Topiramate can cause psychosis, or treat psychosis; worsen cognition, or improve it; cause depression or… You get the point. A look at the paradoxical world of psychopharmacology.
Published On: 08/01/2022
Duration: 14 minutes, 16 seconds
Psychiatric drugs don’t always act as expected, as this tale of topiramate reveals.
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.
CHRIS AIKEN: In this month’s Carlat Report we reviewed a study whose results might seem a little counterintuitive. On the surface, it looked straightforward. It tested topiramate – brand name Topamax - for obesity in schizophrenia, and the drug worked. 1 in 4 patients lost more than 5% of their body weight. But something else in the study might surprise you – topiramate improved both negative and positive symptoms of schizophrenia.
Topiramate has a lot of potential uses in psychiatry, with small studies supporting its benefits in PTSD, borderline personality disorder and in a long list of disorders that occupy the compulsivity-impulsivity spectrum: OCD, bulimia and binge eating, possibly gambling disorder, and a few chemical addictions: alcohol, cocaine, and methamphetamine. But what holds topiramate back is its pejorative nick name: Dopamax.
KELLIE NEWSOME: Around 1 in 10 patients complain of cognitive problems on topiramate, particularly memory and word-finding problems. Usually it’s mild, but it can be severe – one patient we saw had a car accident soon after starting topiramate that appeared to be related to visual-spatial problems on the drug. Cognitive problems are particularly worse at doses above 400 mg. Most psychiatric and weight-loss studies use doses of 100-300 mg, and in our practice we try to stick to 100-200 to avoid the problem.
These cognitive side effects are dose- dependent, so the first step is to lower the dose. You can also reduce the problem when you start the drug, by raising the dose slowly – such as titrating by 25 mg every week. And there’s a scientific explanation for this – rapid increases in topiramate cause a burst of memory-impairing, benzodiazepine-like gaba-ergic effects.
In our practice, we’ve seen a big reduction in cognitive side effects since we started using those precautions about 8 years ago. We still see cognitive side effects, but the rate is closer to what we see with gabapentin, and we no longer call it “Dopamax.” But the idea that topiramate might help cognition – or at least negative symptoms in schizophrenia – that was news to me.
CHRIS AIKEN: To understand where people got the idea to use topiramate in schizophrenia we have to turn to glutamate. Glutamate is the most abundant excitatory neurotransmitter in the brain. Its effects are complex and depend on which brain region it’s acting on and which of the 3-4 glutamate receptors it is binding to. But to keep things simple, it’s low glutamate that is thought to contribute to schizophrenia.
Ever since birth of dopamine-blocking antipsychotics, psychiatrists have assumed that excessive dopamine is the cause of schizophrenia. But a group of doctors from Germany had a different idea. When dopamine is blocked by antipsychotics, glutamate rises, which lead these doctors to speculate that schizophrenia might be due to a glutamate deficiency. This was in the 1970’s, before the advent of sophisticated neuroimaging, so they performed spinal taps on patients with schizophrenia to test glutamate levels, and indeed they were low – about half what they saw in the normal population.
KELLIE NEWSOME: They published their findings in 1980, but the paper was not widely accepted, in fact it was widely ignored – no one cited their work until 10 years later. That’s when the glutamate hypothesis of schizophrenia began to take flight – in the early 1990’s – buoyed in part by the observation that a street drug known as angel dust could cause schizophrenia-like symptoms.
CHRIS AIKEN: Angel dust, or PCP, is a glutamate antagonist and – consistent with the glutamate hypothesis – it is thought to cause hallucinations by blocking glutamate. It not only causes hallucinations, but negative symptoms of schizophrenia like affective blunting. That all happens after a single dose of PCP, but the problem can become self-perpetuating. About 1 in 4 people who experience psychosis after using PCP go on to develop full schizophrenia.
KELLIE NEWSOME: So far this is fairly straight forward – blocking the NMDA receptor can cause psychosis, but how we get from there to topiramate is a bit more complicated, involving downstream effects on GABA-ergic receptors, and high levels of glutamate in the synaptic cleft that active another glutamate receptor – the AMPA receptor – and when this one gets over-excited it can damage nerve cells – something called excitotoxicity. Don’t worry if you’re lost at this point – we’re about to get back to clinical grounds – because that’s what happened in 2001 when these convoluted effects inspired psychiatrists at Georgetown University to test topiramate in schizophrenia.
CHRIS AIKEN: They tested the drug in 3 patients – two had mild improvements in negative symptoms, and one got significantly better. He became more engaged, more self-aware, and more socially appropriate on the drug. He lost that flat affect that is so characteristic of schizophrenia. And here’s what the patient said about the change “I feel more chipper and have a lot more thoughts” on the drug; after topiramate was stopped he went back to his old ways, feeling like his mind was “closed off” and that he “was falling into a sleep”.
