do a head count – we found some “ready for prime time” support for topiramate in 4 disorders:

1. Weight loss

2. Bulimia

3. Binge eating disorder

4. Alcohol use disorders

Then there’s preliminary, “use it as a last resort or if your patient has a bunch of these comorbidities together” support in 7 disorders:

5. Cocaine use disorders

6. Methamphetamine abuse

7. Compulsive gambling

8. Borderline personality disorder

9. Major Depression as antidepressant augmentation

10 .Obsessive compulsive disorder

11. Post-traumatic stress disorder

That’s 11 uses. It’s also FDA approved for prevention of migraines, which are common in psychiatric patients so that could bring us to 12. But what is the unlucky 13^th use – epilepsy?

AIKEN: Number 13 is bipolar disorder. A lot of anticonvulsants were released in the 1990s which promised to improve on the tolerability of this class – gabapentin, oxcarbazepine, levetiracetam, lamotrigine, and topiramate. The thinking at the time was that any anticonvulsant would work in bipolar because carbamazepine and valproate had, and there were lots of uncontrolled trials and case reports coming out suggesting they would. Unfortunately, many of us got on that bandwagon before the large, controlled trials came in. And when they did, one by one they failed, with the exception of lamotrigine. In the case of topiramate, it worked no better than placebo in large studies of bipolar mania and depression, where it was tested as monotherapy in over 1600 patients, and it also failed in a controlled trial of schizoaffective disorder – bipolar type. The same could be said of gabapentin and oxcarbazepine – both of these drugs were pursued in bipolar mania in large, industry-funded trials, and both failed. Many of these studies are unpublished. In the case of levetiracetam – Keppra – we’re not aware of large industry sponsored trials, but it did fail in small controlled trials of bipolar depression and mania.

Side Effects

KELLIE NEWSOME: And finally, a word on tolerability. Topiramate is well known to cause cognitive problems – a side effect that earned it the nick-name Dopamax. We’ve found this improves a lot by starting low – 25 mg a day – and titrating gradually by 25 mg per week, which is actually how they recommend it in the PDR. But it can still be serious, and even lead to traffic accidents. Second, it sometimes has the opposite of the intended effect. There are case reports of mania on it, of worsened OCD, and as Dr. Aiken pointed out of suicidality and depression.

When patients tolerate it, they tolerate it really well, and appreciate the weight loss. But when they don’t it’s usually bad enough to make them stop the med – dizziness, GI distress, fatigue, and coordination problems. These problems are real hit-and-miss – in some of the studies we reviewed today the drop outs were similar to placebo, but in a few of them topiramate’s side effects caused so many patients to drop out that the results were uninterpretable.

AIKEN: Topiramate has 3 main medical risks: Renal stones, and loss of vision, and metabolic disturbances like elevated ammonia. All of these are rare, and here’s how to minimize them. If your patient has a history of renal stones, glaucoma, or other eye disease, avoid topiramate or get approval from their doctor. Topiramate’s ocular side effects are many – from blepharospasm to retinal hemorrhage to glaucoma – so think twice if your patient is seeing an ophthalmologist for anything other than eye glasses. To reduce the risk of elevated ammonia, avoid prescribing topiramate with valproate (Depakote), which can also raise ammonia levels.

KELLIE NEWSOME: And now for the word of the day… blepharospasm

AIKEN: Blepharospasm – you just heard it in the list of topiramate’s side effects – means excessive, involuntary eye blinking. You need to know about it because it can look like tardive dyskinesia, but it’s not. Besides being a rare side effect of topiramate, it’s seen in the tics of Tourette’s disorder, Parkinson’s disease, or can occur on its own usually when there are genetic risks for it. Patients with blepharospasm should reduce caffeine and avoid insomnia which can make it worse.

Closing

KELLIE NEWSOME: Join us next week for an update on how the novel coronavirus affects the brain, and follow us on twitter for daily research updates. Today’s tweet is on a new type of psychotherapy for depression that is based on the ancient moral code of the Greek philosophers.

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