KELLIE NEWSOME: That’s the opposite of what I imagine when I hear the word Dopamax. That case series inspired at least 12 randomized controlled trials which tested topiramate in schizophrenia and found equal benefits in both positive and negative symptoms with a decent effect size around 0.4-0.6 – similar to the effect we see with most psychiatric treatments. There are even studies in treatment resistant schizophrenia. The average dose of topiramate was 165 mg/day with a range from 50-300 mg/day.
CHRIS AIKEN: With 12 studies leading the way, it’s tempting to call topiramate an antipsychotic. But let’s remember it is an anticonvulsant.
KELLIE NEWSOME: Actually topiramate was originally developed in 1969 as a synthetic sugar for diabetes.
CHRIS AIKEN: Our brains are wired to categorize things, and we know where all that organization takes place – in the temporal lobes. When the temporal lobe is damaged, patients may lose the awareness of whole categories – like the names of plants or animals – while other abilities and recognizing other categories remain intact. It’s called semantic aphasia or category-specific agnosia. Categorization is a good thing, but when it comes to psychopharmacology it can create a lot of mischief. Medications get their names from FDA-indications and the randomized controlled trials on which those indications rest, but randomized controlled trials are only designed to tell us one thing about a drug – whether it has a certain effect more often than placebo in a specific population. SSRI antidepressants, for example, are much more likely to cause sexual dysfunction than they are to treat depression, but we don’t call them sexual suppressors. And even while they treat depression they may worsen mood – say, in bipolar folks, or cause suicidal thinking, for example, in children and adolescents – and those effects might get buried in a controlled trial if they are much rarer than the antidepressant benefits.
KELLIE NEWSOME: And we see just that kind of paradox with topiramate. While the controlled trials were stacking up showing antipsychotic effects, a steady stream of case reports was suggesting that topiramate can cause psychosis – first in epilepsy, then in essential tremor, and then in the psychiatric population.
CHRIS AIKEN: And while they were only case reports, they wove a convincing tale of patients getting psychotic soon after starting topiramate and improving just as quickly as the drug was stopped.
Glen Gabbard and Dana Kober described a 32 year old man who was treated at the Menninger Clinic for OCD. After starting topiramate for weight loss, he became “paranoid, believed he was “the messiah,” and intended to sacrifice himself as directed by God. He also developed disorganized and illogical thought processes and a flattened affect. He appeared to be responding to internal stimuli.” Dose reduction and risperidone therapy did not help, but the psychosis resolved when topiramate was stopped.
KELLIE NEWSOME: Neuroscience itself is full of seeming contradictions. Take the serotonin transporter gene – SERT – which we often test in pharmacogenetic panels and which is supposed to make people more vulnerable to depression, and less responsive to SSRIs, when they have the short version of the gene. But those associations are not very strong, and in some cases the short SERT gene has the opposite effect, depending on what else is in the picture. For example, the short SERT makes people more depressed – or less depressed – depending on whether it’s paired with a certain A/B gene for sleep, and on whether the patient goes through a circadian rhythm therapy that involves sleep deprivation to treat depression. Those are just two variables – the sleep gene and the circadian rhythm therapy – now imagine that multiplied by all the genes, neurons, and environmental factors that this SERT gene interactions with.
If neuroscience is that complex, it’s no wonder that psychopharmacology is as well, particularly one like topiramate that has so many different actions in the brain.
CHRIS AIKEN: Besides paradoxical findings for psychosis and cognition, topiramate also has the potential to cause depression or – in one randomized controlled trial – treat depression. The hope is that we’ll identify patient-specific factors, like diagnosis, age, gender, ethnicity, or genetics – that help us predict which way the drug will act, but so far even that is illusory.
KELLIE NEWSOME: If you’ve been knee-deep in the topiramate research you might have heard it said that topiramate treats alcoholism primarily in people with a certain genotype – the rs2832407*CC allele of the GRIK1 gene. It looked promising, but last year two controlled trials tested the theory to no avail. Topiramate helped people stop drinking, but it did not depend on whether they had this gene.
CHRIS AIKEN: But when it comes to alcohol, we at least see a more consistent picture with topiramate. I’m not aware of any cases where it made people drink more. And we’ll close with some reassuring news on that front, from a real-world study of topiramate’s effects on alcoholism consumption in a very large and diverse group of patients – almost 30,000 in this review of electronic medical records. They found that topiramate was associated with reductions in alcohol use across all patient populations, regardless of the reason it was prescribed. Drinking went down in patients who had alcohol use disorders, and in those who did not.
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